topiramate and Epilepsy

Early life epilepsies are common and often debilitating, but no evidence-based management guidelines exist outside of those for infantile spasms. We conducted a systematic review of the effectiveness and harms of pharmacologic and dietary treatments for epilepsy in children aged 1-36 months without infantile spasms.. We searched EMBASE, MEDLINE, PubMed, and the Cochrane Library for studies published from January 1, 1999, to August 19, 2021. Using prespecified criteria, we identified studies reporting data on children aged 1-36 months receiving pharmacologic or dietary treatments for epilepsy. We did not require that studies report etiology-specific data. We excluded studies of neonates, infantile spasms, and status epilepticus. We included studies administering 1 of 29 pharmacologic treatments and/or 1 of 5 dietary treatments reporting effectiveness outcomes at ≥ 12 weeks. We reviewed the full text to find any subgroup analyses of children aged 1-36 months.. Twenty-three studies met inclusion criteria (6 randomized studies, 2 nonrandomized comparative studies, and 15 prestudies/poststudies). All conclusions were rated low strength of evidence. Levetiracetam leads to seizure freedom in some infants (32% and 66% in studies reporting seizure freedom), but data on 6 other medications were insufficient to permit conclusions about effectiveness (topiramate, lamotrigine, phenytoin, vigabatrin, rufinamide, and stiripentol). Three medications (levetiracetam, topiramate, and lamotrigine) were rarely discontinued because of adverse effects, and severe events were rare. For diets, the ketogenic diet leads to seizure freedom in some infants (rates 12%-37%), and both the ketogenic diet and modified Atkins diet reduce average seizure frequency, but reductions are greater with the ketogenic diet (1 RCT reported a 71% frequency reduction at 6 months for ketogenic diet vs only a 28% reduction for the modified Atkins diet). Dietary harms were not well-reported.. Little high-quality evidence exists on pharmacologic and dietary treatments for early life epilepsies. Future research should isolate how treatments contribute to outcomes, conduct etiology-specific analyses, and report patient-centered outcomes such as hospitalization, neurodevelopment, functional performance, sleep quality, and patient and caregiver quality of life.. This systematic review was registered in PROSPERO (CRD42021220352) on March 5, 2021.

Topics: Anticonvulsants; Child; Diet, Ketogenic; Epilepsy; Humans; Infant; Infant, Newborn; Lamotrigine; Levetiracetam; Quality of Life; Spasms, Infantile; Topiramate

Ketogenic diet therapy (KDT) is a nonpharmacological treatment that has been demonstrated to be effective in reducing seizures in patients with drug-resistant epilepsy. As the majority of patients on KDT are also receiving anti-seizure medications (ASMs), questions about their combination often arise. KDT is typically implemented as an add-on, and not a substitute for ASMs. Drug monitoring and specific laboratory studies may be helpful in specific cases of cotherapy. Valproate, topiramate, zonisamide, and lamotrigine may be potentially problematic with KDT, but the evidence for this is not conclusive. ASM reduction is usually attempted after 1 month of KDT if a child is showing seizure reduction (but weaning ASMs does not require seizure freedom). Failure to wean an ASM does not mean KDT has failed and adding a new ASM may be beneficial in those cases after several months of KDT fine-tuning. The purpose of this review was to discuss the evidence for possible negative (or positive) pharmacodynamic interactions between KDT and ASMs. In addition, practical suggestions for the weaning or adding of ASMs in patients on KDT are provided.

Topics: Anticonvulsants; Child; Diet, Ketogenic; Epilepsy; Humans; Ketone Bodies; Topiramate; Valproic Acid

Due to the diverse mechanisms of action of antiseizure drugs, there has been a rise in prescriptions of these drugs for non-epileptic pathologies. One drug that is now being used for a variety of conditions is topiramate. This is a narrative review that used PubMed, Google Scholar, MEDLINE, and ScienceDirect to review literature on the clinical and pharmacologic properties of topiramate. Topiramate is a commonly prescribed second-generation antiseizure drug. The drug works through multiple pathways to prevent seizures. In this regard, topiramate blocks sodium and calcium voltage-gated channels, inhibits glutamate receptors, enhances gamma-aminobutyric acid (GABA) receptors, and inhibits carbonic anhydrase. Topiramate is approved by the Food and Drug Administration (FDA) for epilepsy treatment and migraine prophylaxis. Topiramate in combination with phentermine is also FDA-approved for weight loss in patients with a body mass index (BMI) > 30. The current target dosing for topiramate monotherapy is 400 mg/day and 100 mg/day to treat epilepsy and migraines, respectively. Commonly reported side effects include paresthesia, confusion, fatigue, dizziness, and change in taste. More uncommon and serious adverse effects can include acute glaucoma, metabolic acidosis, nephrolithiasis, hepatotoxicity, and teratogenicity. Related to a broad side effect profile, physicians prescribing this drug should routinely monitor for side effects and/or toxicity. The present investigation reviews various anti-seizure medications before summarizing indications of topiramate, off-label uses, pharmacodynamics, pharmacokinetics, adverse effects, and drug-drug interactions.

Topics: Anticonvulsants; Epilepsy; Fructose; Humans; Migraine Disorders; Topiramate

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

Prenatal exposure to certain anti-seizure medications (ASMs) is associated with an increased risk of major congenital malformations (MCM). The majority of women with epilepsy continue taking ASMs throughout pregnancy and, therefore, information on the potential risks associated with ASM treatment is required.. To assess the effects of prenatal exposure to ASMs on the prevalence of MCM in the child.. For the latest update of this review, we searched the following databases on 17 February 2022: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to February 16, 2022), SCOPUS (1823 onwards), and ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP). No language restrictions were imposed.. We included prospective cohort controlled studies, cohort studies set within pregnancy registries, randomised controlled trials and epidemiological studies using routine health record data. Participants were women with epilepsy taking ASMs; the two control groups were women without epilepsy and untreated women with epilepsy.. Five authors independently selected studies for inclusion. Eight authors completed data extraction and/or risk of bias assessments. The primary outcome was the presence of an MCM. Secondary outcomes included specific types of MCM. Where meta-analysis was not possible, we reviewed included studies narratively.. From 12,296 abstracts, we reviewed 283 full-text publications which identified 49 studies with 128 publications between them. Data from ASM-exposed pregnancies were more numerous for prospective cohort studies (n = 17,963), than data currently available for epidemiological health record studies (n = 7913). The MCM risk for children of women without epilepsy was 2.1% (95% CI 1.5 to 3.0) in cohort studies and 3.3% (95% CI 1.5 to 7.1) in health record studies. The known risk associated with sodium valproate exposure was clear across comparisons with a pooled prevalence of 9.8% (95% CI 8.1 to 11.9) from cohort data and 9.7% (95% CI 7.1 to 13.4) from routine health record studies. This was elevated across almost all comparisons to other monotherapy ASMs, with the absolute risk differences ranging from 5% to 9%. Multiple studies found that the MCM risk is dose-dependent. Children exposed to carbamazepine had an increased MCM prevalence in both cohort studies (4.7%, 95% CI 3.7 to 5.9) and routine health record studies (4.0%, 95% CI 2.9 to 5.4) which was significantly higher than that for the children born to women without epilepsy for both cohort (RR 2.30, 95% CI 1.47 to 3.59) and routine health record studies (RR 1.14, 95% CI 0.80 to 1.64); with similar significant results in comparison to the children of women with untreated epilepsy for both cohort studies (RR 1.44, 95% CI 1.05 to 1.96) and routine health record studies (RR 1.42, 95% CI 1.10 to 1.83). For phenobarbital exposure, the prevalence was 6.3% (95% CI 4.8 to 8.3) and 8.8% (95% CI 0.0 to 9277.0) from cohort and routine health record data, respectively. This increased risk was significant in comparison to the children of women without epilepsy (RR 3.22, 95% CI 1.84 to 5.65) and those born to women with untreated epilepsy (RR 1.64, 95% CI 0.94 to 2.83) in cohort studies; data from routine health record studies was limited. For phenytoin exposure, the prevalence of MCM was elevated for cohort study data (5.4%, 95% CI 3.6 to 8.1) and routine health record data (6.8%, 95% CI 0.1 to 701.2). The prevalence of MCM was higher for phenytoin-exposed children in comparison to children of women without epilepsy (RR 3.81, 95% CI 1.91 to 7.57) and the children of women with untreated epilepsy (RR 2.01. 95% CI 1.29 to 3.12); there were no data from routine health record studies. Pooled data from cohort studies indicated a significantly increased MCM risk for children exposed to lamotrigine in comparison to children b. Exposure in the womb to certain ASMs was associated with an increased risk of certain MCMs which, for many, is dose-dependent.. La exposición prenatal a determinados fármacos anticonvulsivos (FAC) se asocia con un mayor riesgo de malformaciones congénitas graves (MCG). La mayoría de las mujeres con epilepsia continúan tomando FAC durante todo el embarazo y, por lo tanto, se requiere información sobre los riesgos potenciales asociados con el tratamiento con FAC.. Evaluar los efectos de la exposición prenatal a los FAC sobre la prevalencia de MCG en el niño. MÉTODOS DE BÚSQUEDA: Para la última actualización de esta revisión se hicieron búsquedas el 17 de febrero de 2022 en las siguientes bases de datos: Registro Cochrane de Estudios (Cochrane Register of Studies [CRS Web]), MEDLINE (Ovid, 1946 hasta el 16 de febrero de 2022), SCOPUS (1823 en adelante) y ClinicalTrials.gov , Plataforma de registros internacionales de ensayos clínicos (ICTRP). No se impusieron restricciones de idioma. CRITERIOS DE SELECCIÓN: Se incluyeron estudios prospectivos controlados de cohortes, estudios de cohortes establecidos dentro de registros de embarazos, ensayos controlados aleatorizados y estudios epidemiológicos que utilizaron datos rutinarios de los historiales médicos. Las participantes fueron mujeres con epilepsia que tomaban FAC; los dos grupos de control fueron mujeres sin epilepsia y mujeres con epilepsia que no recibían tratamiento. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Cinco autores seleccionaron de forma independiente los estudios para inclusión. Ocho autores completaron la extracción de los datos y las evaluaciones del riesgo de sesgo. El desenlace principal fue la presencia de una MCG. Los desenlaces secundarios incluyeron tipos específicos de MCG. Cuando no fue posible realizar un metanálisis, los estudios incluidos se examinaron de forma narrativa.. De 12 296 resúmenes, se revisaron 283 publicaciones a texto completo que identificaron 49 estudios con 128 publicaciones entre ellos. Los datos de los embarazos expuestos a FAC fueron más numerosos en el caso de los estudios prospectivos de cohortes (n = 17 963), que los datos actualmente disponibles de estudios de registros sanitarios epidemiológicos (n = 7913). El riesgo de MCG en los hijos de mujeres sin epilepsia fue del 2,1% (IC del 95%: 1,5 a 3,0) en los estudios de cohortes y del 3,3% (IC del 95%: 1,5 a 7,1) en los estudios de registros sanitarios. El riesgo conocido asociado con la exposición al valproato de sodio fue evidente en todas las comparaciones, con una prevalencia agrupada del 9,8% (IC del 95%: 8,1 a 11,9) a partir de los datos de los estudios de cohortes y del 9,7% (IC del 95%: 7,1 a 13,4) a partir de los estudios con datos rutinarios de los historiales médicos. Este fue elevado en casi todas las comparaciones con otros FAC como monoterapia, con diferencias absolutas de riesgo que variaron entre el 5% y el 9%. Múltiples estudios han constatado que el riesgo de MCG depende de la dosis. Los niños expuestos a la carbamazepina tuvieron una mayor prevalencia de MCG tanto en los estudios de cohortes (4,7%; IC del 95%: 3,7 a 5,9) como en los estudios con datos rutinarios de los historiales médicos (4,0%; IC del 95%: 2,9 a 5,4), que fue significativamente superior a la de los niños nacidos de mujeres sin epilepsia tanto en los estudios de cohortes (RR 2,30; IC del 95%: 1,47 a 3,59) como en los estudios de historias clínicas habituales (RR 1,14; IC del 95%: 0,80 a 1,64), con resultados significativos similares en comparación con los hijos de mujeres con epilepsia que no reciben tratamiento tanto en los estudios de cohortes (RR 1,44; IC del 95%: 1,05 a 1,96) como en los estudios con datos rutinarios de los historiales médicos (RR 1,42; IC del 95%: 1,10 a 1,83). Para la exposición al fenobarbital, la prevalencia fue del 6,3% (IC del 95%: 4,8 a 8,3) y del 8,8% IC del 95%: 0,0 a 9277,0) a partir de los datos de estudios de cohortes y los datos de estudios con datos rutinarios de los historiales médicos, respectivamente. Este aumento del riesgo fue significativo en comparación con los hijos de mujeres sin epilepsia (RR 3,22; IC del 95%: 1,84 a 5,65) y los nacidos de mujeres con epilepsia que no reciben tratamiento (RR 1,64; IC del 95%: 0,94 a 2,83) en estudios de cohortes; los datos procedentes de estudios con datos rutinarios de los historiales médi. La exposición en el útero a ciertos FAC se asoció con un mayor riesgo de ciertos MCG que, para muchos, depende de la dosis.

Topics: Child; Cohort Studies; Epilepsy; Female; Humans; Lamotrigine; Male; Phenytoin; Pregnancy; Prenatal Exposure Delayed Effects; Prospective Studies; Topiramate

Hyperammonemia can occur after acute overdose or chronic use of valproic acid (VPA). Although VPA-related hyperammonemic encephalopathy (VHE) is a rare complication of VPA therapy, early recognition of VHE and identifying its risk factors are important because VHE can lead to loss of consciousness and increased seizure frequency.. The purpose of our study is to evaluate the risk factors of hyperammonemia in epilepsy patients during treatment with VPA therapy.. We reviewed the medical records of 1084 adult patients with epilepsy and enrolled 116 patients with VPA therapy who had results of blood levels of ammonia over a 3-year period. Hyperammonemia was defined as a blood ammonia level exceeding 80 µg/dL. Correlations of blood levels of ammonia with dosages and blood levels of VPA were evaluated. We further performed univariate and multivariate linear regression analyses to identify risk factors for hyperammonemia in epilepsy patients treated with VPA therapy.. Blood levels of ammonia were well correlated with dosages of VPA (p = 0.036), but not with blood levels of VPA (p = 0.463). Hyperammonemia was more common in patients with higher VPA dosage and higher total drug loads of concurrent antiseizure medications (ASMs). Hyperammonemia was also associated with the use of topiramate and phenobarbital. In multivariate analysis, we identified total drug load of ASMs (p = 0.003) and use of topiramate (p = 0.007) as independent predictors of hyperammonemia. Four patients (4/116, 3.4 %) had clinical symptoms of VHE. Three of them had hyperammonemia while the other patient had normal blood level of ammonia with a high blood level of VPA.. Our study shows that higher total drug loads of concurrent ASMs and use of topiramate were independent risk factors of hyperammonemia in epilepsy patients with VPA therapy. Although the incidence of VHE was not high in our study, clinicians should be aware of this potential adverse effect of VPA therapy, especially in patients with polytherapy of ASMs including topiramate.

Topics: Adult; Ammonia; Anticonvulsants; Epilepsy; Humans; Hyperammonemia; Risk Factors; Topiramate; Valproic Acid

To estimate the safety and efficacy of sodium valproate combined with levetiracetam in paediatric patients with epilepsy based on randomized controlled trials (RCTs).. The Cochrane Library, PubMed, Web of Science, Chinese Journal Full-Text Database (CNKI), WANGFANG DATA and Sino Med were searched between January 1946 and May 2021. The included literature was randomized controlled clinical trials focusing on sodium valproate combined with levetiracetam in paediatric patients with epilepsy. Two evaluators separately collected the data based on the retrieval strategy, filtered the literature in accordance with the inclusion and exclusion criteria, and summarized the literature that satisfied the criteria. The statistical programme used for the meta-analysis was Stata V14.0.. Of 577 original titles screened, data were extracted from 7 studies (617 participants). Compared with sodium valproate alone or sodium valproate combined with topiramate, the application of sodium valproate combined with levetiracetam in the treatment of paediatric epilepsy significantly improved the overall therapeutic effect (RR=1.24, 95% CI: 1.16 to 1.33, p=0.927). The observation group significantly reduced the occurrence of adverse drug reactions (ADRs) (RR=0.54, 95% CI: 0.37 to 0.79, p=0.602). Egger's regression test of the overall therapeutic effect showed no potential publication bias (p=0.122).. Based on this meta-analysis, compared with sodium valproate alone or sodium valproate with topiramate, the application of sodium valproate combined with levetiracetam in the treatment of paediatric epilepsy can significantly improve the overall therapeutic effect and simultaneously reduce the occurrence of ADR. Therefore, we recommend sodium valproate combined with levetiracetam for the therapy of paediatric patients with epilepsy.

Topics: Anticonvulsants; Child; Epilepsy; Humans; Levetiracetam; Topiramate; Valproic Acid

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

Anti-seizure drugs have long been known to affect thyroid hormone levels in epilepsy patients. The current study is a network meta-analysis designed to produce a systematic review and comprehensive evaluation of thyroid hormone changes to inform future research and clinical treatment.. A systematic search of databases, PubMed, EMBASE, Web of Science, and the Cochrane Library, was conducted and all observational studies reporting thyroid hormone levels in epilepsy patients receiving monotherapy and controls were included. Stata MP.14 was used for analysis.. A total of 35 studies, including 4135 participants and 8 anti-seizure drugs, were analyzed. TSH levels were elevated following use of topiramate [mean = 1.86; 95%CI: 0.83 to 2.90], levetiracetam [mean = 1.08; 95%CI: 0.07 to 2.09], and valproic acid [mean = 1.54; 95%CI: 0.58 to 2.50]. FT4 levels may be lowered by oxcarbazepine [mean =  - 6.13; 95%CI: - 8.25 to - 4.02] and T4 was lowered by carbamazepine [mean =  - 1.55; 95%CI: - 2.05 to - 1.05] and phenytoin [mean =  - 1.33; 95%CI: - 1.80 to - 0.85]. No significant changes were reported for FT3, although use of phenobarbital resulted in a non-significant decrease [mean =  - 0.31; 95%CI: - 0.99 to 0.37]. T3 levels were lowered by carbamazepine [mean =  - 0.52; 95%CI: - 0.81 to - 0.24]. Lamotrigine had no significant effect on thyroid hormone levels.. Carbamazepine and phenytoin were the drugs most strongly associated with decreases in T4 and T3 levels while topiramate had the greatest elevating effect on TSH. Oxcarbazepine may lead to decreased serum FT4 and FT3, an effect relevant to central hypothyroidism. Phenobarbital appeared to significantly lower FT3. Use of levetiracetam and valproic acid may result in subclinical hypothyroidism. The anti-seizure drug with the least disruptive effect on thyroid hormone levels was found to be lamotrigine.

Topics: Anticonvulsants; Carbamazepine; Epilepsy; Humans; Lamotrigine; Levetiracetam; Network Meta-Analysis; Oxcarbazepine; Phenobarbital; Phenytoin; Thyroid Hormones; Thyrotropin; Topiramate; Valproic Acid

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

To perform a systematic review searching for differences in the side effects of antiseizure medications (ASMs) with respect to sex in pediatric patients with epilepsy.. We carried out a comprehensive literature search of the PubMed database and all results up to April 2020 were included. Titles, abstracts, and full texts of the articles were screened by two independent reviewers. We included all studies evaluating the side effects of ASMs in patients with epilepsy younger than 18 years, with reference to the two sexes. Studies on ASMs used for indications other than epilepsy were excluded.. A total of 5164 studies were identified. Sixty-seven studies were finally included, 5 of them also including adult patients in the sample. Sixteen studies revealed sex-related differences in side effects of ASMs, disclosing a higher frequency of general side effects in girls: a higher risk of overweight, hyperammonaemia, high leptin levels, and carnitine deficiency in girls on valproic acid; a lower height increase, an increased risk of weight loss, the anecdotical occurrence of acute psychosis in girls on topiramate; a higher risk of retinal toxicity in boys on vigabatrin.. The effect of sex on susceptibility to side effects of ASMs is poorly investigated with sparse results, and it could be underestimated. The findings of our study point to the presence of sex differences which should be thoroughly investigated to be confirmed, highlighting the need for a systematic evaluation of sex as a determinant variable influencing the response to medications in clinical research.

Topics: Adult; Anticonvulsants; Child; Drug-Related Side Effects and Adverse Reactions; Epilepsy; Female; Humans; Male; Sex Characteristics; Topiramate; Vigabatrin

We carried out a systematic review of published information on transfer of antiseizure medications (ASMs) into breastmilk, ASM serum concentrations in breastfed infants, and the wellbeing of infants breastfed by mothers on ASM treatment. Information was extracted from 85 relevant articles. No data on ASM levels in breastmilk or in breastfed infants was identified for cannabidiol, cenobamate, clobazam, eslicarbazepine-acetate, everolimus, felbamate, fenfluramine, retigabine, rufinamide, stiripentol, tiagabine, and vigabatrin. For ASMs, with available information on levels in breastfed infants, very low concentrations (in the order of 10% or less of maternal serum concentrations) were reported for carbamazepine, gabapentin, levetiracetam, oxcarbazepine, phenytoin, valproate, and clonazepam. Slightly higher levels (up to approximately 30% of maternal serum concentrations) have been observed with lamotrigine and topiramate, and in single case reports for brivaracetam, lacosamide, and perampanel. High infant levels (30% up to 100% of maternal serum concentrations) have been reported with ethosuximide, phenobarbital and zonisamide. Adverse infant effects during breastfeeding by mothers on ASMs appear to be rare regardless of the type of ASM, but systematic study is limited. Prospective long-term follow-up studies of developmental outcomes among children who have been breastfed by mothers taking ASMs are sparse and have mainly involved children whose mothers were taking carbamazepine, lamotrigine, levetiracetam, phenytoin or valproate as monotherapy while breastfeeding. Although these studies have not indicated poorer outcome among breastfed children compared with those who were not breastfed, further data on long-term outcomes are needed to draw firm conclusions. It is concluded that breastfeeding should in general be encouraged in women taking ASMs, given the well-established benefits of breastfeeding with regard to both short- and long-term infant health in the general population. Counselling needs to be individualized including information on the current knowledge regarding the woman's specific ASM treatment.

Topics: Breast Feeding; Cannabidiol; Carbamazepine; Child; Clobazam; Clonazepam; Epilepsy; Ethosuximide; Everolimus; Felbamate; Female; Fenfluramine; Gabapentin; Humans; Infant; Lacosamide; Lamotrigine; Levetiracetam; Oxcarbazepine; Phenobarbital; Phenytoin; Prospective Studies; Tiagabine; Topiramate; Valproic Acid; Vigabatrin; Zonisamide

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

Poor adherence to anti-seizure medications (ASMs) is associated with breakthrough seizures and potentially increased toxicity in patients with epilepsy. Extended-release (ER) drugs and immediate-release (IR) drugs with a long half-life (t

Topics: Anticonvulsants; Delayed-Action Preparations; Epilepsy; Half-Life; Humans; Lamotrigine; Topiramate

Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%-20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify postinjury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease-modifying effects, including medications with excellent side effect profiles. These include atorvastatin, ceftriaxone, losartan, isoflurane, N-acetylcysteine, and the antiseizure medications levetiracetam, brivaracetam, topiramate, gabapentin, pregabalin, vigabatrin, and eslicarbazepine acetate. In addition, there are preclinical antiepileptogenic data for anakinra, rapamycin, fingolimod, and erythropoietin, although these medications have potential for more serious side effects. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially "repurposable" medications. We may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically. One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury-treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose-blood level relationship, brain target engagement, and dose-response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing. Here, we review animal and human antiepileptogenic evidence for these medications. We highlight the gaps in our knowledge for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecu

Topics: Acetylcysteine; Animals; Anticonvulsants; Antioxidants; Atorvastatin; Brain Injuries, Traumatic; Ceftriaxone; Dibenzazepines; Drug Repositioning; Epilepsy; Epilepsy, Post-Traumatic; Erythropoietin; Fingolimod Hydrochloride; GABA Agents; Gabapentin; Humans; Immunologic Factors; Inflammation; Interleukin 1 Receptor Antagonist Protein; Isoflurane; Levetiracetam; Losartan; Neuroprotective Agents; Oxidative Stress; Pregabalin; Pyrrolidinones; Sirolimus; Stroke; Topiramate; Translational Research, Biomedical; Vigabatrin

Cognitive and psychiatric problems are common in people with epilepsy. They can have multiple causes, including structural brain lesions, the active epilepsy, and the effect of anti-epileptic therapy. Since patients' treatment compliance and quality of life are affected by cognitive and emotional status, it is crucial for clinicians to understand how anti-seizure medications (ASMs) affect cognition and mood, and to choose the proper ASM.. To conduct a literature review of the impact on cognition and mood status of lacosamide (LCM) in people with epilepsy.. Wesearched PubMed, the Cochrane Database of Systematic Reviews and reference lists of articles for all types of articles with no limitations on publication date.. A total of 251 records were obtained, including 247 articles in PubMed and 4 articles from reference lists. We included 2 meta-analyses, one randomized controlled trials and 14 observational studies after the screening process. Most studies agree LCM has low risk of treatment-emergent adverse events (TEAEs) on cognition. Comparisons with other ASMs, LCM may be preferable to carbamazepine, topiramate and perampanel, and not inferior to lamotrigine. In spite of low incident rate, depression is the most common psychiatric change of LCM. There are no consistent positive or negative psychiatric effects of LCM.. Lacosamide has limited impact on cognitive and mood status in this review. Several factors including mechanism of co-administration of ASMs and personal history of psychiatric disorder should be considered as important in the development of cognitive and psychiatric side effects. However, the heterogeneity between studies make the quality of evidence weaker and further trials are needed.

Topics: Adult; Affect; Anticonvulsants; Carbamazepine; Cognition; Epilepsy; Humans; Lacosamide; Lamotrigine; Nitriles; Pyridones; Quality of Life; Topiramate

Epilepsy is one of the most common neurological disorders, affecting approximately 50 million people worldwide. Despite a dramatic increase in treatment options over the past 30 years, it still ranks fourth in the world's disease burden. There are now close to 30 antiepileptic drugs (AEDs), with more than two thirds introduced to the market after carbamazepine (CBZ) and one third after its derivative, oxcarbazepine (OXC). Following the introduction of these newer AEDs, the role of CBZ and OXC in the therapeutic armamentarium for seizure control and effective epilepsy management needs to be reviewed. The main guidelines list both CBZ and OXC as first-line options or second-line alternatives for the treatment of focal-onset epilepsy and primary generalized tonic-clonic seizures. While evidence suggests that overall AEDs have similar efficacy, some newer AEDs may be better tolerated than CBZ. In line with this, there have been changes in treatment patterns, with many variations across different countries. However, CBZ remains among the two or three most prescribed drugs for focal epilepsy in many countries, and is widely used across Europe, Africa, South America, and Asia, where it represents a good compromise between cost, availability, and effectiveness. OXC is among the first-choice options for the initial treatment of focal-onset seizures in several countries, including the US and China, where the oral suspension is commonly prescribed. This review provides guidance on the optimal use of these two drugs in clinical practice, including in children, the elderly, and in pregnancy.

Topics: Anticonvulsants; Carbamazepine; Epilepsy; Epilepsy, Generalized; Humans; Oxcarbazepine; Topiramate

Seizures are common in patients with brain tumours, even though prophylactic anti-seizure treatment for all patients with brain tumours is not recommended. Newer anti-epileptic drugs have shown benefits that outweigh the side effects of treatment and can also be given in combination with traditional anti-epileptic drugs. The authors have reviewed the literature on the various combinations of anti-epileptics in patients with seizures and brain tumours.

Topics: Anticonvulsants; Brain Neoplasms; Drug Therapy, Combination; Epilepsy; Gabapentin; Glioma; Humans; Lamotrigine; Levetiracetam; Neoplasm Grading; Phenytoin; Survival Rate; Topiramate; Valproic Acid; Zonisamide

Antiepileptic drugs (AEDs) are effective against seizures, but their use is often limited by adverse effects, among them psychiatric and behavioral ones including aggressive behavior (AB). Knowledge of the incidence, risk factors, and the underlying mechanisms of AB induced by AEDs may help to facilitate management and reduce the risk of such side effects. The exact incidence of AB as an adverse effect of AEDs is difficult to estimate, but frequencies up to 16% have been reported. Primarily, levetiracetam (LEV), perampanel (PER), and topiramate (TPM), which have diverse mechanisms of action, have been associated with AB. Currently, there is no evidence for a specific pharmacological mechanism solely explaining the increased incidence of AB with LEV, PER, and TPM. Serotonin (5-HT) and GABA, and particularly glutamate (via the AMPA receptor), seem to play key roles. Other mechanisms involve hormones, epigenetics, and "alternative psychosis" and related phenomena. Increased individual susceptibility due to an underlying neurological and/or a mental health disorder may further explain why people with epilepsy are at an increased risk of AB when using AEDs. Remarkably, AB may occur with a delay of weeks or months after start of treatment. Information to patients, relatives, and caregivers, as well as sufficient clinical follow-up, is crucial, and there is a need for further research to understand the complex relationship between AED mechanisms of action and the induction/worsening of AB.

Topics: Aggression; Anticonvulsants; Epilepsy; Humans; Levetiracetam; Nitriles; Pyridones; Topiramate

Sexual pharmacotoxicity renders patients with epilepsy at a risk for sexual dysfunction (SD). This study is aimed to analyze the relationship between sexual function and topiramate to avoid topiramate-associated SD.. A systematic review following the PRISMA guidelines was performed to elucidate any SD occurrence in patients receiving topiramate.. A total of 17 publications were reviewed. Based on limited polytherapy observational studies, the frequency of self-reported topiramate-associated SD, libido disorder, and orgasmic disorder in patients with polytherapy was 9.0%, 9.0%, and 2.6%, respectively (grade C evidence). Female patients mainly had anorgasmia, whereas male patients principally had erectile dysfunction. The daily dose of topiramate in patients with SD was within the recommended dose. Sexual adversity usually occurred from 4weeks after topiramate use but favorably subsided without eventful complications after topiramate substitution or dose reduction in all patients.. Topiramate can elicit different patterns of SD, especially anorgasmia in women and erectile dysfunction in men, even with a therapeutic dose. Detailed drug education and careful monitoring are necessary to maximize sexual health, especially in persons undergoing polytherapy and with other risks for SD. Moreover, a rapid response, such as substitution or reduction of the dose, is suggested when SD occurs during its use.

Topics: Adult; Anticonvulsants; Epilepsy; Erectile Dysfunction; Female; Fructose; Humans; Libido; Male; Sexual Dysfunction, Physiological; Sexual Dysfunctions, Psychological; Topiramate

There is ongoing concern whether switching between different antiepileptic drug (AED) products may compromise patient care. We systematically reviewed changes in healthcare utilization following AED switch.. We searched MEDLINE and EMBASE databases (1980-October 2016) for studies that assessed the effect of AED switching in patients with epilepsy on outpatient visits, emergency room visits, hospitalization and hospital stay duration.. A total of 14 articles met the inclusion criteria. All were retrospective studies. Four provided findings for specific AEDs only (lamotrigine, topiramate, phenytoin and divalproex), 9 presented pooled findings from multiple AEDs, and 1 study provided both specific (lamotrigine, topiramate, oxcarbazepine, and levetiracetam) and pooled findings. Three studies found an association between a switch of topiramate and an increase in healthcare utilization. Another three studies found that a brand-to-generic lamotrigine switch was not associated with an increased risk of emergently treated events (ambulance use, ER visits or hospitalization). The outcomes of the pooled AED switch studies were inconsistent; 5 studies reported an increased healthcare utilization while 5 studies did not.. Studies that have examined the association between an AED switch and a change in healthcare utilization report conflicting findings. Factors that may explain these inconsistent outcomes include inter-study differences in the type of analysis undertaken (pooled vs individual AED data), the covariates used for data adjustment, and the type of switch examined. Future medical claim database studies employing a prospective design are encouraged to address these and other factors in order to enhance inter-study comparability and extrapolation of findings.

Topics: Adult; Anticonvulsants; Drug Substitution; Drugs, Generic; Epilepsy; Female; Fructose; Humans; Levetiracetam; Male; Patient Acceptance of Health Care; Piracetam; Prospective Studies; Retrospective Studies; Topiramate; Valproic Acid

Epilepsy is a common neurological condition with a worldwide prevalence of around 1%. Approximately 60% to 70% of people with epilepsy will achieve a longer-term remission from seizures, and most achieve that remission shortly after starting antiepileptic drug treatment. Most people with epilepsy are treated with a single antiepileptic drug (monotherapy) and current guidelines from the National Institute for Health and Care Excellence (NICE) in the United Kingdom for adults and children recommend carbamazepine or lamotrigine as first-line treatment for partial onset seizures and sodium valproate for generalised onset seizures; however a range of other antiepileptic drug (AED) treatments are available, and evidence is needed regarding their comparative effectiveness in order to inform treatment choices.. To compare the time to withdrawal of allocated treatment, remission and first seizure of 10 AEDs (carbamazepine, phenytoin, sodium valproate, phenobarbitone, oxcarbazepine, lamotrigine, gabapentin, topiramate, levetiracetam, zonisamide) currently used as monotherapy in children and adults with partial onset seizures (simple partial, complex partial or secondary generalised) or generalised tonic-clonic seizures with or without other generalised seizure types (absence, myoclonus).. We searched the following databases: Cochrane Epilepsy's Specialised Register, CENTRAL, MEDLINE and SCOPUS, and two clinical trials registers. We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators, and experts in the field. The date of the most recent search was 27 July 2016.. We included randomised controlled trials of a monotherapy design in adults or children with partial onset seizures or generalised onset tonic-clonic seizures (with or without other generalised seizure types).. This was an individual participant data (IPD) review and network meta-analysis. Our primary outcome was 'time to withdrawal of allocated treatment', and our secondary outcomes were 'time to achieve 12-month remission', 'time to achieve six-month remission', 'time to first seizure post-randomisation', and 'occurrence of adverse events'. We presented all time-to-event outcomes as Cox proportional hazard ratios (HRs) with 95% confidence intervals (CIs). We performed pairwise meta-analysis of head-to-head comparisons between drugs within trials to obtain 'direct' treatment effect estimates and we performed frequentist network meta-analysis to combine direct evidence with indirect evidence across the treatment network of 10 drugs. We investigated inconsistency between direct estimates and network meta-analysis via node splitting. Due to variability in methods and detail of reporting adverse events, we have not performed an analysis. We have provided a narrative summary of the most commonly reported adverse events.. IPD was provided for at least one outcome of this review for 12,391 out of a total of 17,961 eligible participants (69% of total data) from 36 out of the 77 eligible trials (47% of total trials). We could not include IPD from the remaining 41 trials in analysis for a variety of reasons, such as being unable to contact an author or sponsor to request data, data being lost or no longer available, cost and resources required to prepare data being prohibitive, or local authority or country-specific restrictions.We were able to calculate direct treatment effect estimates for between half and two thirds of comparisons across the outcomes of the review, however for many of the comparisons, data were contributed by only a single trial or by a small number of participants, so confidence intervals of estimates were wide.Network meta-analysis showed that for the primary outcome 'Time to withdrawal of allocated treatment,' for individuals with partial seizures; levetiracetam performed (statistically) significantly better than both current first-line treatments carbamazepine and lamotrigine; lamotrigine performed better than all other treatments (aside from levetiracetam), and carbamazepine performed significantly better than gabapentin and phenobarbitone (high-quality evidence). For individuals with generalised onset seizures, first-line treatment sodium valproate performed significantly better than carbamazepine, topiramate and phenobarbitone (moderate- to high-quality evidence). Furthermore, for both partial and generalised onset seizures, the earliest licenced treatment, phenobarbitone seems to perform worse than all other treatments (moderate- to high-quality evidence).Network meta-analysis also showed that for secondary outcomes 'Time to 12-month remission of seizures' and 'Time to six-month remission of seizures,' few notable differences were shown for either partial or generalised seizure types (moderate- to high-quality evidence). For secondary outcome 'Time to first seizure,' for individuals with partial seizures; phenobarbitone performed significantly better than both current first-line treatments carbamazepine and lamotrigine; carbamazepine performed significantly better than sodium valproate, gabapentin and lamotrigine. Phenytoin also performed significantly better than lamotrigine (high-quality evidence). In general, the earliest licenced treatments (phenytoin and phenobarbitone) performed better than the other treatments for both seizure types (moderate. Overall, the high-quality evidence provided by this review supports current guidance (e.g. NICE) that carbamazepine and lamotrigine are suitable first-line treatments for individuals with partial onset seizures and also demonstrates that levetiracetam may be a suitable alternative. High-quality evidence from this review also supports the use of sodium valproate as the first-line treatment for individuals with generalised tonic-clonic seizures (with or without other generalised seizure types) and also demonstrates that lamotrigine and levetiracetam would be suitable alternatives to either of these first-line treatments, particularly for those of childbearing potential, for whom sodium valproate may not be an appropriate treatment option due to teratogenicity.

Topics: Adult; Amines; Anticonvulsants; Carbamazepine; Child; Cyclohexanecarboxylic Acids; Epilepsies, Partial; Epilepsy; Epilepsy, Generalized; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Isoxazoles; Lamotrigine; Levetiracetam; Network Meta-Analysis; Oxcarbazepine; Phenobarbital; Phenytoin; Piracetam; Remission Induction; Topiramate; Triazines; Valproic Acid; Zonisamide

Epilepsy is a common neurological condition with a worldwide prevalence of around 1%. Approximately 60% to 70% of people with epilepsy will achieve a longer-term remission from seizures, and most achieve that remission shortly after starting antiepileptic drug treatment. Most people with epilepsy are treated with a single antiepileptic drug (monotherapy) and current guidelines from the National Institute for Health and Care Excellence (NICE) in the United Kingdom for adults and children recommend carbamazepine or lamotrigine as first-line treatment for partial onset seizures and sodium valproate for generalised onset seizures; however a range of other antiepileptic drug (AED) treatments are available, and evidence is needed regarding their comparative effectiveness in order to inform treatment choices.. To compare the time to withdrawal of allocated treatment, remission and first seizure of 10 AEDs (carbamazepine, phenytoin, sodium valproate, phenobarbitone, oxcarbazepine, lamotrigine, gabapentin, topiramate, levetiracetam, zonisamide) currently used as monotherapy in children and adults with partial onset seizures (simple partial, complex partial or secondary generalised) or generalised tonic-clonic seizures with or without other generalised seizure types (absence, myoclonus).. We searched the following databases: Cochrane Epilepsy's Specialised Register, CENTRAL, MEDLINE and SCOPUS, and two clinical trials registers. We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators, and experts in the field. The date of the most recent search was 27 July 2016.. We included randomised controlled trials of a monotherapy design in adults or children with partial onset seizures or generalised onset tonic-clonic seizures (with or without other generalised seizure types).. This was an individual participant data (IPD) review and network meta-analysis. Our primary outcome was 'time to withdrawal of allocated treatment', and our secondary outcomes were 'time to achieve 12-month remission', 'time to achieve six-month remission', 'time to first seizure post-randomisation', and 'occurrence of adverse events'. We presented all time-to-event outcomes as Cox proportional hazard ratios (HRs) with 95% confidence intervals (CIs). We performed pairwise meta-analysis of head-to-head comparisons between drugs within trials to obtain 'direct' treatment effect estimates and we performed frequentist network meta-analysis to combine direct evidence with indirect evidence across the treatment network of 10 drugs. We investigated inconsistency between direct estimates and network meta-analysis via node splitting. Due to variability in methods and detail of reporting adverse events, we have not performed an analysis. We have provided a narrative summary of the most commonly reported adverse events.. IPD was provided for at least one outcome of this review for 12,391 out of a total of 17,961 eligible participants (69% of total data) from 36 out of the 77 eligible trials (47% of total trials). We could not include IPD from the remaining 41 trials in analysis for a variety of reasons, such as being unable to contact an author or sponsor to request data, data being lost or no longer available, cost and resources required to prepare data being prohibitive, or local authority or country-specific restrictions.We were able to calculate direct treatment effect estimates for between half and two thirds of comparisons across the outcomes of the review, however for many of the comparisons, data were contributed by only a single trial or by a small number of participants, so confidence intervals of estimates were wide.Network meta-analysis showed that for the primary outcome 'Time to withdrawal of allocated treatment,' for individuals with partial seizures; levetiracetam performed (statistically) significantly better than current first-line treatment carbamazepine and other current first-line treatment lamotrigine performed better than all other treatments (aside from levetiracetam); carbamazepine performed significantly better than gabapentin and phenobarbitone (high-quality evidence). For individuals with generalised onset seizures, first-line treatment sodium valproate performed significantly better than carbamazepine, topiramate and phenobarbitone (moderate- to high-quality evidence). Furthermore, for both partial and generalised onset seizures, the earliest licenced treatment, phenobarbitone seems to perform worse than all other treatments (moderate- to high-quality evidence).Network meta-analysis also showed that for secondary outcomes 'Time to 12-month remission of seizures' and 'Time to six-month remission of seizures,' few notable differences were shown for either partial or generalised seizure types (moderate- to high-quality evidence). For secondary outcome 'Time to first seizure,' for individuals with partial seizures; phenobarbitone performed significantly better than both current first-line treatments carbamazepine and lamotrigine; carbamazepine performed significantly better than sodium valproate, gabapentin and lamotrigine. Phenytoin also performed significantly better than lamotrigine (high-quality evidence). In general, the earliest licenced treatments (phenytoin and phenobarbitone) performed better than the other treatments for both seizure typ. Overall, the high-quality evidence provided by this review supports current guidance (e.g. NICE) that carbamazepine and lamotrigine are suitable first-line treatments for individuals with partial onset seizures and also demonstrates that levetiracetam may be a suitable alternative. High-quality evidence from this review also supports the use of sodium valproate as the first-line treatment for individuals with generalised tonic-clonic seizures (with or without other generalised seizure types) and also demonstrates that lamotrigine and levetiracetam would be suitable alternatives to either of these first-line treatments, particularly for those of childbearing potential, for whom sodium valproate may not be an appropriate treatment option due to teratogenicity.

Topics: Adult; Amines; Anticonvulsants; Carbamazepine; Child; Cyclohexanecarboxylic Acids; Epilepsies, Partial; Epilepsy; Epilepsy, Generalized; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Isoxazoles; Lamotrigine; Levetiracetam; Network Meta-Analysis; Oxcarbazepine; Phenobarbital; Phenytoin; Piracetam; Remission Induction; Topiramate; Triazines; Valproic Acid; Zonisamide

Topics: Anticonvulsants; Blood Coagulation Disorders; Cerebral Palsy; Chemical and Drug Induced Liver Injury; Child; Combined Modality Therapy; Drug Monitoring; Epilepsy; Fructose; Humans; Hyperammonemia; Intellectual Disability; Liver; Liver Failure, Acute; Male; Topiramate; Treatment Outcome

Antiepileptic drugs (AED) are often considered first line for monotherapy in treatment of patients with migraines, and also those with comorbid migraine and epilepsy. Topiramate, a newer generation AED, has broad mechanism of action and evidence of benefit in patients with either episodic or chronic migraine along with epilepsy, both generalized and focal.. Our goal is to review the relevant mechanisms of action along with any supportive evidence published to date on the use of topiramate (TPM) in patients with both migraine headache and epilepsy.. There has been very little published to date on the use of TPM in patients diagnosed with both disorders. Despite this, TPM has been adopted as first line therapy in this patient population. Future studies investigating the effectiveness of this treatment strategy are warranted in order to determine the most effective use of this medication in patients diagnosed with migraine headaches and epilepsy.

Topics: Databases, Bibliographic; Epilepsy; Female; Fructose; Humans; Male; Migraine Disorders; Neuroprotective Agents; Topiramate

Once-daily oral topiramate extended release (USL255; hereafter referred to as topiramate XR) [QUDEXY(®) XR] is approved in the USA for use as initial monotherapy and adjunctive therapy in patients aged ≥2 years with partial-onset seizures (POS) or primary generalized tonic-clonic seizures and as adjunctive therapy in patients aged ≥2 years with seizures associated with Lennox-Gastaut syndrome. Compared with twice-daily topiramate immediate release at the same total daily dose, topiramate XR provided bioequivalent exposure, an extended absorption rate (permitting convenient once-daily dosing) and more constant therapeutic plasma concentrations (potentially minimizing topiramate-associated adverse events). Switching between the two formulations did not affect the maintenance of topiramate concentrations. Moreover, the contents of a topiramate XR capsule may be sprinkled on to soft food for patients who have difficulty swallowing. In a multinational phase III study in adults with refractory POS, adjunctive topiramate XR was associated with significantly greater improvements from baseline in weekly median seizure frequency and the proportion of patients achieving a ≥50 % reduction in seizure frequency compared with placebo. These benefits were sustained during a 55-week open-label extension study. Adjunctive topiramate XR was generally well tolerated in these studies, with the majority of treatment-emergent adverse events being mild or moderate in intensity. In conclusion, current evidence suggests once-daily topiramate XR extends the treatment options currently available for patients aged ≥2 years with epilepsy, with its dosing regimen potentially delivering tolerability and adherence advantages over AEDs that require more frequent administration.

Topics: Anticonvulsants; Drug Administration Schedule; Drug Therapy, Combination; Epilepsy; Fructose; Humans; Topiramate

Topiramate (TPM) is an antiepileptic drug that is also used for other indications (e.g., migraine). Adverse event (AE) data from epilepsy trials could be supplemented by data from trials in other indications. Combining data across trials and indications is a novel method for evaluating AEs. We conducted a multiple-indications review by systematically reviewing randomized placebo-controlled trials of TPM, to compare the nervous system AEs of TPM in epilepsy with those in other indications.. Randomized placebo-controlled trials of TPM including patients with any indication were included. We searched Cochrane Central Register of Controlled Trials (Issue 2, 2012) and MEDLINE (1966-February 2012). Two authors assessed eligibility and risk of bias, and extracted data. For each reported nervous system AE, we extracted event rates, applied random-effects inverse-variance meta-analysis (pooling within-indications then across-indications), and assessed within- and across-indication heterogeneity.. Ninety trials, including 16 epilepsy trials, were included. A difference was detected between TPM and placebo for three events (i.e., drooling, dysgeusia, and hypoesthesia) that were not reported in epilepsy trials but were reported by other trials. A difference between TPM and placebo was detected for speech disorder using epilepsy trials but not when combining all trials. For two events (i.e., cognitive disorder and "language problems"), no difference was detected between TPM and placebo when using epilepsy trials alone, but a difference was identified using all trials. A difference was detected between TPM and placebo for six events (i.e., ataxia, disturbance in attention, dizziness, memory impairment, paraesthesia, and somnolence) when using epilepsy trials alone, and using all trials.. Including trials of any indication enabled detection of differences that would have been missed using epilepsy trials alone. Multiple-indications reviews can improve the synthesis of AEs for antiepileptic drugs.

Topics: Anticonvulsants; Epilepsy; Fructose; Humans; Randomized Controlled Trials as Topic; Topiramate

Topics: Adolescent; Adult; Apoptosis; Autoantibodies; Blood-Brain Barrier; Child; Child, Preschool; Encephalitis; Epilepsy; Female; Fructose; Humans; Male; Matrix Metalloproteinase 9; Receptors, N-Methyl-D-Aspartate; Time Factors; Tissue Inhibitor of Metalloproteinase-1; Topiramate; Young Adult

Recently, the treatment strategy for pediatric epilepsy has been dramatically changed in Japan, because of the approval of new-generation antiepileptic drugs. Since 2006, a total of 6 new antiepileptic drugs, including gabapentin (GBP; adults/pediatric patients: 2006/2011 [year of approval]), topiramate (TPM; 2007/2013), lamotrigine (LTG; 2008/2008), levetiracetam (LEV; 2010/2013), stiripentol (STP; 2012/2012), and rufinamide (RUF; 2013/2013), have been introduced. Thus far, valproate (VPA) and carbamazepine (CBZ) have been first indicated for "generalized" epilepsy and "focal" epilepsy syndromes/types, respectively, in Japan. However, the approval of these new drugs could allow us to choose more effective and less toxic ones at an early stage of treatment. In this chapter, we describe the latest domestic and foreign guidelines for the treatment of pediatric epilepsy.

Topics: Adolescent; Amines; Anticonvulsants; Carbamazepine; Child; Child, Preschool; Cyclohexanecarboxylic Acids; Dioxolanes; Drug Approval; Drug Substitution; Epilepsy; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Infant; Lamotrigine; Levetiracetam; Patient Education as Topic; Piracetam; Practice Guidelines as Topic; Topiramate; Triazines; Triazoles; Valproic Acid

New antiepileptic drugs (AEDs) that have been used in many other countries for more than 10 years have only recently became available for use in Japan. Gabapentin, topiramate, lamotrigine and levetiracetam were licensed for use in Japan between 2006 and 2010. Stiripentol for Dravet syndrome and rufinamide for Lennox-Gastaut syndrome were also approved in 2012 and 2013 as orphan drugs. Clinical trials of other new AEDs such as oxcarbazepine, vigabatrin, lacosamide, and perampanel are in progress. In this review, the general characteristics of the new AEDs are discussed with regards to their effectiveness, tolerability, drug interaction, safety and mechanisms of action. The effectiveness, of the new AEDs compared with established AEDs is also discussed. Clinical applications of the new AEDs, focusing on gabapentin, topiramate, lamotrigine and levetiracetam are also discussed based on our domestic experience as well as overseas reports.

Topics: Amines; Anticonvulsants; Clinical Trials as Topic; Cyclohexanecarboxylic Acids; Dioxolanes; Drug Approval; Drug Interactions; Epilepsy; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Japan; Lamotrigine; Levetiracetam; Piracetam; Safety; Topiramate; Triazines; Triazoles

Benign Epilepsy with Centro Temporal Spikes (BECTS) is a common epilepsy syndrome with onset in childhood which almost always remits by adolescence. It is characterised by focal seizures associated with motor signs and somatosensory symptoms, at times progressing to become generalised. The characteristic interictal EEG shows normal background activity with centrotemporal spikes which are more prominent in sleep. The prognosis is good though subtle cognitive impairment has been implicated. Antiepileptic drug (AED) treatment is used if seizures are frequent or occurring in the daytime.. To evaluate whether or not treatment with AEDs changes the short- or long-term outcome of children with BECTS or both.. We searched the following databases: the Cochrane Epilepsy Group Specialized Register (30 April 2013), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2013, Issue 4: (April 2013)), MEDLINE (Ovid, 1946 to 30 April 2013), SCOPUS (30 April 2013), ClinicalTrials.gov (30 April 2013) and the WHO International Clinical Trials Registry Platform ICTRP (30 April 2013). We also handsearched the reference lists of articles that were considered for inclusion in the review.. All randomised controlled trials (RCTs) that compared the use of different AEDs, or compared the use of AEDs with no treatment, or placebo in children with BECTS.. Data were independently extracted by all four of the review authors and discrepancies were resolved by discussion. Analysis included assessment of risk of bias, quality of evidence of individual studies, heterogeneity, and statistical analysis of the effects on seizure remission and cognition.. There were six eligible studies but only four had sufficient data at the time of this review. The four RCTs included in this review reported on a total of 262 participants. One study, a placebo-controlled trial with a low risk of bias, found that individuals on sulthiame were significantly more likely to remain in seizure remission during the three and six months from commencement of treatment than those on placebo (3 months: RR 2.26, 95% CI 1.48 to 3.44; 6 months: RR 2.63, 95% CI 1.43 to 4.86, 66 participants, moderate quality evidence). The other three trials, all open-labelled studies, had a high risk of bias and did not show any significant differences in terms of seizure remission between AEDs. One compared levetiracetam with oxcarbazepine (3 months: RR 1.13, 95% CI of 0.93 - 1.36; 12 months: RR of 1.29 with 95% CI of 0.89 - 1.86, 39 participants, low to very low quality evidence), one clobazam with carbamazepine (4-40 weeks: RR of 1.04, 95% CI of 0.67 - 1.62; last 9 months: RR of 1.06 with 95% CI of 0.84, 1.34, 45 participants, low quality evidence), and one carbamazepine with topiramate (28 weeks: RR 1.02 with 95% CI of 0.8 - 1.3, 112 participants, low quality evidence).Other outcome measures assessed included time to first seizure after randomisation which was only obtained in the sulthiame versus placebo study as a hazard ratio of 7.8 (95% CI 2.66 - 22.87). There were no significant differences between the proportion of participants who had adverse events, apart from a higher incidence of rash in the carbamazepine group (14.8%) when compared with topiramate (1.7%), or the proportion who withdrew from treatment due to adverse events, when this was reported. Two trials (carbamazepine versus topiramate, and clobazam versus carbamazepine) evaluated the effects on cognition. The studies were of low to very low quality evidence showing no clear difference in cognition at the end of the study periods between the AEDs compared. A meta-analysis was not performed as the RCTs evaluated different therapies.. There is evidence from one trial reviewed that sulthiame is effective for seizure remission in the short term in children with BECTS although the precision of the effect estimate is uncertain due to its small sample size. There were no significant differences in the proportion of adverse events between treatment groups studied, including those resulting in withdrawal of treatment. There is insufficient evidence about the medium to longer term effects on seizure control, the optimum antiepileptic drug treatment and the effects of AED treatment on cognition. There is a need for more good quality randomised controlled trials to address these questions to aid the management of children with BECTS.

Topics: Anticonvulsants; Benzodiazepines; Carbamazepine; Child; Clobazam; Epilepsy; Fructose; Humans; Induction Chemotherapy; Levetiracetam; Oxcarbazepine; Piracetam; Placebos; Randomized Controlled Trials as Topic; Thiazines; Topiramate; Watchful Waiting

USL255 is a once-daily, extended-release formulation of the well-established antiepileptic drug topiramate that was recently approved by the US FDA. As a capsule formulation, USL255 can be swallowed intact or opened and sprinkled onto soft food for patients with swallowing difficulties, including children (≥2 years old) and older patients. USL255 has been evaluated in seven key Phase I and III studies. Compared with immediate-release topiramate taken twice daily, once-daily USL255 provides equivalent topiramate exposure with a 26% reduction in plasma fluctuations. A multinational, Phase III, randomized, double-blind, placebo-controlled clinical trial in patients with refractory partial-onset seizures (PREVAIL) demonstrated that USL255 (200 mg/day) significantly improved seizure control and clinical outcomes versus placebo. USL255 is generally safe and well-tolerated, with a low incidence of neuropsychiatric and neurocognitive adverse events. These data suggest that USL255 may provide a useful treatment option for seizure control with convenient once-daily dosing.

Topics: Anticonvulsants; Drug Administration Schedule; Drug Delivery Systems; Epilepsy; Fructose; Humans; Topiramate; Treatment Outcome

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

Topics: Adult; Anticonvulsants; Corpus Callosum; Electroencephalography; Epilepsy; Female; Fructose; Humans; Lamotrigine; Topiramate; Triazines; Vagus Nerve; Video Recording

Although epilepsy surgery is most effective for patients with intractable epilepsy, a majority of them is not eligible for the surgery. Most of patients with refractory epilepsy are eventually treated with polypharmacy in hope of seizure control. Therefore, rational combinations of antiepileptic drugs are needed to control intractable seizures. Drug combinations should be rationally chosen based on the evidence of synergic efficacy and on avoidance of neurotoxicity. Several clinical studies suggest that the combination of valproate with lamotrigine has synergic antiepileptic effect. It has also been reported that the combination of carbamazepine with lamotrigine paradoxically decreases efficacy and increases toxicity. Animal studies using isobolography suggest that the combinations of topiramate with lamotrigine or levetiracetam are also promising on both seizure control and neurotoxicity. Clinical research is needed to examine these combinations.

Topics: Animals; Anticonvulsants; ATP Binding Cassette Transporter, Subfamily B, Member 1; Carbamazepine; Clinical Trials as Topic; Disease Models, Animal; Drug Interactions; Drug Resistance; Drug Therapy, Combination; Epilepsy; Fructose; Humans; Lamotrigine; Levetiracetam; Multidrug Resistance-Associated Proteins; Piracetam; Prognosis; Topiramate; Triazines; Valproic Acid

Weight loss can occur during topiramate (TPM) treatment and it should be evaluated by clinicians, especially in children, whose growth could be compromised. In international literature, the reported body weight loss incidences linked to TPM therapy vary widely and, in some cases, are very conflicting.. The aims of this review are to quantify TPM-induced weight loss, analyze the pathogenetic mechanisms and evaluate its clinical implications in patients with epilepsy.. The amount of weight loss appears to be related to some factors such as the duration of the treatment and a high baseline body mass index (BMI), while the role of daily dosage and gender of patients is controversial. The mechanism through which TPM may induce weight loss is still unclear.. TPM is able to induce weight loss, especially in high baseline BMI patients, not strictly depending on daily dosage and perhaps not influenced by gender. This makes TPM a good choice, especially in obese patients suffering from seizures. However, TPM can make nutritionally vulnerable children or adult patients, with epilepsy associated with other neuropsychiatric diseases, who cannot voluntarily increase their caloric intake.

Topics: Anti-Obesity Agents; Databases, Factual; Energy Metabolism; Epilepsy; Fructose; Hormones; Humans; Obesity; Sex Factors; Topiramate; Weight Loss

Individuals over 65 years of age experience the new onset of seizures at a prevalence rate of roughly twice that of younger adults. Differences in physiology, need of concomitant medications, and liability for cognitive deficits in this population, make the choice of anticonvulsant drugs especially important. This paper reviews topiramate (TPM), a treatment for many types of seizures, with the above risks in mind. In particular, we discuss efficacy and pharmacokinetics with emphasis on the older patient, and adverse events in both the younger and older adult. With most studies of TPM-induced cognitive deficits having been performed in younger adults and volunteers, we discuss the implications for the older adult. Even in studies of younger individuals, up to 50% discontinue TPM because of intolerable cognitive deficits. Most studies find specific declines in working memory and verbal fluency. In conclusion, we give recommendations for use of this antiepileptic drug in this population.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Child; Child, Preschool; Dose-Response Relationship, Drug; Epilepsy; Fructose; Humans; Infant; Middle Aged; Topiramate; Young Adult

To compare adverse drug reactions (ADRs) to topiramate in patients with migraine and patients with epilepsy, we systematically reviewed all published randomized controlled trials (RCTs) that compare topiramate monotherapy in epilepsy and migraine. We included four epilepsy RCTs (N = 1,179 patients; vs. active comparators) and six migraine RCTs (N = 1,723 patients; vs. placebo). Behavioral ADRs and headache were found only in the case of epilepsy, whereas cognitive complaints and alteration of taste were found only in the case of migraine. The risk ratios (RRs) for paresthesia in migraine vs. epilepsy trials were 2.5 (99% confidence interval (CI): 1.66-3.77) for 50 mg, 2.7 (99% CI: 1.80-3.97) for 100 mg, and 3.0 (99% CI: 1.95-4.56) for 200 mg. For ADR-related dropouts, the RR was 2.5 (95% CI: 2.03-2.98) for 50 mg but no different for the other doses. We conclude that when treated with the same doses of topiramate, migraineurs show different ADRs than patients with epilepsy and are more likely to drop out because of ADRs.

Topics: Drug-Related Side Effects and Adverse Reactions; Epilepsy; Fructose; Humans; Migraine Disorders; Randomized Controlled Trials as Topic; Risk Factors; Topiramate

In this paper we review the current information regarding the use of new antiepileptic drugs (AEDs) used as monotherapy in children. We specifically include the following AEDs: lamotrigine (Lamictal), topiramate (Topamax), zonisamide (Zonegran), levetiracetam (Keppra), and oxcarbazepine (Trileptal). All of these AEDs have a broad spectrum of action in the treatment of partial and generalized seizures, except Oxcarbazepine, which is effective only in partial seizures. It is unclear whether or not monotherapy with the new AEDs offers higher efficacy and/or lower side effects compared to classic AEDs (phenobarbital, phenytoin, carbamazepine, or valproate) thereby significantly improving the quality of life in children with epilepsy. More studies are needed to answer these questions.

Topics: Anticonvulsants; Carbamazepine; Child; Drug Administration Schedule; Epilepsy; Fructose; Humans; Isoxazoles; Lamotrigine; Levetiracetam; Piracetam; Topiramate; Triazines; Zonisamide

Open-label extension studies, or follow-on randomised controlled trials (FORCTs) are widely believed to be prone to patient selection biases which may inflate effect estimates. This study investigates the reporting and analysis of efficacy outcomes in FORCTs and critically evaluates the associated underlying assumptions. We propose an alternative method of analysis, in line with that recommended in the analysis of RCTs, the intention to treat (ITT) approach, in which it is assumed that all patients who discontinue treatment are non-responders.. A systematic review of FORCTs and randomised controlled trials (RCT) of topiramate, levetiracetam and gabapentin as adjuvant therapy in refractory adult epilepsy was conducted. Sample sizes and numbers of responders, along with reported outcomes were extracted. To evaluate the feasibility of the assumptions underlying the various methods of analysis, the most common causes of discontinuation were evaluated. For each FORCT, we compared the reported outcome to the proposed ITT analysis.. The 10 FORCT reports identified all excluded from the analysis patients who dropped out of the RCT. Adverse events or inefficacy were the main reasons for treatment discontinuation. Analysis based on the ITT method, led to smaller effect estimates than those reported. For example, a FORCT of levetiracetam reported a responder rate of 43%, which reduced to 28% under an ITT analysis, comparable to an ITT analysis outcome of 26% for the parent RCT.. FORCTs can provide important information about long-term efficacy and tolerability of newer therapies. However, current reporting methods are likely to be misleading as outcomes are reported for the subset of patients continuing with treatment at the end of the FORCT. Since the majority of patients who discontinue treatment do so for reasons associated with inefficacy, an analysis based on the ITT approach more closely reflects the outcomes of the patients.

Topics: Amines; Anticonvulsants; Cyclohexanecarboxylic Acids; Databases, Factual; Drug Resistance; Epilepsy; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Levetiracetam; Patient Dropouts; Piracetam; Randomized Controlled Trials as Topic; Research Design; Topiramate

The efficacy of topiramate (TPM) as an adjunctive treatment for epilepsy has been established in placebo-controlled clinical trials. Clinical trials of antiepileptic monotherapy usually evaluate low and high doses of study drug or compare study drug with another active agent.. This article reviews available evidence for the use of TPM as monotherapy in patients with newly or recently diagnosed epilepsy.. A search of MEDLINE, EMBASE, BIOSIS, SCISEARCH, and the Cochrane Database of Systematic Reviews (all years) for reports of controlled trials of TPM monotherapy in patients with recently diagnosed (within the previous 3 years) epilepsy was conducted in January 2008 using the terms topiramate, epilepsy, newly diagnosed, recently diagnosed, and monotherapy. Identified trials were included in the review if they were published in peer-reviewed journals and enrolled > or = 20 patients.. Three randomized, double-blind, controlled trials met the criteria for inclusion in the review. In a comparison of TPM 50 and 500 mg/d, the higher dose was associated with significantly greater freedom from seizures at 6 months compared with the lower dose (54% vs 39%, respectively; P = 0.02). The time to first seizure was significantly associated with mean plasma TPM concentrations (P = 0.015). In a comparison of TPM 50 and 400 mg/d, the time to first seizure was significantly longer with the higher dose compared with the lower dose (P<0.001, Kaplan-Meier analysis), and the probability of 12-month seizure freedom was significantly higher (76% vs 59%, respectively; P = 0.001). Again, the time to first seizure was significantly associated with mean plasma TPM concentrations (P = 0.029). In a comparative study of TPM 100 and 200 mg/d, carbamazepine 600 mg/d, and valproate 1250 mg/d, there was no significant difference in rates of 6-month seizure freedom with TPM 100 and 200 mg/d (49% and 44%, respectively), carbamazepine (44%), and valproate (44%). Adverse events in the 3 studies were similar between TPM dose groups, although the incidence generally increased with increasing doses, occurred early in treatment, and decreased with prolonged therapy. In a pooled analysis of the 3 trials, the most commonly occurring adverse events during dose titration were paresthesia (25%), fatigue (16%), dizziness (13%), somnolence (13%), and nausea (10%); the most frequent adverse events during maintenance therapy were headache (20%), decreased appetite (11%), and weight loss (11%).. In the 3 studies reviewed, TPM monotherapy was effective and generally well tolerated in patients with newly diagnosed epilepsy.

Topics: Anticonvulsants; Epilepsy; Fructose; Humans; Randomized Controlled Trials as Topic; Topiramate

Topiramate (Topamax) is a structurally novel broad-spectrum antiepileptic drug (AED) with established efficacy as monotherapy or adjunctive therapy in the treatment of adult and paediatric patients with generalized tonic-clonic seizures, partial seizures with or without generalized seizures, and seizures associated with Lennox-Gastaut syndrome. The incidence and severity of many adverse events, including CNS-related events, may be reduced through the use of slow titration to effective and well tolerated dosages. It is associated with few clinically significant interactions with other drugs, is effective when used with other AEDs, is not associated with drug-induced weight gain and, at lower dosages, does not interfere with the effectiveness of oral contraceptives. Therefore, topiramate is a valuable option as monotherapy or adjunctive therapy in the treatment of epilepsy in adult and paediatric patients.

Topics: Anticonvulsants; Drug Evaluation; Epilepsy; Fructose; Humans; Topiramate

Since 1990 eight new antiepileptic drugs (AEDs) have been developed. Among these new drugs, Topiramate (TPM) is one of the latest AEDs available for treating drug resistant partial epilepsy both in adults and in children. The mechanisms underlying TPM antiepileptic activity are still incompletely understood. However, TPM, a sulfamate-substituted derivative of the naturally occurring monosaccharide D-fructose, has a different structure from other known AEDs. The antiepileptic activity of TPM in animal models of partial and generalized tonic-clonic seizures has been shown to be more effective as compared to other AEDs. Proposed mechanisms of action include reduction of epileptiform discharges through a voltage-dependent block of Na(+) channels, enhancement of the activity of gamma-aminobutyrate at some subtypes of gamma-aminobutyrate receptors, and antagonism of non- N-methyl-D-aspartate (NMDA) glutamate receptors. The pharmacokinetic profile of TPM, which is characterized by its rapid and almost complete absorption after oral administration, linear pharmacokinetics, minimal protein binding and predominantly renal excretion, makes the drug a good option for the treatment. TPM was found to be effective and well tolerated in many studies conducted in adults and pediatric patients suffering from epilepsy. This review, summarising the main studies in this field, provides an overview of the current knowledge about the relevant pharmacological and clinical information on the efficacy and tolerability of TPM.

Topics: Anticonvulsants; Epilepsy; Fructose; Humans; Topiramate; Treatment Outcome

Principles of complex mechanisms of action of anticonvulsants including latest reports concerning new antiepileptic drugs (AED) are considered. Different aspects of new anticonvulsant drugs (2nd generation) from preclinical and clinical testing, pharmacokinetics, and mono or combination therapy in children and adults are summarized. In the following condensed synopsis pharmacological and clinical characteristics of gabapentin (GBP), lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXC), pregabalin (PGB) and tiagabine (TGB) as well as topiramate (TPM) and zonisamide (ZNS) are discussed. In addition to the mechanisms of action, pharmacokinetics, interactions, indications and dosages as well as side effects are considered. Important data concerning the effect and tolerability of anticonvulsant drugs can be obtained from controlled studies. In comparison to drugs of the first generation (phenobarbital [PB], primidon [PRD], phenytoin [PHT], carbamazepine [CBZ] and valproic acid [VPA]) the potential for interactions and side effects due to enzyme induction or inhibition is reduced by most of the anticonvulsant drugs of the second generation. New anticonvulsant drugs increase the spectrum of treatment and represent further steps with regard to the optimization of an individual therapy of the epilepsies.

Topics: Amines; Animals; Anticonvulsants; Carbamazepine; Cyclohexanecarboxylic Acids; Epilepsy; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Isoxazoles; Lamotrigine; Levetiracetam; Nipecotic Acids; Piracetam; Pregabalin; Tiagabine; Topiramate; Treatment Outcome; Triazines; Zonisamide

Ten newer antiepileptic drugs have been developed since 1990s. These drugs have wider therapeutic spectra, fewer side-effects, and lesser drug-to-drug interactions compared with the older typical antiepileptic drugs. Among them, zonisamide was developed in Japan and has been used from 1989. Gabapentin was at length approved in 2006. The other newer antiepileptic drugs are not approved yet in Japan. Felbamate can not be used in Europe because it may induce lethal hepatic toxicity and aplastic anemia. Vigabatrin is not approved in USA because it may induce permanent visual field deficit. The USA guideline for epilepsy treatment recommends that patients with newly diagnosed epilepsy can be treated with gabapentin, lamotrigine, topiramate, and oxcarbazepine. In contrast, based on epilepsy treatment guideline in England, newer antiepileptic drugs are considered only when patients with newly diagnosed epilepsy are unable to use the older antiepileptic drugs for some reasons. All newer antiepileptic drugs are used for intractable partial epilepsies, and lamotrigine and topiramate can also be used for idiopathic generalized epilepsies. The response rate (seizure reduction rate with 50% or more) and drop-out rate are overlapping among all newer antiepileptic drugs. Gabapentin, levetiracetam, and pregabalin are eliminated from kidney, and they had no drug-to-drug interactions and can be titrated rapidly. The serum concentration of lamotrigine is decreased with co-administration of hepatic enzyme inducing drugs and is increased with co-administration of valproic acid. Hypersensitivity reactions are rare with gavapentin, levetiracetam, topiramate, and tiagabin. Psychoses are reported to be induced with zonisamide, however, they can be induced with the other newer drugs (topiramate, levetiracetam, etc.). Drug-induced psychiatric symptoms, especially depression, may be often underdiagnosed. Many of these newer drugs (gabapentine, lamotrigine, levetiracetam, oxycarbazepine, etc.) have effects on chronic neuropathic pain. Some newer drugs show mood stabilizing effects (lamotrigine, oxycarbazepine, etc.), or antianxiety effect (gabapentin, topiramate, levetiracetam, pregavalin, etc.). Wide range of action to central nervous system of these newer antiepileptic drugs may serve not only for clinical seizure suppression, but also for neuroprotection.

Topics: Amines; Animals; Anti-Anxiety Agents; Anticonvulsants; Calcium Channel Blockers; Carbamazepine; Cyclohexanecarboxylic Acids; Drug Approval; Drug Design; Drug Interactions; Epilepsy; Felbamate; Fructose; GABA Agonists; Gabapentin; gamma-Aminobutyric Acid; Humans; Isoxazoles; Lamotrigine; Neuroprotective Agents; Oxcarbazepine; Phenylcarbamates; Propylene Glycols; Sodium Channel Blockers; Topiramate; Triazines; Zonisamide

Migraine and epilepsy share several clinical features, and epilepsy is a comorbid condition of migraine. Clinical studies have shown that some antiepileptic drugs are effective at preventing migraine attacks. A rationale for their use in migraine prophylaxis is the hypothesis that migraine and epilepsy share several common pathogenetic mechanisms. An imbalance between excitatory glutamate-mediated transmission and GABA-mediated inhibition in specific brain areas has been postulated in these two pathological conditions. Moreover, abnormal activation of voltage-operated ionic channels has been implicated in both migraine and epilepsy. Cortical spreading depression has been found to be involved in the pathophysiology of epilepsy, in addition to the generation of migraine aura.

Topics: Amines; Animals; Anticonvulsants; Cyclohexanecarboxylic Acids; Epilepsy; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Migraine Disorders; Topiramate; Valproic Acid

Nongenetic biologic and lifestyle-related factors, including age, sex, hepatic/renal function, diet/exercise practices, illness severity, smoking, and alcohol consumption habits can account for the heterogeneity of treatment effects (HTE). However, even when these factors are taken into account, considerable variation remains unexplained and could potentially be attributable to genetic differences between patients. Drug response may be dictated by variation in genes involved in both pharmacokinetic (PK) (absorption, distribution, metabolism, excretion [ADME]) and pharmacodynamic (PD) (receptors, ion channels, enzymes, immune system) pathways. Functional variants of the ADME genes can result in patients being poor, intermediate, efficient, or ultrarapid metabolizers of specific agents, thereby affecting efficacy and/or susceptibility to adverse drug reaction and necessitating individualized dosing. A well-documented example of ADME gene variation is the debrisoquine polymorphism, which is characterized by markedly different metabolism of numerous commonly prescribed drugs based on variants of the cytochrome P450 2D6 gene. Variants of genes regulating PD pathways cause altering of drug target pathways, which may affect efficacy in a more pronounced manner. Examples of gene variants affecting PD pathways include those coding for dopamine metabolism, synthesis, and transport. These gene variants may act independently, in combination with each other, and/or in combination with PK genes to affect drug response, for example to antipsychotic medications. Increased understanding of a patient's genotype and its corresponding effect on drug response would be useful to the practicing clinician in choosing an effective drug and in optimizing the dose in a timely manner.

Topics: Adolescent; Adult; Age Factors; Clinical Trials as Topic; Cognition Disorders; Dose-Response Relationship, Drug; Epilepsy; Female; Fructose; Genetics, Population; Humans; Male; Middle Aged; Pharmacogenetics; Risk Assessment; Sex Factors; Topiramate; Treatment Outcome

Topiramate (Topamax) is a structurally novel broad-spectrum antiepileptic drug (AED) with established efficacy as monotherapy or adjunctive therapy in the treatment of adult and paediatric patients with generalised tonic-clonic seizures, partial seizures with or without generalised seizures, and seizures associated with Lennox-Gastaut syndrome. The incidence and severity of many adverse events, including CNS-related events, may be reduced through the use of slow titration to effective and well tolerated dosages. It is associated with few clinically significant interactions with other drugs, is effective when used with other AEDs, is not associated with drug-induced weight gain and, at lower dosages, does not interfere with the effectiveness of oral contraceptives. Therefore, topiramate is a valuable option as monotherapy or adjunctive therapy in the treatment of epilepsy in adult and paediatric patients.

Topics: Animals; Anticonvulsants; Epilepsy; Fructose; Humans; Topiramate

This article deals with the effect of antiepileptic drugs on mood when applied in epileptic patients. The author points that depressive symptoms occur significantly more frequently in epilepsy and there are more common factor in the mechanism of action of the antiepileptic and antidepressive agents. The relevant literature is surprisingly poor. Primary and large analysis regarding affective disorders coexisting with epilepsy is still lacking. From this aspect some antiepileptic drugs have not been investigated at all. The consequences of the papers originates from indirect sources like adverse events profiles of the study drugs or from psychometric tests performed for avoiding exclusion criteria of psychological nature. On the other hand the paper deals also with the difficulties of such kind of investigations concerning the classification of depressive signs presenting with epilepsy, special considerations of inclusion of appropriate patients and particular limits of the measuring and follow-up of the observed effect. As the result of the detailed analysis of the literature the author recommends lamotrigine, carbamazepine and oxcarbazepine as first choice antiepileptic drug for epileptic patients suffering from depressive disorder, too. On the contrary, phenobarbital, topiramate and vigabatrin are able to worsen the affective symptoms. Aimed, randomized, controlled studies are necessary for recognizing the whole spectrum of psychotropic effects of antiepileptic drugs and for their successful and individually tailored application in patients in their comorbid states. Author calls the attention for the importance of the treatment of depressive states frequently occurring in epileptic patients. These symptoms modify patient compliance and are able to influence even the epileptic process itself.

Topics: Affect; Anticonvulsants; Antidepressive Agents; Carbamazepine; Depressive Disorder; Epilepsy; Fructose; Humans; Lamotrigine; Mood Disorders; Oxcarbazepine; Patient Compliance; Phenobarbital; Psychometrics; Topiramate; Triazines; Vigabatrin

Topics: Amines; Anticonvulsants; Carbamazepine; Child; Cyclohexanecarboxylic Acids; Dioxolanes; Epilepsies, Partial; Epilepsy; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Isoxazoles; Lamotrigine; Levetiracetam; Oxcarbazepine; Piracetam; Pregabalin; Topiramate; Triazines; Vigabatrin; Zonisamide

Special issues are related to AED testing in several populations. Pharmacokinetics, pharmacodynamics and underlying neurochemistry and developing systems require specific testing in appropriate infants with refractory seizures. EEG monitoring is an essential part of seizure definition and recognition, making it a necesssity along with clinical semiology to define the seizure types and changes in seizure frequency. (1) Neonates: A trial design for neonatal seizures should be similar to those used for the treatment of status epilepticus. Proposed study end points should be seizure cessation for some period of time, or time to next seizure. The use of placebo is questionable. (2) Partial seizures occurring in young infants: A trial designed for topirimate included a placebo controlled, double blind study with fixed dose trials exploring the range of tolerated doses. Forty-eight hour video EEGs were used for quantification of seizures. (3) Uncommon forms of encephalopathic epilepsy: a proposed design includes randomization to sequential monotherapy with prescribed titration/dose defined by seizure control or tolerance. Outcome variables include seizure reduction, tolerability, and time continued on AED.

Topics: Anticonvulsants; Clinical Trials as Topic; Electroencephalography; Epilepsies, Partial; Epilepsy; Fructose; Humans; Infant; Infant, Newborn; Topiramate; Video Recording

Initially synthesized as an oral hypoglycemic agent, topiramate was approved for use as an anticonvulsant in 1996. Its broad spectrum efficacy in epilepsy, including as monotherapy and in children, is well established. Topiramate has also been used in the management of nonepileptic neurologic and psychiatric conditions, including migraine prophylaxis (with firmly established efficacy), obesity (with some evidence of long-term maintenance of weight loss), substance dependence, bipolar disorder and neuropathic pain, and it has been investigated as a possible neuroprotective agent. Paresthesias and cognitive side effects are the most common troublesome adverse effects. Recent trends towards lower doses may help achieve the best combination of efficacy and tolerability.

Topics: Clinical Trials as Topic; Drug Tolerance; Drug-Related Side Effects and Adverse Reactions; Epilepsy; Expert Testimony; Fructose; Humans; Nervous System Diseases; Neuroprotective Agents; Topiramate

Topiramate, a derivative of the monosaccharide d-fructose, has shown a wide spectrum of antiepileptic efficacy in both animal models and clinical trials. Multiple putative mechanisms of action include voltage-sensitive sodium channel blockade, calcium channel inhibition, increase of potassium conductance, GABA-mediated chloride current increment, glutamate-mediated neurotransmission inhibition and carbonic anhydrase isoenzyme inhibition. In general, the clinical response is maintained in the long-term. The most common side effects include somnolence, fatigue, headache, psychomotor slowing, confusion, difficulty with memory, impaired concentration and attention, speech and language problems and weight loss. If slowly titrated and used at a low-to-medium dosage, it is well tolerated and offers a valid therapeutic option, the relevance of which is comparable to that of the most widely used 'old' antiepileptic drugs. As it is not yet wholly clear which specific epilepsy syndromes may benefit most from topiramate with respect to other drugs, more accurate indications for initial monotherapy would require syndrome-oriented trials and more clinical experience.

Topics: Animals; Epilepsy; Fructose; Humans; Topiramate

On the basis of the relevance of adequate epilepsy treatment (antiepileptic drugs, surgery and vagus nerve stimulation) for people with intellectual disabilities, all articles, published from the beginning of 2005 to March 2006 and searched by MEDLINE, on this topic were reviewed.. On pharmacological treatment of epilepsy in people with intellectual disabilities, there were two articles on topiramate and one on levetiracetam. Two studies described the effect of surgical interventions, one of epilepsy surgery in the narrow sense and one of vagus nerve stimulation. Two papers were published on clinical conditions and therapeutic aspects of Angelman syndrome. They highlight the importance of gamma-aminobutyric acidergic mechanism in Angelman syndrome and the antiepileptic drug effects in this syndrome.. A contradiction exists between the relevance of epilepsy treatment in people with intellectual disabilities and the small number of published studies on pharmacological treatment. Some of the reasons are addressed and some alternatives are proposed.

Topics: Anticonvulsants; Brain; Electric Stimulation Therapy; Epilepsy; Fructose; Humans; Intellectual Disability; Levetiracetam; Neurosurgical Procedures; Piracetam; Postoperative Complications; Topiramate; Vagus Nerve

A new generation of antiepileptic drugs (AEDs) has reached the market in recent years with ten new compounds: felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin and zonisamide. The newer AEDs in general have more predictable pharmacokinetics than older AEDs such as phenytoin, carbamazepine and valproic acid (valproate sodium), which have a pronounced inter-individual variability in their pharmacokinetics and a narrow therapeutic range. For these older drugs it has been common practice to adjust the dosage to achieve a serum drug concentration within a predefined 'therapeutic range', representing an interval where most patients are expected to show an optimal response. However, such ranges must be interpreted with caution, since many patients are optimally treated when they have serum concentrations below or above the suggested range. It is often said that there is less need for therapeutic drug monitoring (TDM) with the newer AEDs, although this is partially based on the lack of documented correlation between serum concentration and drug effects. Nevertheless, TDM may be useful despite the shortcomings of existing therapeutic ranges, by utilisation of the concept of 'individual reference concentrations' based on intra-individual comparisons of drug serum concentrations. With this concept, TDM may be indicated regardless of the existence or lack of a well-defined therapeutic range. The ten newer AEDs all have different pharmacological properties, and therefore, the usefulness of TDM for these drugs has to be assessed individually. For vigabatrin, a clear relationship between drug concentration and clinical effect cannot be expected because of its unique mode of action. Therefore, TDM of vigabatrin is mainly to check compliance. The mode of action of the other new AEDs would not preclude the applicability of TDM. For the prodrug oxcarbazepine, TDM is also useful, since the active metabolite licarbazepine is measured. For drugs that are eliminated renally completely unchanged (gabapentin, pregabalin and vigabatrin) or mainly unchanged (levetiracetam and topiramate), the pharmacokinetic variability is less pronounced and more predictable. However, the dose-dependent absorption of gabapentin increases its pharmacokinetic variability. Drug interactions can affect topiramate concentrations markedly, and individual factors such as age, pregnancy and renal function will contribute to the pharmacokinetic

Topics: Amines; Anticonvulsants; Carbamazepine; Cyclohexanecarboxylic Acids; Drug Interactions; Drug Monitoring; Epilepsy; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Isoxazoles; Lamotrigine; Levetiracetam; Nipecotic Acids; Oxcarbazepine; Phenylcarbamates; Piracetam; Pregabalin; Propylene Glycols; Tiagabine; Topiramate; Triazines; Vigabatrin; Zonisamide

The purposes of this review were to assess the efficacy of topiramate as monotherapy for epilepsy and migraine prevention, describe how it should be used, and give clinical advice on how to manage the practical aspects of dosing, titration, and possible adverse events in these 2 indications.. We searched the PubMed and BIOSIS databases using the key words topiramate, epilepsy, and migraine from the year 1987 onward, and subsequently focused the search on larger controlled trial studies of topiramate as monotherapy.. Studies have evaluated the use of topiramate as monotherapy in the treatment of partial-onset and generalized seizures and in the prevention of migraine. In a randomized study, 75% of epilepsy patients treated with 400 mg/d topiramate remained seizure free at 1 year. Patients in the same study treated with a lower dose of topiramate (50 mg/d) also experienced notable seizure reductions, with 59% of patients free of seizures at 1 year. A comparison trial of topiramate (100 or 200 mg/d), valproate, and carbamazepine found that topiramate was associated with a similar time to first posttreatment seizure as the other 2 agents (P = NS). Trials of topiramate monotherapy in migraine prevention found that 100 mg/d was associated with a > or =50% reduction in monthly migraine frequency in 49% to 54% of patients. The migraine prevention trials typically used a starting dose of 25 mg/d, with weekly increases of 25 mg and an initial monotherapy target dose of 100 mg/d. The most common adverse events associated with topiramate are paresthesia, weight loss, and other centrally mediated symptoms, many of which may be ameliorated by proper titration and dosing and by good communication between physician and patient.. Data from controlled trials suggest that 100 mg/d topiramate as monotherapy is effective in the treatment of partial-onset and generalized seizures and in the prevention of migraine.

Topics: Anticonvulsants; Drug Therapy, Combination; Epilepsy; Fructose; Humans; Migraine Disorders; Randomized Controlled Trials as Topic; Topiramate

The aim of this paper was to summarize of current knowledge about neuronal injuries during epileptogenesis process and possibilities of neuroprotection.. Many of agents from a wide range of classes have been proposed to possess neuroprotective potential, but especially in experimental and preclinical conditions. Among the antiepileptic drugs topiramate (TPM) and levetiracetam (LEV) possess neuroprotective effects in experimental models of brain damage. Promising protection against cell loss display antioxidants and neurotrophins.. Important and difficult problem of neuroprotective therapy in childhood epilepsy require further experimental and clinical investigations.

Topics: Anticonvulsants; Brain Diseases; Child; Epilepsy; Fructose; Humans; Levetiracetam; Neuroprotective Agents; Piracetam; 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

Topics: Adolescent; Amines; Animals; Anticonvulsants; Carbamazepine; Child; Child, Preschool; Cyclohexanecarboxylic Acids; Epilepsy; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Isoxazoles; Lamotrigine; Levetiracetam; Nipecotic Acids; Pediatrics; Piracetam; Tiagabine; Topiramate; Treatment Outcome; Triazines; Vigabatrin; Zonisamide

To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs (AEDs) (gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, and zonisamide-reviewed in the order in which these agents received approval by the US Food and Drug Administration) in the treatment of children and adults with newly diagnosed partial and generalized epilepsies.. A 23-member committee, including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy, evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane library for relevant articles from 1987 until September 2002, with selected manual searches up until 2003.. There is evidence either from comparative or dose-controlled trials that gabapentin, lamotrigine, topiramate, and oxcarbazepine have efficacy as monotherapy in newly diagnosed adolescents and adults with either partial or mixed seizure disorders. There is also evidence that lamotrigine is effective for newly diagnosed absence seizures in children. Evidence for effectiveness of the new AEDs in newly diagnosed patients with other generalized epilepsy syndromes is lacking.. The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with newly diagnosed epilepsy and identify those seizure types and syndromes where more evidence is necessary.

Topics: Acetates; Acute Disease; Adolescent; Adult; Amines; Anticonvulsants; Carbamazepine; Child; Controlled Clinical Trials as Topic; Cyclohexanecarboxylic Acids; Drug Interactions; Epilepsy; Evidence-Based Medicine; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Lamotrigine; Oxcarbazepine; Topiramate; Treatment Outcome; Triazines

Treatment of the catastrophic epilepsies [infantile spasms (IS), Lennox-Gastaut syndrome (LGS), and progressive myoclonic epilepsy (PME)] remains a challenge to clinicians. For IS, adrenocorticotropic hormone has traditionally been the drug of choice in the United States but may be associated with serious side effects in some patients. Vigabatrin has shown promise in treating IS patients, particularly those with tuberous sclerosis. However, the drug is associated with visual field loss and is not commercially available in the United States. Newer antiepilepsy drugs (AEDs), such as zonisamide, topiramate (TPM), and lamotrigine (LTG), may be useful in patients with IS. Although LTG, TPM, and felbamate are approved in the United States for the treatment of LGS, the overall effectiveness of therapy in patients with LGS is poor. For PME, valproate is a first-line treatment. Zonisamide and levetiracetam also show promise. Supplementation with certain cofactors to correct deficiencies and increase mitochondrial function may be useful in some patients with PME, but response to such therapy is not well documented. Advances in our understanding of the etiologies, mechanisms, and genetics underlying the catastrophic epilepsies may facilitate more effective pharmacologic interventions.

Topics: Anticonvulsants; Child, Preschool; Epilepsies, Myoclonic; Epilepsy; Fructose; Humans; Infant; Isoxazoles; Lamotrigine; Spasms, Infantile; Topiramate; Treatment Outcome; Triazines; Vigabatrin; Zonisamide

Topiramate is a new antiepileptic drug (AED) that has been approved worldwide (in more than 80 countries) for the treatment of various kinds of epilepsy. It is currently being evaluated for its effect in various neurological and psychiatric disorders. The pharmacokinetics of topiramate are characterised by linear pharmacokinetics over the dose range 100-800 mg, low oral clearance (22-36 mL/min), which, in monotherapy, is predominantly through renal excretion (renal clearance 10-20 mL/min), and a long half-life (19-25 hours), which is reduced when coadministered with inducing AEDs such as phenytoin, phenobarbital and carbamazepine. The absolute bioavailability, or oral availability, of topiramate is 81-95% and is not affected by food. Although topiramate is not extensively metabolised when administered in monotherapy (fraction metabolised approximately 20%), its metabolism is induced during polytherapy with carbamazepine and phenytoin, and, consequently, its fraction metabolised increases. During concomitant treatment with topiramate and carbamazepine or phenytoin, the (oral) clearance of topiramate increases 2-fold and its half-life becomes shorter by approximately 50%, which may require topiramate dosage adjustment when phenytoin or carbamazepine therapy is added or discontinued. From a pharmacokinetic standpoint, topiramate is a unique example of a drug that, because of its major renal elimination component, is not subject to drug interaction due to enzyme inhibition, but nevertheless is susceptible to clinically relevant drug interactions due to induction of its metabolism. Unlike old AEDs such as phenytoin and carbamazepine, topiramate is a mild inducer and, currently, the only interaction observed as a result of induction by topiramate is that with ethinylestradiol. Topiramate only increases the oral clearance of ethinylestradiol in an oral contraceptive at high dosages (>200 mg/day). Because of this dose-dependency, possible interactions between topiramate and oral contraceptives should be assessed according to the topiramate dosage utilised. This paper provides a critical review of the pharmacokinetic interactions of topiramate with old and new AEDs, an oral contraceptive, and the CNS-active drugs lithium, haloperidol, amitriptyline, risperidone, sumatriptan, propranolol and dihydroergotamine. At a daily dosage of 200 mg, topiramate exhibited no or little (with lithium, propranolol and the amitriptyline metabolite nortriptyline) pharmacokinetic int

Topics: Anticonvulsants; Area Under Curve; Contraceptives, Oral; Drug Interactions; Epilepsy; Fructose; Half-Life; Humans; Lithium; Metabolic Clearance Rate; Psychotropic Drugs; Serotonin Receptor Agonists; Sumatriptan; Topiramate

The pharmacokinetic properties of a drug are the primary deter-minant of the extent and duration of drug action, and influence susceptibility to clinically important drug interactions. Most of the older-generation antiepileptic drugs (AEDs) are far from ideal in terms of pharmacokinetics and interaction potential. For example, phenytoin, carbamazepine, and valproic acid exhibit non-linear kinetics; carbamazepine and valproic acid have relatively short half-lives; and most of these drugs cause either enzyme induction (phenytoin, phenobarbital, primidone, carbamazepine) or enzyme inhibition (valproic acid). Compared with older agents, certain new-generation AEDs offer a num-ber of pharmacokinetic advantages, particularly in terms of reduced inter-patient variability in drug clearance and a lower interaction potential. One of the most recently developed of these drugs, levetiracetam, comes especially close to fulfilling the desirable pharmacokinetic characteristics for an AED: (1) it has a high oral bioavailability, which is unaffected by food; (2) it is not significantly bound to plasma proteins; (3) it is eliminated partly in unchanged form by the kidneys and partly by hydrolysis to an inactive metabolite, without involvement of oxidative and conjugative enzymes; (4) it has linear kinetics; and (5) it is not vulnerable to important drug interactions, nor does it cause clinically significant alterations in the kinetics of concomitantly administered drugs. Although its half-life is relatively short (6 to 8 hours), its duration of action is longer than anticipated from its pharmacokinetics in plasma, and a twice-daily dosing regimen is adequate to produce the desired response.

Topics: Acetates; Amines; Animals; Anticonvulsants; Carbamazepine; Cyclohexanecarboxylic Acids; Drug Interactions; Epilepsy; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Half-Life; Humans; Isoxazoles; Lamotrigine; Levetiracetam; Nipecotic Acids; Oxcarbazepine; Phenylcarbamates; Piracetam; Propylene Glycols; Tiagabine; Topiramate; Triazines; Vigabatrin; Zonisamide

Topiramate is an antiepileptic drug that has a broad spectrum of antiseizure effects, which appear to be the result of several neurostabilising pharmacological mechanisms. These include blockade of ion channels, potentiation of GABA neuroinhibition and glutamate receptor antagonism at non-NMDA receptors, as well as mild inhibition of carbonic anhydrase. Topiramate monotherapy dose dependently reduced the number of patients who met seizure related exit criteria in children (aged > or =6 years) and adults with epilepsy. This effect was also observed in patients who had previously experienced partial onset seizures and for those who had experienced generalised tonic clonic seizures. Six-month and 1-year seizure-free rates were dose-dependently reduced. In epilepsy, topiramate monotherapy 100 or 200 mg/day was as effective as carbamazepine 600 mg/day or valproate 1250 mg/day as measured by time to study exit for any reason, time to first seizure and percentage of patients seizure-free in the final 6 months of treatment (mean treatment duration 244 days). Adverse events associated with topiramate monotherapy that were dosage related included paraesthesia, weight loss and diarrhoea. Renal calculi were also reported in both fully published trials.

Topics: Animals; Clinical Trials as Topic; Epilepsy; Fructose; Humans; Topiramate

To evaluate the efficiency of topiramate (TPM), an antiepileptic medication (AEM) which possesses multiple mechanisms of action and good pharmacokinetics, in the different types of childhood epilepsy and to make an appraisal of its value in migraines, bipolar disorder, eating disorders and neuropathic pain, according to studies that have been published. To do so, we have made use of an analysis of the literature, together with a multi centre study conducted in Spain and personal casuistry.. We consider the percentage of seizure free patients and of patients who responded (reduction of 50% or above in the frequency of the seizures) in childhood epilepsy, partial epilepsy, generalized tonic clonic seizures, absence seizures, tonic seizures, patients with diverse types of seizures, juvenile myoclonic epilepsy, Lennox Gastaut syndrome, falling sickness and GTCS, West s syndrome and Dravet s syndrome. With monotherapy, in partial epilepsy, between 39 and 54% of patients treated were seizure free. TPM has also proved to be efficient in experiments with animals, as a neuroprotector, and in clinical trials, in type I bipolar disorder, eating disorders, neuropathic pain and migraine.. TPM is an AEM offering a wide therapeutic spectrum that has proved to be efficient in clinical trials, expansion phases and observational studies, as an associated drug in partial epilepsy, generalized epilepsy, Lennox Gastaut syndrome, West s syndrome and Dravet s syndrome. It has proved to be more efficient in monotherapy, in partial epilepsy, as a first line AEM. TPM has also proved to be useful in mood disorders, eating disorders, neuropathic pain and tremor in observational studies, although this efficiency has not been backed up by clinical trials. In migraine and in clinical trials TPM has shown its efficiency. Its neuroprotective effect opens up new therapeutic perspectives.

Topics: Animals; Anticonvulsants; Bipolar Disorder; Clinical Trials as Topic; Drug Interactions; Epilepsy; Feeding and Eating Disorders; Fructose; Humans; Migraine Disorders; Multicenter Studies as Topic; Neuroprotective Agents; Pain; Spain; Topiramate

Although antiepileptic drugs (AEDs) are commonly used to control and prevent seizures, their long-term use carries a considerable risk of morbidity. The decision to start AEDs is made once the risks of further seizures outweigh the risks of treatment. Despite a large body of literature on the subject, this common clinical issue perplexes many practitioners because of its neurologic, psychological, and, at times, legal implications. Adding to the confusion is the recent approval of several new AEDs. This article summarizes the current evidence to support individual clinical decisions regarding initiation of AEDs in adults and considers the use of AEDs as seizure prophylaxis. Recently approved AEDs are discussed to help the practitioner understand when to initiate and how to choose the appropriate AED for the patient with seizures.

Topics: Acetates; Adult; Amines; Anticonvulsants; Carbamazepine; Cyclohexanecarboxylic Acids; Epilepsy; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Isoxazoles; Lamotrigine; Levetiracetam; Nipecotic Acids; Oxcarbazepine; Phenylcarbamates; Piracetam; Propylene Glycols; Recurrence; Risk Factors; Tiagabine; Topiramate; Treatment Outcome; Triazines; Zonisamide

The introduction of these new antiepileptic drugs, from felbamate to levetiracetam, raised hope of control of epilepsy with fewer adverse effects and improved quality of life. Unfortunately, many patients continue to experience refractory epilepsy despite the use of these new agents, and dose-related adverse effects and idiosyncratic reactions continue to be problematic. A recent report describes six new compounds in preclinical development, and five in clinical trials [131]. As the number of available, effective, but imperfect antiepileptic drugs increases, many challenges remain. These include: choosing the drug appropriate for the epileptic syndrome, assessing accurately the range of a drug's adverse effects in an individual patient, and considering carefully the drug's interactions in combination drug therapy. In considering drug combinations, differing mechanisms of drug action and favorable pharmacodynamic interactions (an area requiring additional studies) are of importance. Clinicians caring for children who have epilepsy anticipate further advances in the pharmacogenetics and molecular pathophysiology of epilepsy, leading to individually tailored, effective, and safe therapy.

Topics: Acetates; Amines; Anticonvulsants; Carbamazepine; Child; Cyclohexanecarboxylic Acids; Dioxolanes; Epilepsy; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Isoxazoles; Lamotrigine; Levetiracetam; Nipecotic Acids; Oxcarbazepine; Phenylcarbamates; Phenytoin; Piracetam; Propylene Glycols; Thiazines; Tiagabine; Topiramate; Triazines; Vigabatrin; Zonisamide

Tuberous sclerosis complex is characterized by hamartomatous lesions involving skin, brain, kidneys, eyes and heart. Pathologically, tuberous sclerosis is a disorder of cell migration, proliferation and differentiation. Cell lineage and cell migration disorders in the developing cortex of tuberous sclerosis complex patients might produce very different neurological phenotypes including epilepsy, cognitive impairment and autism. Cortical tubers constitute the hallmark of the disease and are pathognomonic of cerebral tuberous sclerosis. Epilepsy is the most common neurological feature, occurring in 96% of patients. Seizures often begin in the first months of life and are frequently severe and intractable. The treatment of seizures has recently benefited from the advent of the new anti-epileptic drugs. Selected drug-resistant patients with tuberous sclerosis complex could be considered for surgical treatment. Clear localization of the most active epileptogenic focus and the zone of the cortical abnormality may lead to tuberectomy and improved seizure control in selective drug-resistant patients. The finding of multiple areas of cerebral involvement should not automatically preclude epilepsy surgery in a child with intractable seizures and a well defined seizure origin.

Topics: Anticonvulsants; Brain; Cell Movement; Diagnosis, Differential; Electroencephalography; Epilepsy; Fructose; Humans; Intellectual Disability; Topiramate; Tuberous Sclerosis

Topics: Amyotrophic Lateral Sclerosis; Analgesics; Anticonvulsants; Epilepsy; Humans; Ion Channel Gating; Models, Molecular; Mutation; Nerve Tissue Proteins; Neuroprotective Agents; Protein Binding; Sodium Channel Blockers; Sodium Channels; Stroke

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

The increasing use of anticonvulsant drugs in psychiatry has prompted greater awareness of their effects on a range of psychiatric domains, including cognition. Older versus newer antiepileptic drugs have been reported to either worsen or enhance cognitive performance in clinical populations, and the extent to which cognitive disturbances may reflect iatrogenic factors versus psychopathology is subject to debate. We review current information about the role of anticonvulsants in cognition, with particular emphasis on newer compounds (such as lamotrigine, gabapentin, and topiramate), the cognitive dimensions of affective illness, and the clinical approach to evaluating cognition in psychiatric patients taking anticonvulsant drugs over time.

Topics: Acetates; Amines; Anticonvulsants; Bipolar Disorder; Carbamazepine; Cognition Disorders; Cyclohexanecarboxylic Acids; Epilepsy; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Lamotrigine; Mood Disorders; Topiramate; Triazines; Valproic Acid

Idiopathic epilepsies comprise a wide variety of partial and generalized syndromes that have in common a known or presumed genetic etiology and the lack of overt abnormalities other than the epilepsy itself. Most of these epilepsies have a benign natural history and/or show a favorable response to antiepileptic drug (AED) therapy, but pharmacoresistance does occur in some patients. In general, therapeutic algorithms in idiopathic partial epilepsies (IPEs) are similar to those used for symptomatic partial epilepsies, but aggressive pharmacologic therapy is rarely indicated in these patients. In self-limited conditions such as benign epilepsy of childhood with centrotemporal spikes or some forms of benign epilepsy with occipital paroxysms, AED treatment may not even be indicated unless seizures interfere significantly with quality of life. Valproate (VPA) is usually regarded as the drug of choice in idiopathic generalized epilepsies (IGEs). Most patients become rapidly seizure free, and poor compliance or prescription of an inappropriate AED because of misdiagnosis are the most common causes of treatment failure in IGEs. In those patients who did not respond well to VPA (or in whom VPA is considered contraindicated), the choice of alternative AEDs is guided by syndromic diagnosis and associated possible coexistence of multiple seizure types. Lamotrigine is establishing itself as a useful agent for many refractory IGEs, and might be considered for first-line use in selected patients. Topiramate (TPM) is another promising new agent in the management of refractory tonic-clonic seizures of nonfocal onset, but its potential efficacy against other primarily generalized seizure types has not been clearly established. Some of the older drugs, particularly ethosuximide (ESM), barbiturates, and benzodiazepines (BZDs), still have an important role in the management of refractory IGEs, especially in combination with VPA. Because carbamazepine (CBZ), phenytoin (PHT), tiagabine (TGB), vigabatrin (VGB), and gabapentin (GBP) may precipitate or aggravate absence and/or myoclonic jerks, their role in IGE syndromes associated with multiple seizure types is limited mostly to adjunctive use in patients unresponsive to first-line therapy.

Topics: Adolescent; Anticonvulsants; Child; Clinical Protocols; Drug Administration Schedule; Drug Therapy, Combination; Epilepsies, Partial; Epilepsy; Epilepsy, Generalized; Fructose; Humans; Lamotrigine; Topiramate; Treatment Outcome; Triazines; Valproic Acid

There is controversy between clinicians and statisticians on the appropriateness of the number needed to treat (NNT) as a summary statistic to report the effectiveness of a treatment. We examine the two viewpoints and make proposals concerning the reporting of clinical trial results.. In the context of antiepileptic treatments, we explain the two different viewpoints and illustrate the use of the odds ratio, relative risk, absolute difference, and NNT on the results of randomized clinical trials with topiramate (TPM). Special attention is paid to the use of these summary statistics in meta-analyses. Here, the NNT is the expected number of patients one would need to treat to achieve a single occurrence of a specified good outcome (e.g., 50% reduction in seizure rate) in comparison to no (or placebo) treatment.. Although the NNT is readily interpretable in some instances, it exhibits undesirable statistical behavior in other cases. In particular, confidence intervals for the NNT may split into two intervals and extend to positive and negative infinity when treatment efficacy is not clearly established by the data. Meta-analyses cannot be sensibly conducted directly on the NNT scale.. Although other measures, such as the odds ratio, have been more commonly used in the context of meta-analyses, clinicians prefer the NNT because it gives them a clearer clinical interpretation of the effectiveness of a (new) treatment. On the other hand, statisticians do not recognize the value of the NNT, as it has undesirable statistical properties. Some reconciliation between the two views could be achieved when the clinicians acknowledge the weak aspects of the NNT and when statisticians realize that statistical appropriateness is not the same as clinical relevance. It is suggested that the NNT be used as a secondary reporting tool not on an equal footing with the classic scales.

Topics: Anticonvulsants; Double-Blind Method; Drug Therapy, Combination; Epilepsy; Fructose; Humans; Odds Ratio; Outcome Assessment, Health Care; Patient Selection; Placebos; Research Design; Risk; Topiramate; Treatment Outcome

In this overview, we discuss the discovery and development of topiramate (TPM) as an anticonvulsant, including notable aspects of its chemical, biologic, and pharmacokinetic properties. In particular, we highlight its anticonvulsant profile in traditional seizure tests and animal models of epilepsy and the results of recent electrophysiological and biochemical studies using cultured neurons that have revealed a unique combination of pharmacologic properties of TPM. Finally, we present a hypothesis for the mechanistic basis of the anticonvulsant activity of TPM, which proposes that TPM binds to certain membrane ion channel proteins at phosphorylation sites and thereby allosterically modulates channel conductance and secondarily inhibits protein phosphorylation.

Topics: Animals; Anticonvulsants; Calcium Channels; Disease Models, Animal; Epilepsy; Evoked Potentials; Fructose; Hippocampus; Humans; Male; Membrane Potentials; Mice; Patch-Clamp Techniques; Phosphorylation; Rats; Rats, Wistar; Receptors, AMPA; Receptors, GABA; Receptors, Kainic Acid; Sodium Channel Blockers; Sodium Channels; Topiramate

Topics: Acetates; Amines; Animals; Anticonvulsants; Carbamazepine; Cyclohexanecarboxylic Acids; Drug Interactions; Epilepsy; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Isoxazoles; Lamotrigine; Nipecotic Acids; Phenylcarbamates; Propylene Glycols; Tiagabine; Topiramate; Triazines; Vigabatrin; Zonisamide

Topics: Anticonvulsants; Child; Clinical Trials as Topic; Epilepsy; Fructose; Humans; Israel; Topiramate

To review current knowledge regarding the mechanisms of action, pharmacokinetics, clinical efficacy and the tolerance of topirimate (TPM) and describe the Spanish experience of the use of this drug in 224 patients of all ages.. TPM is a new drug which affects practically all the mechanisms involved in the production of epileptic seizures, which means that it is a broad-spectrum antiepileptic drug. After reviewing the mechanisms of action and pharmacokinetic characteristics of TPM, we consider the efficacy of the drug in 224 patients of all ages with all types of epileptic seizures.. In patients of all ages with uncontrolled epileptic seizures treated with TPM, the frequency of their seizures was reduced by over 50% in 78% of the patients and the seizures were abolished in 25% of the total cases. The drug was generally well tolerated. Side-effects leading to suspension of the drug occurred in only 5% of the cases. TPM is an effective drug which is well tolerated in patients of all ages and with all kinds of epilepsy.

Topics: Anticonvulsants; Child, Preschool; Epilepsy; Fructose; Humans; Infant; Topiramate

This review focuses on the safety problems associated with antiepileptic drugs (AEDs) as revealed by laboratory testing and clinical examination. There are two classes of side effects: (a) common and mild and (b) rare and severe. Allergic reactions to AEDs are common and usually mild. However, on rare occasions, they can progress to more severe cutaneous disorders, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Severe allergic reactions to AEDs range from immune responses with fever to multiorgan dysfunction. Allergic rashes may be genetically or immunologically determined. Laboratory abnormalities produced by AEDs are common and mild, and include hepatic enzyme elevation associated with phenytoin and mild elevation in ammonia associated with valproate. Serious, although rare, idiosyncratic side effects, such as aplastic anemia, hepatotoxicity, and thrombocytopenia, have also occurred with AEDs. These reactions are largely confined to the "classic" AEDs. With the exception of felbamate, AEDs approved in the past decade have not been plagued by severe idiosyncratic reactions. Subtle endocrine abnormalities, including variations in thyroid function tests and bone metabolism, and the often subclinical effects on peripheral nerve conduction produced by phenytoin and carbamazepine, are also examined.

Topics: Acetates; Amines; Anticonvulsants; Carbamazepine; Cyclohexanecarboxylic Acids; Drug Monitoring; Epilepsy; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Lamotrigine; Phenobarbital; Phenytoin; Practice Guidelines as Topic; Topiramate; Triazines; Valproic Acid; Vigabatrin

Epilepsy affects 1.2% to 4.4% of the general population. Given the clinical profile of the newer antiepileptic agents, it is likely their usage will increase in the coming years, thus increasing the emergency physician's exposure to these medications and their side effects. Several of these side effects can have high morbidity, such as the aplastic anemia and hepatotoxicity caused by felbamate, and the Stevens-Johnson syndrome associated with lamotrigine. Overdoses of these medications also could increase, as will our knowledge of recognizing and managing them. The clinical spectrum of the newer medications is the treatment of partial seizures. None of the newer medications can be orally loaded nor are they available in an i.v. preparation. Serum drug levels are not available in most institutions and are not routinely measured in the ED. The new preparations of phenytoin, diazepam, and valporic acid add increased efficiency in drug administration, providing a new method for prehospital treatment of seizures and a more tolerable means of administration in the ED.

Topics: Acetates; Administration, Rectal; Age Factors; Amines; Anticonvulsants; Cyclohexanecarboxylic Acids; Diazepam; Drug Overdose; Epilepsy; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Injections, Intravenous; Lamotrigine; Phenylcarbamates; Phenytoin; Propylene Glycols; Topiramate; Triazines; Valproic Acid

Topics: Acetates; Amines; Anti-Anxiety Agents; Anticonvulsants; Barbiturates; Benzodiazepines; Clobazam; Clonazepam; Cyclohexanecarboxylic Acids; Diethylcarbamazine; Epilepsy; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Topiramate; Valproic Acid; Vigabatrin

Data accrued from clinical trials of five new antiepileptic drugs (AEDs) are compared for efficacy in reducing seizures and self-reported adverse events as a basis of selection among new AEDs. Drawbacks to use of these data also are demonstrated.. A review of double-blind, placebo-controlled clinical trials of a new AED or placebo added to a standard AED provided data on reduction of complex partial seizures (CPSs). Success is > or =50% fewer CPSs with a new AED or placebo; Overall Improvement is the success rate with drug minus the success rate with placebo. Adverse events were tabulated from product-labeling lists of COSTART items (incidence, > or =5%). The Summary Complaint score is the total number of reports of individual events for each AED.. Efficacy data demonstrate differences in Overall Improvement rates among five new AEDs and placebos (p = 0.001). However, rates of response to placebo also differed significantly among trials (p = 0.01). Adverse events predominantly affect central nervous system, psychiatric, and general body systems. However, patients in the placebo control groups did not consistently report adverse effects. Summary Complaint scores differ among the five new AEDs, but variability in use of COSTART terms nullifies comparisons.. Comparisons of data for five new AEDs provide information for selection among treatments when a second drug is needed to improve control of CPSs. However, significant differences among the control groups and other problems make comparisons between trials problematic. The final choice should be based on the need of the individual patient for superior seizure control versus minimal adverse effects.

Topics: Acetates; Amines; Anticonvulsants; Controlled Clinical Trials as Topic; Cyclohexanecarboxylic Acids; Double-Blind Method; Epilepsy; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Lamotrigine; Nipecotic Acids; Placebos; Research Design; Tiagabine; Topiramate; Treatment Outcome; Triazines; Vigabatrin

The concept of the average number of patients needed to treat to prevent a single bad outcome is becoming increasingly popular among clinicians. Defined as the inverse of the absolute risk reduction (delta), its sample estimate is denoted as NNT. Here we discuss the mathematical and statistical properties of NNT and show that simple calculations, like taking sums of different NNTs, can give nonsensical results. The implication for a meta-analysis expressed in NNTs is that we can best calculate the combined NNT by taking the inverse of the combined estimate for delta. Simulations illustrate the better performance of the combined NNT estimate on the delta-scale (NNT(P)) in comparison with the combined estimate of NNT on the NNT-scale (NNT(O)), even in cases where it is reasonable to take sums. The calculations are illustrated using data from anti-epileptic trials.

Topics: Anticonvulsants; Bias; Clinical Trials as Topic; Epilepsy; Fructose; Humans; Sample Size; Topiramate

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

Topics: Acetates; Adult; Age Factors; Amines; Anticonvulsants; Child; Clinical Trials as Topic; Cyclohexanecarboxylic Acids; Epilepsy; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Lamotrigine; Nipecotic Acids; Phenylcarbamates; Propylene Glycols; Spasms, Infantile; Tiagabine; Topiramate; Triazines; Vigabatrin

Six studies are cited to demonstrate that topiramate is effective as adjunctive therapy for refractory partial-onset seizures in adults. Subsequent studies indicate that topiramate is also effective as monotherapy in adults and as adjunctive therapy for partial-onset seizures in children, tonic-clonic seizures of nonfocal origin in children and adults, and drop attacks in Lennox-Gastaut syndrome. Adverse effects for adults and children included dizziness, fatigue, ataxia, confusion, somnolence, nephrolithiasis, paresthesia, and weight loss. More adverse effects were observed at higher doses. Topiramate exhibits rapid absorption, long duration of action, and minimal interaction with other antiepileptic drugs.

Topics: Adult; Anticonvulsants; Ataxia; Child; Clinical Trials as Topic; Dizziness; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epilepsies, Partial; Epilepsy; Fatigue; Fructose; Humans; Topiramate; Treatment Outcome

The management of epilepsy in the pediatric patient requires careful evaluation, classification, and pharmacologic treatment. Despite best efforts on the part of clinicians, approximately 25% of children remain refractory to appropriate medical therapies. The development of an improved classification system and the emergence of several new antiepileptic drugs have enabled some progress in this area, specifically in children with disorders such as Lennox-Gastaut syndrome and infantile spasms, which are notoriously difficult to control. However, limited data are available that define the optimal use of new antiepileptic agents in pediatric patients. To most effectively treat children with epilepsy syndromes, further research must be completed to validate the positive effects described in case reports, open-label clinical trials, and early controlled clinical trials.

Topics: Acetates; Amines; Anticonvulsants; Child; Cyclohexanecarboxylic Acids; Epilepsy; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Lamotrigine; Nipecotic Acids; Phenylcarbamates; Propylene Glycols; Tiagabine; Topiramate; Triazines; Vigabatrin

Because pharmacokinetics is a major determinant of the magnitude and duration of pharmacologic response, understanding the kinetic properties of the new antiepileptic drugs (AEDs) is essential for the correct use of these compounds in clinical practice. After oral administration, absorption is rapid and relatively efficient for the new AEDs, the most notable exception being gabapentin, whose bioavailability decreases with increasing dosage. None of the new AEDs is extensively bound to plasma proteins except for tiagabine, which is over 95% protein-bound. The route of elimination differs to an important extent from one compound to another, and elimination half-lives range from over 30 h for zonisamide to 5-7 h for gabapentin. For all drugs that are metabolized, half-life is shortened and clearance is increased when patients receive concomitant enzyme-inducing agents such as barbiturates, phenytoin, and carbamazepine. Lamotrigine metabolism is markedly inhibited by valproic acid, and felbamate may increase the serum levels of most other AEDs. Felbamate, topiramate, and oxcarbazepine may also reduce the efficacy of the contraceptive pill by stimulating its metabolism.

Topics: Acetates; Amines; Anticonvulsants; Biological Availability; Cyclohexanecarboxylic Acids; Dose-Response Relationship, Drug; Drug Interactions; Epilepsy; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Isoxazoles; Lamotrigine; Nipecotic Acids; Phenylcarbamates; Propylene Glycols; Tiagabine; Topiramate; Triazines; Zonisamide

Treatment options for epilepsy, especially using antiepileptic drugs, have increased substantially in the past five years. Since 1993, four novel antiepileptic drugs have been approved and marketed in the United States: felbamate, gabapentin, lamotrigine, and topiramate. Two others, tiagabine and vigabatrin, are likely to be approved in the near future. For many patients, these agents offer the realistic promise of improved seizure control, often with fewer adverse effects and less significant drug interactions compared with older agents. In addition, fosphenytoin, a water-soluble phenytoin prodrug with a number of advantages over intravenous phenytoin, has been released. There are new administration options for carbamazepine, diazepam, and valproic acid. For drug-resistant or -intolerant patients, there has been renewed interest in alternative therapies, especially the ketogenic diet. Taken together, these represent significant therapeutic advances that are benefiting patients with epilepsy. At the same time, improved understanding of the basic mechanisms of epileptogenesis, and of the cellular and molecular actions of available antiepileptic drugs, creates a framework for designing unique therapeutic strategies that are targeted at key sites of vulnerability involved in the development and maintenance of the epileptic state.

Topics: Acetates; Amines; Anticonvulsants; Carbamazepine; Cyclohexanecarboxylic Acids; Diazepam; Drug Approval; Drug Design; Drug Interactions; Drug Resistance; Epilepsy; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Injections, Intravenous; Ketones; Lamotrigine; Neurotransmitter Uptake Inhibitors; Nipecotic Acids; Phenylcarbamates; Phenytoin; Prodrugs; Propylene Glycols; Tiagabine; Topiramate; Triazines; United States; Valproic Acid; Vigabatrin

Topiramate, a sulfamate-substituted monosaccharide, is a new antiepileptic drug (AED) approved as adjunctive therapy for partial-onset seizures in adults. Topiramate is rapidly absorbed, has linear pharmacokinetics, minimal protein binding and a long half-life facilitating a twice-daily dosage regimen. Topiramate has little effect on the plasma concentrations of other AEDs with the exception of phenytoin, concentrations of which may increase in some patients when topiramate is added to the therapy. Topiramate metabolism is increased when administered with carbamazepine or phenytoin. In the absence of enzyme-inducing AEDs, topiramate is eliminated primarily by renal excretion, with 50 to 80% of a dose excreted as unchanged topiramate. In 6 double-blind, placebo-controlled trials, topiramate was shown to be well tolerated and effective as adjunctive therapy for partial-onset seizures in adults. Topiramate consistently reduced seizures across all patient groups defined by age, gender and baseline seizure frequency. Adverse effects were generally mild-to-moderate CNS-related effects and often resolved spontaneously or with slowing of topiramate titration and/or reduction of the dosage of concomitant AEDs. Clinical studies are currently evaluating the effectiveness and safety of topiramate as monotherapy and adjunctive therapy in children with partial seizures, in patients with Lennox-Gastaut syndrome and in patients with generalised tonic-clonic seizures of non-focal onset. Preliminary findings suggest that topiramate has a broad spectrum of clinical use.

Topics: Adult; Aged; Anticonvulsants; Child; Drug Interactions; Epilepsy; Fructose; Humans; Kidney Diseases; Liver Diseases; Topiramate

Topiramate is a new novel drug for the treatment of intractable seizures that is to be used in an adjunctive fashion. A review of the seven double-blind controlled studies was undertaken with special attention paid to safety and tolerability data. The studies were similar in design but used varying doses of the drug. To date there has been no evidence of serious systemic side effects such as rash, hepatotoxicity, cardiotoxicity, serious gastrointestinal toxicity or aplastic anemia. Renal stones were reported in 1.5% of patients with over 80% choosing to remain on the drug because of an improved quality of life. The unique observation of "abnormal thinking" was seen that seemed to be related to high doses and introducing the drug too rapidly. Patients, rather than describing psychomotor slowing, described a phenomenon of slow thoughts, decreased cognition, intermittent difficulty calculating, dulled thinking, blunted mental reactions. Lastly, weight loss appears in approximately 10-20% of patients and is probably related to dulling of appetite. Although increasing doses gave increasing degrees of seizure freedom, it appeared that doses beyond 600 mg/day are often not well tolerated.

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

Clinical trials are important in determining the relative efficacy and safety of a new antiepileptic drug (AED); however, experience acquired in clinical practice will eventually determine its position in the antiepileptic armamentarium. Topiramate (TPM), a new AED has been available in the United Kingdom since mid-1995 and a considerable number of patients have being treated. As a result of this experience, a number of changes have being made in the way TPM is used, particularly in the starting doses and titration rates. This seems to have improved patients' tolerability of treatment, an important consideration if a drug is to be used to its optimum level. In this article, practical tips for the use of TPM are given and these include starting doses, titration rates, options for managing side effects occurring early in treatment, advice concerning the withdrawal of concomitant AEDs and indications for discontinuation of TPM. The need for adequate patient counseling regarding potential side effects and expectations of treatment is also reviewed.

Topics: Anticonvulsants; Epilepsy; Fructose; Humans; Topiramate

Topics: Animals; Anticonvulsants; Clinical Trials as Topic; Drug Interactions; Epilepsies, Partial; Epilepsy; Felbamate; Fructose; gamma-Aminobutyric Acid; Humans; Lamotrigine; Nipecotic Acids; Phenylcarbamates; Propylene Glycols; Teratogens; Tiagabine; Topiramate; Triazines; Vigabatrin

The current developments in the availability of new antiepileptic drugs (AEDs) are unprecedented. After a period of many years during which no new AED became available, 5 new AEDs were introduced in the United States between 1993 and 1997, and 2 more are expected to be approved soon. These new drugs are a most welcome addition to the therapeutic options in the treatment of epilepsy, but they also create a dilemma for the clinician because their individual places and their optimal use in the treatment of various forms of epilepsy are yet to be determined. This review serves to summarize the main characteristics of the newer AEDs.

Topics: Acetates; Amines; Anticonvulsants; Carbamazepine; Cyclohexanecarboxylic Acids; Drug Approval; Epilepsy; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Lamotrigine; Nipecotic Acids; Oxcarbazepine; Phenylcarbamates; Propylene Glycols; Tiagabine; Topiramate; Triazines; United States; Vigabatrin

Topics: Acetates; Amines; Anticonvulsants; Cyclohexanecarboxylic Acids; Epilepsy; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Lamotrigine; Nipecotic Acids; Phenylcarbamates; Propylene Glycols; Tiagabine; Topiramate; Triazines

More than 50 million persons worldwide suffer from epilepsy, many of whom are refractory to treatment with standard antiepileptic drugs (AEDs). Fortunately, new AEDs commercialized since 1990 are improving the clinical outlook for many patients. Our growing understanding of anticonvulsant mechanisms and the relevance of preclinical animal studies to clinical antiepileptic activity have already contributed to the design of several new AEDs and should be increasingly beneficial to further efforts at drug development. Mechanisms have been identified for older AEDs [phenytoin (PHT), carbamazepine (CBZ), valproate (VPA), barbiturates, benzodiazepines (BZDs), ethosuximide (ESM)] and newer AEDs [vigabatrin (VGB), lamotrigine (LTG), gabapentin (GBP) tiagabine (TGB), felbamate (FBM), topiramate (TPM)]. Several novel anticonvulsant mechanisms have recently been discovered. FBM appears to be active at the strychnine-insensitive glycine binding site of the NMDA receptor. TPM is active on the kainate/AMPA subtype of glutamate receptor and at a potentially novel site on the GABA(A) receptor. For several reasons, availability of a single AED with multiple mechanisms of action may be preferred over availability of multiple AEDs with single mechanisms of action. These reasons include ease of titration, lack of drug-drug interactions, and reduced potential for pharmacodynamic tolerance.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Synergism; Drug Therapy, Combination; Electric Stimulation; Electroshock; Epilepsy; Fructose; Kindling, Neurologic; Mice; Papio; Pentylenetetrazole; Rats; Receptors, GABA; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission; Topiramate

Standard antiepileptic drugs (AEDs) have a number of pharmacokinetic shortcomings, and AEDs with more favorable profiles would be preferred. The pharmacokinetics and interaction profile of the recently developed AED topiramate (TPM), is reviewed and compared with those of other newer AEDs including lamotrigine (LTG), gabapentin (GBP), vigabatrin (VGB), and oxcarbazepine (OCBZ). Although none of these agents meets all of the criteria of the "ideal" AED from the pharmacokinetic standpoint, a number of these drugs, including TPM, have desirable properties that distinguish them from the older AEDs and should contribute to their clinical utility.

Topics: Acetates; Amines; Anticonvulsants; Cyclohexanecarboxylic Acids; Drug Interactions; Drug Monitoring; Epilepsy; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Lamotrigine; Topiramate; Triazines; Vigabatrin

Standard antiepileptic drugs (AEDs) are associated with a wide variety of acute and chronic adverse events and with many interactions with each other and with non-AEDs that complicate patient management. The safety and interaction profiles of the newer AEDs have also been intensively studied. Safety data are available for six of the newer AEDs, lamotrigine (LTG), vigabatrin (VGB), gabapentin (GBP), tiagabine (TGB), felbamate (FBM), and topiramate (TPM). The potential for the most recently developed AEDs for producing rare idiosyncratic reactions cannot be ascertained until additional patient exposures have been reported from careful postmarketing surveillance.

Topics: Acetates; Amines; Anticonvulsants; Clinical Trials as Topic; Cyclohexanecarboxylic Acids; Drug Interactions; Epilepsy; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Lamotrigine; Nipecotic Acids; Phenylcarbamates; Propylene Glycols; Tiagabine; Topiramate; Triazines; Vigabatrin

Practical recommendations for the treatment of patients with the new antiepileptic drug (AED) topiramate (TPM) were developed on the basis of review of the results of controlled and open studies of TPM reported to date and on postmarketing clinical experience with TPM at two specialized epilepsy clinics in the United Kingdom. Recommendations considered important for optimal utilization of TPM include dosage titration guidelines, options for managing side effects occurring early in treatment, advice concerning the withdrawal of concomitant AEDs, indications for discontinuation of TPM, and recognition of the need for adequate patient counseling.

Topics: Anticonvulsants; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Epilepsy; Fructose; Humans; Patient Education as Topic; Practice Guidelines as Topic; Topiramate

Clinical evidence is emerging that topiramate (TPM) may be effective in pediatric epilepsies. Topiramate pharmacokinetics appear to be linear in children when administered in dosages up to 9 mg/kg/d. Mean oral clearance is 44% to 54% higher in children when compared with historical data from adults; steady-state plasma TPM concentrations for the same mg/kg dose are expected to be 33% lower in children. While double-blind, placebo-controlled trials of adjunctive TPM therapy in Lennox-Gastaut syndrome, primary generalized tonic-clonic seizures, and refractory partial-onset seizures in children are ongoing, preliminary results of pilot studies and the open-label extension phases of these double-blind studies suggest TPM may be effective as adjunctive therapy in a broad range of seizure disorders. In the open-label extension phase of a double-blind trial, the proportion of patients with Lennox-Gastaut syndrome experiencing 50% or greater reduction in seizures was 47%. Likewise, seizures were reduced 50% or more with TPM adjunctive therapy in 64% of children with partial-onset seizures and in 67% of patients with primary generalized tonic-clonic seizures treated with open-label during the extension phase of two separate double-blind studies. Preliminary experience suggests that TPM monotherapy can be successfully substituted for another antiepileptic drug in some children. The results of the well-controlled trials are needed to confirm these preliminary observations of TPM effectiveness in pediatric epilepsies.

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

This article reviews selected medical and surgical advances that the authors view as important to improving the treatment of patients with epilepsy. This includes a review of six new antiepileptic drugs (fosphenytoin, felbamate, gabapentin, lamotrigine, toprimimate, and vigabatrin), recent studies of the surgical technique of Multiple Subpial Transections, and a summary of a prospective longitudinal study on anterior temporal lobectomy.

Topics: Acetates; Amines; Anticonvulsants; Cyclohexanecarboxylic Acids; Epilepsy; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Lamotrigine; Neurosurgery; Phenylcarbamates; Phenytoin; Pia Mater; Propylene Glycols; Temporal Lobe; Topiramate; Triazines; Vigabatrin

Topiramate is a new antiepileptic drug which has recently become available in the United States and in a number of European countries. Pharmacological studies suggest that its mode of action is multifactorial and involves blockade of voltage-dependent sodium channels, potentiation of GABAergic transmission and inhibition of excitatory pathways through an action at AMPA receptor sites. Carbonic anhydrase inhibiting properties have also been demonstrated but they are considered not to be relevant to anticonvulsant activity. Topiramate is well absorbed from the gastrointestinal tract, peak plasma levels being usually attained in 2-3 hours. The drug is negligibly (9-17%) bound to plasma proteins and is eliminated partly by renal excretion in unchanged form and partly by oxidation and hydrolysis. In healthy volunteers, the half-life is about 20-30 hours, but elimination rate is accelerated in patients taking concomitant enzyme inducing drugs such as phenytoin, carbamazepine and barbiturates. Topiramate has no major effects on plasma levels of concurrent anticonvulsants, except for a rise in plasma phenytoin in occasional patients. In double-blind add-on trials in refractory partial epilepsy, a significant reduction in seizure frequency has been demonstrated in over 40% of topiramate-treated patients (vs about 10% of those treated with placebo), a response rate which compares favourably with that observed with other new antiepileptic drugs. Dosages found to be effective in add-on controlled trials range between 200 and 1000 mg day-1, although most patients are likely to benefit from receiving 400 mg day-1 or less. Preliminary data suggest that topiramate may be effective also in generalized epilepsies, but this needs to be confirmed in prospective studies. The most common adverse effects of topiramate are CNS-related and include dizziness, fatigue, visual disturbances, ataxia, mental slowing and impaired concentration. Paresthesias, anorexia, weight loss and increased risk of nephrolithiasis have been also reported. Many of these effects are related to dose and/or to rate of dose titration. Based on these data, topiramate appears to be a valuable new drug, whose main current indication is in the add-on management of refractory partial and secondarily generalized seizures. Studies on its potential-value as monotherapy are in progress.

Topics: Animals; Anticonvulsants; Drug Interactions; Epilepsy; Fructose; Humans; Topiramate

The characteristics of the new anti-epileptic drug topiramato (TPM) are described: multiple mechanism of action, favourable pharmaco-kinetics, wide therapeutic range and is relatively well tolerated, Development. Its initial usefulness in patients with partial crises resistant to other anti-epileptic drugs has been shown. TPM is equally effective in primary generalized crises, and in patients with the Lennox-Gastaut syndrome, in whom no problem of tolerance has been seen.. TPM is a valuable drug for the treatment of epilepsy.

Topics: Anticonvulsants; Epilepsy; Fructose; Humans; Topiramate

Topiramate is a sulphamate-substituted monosaccharide derived from D-fructose and is structurally unrelated to other antiepileptic drugs. It acts by multiple mechanisms that suggest it may be effective in several types of epilepsy. In double-blind placebo-controlled trials, add-on therapy with topiramate 400 to 1000 mg/day reduces the seizure rate by > or = 50% in 35 to 52% of adult patients with resistant partial epilepsy (with or without secondarily generalised seizures) compared with 0 to 19% of placebo recipients; a 200 mg/day dosage was less effective. Topiramate has also been shown to be superior in efficacy to placebo in well controlled trials in patients with generalised tonic-clonic seizures, Lennox-Gastaut syndrome and in paediatric patients with partial epilepsy. Efficacy has been maintained for 7 years and some patients may also be satisfactorily treated with topiramate monotherapy. Further study is needed to follow up on the promising results of topiramate use in other paediatric epilepsies. Adverse CNS events are the most common untoward effects during topiramate therapy and are most likely to lead to withdrawal of the drug. However, most adverse events are mild to moderate in severity and lessen with continued drug therapy. In clinical trials, most adverse events which were dose limiting or led to discontinuation of treatment occurred during the titration phase. The overall incidence of adverse events may be reduced by slower upward dosage titration. In summary, topiramate appears to be a suitable agent for add-on therapy in adult patients with partial epilepsy. Preliminary reports support the use of add-on topiramate in adults with generalised epilepsy, in childhood epilepsies and in patients with Lennox-Gastaut syndrome, as well as the use of topiramate monotherapy in patients with partial epilepsy. Thus, topiramate can be considered an important new drug for the management of patients with refractory epilepsy.

Topics: Adult; Animals; Anticonvulsants; Area Under Curve; Epilepsy; Fructose; Humans; Intestinal Absorption; Kidney; Liver; Topiramate

Gabapentin (GBP), lamotrigine (LTG), tiagabine (TGB), topiramate (TPM), vigabatrin (VGB), and zonisamide (ZNS) are all in use as "add-on" treatment for patients with refractory epilepsy. There have been no comparative randomized controlled trials allowing an evidence-based choice between these drugs. We report a series of meta-analyses of randomized placebo-controlled add-on trials in which these drugs have been tested in patients with partial epilepsy. This work provides an estimate of each drug's efficacy and tolerability compared with placebo. These estimates are compared across drugs to give broad estimates of comparative efficacy and tolerability.. Trial reports were found by searching Medline, by searching through journals by hand, and by contacting the pharmaceutical industry. The outcomes chosen were the proportion of patients who (a) have a > or = 50% reduction in seizure frequency (50% responders); (b) withdrew from the study (any reason); or (c) reported the following side effects: ataxia, dizziness, fatigue, nausea, or somnolence. Overall odds ratio (OR) with 95% confidence intervals (CIs; 50% responders) or 99% CIs; side effects) were calculated.. Twenty-nine trials were included, representing 4,091 randomized patients. The ORs for 50% response (95% CI) were GBP, 2.29 (1.53-3.43); LTG, 2.32 (1.47-3.68); TGB, 3.03 (2.01-4.58); TPM, 4.07 (2.87-5.78); VGB, 3.67 (2.44-5.51); and ZNS, 2.7 (1.36-4.47). ORs for discontinuation were GBP, 1.36 (0.75-2.49); LTG, 1.19 (0.79-1.79); TGB, 1.81 (1.21-2.70); TPM, 2.56 (1.64-4.00); VGB, 2.58 (126-5.27); and ZNS, 4.23 (1.71-10.49).. We have clear evidence that each of these drugs is better than placebo at preventing seizures. When results are compared across drugs, the confidence intervals overlap, and we have no conclusive evidence of differences in efficacy or tolerability. Despite this, the agent that appears most effective may be twice as effective as the agent that appears least effective, and the agent that appears most likely to cause discontinuation may be 4 times more likely to do so than the treatment that appears least likely to do so. Comparative randomized studies are needed further to evaluate these drugs.

Topics: Acetates; Adolescent; Adult; Aged; Amines; Anticonvulsants; Child; Cyclohexanecarboxylic Acids; Drug Therapy, Combination; Epilepsy; Female; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Isoxazoles; Lamotrigine; Male; Middle Aged; Randomized Controlled Trials as Topic; Topiramate; Treatment Outcome; Triazines; Vigabatrin; Zonisamide

In developed countries, the incidence of epilepsy is 50-100 cases per 100,000 population per year and the prevalence is approximately 5 to 8 cases per 1,000 population. Epilepsy is by far the most prevalent serious neurologic condition. Mortality rates in epilepsy are two to four times those found in matched nonepileptic populations. The prognosis of epilepsy can be classified into at least four categories, with chronic and refractory cases comprising about 40% of all cases. A detailed approach to the management of chronic epilepsy cases is recommended. Approximately 20% of patients cannot achieve seizure control with existing agents and new antiepileptic drugs are required for these patients.

Topics: Adolescent; Adult; Age Factors; Anticonvulsants; Child; Chronic Disease; Developed Countries; Developing Countries; Drug Therapy, Combination; Epilepsy; Fructose; Humans; Incidence; Middle Aged; Minnesota; Prevalence; Prognosis; Topiramate; Treatment Outcome

In separate studies, potential pharmacokinetic interactions of topiramate (TPM) with phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA) were evaluated. TPM was added to the baseline antiepileptic drug (AED) at a dosage of up to 800 mg/day, after which the baseline drug was discontinued, when possible. Addition of TPM produced no change in plasma levels of CBZ or CBZ epoxide (CBZ-E). Modest increases in PHT plasma levels in six of 12 patients treated with PHT and TPM, and a small mean decrease in VPA levels noted in patients receiving VPA with TPM, were considered unlikely to require adjustments in the dosage of the concomitant AED when TPM is added or discontinued. When patients were changed from concomitant therapy with PHT or CBZ to TPM monotherapy, TPM clearance was reduced by approximately 50%, suggesting that an adjustment in TPM dose may be required when PHT or CBZ is discontinued from TPM-treated patients. A slight increase in plasma TPM levels during monotherapy compared to concomitant therapy with VPA was considered clinically insignificant and not likely to require TPM dosage adjustment. In another study, oral clearance of digoxin was slightly increased when TPM was added, resulting in a small decrease in peak plasma levels of digoxin. In vitro studies conducted to date on a number of specific cytochrome P450 isoforms show an effect of TPM only on the CYP2Cmeph isoform. The risk for clinically meaningful changes in plasma levels of traditional AEDs when TPM is added to or discontinued from concomitant regimens appears to be minimal. However, adjustments in TPM dosages are likely to be needed when potent enzyme inducers, such as PHT or CBZ, are added or discontinued. TPM has a relatively low propensity for clinically significant drug interactions, and its pharmacokinetic and drug interaction profiles represent a clear advance over those of the traditional AEDs.

Topics: Anticonvulsants; Carbamazepine; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Male; Phenytoin; Topiramate; Treatment Outcome; Valproic Acid

Antiepileptic drugs (AEDs) in broad use today have a number of pharmacokinetic liabilities, including a propensity for clinically meaningful drug interactions. Therefore, new AEDs with improved pharmacokinetic characteristics would be welcomed. The pharmacokinetic profiles of six newer AEDs--topiramate (TPM), gabapentin (GBP), vigabatrin (VGB), lamotrigine (LTG), oxcarbazepine (OCBZ), and felbamate--were reviewed. Some of these AEDs offer an improvement in one or more pharmacokinetic parameters compared with traditional AEDs, with TPM, GBP, VGB, and OCBZ demonstrating the most advantageous overall pharmacokinetic profiles.

Topics: Acetates; Amines; Anticonvulsants; Biological Availability; Carbamazepine; Clinical Trials as Topic; Cyclohexanecarboxylic Acids; Drug Interactions; Drug Therapy, Combination; Epilepsy; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Half-Life; Humans; Lamotrigine; Phenylcarbamates; Propylene Glycols; Topiramate; Triazines; Vigabatrin

Topiramate is a recently licensed and marketed antiepileptic drug in the UK for use as add-on therapy for refractory partial epilepsy. It has multiple modes of action involving voltage-dependent sodium channels, GABA receptors and glutamate receptors. Topiramate has very favourable pharmacokinetics as it is primarily excreted unchanged. Its metabolism is, however, increased by enzyme inducers, and it can inhibit the metabolism of phenytoin in some patients. Its efficacy as adjunctive treatment in refractory partial epilepsy in adults appears good, over 40% of patients have a 50% or greater reduction in seizure frequency when topiramate is added to their regime with up to 7% becoming seizure free. The main adverse events are ataxia, impaired concentration, confusion, dizziness, fatigue, parasthesia, somnolence and "thinking abnormal'. Most of these occurred during rapid titration. During long-term treatment, weight loss also occurred and nephrolithiasis occurred in 1.5% of patients receiving topiramate. Topiramate is a useful and well-tolerated addition to our treatment of refractory epilepsy, but it should be titrated slowly in order to avoid adverse events.

Topics: Administration, Oral; Animals; Anticonvulsants; Biotransformation; Drug Therapy, Combination; Epilepsy; Fructose; Humans; Long-Term Care; Metabolic Clearance Rate; Randomized Controlled Trials as Topic; Topiramate

To evaluate the efficacy and tolerability of the newly developed antiepileptic drugs gabapentin, lamotrigine, tiagabine, topiramate, vigabatrin, and zonisamide in patients with refractory partial epilepsy.. Systematic review of published and unpublished randomised controlled trials of add-on treatment with new antiepileptic drugs.. 20 published and eight unpublished trials representing 3883 patients with refractory partial epilepsy.. Proportion of patients who (a) showed 50% or greater reduction in frequency of seizures (50% responders) and (b) withdrew from each study for any reason.. Odds ratios (95% confidence intervals) relative to placebo for 50% responders were 2.29 (1.53 to 3.43) for gabapentin, 2.32 (1.47 to 3.68) for lamotrigine, 3.03 (2.01 to 4.58) for tiagabine, 4.22 (2.80 to 6.35) for topiramate, 3.68 (2.45 to 5.51) for vigabatrin, and 2.47 (1.36 to 4.47) for zonisamide. Odds ratios for withdrawal were 1.36 (0.75 to 2.49) for gabapentin, 1.19 (0.79 to 1.79) for lamotrigine, 1.81 (1.21 to 2.70) for tiagabine, 2.42 (1.43 to 4.11) for topiramate, 2.58 (1.26 to 5.27) for vigabatrin, and 5.70 (1.76 to 18.49) for zonisamide. Comparing results for each drug showed that all of the 95% confidence intervals overlapped, indicating that they were not significantly different in terms of efficacy and tolerability.. All six drugs were significantly better than placebo at reducing frequency of seizures. These results do not allow an evidence based choice between these drugs as we have no conclusive indication of differences in efficacy or tolerability.

Topics: Acetates; Adolescent; Adult; Aged; Amines; Anticonvulsants; Child; Cross-Over Studies; Cyclohexanecarboxylic Acids; Epilepsy; Female; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Isoxazoles; Lamotrigine; Male; Middle Aged; Nipecotic Acids; Randomized Controlled Trials as Topic; Tiagabine; Topiramate; Treatment Outcome; Triazines; Vigabatrin; Zonisamide

This article surveys the pharmacokinetic parameters for the new antiepileptic drugs (AEDs): felbamate, gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, and vigabatrin. Compared to the pharmacokinetics of standard AEDs, these new AEDs have progressed in terms of (a) longer half-lives, permitting once- or twice-daily dosing, (b) greatly reduced potential for drug interactions, thus increasing ease of treatment, and (c) general lack of hepatic enzyme induction, which facilitates polytherapy as well as other aspects of treatment.

Topics: Acetates; Amines; Anticonvulsants; Biological Availability; Carbamazepine; Cyclohexanecarboxylic Acids; Enzyme Induction; Epilepsy; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Half-Life; Humans; Lamotrigine; Nipecotic Acids; Oxcarbazepine; Phenylcarbamates; Propylene Glycols; Tiagabine; Topiramate; Triazines; Vigabatrin

Novel antiepileptic drugs (AEDs) are thought to act on voltage-sensitive ion channels, on inhibitory neurotransmission or on excitatory neurotransmission. Two successful examples of rational AED design that potentiate GABA-mediated inhibition are vigabatrin (VGB) by irreversible inhibition of GABA-transaminase, and tiagabine (TGB) by blocking GABA uptake. Lamotrigine (LTG) prolongs inactivation of voltage-dependent sodium channels. The anticonvulsant action of remacemide (RCM) is probably largely due to blockade of NMDA receptors and prolonged inactivation of sodium channels induced by its desglycinated metabolite. Felbamate (FBM) apparently blocks NMDA receptors, potentiates GABA-mediated responses, blocks L-type calcium channels, and possibly also prolongs sodium channel inactivation. Similarly, topiramate (TPM) has multiple probable sites of action, including sodium channels, GABA receptors, and glutamate (AMPA) receptors. Gabapentin (GBP) apparently has a completely novel type of action, probably involving potentiation of GABA-mediated inhibition and possibly also inactivation of sodium channels. The therapeutic advantages of the novel AEDs are as yet only partially explained by our present understanding of their mechanisms of action.

Topics: 4-Aminobutyrate Transaminase; Acetamides; Acetates; Amines; Animals; Anticonvulsants; Cyclohexanecarboxylic Acids; Epilepsy; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Ion Channels; Lamotrigine; Membrane Potentials; Mice; Neurotransmitter Agents; Nipecotic Acids; Phenethylamines; Phenylcarbamates; Propylene Glycols; Rats; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission; Tiagabine; Topiramate; Triazines; Vigabatrin

Gabapentin, lamotrigine, tiagabine, topiramate, vigabatrin, and zonisamide are all administered as add-on therapy for treatment of patients with refractory epilepsy. To date, no comparative randomized trials have been performed that could potentially allow an evidence-based choice to be made between these antiepileptic drugs (AEDs). We report a series of meta-analyses of placebo-controlled, randomized add-on trials in patients with partial epilepsy. Results of these meta-analyses are compared, thus giving broad estimates of the comparative efficacy and tolerability of these AEDs. The efficacy outcome is the odds ratio for the number of patients with a > or = 50% reduction in seizure frequency. Reported side effects are also used as tolerability outcomes, and study withdrawal is used as a global outcome measure. Results are summarized as odds ratios with 95% confidence intervals (CIs). When each outcome is compared among drugs, the 95% CIs overlap. Therefore, no conclusive evidence of a difference in efficacy or tolerability between these AEDs was derived, even though the apparently most effective agent (topiramate) may be twice as effective as the apparently least effective agent (lamotrigine). Comparative randomized studies are needed to further evaluate these drugs.

Topics: Acetates; Amines; Anticonvulsants; Confidence Intervals; Cyclohexanecarboxylic Acids; Drug Interactions; Drug Therapy, Combination; Epilepsy; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Isoxazoles; Lamotrigine; Nipecotic Acids; Odds Ratio; Placebos; Randomized Controlled Trials as Topic; Tiagabine; Topiramate; Treatment Outcome; Triazines; Zonisamide

New advances in the knowledge on the physiopathogenesis of epilepsy and their relationship with sodium and calcium channels and with the excitatory and inhibitory neurotransmitters actions have recently been developed. These knowledges have produced the research on new antiepileptic drugs which action places have specially based on the known impaired mechanisms. As the conventional drugs, the new therapeutic tool have produced a great advance in the therapy of epileptic events, specially in the refractory seizures, which represent 25-30% of the whole group of epilepsies. In the present work, we review the new drugs, ones have been registered, in order to their pharmacological properties, their efficacy their safety and their clinical indications as first-election or adjuvant drugs. We also discuss their known side adverse effects.

Topics: Acetates; Amines; Anti-Anxiety Agents; Anticonvulsants; Benzodiazepines; Benzodiazepinones; Carbamazepine; Clobazam; Cyclohexanecarboxylic Acids; Dioxolanes; Epilepsy; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Isoxazoles; Lamotrigine; Oxcarbazepine; Phenylcarbamates; Propylene Glycols; Topiramate; Triazines; Vigabatrin; Zonisamide

For many years, the medical treatment of epilepsy was based on the use of the same few drugs, which were chosen according to the seizure type in a fairly standardized manner. In the recent past, there have been several changes, and more are expected in the near future. Since 1993, three new antiepileptic drugs have been released in the United States, and two more are expected to be released before the end of 1997. Because the full spectrum of efficacy and side effects of these drugs has not yet been established, the present management of epilepsy requires a larger degree of flexibility, and it is necessary to become acquainted with the new drugs and to follow closely new reports on the experience with new drugs. This is particularly true for the management of epilepsy in children, because controlled studies in children tend to be completed later than those in adults and antiepileptic drug use in children is often "off label." The present review of newer antiepileptic drug consists of a brief summary of background information on each drug, followed by a closer analysis of recently published papers. Information on pediatric use is reviewed, when available. The new antiepileptic drugs selected for discussion are gabapentin, lamotrigine, felbamate, vigabatrin, and topiramate.

Topics: Acetates; Adult; Amines; Anticonvulsants; Child; Cyclohexanecarboxylic Acids; Epilepsy; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Lamotrigine; Phenylcarbamates; Propylene Glycols; Topiramate; Triazines; Vigabatrin

No fewer than eight new antiepileptic drugs (AEDs) with diverse mechanisms of action have been introduced into clinical practice in the 1990s. Short monographs on lamotrigine, vigabatrin, gabapentin, oxcarbazepine, felbamate, topiramate and vigabatrin have been prepared for this review. Details are provided of mechanisms of action, clinical pharmacokinetics and adverse drug interactions. Each section concentrates on the efficacy, tolerability and practical use of these drugs. The areas where they have potential for superiority over the established AEDs have been highlighted. Specific indications and dosage schedules have been provided. As many of these AEDs have, as yet, limited licences, an attempt has been made to identify ongoing studies and important omissions. Where possible, the eventual place of the new agent in the pharmacological management of epilepsy has been assessed. A more limited summary has been included of zonisamide which, although licensed in Japan, is still regarded as an investigational drug elsewhere. Short discussions of three of the most promising investigational compounds, namely remacemide, losigamone and levetiracetam, complete the picture.

Topics: Acetates; Amines; Anticonvulsants; Carbamazepine; Cyclohexanecarboxylic Acids; Epilepsy; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Lamotrigine; Nipecotic Acids; Oxcarbazepine; Phenylcarbamates; Propylene Glycols; Tiagabine; Topiramate; Triazines; Vigabatrin

Clinical investigators recently have studied at least 21 new antiepileptic drugs (AEDs) in people with epilepsy. This review briefly examines 15 of these new AEDs: clobazam (CLB), dezinamide, flunarizine (FNR), loreclezole, milacemide (MLM), MK-801, nafimidone, ORG-6370, oxcarbazepine (OCBZ), progabide (PGB), ralitoline, stiripentol, tiagabine (TGB), topiramate (TPM), and zonisamide (ZNS). CLB, PGB, and TGB represent agents that act on the GABA system, and MLM acts on the glycine system. MK-801 and ZNS (in part) are excitatory amino acid antagonists, and FNR is a calcium-channel antagonist. OCBZ is a keto analogue of carbamazepine, which is not metabolized to the epoxide and may have fewer side effects. The remaining agents are novel compounds with a variety of suspected mechanisms. TPM appears especially effective for intractable partial seizures but has a high incidence of cognitive side effects. None of these new AEDs is useful for all patients with inadequate seizure control or ongoing toxicity. The role of each will require further clinical study and experience.

Topics: Animals; Anti-Anxiety Agents; Anticonvulsants; Benzodiazepines; Benzodiazepinones; Carbamazepine; Clinical Trials as Topic; Clobazam; Disease Models, Animal; Epilepsy; Fructose; Humans; Nipecotic Acids; Oxcarbazepine; Rats; Tiagabine; Topiramate

The choice of an antiepileptic drug (AED) is guided primarily by efficacy and safety criteria. However, the pharmacokinetic properties of an AED determine its ease of use, i.e., its ability to predictably produce and maintain optimal plasma concentrations. Desirable and clinically important pharmacokinetic properties of an AED include complete or constant bioavailability, slow enteral absorption or availability of a sustained-release formulation, availability of a parenteral formulation for acute treatment, rapid penetration into the brain, a single-compartment volume of distribution, low and nonsaturable protein binding, and linear elimination kinetics, with an elimination half-life of about 24 h. The absence of autoinduction of enzymatic biotransformation, active metabolites, and pharmacokinetic drug interactions is also important. In clinical practice, the most undesirable pharmacokinetic properties are lack of a parenteral formulation, short elimination half-life, nonlinear elimination kinetics, autoinduction of enzymatic biotransformation, and interaction with other drugs. No AED is presently marketed or under development that meets all of the desirable criteria. Some of the newer AEDs, although not "ideal" agents, have pharmacokinetic profiles that are not shared by their predecessors, including elimination exclusively by the kidney, absence of drug interactions, and dose-related bioavailability.

Topics: Acetates; Amines; Anticonvulsants; Biological Availability; Biopharmaceutics; Carbamazepine; Cyclohexanecarboxylic Acids; Drug Interactions; Epilepsy; Fructose; Gabapentin; gamma-Aminobutyric Acid; Half-Life; Humans; Intestinal Absorption; Lamotrigine; Oxcarbazepine; Topiramate; Triazines; Vigabatrin

Epilepsy is one of the most common neurological disorders. Even though existing antiepileptic drugs can render 80% of newly diagnosed patients seizure free, a significant number of patients have chronic intractable epilepsy causing disability with considerable socioeconomic implications. There is, therefore, a need for more potent and effective antiepileptic drugs and drugs with fewer adverse effects, particularly CNS effects. Drugs for the treatment of partial seizures are particularly needed. With major advances in our understanding of the basic neuropathology, neuropharmacology and neurophysiology of epilepsy, numerous candidate novel antiepileptic drugs have been developed in recent years. This review comparatively evaluates the pharmacokinetics, efficacy and adverse effects of 12 new antiepileptic drugs namely vigabatrin, lamotrigine, gabapentin, oxcarbazepine, felbamate, tiagabine, eterobarb, zonisamide, remacemide, stiripentol, topiramate and levetiracetam (ucb-L059). Of the 12 drugs, vigabatrin, lamotrigine and gabapentin have recently been marketed in the UK. Five of these new drugs have known mechanisms of action (vigabatrin, lamotrigine, tiagabine, oxcarbazepine and eterobarb), which may provide for a more rational approach to the treatment of epilepsy. Oxcarbazepine, remacemide and eterobarb are prodrugs. Vigabatrin, gabapentin and topiramate are more promising on the basis of their pharmacokinetic characteristics in that they are excreted mainly unchanged in urine and not susceptible to significant pharmacokinetic interactions. In contrast, lamotrigine, felbamate and stiripentol exhibit significant drug interactions. Essentially, all the drugs are effective in partial or secondarily generalised seizures and are effective to varying degrees in other seizure types. Particularly welcome is the possible effectiveness of zonisamide in myoclonus and felbamate in Lennox-Gastaut syndrome. In relation to adverse effects, CNS effects are observed with all drugs, however, gabapentin, remacemide and levetiracetam appear to exhibit least. There is also the possibility of rational duotherapy, using drugs with known mechanisms of action, as an additional therapeutic approach. The efficacy of these 12 antiepileptic drug occurs despite the fact that candidate antiepileptic drugs are evaluated under highly unfavourable conditions, namely as add-on therapy in patients refractory to drug management and with high seizure frequency. Thus, whilst candidate drugs wh

Topics: Acetamides; Acetates; Amines; Anticonvulsants; Carbamazepine; Cyclohexanecarboxylic Acids; Dioxolanes; Epilepsy; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Isoxazoles; Lamotrigine; Levetiracetam; Nipecotic Acids; Oxcarbazepine; Phenobarbital; Phenylcarbamates; Piracetam; Propylene Glycols; Risk Factors; Tiagabine; Topiramate; Triazines; Vigabatrin; Zonisamide

Topics: Acetates; Amines; Aminocaproates; Anticonvulsants; Brain; Clinical Trials as Topic; Cyclohexanecarboxylic Acids; Epilepsy; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Lamotrigine; Nipecotic Acids; Phenylcarbamates; Propylene Glycols; Structure-Activity Relationship; Synaptic Transmission; Tiagabine; Topiramate; Triazines; Vigabatrin

Lesional and symptomatic causes of epilepsy are the most common neurological disorders of the brain. Topiramate effectively controls newly diagnosed epilepsy and refractory focal seizures, but high-dose topiramate does not improve seizure control. This study aimed to evaluate the clinical efficacy and safety of dose-escalated topiramate as first-line monotherapy and add-on therapy in patients with neurosurgery-related epilepsy.. A total of 55 neurosurgical patients with epilepsy were divided into monotherapy and add-on therapy groups and both groups received topiramate via the dose-escalation method. The primary efficacy outcomes were seizure-free rate and seizure response rate. Adverse events and seizure frequency were recorded.. The seizure response rate in the first month of monotherapy was significantly better than that of add-on therapy (89% vs 65%, P < .05), but no significant differences were found in seizure response rates between the 2 groups after 2 months of treatment. Both monotherapy and add-on therapy were effective in controlling seizures, with mean seizure frequency of 0.725 vs 0.536 and seizure-free rate of 88% vs 78.6%. Both treatments showed good improvement of seizure frequency in patients without tumor. The efficacy of monotherapy was better than that of add-on therapy (80% vs 29.2%) in patients with body mass index (BMI) ≤24. However, add-on therapy was better than monotherapy (76.7% vs 21.4%) in patients with BMI > 24. Dizziness (25.5%) and headache (16.4%) were the most common adverse events. No severe adverse event such as cognitive impairment was observed.. Dose-escalated topiramate monotherapy and add-on therapy demonstrate good efficacy and safety, with fewer adverse events in seizure control in neurosurgical patients.

Topics: Adult; Anticonvulsants; Dose-Response Relationship, Drug; Drug Monitoring; Drug Therapy, Combination; Epilepsy; Female; Humans; Male; Neurosurgical Procedures; Outcome and Process Assessment, Health Care; Postoperative Complications; Topiramate; Treatment Outcome

There are no reliable prospective studies on the effectiveness of topiramate in Bulgarian adult patients with drug-resistant epilepsy.. The aim of the study was to conduct an open, prospective study on various aspects of topiramate (TPM) effectiveness in Bulgarian patients with drug-resistant epilepsy.. The study included patients with epilepsy who attended the Clinic of Neurology at the University Hospital in Plovdiv, Bulgaria. Patients completed diaries for seizure frequency, seizure severity, and adverse events. There were regular documented visits at 3 or 6 months during the first year of TPM treatment and at 6 months afterwards, with a dynamic assessment of seizure fre-quency, severity, adverse events, and EEG recordings.. TPM was used as an add-on treatment in 120 patients (69 males, mean age 37 years). There was a relatively mild and stable dynamic improvement of seizure severity, a satisfactory seizure frequency reduction in 37% of participants, a stable mean seizure fre-quency reduction (47%) from month 6 to month 24 of treatment and a stable responder rate (48-51%) during the same period. New seizure types (focal with impaired awareness with/without evolution to bilateral tonic-clonic seizures) occurred in 5 patients. There were adverse events (dizziness/vertigo, irritability, speech disturbances, memory impairment, concentration problems, tremor, loss of appe-tite and weight, weakness, numbness, bradypsychia, confusion, visual hallucinations, sleepiness, insomnia, headache, itching, unstable gait, nausea, and vomiting) in 20% of patients.. TPM treatment is associated with low and stable improvement of seizure severity, good and stable improvement of sei-zure frequency, possible worsening of seizure control and appearance of new seizure types, good safety and tolerability.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Bulgaria; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance; Drug Therapy, Combination; Epilepsy; Female; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Prospective Studies; Topiramate; Young Adult

For extended-release drugs with multi-compartment kinetics, such as topiramate, effective half-life (t. The t. As previously reported, mean t. As expected for the same moiety, t

Topics: Anticonvulsants; Clinical Decision-Making; Computer Simulation; Delayed-Action Preparations; Epilepsy; Fructose; Half-Life; Humans; Models, Theoretical; Topiramate

To study the impact on seizure frequency and epileptiform discharges of children with epilepsy from topiramate (TPM) and phenobarbital (PB).. Two hundred cases children with epilepsy from August 2010 to August 2013 in our hospital were sampled and randomly divided into two groups. The observation group was treated with TPM while the control group with PB, and then comparing seizure frequency, efficiency, and adverse reactions of two groups.. The reduced number of partial seizures, generalized seizures, and total seizures in the observation group were significantly higher than those in the control group, and the rate of cure, markedly effective and total efficiency in observation group were significantly higher than those in the control group. However, the adverse reactions in observation group were significantly lower than those in the control group. Thus, differences were statistically significant (p<0.05).. Compared with PB, TPM showed a better effect on epilepsy treatment with less adverse reactions which were worthy of clinical recommendation.

Topics: Anticonvulsants; Child; Child, Preschool; Epilepsy; Female; Fructose; Humans; Male; Phenobarbital; Topiramate

We assessed the likelihood of 12-month seizure remission and treatment failure after failure of a first antiepileptic drug, and identified factors influencing these outcomes.. SANAD (Standard and New Antiepileptic Drug) was a randomized controlled trial comparing monotherapy with standard and new antiepileptic drugs. Patients were followed up to study completion, even if they were switched from their randomized treatment. After a first treatment failure, we assessed the probability of 12-month seizure remission and treatment failure. Prognostic modeling identified predictors of these outcomes.. Forty-four percent of patients in the SANAD trial had a first treatment failure. Seventy-five percent of these subsequently achieved 12-month remission by 6 years of follow-up. Significant prognostic factors included sex, age at treatment failure, time on randomized treatment at treatment failure, neurologic insult, total number of tonic-clonic seizures at treatment failure, reason for treatment failure, seizure type, and CT/MRI scan result. After a first treatment failure, young patients without tonic-clonic seizures, with a normal CT/MRI scan and failing their treatment because of unacceptable adverse events, had the highest likelihood of 12-month remission. Approximately 50% of patients who failed a first treatment also failed their second. Significant prognostic factors included total number of tonic-clonic seizures at first treatment failure, reason for first treatment failure, and CT/MRI scan result. Patients with tonic-clonic seizures and failing because of inadequate seizure control had the highest risk of a second treatment failure.. A high proportion of patients will achieve 12-month remission after a first treatment failure. Clinical factors can stratify patients according to likely outcome.

Topics: Adolescent; Adult; Anticonvulsants; Epilepsy; Female; Fructose; Humans; Lamotrigine; Male; Middle Aged; Time Factors; Topiramate; Treatment Failure; Treatment Outcome; Triazines; Valproic Acid; Young Adult

Although topiramate is widely prescribed for epilepsy and migraine, there is no intravenous product. We have developed an injectable topiramate formulation in which the drug is solubilized in a cyclodextrin matrix, Captisol(®) (Ligand Pharmaceuticals, Inc., La Jolla, CA). Our long-term goal is to evaluate intravenous topiramate for the treatment of neonatal seizures. Prior to studies in newborns, we carried out an investigation of injectable topiramate's safety and pharmacokinetics in adult patients.. Twenty adult volunteers with epilepsy or migraine on stable, on maintenance topiramate therapy were given 25 mg of a stable-labeled intravenous topiramate over 10 min, followed by their usual oral doses. Vital signs were taken, electrocardiography studies (ECGs) were recorded, and the infusion sites were periodically examined prior to and up to 24 h after dosing. Blood samples were collected prior to administration and serially for 96 h thereafter. Plasma concentrations of both stable-labeled and regular topiramate were measured using liquid chromatography-mass spectrometry (LC-MS). Concentration-time data were analyzed using a noncompartmental approach with WinNonlin 5.2 (Pharsight Corporation, Mountain View, CA, U.S.A.).. Seven patients experienced one or more of the following minor adverse events including nausea and vomiting (1), tingling around the lips (1), paresthesia in the arms and legs (1), and a mild vasovagal response with intravenous catheter placement (1). Included in the adverse events were four patients with epilepsy who had seizures consistent with their histories. There were no changes in heart rate, blood pressure, or ECG results, and there were no infusion site reactions. Pharmacokinetic parameters (mean ± standard deviation [SD]) determined following the intravenous dose included absolute bioavailability: 110 ± 16%, distribution volume: 0.79 ± 0.22 L/kg, clearance: 2.03 ± 1.07 L/h, and elimination half-life: 27.6 ± 9.7 h. Distribution volume, half-life, and clearance were significantly altered by enzyme-inducing drugs.. A single 25-mg dose of intravenous topiramate caused minimal infusion site or systemic adverse effects in patients taking oral topiramate. Pharmacokinetic results show that oral topiramate is completely absorbed and that its steady-state elimination half-life is longer than previously assumed, which permits once or twice daily dosing even in the presence of enzyme-inducing drugs. The information from this study can inform the design of subsequent studies in adults, older children, and newborns, including controlled clinical trials intended to determine the efficacy and safety of intravenous topiramate for neonatal seizures.

Topics: Administration, Oral; Adult; Aged; Anticonvulsants; Blood Pressure; Electrocardiography; Epilepsy; Female; Fructose; Heart Rate; Humans; Infusions, Intravenous; Male; Middle Aged; Migraine Disorders; Topiramate

In this communication, the effect of acute treatment with lamotrigine (LTG) and topiramate (TPM) was investigated on release of the main excitatory amino acids (EAA) such as glutamate (Glu) and aspartate (Asp) in the hippocampus of pentylenetetrazol (PTZ)-kindled freely moving rats using microdialysis. The results showed that the level of Glu and Asp significantly decreased in the PTZ-kindled epileptic (EP) rat hippocampus after the 20 mg/kg LTG or 40 mg/kg TPM administration. But LTG gave rise to a better result than TPM in controlling EAA release.

Topics: Animals; Anticonvulsants; Epilepsy; Excitatory Amino Acid Agents; Excitatory Amino Acid Antagonists; Fructose; Hippocampus; Lamotrigine; Male; Pentylenetetrazole; Rats; Rats, Sprague-Dawley; Topiramate; Treatment Outcome; Triazines

The objective of the study was to develop population pharmacokinetic model of topiramate (TPM) using nonlinear mixed effects modelling approach. Data were collected from 78 adult epileptic patients on mono- or co-therapy of TPM and other antiepileptic drugs, such as carbamazepine (CBZ), valproic acid, lamotrigine, levetiracetam, phenobarbital and pregabalin. Steady-state TPM concentrations were determined in blood samples by high performance liquid chromatography with fluorescence detection. A one-compartment model with first order absorption and elimination was used to fit the concentration-time TPM data. Volume of distribution of TPM was estimated at 0.575 l/kg. The influence of demographic, biochemical parameters and therapy characteristics of the patients on oral clearance (CL/F) was evaluated. Daily carbamazepine dose (DCBZ) and renal function estimated by Modification of diet in renal disease (MDRD) formula significantly (p<0.001) influenced CL/F and were included in the final model: CL/F · (l/h)=1.53(l/h) · [1+0.476 · DCBZ(mg/day)/1000(mg/day)] · EXP[0.00476 · [MDRD(ml/ min)-95.72(ml/min)]]. Increase of CL/F with DCBZ and MDRD was best described by linear and exponential models. Mean TPM CL/F during CBZ co-therapy was 2.46 l/h, which is higher for 60.8% than in patients not co-treated with CBZ. Evaluation by bootstrapping showed that the final model was stable. The predictive performance was evaluated by adequate plots and indicated satisfactory precision. This model allows individualisation of TPM dosing in routine patient care, especially useful for patients on different CBZ dosing regimen.

Topics: Adult; Aged; Anticonvulsants; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Models, Biological; Topiramate

New-generation antiepileptic drugs (AEDs) tend to replace traditional AEDs as the first-line choice for epilepsy. However, whether this change results in better outcome, especially in China, remains unknown.. Two broad spectrum AEDs, the traditional drug of sustained-release formulation of valproate (SRVPA) and the new-generation drug of topiramate, were compared in patients with epilepsy as monotherapy in this multi-centre, observational cohort study from 2000 to 2011. The primary outcome was time to treatment failure. The secondary outcomes included time to first seizure, time to 12-month remission, and time to 24-month remission. Drug tolerability was assessed. Cox proportional hazard models (95% confidence interval [CI]) were used to analyse the relative risks expressed as hazard ratios (HR). Of the 1008 recruited patients, 519 received SRVPA and 489 received topiramate. SRVPA was better than topiramate (28.3% vs. 41.5%; HR = 0.62, [95% CI 0.49-0.77]; p<0.0001) in primary outcome, and in time to first seizure (56.1% vs. 69.3%; HR = 0.73, [95% CI 0.62-0.86]; p = 0.0002). No significant difference was observed between two groups in time to 12-month remission (52.6% vs. 42.5%; HR = 1.01, [95% CI 0.84-1.23]; p = 0.88) and time to 24-month remission (34.7% vs. 25.2%; HR = 1.11, [95% CI 0.88-1.42]; p = 0.38). 36 patients (6.9%) in SRVPA group and 37 patients (7.6%) in topiramate group presented treatment failure associated with intolerable adverse events, there was no significant difference between the two groups (p = 0.70).. The SRVPA is more suitable than topiramate for Chinese epileptic patients, and our results support the viewpoint that traditional AEDs should be the first-line choice for epilepsy rather than new-generation AEDs.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Child; Child, Preschool; China; Cohort Studies; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Proportional Hazards Models; Topiramate; Treatment Outcome; Valproic Acid

This study evaluated the effect of topiramate (TPM) on the quality of life (QOL) in childhood epilepsy, using the Korean quality of life in childhood epilepsy (K-QOLCE) questionnaire. An open label, prospective, observational study of the families of 664 children with epilepsy from 41 centers was conducted. The parents completed the K-QOLCE at the baseline visit and again 6months after starting TPM treatment. The parents reported the seizure frequency at both assessment dates. Statistically significant improvements in all K-QOLCE domains except social functioning were found at 6months after starting TPM treatment from the baseline-scores (P<0.05). However, improved QOL scores were not dependent on the reduction in seizure frequency. TPM significantly improved QOL in children with epilepsy, suggesting its potential clinical benefits.

Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Epilepsy; Female; Fructose; Humans; Male; Prospective Studies; Quality of Life; Surveys and Questionnaires; Topiramate; Treatment Outcome

To investigate the effect of topiramate on bone mass and metabolism in premenopausal women with epilepsy.. Thirty-six women on long-term (at least 1 year) topiramate monotherapy were compared with 36 women taking carbamazepine, 32 women taking valproate, and 36 age- and sex-matched controls. Subjects completed bone mineral density (BMD) studies. Serum was analyzed for indices of bone metabolism.. BMD Z-scores, and serum 25-hydroxyvitamin D and 1alpha,25-dihydroxyvitamin D(3) concentrations did not differ among the groups. Serum calcium concentrations were significantly lower in patients receiving topiramate than in those receiving valproate, and in patients receiving carbamazepine than in those receiving valproate and controls. Patients taking topiramate had lower levels of parathyroid hormone compared with controls and those taking carbamazepine or valproate. Patients receiving topiramate had higher levels of bone-specific alkaline phosphatase and osteocalcin when compared with controls and higher levels of C-terminal telopeptide of type 1 collagen when compared with those taking carbamazepine or valproate. Patients receiving carbamazepine had higher levels of bone-specific alkaline phosphatase compared with controls and those receiving valproate. Serum bicarbonate concentrations were significantly lower in patients receiving topiramate than in the other groups.. Our results demonstrate that use of topiramate is associated with lower parathyroid hormone and bicarbonate concentrations along with mild hypocalcemia and increased bone turnover, which suggests that topiramate may have long-term effects on bone.

Topics: Adult; Alkaline Phosphatase; Anticonvulsants; Bicarbonates; Bone and Bones; Bone Density; Calcification, Physiologic; Calcitriol; Calcium; Carbamazepine; Epilepsy; Female; Fructose; Humans; Topiramate; Valproic Acid; Vitamin D

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

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

To evaluate topiramate (TPM) and phenytoin (PHT) monotherapy following rapid oral initiation in new-onset epilepsy.. Randomized, double-blind, 28-day trial of TPM (100 mg/day beginning on day 1) versus PHT (1,000 mg on day 1 followed by 300 mg/day maintenance dosing) in 261 patients with new-onset epilepsy. The primary end point was time to seizure, and the primary objective was to establish noninferiority of TPM to PHT in the risk of seizure.. At day 28, the estimated seizure-free rate was 81.1% for TPM treatment in comparison with 90.3% for PHT treatment. Noninferiority of TPM to PHT (primary objective) could not be established [hazard ratio (HR) 2.0, 95% confidence interval (CI), 0.98 to 4.12, p = 0.366), and PHT could not be shown to be superior to TPM. A higher percentage discontinued with PHT compared to TPM for all reasons (21.1 vs. 12.8%) and due to adverse events (13.4 vs. 6.8%). The most common treatment-related adverse events in both groups were dizziness, paresthesia, and somnolence. A post hoc analysis showed that TPM was superior to PHT in time to discontinuation (retention rate) for all causes (89.4% vs. 80.3%, p = 0.047).. This study was inconclusive in establishing noninferiority of TPM 100 mg/day compared to a standard regimen of oral PHT in seizure risk in this population of patients with new-onset epilepsy. Given the superiority of TPM in overall retention and favorable tolerability without titration, it may nonetheless be an appropriate option in some patients with new-onset epilepsy requiring rapid treatment initiation.

Topics: Administration, Oral; Adolescent; Adult; Aged; Anticonvulsants; Child; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Emergency Medical Services; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Phenytoin; Recurrence; Risk Factors; Topiramate; Treatment Outcome

To evaluate the effect of topiramate (TPM) on event-related potentials (ERPs) in patients with epilepsy.. Neuropsychological tests and ERP study using auditory oddball paradigm were conducted before and after treatment with TPM in drug-naive epilepsy patients. To detect target brain regions in which ERP changed during the cognitive task, cortical current densities of ERP components were analysed using standardised low-resolution electromagnetic tomography (sLORETA).. Neuropsychological tests (n=18 patients) showed that TPM significantly decreased the score in digit span, Corsi block and Controlled Oral Word Association word fluency. Repeated-measures analysis of variance of ERP data (n=13 patients) revealed that P2 amplitude was significantly increased at Fz electrode following treatment with TPM. Statistical non-parametric map of sLORETA between pre- and post-TPM ERPs revealed that current density of P200 component was significantly reduced by TPM in bilateral parieto-occipital, temporolimbic and dorsolateral right prefrontal regions.. Our findings suggest that TPM affects selective brain regions which may be related to cognitive side effects.. Source localisation of ERPs can be helpful in identifying target brain regions for the cognitive side effects of anti-epileptic drugs.

Topics: Adult; Anticonvulsants; Brain; Brain Mapping; Cognition; Epilepsy; Evoked Potentials; Female; Fructose; Humans; Male; Middle Aged; Neuropsychological Tests; Reaction Time; Statistics, Nonparametric; Topiramate; Young Adult

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

To determine long-term retention, percentage of patients withdrawing because of adverse events, percentage of patients achieving seizure freedom, safety profile of the new anti-epileptic drugs lamotrigine, levetiracetam and topiramate.. All patients treated with lamotrigine, levetiracetam or topiramate in the Epilepsy Centre were identified. Each drug was analyzed from introduction of the drug in the Netherlands up to a final assessment point 2 years later.. Data from 1066 patients were included: 336 for lamotrigine, 301 for levetiracetam, 429 for topiramate. Two-year retention rates were 69.2% (lamotrigine), 45.8% (levetiracetam), 38.3% (topiramate); (LTG vs. LEV at p<0.001; LTG vs. TPM at p<0.001; LEV vs. TPM at p=0.005). Seizure freedom rates were lowest for lamotrigine and highest for levetiracetam. Adverse events played a role in drug discontinuation in 154/429 patients (35.9%) on topiramate, 52/336 patients (15.5%) on lamotrigine (p<0.001), 68/301 patients (22.5%) on levetiracetam (p<0.001). Mood and general CNS-effects are common in patients on lamotrigine and levetiracetam, and neurocognitive side effects are most prevalent in patients on topiramate. A positive effect on cognition is frequently noted in patients on lamotrigine.. A drug that is only modestly efficacious but has a favourable safety profile may look better than a drug that is more efficacious but produces clinically meaningful adverse events. Therefore, a drug's retention rate is mainly determined by its side effect profile. As a consequence, retention rate was highest for lamotrigine and lowest for topiramate. Intermediate retention rates were seen with levetiracetam use.

Topics: Anticonvulsants; Drug Utilization; Epilepsy; Fructose; Humans; Lamotrigine; Levetiracetam; Longitudinal Studies; Patient Compliance; Piracetam; Time Factors; Topiramate; Treatment Outcome; Triazines

To explore efficacy and tolerability outcomes of topiramate (TPM) in patients with epilepsy transitioning from valproic acid (VPA) because of insufficient efficacy and/or tolerability onto TPM.. Multicenter, open label, single arm, non-interventional study examining patients (> or =12 years) with epilepsy, transitioning onto TPM from baseline mono-or combination therapy with VPA. TPM was added onto the existing antiepileptic drug (AED) treatment and started at a dose of 25 mg once daily. The dose was titrated up with 25 mg/day increments, once every 1-2 weeks, until a final dose between 50-200 mg/day was reached. Based on clinical judgment, the treating physician decided whether or not and when the existing AED treatment especially with VPA could be withdrawn. Documented were type and frequency of seizures, TPM dose, quality of life (QOLIE-10 questionnaire), subjective perception of improvement, and adverse events (AE).. One hundred and forty-seven patients (59% women, mean age 41 years) switched from baseline VPA treatment onto TPM because of insufficient efficacy (61%) and/or poor tolerability (81%). Average duration of follow-up was 20.3 weeks with an overall discontinuation rate of 16.3% of patients, mainly because of AE (in 8.2% of 147 patients). At study endpoint, the intended shift to TPM monotherapy was achieved in 70% of patients at a median dose of 150 mg/day. A seizure reduction of > or =50% was achieved in 75% of patients in the last scheduled period (week 8-20), and 51% of patients entering that period remained seizure-free. Quality of life improved significantly as compared with baseline for all domains of QOLIE-10 (P < 0.001). Most frequent AEs were weight decrease (4.8%), paraesthesia and fatigue (4.1% each), speech disorder and headaches (2.7% each).. In patients with epilepsy not satisfactorily treated with VPA, conversion to TPM was associated with improved seizure control as well as improvement in several aspects of quality of life.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Child; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Patient Satisfaction; Quality of Life; Surveys and Questionnaires; Topiramate; Treatment Outcome; Valproic Acid; Young Adult

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

This prospective, observational, single arm, monocentric study explored efficacy and tolerability outcomes of rapid oral initiation of topimarate in children with difficult to treat epilepsy. The study population consisted of 19 multiply handicapped children (mean age 4.4 years, range 0.6-15.3 years). The observation period was 12 weeks and included 7 visits. The mean initial dose of topiramate was 1.1 mg/kg body weight/d (range: 0.66-2.67 mg/kg/d) following rapid titration. The mean final dose was 3.3 mg/kg/d (range 0.5-6.7 mg/kg/d). An at least 50% reduction of seizure frequency compared to baseline was observed in 9 of 19 patients (47.4%). Six patients (31.6%) had a slight reduction of seizure frequency (<50%) and 4 patients (21.1%) experienced an increase of seizure frequency. A total number of 29 adverse events were documented in 17 of 19 patients. Most frequently captured were fatigue (26.3% of patients), decreased appetite (15.8%) and psychiatric disturbances (15.8%). No serious adverse events were reported. These data might suggest that in certain clinical circumstances rapid dose escalation with topiramate followed by a low maintenance dose might be a good therapeutic option for pediatric patients with difficult to treat epilepsy.

Topics: Adolescent; Anticonvulsants; Body Weight; Child; Child, Preschool; Disabled Children; Dose-Response Relationship, Drug; Electroencephalography; Epilepsy; Female; Follow-Up Studies; Fructose; Humans; Infant; Male; Observation; Prospective Studies; Severity of Illness Index; Topiramate; Treatment Outcome

Topiramate (TPM) is a new, effective and safe antiepileptic drug. TPM is also effective in treating a wide spectrum of conditions such as eating disorders and related anomalies, bulimia nervosa and other conditions in which serotonin (5-hydroxytryptamine, 5-HT) is involved pathogenetically. Plasma serotonin mainly derives from blood platelets, which represent a valid model of serotoninergic neurons. We measured plasma 5-HT levels in 12 children affected by epilepsy who underwent TPM therapy. Inclusion criteria were (i) age range 2-12 years, (ii) weight greater than 12 kg, (iii) no more than one antiepileptic drug used when TPM therapy was instituted, and (iv) a minimum study period of 3 months. After a mean period of 3 months of TPM treatment, a significant increase in mean plasma serotonin levels was observed with respect to the basal levels and those of a control group. There were no significant correlations between the changes in serotonin concentrations and the antiepileptic efficacy or doses of TPM used. TPM may influence serotonin metabolism in children affected by epilepsy. Further studies are needed to establish whether these serotonin plasma changes represent an epiphenomenon or indicate direct effects of TPM on the serotoninergic system.

Topics: Anticonvulsants; Case-Control Studies; Child; Child, Preschool; Chromatography, High Pressure Liquid; Electrochemistry; Epilepsy; Female; Fructose; Humans; Linear Models; Male; Serotonin; Time Factors; Topiramate

Medical management of brain tumor-related epilepsy is complicated by interactions between antiepileptic and chemotherapeutic drugs. We studied the effect of temozolomide therapy on the disposition of the new antiepileptic drugs topiramate (TPM) or oxcarbazepine (OXC).. Fifteen patients chronically treated with TPM or OXC in monotherapy starting a chemotherapeutic treatment with temozolomide were enrolled in the study, of which ten were available for the final analyses. Blood samples were collected before temozolomide treatment (T(0)), at its end (T(7)) and after further 1-3 weeks (T(14)-T(28)). For each patient, more than one treatment cycle was studied. Topiramate and OXC mono-10-hydroxy derivative (MHD) plasma concentrations were determined by hplc coupled with ion spray mass spectrometer (TPM) or ultraviolet (MHD) detection.. Mean TPM concentrations were 5.4 +/- 2.4 microg/ml at T(0) vs. 5.5 +/- 2.4 microg/ml at T(7) (n = 14), and 5.4 +/- 2.4 microg/ml at T(0) vs. 5.6 +/- 2.8 microg/ml at T(14)-T(28) (n = 14). Mean MHD concentrations were 16.4 +/- 7.6 microg at T(0) vs. 18.5 +/- 9.0 microg/ml at T(7) (n = 5), and 16.8 +/- 7.0 microg/ml at T(0) vs. 18.0 +/- 8.7 microg/ml at T(14)-T(28) (n = 8) (all comparisons not statistically significant; Student's t-test for paired samples).. Temozolomide treatment did not affect TPM plasma concentrations in chronically treated patients. Data for MHD in OXC-treated patients were similar, but, due to the small sample size, results should be interpreted cautiously.These findings confirm that TPM (and possibly OXC) are a reasonable choice of antiepileptic drug in patients with brain tumor-related epilepsy.

Topics: Adult; Anticonvulsants; Antineoplastic Agents, Alkylating; Brain Neoplasms; Carbamazepine; Dacarbazine; Epilepsy; Female; Follow-Up Studies; Fructose; Humans; Male; Middle Aged; Oxcarbazepine; Temozolomide; Topiramate; Young Adult

Epilepsy in brain tumor patients is often refractory to pharmacological treatments and can complicate the therapeutic management of these patients. We conducted a prospective, observational study. The aim of this study was to investigate the efficacy and tolerability of topiramate (TPM) in brain tumor associated epilepsy. We studied 47 patients with brain tumors and epilepsy. The entire group was administered AEDs. TPM was the first therapeutic choice in 14 patients, while in the remaining 33 patients previous AEDs were modified and TPM was introduced due to side effects or inefficacy of the first drug. Follow-up ranged from 3 to 48 months (mean 16.5 months). Considering the final follow-up of each patient who assumed TPM for at least 3 months, we observed 45 patients: 25 were seizure free (55.6%), 9 had a reduction of seizure frequency (SF) higher than 50% (20%) and 11 were stable (24.4%). TPM responder rate was 75.6%. Three patients (6.4%) discontinued TPM for severe side effects (1 after 4 months and 2 after 1 month) and 4 (8.5%) had mild and reversible side effects. In the group of patients who had been in therapy with other AEDs prior to entering the study (n = 33), 19 patients had side effects (57.6%). During follow-up, the haematological parameters were in the normative ranges. Tumor-related seizures are difficult to control with AEDs; the precise reasons for this difficulty are not yet clear. Using TPM, we obtained good seizure control with a low incidence of side effects.

Topics: Adult; Aged; Anticonvulsants; Brain Neoplasms; Drug Evaluation; Epilepsy; Female; Follow-Up Studies; Fructose; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Retrospective Studies; Time Factors; Topiramate

The aim of the present study was to assess the behavioral and cognitive effects following treatment with topiramate in children and adolescents with epilepsy with mild to profound mental retardation. The study group comprised 29 children, 16 males and 13 females, aged 3 to 19 years, affected by partial (4) and generalized (25) crypto/symptomatic epilepsy and mental retardation (7 mild, 5 moderate, 15 severe, 2 profound), who were administered topiramate (TPM) as add-on therapy to their baseline antiepileptic treatment. At baseline, 3 months, 6 months, and 12 months, parents or caregivers of each patient were administered a questionnaire based on the Holmfrid Quality of Life Inventory. After a 3-month follow-up, the add-on topiramate caused overall mild to moderate cognitive/behavioral worsening in about 70% of children and adolescents with mental retardation and epilepsy. After 6 and 12 months of follow-up, global worsening persisted in 31 and 20.1% of cases, respectively. In conclusion, this trial confirms that TPM can have significant adverse cognitive and behavioral side effects, even in mentally disabled children and adolescents.

Topics: Adolescent; Adult; Anticonvulsants; Behavior; Child; Child, Preschool; Cognition Disorders; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Intellectual Disability; Male; Mental Disorders; Prospective Studies; Severity of Illness Index; Statistics, Nonparametric; Topiramate; Treatment Outcome

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 changes in quality of life in patients with epilepsy converting to topiramate (TPM) from carbamazepine (CBZ) or oxcarbazepine (OXC) due to insufficient effectiveness and/or tolerability.. A multicenter, open-label, non-interventional trial was used to examine patients (> or = 12 years) with epilepsy, changing to TPM monotherapy from baseline mono- or combination therapy with CBZ or OXC. TPM was added to the existing antiepileptic drug (AED) treatment and started at a dose of 25 mg once daily. The dose was titrated up with 25 mg/day increments, once every 1-2 weeks, until a final dose between 50 and 200 mg/day was reached. On the basis of clinical judgment, the treating physician decided whether or not the existing AED treatment with CBZ or OXC could then be withdrawn. Type and number of seizures, preferred TPM dose, quality of life (QOLIE-10 questionnaire), subjective perception of improvement and adverse events (AE) were documented.. 140 patients (53.5% women, mean age 47 years) decided to switch to TPM due to insufficient effectiveness (75% of patients) and/or poor tolerability (80%) of the CBZ/OXC treatment. Average duration of follow-up was 24 weeks with an overall discontinuation rate of 19.3%, mainly due to AEs (12.1%). At study endpoint, the intended shift to TPM monotherapy was achieved in 73% of patients at a median TPM dose of 100 mg/day. A seizure reduction of > or = 50% was achieved in 91% of patients in the last scheduled period (weeks 12-26); 62% of patients entering that period remained seizure free. Quality of life at endpoint improved significantly when compared with baseline for all domains of QOLIE-10 (P < 0.001). Most frequent AEs (reported by > or = 5% of patients) were paresthesia (9.3%), weight loss (7.9%), convulsions (5.7%) and memory disorders (5.0%).. In patients with epilepsy, previously not satisfactorily treated with CBZ or OXC, conversion to TPM may result in an improvement in seizure control as well as in quality of life.

Topics: Adolescent; Adult; Anticonvulsants; Carbamazepine; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Oxcarbazepine; Quality of Life; Retrospective Studies; Topiramate; Treatment Failure

The present study was designed to reveal changes of cognitive processes in epilepsy (EP) patients with Topiramate (TPM) or Valproate (VPA) treatment using Wechsler Adult Intelligence Scale (WAIS-CR) and event-related potential (ERP). Thirty untreated epilepsy patients were randomly divided into two groups receiving TPM or VPA, respectively. Fifteen healthy volunteers were included as controls. All the patients were examined by WAIS-CR and ERP before and 3 months after drug treatment. Controls were examined by ERP at the time recruited into the study and 3 months later. Unfamiliar grey-scale photographs of faces (front view) were used as stimuli. ERP were recorded at the same time. Mean Intelligence Quotient (IQ) in TPM group decreased after the 3-month treatment (90.40 vs. 81.00, P<0.05). One component of ERP-P300 was smaller in epilepsy patients than controls (P<0.05), but remained unchanged after TPM or VPA treatment (P>0.05). A delayed and smaller N270 was detected in patients compared to controls (P<0.05). After 3 months TPM treatment, it decreased further compared to before treatment (P<0.05). N170 was lower in patient groups, and it became lower after TPM treatment than before. Our results demonstrate that in all epilepsy patients with mild cognitive impairment ERP changes were found. TPM affected the cognitive functions in epilepsy patients reflected by the decreased full-scale intelligence quotient (FIQ). The imperative effects of TPM on visual perception function reflected by N170 were more obvious than that of VPA. Attention reflected by N270 was impaired after TPM treatment.

Topics: Adolescent; Adult; Attention; Case-Control Studies; Electroencephalography; Epilepsy; Evoked Potentials; Female; Follow-Up Studies; Fructose; Humans; Male; Pattern Recognition, Visual; Photic Stimulation; Topiramate; Valproic Acid

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

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

To determine the prevalence of renal calculi in patients treated with zonisamide during randomized, controlled and open-label clinical trials, and from post-marketing surveillance data.. Reports of renal calculi from four placebo-controlled double-blind trials of zonisamide, their long-term open-label treatment extension phases, and the US/European zonisamide clinical trial programme were reviewed. One double-blind study and its extension included routine ultrasound screening to identify asymptomatic calculi. Post-marketing surveillance data were also investigated, as was concomitant treatment with topiramate.. No symptomatic renal calculi were reported during four randomized double-blind, placebo-controlled trials involving 848 subjects (including 498 zonisamide recipients) treated for up to 3 months. In long-term extension studies with treatment for up to 24 months, symptomatic renal calculi were reported in 9/626 (1.4%) patients. Pooled safety data from all US/European clinical trials identified 15/1296 (1.2%) patients with symptomatic renal calculi during treatment for up to 8.7 years. Post-marketing surveillance revealed nine cases from 59 667 patient-years of exposure in the USA, and 14 from 709 294 patient-years of exposure in Japan; only one case occurred during concomitant topiramate and zonisamide treatment. No imbalance in electrolyte levels was found from 35 patients receiving such co-treatment in clinical trials.. The available data suggest that the risk of developing renal calculi during zonisamide treatment is low. Data are insufficient to determine whether concomitant treatment with topiramate increases the risk of renal stones.

Topics: Adolescent; Adult; Anticonvulsants; Child; Double-Blind Method; Epilepsy; Female; Fructose; Humans; Isoxazoles; Kidney Calculi; Male; Middle Aged; Placebos; Product Surveillance, Postmarketing; Topiramate; Ultrasonography; Zonisamide

A double-blind, dose-controlled study evaluated topiramate as monotherapy in 470 patients with newly diagnosed (< or = 3 months) epilepsy or epilepsy relapse in the absence of therapy. In addition to having at least 2 lifetime-unprovoked seizures, patients had 1 or 2 partial-onset seizures or generalized-onset tonic-clonic seizures during a 3-month retrospective baseline. The trial included a large cohort (N = 151, 32%) of children and adolescents 6 to 15 years of age. Eligible patients were randomized to treatment groups in which topiramate was titrated to target maintenance dosages of either 400 mg/day (n = 77) or 50 mg/day (n = 74). Patients were followed for at least 6 months. Based on Kaplan-Meier analyses, the primary efficacy endpoint of time to first seizure favored the higher topiramate dose in both the overall population and the cohort of children/adolescents. The probability that children/adolescents remaining in the study were seizure free at 6 months was 78% in the 50-mg target dose group and 90% with the higher dose. At 12 months, the probability of being seizure free was 62% and 85%, respectively. The incidence of treatment-limiting adverse events was 4% in the 50-mg target dose group and 14% in the group assigned to 400 mg as a target dose. The most common adverse events, excluding typical childhood illnesses, were headache, appetite decrease, weight loss, somnolence, dizziness, concentration/attention difficulty, and paresthesia. As shown in this subset analysis, topiramate is effective and well tolerated as monotherapy in children and adolescents.

Topics: Adolescent; Anticonvulsants; Child; Cohort Studies; Dose-Response Relationship, Drug; Double-Blind Method; Electroencephalography; Epilepsy; Female; Fructose; Humans; International Cooperation; Male; Retrospective Studies; Topiramate; Treatment Outcome

To determine whether levetiracetam (LEV) affects plasma concentrations of carbamazepine, valproic acid, topiramate, and lamotrigine in children with epilepsy.. The potential for interaction of LEV with other antiepileptic drugs (AEDs) was assessed using plasma drug levels obtained in a randomized placebo-controlled phase III trial of adjunctive LEV in children receiving one or two concomitant AEDs. Multiple plasma AED levels at baseline and during adjunctive treatment with LEV or placebo were compared by repeated measures analysis of covariance and mean concentration ratios (treatment/baseline) were estimated with their 90% confidence intervals (CI).. The study population included 187 children receiving any concomitant AED alone or in combination. The geometric mean concentrations at baseline and during LEV treatment were carbamazepine 8.4 microg/ml versus 8.1 microg/ml (coefficient of variation, CV = 30%; n = 35); valproic acid 83.8 versus 82.5 microg/ml (CV = 38%; n = 23); topiramate 7.3 versus 7.2 microg/ml (CV = 82%; n = 28); lamotrigine 8.2 versus 7.7 microg/ml (CV = 62%; n = 22). For each AED, the mean concentration ratios (LEV/baseline) and their 90% CIs showed that AED concentrations were unaffected by concomitant LEV administration. No differences were observed between LEV and placebo.. LEV does not affect plasma concentrations of carbamazepine, valproic acid, topiramate, or lamotrigine in children with epilepsy.

Topics: Adolescent; Anticonvulsants; Carbamazepine; Child; Child, Preschool; Drug Interactions; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Lamotrigine; Levetiracetam; Male; Outcome Assessment, Health Care; Piracetam; Placebos; Topiramate; Triazines; Valproic Acid

The aim of the present work was to assess the efficacy and tolerance of topiramate (Topamax) in patients of different ages with different types of epilepsy. This agent was used as monotherapy and combined therapy in 114 patients (53 male, 61 female) of the following age groups: early childhood (16), preschool and school age (20), pubertal (16), young (23), adult (38), and elderly (1). Treatment produced complete clinical remission in 48% of patients and decreases in fit frequency by more than 50% in 44% of patients. In terms of remission, Topamax was more effective in adolescents, youths and adults than in younger children, and this pattern was also seen in the treatment of symptomatic epilepsy. Tolerance was good in patients of all groups, and cases of side effects (weight loss, irritability, allergic skin reactions, paresthesia) were occasional.

Topics: Adolescent; Adult; Age Factors; Anticonvulsants; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Topiramate; Treatment Outcome

This study focused on (i) evaluating the long-term tolerability and safety of topiramate in Chinese patients with epilepsy, and (ii) comparing the tolerability and safety of topiramate monotherapy versus polytherapy in the same population.. This was a prospective, open-label, long-term (36 months) clinical trial. 320 patients (275 adults and 45 children) with epilepsy were recruited into the study; of these, 156 patients had generalised seizures, 151 patients had partial seizures and 13 patients had unclassifiable seizures. All patients received topiramate approximately 200 mg/day either as monotherapy or as adjunctive therapy. At each visit, a physical examination and routine laboratory analysis were performed, and the adverse event (AE) profile was obtained by face-to-face interview.. 268 patients received topiramate

Topics: Adolescent; Adult; Anticonvulsants; Child; China; Dizziness; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Longitudinal Studies; Male; Memory Disorders; Paresthesia; Prospective Studies; Topiramate; Weight Loss

We analysed patients with focal epilepsies treated with zonisamide (ZNS) as add-on treatment to topiramate (TPM) and other antiepileptic drugs (mean 2). Twenty-five patients were evaluated, and follow-up data were available in 19 (12 women, seven men, mean age 34 years). The mean time until first follow-up investigation was 17 weeks. At that point in time the mean ZNS dosage was 344 mg and mean TPM dosage was 398 mg. Eight patients (42%) achieved seizure frequency reduced by at least 50%. Six patients (31%) reported side effects, especially cognitive impairment and weight loss (>5 kg) in two patients. In the further course of treatment, ZNS was discontinued in two of three patients because of cognitive impairment. We conclude that add-on treatment including ZNS and TPM can not be recommended for chronic treatment of epilepsy.

Topics: Adult; Aged; Anticonvulsants; Child; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Isoxazoles; Male; Middle Aged; Pilot Projects; Topiramate; Treatment Outcome; Zonisamide

To compare clinicians' choice of one of the standard epilepsy drug treatments (carbamazepine or valproate) versus appropriate comparator new drugs.. A clinical trial comprising two arms, one comparing new drugs in carbamazepine and the other with valproate.. A multicentre study recruiting patients with epilepsy from hospital outpatient clinics.. Patients with an adequately documented history of two or more clinically definite unprovoked epileptic seizures within the last year for whom treatment with a single antiepileptic drug represented the best therapeutic option.. Arm A was carbamazepine (CBZ) versus gabapentin (GBP) versus lamotrigine (LTG) versus oxcarbazepine (OXC) versus topiramate (TPM). Arm B valproate (VPS) versus LTG versus TPM.. Time to treatment failure (withdrawal of the randomised drug for reasons of unacceptable adverse events or inadequate seizure control or a combination of the two) and time to achieve a 12-month remission of seizures. Time from randomisation to first seizure, 24-month remission of seizures, incidence of clinically important adverse events, quality of life (QoL) outcomes and health economic outcomes were also considered.. Arm A recruited 1721 patients (88% with symptomatic or cryptogenic partial epilepsy and 10% with unclassified epilepsy). Arm B recruited 716 patients (63% with idiopathic generalised epilepsy and 25% with unclassified epilepsy). In Arm A LTG had the lowest incidence of treatment failure and was statistically superior to all drugs for this outcome with the exception of OXC. Some 12% and 8% fewer patients experienced treatment failure on LTG than CBZ, the standard drug, at 1 and 2 years after randomisation, respectively. The superiority of LTG over CBZ was due to its better tolerability but there is satisfactory evidence indicating that LTG is not clinically inferior to CBZ for measures of its efficacy. No consistent differences in QoL outcomes were found between treatment groups. Health economic analysis supported LTG being preferred to CBZ for both cost per seizure avoided and cost per quality-adjusted life-year gained. In Arm B for time to treatment failure, VPS, the standard drug, was preferred to both TPM and LTG, as it was the drug least likely to be associated with treatment failure for inadequate seizure control and was the preferred drug for time to achieving a 12-month remission. QoL assessments did not show any between-treatment differences. The health economic assessment supported the conclusion that VPS should remain the drug of first choice for idiopathic generalised or unclassified epilepsy, although there is a suggestion that TPM is a cost-effective alternative to VPS.. The evidence suggests that LTG may be a clinical and cost-effective alternative to the existing standard drug treatment, CBZ, for patients diagnosed as having partial seizures. For patients with idiopathic generalised epilepsy or difficult to classify epilepsy, VPS remains the clinically most effective drug, although TPM may be a cost-effective alternative for some patients. Three new antiepileptic drugs have recently been licensed in the UK for the treatment of epilepsy (levetiracetam, zonisamide and pregabalin), therefore these drugs should be compared in a similarly designed trial.

Topics: Adult; Amines; Anticonvulsants; Carbamazepine; Cyclohexanecarboxylic Acids; Epilepsy; Female; Fructose; Gabapentin; gamma-Aminobutyric Acid; Health Status Indicators; Humans; Lamotrigine; Male; Oxcarbazepine; Topiramate; Treatment Outcome; Triazines; Valproic Acid

The present controlled study aims to evaluate topiramate (TPM) effect on total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein, very low-density lipoprotein, apolipoproteins A1, B and lipoprotein (a). Seventy patients in evolving age suffering from various types of epilepsy, treated with TPM, (age range: 6 months-22 years) were evaluated before and after 12 months of treatment and compared with 110 sex- and age-matched subjects. At baseline, no significant difference was present between controls and children treated with TPM. After a year, the BMI did not show significant change in adults and remained into respective growth curve. No significant difference in lipids and lipoproteins neither between first and second evaluation nor between patients and controls was found. Some intra-group variation has been noticed: whilst controls maintained similar levels, the 70 patients on TPM monotherapy showed a slight decrease in TC, triglycerides and HDL. These fluctuations, however, occurred in the normal range so neither dietary nor pharmacological treatment of hyperlipidaemia after a year of TPM was necessary.

Topics: Adolescent; Adult; Age Factors; Anticonvulsants; Apolipoproteins; Child; Child, Preschool; Cholesterol; Dyslipidemias; Epilepsy; Female; Fructose; Humans; Infant; Lipids; Lipoprotein(a); Lipoproteins; Lipoproteins, HDL; Lipoproteins, LDL; Male; Prospective Studies; Time; Topiramate; Treatment Outcome

This study was performed to evaluate carnitine deficiency in a large series of epilepsy children and adolescents treated with old and new antiepileptic drugs with or without ketogenic diet. Plasma free carnitine was determined in 164 epilepsy patients aged between 7 months and 30 years (mean 10.8 years) treated for a mean period of 7.5 years (range 1 month-26 years) with old and new antiepileptic drugs as mono or add-on therapy. In 16 patients on topiramate or lamotrigine and in 11 on ketogenic diet, plasma free carnitine was prospectively evaluated before starting treatment and after 3 and 12 months, respectively. Overall, low plasma levels of free carnitine were found in 41 patients (25%); by single subgroups, 32 out of 84 patients (38%) taking valproic acid and 13 of 54 (24%) on carbamazepine, both as monotherapy or in combination, showed low free carnitine levels. A higher though not statistically significant risk of hypocarnitinemia resulted to be linked to polytherapy (31.5%) versus monotherapy (17.3%) (P=.0573). Female sex, psychomotor or mental retardation and abnormal neurological examination appeared to be significantly related with hypocarnitinemia, as well. As to monotherapy, valproic acid was associated with a higher risk of hypocarnitinemia (27.3%) compared with carbamazepine group (14.3%). Neither one of the patients on topiramate (10), lamotrigine (5) or ketogenic diet (11) developed hypocarnitinemia during the first 12 months of treatment. Carnitine deficiency is not uncommon among epilepsy children and adolescents and is mainly linked to valproate therapy; further studies are needed to better understand the clinical significance of serum carnitine decline.

Topics: Adolescent; Adult; Anticonvulsants; Carbamazepine; Carnitine; Child; Child, Preschool; Dietary Fats; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Infant; Ketosis; Lamotrigine; Male; Prospective Studies; Risk Factors; Topiramate; Triazines; Valproic Acid

Outcomes research emphasizes patient self-assessment and preferences in optimizing treatment. We previously showed that lamotrigine produces significantly less cognitive and behavioral impairment compared with topiramate. In the current study we extend these observations to subject self-report of preference for lamotrigine or topiramate independent of potentially confounding effects of seizures or seizure control. Additionally, drug preference was related to effects of lamotrigine and topiramate on objective neuropsychological tests as well as self-perception on behavioral instruments.. Thirty-seven healthy volunteers completed a double-blind, randomized crossover design incorporating two 12-week treatment periods of lamotrigine and topiramate each titrated to a dose of 300 mg/day. Evaluation of 23 objective neuropsychological and 15 subjective behavioral measures occurred at four times: pretreatment baseline, first treatment, second treatment, and posttreatment baseline. Preference for lamotrigine or topiramate was assessed, while blinding was maintained, at the final study visit when each subject was asked which drug he or she would prefer to take.. A large majority (70%) preferred lamotrigine, 16% stated preference for topiramate, and 14% had no preference (drugs equivalent). Consistent with preference, those preferring lamotrigine performed better on 19 of 23 objective and 13 of 15 subjective behavioral measurements while on lamotrigine. Inconsistent with preference, subjects preferring topiramate performed better on 19 of 23 objective and 9 of 15 subjective behavioral measures while on lamotrigine. Topiramate preference also did not correlate with IQ, serum concentration, body mass index, age, or gender. Topiramate preference did relate to responses on the Profile of Mood States.. Lamotrigine was preferred by the majority of subjects, congruent with objective neuropsychological and subjective behavioral measures. In contrast, for those stating a preference for topiramate the results on objective neuropsychological measures were impaired while fewer complaints were noted on the Profile of Mood States. This suggests that preference for topiramate may be determined by an effect on mood.

Topics: Adult; Anticonvulsants; Attention; Behavior; Cognition; Cross-Over Studies; Double-Blind Method; Epilepsy; Female; Fructose; Humans; Lamotrigine; Male; Memory; Middle Aged; Neuropsychological Tests; Patient Satisfaction; Quality of Life; Topiramate; Triazines

The present study was conducted to evaluate the long-term effects of low-dose topiramate (TPM) monotherapy on the cognitive function of epilepsy patients. Forty-seven epilepsy patients received TPM, with target doses of 50, 75, and 100 mg/day. Cognitive tests were performed twice, at baseline and 1 year after starting medication. Thirty-six patients completed the follow-up neuropsychological tests. After a year of treatment, 16 patients (44%) complained of cognitive problems. Although it improved seizure frequency and EEG abnormalities, TPM had significantly negative effects on the digit span and verbal fluency tests. These cognitive effects were dose-related and significantly improved after withdrawal from TPM and substitution with older antiepileptic drugs. In conclusion, even at a low dose, TPM has long-term, negative effects on working memory and verbal fluency.

Topics: Adolescent; Adult; Anticonvulsants; Cognition; Epilepsy; Female; Follow-Up Studies; Fructose; Humans; Male; Memory; Middle Aged; Neuropsychological Tests; Prospective Studies; Topiramate

To compare the cognitive effects of lamotrigine vs topiramate as adjunctive therapy in adults with epilepsy.. A multicenter, double-blind, randomized, prospective study was conducted in adults with partial seizures. Lamotrigine or topiramate was introduced as an adjunctive therapy to carbamazepine or phenytoin and titrated over 8 weeks to target doses. These drugs were maintained another 8 weeks (maintenance phase) without dosage changes. The primary endpoint was change from screening to the end of the maintenance phase in a combined analysis of standardized measures of cognition (Controlled Oral Word Association Task [COWA]; Stroop Color-Word Interference; Digit Cancellation; Lafayette Grooved Pegboard, dominant hand; Rey Auditory Verbal Learning Test, delayed recall; and Symbol-Digit Modalities test).. For the primary endpoint, cognitive performance at the end of the maintenance phase was better with lamotrigine than with topiramate (415.3 vs 315.1; p < 0.001). On the individual cognitive tests, performance was better with lamotrigine than with topiramate in mean changes from screening on the COWA (p < 0.001), Stroop Color-Word Interference (p = 0.038), and Symbol-Digit Modalities tests (p < 0.001). The treatment effect exceeded the minimum clinically important difference for the COWA and the Symbol-Digit Modalities test. Mean changes from screening in the Performance-On-Line test simulating driving skills reflected better performance with lamotrigine than with topiramate (p = 0.021). The median percentage change from baseline in seizure frequency was lower with lamotrigine than with topiramate during the escalation phase (-80% vs -100%; p = 0.028) but not during the maintenance phase (-75% vs -100%; p = 0.062). The frequencies of cognitive adverse events and of premature withdrawals related to cognitive decline were higher with topiramate than with lamotrigine (6% vs 0%; p = 0.013).. Lamotrigine had significantly less impact than topiramate on measures of cognition when used as adjunctive therapy for partial seizures.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Cognition; Double-Blind Method; Epilepsy; Female; Fructose; Humans; Lamotrigine; Male; Prospective Studies; Topiramate; Treatment Outcome; Triazines

Adverse effects are the most common cause for failure of an antiepileptic drug (AED), especially when an AED is added to existing therapy. With the increased drug load, it may not be possible to titrate the newly added AED to effective doses. Reducing the dosage of AED cotherapy as the new drug is introduced may improve tolerability.. To evaluate reduction of AED cotherapy as a strategy to improve tolerability and patient retention when a new AED is added to existing therapy.. In a 20-week, randomized, open-label study, topiramate was initiated as add-on therapy in adults and adolescents (> or =12 y of age) with inadequately controlled partial-onset seizures. Patients were randomized to receive treatment in which adverse events could be managed by adjustments in AED cotherapy (flex-dose group) or treatment in which AED cotherapy dosages remained fixed (fixed-dose group). Topiramate could be adjusted as needed in both groups. In the flex-dose group, patients exited randomized treatment when topiramate was discontinued. In the fixed-dose group, patients exited when AED cotherapy was reduced due to adverse events or when topiramate was discontinued. The primary study outcome was the percentage of patients exiting randomized treatment due to adverse events.. The flex-dose group comprised 297 patients; 302 patients were in the fixed-dose group. Significantly fewer patients in the flex-dose group exited the study due to adverse events (16% vs 23% in the fixed-dose group; p = 0.02). In the flex-dose group, 10% (17 of 168) of patients discontinued topiramate due to adverse events after AED cotherapy was reduced versus 22% (29 of 129) when AED cotherapy was not reduced.. Reduction of AED cotherapy is a useful strategy to improve tolerability and retention when topiramate is initiated as adjunctive therapy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Child; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Topiramate

To study the effectiveness of topiramate (TPM) in refractory epilepsy in patients who have intellectual disability (ID).. A representative population sample of 57 patients with ID (age range 2-61, mean 32.8) was administered add-on TPM for drug-refractory epilepsy.. Seizure freedom for at least for 6 months was attained by 10 (17%), and seizure reduction of > or = 50% by further 26 (46%). Less than 50% decrease in seizure frequency was found in 16 (29%). TPM was more efficacious in localisation-related than in generalised epilepsies (81% vs. 50%, P=0.019). An at least 50% decrease in seizure frequency was achieved by patients with temporal lobe epilepsy in 100%, continuous spike-waves during sleep syndrome in 75%, Lennox-Gastaut syndrome in 52%, and those with infantile spasms in 25% of cases. As great decrease in seizure frequency was found in most patients with cortical dysplasia (83%), acquired encephalopathy with mesial temporal sclerosis (MTS) (75%), and genetic disease associated with MTS (66%). Adverse effects occurred in 10% including two (3%) with seizure aggravation and three (5%) necessitating discontinuation.. TPM is an effective antiepileptic drug which is of value in treating people with seizures that are resistant to other antiepileptic medication. As a broad-spectrum drug it may substitute for polypharmacy and, at the same time decrease adverse effects and costs of therapy.

Topics: Adult; Anticonvulsants; Brain; Electroencephalography; Epilepsy; Female; Follow-Up Studies; Fructose; Humans; Intellectual Disability; Magnetic Resonance Imaging; Male; Middle Aged; Periodicity; Retrospective Studies; Topiramate

Studies of the efficacy of topiramate (TPM) in infants and young children are few. Here we report an open, prospective, and pragmatic study of effectiveness of TPM in terms of epilepsy syndromes, in children aged less than 2 years. The median follow-up period was 11 months. We enrolled 59 children in the study: 22 affected by localization-related epilepsy (LRE), 23 by generalized epilepsy, six by Dravet's syndrome, and eight with unclassifiable epilepsy. TPM was effective (responders showed a decrease of more than 50% in seizure frequency) in 47% of patients, including 13% who were seizure-free at the last visit. TPM was more effective in localization-related epilepsy (48% of responders) than in generalized epilepsy (32% of responders). In the latter group, 19 patients suffered from infantile spasms. Four of six patients with cryptogenic infantile spasms became seizure-free. Of the 13 patients with symptomatic infantile spasms, only one was seizure-free. Results were poor for patients with Dravet's syndrome. In general, TPM was well tolerated. The most frequently reported adverse effects were drowsiness, irritability, hyperthermia, and anorexia. The present study concludes that TPM is effective for a broad range of seizures in infants and young children and represents a valid therapeutic option in this population.

Topics: Anorexia; Anticonvulsants; Epilepsy; Female; Fever; Follow-Up Studies; Fructose; Humans; Infant; Infant, Newborn; Male; Retrospective Studies; Sleep Stages; Spasm; Topiramate; Treatment Outcome

Mood-modulating profiles of antiepileptic drugs (AEDs) have been classified by Ketter, Post, and Theodore [Neurology 1999; 53 (5, Suppl. 2) S53-76] into two classes: the first class is assumed to have deactivating effects related to GABA potentiation, and the second class is assumed to have activating effects that are associated with glutamate attenuation. We tested this hypothesis by reviewing the multiple mechanisms of action of topiramate (TPM) and levetiracetam (LEV) together with clinical behavioral side effects of patients who had been treated with TPM and LEV in a tertiary referral center for epilepsy. We found LEV to manifest activating and deactivating side effects equally and TPM to act as a deactivating AED, with tiredness/sleepiness side effects being predominant. TPM, in comparison to LEV, was found to be associated with a high incidence of side effects. Testing the hypothesis of Ketter et al. (1999) the deactivating effects of TPM may be coupled to a predominance of potentiation of GABA, but the oversimplified basis of the model needs to be acknowledged.

Topics: Adult; Anticonvulsants; Chi-Square Distribution; Demography; Drug Therapy, Combination; Epilepsy; Female; Follow-Up Studies; Fructose; gamma-Aminobutyric Acid; Glutamic Acid; Humans; Levetiracetam; Male; Middle Aged; Models, Biological; Mood Disorders; Odds Ratio; Piracetam; Time Factors; Topiramate

Whereas the efficacy of the newer antiepileptic drugs (AEDs) is well established, there remain questions regarding their cognitive side effects. Therefore, we performed a comparative open randomized trial with TPM and TGB as add-on therapy, with particular consideration of cognition, mood, and health-related quality of life (HRQOL).. Forty-one patients with refractory epilepsy were randomly assigned to one of the two treatment groups (TPM vs TGB) and received neuropsychological testing at baseline (T1), after titration (3 months, T2), and during the maintenance phase (another 3 months, T3). Tests included measures of intelligence, attention, working memory, episodic memory, language, and self-report questionnaires regarding mood and HRQOL. Twenty patients (8 TPM, 12 TGB) discontinued the trial for different reasons (no group difference).. Seizure outcome (intention-to-treat analysis) was comparably good in both groups (8.1% seizure free, 29.7% seizure reduction>50%). From baseline to after the titration paired sample t tests revealed significant deterioration in verbal fluency, language comprehension, working memory, and visual block tapping under TPM and a deterioration in verbal memory (delayed free recall) in the TGB group. These functions remained stable in the maintenance phase. Self-report measures initially indicated concerns about AED side effects in both groups and concerns about worse cognitive functioning and depression under TPM. In the maintenance phase the TGB group reported feeling a lack of energy, whereas patients on TPM demonstrated improvement on all QOLIE scales on a descriptive level.. This study demonstrates the comparable efficacy of TPM and TGB. Consistent with previous reports, TPM but not TGB appears to be associated with persistent negative cognitive side effects on frontal lobe-associated functions, the degree of which may be estimated by the fact that this effect was observed with a very small sample size. In contrast, in patients taking TPM, initially negatively affected HRQOL returns to baseline in the long run on a descriptive level. The latter finding may be interpreted in accordance with the observation that objective performance and subjective self-report under TPM can be dissociated.

Topics: Adolescent; Adult; Anticonvulsants; Attention; Cognition Disorders; Drug Evaluation; Epilepsy; Female; Fructose; Humans; Intelligence; Male; Memory, Short-Term; Middle Aged; Mood Disorders; Neuropsychological Tests; Nipecotic Acids; Tiagabine; Topiramate; Treatment Outcome; Verbal Behavior

Topiramate was assessed in an open-label trial as broad-spectrum antiepileptic monotherapy, independently from the epilepsy type or syndrome. Adults and children aged 2 years and older, who were diagnosed with epilepsy within the last 5 years, treatment-naive or failing prior treatment with one antiepileptic drug (AED), received individually adjusted doses of topiramate, after escalation to 100mg/day over 4 weeks (maximum 400mg/day) or 3mg/kg/day over 6 weeks (maximum 9 mg/kg/day), respectively. Patients were followed for >or=7 months and optionally up to a maximum of 13 months. Data were analysed for all patients (n=692), as well as for focal (n=421) and generalized epilepsies (n=148). The median topiramate dose used was 125 mg/day in adults and 3.3mg/kg/day in children (or=50% reduction in mean monthly seizure frequency. Patients with focal and generalized epilepsies alike responded to treatment (73.9 and 83.8% with at least 50% seizure reduction): 39.4% of patients with focal epilepsy and 61.5% of those with generalized epilepsy were seizure-free. The mean monthly seizure frequency was significantly reduced versus baseline at all visits (p<0.001). Similar response rates were obtained from the 237 patients completing the 1-year observation period. During the mandatory 7-month period of study, 8.8% of patients reported insufficient tolerability as a reason for dropout. The most frequent adverse event was paraesthesia. Our results support findings that emerge from controlled studies that topiramate is effective and well tolerated when used as initial or second monotherapy. They also suggest that in a naturalistic setting, overall good retention on treatment and seizure freedom are observed at low doses in a broad spectrum of epilepsies.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Anticonvulsants; Body Weight; Child; Child, Preschool; Epilepsy; Female; Fructose; Humans; Infant; Male; Middle Aged; Patient Satisfaction; Topiramate

The relative cognitive and behavioral effects of lamotrigine (LTG) and topiramate (TPM) are unclear.. The authors directly compared the cognitive and behavioral effects of LTG and TPM in 47 healthy adults using a double-blind, randomized crossover design with two 12-week treatment periods. During each treatment condition, subjects were titrated to receive either LTG or TPM at a target dose of 300 mg/day for each. Neuropsychological evaluation included 17 measures yielding 41 variables of cognitive function and subjective behavioral effects. Subjects were tested at the end of each antiepileptic drug (AED) treatment period and during two drug-free conditions (pretreatment baseline and 1 month following final AED withdrawal).. Direct comparison of the two AEDs revealed significantly better performance on 33 (80%) variables for LTG, but none for TPM. Even after adjustment for blood levels, performance was better on 19 (46%) variables for LTG, but none for TPM. Differences spanned both objective cognitive and subjective behavioral measures. Comparison of TPM to the non-drug average revealed significantly better performance for non-drug average on 36 (88%) variables, but none for TPM. Comparison of LTG to non-drug average revealed better performance on 7 (17%) variables for non-drug average and 4 (10%) variables for LTG.. Lamotrigine produces significantly fewer untoward cognitive and behavioral effects compared to topiramate (TPM) at the dosages, titrations, and timeframes employed in this study. The dosages employed may not have been equivalent in efficacy. Future studies are needed to delineate the cognitive and behavioral effects of TPM at lower dosages.

Topics: Adult; Anticonvulsants; Brain; Cognition Disorders; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Epilepsy; Female; Fructose; Humans; Lamotrigine; Male; Memory; Memory Disorders; Middle Aged; Mood Disorders; Neuropsychological Tests; Psychomotor Performance; Reaction Time; Reference Values; Topiramate; Treatment Outcome; Triazines; Verbal Behavior

This study has been conducted to assess the efficacy and safety of topiramate in refractory epilepsies in infants and young children.. A prospective clinical trial was performed in three tertiary care hospitals, on 47 children aged 6-60 months with refractory epilepsy. Topiramate was added to at least two baseline anti-epileptic drugs. The efficacy was rated according to seizure type, frequency and duration.. Children with refractory epilepsy were classified according to their clinical, neuro-imaging, and neurophysiological profile into infantile spasms (IS) (9 cases, 19%), Lennox-Gastaut syndrome (LGS) (25 cases, 53%) and other epilepsies (13 cases, 28%). Children were also classified into cryptogenic and symptomatic epilepsy. Topiramate was introduced as add-on therapy in a daily dose of 1 mg/kg/day for 2 weeks, followed by increments of 1-3 mg/kg/day at 2-week intervals, up to a maximum of 10 mg/kg/day. After a minimum treatment period of 6 months, 28 (60%) of the children had a satisfactory response (completely seizure free, or more than a 50% seizure reduction). The remaining 19 children (40%) had an unsatisfactory response (50% or less reduction in seizure frequency, no change or increased seizure frequency). Topiramate appeared to be equally effective in infantile spasms, Lennox-Gastaut syndrome and children with other types of epilepsy, with no significant difference between those with a satisfactory and an unsatisfactory response (p=0.089). There was also no significant difference in response between patients with cryptogenic and symptomatic epilepsy (p=0.360). Mild to moderate adverse effects, mainly somnolence, anorexia and nervousness, were present in 25 (53%) of children. One of the children developed hypothyroidism.. Although the long term safety and possible adverse effects of topiramate have not been fully established in infants and young children, this study has shown that it is a useful option for children with frequent seizures unresponsive to standard anti-epileptic drugs.

Topics: Child, Preschool; Demography; Drug Administration Schedule; Epilepsy; Female; Fructose; Humans; Infant; Male; Neuroprotective Agents; Prospective Studies; Topiramate; Treatment Outcome

To evaluate the effect of topiramate in elderly patients with onset of epilepsy after the age of 60, treatment-naive or non-responding to an initial antiepileptic drug.. Analysis of patients with epilepsy diagnosed in the preceding 5 years, aged>/=65 years (n=43), enrolled in a larger open-label trial (n=692). After titration to topiramate 100 mg/day over 4 weeks, the dose was adjusted according to individual response (maximum 400 mg/day). Patients were followed up for at least 7 months.. After 7 months, 79% of patients remained in the study. Seizure frequency decreased significantly vs baseline (P<0.001); >/=50% reduction in seizure frequency was achieved in 87% of patients, 64% remained seizure-free. Both previously treated and naive patients responded. Fourteen per cent dropped out because of insufficient tolerability. No unexpected or unusual adverse events were observed.. The results indicate that elderly patients respond well to topiramate monotherapy. The high patient retention rate reflects a favourable tolerability profile in this population.

Topics: Age of Onset; Aged; Aged, 80 and over; Anticonvulsants; Body Weight; Epilepsy; Female; Fructose; Humans; Male; Prospective Studies; 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

To evaluate the efficacy and tolerability of topiramate as monotherapy, using a dose-controlled study design.. We conducted a multinational, randomized, double-blind trial in adults and children (> or =6 years old) with epilepsy that was not being treated when randomized to 400 or 50 mg/day topiramate as target maintenance dosages. In addition to > or =2 lifetime unprovoked seizures, patients had to have one or two partial-onset seizures or generalized-onset tonic-clonic seizures in the 3-month retrospective baseline. The primary efficacy end point was time to first seizure; a secondary efficacy measure was the seizure-free rate at 6 months and 1 year. Double-blind treatment continued until 6 months after the last patient was randomized.. Kaplan-Meier survival analyses for time to first seizure (intent-to-treat, n = 470) favored 400 mg/day over 50 mg/day (P = 0.0002) as a target maintenance dosage. The first evaluation point with a significant difference (P = 0.046) favoring the higher dose was at day 14 when patients were receiving 100 or 25 mg/day. The probability of being seizure-free at 6 months was 83% in patients randomized to 400 mg/day and 71% in those randomized to 50 mg/day (P = 0.005). Seizure-free rates at 12 months were 76% and 59%, respectively (P = 0.001). Differences favoring the higher dose were significant in patients with partial-onset seizures (P = 0.009) and in those with generalized-onset tonic-clonic seizures (P = 0.005). The most common dose-related adverse events were paresthesia, weight loss, and decreased appetite. Discontinuations due to cognitive-related adverse events were 2% in the 50-mg group and 7% in the 400-mg group. Overall, 7% and 19%, respectively, discontinued with adverse events during the median treatment duration of 9 months.. Topiramate is effective as monotherapy in adults and children. Because a therapeutic effect emerges during titration, clinicians should adjust dosages in step-wise fashion with intermediate stopping points, e.g., 100 mg/day, to evaluate patient response and achieve the optimal maintenance dosage.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Disease-Free Survival; Double-Blind Method; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Topiramate; Treatment Outcome

The relationship between topiramate (TPM) concentration, dosage and adverse events in patients with epilepsy is still controversial. We therefore performed a prospective study in patients with poorly controlled epilepsy treated with TPM, predominantly in combination with other antiepileptic drugs. The goal of the study was to investigate the relationship between the occurrence of adverse events due to TPM and its serum concentration or dosage, respectively.. The relationship between the occurrence of adverse events and TPM serum concentration or dosage, respectively, was examined in a group of 42 young adult and adult patients with poorly controlled epilepsy. Within 22 months, all patients treated with TPM had been included in the study. The 8 adverse events occurring most frequently (difference > or = 10%) in TPM-treated patients in 5, double-blind, placebo-controlled, parallel group studies, were checked regularly. This side effect profile has been presented by Reife et al. (1995a). Other possible or probable adverse events were also documented.. The difference in TPM serum concentrations and TPM dosages (mg/kg) for patients without an adverse event, and patients with a given adverse event was statistically significant for "abnormal thinking, impaired concentration, weight loss, dizziness, speech problems, somnolence, ataxia, increased seizure frequency and paresthesia". To avoid adverse events, we recommend an initial "maintenance serum concentration" of below 4 microg/mL. As regards the TPM dosage, our results suggest initial maintenance dosages of 100 TPM or lower, 1.5 mg/kg or lower, respectively. These conclusions are limited by the relatively small number of patients.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Cognition; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Logistic Models; Male; Middle Aged; Prospective Studies; Topiramate

To evaluate the efficacy and tolerability of topiramate in children with epilepsy younger than 2 years of age, we retrospectively reviewed the records of patients treated at our institution between 2001 and 2003. Thirteen children ages 5 to 23 months, five boys and eight girls, were identified. Seizure types were partial (five), generalized tonic-clonic (three), myoclonic (one), and infantile spasms (four). The mean age at seizure onset was 9.7 months. Topiramate was started at a mean age of 11.4 months (4-23 months). The number of antiepileptic drugs prior to topiramate therapy ranged from zero to four. One patient had been on the ketogenic diet. Topiramate was used as monotherapy in seven children and as polytherapy in six children. Mean follow-up was 14 months. The mean dose of topiramate was 8.8 mg/kg/day (2.5-18 mg/kg/day). The degree of seizure reduction was as follows: > 75% in five (38.5%) children, 50% to 75% in three (23%) children, and 0 to 25% in five (38.5%) children. Three of four (75%) patients with infantile spasms had a > 75% reduction in seizures. Adverse effects occurred in two children, including lethargy, hyperthermia, and anorexia. In children younger than 2 years of age, for whom the antiepileptic drug armamentarium is limited, topiramate appears to be an efficacious and safe therapeutic alternative for a variety of seizure types.

Topics: Age Factors; Anticonvulsants; Dose-Response Relationship, Drug; Epilepsy; Female; Fructose; Humans; Infant; Male; Retrospective Studies; Topiramate

This study aimed to evaluate the long-term efficacy and safety of topiramate in treating children with drug-resistant epilepsy. A multicentric, retrospective, open-label, add-on study was undertaken of 277 children (mean age 8.4 years; range 12 months to 16 years) affected by drug-resistant epilepsy. The efficacy was rated according to the seizure types and epilepsy syndrome. After a mean period of 27.5 months of treatment (range 24-61 months), 11 patients (4%) were seizure free and 56 (20%) had more than 50% reduction in seizure frequency. The efficacy of topiramate treatment was noted in localization-related epilepsy and in generalized epilepsy. In addition, in a group of 114 patients, we compared the initial efficacy (evaluated after a mean of 9 months of follow-up) and the retention at a mean of 30 months of topiramate with regard to loss of efficacy (defined as the return to the baseline seizure frequency). Fifty-five (48%) of 114 patients were initial responders. The retention at a mean of 30 months was 23 of 114 patients (20%), 4 of whom (3.5%) were still seizure free. A loss of efficacy occurred in 32 of the 55 initial responders (58%). It was prominent in patients with generalized epilepsy, such as symptomatic infantile spasms and Lennox-Gastaut syndrome, as well as in those with Dravet syndrome. By contrast, a well-sustained topiramate efficacy was noted among patients with localization-related epilepsy. Globally, adverse events were observed in 161 patients (58%) and were mainly represented by weight loss, hyperthermia, sedation, and nervousness, which, in most cases, disappeared after slowing titration or reducing the dosage of the drug. In conclusion, the present long-term study confirms that topiramate represents a useful drug effective in a wide range of seizures and epilepsy syndromes. Moreover, preliminary data seem to suggest that the efficacy of topiramate, when evaluated in the long-term perspective, is more sustained in localization-related epilepsy than in generalized epilepsy.

Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Resistance; Epilepsy; Female; Follow-Up Studies; Fructose; Humans; Infant; Male; Retrospective Studies; Topiramate; Treatment Outcome

Topics: Adolescent; Adult; Aged; Electroencephalography; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Neuroprotective Agents; Topiramate

In a novel double-blind trial, topiramate was compared with the investigator's choice of carbamazepine or valproate as first-line therapy in patients as young as 6 years of age with newly diagnosed epilepsy. Among 613 patients enrolled in the trial, 119 (19%) were children or adolescents (6-16 years of age). No differences between fixed doses of topiramate (100 and 200 mg/day) and carbamazepine (600 mg/day) or valproate (1250 mg/day) were observed in efficacy measures: time to exit, time to first seizure, and the proportion of patients who were seizure free during the last 6 months of treatment. Topiramate 100 mg/day (2.0 mg/kg/day in this study population) was associated with the fewest discontinuations owing to side effects. Based on efficacy and tolerability, the recommended target dose for topiramate as first-line therapy in children and adolescents is 100 mg/day.

Topics: Adolescent; Anticonvulsants; Carbamazepine; Child; Dose-Response Relationship, Drug; Double-Blind Method; Drug Tolerance; Epilepsy; Female; Fructose; Humans; Male; Topiramate; Valproic Acid

For the treatment of patients with chronic refractory epilepsies, information about the long-term efficacy and safety profile of any new antiepileptic drug is crucial. Topiramate has been proven to be effective in patients with refractory chronic partial epilepsies in short-term controlled clinical trials, but the long-term retention, long-term efficacy, and long-term side-effect profile have not been sufficiently investigated. We analyzed all patients who had been treated with topiramate in the Epilepsy Centre Kempenhaeghe from the introduction of the drug in the spring of 1993 up to a final assessment point in mid-2002. In total, 470 patients were identified. The data show that the clinical dose achieved was about 200mg/day, reached after approximately 6 months of treatment. Further dose escalation in the survivors was slow, with a mean dose of about 300 mg/day after 24 months of treatment. Mean titration dose is 25mg/week, but titration strategy is mostly individual and responds to patient complaints. With respect to seizure frequency, 10-15% of the patients were seizure-free at the 6-month evaluation; 4 patients achieved a 2-year remission. Retention rate was 53% after 1 year, 45% after 2 years, 38% after 3 years, and 30% after 4 years. At 4 years, almost 70% of the patients had discontinued topiramate. The main reason was adverse events, which accounted for about 65% of the discontinuations. Behavioral side effects were dominant, with mental slowing (27.6%), dysphasia (16.0%), and mood problems (agitation: 11.9%) being the most frequently reported side effects. In about 10% of the patients side effects led to discontinuation despite the obvious favorable effects on seizure frequency. Comparisons between the patients who discontinued topiramate treatment and those who continued topiramate showed that discontinuation was associated with comedication (vigabatrin and lamotrigine). Our conclusion is that TPM is associated with a high incidence of side effects in clinical practice, affecting long-term retention. Meaningful prognostic factors that may help us in clinical decision making, i.e., to prevent the side effects or to help us identify those at risk, have not been found.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Child; Child, Preschool; Drug Administration Schedule; Epilepsy; Female; Fructose; Humans; Infant; Longitudinal Studies; Male; Middle Aged; Retrospective Studies; Time Factors; Topiramate; Treatment Outcome

To study the pharmacokinetics of topiramate (TPM) at steady state in children younger than 4 years comedicated with other antiepileptic drugs (AEDs).. Twenty-two children aged 6 months to 4 years with pharmacoresistant partial or generalized epilepsy were enrolled in an open-label prospective study. Children were assigned to different groups according to comedication with enzyme-inducing AEDs (n = 8), valproic acid (VPA) (n = 6), or other AEDs not known to affect drug metabolism (neutral AEDs, n = 7). One child was receiving treatment with both enzyme-inducing AEDs and VPA. After dose titration, blood samples were collected at steady state just before and 0.5, 1, 1.5, 2, 4, 6, 8, and 12 h after the morning dose of TPM. Pharmacokinetic parameters were determined by a noncompartmental method.. TPM apparent oral clearance (CL/F) was significantly higher in children taking enzyme-inducing AEDs (85.4 +/- 34.0 ml/h/kg) than in those receiving VPA (49.6 +/- 13.6 ml/h/kg) or neutral AEDs (46.5 +/- 12.8 ml/h/kg). Conversely, dose-normalized areas under the plasma TPM concentration curves (0-12 h) were significantly lower in enzyme-induced patients than in patients receiving VPA or other AEDs.. Compared with children not receiving enzyme inducers, children younger than 4 years who receive concomitant enzyme-inducing AEDs need higher doses (milligrams per kilogram) to achieve comparable plasma TPM concentrations.

Topics: Age Factors; Anticonvulsants; Area Under Curve; Biological Availability; Child, Preschool; Drug Administration Schedule; Drug Therapy, Combination; Epilepsy; Female; Fructose; Half-Life; Humans; Infant; Male; Prospective Studies; Topiramate; Valproic Acid

Topiramate is an effective treatment for several types of seizures. The aim of this study is to assess the efficacy and tolerability of slow topiramate dose titration as add-on therapy in childhood epilepsy. This investigation is a prospective open-label, single-center, add-on study in 22 children with a diagnosis of refractory epilepsy. Topiramate (dose 0.5-2 mg/kg/day) was titrated at 2-week intervals up to the recommended dose of 6-12 mg/kg/day. Seizure frequency rate reduction was significant, declining from 23 +/- 5.1 seizures/week (mean +/- S.E.M.) at baseline phase to 3.5 +/- 1.2 seizures/week at the end of the 16-week stabilization phase (P < 0.001). After 16 weeks of stabilization, 19 patients (86%) had more than 50% seizure reduction. Seven patients (31%) were 100% seizure-free. Two patients (9%) manifested no improvement; only one patient (5%) did not tolerate the added drug and discontinued topiramate. One patient manifested severe side effects, whereas 21 patients experienced mild to moderate side effects mostly represented by somnolence, nervousness, and anorexia with or without weight loss. We conclude that slow dose titration improves efficacy and tolerability of topiramate as add-on therapy in the treatment in refractory epilepsy.

Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Epilepsies, Partial; Epilepsy; Epilepsy, Tonic-Clonic; Female; Fructose; Humans; Infant; Male; Prospective Studies; Spasms, Infantile; Topiramate; Treatment Outcome

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

We examined predictors of weight loss with topiramate, an anticonvulsant associated with weight loss in adults.. In this uncontrolled, prospective clinical trial, topiramate was added to existing anticonvulsants in adults (40 to 110 kg) with partial-onset seizures. Primary measurements were change from baseline weight after 3 months and 1 year in patients completing 1 year of topiramate treatment (N = 38). Physiological and metabolic measures were analyzed for correlation with weight loss during topiramate treatment.. In patients who completed 1 year of topiramate treatment, baseline weight was reduced in 82% at 3 months and in 86% at 1 year. Mean body weight was reduced 3.0 kg (3.9% of baseline) at 3 months and 5.9 kg (7.3%) at 1 year. In obese patients [body mass index (BMI) >/= 30 kg/m(2)], mean weight loss was 4.2 kg (4.3%) at 3 months and 10.9 kg (11.0%) at 1 year. Weight loss was primarily caused by reduction in body fat mass. For all patients, weight loss at 3 months correlated most strongly with reduced caloric intake (p = 0.02). At 1 year, caloric intake had returned to baseline levels; weight loss correlated most strongly with higher baseline BMI (p = 0.0007).. Our results suggest that weight loss occurs in most adults treated with topiramate and is sustained for at least 1 year. Reduced caloric intake may account, in part, for weight loss during early treatment. The pattern of weight loss differs according to baseline BMI, with obese patients experiencing greater weight loss during continued therapy.

Topics: Adult; Anticonvulsants; Blood Glucose; Body Composition; Body Mass Index; Cholesterol; Energy Intake; Epilepsy; Female; Fructose; Glucose Tolerance Test; Humans; Leptin; Male; Middle Aged; Obesity; Prospective Studies; Regression Analysis; Topiramate; Weight Loss

To evaluate the efficacy and tolerability of topiramate (TPM) as add-on therapy in children less than 12 years of age with refractory epilepsy, according to epilepsy syndromes, we conducted an open, prospective, pragmatic and multicenter study in France. Efficacy was assessed, especially according to epilepsy syndromes, as well as tolerability. We included 207 children (41 of whom were less than 4 years of age). TPM was effective (responders with >50% decrease in seizure frequency) in 50% of 128 patients with partial epilepsy, and in 44% of 79 patients with generalized epilepsy. In case of generalized epilepsy, responders more frequently had generalized symptomatic epilepsy, severe myoclonic epilepsy and myoclono-astatic epilepsy, whereas response rate was mild in both infantile spasms and Lennox-Gastaut syndrome (LGS). Improvement was well maintained in all patients during the treatment period (median 5.6 months). Seizure frequency/severity increased (worsening) in 13% of patients with partial epilepsy and 17% with generalized epilepsy (particularly in those with infantile spasms), and resulted in withdrawal of TPM for 8%. The most frequently reported adverse events were moderate neurobehavioral and gastrointestinal disorders. Adverse events led to withdrawal of TPM from 13.5% of patients. Children less than 4 years of age had particularly good tolerability. Results confirm that TPM is effective and well tolerated in children under 12 years of age in a broad range of epilepsy syndromes, including refractory partial epilepsy, and symptomatic and myoclonic generalized epilepsy. Use of TPM should be considered in children under 4 years of age, and slow and progressive titration is important.

Topics: Anticonvulsants; Child; Child Behavior Disorders; Child, Preschool; Epilepsy; Female; Fructose; Gastrointestinal Diseases; Humans; Infant; Male; Nervous System Diseases; Prospective Studies; Syndrome; Topiramate; Treatment Outcome

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 determine at steady state (in the same group of patients): (a) the pharmacokinetics (PK) of lamotrigine (LTG) with LTG monotherapy, (b) the PK of LTG concomitantly administered with topiramate (TPM) at three escalating TPM doses (100, 200, and 400 mg/day), (c) the PK of TPM at three escalating TPM doses while receiving fixed-dose LTG therapy, and (d) the PK of TPM with TPM monotherapy.. This was an open-label, sequential, single-group, dose-escalating PK study in which 13 patients with epilepsy not optimally controlled with LTG received stable-dose LTG monotherapy for 2 weeks, followed by stable-dose LTG therapy combined with escalating doses of TPM for

Topics: Adult; Analysis of Variance; Anticonvulsants; Area Under Curve; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Lamotrigine; Male; Middle Aged; Topiramate; Triazines

Topiramate (TPM) is a new antiepileptic drug (AED) that has been found to be associated with a high prevalence of cognitive adverse events (CAEs). The prevalence of psychiatric adverse events (PAEs) has yet to be established. The purpose of this study was to determine the prevalence of PAEs related to TPM when used in polytherapy regimens in a large cohort of adult patients with epilepsy, to identify any association between the occurrences of CAEs and PAEs and to identify predictors of PAEs and CAEs.. Investigators from 16 epilepsy centers (PADS group) prospectively obtained postmarketing safety and efficacy data on 596 patients aged 16 years and older. All data were recorded on standardized data retrieval forms, completed at the initial visit, while follow-up data were obtained every 6 months or at the time of discontinuation.. PAEs were identified in 75 (12.6%) patients: 30 (5%) experienced symptoms of depression and 34 (5.7%) of aggressive behavior and irritability, while 9 patients experienced symptoms of psychosis (1.5%). CAEs were reported by 247 (41.5%) patients. There was a significant association between the occurrences of CAEs and PAEs. A past psychiatric history was a predictor of CAEs, while older age and past psychiatric history were predictors of PAEs.. The use of TPM in polytherapy regimens can cause PAEs and CAEs and their occurrence is significantly correlated. Patients with a past psychiatric history may be at a higher risk for experiencing PAEs and CAEs.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Cognition Disorders; Epilepsy; Female; Fructose; Humans; Male; Mental Disorders; Middle Aged; Prospective Studies; Risk Factors; Topiramate

Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Epilepsy; Female; Fructose; Humans; Infant; Male; Time Factors; Topiramate; Treatment Outcome

The purpose of the study was to evaluate the efficacy and safety of topiramate (TPM) as adjunctive therapy in children, adolescents and young adults with Lennox-Gastaut syndrome (LGS). We performed a prospective open label add-on study in 45 patients (age 4-34 years, mean 15.9 years) with LGS and refractory seizures. TPM was added to one or two other baseline drugs and the efficacy was rated according to seizure type and frequency. TPM was initiated at the daily dose of 0.5-1 mg/kg, followed by a 2-week titration at increments of 1-3 mg/kg/24 h, up to a maximum daily dose of 12 mg/kg. After a mean period of 15.8 months of treatment (range 3-98 months), at a mean dose of 4.1 mg/kg/24 h (range 1.4-12 mg/kg), 18 patients (40%) had a seizure reduction more than 50%. TPM appeared to be effective mainly in major seizures (drop attacks, tonic and tonic-clonic seizures). Mild to moderate adverse events were present in 24 patients (53.3%), mostly represented by drowsiness, nervousness, hyporexia with or without weight loss and cognitive dulling. In conclusion, TPM adjunctive therapy reduced the number of drop attacks and major motor seizures in 40% of patients with LGS and produced only mild or moderate adverse events.

Topics: Adolescent; Adult; Anticonvulsants; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation; Drug Therapy, Combination; Epilepsy; Female; Follow-Up Studies; Fructose; Humans; Italy; Male; Topiramate; Treatment Outcome

Management of seizures in learning disabled people is challenging. This prospective study explored the efficacy and tolerability of adjunctive topiramate (TPM) in patients with learning disability and refractory epilepsy attending a single centre.. Sixty-four patients (36 men, 28 women, aged 16-65 years) were begun on adjunctive TPM after a 3-month prospective baseline on unchanged medication. Efficacy end points were reached when a consistent response was achieved over a 6-month period at optimal TPM dosing. These were seizure freedom or > or =50% seizure reduction (responder). Appetite, behaviour, alertness, and sleep were assessed by caregivers throughout the study.. Sixteen (25%) patients became seizure free with adjunctive TPM. There were 29 (45%) responders. A further 10 (16%) patients experiencing a more modest improvement in seizure control continued on treatment at the behest of their family and/or caregivers. TPM was discontinued in the remaining nine (14%) patients, mainly because of side effects. Final TPM doses and plasma concentrations varied widely among the efficacy outcome groups. Many patients responding well to adjunctive TPM did so on < or =200 mg daily. Mean carer scores did not worsen with TPM therapy.. TPM was effective as add-on therapy in learning-disabled people with difficult-to-control epilepsy. Seizure freedom is a realistic goal in this population.

Topics: Adolescent; Adult; Anticonvulsants; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Learning Disabilities; Male; Middle Aged; Prospective Studies; Topiramate; Treatment Outcome

The authors assessed the effect of concomitant antiepileptic therapy on steady-state plasma concentrations of the new antiepileptic drug (AED) topiramate and the potential relation between topiramate plasma levels and side effects in a cohort of 116 patients with epilepsy. On the basis of concomitant AEDs, patients were divided into two subgroups, otherwise comparable for age and weight-adjusted daily dose of topiramate. Group A (n = 73) received topiramate plus AED inducers of cytochrome P450 (CYP) metabolism, such as carbamazepine, phenobarbital, and phenytoin. Group B (n = 43) received topiramate plus AEDs without inducing properties of CYP metabolism (namely valproic acid and lamotrigine). Weight-normalized topiramate clearance values, calculated as dosing rate/steady-state plasma drug concentration, were about 1.5-fold in patients receiving AED inducers compared with patients receiving AED noninducers. Topiramate plasma concentrations were linearly related to daily drug doses, regardless of concomitant AED therapy, over a dose range from 25 to 800 mg/d, although, at a given daily dose, a large interpatient variability was observed in matched plasma drug concentrations within each group of patients. Thirty-nine patients (34%) reported side effects associated with topiramate, mostly central nervous system effects. No consistent relation was observed between topiramate plasma concentrations and adverse effects, either in the cohort of patients as a whole or within each subgroup. From a clinical point of view, patients receiving concurrent treatment with enzyme-inducing AEDs can show twofold lower topiramate plasma concentrations compared with patients receiving valproic acid or lamotrigine, and appropriate topiramate dosage adjustments may be required when concomitant AED inducers are either added or withdrawn. Due to the observed variability in topiramate metabolic variables and the complex spectrum of possible pharmacokinetic and pharmacodynamic interactions with the most commonly coprescribed AEDs, monitoring of plasma topiramate concentrations may help the physician in the pharmacokinetic optimization of the drug dosage schedule in individual patients.

Topics: Adult; Anticonvulsants; Carbamazepine; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Lamotrigine; Male; Phenobarbital; Phenytoin; Prospective Studies; Topiramate; Triazines; Valproic Acid

To evaluate the tolerability and efficacy of two titration rates for topiramate initiated as adjunctive therapy in adults with partial-onset seizures, with or without secondary generalization, in a multicenter, double-blindtrial.. After a two-week baseline phase, 188 patients were randomized to either a 50/50 titration schedule (initial dosage 50 mg/d increased in 50-mg/d increments at weekly intervals; n = 95) or to a 100/200 titration schedule (initial dosage 100 mg/d increased by 100-200 mg/d at weekly intervals; n = 93). The maximum dosage of 400 mg/d was therefore achieved in eight weeks or three weeks, respectively.. Compared with the 100/200 titration rate, the 50/50 titration rate significantly reduced the cumulative incidence of treatment-emergent adverse events (TEAEs) leading to changes in topiramate therapy (ie., dosage reductions, interruptions or discontinuations of therapy) (p = 0.048) and significantly reduced treatment interruptions or withdrawals due to TEAEs (p = 0.040). Mild or moderate effects involving the central nervous system were the most frequent adverse events. At the final visit, therapeutic responses were comparable in the 50/50 and 100/200 titration groups: median percent seizure reduction was 42% vs. 33%, proportion of patients with 250% seizure reduction was 42% vs. 38%, and proportion of patients with no seizures during double-blind treatment was 14% vs. 10%, respectively. Seizure frequency was substantially reduced from baseline during topiramate titration. At day 22, with the 50/50 titration group receiving 150 mg/d and the 100/200 titration group receiving 400 mg/d, the mean percent seizure reduction was 51% and 54%, respectively.. Gradual initiation of topiramate therapy can significantly enhance patient tolerability without delaying therapeutic response.

Topics: Adolescent; Adult; Anticonvulsants; Double-Blind Method; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Topiramate

In an open study, 37 epilepsy patients were investigated with regard to cognitive impairments in anticonvulsant add-on therapy with topiramate (TPM). In addition to a preexisting antiepileptic medication, TPM administration was started and increased by 25 mg/week. Cognitive side effects noted by the patient or doctor were assessed by a neuropsychological test battery. In 18/37 patients (49%), cognitive deficits consisting of impaired concentration, psychomotoric slowing, memory deficits, and dysphasia were observed. The adverse effects became apparent at dosages of 50-575 mg TPM/day (average 210 mg). In four patients, they were reversible after reducing the dose of TPM by 25-150 mg/day. In eight patients, the adverse effects led to withdrawal of TPM. In spite of slow titration, the present study showed a higher frequency of cognitive side effects under TPM than was previously reported. In some patients, these side effects led to substantial impairments in daily life and at work. For early recognition of cognitive impairments, neuropsychological baseline and follow-up investigations of verbal fluency, psychomotor processing speed, and verbal memory are recommended.

Topics: Adult; Aged; Anticonvulsants; Cognition Disorders; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Neuropsychological Tests; Remission Induction; Topiramate; Treatment Outcome

Only a limited topiramate dosing range (5-9 mg/kg/day) is approved by the U.S. Food and Drug Administration (FDA). We reviewed our topiramate dosing (mg/kg/d) and corresponding serum levels (microg/mL) (n = 77) in 41 children who were treated to clinical response or tolerability. The patients were divided into older (6-12 years [n = 21]) and younger (< or = 5 years [n = 20]) groups. Topiramate was given as monotherapy (n = 9), with an enzyme-inducing antiepileptic drug (n = 16) (phebarbital, phenytoin, or carbamazepine), or as polytherapy (n =17) (another antiepileptic drug). In the older children, there was a good dosage to serum level correspondence. However, younger children on topiramate monotherapy or cotherapy with an enzyme-inducing antiepileptic drug had relatively lower serum levels, but the serum level was increased if they were on polytherapy without an enzyme-inducing drug. This study supports a wider dosing range (7-22 mg/kg/day) of topiramate and dosage escalation beyond the approved range. Serum levels are useful in guiding topiramate dosing, especially in young children.

Topics: Anticonvulsants; Child; Drug Monitoring; Epilepsy; Female; Fructose; Humans; Infant; Male; Topiramate

There is controversy between clinicians and statisticians on the appropriateness of the number needed to treat (NNT) as a summary statistic to report the effectiveness of a treatment. We examine the two viewpoints and make proposals concerning the reporting of clinical trial results.. In the context of antiepileptic treatments, we explain the two different viewpoints and illustrate the use of the odds ratio, relative risk, absolute difference, and NNT on the results of randomized clinical trials with topiramate (TPM). Special attention is paid to the use of these summary statistics in meta-analyses. Here, the NNT is the expected number of patients one would need to treat to achieve a single occurrence of a specified good outcome (e.g., 50% reduction in seizure rate) in comparison to no (or placebo) treatment.. Although the NNT is readily interpretable in some instances, it exhibits undesirable statistical behavior in other cases. In particular, confidence intervals for the NNT may split into two intervals and extend to positive and negative infinity when treatment efficacy is not clearly established by the data. Meta-analyses cannot be sensibly conducted directly on the NNT scale.. Although other measures, such as the odds ratio, have been more commonly used in the context of meta-analyses, clinicians prefer the NNT because it gives them a clearer clinical interpretation of the effectiveness of a (new) treatment. On the other hand, statisticians do not recognize the value of the NNT, as it has undesirable statistical properties. Some reconciliation between the two views could be achieved when the clinicians acknowledge the weak aspects of the NNT and when statisticians realize that statistical appropriateness is not the same as clinical relevance. It is suggested that the NNT be used as a secondary reporting tool not on an equal footing with the classic scales.

Topics: Anticonvulsants; Double-Blind Method; Drug Therapy, Combination; Epilepsy; Fructose; Humans; Odds Ratio; Outcome Assessment, Health Care; Patient Selection; Placebos; Research Design; Risk; Topiramate; Treatment Outcome

A total of 292 adult patients (mean age, 33 years) with partial and/or generalized seizures previously resistant to antiepileptic drug (AED) therapy (median baseline seizure rate, 12 seizures/month) were treated with open-label topiramate (TPM) in dosages of 100-1,600 mg/day.. The mean duration of TPM treatment was 413 days (range, 84-804 days), and the mean TPM dosage was 503 mg/day (range, 100-1,600 mg/day; median TPM dosage, 300 mg/day). Seizure reduction was calculated from seizure counts during the last 3 months and last 6 months of TPM therapy compared with baseline.. Overall, >50% of patients achieved > or =50% seizure reduction. More important, 11% of patients were seizure-free for > or =3 months at the last visit; 10% of patients were seizure free for > or =6 months at the last visit. This robust therapeutic response was consistent for patients receiving TPM dosages >400 and <400 mg/day. The most commonly reported adverse events were related to the central nervous system. Over the 2.2-year treatment period, 19% of patients discontinued TPM therapy because of inadequate seizure control; 32% discontinued because of adverse events. Findings from this study show that TPM is a useful agent for long-term seizure control, with some patients becoming seizure free for extended periods despite failing previous AED therapy.

Topics: Adolescent; Adult; Aged; Anorexia; Anticonvulsants; Double-Blind Method; Drug Administration Schedule; Epilepsies, Partial; Epilepsy; Epilepsy, Generalized; Fatigue; Female; Fructose; Headache; Humans; Incidence; Male; Middle Aged; Placebos; Sleep Wake Disorders; Topiramate; Treatment Outcome; Weight Loss

The response to topiramate (TPM) as long-term adjunctive therapy was evaluated in patients with Lennox-Gastaut syndrome (LGS) in a long-term, open-label extension to a double-blind, placebo-controlled trial.. In 97 patients with LGS (mean age, 11 years), dosages of TPM and concomitant antiepileptic drugs (AEDs) were adjusted to optimal clinical response (mean TPM dosage, 10 mg/kg/day).. For those patients who had completed 6 months of TPM therapy, drop attacks were reduced > or =50% in 55% of patients; 15% of patients had no drop attacks for > or =6 months at the last visit. After treatment up to 3+ years, 71% of patients who started open-label TPM were continuing therapy at the last visit.. During long-term therapy, TPM is effective and well tolerated in controlling the treatment-resistant drop attacks and seizures associated with LGS.

Topics: Adolescent; Adult; Anticonvulsants; Child; Child, Preschool; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Male; Placebos; Topiramate; Treatment Outcome

This prospective observational study explored the efficacy and tolerability of topiramate (TPM) in patients with refractory epilepsy attending a single outpatient clinic.. One hundred seventy patients (82 men, 88 women, aged 18-75 years) with refractory localization-related (n = 134) or idiopathic generalized epilepsy (n = 36) were started on adjunctive TPM using a standard titration schedule. TPM was introduced after a 3-month prospective baseline, and doses were adjusted according to clinical response. End points were seizure freedom for 6 months, > or =50% seizure reduction for 6 months compared with baseline at the highest tolerated TPM dose (responder), or discontinuation of TPM because of side effects, lack of efficacy, or both.. Thirty-nine (23%) patients were seizure-free, and 80 (47%) more patients had a useful therapeutic response. Thirteen seizure-free patients and 16 responders took 100 mg of TPM daily or less. TPM was discontinued in 51 (30%) patients. The most common side effects resulting in withdrawal were fatigue, weight loss, irritability, paresthesia, depression, and headache. Concomitant antiepileptic drugs (AEDs) were stopped in 30 patients. Twelve were established on TPM monotherapy, eight of whom remained seizure-free. Final TPM doses and concentrations varied widely among the three outcome groups.. TPM was efficacious as add-on and monotherapy in patients with refractory partial and generalized seizures in everyday clinical use. A good response was obtained in many patients with TPM doses substantially lower than those studied in regulatory clinical trials. The wide variation in dose-response and dose-toxicity relationships may reflect different neurobiologies causing refractory epilepsy and differential efficacy of AED combinations.

Topics: Adolescent; Adult; Aged; Ambulatory Care; Anticonvulsants; Carbamazepine; Drug Administration Schedule; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Lamotrigine; Male; Middle Aged; Phenytoin; Prospective Studies; Topiramate; Treatment Outcome; Triazines

To better define the efficacy and tolerability of the new anticonvulsant topiramate in pediatric patients, the clinical courses of 49 children with intractable seizures were monitored during topiramate therapy. The 80% of children who had complex partial seizures experienced better seizure control with topiramate than the 20% who had generalized seizures. Efficacy was greatest with doses between 2.5 and 7.5 mg/kg/day. More than half the children on topiramate experienced adverse effects which could interfere with learning at school, but 20% demonstrated increased alertness or improved behavior. Topiramate is effective and may be considered as part of the treatment pathway for complex partial seizures in children, although careful monitoring of cognitive function is required.

Topics: Adult; Anticonvulsants; Child; Child, Preschool; Dose-Response Relationship, Drug; Epilepsy; Female; Fructose; Humans; Infant; Male; Topiramate

The pharmacokinetic and safety profile of topiramate as adjunctive therapy was assessed in pediatric patients with epilepsy in an open-label, 4-week, single-center study. Six children from each of the following age groups were enrolled: 4-7 years, 8-11 years, and 12-17 years. Patients received topiramate 1 mg/kg/day for 1 week, with subsequent progressive weekly increases in dosage to 3, 6, and then 9 mg/kg/day or 800 mg/day, whichever was less. Topiramate oral plasma clearance (CI/F) was independent of dose, and steady-state plasma concentrations increased in proportion to dose. Weight-normalized topiramate CL/F was higher (P = 0.003) in pediatric patients receiving enzyme-inducing concomitant antiepileptic drugs (AEDs) (mean = 70.1 ml/minute/70 kg) than in those not receiving enzyme-inducing AEDs (mean = 33.1 mL/ minute/kg). Topiramate CL/F in children was approximately 50% greater than that observed in adults regardless of the type of concomitant AED therapy. Thus steady-state plasma topiramate concentrations for the same mg/kg dose will be approximately 33% lower in pediatric patients than in adult patients. The most frequently reported treatment-emergent adverse events considered related to topiramate therapy included anorexia, fatigue, and nervousness, and no patient discontinued therapy. This study indicates that, in children 4-17 years of age, topiramate has linear pharmacokinetics, 50% higher clearance than in adults, and is generally well tolerated.

Topics: Adolescent; Age Factors; Anticonvulsants; Area Under Curve; Child; Child, Preschool; Drug Interactions; Drug Therapy, Combination; Enzyme Induction; Epilepsy; Female; Fructose; Humans; Male; Prospective Studies; Topiramate; Treatment Outcome

To evaluate the efficacy and safety of topiramate as adjunctive therapy for Lennox-Gastaut syndrome in a multicenter, double-blind, placebo-controlled trial.. Conventional antiepileptic drugs are frequently ineffective against multiple-seizure types of Lennox-Gastaut syndrome.. Ninety-eight patients >1 year to <30 years of age, with slow spike-and-wave patterns on EEG, seizure types including drop attacks, and either a history of or active atypical absence seizures, were assigned to an 11-week, double-blind treatment phase with either topiramate or placebo. Topiramate was titrated to target doses of approximately 6 mg/kg/d.. For drop attacks, the most severe seizures associated with this syndrome, the median percentage reduction from baseline in average monthly seizure rate was 14.8% for the topiramate group and -5.1% (an increase) for the placebo group (p = 0.041). Topiramate-treated patients demonstrated greater improvement in seizure severity than did placebo-treated patients based on parental global evaluations (p = 0.037). The percentage of patients with a > or = 50% reduction from baseline in major seizures (drop attacks and tonic-clonic seizures) was greater in the topiramate group (15/46 or 33%) than in the control group (4/50 or 8%; p = 0.002). The most common adverse events in both groups were CNS related; there were no discontinuations from topiramate therapy due to adverse events.. Topiramate adjunctive therapy was effective in reducing the number of drop attacks and major motor seizures and in improving seizure severity as determined by parental global evaluation.

Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Double-Blind Method; Epilepsy; Female; Fructose; Humans; Male; Topiramate

We conducted an open, add-on study with topiramate (TPM) as adjunctive therapy in Lennox-Gastaut syndrome (LGS), to assess the long-term efficacy and safety and to evaluate quality of life (QL) measurements in the chronic use of TPM. We studied 19 patients (11 male; age ranging from 4 to 14 years) with uncontrolled seizures receiving 2-3 anti-epileptic drugs. Patients were followed up to 36 months of treatment. A questionnaire was used to query parents about QL. Seven patients completed the study at 36 months and seizure frequency was reduced > or = 75% in 4, and < 50% in 3 patients. Two children became seizure free for more than 24 months. Most side effects were CNS related, with the most frequent being somnolence and anorexia. These were generally transient. One patient dropped-out due to powder in the urine. None of the patients required hospitalization. At 36 months, patients' alertness (2/7), interaction with environment (5/7), ability to perform daily activities (5/7), and verbal performance (6/7) improved on TPM. We conclude that TPM may be useful as adjunctive therapy in the treatment of LGS. The efficacy of TPM was maintained in long-term treatment in more than 40% of patients, long term safety was confirmed and QL improved on TPM.

Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Epilepsy; Female; Follow-Up Studies; Fructose; Humans; Male; Pilot Projects; Topiramate

At a tertial referral epilepsy centre 39 children were consecutively enrolled in an open add-on study with topiramate (TPM). All children had intractable epilepsy; the mean seizure frequency was 36 per month, and 31 children were treated with polypharmacy. All but five children were mentally retarded. The initial dose of TPM was 0.5-1 mg/kg daily, slowly titrated with 1-3 mg/kg daily every second week with an estimated target dose of 10 mg/kg daily. At latest follow-up 19 children continued on TPM, three (8%) were seizure-free, eight (21%) had a seizure reduction of more than 50% and eight (21%) improved their general condition. Mean follow-up was 13 months (range 9-36 months). Seizure reduction was seen in focal as well as generalized epilepsies. Adverse effects were reported in 21 cases (54%), weight loss and sedation being most frequent. The mean steady state dose in the children continuing on TPM was at latest follow-up: 14 mg/kg daily (< 5 years), 10 mg/kg daily (5-7 years), 5.8 mg/kg daily (8-17 years). The corresponding plasma level varied from 3 to 45 mumol/litre, and a significant correlation between the daily dose in mg/kg and the plasma level was found. Two patients with progressive myoclonus epilepsy are described separately; one had a dramatic general improvement. It is concluded that TPM seems to be a promising new broad-spectrum anti-epileptic drug, which is efficacious even in epilepsy syndromes, intractable to other new anti-epileptic drugs such as vigabatrin and lamotrigine.

Topics: Adolescent; Anticonvulsants; Body Weight; Child; Child, Preschool; Dose-Response Relationship, Drug; Epilepsies, Myoclonic; Epilepsy; Female; Fructose; Humans; Male; Topiramate; Treatment Outcome

To investigate the relationship between the percentage reduction in seizure frequency in patients with epilepsy and plasma concentrations after oral administration of 4 anticonvulsant drugs.. Patients with a minimum of 25% reduction in their seizure frequency from their baseline value were declared responders. The percentage reduction in seizure frequency was plotted against plasma concentrations with use of pharmacodynamic models (linear, log-linear, Emax, and sigmoidal Emax models). In addition to pharmacodynamic models, a logistic regression model was also fitted to the concentration-response data, with a value of 1 for responders and 0 for nonresponders.. The concentration-effect relationship could not be adequately described either by the pharmacodynamic models or by the logistic regression analysis.. Based on the results obtained from both pharmacodynamic models and logistic regression analysis the percentage reduction in seizure frequency may not be a true surrogate marker for anticonvulsant drugs to establish a pharmacodynamic relationship with plasma concentrations.

Topics: Anticonvulsants; Double-Blind Method; Epilepsy; Flunarizine; Fructose; Humans; Lamotrigine; Linear Models; Logistic Models; Nipecotic Acids; Tiagabine; Topiramate; Triazines

The steady-state pharmacokinetics of valproate (VPA) and topiramate (TPM) were compared during VPA monotherapy, concomitant VPA and TPM therapy, and TPM monotherapy to evaluate pharmacokinetic interactions.. After a 3-week baseline period, 12 patients receiving VPA monotherapy (500 to 2,250 mg every 12 h) received TPM at three escalating doses (from 100 to 200 to 400 mg every 12 h), each for 2 weeks. Thereafter, the VPA dose was tapered by 25% weekly. Blood and urine samples were collected over 12-h intervals during VPA monotherapy and at the end of each stage of TPM dose escalation and TPM monotherapy.. All patients reached TPM monotherapy, and nine achieved satisfactory seizure control for > or = 2 weeks without VPA. TPM plasma peak concentration (C(max)) and area under the concentration-versus-time curve during a 12-h dosing interval (AUC(0-12)) were slightly higher (17%; n = 8) during TPM monotherapy than during concomitant VPA therapy. TPM oral and renal clearances (n = 8) were 25.9 +/- 4.6 and 11.6 +/- 3.2 ml/min during TPM monotherapy and were 29.8 +/- 4.2 and 12.4 +/- 2.7 ml/min during VPA concomitant therapy. VPA AUC(0-12) decreased (11.3%; n = 10) with the addition of TPM 400 mg every 12 h. VPA oral clearance was 12.8 +/- 4.1 ml/min during monotherapy and was 13.8 +/- 4.0, 14.1 +/- 3.9, and 14.5 +/- 5.2 ml/min during coadministration of TPM 100, 200, and 400 mg every 12 h, respectively. Cognitive dysfunction, observed in some patients receiving high doses of VPA with TPM, reversed or improved with VPA dose reduction and discontinuation. The lower-than-normal prestudy platelet count measured in one patient increased to normal levels when VPA was discontinued.. Because changes in TPM and VPA pharmacokinetics were small, it is unlikely that their concomitant use will have a significant impact on the clinical condition of the patient.

Topics: Adult; Anticonvulsants; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Topiramate; Treatment Outcome; Valproic Acid

Preliminary results of studies of topiramate (TPM) in children are now available. In a pharmacokinetic study among 18 male and female children, target daily dosages of up to 9 mg/kg/day were evaluated. TPM pharmacokinetics in children were linear. Mean TPM oral clearance (CL/F) was 44-54% higher in children [depending on concomitant antiepileptic drugs (AEDs)] compared with historical data from adults, and steady-state plasma TPM concentrations for the same mg/kg dose were 33% lower in children compared with historical adult data. In a long-term, open-label pilot study of adjunctive TPM therapy in 18 patients with Lennox-Gastaut syndrome, six of the eight patients (75%) still receiving TPM report a greater than 50% reduction in total seizures, with the best results observed in tonic-atonic, atypical absence, and generalized tonic-clonic seizures. Subsequent large double-blind, placebo-controlled trials of adjunctive TPM therapy in Lennox-Gastaut syndrome and refractory partial-onset pediatric epilepsy are ongoing, with high percentages of enrolled patients in both studies completing double-blind treatment and entering long-term TPM open extension trials. A small TPM monotherapy substitution trial in children with well controlled partial onset seizures showed that TPM monotherapeutic substitution can be achieved successfully with an acceptable amount of adverse experiences with a weekly increase of 1 mg/kg/day to a maximal dose of 3 mg/kg/day. These preliminary results suggest that TPM may be a useful new AED in pediatric patients with a variety of seizure disorders.

Topics: Adolescent; Adult; Age Factors; Anticonvulsants; Child; Child, Preschool; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Epilepsy; Female; Fructose; Functional Laterality; Hemiplegia; Humans; Male; Pilot Projects; Placebos; Topiramate; Treatment Outcome

Impaired attention is a frequently reported side effect of anti-epileptic medication, as well as a frequent general complaint of epilepsy. It is thus important to evaluate the effect of new medications on attention processes. Attention was assessed weekly in ten subjects receiving topiramate over a 3 month period. Attention was evaluated with digit span, a widely used index of attention. Different number sequences were constructed and randomized to allow for repeated use. Four of nine subjects showed significant correlations between topiramate dosage and forward digit span measured weekly, such that higher dosage was associated with poorer attention. The average topiramate dosage and seizure reduction did not differ between these subjects and those who did not show a significant relationship.

Topics: Adult; Anticonvulsants; Attention; Dose-Response Relationship, Drug; Double-Blind Method; Epilepsy; Female; Fructose; Humans; Male; Memory; Psychomotor Performance; Topiramate

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

This study was undertaken to examine the comparative safety of antiseizure medication (ASM) monotherapy in pregnancy with respect to risk of major congenital malformations (MCMs), overall and by MCM subtype.. We conducted a population-based cohort study using national health register data from Denmark, Finland, Iceland, Norway, and Sweden (1996-2020). We compared pregnancies with first trimester exposure to lamotrigine monotherapy to ASM-unexposed, carbamazepine, valproate, oxcarbazepine, levetiracetam, and topiramate to lamotrigine monotherapy, and stratified monotherapy groups by dose. The outcome was nongenetic MCM and specific subtypes. We estimated adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) with log-binomial regression and propensity score weights.. There was a higher crude risk of any MCM in pregnancies exposed to lamotrigine monotherapy (n = 8,339) compared to ASM-unexposed pregnancies (n = 4,866,362), but not after confounder adjustment (aRR = 0.97, 95% CI = 0.87-1.08). Compared to lamotrigine, there was an increased risk of malformations associated with valproate (n = 2,031, aRR = 2.05, 95% CI = 1.70-2.46) and topiramate (n = 509, aRR = 1.81, 95% CI = 1.26-2.60), which increased in a dose-dependent manner. We found no differences in malformation risk for carbamazepine (n = 2,674, aRR = 0.91, 95% CI = 0.72-1.15), oxcarbazepine (n = 1,313, aRR = 1.09, 95% CI = 0.83-1.44), or levetiracetam (n = 1,040, aRR = 0.78, 95% CI = 0.53-1.13). Valproate was associated with several malformation subtypes, including nervous system, cardiac, oral clefts, clubfoot, and hypospadias, whereas lamotrigine and carbamazepine were not.. Topiramate is associated with an increased risk of MCM similar to that associated with valproate, but lower doses may mitigate the risks for both drugs. Conversely, we found no increased risks for lamotrigine, carbamazepine, oxcarbazepine, or levetiracetam, which is reassuring. ANN NEUROL 2023;93:551-562.

Topics: Abnormalities, Drug-Induced; Anticonvulsants; Benzodiazepines; Carbamazepine; Cohort Studies; Epilepsy; Female; Humans; Lamotrigine; Levetiracetam; Male; Oxcarbazepine; Pregnancy; Topiramate; Valproic Acid

To determine trends in the use of antiseizure medications (ASMs) among women of childbearing age (WOCA) and girls aged 12-14 years with epilepsy between 2015 and 2019 in Poland.. The study used data from the Pex database, which captures information on prescriptions dispensed from 85% of community pharmacies in Poland. The prescriptions issued by neurologists who provide epilepsy care in Poland were studied. Six of the most commonly prescribed ASMs were analyzed: carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, topiramate, and valproate.. The use of valproate and carbamazepine decreased in all age groups. Among the newer ASMs, the use of lamotrigine, levetiracetam, and topiramate increased and oxcarbazepine decreased significantly in WOCA. The only subgroup with statistically significant changes in all ASMs prescriptions were women aged 19-34 years. For girls aged 12-14 years, significant changes were found only for valproate and carbamazepine. In the last year of observation (2019) valproate and lamotrigine accounted for two-thirds of ASMs units prescribed to WOCA. Valproate accounted for half of the prescribed drug units in girls aged 12-14 years. The lowest rates of VPA prescriptions were found in women aged 19-34 years.. There is a change in prescribing habits in WOCA with epilepsy in Poland with trends toward using less teratogenic ASMs. However, many WOCAs are treated with valproate and topiramate despite their known teratogenicity risk. Valproate is still the most commonly prescribed ASM in WOCA and girls aged 12-14 years. Educational interventions for healthcare professionals are needed to improve prescribing practices in WOCA with epilepsy in Poland.

Topics: Anticonvulsants; Benzodiazepines; Carbamazepine; Epilepsy; Female; Humans; Lamotrigine; Levetiracetam; Male; Oxcarbazepine; Poland; Topiramate; Valproic Acid

Many women with epilepsy need to continue anti-seizure medications (ASMs) throughout pregnancy. The current study investigated adaptive behaviour outcomes in children exposed to topiramate in the womb.. An observational, cross-sectional study was designed, recruiting mother-child-pairs from the UK Epilepsy and Pregnancy Register (UKEPR). Health, developmental histories and Vineland Adaptive Behaviour Scale-Third Edition (VABS-III) assessments were administered via telephone by a blinded researcher, supplemented with prospectively collected pregnancy and medication information. Topiramate monotherapy exposed children were compared to VABS-III normative data as recruitment was disrupted by the COVID-19 pandemic.. Thirty-four women with epilepsy from 135 (25%) initially agreed to participate in the study, of whom 26 women completed telephone interviews about their children (n = 28). Children ranged from 2.5 to 17 years of age at the time of assessment. Six topiramate-exposed children were born small for gestational age, and there were significant associations between birthweight, dose and VABS-III scores. Significantly lower scores were observed in topiramate-exposed children (n = 21) with a significant dose-response relationship established after adjustment for parental educational level. Daily mean dosage was 280.21 mg, with high dosages of topiramate associated with a 12-point reduction in VABS-III scores. Additionally, four topiramate-exposed children (19.05%) had diagnoses of Autism Spectrum Disorder, which was significantly higher than UK prevalence rates (1.1%).. The findings of poorer adaptive behaviour, higher incidence of ASD and associations with birth weight are of concern and require further validation and replication using larger prospectively-recruited samples and comparator cohorts. Implications for research and clinical practice are discussed.

Topics: Adaptation, Psychological; Anticonvulsants; Autism Spectrum Disorder; Cohort Studies; COVID-19; Cross-Sectional Studies; Epilepsy; Female; Humans; Pandemics; Pregnancy; Topiramate

Current treatment options for feline epilepsy are limited to medications that require administration of multiple doses per day or administration of a capsule or large tablet. Expanding the current treatment options could improve patient and owner compliance and optimize seizure control. Topiramate has been used sparingly in veterinary medicine, and limited pharmacokinetic studies have focused on immediate release formulations in dogs. If effective and safe, topiramate extended-release (XR) could broaden the current treatment options for feline epilepsy. The aims of this two-phase study were to establish single-dose pharmacokinetics for topiramate XR in cats, identify a dosing regimen that maintains steady-state plasma drug concentrations within a reference range extrapolated from human medicine (5-20 μg/mL), and evaluate the safety of topiramate XR in cats following multidose administration. Topiramate XR administered orally at 10 mg/kg once daily for 30 days was sufficient to achieve the desired concentrations in all cats. While no clinically apparent adverse effects were observed, four out of eight cats developed subclinical anemia, calling into question the safety of topiramate XR with chronic administration. Further studies are necessary to better understand the potential adverse effects and overall efficacy of topiramate XR for the treatment of feline epilepsy.

Topics: Administration, Oral; Animals; Anticonvulsants; Cat Diseases; Cats; Delayed-Action Preparations; Dog Diseases; Dogs; Epilepsy; Fructose; Humans; Topiramate

Patients with epilepsy often show treatment-related psychiatric symptoms. Among the novel antiseizure medications (ASM), Perampanel (PER), Levetiracetam (LEV), and Topiramate (TPM) have been reported to have a relatively high frequency of psychiatric adverse events. However, these psychiatric symptoms are not identical; PER and LEV show adverse events of irritability and aggression, while TPM shows typical symptoms of depression and schizophrenia. It is important to understand the characteristics of these psychiatric adverse events to design appropriate treatment regimens for epileptic patients. (Received August 1, 2022; Accepted December 24, 2022; Published April 1, 2023).

Topics: Anticonvulsants; Epilepsy; Humans; Levetiracetam; Mental Disorders; 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

Prenatal antiseizure medication (ASM) exposure has been associated with adverse early neurodevelopment, but associations with a wider range of psychiatric end points have not been studied.. To examine the association between prenatal exposure to ASM with a spectrum of psychiatric disorders in childhood and adolescence in children of mothers with epilepsy.. This prospective, population-based register study assessed 4 546 605 singleton children born alive in Denmark, Finland, Iceland, Norway, and Sweden from January 1, 1996, to December 31, 2017. Of the 4 546 605 children, 54 953 with chromosomal disorders or uncertain birth characteristics were excluded, and 38 661 children of mothers with epilepsy were identified. Data analysis was performed from August 2021 to January 2023.. Prenatal exposure to ASM was defined as maternal prescription fills from 30 days before the first day of the last menstrual period until birth.. The main outcome measure was diagnosis of psychiatric disorders (a combined end point and 13 individual disorders). Estimated adjusted hazard ratios (aHRs) using Cox proportional hazards regression and cumulative incidences with 95% CIs are reported.. Among the 38 661 children of mothers with epilepsy (16 458 [42.6%] exposed to ASM; 19 582 [51.3%] male; mean [SD] age at the end of study, 7.5 [4.6] years), prenatal valproate exposure was associated with an increased risk of the combined psychiatric end point (aHR, 1.80 [95% CI, 1.60-2.03]; cumulative risk at 18 years in ASM-exposed children, 42.1% [95% CI, 38.2%-45.8%]; cumulative risk at 18 years in unexposed children, 31.3% [95% CI, 28.9%-33.6%]), which was driven mainly by disorders within the neurodevelopmental spectrum. Prenatal exposure to lamotrigine, carbamazepine, and oxcarbazepine was not associated with an increased risk of psychiatric disorders, whereas associations were found for prenatal exposure to topiramate with attention-deficit/hyperactivity disorder (aHR, 2.38; 95% CI, 1.40-4.06) and exposure to levetiracetam with anxiety (aHR, 2.17; 95% CI, 1.26-3.72) and attention-deficit/hyperactivity disorder (aHR, 1.78; 95% CI, 1.03-3.07).. Findings from this explorative study strengthen the evidence for the warning against the use of valproate in pregnancy and raise concern of risks of specific psychiatric disorders associated with topiramate and levetiracetam. This study provides reassuring evidence that lamotrigine, carbamazepine, and oxcarbazepine are not associated with long-term behavioral or developmental disorders but cannot rule out risks with higher doses.

Topics: Adolescent; Anticonvulsants; Attention Deficit Disorder with Hyperactivity; Carbamazepine; Child; Child, Preschool; Epilepsy; Female; Humans; Incidence; Lamotrigine; Levetiracetam; Male; Oxcarbazepine; Pregnancy; Prenatal Exposure Delayed Effects; Prospective Studies; Topiramate; Valproic Acid

Antiseizure medication (ASM) as monotherapy or in combination is the treatment of choice for most patients with epilepsy. Therefore, knowledge about the typical adverse events (AEs) for ASMs and other coadministered drugs (CDs) is essential for practitioners and patients. Due to frequent polypharmacy, it is often difficult to clinically assess the AE profiles of ASMs and differentiate the influence of CDs.. This retrospective analysis aimed to determine typical AE profiles for ASMs and assess the impact of CDs on AEs in clinical practice.. The Liverpool AE Profile (LAEP) and its domains were used to identify the AE profiles of ASMs based on data from a large German multicenter study (Epi2020). Following established classifications, drugs were grouped according to their mode of action (ASMs) or clinical indication (CDs). Bivariate correlation, multivariate ordinal regression (MORA), and artificial neural network (ANNA) analyses were performed. Bivariate correlation with Fisher's z-transformation was used to compare the correlation strength of LAEP with the Hospital Anxiety and Depression Scale (HADS) and Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) to avoid LAEP bias in the context of antidepressant therapy.. Data from 486 patients were analyzed. The AE profiles of ASM categories and single ASMs matched those reported in the literature. Synaptic vesicle glycoprotein 2A (SV2A) and voltage-gated sodium channel (VGSC) modulators had favorable AE profiles, while brivaracetam was superior to levetiracetam regarding psychobehavioral AEs. MORA revealed that, in addition to seizure frequency, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) modulators and antidepressants were the only independent predictors of high LAEP values. After Fisher's z-transformation, correlations were significantly lower between LAEP and antidepressants than between LAEP and HADS or NDDI-E. Therefore, a bias in the results toward over interpreting the impact of antidepressants on LAEP was presumed. In the ANNA, perampanel, zonisamide, topiramate, and valproic acid were important nodes in the network, while VGSC and SV2A modulators had low relevance for predicting relevant AEs. Similarly, cardiovascular agents, analgesics, and antipsychotics were important CDs in the ANNA model.. ASMs have characteristic AE profiles that are highly reproducible and must be considered in therapeutic decision-making. Therapy using perampanel as an AMPA modulator should be considered cautiously due to its relatively high AE profile. Drugs acting via VGSCs and SV2A receptors are significantly better tolerated than other ASM categories or substances (e.g., topiramate, zonisamide, and valproate). Switching to brivaracetam is advisable in patients with psychobehavioral AEs who take levetiracetam. Because CDs frequently pharmacokinetically interact with ASMs, the cumulative AE profile must be considered.. DRKS00022024, U1111-1252-5331.

Topics: Adult; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Anticonvulsants; Epilepsy; Humans; Levetiracetam; Retrospective Studies; Topiramate; Valproic Acid; Zonisamide

Antiseizure medications (ASMs) are frequently used for other indications, such as migraine, pain syndromes, and psychiatric disorders. Possible teratogenic effects are therefore of wide concern and the risks imposed by the medications must be weighed against the risk with the disorder treated. It is our objective to update family practitioners on the implications of starting ASM for women with epilepsy during childbearing age. We hypothesized that clinicians would prescribe ASM based on avoiding teratogenesis and treating associated comorbidities simultaneously.. The study cohort was derived from women veterans with epilepsy (WVWE) prescribed ASM who received Veterans Health Administration care for at least 3 years in Veterans Health Administration between fiscal years (FY)01 and FY19. Regimens were classified as monotherapy or polytherapy. Multivariant logistic regression examined the association between demographics, military characteristics, physical/psychiatric comorbidities, neurological care, and use of each ASM.. Among 2,283 WVWE, in ages between 17 and 45, the majority (61%) received monotherapy in FY19. Commonly prescribed ASM included 29% gabapentin, 27% topiramate, 20% lamotrigine, 16% levetiracetam, and 8% valproate (VPA). Comorbid diagnosis of headache predicted use of topiramate and VPA, bipolar disease predicted use of LMT and VPA, pain predicted gabapentin, and schizophrenia was associated with VPAs use. Women receiving levetiracetam and lamotrigine were significantly more likely to receive neurology care previously.. The presence of medical comorbidities influences the selection of ASM. VPAs use in WVWE during childbearing age continues, despite the high teratogenic risk, especially in women with bipolar disorder and headaches. Multidisciplinary care integrating family practice doctors, mental health, and neurology can prevent the enduring problem of teratogenesis in women taking ASM.

Topics: Adolescent; Adult; Anticonvulsants; Epilepsy; Female; Gabapentin; Humans; Lamotrigine; Levetiracetam; Middle Aged; Pain; Pharmaceutical Preparations; Teratogenesis; Topiramate; Valproic Acid; Veterans; Young Adult

Antiseizure medications (ASMs) are among the most commonly prescribed teratogenic drugs in women of childbearing age. Limited data exist on utilization patterns across different indications for therapy and for the newer-generation ASMs in this population. Thus, we assessed the pattern of ASM use in women of childbearing age with epilepsy and nonepilepsy indications (pain and psychiatric disorders).. We conducted a retrospective analysis of deidentified administrative data submitted to the Optum Clinformatics database. Eligible participants included women aged 12-50 years who filled ASMs between year 2011 and 2017. Participants were followed from date of index prescription filled to study end or insurance disenrollment, whichever came first. For the overall cohort and potential therapy indications, we assessed the type and frequency of ASMs filled; proportion of participants on monotherapy, polytherapy, or treatment switching; and duration of continuous use. Trends were characterized using annual percent change from study start to study end.. Our analysis included 465,131 participants who filled 603,916 distinct ASM prescriptions. At baseline, most of the participants had chronic pain (51.0%) and psychiatric disorders (32.7%), with epilepsy the least common (0.9%). The most frequently dispensed were diazepam (24.3%), lorazepam (20.1%), gabapentin (17.4%), clonazepam (12.7%), topiramate (11.3%), and lamotrigine (4.6%). Significant linear increase in trends were observed with gabapentin (annual percent change [95% CI]: 8.4 [7.3-9.4];. Decreasing trends were observed with older ASMs in the overall cohort and across the potential indications for therapy. Conversely, increasing trends were seen with the newer ASMs. Considering the risk of teratogenicity associated with the newer medications largely unknown, counseling and education in addition to a careful consideration of the benefits vs potential risks should remain pivotal when prescribing ASMs for women of childbearing age.

Topics: Anticonvulsants; Clonazepam; Diazepam; Epilepsy; Female; Gabapentin; Humans; Lamotrigine; Lorazepam; Retrospective Studies; Topiramate; Valproic Acid

The specific effects of antiseizure medications (ASMs) on cognition are a rich field of study, with many ongoing questions. The aim of this study was to evaluate these effects in a homogeneous group of patients with epilepsy to guide clinicians to choose the most appropriate medications.. We retrospectively identified 287 refractory patients with medial temporal lobe epilepsy associated with hippocampal sclerosis. Scores measuring general cognition (global, verbal and performance IQ), working memory, episodic memory, executive functions, and language abilities were correlated with ASM type, number, dosage and generation (old vs. new). We also assessed non-modifiable factors affecting cognition, such as demographics and epilepsy-related factors.. Key parameters were total number of ASMs and specific medications, especially topiramate (TPM) and sodium valproate (VPA). Four cognitive profiles of the ASMs were identified: (i) drugs with an overall detrimental effect on cognition (TPM, VPA); (ii) drugs with negative effects on specific areas: verbal memory and language skills (carbamazepine), and language functions (zonisamide); (iii) drugs affecting a single function in a specific and limited area: visual denomination (oxcarbazepine, lacosamide); and (iv) drugs without documented cognitive side effects. Non-modifiable factors such as age at testing, age at seizure onset, and history of febrile seizures also influenced cognition and were notably influenced by total number of ASMs.. We conclude that ASMs significantly impact cognition. Key parameters were total number of ASMs and specific medications, especially TPM and VPA. These results should lead to a reduction in the number of drugs received and the avoidance of medications with unfavorable cognitive profiles.

Topics: Anticonvulsants; Cognition; Epilepsy; Epilepsy, Temporal Lobe; Fructose; Humans; Memory, Short-Term; Retrospective Studies; Topiramate

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

Astrocytes and microglia are involved in the pathophysiology of epilepsy and bipolar disorder with a link to inflammation. We aimed to investigate the effects of the antiepileptic and mood-stabilizing drugs lamotrigine (LTG) and topiramate (TPM) on glial viability, microglial activation, cytokine release, and expression of gap-junctional protein connexin 43 (Cx43) in different set-ups of an in vitro astrocyte-microglia co-culture model of inflammation.. Primary rat co-cultures of astrocytes containing 5% (M5, representing "physiological" conditions) or 30% (M30, representing "pathological, inflammatory" conditions) of microglia were treated with different concentrations of LTG and TPM for 24 hours. An 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed to measure the glial cell viability. The microglial activation state was analyzed by immunocytochemistry. The pro-inflammatory tumor necrosis factor-α (TNF-α) and anti-inflammatory transforming growth factor-ß1 (TGF-ß1) cytokine levels were measured by enzyme-linked immunosorbent assay. The astroglial Cx43 expression was quantified by western blot.. A significant reduction of the glial cell viability after incubation with LTG or TPM was observed in a concentration-dependent manner under all conditions. LTG caused no significant alterations of the microglial phenotypes. Under pathological conditions, TPM led to a significant concentration-dependent reduction of microglial activation. This correlated with increased astroglial Cx43 expression. TNF-α levels were not affected by LTG and TPM. Treatment with higher concentrations of LTG, but not with TPM, led to a significant increase in TGF-ß1 levels in M5 and M30 co-cultures.. Despite the possible glial toxicity of LTG and TPM, both drugs reduced inflammatory activity, suggesting potential positive effects on the neuroinflammatory components of the pathogenesis of epilepsy and bipolar disorder.

Topics: Animals; Anticonvulsants; Astrocytes; Coculture Techniques; Connexin 43; Cytokines; Epilepsy; Inflammation; Lamotrigine; Microglia; Rats; Topiramate; Tumor Necrosis Factor-alpha

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

During pregnancy in women with epilepsy, lower blood concentrations of antiseizure medications can have adverse clinical consequences.. To characterize pregnancy-associated concentration changes for several antiseizure medications among women with epilepsy.. Enrollment in this prospective, observational cohort study, Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD), occurred from December 19, 2012, to February 11, 2016, at 20 US sites. Enrolled cohorts included pregnant women with epilepsy and nonpregnant control participants with epilepsy. Inclusion criteria were women aged 14 to 45 years, an intelligence quotient greater than 70 points, and, for the cohort of pregnant women, a fetal gestational age younger than 20 weeks. A total of 1087 women were assessed for eligibility; 397 were excluded and 230 declined. Data were analyzed from May 1, 2014, to June 30, 2021.. Medication plasma concentrations in women taking monotherapy or in combination with noninteracting medications. The cohort of pregnant women was monitored through 9 months post partum, with similar time points for control participants.. Dose-normalized concentrations were calculated as total or unbound plasma medication concentrations divided by total daily dose. Phlebotomy was performed during 4 pregnancy study visits and 3 postpartum visits for the pregnant women and 7 visits over 18 months for control participants. The primary hypothesis was to test pregnancy changes of dose-normalized concentrations from nonpregnant postpartum samples compared with those of control participants.. Of the 351 pregnant women and 109 control participants enrolled in MONEAD, 326 pregnant women (median [range] age, 29 [19-43] years) and 104 control participants (median [range] age, 29 [16-43] years) met eligibility criteria for this analysis. Compared with postpartum values, dose-normalized concentrations during pregnancy were decreased by up to 56.1% for lamotrigine (15.60 μg/L/mg to 6.85 μg/L/mg; P < .001), 36.8% for levetiracetam (11.33 μg/L/mg to 7.16 μg/L/mg; P < .001), 17.3% for carbamazepine (11.56 μg/L/mg to 7.97 μg/L/mg; P = .03), 32.6% for oxcarbazepine (11.55 μg/L/mg to 7.79 μg/L/mg; P < .001), 30.6% for unbound oxcarbazepine (6.15 μg/L/mg to 4.27 μg/L/mg; P < .001), 39.9% for lacosamide (26.14 μg/L/mg to 15.71 μg/L/mg; P < .001), and 29.8% for zonisamide (40.12 μg/L/mg to 28.15 μg/L/mg; P < .001). No significant changes occurred for unbound carbamazepine, carbamazepine-10,11-epoxide, and topiramate, although a decrease was observed for topiramate (29.83 μg/L/mg to 13.77 μg/L/mg; P = .18). Additionally, compared with dose-normalized concentrations from control participants, pregnancy dose-normalized median (SE) concentrations decreased significantly by week of gestational age: carbamazepine, -0.14 (0.06) μg/L/mg (P = .02); carbamazepine unbound, -0.04 (0.01) μg/L/mg (P = .01); lacosamide, -0.23 (0.07) μg/L/mg (P < .001); lamotrigine, -0.20 (0.02) μg/L/mg (P < .001); levetiracetam, -0.06 (0.03) μg/L/mg (P = .01); oxcarbazepine, -0.14 (0.04) μg/L/mg (P < .001); oxcarbazepine unbound, -0.11 (0.03) μg/L/mg (P < .001); and zonisamide, -0.53 (0.14) μg/L/mg (P < .001) except for topiramate (-0.35 [0.20] μg/L/mg per week) and carbamazepine-10,11-epoxide (0.02 [0.01] μg/L/mg).. Study results suggest that therapeutic drug monitoring should begin early in pregnancy and that increasing doses of these anticonvulsants may be needed throughout the course of pregnancy.

Topics: Adult; Anticonvulsants; Carbamazepine; Epilepsy; Female; Humans; Lacosamide; Lamotrigine; Levetiracetam; Oxcarbazepine; Pregnancy; Prospective Studies; Topiramate; Zonisamide

Anti-seizure medications (ASMs) are the first line of treatment for seizure control in children with epilepsy. Cumulative evidence suggests an imbalanced gut microbiota in refractory epilepsy patients. We systematically investigated the differential antimicrobial impacts of nine ASM active ingredients, seven common excipients of ASMs, and four syrup formulations on core early-life gut microbiota strains. Additionally, we evaluated the toxicity and gene expression profiles of HT-29 colon epithelial cells when exposed to active ingredients with or without bacterial supernatants. The physicochemical structure of ASM active ingredients and bacterial phylogeny were found to be related to ASM toxicity. Carbamazepine, lamotrigine, and topiramate reduced the growth of more than ten strains along with syrup excipient propyl-paraben. Various artificial sweeteners present in ASM formulations stimulated the growth of gut bacterial strains. The active ingredients that were more toxic to bacterial strains also exhibited toxicity towards HT-29 cells, yet Bifidobacterium longum supernatant reduced cytotoxic effects of carbamazepine and lamotrigine. Akkermansia muciniphila or mixed community supernatants reduced the expression of drug resistance genes in HT-29 cell lines. In summary, our results indicate that several ASM active ingredients and their excipients regulate the growth of gut bacterial strains in a species-specific manner. Interactions between ASMs and gut epithelial cells might be modulated by gut microbial metabolites.

Topics: Anticonvulsants; Child; Epilepsy; Gastrointestinal Microbiome; Humans; Lamotrigine; Topiramate

Women with epilepsy frequently need antiseizure medication (ASM) to prevent seizures in pregnancy. Risk of neurodevelopmental disorders after prenatal exposure to AMSs is uncertain.. To determine whether children exposed prenatally to ASMs in monotherapy and duotherapy have increased risk of neurodevelopmental disorders.. The Nordic register-based study of antiepileptic drugs in pregnancy (SCAN-AED) is a population-based cohort study using health register and social register data from Denmark, Finland, Iceland, Norway, and Sweden (1996-2017; analysis performed February 2022). From 4 702 774 alive-born children with available mother-child identities and maternal prescription data, this study included 4 494 926 participants. Children from a multiple pregnancy or with chromosomal disorders or uncertain pregnancy length were excluded (n = 207 848).. Prenatal exposure to ASM determined from maternal prescription fills between last menstrual period and birth.. We estimated cumulative incidence at age 8 years in exposed and unexposed children. Cox regression adjusted for potential confounders yielded adjusted hazard ratios (aHRs) with 95% CIs for autism spectrum disorder (ASD), intellectual disability (ID), or any neurodevelopmental disorder (ASD and/or ID).. A total of 4 494 926 children were included; 2 306 993 (51.3%) were male, and the median (IQR) age at end of follow-up was 8 (4.0-12.1) years. Among 21 634 unexposed children of mothers with epilepsy, 1.5% had a diagnosis of ASD and 0.8% (numerators were not available because of personal data regulations in Denmark) of ID by age 8 years. In same-aged children of mothers with epilepsy exposed to topiramate and valproate monotherapy, 4.3% and 2.7%, respectively, had ASD, and 3.1% and 2.4% had ID. The aHRs for ASD and ID after topiramate exposure were 2.8 (95% CI, 1.4-5.7) and 3.5 (95% CI, 1.4-8.6), respectively, and after valproate exposure were 2.4 (95% CI, 1.7-3.3) and 2.5 (95% CI, 1.7-3.7). The aHRs were elevated with higher ASM doses compared with children from the general population. The duotherapies levetiracetam with carbamazepine and lamotrigine with topiramate were associated with increased risks of neurodevelopmental disorders in children of women with epilepsy: levetiracetam with carbamazepine: 8-year cumulative incidence, 5.7%; aHR, 3.5; 95% CI, 1.5-8.2; lamotrigine with topiramate: 8-year cumulative incidence, 7.5%; aHR, 2.4; 95% CI, 1.1-4.9. No increased risk was associated with levetiracetam with lamotrigine (8-year cumulative incidence, 1.6%; aHR, 0.9; 95% CI, 0.3-2.5). No consistently increased risks were observed for neurodevelopmental disorders after prenatal exposure to monotherapy with lamotrigine, levetiracetam, carbamazepin, oxcarbazepine, gapapentin, pregabalin, clonazepam, or phenobarbital.. In this cohort study, prenatal exposure to topiramate, valproate, and several duotherapies were associated with increased risks of neurodevelopmental disorders.

Topics: Anticonvulsants; Autism Spectrum Disorder; Autistic Disorder; Carbamazepine; Child; Cohort Studies; Epilepsy; Female; Humans; Intellectual Disability; Lamotrigine; Levetiracetam; Male; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Topiramate; Valproic Acid

To determine which antiepileptic drugs pregnant women receive by trimester.. This retrospective cohort study using the IBM Watson Health MarketScan Research Databases evaluated which antiepileptic drugs pregnant women with epilepsy received by trimester. Women with aged 15-54 years with a history of seizure disorder who underwent a delivery hospitalization between 2008 and 2017 were included in the analysis. Descriptive statistics were performed.. Of 34,144 women with a seizure disorder diagnosis and a delivery hospitalization, 10,289 (30.1%) received an anti-epileptic medication during pregnancy of which more than half received lamotrigine or levetiracetam. Other antiepileptic medications used by >5% of the population during any one trimester in the study period included carbamazepine, clonazepam, and topiramate. In evaluating medication use in the 1st trimester versus the 2nd trimester, clonazepam use decreased 32.0% (95% CI 60.0%, 77.0%) from 5.6% to 3.8% of patients receiving antiepileptics from the 1st to the 2nd trimester, gabapentin deceased 22.1% (95% CI 0.68%, 0.90%) from 4.1% to 3.2%, and topiramate decreased 30.0% (95% CI 62.8%, 77.9%) from 7.2% to 5.1%. In comparison, levetiracetam increased from 22.5% to 33.3% between the 1st and 3rd trimester and lamotrigine 22.2% to 27.5% between the 1st and 3rd trimester, 48.3% and 24.0% increases respectively.. Antiepileptic drugs with less favorable fetal risk profiles such as topiramate decreased by trimester while medications with more favorable fetal risk profiles such as lamotrigine and levetiracetam increased. These findings broadly support that there are opportunities to improve pre-conceptional counseling of women with epilepsy.

Topics: Anticonvulsants; Clonazepam; Epilepsy; Female; Humans; Lamotrigine; Levetiracetam; Pregnancy; Retrospective Studies; Topiramate

The management of pregnant women with epilepsy (WWE) treated with antiepileptic drugs (AEDs) polytherapy poses a great challenge. The purpose of this study was to evaluate the major congenital malformations (MCMs) associated with AED polytherapy, to assess the impacts of polytherapy regimens on seizure control and breastfeeding, and to determine the potential predictors for pregnancy outcomes.. This study was based on prospectively acquired data from a registry enrolling WWE in early pregnancy from Feb 2010 to July 2019, in which 123 pregnancies in 110 WWE were exposed to 27 different AED combinations.. There were 123 pregnancies in 110 WWE analyzed in our study. The live birth rate was 86.2 % and the risk of MCMs was 10.4 %. Multivariate analysis indicated that prenatal exposure to phenobarbital (odds ratio [OR], 17.424; 95 %CI, 1.510-201.067; P = 0.022) and topiramate (OR, 9.469; 95 %CI, 1.149-62.402; P = 0.036) was associated with increased risk of MCMs. Valproate (OR, 4.441; 95 %CI, 1.165-16.934; P = 0.029), phenobarbital (OR, 13.636; 95 %CI, 2.146-86.660; P = 0.006) and topiramate (OR, 7.527; 95 %CI, 1.764-32.118; P = 0.006) were significantly correlated with adverse pregnancy outcomes. Among 67 pregnancies in four combinations over 10 patients, 15 (22.4 %) remained seizure free through pregnancy, seizure frequency increased in 17 (25.4 %), decreased in 24 (35.8 %) women, in 26 (38.8 %) remained unchanged. Only 23.6 % of mothers undertook exclusive breastfeeding. Planned pregnancy was the only independent factor significantly associated with decreased risk of adverse pregnancy outcomes (OR, 0.139; 95 % CI, 0.051-0.382; P < 0.001). Notably, no adverse pregnancy outcome was recorded in pregnancies exposed to the combination of lamotrigine plus levetiracetam.. Prenatal exposure to the combinations containing valproate, phenobarbital, or topiramate was associated with increased risk of adverse pregnant outcomes. AED-related teratogenicity may be reduced by planned pregnancy in WWE exposed to polytherapy. Our findings also suggest the combination of lamotrigine and levetiracetam seems to be most desirable to balance seizure control and fetal safety.

Topics: Anticonvulsants; Epilepsy; Female; Humans; Lamotrigine; Levetiracetam; Male; Phenobarbital; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prenatal Exposure Delayed Effects; Registries; Topiramate; Valproic Acid

Topiramate (TPM) is effective for treating epilepsy, but executive dysfunction is a common side effect that could significantly affect everyday life. Additionally, previous studies have suggested that patients might be unaware of these changes.. To evaluate a rapid TPM titration scheme for the early detection of adverse cognitive side effects.. In this retrospective study, we assessed changes in objective cognitive performance (EpiTrack. Using Bayesian statistics, analyses revealed decisive evidence of a negative effect on cognitive performance when TPM was introduced (BF 31480000000) independent of the titration speed (BF 0.739). When using a fast titration rate, deficits in executive function increased from a baseline of 53.1 to 73.5% at follow-up, and 55.1% experienced a statistically significant intraindividual decline. When using the standard titration scheme, impairments increased from 52.2 to 65.2%, with an intraindividual deterioration found in 52.2% of the patients.. Physicians might be able to detect adverse cognitive side effects sooner in epilepsy patients if TPM is administered using a faster titration rate while applying repeated cognitive assessments within days. This approach might help prevent any unnoticed intolerance and eventual negative consequences for the patient. Therefore, we recommend monitoring early on for adverse changes instead of withholding a potentially effective treatment option because of anticipated side effects.

Topics: Anticonvulsants; Bayes Theorem; Cognition; Epilepsy; Fructose; Humans; Retrospective Studies; Topiramate

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

Two sets of benzenesulfonamide-based effective human carbonic anhydrase (hCA) inhibitors have been developed using the tail approach. The inhibitory action of these novel molecules was examined against four isoforms: hCA I, hCA II, hCA VII, and hCA XII. Most of the molecules disclosed low to medium nanomolar range inhibition against all tested isoforms. Some of the synthesized derivatives selectively inhibited the epilepsy-involved isoforms hCA II and hCA VII, showing low nanomolar affinity. The anticonvulsant activity of selected sulfonamides was assessed using the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (sc-PTZ) in vivo models of epilepsy. These potent CA inhibitors effectively inhibited seizures in both epilepsy models. The most effective compounds showed long duration of action and abolished MES-induced seizures up to 6 h after drug administration. These sulfonamides were found to be orally active anticonvulsants, being nontoxic in neuronal cell lines and in animal models.

Topics: Animals; Anticonvulsants; Carbonic Anhydrase I; Carbonic Anhydrase II; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Drug Design; Drug Discovery; Epilepsy; Humans; Male; Rats, Wistar

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

Certain antiepileptic drugs are associated with an increased risk for major congenital malformations (MCM). However, little is known regarding recent patterns of antiepileptic drug (ASM) prescriptions to women of childbearing age with epilepsy (WCE) in the United States.. Data from the Medical Expenditure Panel Survey was analyzed between the years 2004-2015 to determine trends in national antiepileptic drug prescriptions for WCE. Analysis of associations between demographic covariates and prescription of ASMs with MCM rate > 5% (topiramate, valproate, or phenobarbital) was performed with logistic regression.. There was a weighted total of 395,292 WCE. 29.1% (23.2%-35.8%) of WCE were prescribed an AED with MCM rate > 5%. The odds of a LEV prescription significantly increased in the 2010-2012 (OR 2.91, 95% CI 1.09-7.79) and 2013-2015 (OR 5.06, 95% CI 2.02-12.67) intervals compared to 2004-2006. Conversely, the odds of PB prescriptions significantly decreased in 2010-2012 (OR 0.13, 95% CI 0.02-0.83) and 2013-2015 (OR 0.13, 95% CI 0.02-0.93) compared to 2004-2006. WCE between the ages of 25-34 (OR = 2.67, 95% CI = 1.32-5.41) and 35-44 years (OR = 2.59, 95% CI = 1.23-5.45), had lower odds of being prescribed ASMs with MCM rate > 5% compared to those between the ages of 15-24 years.. Between 2004 and 2015, the prescriptions of ASMs given to WCE has changed. Regardless, nearly one third were prescribed potentially teratogenic medications despite available and affordable safer alternatives. Identifying factors associated with the prescription of teratogenic drugs to WCE is critical so that it may be further limited in the future.

Topics: Abnormalities, Drug-Induced; Adult; Anticonvulsants; Epilepsy; Female; Humans; Pregnancy; Pregnancy Complications; Topiramate; United States; Valproic Acid

Extended-release topiramate (TPM-XR) was recently approved for the treatment of epilepsy, but there is only limited real-world information on the clinical usefulness of TPM-XR in epilepsy patients. We investigated the usefulness of TPM-XR in clinical practice by analysing the retention of TPM-XR in adult epilepsy patients.. We performed a single-centre retrospective study covering two years. Epilepsy patients taking TPM-XR were included in the study and classified into one of three groups: the monotherapy group, in which patients took only TPM-XR; the adjunctive therapy group, in which patients took TPM-XR concomitant with other AEDs; and the switching AED regimen group, in which patient's AED was switched from immediate-release TPM (TPM-IR) to TPM-XR. We evaluated the retention rates of TPM-XR and analysed the differences in retention rate among the three patient groups.. We included 164 epilepsy patients who received TPM-XR for the treatment of epilepsy. The overall retention rate of TPM-XR was generally favourable: 79.1% after one year and 77.7% after two years. The switching AED regimen group had a better retention rate than the other two groups (p = 0.04), with a one-year retention rate of 90.6% and a two-year retention rate of 88.1%.. The favourable retention rate of TPM-XR shows that TPM-XR can be an effective treatment option for epilepsy patients, as either a monotherapy or as an adjunctive therapy. Additionally, switching AED regimen to TPM-XR from TPM-IR can be considered in selected epilepsy patients with poor adherence to TPM-IR.

Topics: Adult; Aged; Aged, 80 and over; Anticonvulsants; Delayed-Action Preparations; Drug Therapy, Combination; Epilepsy; Female; Humans; Longitudinal Studies; Male; Middle Aged; Patient Dropouts; Retrospective Studies; Topiramate; Young Adult

A 22-year-old female was admitted to our hospital due to acute onset of severe headache, confusion, and deterioration of consciousness. Results of initial examinations did not suggest cerebrovascular diseases, encephalitis, or nonconvulsive status epilepticus. Over the next several weeks, her level of consciousness fluctuated in parallel with the severity of headache. The electroencephalogram, recorded during a symptomatic episode, showed lack of posterior dominant rhythm, and the single-photon emission CT (SPECT) also revealed a decrease in cerebral blood flow predominantly in the occipital lobes. Administration of sodium valproate and topiramate, recommended as treatment for migraine, dramatically ameliorated her headache and consciousness. Although this was an adult-onset case, her symptoms and clinical course were similar with the diagnosis of ICHD-3-unlisted confusional migraine rather than other listed subtypes of migraine with aura. Further accumulation of similar adult-onset cases is necessary to clarify the nature of this illness.

Topics: Adult; Epilepsy; Female; Humans; Migraine Disorders; Topiramate; Valproic Acid; Young Adult

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

Cognitive impairment is one of the most common complaints for persons with epilepsy (PWE). These impairments are not only associated with seizures, but are also regularly reported as adverse effects of antiepileptic drugs (AEDs). Previous studies have examined cognitive effects of both AED monotherapy and polytherapy, yet there is limited research on these differences with respect to both subjective and objective cognition. The current study uses data from previous research conducted by the Centers for Disease Control and Prevention (CDC)-sponsored Managing Epilepsy Well (MEW) Network collaborative. We used three distinct archival datasets from the following: (1) the HOBSCOTCH efficacy trial at Dartmouth-Hitchcock Medical Center (HOB-1), (2) the multisite replication trial (HOB-2), and (3) epilepsy self-management research conducted at the NYU School of Medicine.. This retrospective analysis combined baseline data from three datasets to determine how the number of AEDs and the type of AEDs were associated with subjective (patient-reported) and objective (examiner-assessed) cognition. Subjective cognition was captured using the cognitive subscale of the Quality of Life in Epilepsy Inventory (QOLIE-31) in all three datasets (n = 224), while objective cognition was measured using the Repeated Battery for the Assessment of Neuropsychological Status (RBANS) in the HOB-1 dataset (n = 65) and the Brief Test of Adult Cognition by Telephone (BTACT) in the HOB-2 dataset (n = 91). Multivariable linear regression was utilized for our initial assessments, followed by propensity score matching to provide stronger control of covariates. Matching was based on significantly different covariates, such as education, depression, and history of prior epilepsy surgery. Nonparametric statistical tests were utilized to compare these matched subjects.. Subjective cognitive impairment was significantly worse among individuals on polytherapy (2 + AEDs) compared with those on monotherapy (1 AED) (adjusted p  =  0.041). These findings were consistent with our propensity score matched comparison of monotherapy and polytherapy, which indicated that polytherapy was associated with worse overall subjective cognition (adjusted p = 0.01), in addition to impairments on the RBANS (Total score p = 0.05) and specific subdomains of the BTACT (Episodic Verbal Memory p < 0.01, Working Memory p < 0.01, Processing Speed p < 0.01). Interestingly, older generation AEDs were associated with better language performance than newer generation and combined generation AED therapy (RBANS Language p = 0.03). These language-specific findings remained significant after controlling for the effects of topiramate and zonisamide (p = 0.04).. A greater number of AEDs is significantly and negatively associated with subjective and objective cognition in PWE, and is in line with previous research. Antiepileptic drug type did not, in itself, appear to be associated with subjective cognition. Our findings suggest that ineffective AEDs should be replaced, rather than introducing additional AEDs to a treatment regimen. Further, while subjective and objective cognition assessments were both sensitive at detecting differences based on AED status, the neuropsychological objective subdomains offer additional and specific insights into how cognition is impaired with AEDs.

Topics: Adult; Anticonvulsants; Cognition; Cognitive Dysfunction; Diagnostic Self Evaluation; Epilepsy; Female; Humans; Male; Memory, Short-Term; Neuropsychological Tests; Quality of Life; Retrospective Studies; Topiramate; Zonisamide

Antiseizure drugs (ASDs) are known to cause a wide range of adverse drug reactions (ADRs). Recently, electronic health care data using the common data model (CDM) have been introduced and commonly adopted in pharmacovigilance research. We aimed to analyze ASD-related ADRs using CDM and to assess the feasibility of CDM analysis in monitoring ADR in a single tertiary hospital.. We selected five ASDs: oxcarbazepine (OXC), lamotrigine (LTG), levetiracetam (LEV), valproic acid (VPA), and topiramate (TPM). Patients diagnosed with epilepsy and exposed to monotherapy with one of the ASDs before age 18 years were included. We measured four ADR outcomes: (1) hematologic abnormality, (2) hyponatremia, (3) elevation of liver enzymes, and (4) subclinical hypothyroidism. We performed a subgroup analysis to exclude the effects of concomitant medications.. From the database, 1344 patients were included for the study. Of the 1344 patients, 436 were receiving OXC, 293 were receiving LTG, 275 were receiving LEV, 180 were receiving VPA, and 160 were receiving TPM. Thrombocytopenia developed in 14.1% of patients taking VPA. Hyponatremia occurred in 10.5% of patients taking OXC. Variable ranges of liver enzyme elevation were detected in 19.3% of patients taking VPA. Subclinical hypothyroidism occurred in approximately 21.5% to 28% of patients with ASD monotherapy, which did not significantly differ according to the type of ASD. In a subgroup analysis, we observed similar ADR tendencies, but with less thrombocytopenia in the TPM group.. The incidence and trends of ADRs that were evaluated by CDM were similar to the previous literature. CDM can be a useful tool for analyzing ASD-related ADRs in a multicenter study. The strengths and limitations of CDM should be carefully addressed.

Topics: Anticonvulsants; Common Data Elements; Drug-Related Side Effects and Adverse Reactions; Electronic Health Records; Epilepsy; Humans; Lamotrigine; Levetiracetam; Oxcarbazepine; Topiramate; Valproic Acid

A case of carbonation dysgeusia associated with the use of topiramate is reported in order to bring awareness to a lesser-known adverse effect of the medication so that providers may be able to more effectively counsel patients and provide potential solutions.. A 39-year-old Caucasian woman with longstanding epilepsy was initiated on topiramate therapy after experiencing a generalized seizure (she reported not taking any antiepileptic medication for years). Topiramate was started at a dosage of 25 mg by mouth twice daily and after 3 weeks titrated to a dosage of 100 mg by mouth twice daily for maintenance therapy. After initiation of topiramate therapy, the patient began to experience an immediate change in her carbonation perception when drinking carbonated beverages; all carbonated beverages, including seltzer and beer, tasted "flat." The patient remained on topiramate for the subsequent 12 months without her carbonation perception returning to normal but noted that drinking carbonated beverages through straws slightly mitigated the adverse effect. Case assessment using the adverse drug reaction probability scale of Naranjo et al indicated that topiramate was the probable cause of the patient's carbonation taste perversion.. A 39-year-old Caucasian woman developed chronic carbonation dysgeusia after initiation of topiramate following a generalized seizure.

Topics: Adult; Anticonvulsants; Carbonated Beverages; Dysgeusia; Epilepsy; Female; Humans; Topiramate

We aim to evaluate the impact of zonisamide (ZNS) compared to topiramate (TPM) on cognition in patients with epilepsy. Although the risk of cognitive side effects has been clearly demonstrated for TPM, comparable side effects in ZNS have been suggested but evidence from studies is inconclusive.. In this retrospective observational study, we analyzed patients' records from before and after introduction or withdrawal of ZNS vs TPM. Data were gathered during routine clinical care protocols. Standardized monitoring of executive functions (EpiTrack), verbal memory (short version of verbaler lern- und merkfähigkeitstest, VLMT), and subjective health (extended Adverse Events Profile; quality of life in epilepsy inventory, QOLIE-10) was performed in 73 patients when TPM (n = 45) or ZNS (n = 28) was introduced and 62 patients when TPM (n = 29) or ZNS (n = 33) was withdrawn. The data were analyzed using Bayes statistics that quantify evidence for or against an effect through Bayes factors (BFs).. There was decisive evidence for a negative effect of adjunctive ZNS and TPM on executive function (BF = 965.08) and a positive effect of their withdrawal (BF = 429.51). The ZNS effect seemed smaller, although the difference was inconclusive. Verbal memory and subjective quality of life were not significantly affected. Subjectively, ZNS was connected to lower anxiety and fewer headaches, whereas TPM had a perceived effect on weight, fluent speech and comprehension, headaches, and balance.. This is the first study to provide objective evidence for a considerable negative effect of ZNS treatment on executive function in a naturalistic treatment setting. Comparable to the well-known TPM effect, cognition worsens with adjunction and recovers with withdrawal of ZNS. However, the majority of patients do not show a significant negative effect, suggesting disparate susceptibilities to adverse events. The findings emphasize the need for routine monitoring of cognitive side effects to identify early on those patients who are negatively affected by new AED.

Topics: Adolescent; Adult; Anticonvulsants; Bayes Theorem; Cognition; Epilepsy; Executive Function; Female; Humans; Longitudinal Studies; Male; Middle Aged; Retrospective Studies; Topiramate; Withholding Treatment; Young Adult; Zonisamide

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

This article presents an additional case of concomitant topiramate and phenobarbital administration that resulted in 8 hospital admissions for hypothermia that resolved after discontinuation of phenobarbital.. A 56-year-old white female with cerebral palsy and quadriplegia, epilepsy, and hypothyroidism was admitted to a community teaching hospital multiple times with documented hypothermia. These admissions followed a subsequent dose increase of topiramate in December 2014. In February 2015, the patient was admitted with 35°C rectal temperature. Her 2 admissions in April were for hypothermia with temperatures of 34.6°C and 33.6°C, respectively. The patient had 5 other admissions with hypothermia through December 2015. All other causes of hypothermia were ruled out. The hypothermia resolved when phenobarbital was discontinued.. A recent case series noted an association between phenobarbital and topiramate causing hypothermia. The patient's hypothermia developed while on concomitant phenobarbital and topiramate but only after an increase in topiramate. No other causes for hypothermia were found based upon physical examination or lab work. The Naranjo nomogram noted a probable causation.. This case report points to an association of hypothermia with concomitant topiramate and phenobarbital with resolution after phenobarbital discontinuation. Improvement after discontinuation of phenobarbital seems to support a drug-effect relationship.

Topics: Anticonvulsants; Drug Interactions; Epilepsy; Female; Hospitalization; Humans; Hypothermia; Middle Aged; Phenobarbital; Topiramate

Topiramate, an anticonvulsant used for prophylaxis of migraines and epilepsy, is commonly associated with adverse effects of cognitive dulling and fatigue. Chest pain is a potential adverse effect that to our knowledge has not been reported with the use of topiramate.. We present the case of a 38-year-old female with a seizure disorder who experienced chest pain after the first dose of topiramate. On day 1, she presented to the emergency department, was admitted, and over the course of 3 days had a chest X-ray, electrocardiogram (ECG), and echocardiogram, and her vitals, basic metabolic panel, complete blood counts, troponin, and d-dimer levels were monitored. The chest pain improved when the topiramate was held. No identifiable causes of chest pain were apparent, other than the topiramate.. The Naranjo probability scale was utilized to determine the causality of topiramate. The resulting score of 3 indicates that it is possible that the chest pain was due to the topiramate.. This report demonstrates an example of a patient who experienced chest pain possibly caused by the initiation of topiramate. The objective of this case report is to increase the awareness of chest pain as an adverse effect of topiramate.

Topics: Adult; Anticonvulsants; Chest Pain; Drug-Related Side Effects and Adverse Reactions; Emergency Service, Hospital; Epilepsy; Female; Hospitalization; Humans; Topiramate

This study was performed to identify an efficacious dosing regimen for U.S. Food and Drug Administration approval of topiramate for initial monotherapy in pediatric patients aged 2-9 years diagnosed with partial onset seizures and primary generalized tonic-clonic seizures using a pharmacometric bridging approach. The approval of topiramate in monotherapy of epilepsy for adult and pediatric patients (10-15 years) was based on efficacy and safety data from clinical trials. Our analysis showed that exposure-response relationship was similar between adult and pediatric patients (6-15 years) treated with topiramate as monotherapy for epilepsy. Specific dosing in pediatric patients 2-9 years of age was derived and included in the simulations by matching predicted exposures in pediatric patients (2-9 years) to a range of exposures observed in adult and pediatric patients (6-9 years) in a previously conducted clinical trial. The analysis allowed for U.S. Food and Drug Administration approval of topiramate for initial monotherapy in pediatric patients (2-9 years).

Topics: Adolescent; Age Factors; Anticonvulsants; Child; Child, Preschool; Clinical Trials as Topic; Computer Simulation; Drug Administration Schedule; Drug Approval; Epilepsy; Female; Humans; Male; Models, Biological; Time Factors; Topiramate; Treatment Outcome; United States; United States Food and Drug Administration

This active, open observational study aimed to investigate adverse drug reactions (ADRs) associated with six commonly used antiepileptic drugs (AEDs) in southern Chinese outpatients with epilepsy from 2003 to 2015.. The Wenzhou Epilepsy Follow-Up Registry Database (WEFURD) was established by a single epilepsy center in China in January 2003 to record AED efficacy and the associated ADRs by registered outpatients diagnosed with epilepsy. We reviewed the data of outpatients who had only taken one or more of six commonly used AEDs, namely, carbamazepine (CBZ), valproate (VPA), lamotrigine (LTG), oxcarbazepine (OXC), topiramate (TPM) and levetiracetam (LEV), and were registered in the WEFURD between 2003 and 2015. We evaluated the ADRs caused by the single or combined use of the above six specific AEDs based on the WHO-UMC scale. The data of the ADRs were categorized by age, sex, number of AEDs related to ADRs, medications, seriousness of ADRs, causality levels of the WHO-UMC scale and system organ class (SOC). The unit of analysis was one ADR.. A total of 3069 epilepsy outpatients (1807 outpatients with 5049 eligible ADRs and 1262 outpatients without ADRs) were included. The overall ADR rate was 58.88% (1807/3069). An average of 2.79 ADRs (5049/1807) occurred per patient with an ADR; 53.8% of the 5049 ADRs were recorded in females, and 50.4% were caused by monotherapy. Of the ADRs, 10.6% (537/5049) were severe adverse reactions (SARs), including 34 serious adverse effects (SAEs). The SAR rates caused by one, two and three or more AEDs were 9.9, 10.0 and 19.6%, respectively (p <  0.001). Eighteen SOC categories were identified, and the top three were psychiatric disorders (1633/5049, 32.3%), neurological disorders (1222/5049, 24.2%) and gastrointestinal disorders (564/5049, 11.2%). Of the 537 SARs, skin and appendage disorders accounted for 24.4% (131/537). Among the 34 SAEs, serious allergies, fetal malformations, renal calculus and pancreatitis accounted for the majority.. Our findings suggest that clinicians should pay attention to psychiatric ADRs and be alert for SARs, especially when three or more AEDs are used together. Moreover, active surveillance might provide another method of pharmacovigilance in China.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Child; Child, Preschool; China; Epilepsy; Female; Humans; Infant; Lamotrigine; Levetiracetam; Male; Middle Aged; Outpatients; Oxcarbazepine; Topiramate; Valproic Acid; Young Adult

The aims of this study were to identify the influencing factors such as gender, age, dose and combinations of other antiepileptic drugs (AEDs), especially in triple combinations on the pharmacokinetic of Lamotrigine (LTG) in epilepsy patients of Northwest Chinese Han population.. Data of the LTG concentration and clinical information were analyzed retrospectively from a therapeutic drug monitoring (TDM) database at the Clinical Pharmacy Laboratory of Xi'an Central Hospital between January 1, 2016 and January 1, 2018. The independent-sample t-test, one-way ANOVA analysis and Bonferroni and Tamhane T3 post-hoc test, the stepwise multivariate regression analysis were adopted by IBM SPSS, version 22.0.. 226 serum samples met the inclusion criteria and were evaluated. The mean LTG serum concentration was 5.48±3.83 μg/mL. There were no gender differences (P = 0.64), and there were no significant effects by age on LTG serum concentration after age stratification (3-14 years old, 14-45 years old, 45-59 years old) (P = 0.05). Multiple regression analysis showed that the daily LTG dose and co-administration of other AEDs significantly affected LTG serum concentrations. Combination with enzyme-inducer AEDs, the mean steady-state LTG concentration could be decreased by 30.73% compared with LTG monotherapy. Among enzyme-inducer AEDs, particularly strong inducer Carbamazepine (CBZ) could decrease the mean LTG concentration by 53.65%, but weak inducer AEDs such as Oxcarbazepine (OXC) and Topiramate (TPM) had no effect, Valproic acid (VPA) could increase the mean LTG concentration by 93.95%, and the inducer only partially compensated for the inhibitory effect of VPA in triple combination.. There were no significant gender and age effects, but the LTG daily dose and co-administration of other AEDs significantly affected LTG serum concentration. Combination with enzyme-inducer AEDs, especially CBZ could significantly decrease LTG serum concentrations, VPA could significantly increase LTG serum concentrations, and the inducer only partially compensated for the inhibitory effect of VPA in triple combination. In the clinical setting, these findings can help to estimate LTG concentrations and adjust dosage and evaluate adverse drug reactions.

Topics: Adolescent; Adult; Anticonvulsants; Asian People; Carbamazepine; Child; Child, Preschool; China; Drug Therapy, Combination; Epilepsy; Female; Humans; Lamotrigine; Male; Middle Aged; Oxcarbazepine; Retrospective Studies; Topiramate; Triazines; Valproic Acid; Young Adult

The aim was to study the impact of therapeutic drug monitoring (TDM) on paediatric patients on lamotrigine therapy and the evaluation of possible drug interactions, especially in triple antiepileptic drug combinations. During the period of 2001-2015, 1308 pre-dose samples were taken from 430 patients <15 years of age as part of routine TDM. Drug interactions were evaluated using calculation of lamotrigine clearance. Valproic acid decreased lamotrigine clearance by 54% in bitherapy, and by 21% in triple therapy with carbamazepine. Carbamazepine increased lamotrigine clearance by 191% in bitherapy. Levetiracetam and topiramate had no effect. The upper limit of lamotrigine therapeutic range (TR) was exceeded in 2% of cases in monotherapy, and in 6%-7% of cases in bi- or triple therapy. About 61% of plasma levels were found within the TR during 2001-2005, compared to 75% and 74% during 2006-2010 and 2011-2015, respectively. Adverse drug reactions (ADRs) were reported in 22 cases. Higher number of supratherapeutic levels in combination therapy led to a 3-fold increase in incidence of ADRs. Seizures occurred more often daily and monthly during 2001-2005 and in patients with three or four antiepileptic drugs in combination. Carbamazepine only partially compensated for the inhibitory effect of valproic acid. Lamotrigine clearance in monotherapy in children is similar to adults, but in polytherapy was found higher susceptibility to induction. A significantly higher number of supratherapeutic lamotrigine levels were found in combinations with valproate. Despite poor correlation with TR, both seizure frequency and ADRs declined after the implementation of TDM.

Topics: Adolescent; Anticonvulsants; Carbamazepine; Child; Child, Preschool; Czech Republic; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Epilepsy; Female; Humans; Incidence; Lamotrigine; Levetiracetam; Male; Metabolic Clearance Rate; Severity of Illness Index; Topiramate; Valproic Acid

This study was aimed to assess the accurate incidence of renal stones in severely disabled children treated with topiramate (TPM).. We reviewed the medical records of severely disabled children with epilepsy under 15 years old who underwent radiological examinations to investigate urinary stones. The study enrolled 26 patients who were divided into two groups. One group had been treated with TPM for at least 1 year and the other had not been treated with TPM, zonisamide, acetazolamide, or other diuretic drugs. We collected parameters from the medical records and compared the groups.. There is a high incidence of renal stone formation in severely disabled children treated with TPM.

Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Disabled Children; Epilepsy; Female; Humans; Incidence; Kidney Calculi; Male; Retrospective Studies; Severity of Illness Index; Topiramate

Topiramate, 2,3:4,5-di-O-isopropylidene-β-d-fructopyranose sulfamate, is a potent antiepileptic drug with a broad spectrum of activity. It is effective in both partial and generalized seizures. Topiramate was also found to have significant efficacy in migraine prevention with considerable reductions in the frequency of migraine headaches. The most common adverse events, which may accompany the use of topiramate, are paresthesia, fatigue, decreased appetite, nausea, diarrhea, weight decrease and taste perversion. The weight loss observed with the use of topiramate in obese, epileptic patients, afforded the approval of this drug as an anti-obesity medication. This action is thought to be based on the selective inhibition of mitochondrial carbonic anhydrase isoforms. This profile is prepared to discuss and explain physical characteristics, proprietary and nonproprietary names of topiramate. It also includes methods of preparation, thermal and spectral behavior and methods of analysis. Pharmacokinetics, metabolism, excretion and pharmacology together with its uses and applications are also discussed.

Topics: Anticonvulsants; Epilepsy; Humans; Migraine Disorders; Topiramate

Oxcarbazepine (OXC) is almost completely metabolized to its10-monohydroxy derivative (MHD), which is responsible for the pharmacological effects of the drug. Several studies have described the population pharmacokinetics (PPK) of MHD in pediatric patients, but little is known about its pharmacokinetics in adult patients. In addition, no study to date has proposed a model to investigate the influence of genetic polymorphisms on MHD pharmacokinetics. The aim of this study was to establish a PPK model of MHD to investigate the effects of genetic polymorphisms in UGT2B7, UGT1A9, ABCB1, and ABCB2 in adult Chinese patients with epilepsy and to develop a new dosage guideline for OXC.. Data were prospectively collected from 187 adult patients with epilepsy who were taking OXC. MHD trough concentrations were detected by enzyme-multiplied immunoassay. Patients were genotyped for 4 single nucleotide polymorphisms (UGT2B7 802T>C, UGT1A9 I399C>T, ABCB1 3435C>T, and ABCB2 1249G>A). Other covariates included sex, age, body weight (BW), hepato-renal function, and concomitant medications. Data were analyzed using the nonlinear mixed effects modelling software.. The apparent clearance (CL) of MHD was significantly influenced by glomerular filtration rate and BW, and was unrelated to other covariates such as genetic polymorphisms and coadministration with levetiracetam, lamotrigine, and topiramate. Moreover, a new dosage guideline was proposed based on the final model to individualize OXC regimens for adult patients with varying BW and renal function.. Glomerular filtration rate was first found as an important covariate influencing MHD CL. A PPK model was established to estimate the individual MHD CL for adult patients taking OXC and may be applied for individualizing doses in the target population.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Asian People; Body Weight; Drug Monitoring; Epilepsy; Female; Genotype; Glomerular Filtration Rate; Humans; Kinetics; Lamotrigine; Levetiracetam; Male; Middle Aged; Oxcarbazepine; Polymorphism, Single Nucleotide; Topiramate; Young Adult

Dravet syndrome (DS) is an intractable epilepsy syndrome. The three-drug combination therapy of sodium valproate (VPA), clobazam (CLB) and stiripentol (STP) is recommended worldwide.. We present a case of DS, in which treatment with CLB could not be continued because of the appearance of adverse reactions to it. Replacement with topiramate (TPM) proved to be markedly effective.. It is suggested that combination therapy with VPA, TPM and STP is for DS epilepsy.

Topics: Anticonvulsants; Child, Preschool; Dioxolanes; Drug Therapy, Combination; Epilepsies, Myoclonic; Epilepsy; Female; Fructose; Humans; Topiramate; Valproic Acid

To assess the relative risk of oral clefts associated with maternal use of high and low doses of topiramate during the first trimester for epilepsy and nonepilepsy indications.. This population-based study nested in the US 2000-2010 Medicaid Analytic eXtract included a cohort of 1,360,101 pregnant women with a live-born infant enrolled in Medicaid from 3 months before conception through 1 month after delivery. Oral clefts were defined as the presence of a recorded diagnosis in claims during the first 90 days after birth. Women with a topiramate dispensing during the first trimester were compared with those without any dispensing and with an active reference group of women with a lamotrigine dispensing during the first trimester. Risk ratios (RRs) were estimated with generalized linear models with fine stratification on the propensity score of treatment to control for potential confounders. Stratified analyses by indication of use and dose were conducted.. The risk of oral clefts at birth was 4.1 per 1,000 in the 2,425 infants born to women exposed to topiramate compared with 1.1 per 1,000 in the unexposed group (RR 2.90, 95% confidence interval [CI] 1.56-5.40). The RR among women with epilepsy was 8.30 (95% CI 2.65-26.07); among women with other indications such as bipolar disorder, it was 1.45 (95% CI 0.54-3.86). The median daily dose for the first prescription filled during the first trimester was 200 mg for women with epilepsy and 100 mg for women without epilepsy. For topiramate monotherapy, the RR for oral clefts associated with doses ≤100 mg was 1.64 (95% CI 0.53-5.07) and for doses >100 mg it was 5.16 (95% CI 1.94-13.73). Results were similar when lamotrigine was used as a reference group.. The increased risk of oral clefts associated with use of topiramate early in pregnancy was more pronounced in women with epilepsy, who used higher doses.

Topics: Abnormalities, Drug-Induced; Adult; Anticonvulsants; Cleft Palate; Cohort Studies; Dose-Response Relationship, Drug; Epilepsy; Female; Humans; Lamotrigine; Pregnancy; Pregnancy Complications; Pregnancy Trimester, First; Risk; Topiramate; United States; Young Adult

Topiramate is a well-known anticonvulsant drug with a broad spectrum of actions. It has been proposed in the treatment of several types of epileptic seizures both in monotherapy and in add-on. Its usage has been extended to other disorders including migraine, essential tremor, obesity, alcohol and drug addiction. The most frequent side-effects of topiramate include dizziness, somnolence, insomnia, and ataxia. Paraesthesia, metabolic acidosis, kidney stones, hypohidrosis, cognitive impairment and eye symptoms have also been reported.. We report on a girl affected by epileptic seizures treated with levetiracetam for five years. Due to worsening of the seizures, the dosage of this drug was increased and afterwards lowdosage topiramate was initiated. After 12 days from the introduction of topiramate, the girl began to present neurologic signs including limbs rigidity, pain, incoordination and flexed fingers. Gradual withdrawn of the topiramate resulted in progressive resolution of the symptomatology. This clinical episode could represent a probable topiramate-related side effect (Naranjo score 5), never reported before in this form.

Topics: Anticonvulsants; Child; Epilepsy; Female; Fingers; Fructose; Humans; Paresthesia; Topiramate

To estimate the effect size of concomitant antiepileptic therapy on the concentrations of lamotrigine, a drug often prescribed in combination with other antiepileptic drugs (AED), which can act as enzyme inducers or inhibitors.. A total of 304 patients with epilepsy, aged 18-70 years, were divided into a lamotrigine monotherapy group and groups receiving lamotrigine with AEDs that act as enzyme inducers, enzyme inhibitors, or both. We compared lamotrigine monotherapy serum concentrations with those where lamotrigine was administered with a metabolic inhibitor valproate, metabolic inducers carbamazepine, oxcarbazepine, phenobarbital, phenytoin, or topiramate, and both an inducer and an inhibitor.. Comparison of trough lamotrigine monotherapy concentrations and lamotrigine polytherapy concentrations showed an almost similar median concentration in case of drug-inducers, and higher lamotrigine concentration in case of comedication with valproate as an inhibitor. A significant difference was confirmed after dose correction (P<0.001). Significant positive correlations of lamotrigine trough serum concentrations with valproate were observed before and after the dose correction (r=0.480, P<0.001 and r=0.561, P<0.001, respectively). Positive correlations between the dose-corrected lamotrigine trough concentration and carbamazepine (r=0.439; PP<0.001) or monohydroxy metabolite of oxcarbazepine (MHD) (r=0.675; PP<0.001) were also significant.. Higher valproate levels resulted in higher inhibition potency and higher lamotrigine levels. Increased dose-corrected concentrations of inducers carbamazepine and MHD, after the process of induction was finished, did not lower lamotrigine concentrations. These findings can be of clinical significance for optimal AED dosing.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Carbamazepine; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Lamotrigine; Male; Middle Aged; Retrospective Studies; Topiramate; Triazines; Valproic Acid; Young Adult

Topics: Anticonvulsants; Drug Monitoring; Electric Conductivity; Electrophoresis, Capillary; Epilepsy; Humans; Limit of Detection; Linear Models; Reproducibility of Results; Topiramate

Intellectual disability (ID) is associated with weight gain caused by antiepileptic drugs such as valproic acid. The present study analyzed the relationship between ID and weight loss caused by topiramate (TPM).. Seventy-eight patients with epilepsy (35 women, aged 18 to 70years) were enrolled in this prospective study. Body weight was measured before and 1, 6, 12, and 18months after initiation of TPM treatment. Both patients and caregivers were provided information about TPM-related weight loss. The patients were divided into the group with no or mild ID (intelligence quotient >50) and the group with moderate to profound ID (intelligence quotient ≤50).. Body weight of both groups significantly decreased until 6months but stabilized after 12months. Weight loss at 6, 12, and 18months was significantly greater in the group with no or mild ID than in the group with moderate to profound ID. Body weight change at 18months was correlated with intellectual levels (β=0.274, p=0.011) and baseline body mass index (β=-0.322, p=0.002) by multiple linear regression analysis.. The present study suggests that the pattern of weight loss during TPM administration differs according to intellectual levels. Patients with ID maintained their body weight. Weight loss due to TPM might be weakened by caregiver control of food intake or inactivity.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Body Mass Index; Body Weight; Cohort Studies; Epilepsy; Female; Humans; Intellectual Disability; Male; Middle Aged; Prospective Studies; Topiramate; Weight Gain; Weight Loss; Young Adult

Although some drugs used in the treatment of epilepsy are known to affect body weight, the hormonal factors responsible have not been sufficiently described. The purpose of this study was to compare insulin, leptin, neuropeptide Y and ghrelin levels in children with epilepsy receiving monotherapy with topiramate (TPM) and valproic acid (VPA), the drugs whose effects on body weight have been most discussed, with those of a control group.. 48 patients (25 VPA, 23 TPM) aged between 6 and 15.5 years, presenting to the Karadeniz Technical University Medical Faculty Pediatric Neurology Clinic, diagnosed with idiopathic epilepsy or location-related idiopathic epilepsy, and receiving VPA or TPM monotherapy for at least 6 months were included in the study. Twenty-five healthy subjects with similar demographic characteristics were enrolled as the control group. Blood samples were collected from the patient and control groups after fasting for at least 10-12 h and again 1 and 2 h postprandially. Body mass index (BMI) values were calculated for all cases. VPA levels, glucose, insulin, leptin, neuropeptide Y and ghrelin were investigated in all three separate blood samples.. Age, height, weight and BMI were similar between the patient and control groups. Significant weight gain was observed throughout treatment in the VPA group compared to the TPM group. High fasting and postprandial insulin levels were observed in the VPA group. VPA group leptin and neuropeptide Y (NPY) levels were also higher than in the TPM and control groups. No significant difference was determined in ghrelin levels in the patient groups compared to the controls.. Low blood sugar not being observed, even though insulin levels are high, after fasting and in the postprandial period in epileptic children receiving VPA is indicative of insulin resistance. The elevation in leptin and neuropeptide Y levels observed in the VPA group also suggest this.

Topics: Adolescent; Anticonvulsants; Biomarkers; Blood Glucose; Body Mass Index; Child; Epilepsy; Fructose; Ghrelin; Humans; Insulin; Leptin; Neuropeptide Y; Topiramate; Treatment Outcome; Valproic Acid; Weight Gain

Evidence for the comparative teratogenic risk of antiepileptic drugs is insufficient, particularly in relation to the dosage used. Therefore, we aimed to compare the occurrence of major congenital malformations following prenatal exposure to the eight most commonly used antiepileptic drugs in monotherapy.. We did a longitudinal, prospective cohort study based on the EURAP international registry. We included data from pregnancies in women who were exposed to antiepileptic drug monotherapy at conception, prospectively identified from 42 countries contributing to EURAP. Follow-up data were obtained after each trimester, at birth, and 1 year after birth. The primary objective was to compare the risk of major congenital malformations assessed at 1 year after birth in offspring exposed prenatally to one of eight commonly used antiepileptic drugs (carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, and valproate) and, whenever a dose dependency was identified, to compare the risks at different dose ranges. Logistic regression was used to make direct comparisons between treatments after adjustment for potential confounders and prognostic factors.. Between June 20, 1999, and May 20, 2016, 7555 prospective pregnancies met the eligibility criteria. Of those eligible, 7355 pregnancies were exposed to one of the eight antiepileptic drugs for which the prevalence of major congenital malformations was 142 (10·3%) of 1381 pregnancies for valproate, 19 (6·5%) of 294 for phenobarbital, eight (6·4%) of 125 for phenytoin, 107 (5·5%) of 1957 for carbamazepine, six (3·9%) of 152 for topiramate, ten (3·0%) of 333 for oxcarbazepine, 74 (2·9%) of 2514 for lamotrigine, and 17 (2·8%) of 599 for levetiracetam. The prevalence of major congenital malformations increased with the dose at time of conception for carbamazepine (p=0·0140), lamotrigine (p=0·0145), phenobarbital (p=0·0390), and valproate (p<0·0001). After adjustment, multivariable analysis showed that the prevalence of major congenital malformations was significantly higher for all doses of carbamazepine and valproate as well as for phenobarbital at doses of more than 80 mg/day than for lamotrigine at doses of 325 mg/day or less. Valproate at doses of 650 mg/day or less was also associated with increased risk of major congenital malformations compared with levetiracetam at doses of 250-4000 mg/day (odds ratio [OR] 2·43, 95% CI 1·30-4·55; p=0·0069). Carbamazepine at doses of more than 700 mg/day was associated with increased risk of major congenital malformations compared with levetiracetam at doses of 250-4000 mg/day (OR 2·41, 95% CI 1·33-4·38; p=0·0055) and oxcarbazepine at doses of 75-4500 mg/day (2·37, 1·17-4·80; p=0·0169).. Different antiepileptic drugs and dosages have different teratogenic risks. Risks of major congenital malformation associated with lamotrigine, levetiracetam, and oxcarbazepine were within the range reported in the literature for offspring unexposed to antiepileptic drugs. These findings facilitate rational selection of these drugs, taking into account comparative risks associated with treatment alternatives. Data for topiramate and phenytoin should be interpreted cautiously because of the small number of exposures in this study.. Bial, Eisai, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Sanofi-Aventis, UCB, the Netherlands Epilepsy Foundation, and Stockholm County Council.

Topics: Abnormalities, Drug-Induced; Adult; Anticonvulsants; Carbamazepine; Dose-Response Relationship, Drug; Epilepsy; Female; Humans; Lamotrigine; Levetiracetam; Logistic Models; Male; Oxcarbazepine; Phenobarbital; Phenytoin; Pregnancy; Pregnancy Complications; Topiramate; Valproic Acid; Young Adult

Management of epilepsy during pregnancy in a resource-limited setting (RLS) is challenging. This study aimed to assess obstetric outcomes and effects on babies of women with epilepsy (WWE) exposed to Anti-epileptic drugs (AEDs) compared to non-exposed controls in a RLS.. Pregnant WWE were recruited from antenatal and neurology clinics of a tertiary care hospitals in Sri Lanka. Patients were reviewed in each trimester and post-partum. Medication adherence, adverse effects, seizure control and carbamazepine blood levels were monitored. Post-partum, measurements for anthropometric and dysmorphic features of the babies and congenital abnormalities were recorded. Age and sex matched babies not exposed to AED recruited as controls were also examined.. Ninety-six pregnant WWE were recruited (mean period of gestation 22.9 weeks). Mean age was 28 years and 48(50%) were primigravidae. Fifty percent (48) were on monotherapy, while 23.8, 15.9 and 4.1% were on two, three and four AEDs respectively. AEDs in first trimester (TM1) were carbamazepine (71%), valproate (25.8%) clobazam (29.5%), lamotrigine (7%) topiramate (5%) and others (3.4%). Sodium valproate use reduced significantly from T1 to T2(p < 0.05). Sub-therapeutic carbamazepine levels correlated positively (r = 0.547) with poor medication adherence (p = 0.009) and negatively (r = 0.306) with adverse effects (p = 0.002). Seventy-six WWE completed follow-up reporting w 75 (98.6%) live births and one T1 miscarriage (1.3%). Three (4.3%) were preterm. Majority (73.33%) were normal vaginal deliveries. Cesarean sections were not increased in WWE. Fifty-nine (61.45%) babies were examined. For those examined during infancy, 53 age and sex matched controls were recruited and examined.. Congenital abnormalities occurred in 5 (9.43%) babies of WWE [atrio-ventricular septal defect (2), renal hypoplasia (1), cryptorchidism (1), microcephaly (1)] compared to 2 (3.77%) in controls (2 microcephaly; p = 0.24). Fetal exposure to AEDs increased a risk of low birth weight (RR 2.8; p = 0.049). Anthropometric parameters of AED exposed babies were lower at birth but not statistically significant between the two groups (weight p = 0.263, length p = 0.363, occipito-frontal circumference (OFC) p = 0.307). However, weight (p = 0.009), length (p = 0.016) and OFC (p = 0.002) were significantly lower compared to controls at an average of 3.52 months.. Most pregnancies are unplanned in the RLS studied, and AEDs were altered during pregnancy. Congenital anomalies occurred at rates comparable to previous reports. Fetal exposure to AED had growth retardation in infancy compared to non-exposed babies.

Topics: Abortion, Spontaneous; Adolescent; Adult; Anticonvulsants; Body Height; Body Weight; Carbamazepine; Case-Control Studies; Child Development; Clobazam; Congenital Abnormalities; Developing Countries; Drug Therapy, Combination; Epilepsy; Female; Humans; Infant; Infant, Low Birth Weight; Infant, Newborn; Lamotrigine; Live Birth; Medication Adherence; Pregnancy; Pregnancy Complications; Premature Birth; Prenatal Exposure Delayed Effects; Sri Lanka; Topiramate; Valproic Acid; Young Adult

To ascertain the risk of spontaneous fetal loss (SPFL) in women with epilepsy (WWE) on antiepileptic drugs (AED), and explore the association between specific AED usage and risk of SPFL.. We identified all SPFL (including stillbirths) among pregnancies registered at Kerala Registry for Epilepsy and Pregnancy between 1998 and 2015. Rates of SPFL were compared between the AED exposed and unexposed groups.. There were 139 SPFL out of 1987 eligible pregnancies. The AED exposed had excess SPFL (7.4%, 134 out of 1809, Odds Ratio [OR] 2.77, 95% Confidence Interval [CI] 1.17-6.39) than AED unexposed (2.8%, 5 out of 178). The adjusted OR (95% CI) for SPFL for monotherapies with levetiracetam, phenobarbitone and clobazam were comparable to unexposed, while it was significantly higher for topiramate (OR 38.86, CI 5.02-301.19), lamotrigine (OR 13.33, CI 1.41-125.78), oxcarbazepine (OR 7.53, CI 1.54-36.89), valproate (OR 6.92, CI 1.70-28.18), phenytoin (OR 5.82, CI 1.43-23.73) and carbamazepine (OR 3.53, CI 1.15-10.90). With reference to levetiracetam, only topiramate had significantly higher SPFL (OR 11.14, CI 1.56-79.55).. SPFL risk is increased in pregnancies with AED exposure, being least with levetiracetam and highest with topiramate.

Topics: Abortion, Spontaneous; Adult; Anticonvulsants; Epilepsy; Female; Humans; India; Levetiracetam; Prospective Studies; Registries; Risk Factors; Topiramate

Background The impact of adverse events (AEs) of antiepileptic drugs (AEDs) have an impact on compliance and dropouts. We compared tolerability of AEs of AEDs among patients with migraine, epilepsy, or both. Methods Overall, 335 patients (epilepsy (n = 142), migraine (n = 131), and both (n = 62)), were evaluated with the Liverpool Adverse Events Profile (LAEP) to assess the magnitude, profile and occurrence rate of the AEs of valproate, topiramate, and lamotrigine. Results AEs were significantly more common with topiramate treatment (71.0%) and among migraineurs (69.5%), the latter being more prone to discontinue AEDs (46.6%). The profile of AEs with topiramate and valproate differed among groups. Moreover, treatment with both topiramate and valproate was associated, for all groups, with a worse tolerability profile compared to lamotrigine. Conclusion Our data suggest a specific drug and disease AE profile of AEDs. Specifically, migraineurs are the most affected by AEs, even though they receive very low dosages of AEDs. This finding might be considered a clinical implication of central sensitization mechanisms. Both the profile and tolerability of AEs, highly influencing quality of life, depended on the underlying conditions, and deeply impacted on treatment dropout. Therefore, before starting, switching or stopping AED treatment, all options need to be considered.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Child; Epilepsy; Female; Humans; Lamotrigine; Male; Middle Aged; Migraine Disorders; Topiramate; Valproic Acid; Young Adult

Optimization of the previously reported benzothiazine analogue A led to the identification of compound 1, which showed anti-convulsant activity in two golden standard animal models of seizure, the MES and scPTZ models. Structure-activity relationship investigation of compound 1 revealed compounds 2, 6 and 19 as attractive anti-epileptic drug (AED) candidates with potent anticonvulsant effect in both the MES and scPTZ models. As these compounds are structurally different from existing AEDs, determination of their mechanism of actions could provide clues to understanding current therapy-resistant seizures. Moreover, these simple phenylsulfoneamide compounds could be good starting points for searching broad spectrum AEDs by such in vivo screening.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Epilepsy; Molecular Structure; Pentylenetetrazole; Rats; Sulfonamides

In order to develop phenyl sulfonamides as a novel class of anti-epileptic drugs (AED) for both general and partial seizure, we initiated in vivo screening of our chemical library in the mice MES and sc-PTZ models and found compounds 1 and 2 as lead compounds. Optimization of 1 and 2 led to the discovery of compound 21, which showed potent anticonvulsant effect in MES, scPTZ and rat amygdala kindling models. These findings indicate that compound 21 could be a useful new broad spectrum AED like sodium valproate and provide an opportunity to struggle current therapy-resistant epilepsy.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Epilepsy; Mice; Molecular Structure; Rats; Structure-Activity Relationship; Sulfonamides; Valproic Acid

Topics: Adult; Central Nervous System Agents; Epilepsy; Fructose; Humans; Male; Mental Disorders; Migraine Disorders; Topiramate

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

Antiepileptics (AEDs) and antipsychotics are often coprescribed. Interactions between these drugs may affect both efficacy and toxicity. Therefore, drug monitoring is necessary for appropriate dosage adjustments.. Specific 'turn-on' chemosensor, 4-chloro-7-nitrobenzofurazan is used for selective and sensitive determination of two AEDs: zonisamide (ZON) and topiramate (TOP) with the antipsychotic sulpiride (SUL) in epileptic patients' plasma followed by reversed-phase-HPLC separation without any interference.. Linear behavior was observed in the range of 0.1-3 μg/ml and 0.01-0.5 μg/ml for the AEDs and SUL, respectively, with LOD of 33, 46 and 4 ng/ml and LOQ of 86, 93 and 9 ng/ml for ZON, TOP and SUL, respectively. The proposed method was successfully applied for determination of different pharmacokinetic parameters of ZON and TOP, and for clinical monitoring of the three drugs in healthy volunteers following oral administration.. The developed method is suitable for the routine therapeutic drug monitoring of these drugs.

Topics: Adult; Anticonvulsants; Blood Chemical Analysis; Chromatography, High Pressure Liquid; Epilepsy; Female; Fructose; Humans; Hydrogen-Ion Concentration; Isoxazoles; Limit of Detection; Linear Models; Male; Spectrometry, Fluorescence; Sulpiride; Time Factors; Topiramate; Water; Zonisamide

To identify potential pharmacokinetic interactions between the pharmaceutical formulation of cannabidiol (CBD; Epidiolex) and the commonly used antiepileptic drugs (AEDs) through an open-label safety study. Serum levels were monitored to identify interactions between CBD and AEDs.. In 39 adults and 42 children, CBD dose was started at 5 mg/kg/day and increased every 2 weeks by 5 mg/kg/day up to a maximum of 50 mg/kg/day. Serum AED levels were obtained at baseline prior to CBD initiation and at most study visits. AED doses were adjusted if it was determined that a clinical symptom or laboratory result was related to a potential interaction. The Mixed Procedure was used to determine if there was a significant change in the serum level of each of the 19 AEDs with increasing CBD dose. AEDs with interactions seen in initial analysis were plotted for mean change in serum level over time. Subanalyses were performed to determine if the frequency of sedation in participants was related to the mean serum N-desmethylclobazam level, and if aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were different in participants taking concomitant valproate.. Increases in topiramate, rufinamide, and N-desmethylclobazam and decrease in clobazam (all p < 0.01) serum levels were seen with increasing CBD dose. Increases in serum levels of zonisamide (p = 0.02) and eslicarbazepine (p = 0.04) with increasing CBD dose were seen in adults. Except for clobazam and desmethylclobazam, all noted mean level changes were within the accepted therapeutic range. Sedation was more frequent with higher N-desmethylclobazam levels in adults (p = 0.02), and AST/ALT levels were significantly higher in participants taking concomitant valproate (p < 0.01).. Significantly changed serum levels of clobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine were seen. Abnormal liver function test results were noted in participants taking concomitant valproate. This study emphasizes the importance of monitoring serum AED levels and LFTs during treatment with CBD.

Topics: Adolescent; Adult; Age Factors; Anticonvulsants; Benzodiazepines; Cannabidiol; Child; Child, Preschool; Clobazam; Dose-Response Relationship, Drug; Drug Interactions; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Topiramate; Triazoles; Young Adult

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 Cav2.3 (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 topiramate and lacosamide in Cav2.3-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 either 30 mg/kg LTG, 50 mg/kg topiramate (TPM) or 30 mg/kg lacosamide (LSM).. Ablation of Cav2.3 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 Cav2.3-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 tested AEDs reduced seizure activity in control mice, however only the non-calcium channel modulating AED, LSM had an anticonvulsive effect in Cav2.3-deficient mice. Furthermore LTG altered electrocorticographic parameters differently in the two genotypes, decreasing relative power of ictal spikes in control mice compared to Cav2.3-defcient mice.. These findings give first in vivo evidence for an essential role for Cav2.3 in LTG pharmacology and shed light on a paradoxical effect of LTG in their absence. Furthermore, LTG appears to promote ictal activity in Cav2.3-deficient mice resulting in increased neurotoxicity in the CA1 region. 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; Behavior, Animal; Calcium Channels, R-Type; Electrocorticography; Epilepsy; Fructose; Genotype; Immunohistochemistry; Kainic Acid; Lacosamide; Lamotrigine; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuroprotective Agents; Pyramidal Cells; Topiramate; Triazines

Topics: Adolescent; Anticonvulsants; Child; Child Health; Child, Preschool; Epilepsy; Female; Hong Kong; Humans; Infant; Kidney Calculi; Male; Retrospective Studies; Topiramate

This study investigated the pharmacokinetic interactions between topiramate (TPM) and concomitant antiepileptic drugs and evaluated the therapeutic concentration range of TPM and the effect of the achieved plasma concentration on the retention rate of TPM therapy.. A total of 1217 plasma samples obtained from 610 patients were retrospectively investigated, and the concentration-to-dose ratio (CD ratio) of TPM was compared among patients on various antiepileptic drug regimens. In addition, the therapeutic concentration of TPM was reviewed in patients on long-term therapy, and factors influencing the retention rate of TPM were analyzed by the Kaplan-Meier method.. Among patients using hepatic enzyme inducers (phenytoin, phenobarbital, and carbamazepine), the CD ratio was reduced by 45.4% in adults and 33.3% in children. Patients taking phenytoin concomitantly had a significantly lower CD ratio than patients taking phenobarbital or carbamazepine. Among noninducers, concomitant use of stiripentol increased the CD ratio. In 276 patients who remained on TPM therapy for more than 2 years, the mean therapeutic concentration was 5.1 mcg/mL (15.0 μmol/L). The estimated retention day was significantly higher for patients with a TPM concentration >5 mcg/mL than that for patients with a concentration <5 mcg/mL (945 versus 802 days; P = 0.007 by the log-rank test). Also, patients without hepatic enzyme inducers had a significantly higher retention rate than patients using such inducers (P = 0.002).. Concomitant use of hepatic enzyme inducers markedly reduced the plasma TPM concentration and can decrease its antiepileptic effect. A therapeutic concentration of >5 mcg/mL TPM was significantly associated with continuation of therapy, and therapeutic drug monitoring can be helpful.

Topics: Adult; Age Factors; Anticonvulsants; Child; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 Enzyme Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Male; Retrospective Studies; Topiramate

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 endoplasmic reticulum-lysosome-Golgi network plays an important role in Reelin glycosylation and its proteolytic processing. Golgi complex fragmentation is associated with the separation of Reelin from this network. Kainic acid (KA) is an excitotoxic agent commonly used to induce epilepsy in rodents. The relationship between KA-induced neuronal damage and Golgi complex fragmentation has not been investigated, leaving a major gap in our understanding of the molecular mechanism underlying the development of pathophysiology in epilepsy. We cultured primary rat cortical neurons eitherin ambient condition (control) or treated with a range of KA doses to reveal whether Golgi complex fragmentation impaired neuronal function. The half-life maximal inhibitory concentration (IC50) value of KA was detected to be approximately 5 μM, whereby at these concentrations, KA impaired neuronal viability, which was closely associated with initial Golgi complex fragmentation and subsequent reduction in both the expression and glycosylation patterns of Reelin. These findings implicate that Golgi complex fragmentation and Reelin dysfunction are key contributors to neuronal cell death in the early stage of epilepsy pathophysiology, thereby representing as novel disease biomarkers, as well as potent therapeutic targets for epilepsy.

Topics: Animals; Autoantigens; Blotting, Western; Cell Adhesion Molecules, Neuronal; Cell Survival; Cells, Cultured; Endoplasmic Reticulum; Epilepsy; Extracellular Matrix Proteins; Fluorescent Antibody Technique; Fructose; Golgi Apparatus; Kainic Acid; Lysosomes; Membrane Proteins; Mitochondria; Models, Biological; Nerve Tissue Proteins; Neurons; Protein Processing, Post-Translational; Proteolysis; Rats; Reelin Protein; Serine Endopeptidases; Topiramate

Topics: Adrenal Cortex Hormones; Adult; Anticonvulsants; Drug Hypersensitivity Syndrome; Drug Substitution; Epilepsy; Exanthema; Fructose; Humans; Male; Phenytoin; Remission Induction; Risk Factors; Time Factors; Topiramate; Treatment Outcome

Topics: Adult; Anti-Bacterial Agents; Anticonvulsants; Drug Interactions; Epilepsy; Female; Fructose; Humans; Meropenem; Peritonitis; Postoperative Complications; Thienamycins; Topiramate; Valproic Acid

Topiramate is an approved and effective drug in migraine prophylaxis. Paresthesia is the most commonly reported side effect. The primary objective of this study was to compare the frequency of topiramate-induced paresthesia in migraine headache to epileptic patients. Patients with migraine without aura and epilepsy were enrolled in this observational study. All cases were interviewed by telephone about their history of paresthesia. Confounding factors were controlled through logistic regression. The odds ratio of developing topiramate-induced paresthesia in migraine compared to epilepsy patients was 3.4. Three factors were independent contributors to developing topiramate-induced paresthesia: female sex (odds ratio 2.1), topiramate dosage (odds ratio 0.3) and duration of therapy. Our findings indicate an independent association between migraine and development of paresthesia. Migraineurs were more likely than epileptic patients to report paresthesia as topiramate adverse effects. Female sex, treatment duration and topiramate dosage contribute significantly to subsequent development of paresthesia.

Topics: Adolescent; Adult; Central Nervous System Agents; Child; Epilepsy; Female; Fructose; Humans; Logistic Models; Male; Middle Aged; Migraine Disorders; Odds Ratio; Paresthesia; Topiramate; Young Adult

To identify the factors influencing topiramate pharmacokinetics (PK) in a large population of adult patients with epilepsy using population PK analysis.. Clinical data and blood samples were collected from 550 adult patients with epilepsy treated using topiramate. Nonlinear mixed effects modeling software (NONMEM, version 7.2) was used to fit the plasma concentration to a one-compartment PK model. Demographic and clinical variables tested as potential covariates were age, sex, body weight, height, serum creatinine, creatinine clearance (CLcr), total bilirubin, prothrombin time, albumin, aspartate transaminase (AST), alanine transaminase (ALT), daily dose (DOSE), and concomitant medications (phenytoin [PHT], clobazam, carbamazepine [CBZ], valproic acid, lamotrigine, levetiracetam, oxcarbazepine [OXC], pregabalin, clonazepam, and phenobarbital [PB]).. The final PK model was CL/F (L/h)=(1.16+1.36 × PHT+1.01 × CBZ+0.643 × OXC+0.476 × PB)×(CLcr/90)(0.310)×(DOSE/100)(0.0929) (1 in patients co-medicated with each drug, 0 in otherwise) and V/F (L)=109 × (WT/62). For a typical patient with CLcr of 90 mL/min and DOSE of 100mg, co-medication with PHT, CBZ, OXC, and PB increased the CL/F to 2.52 (1.16+1.36)L/h, 2.17 (1.16+1.01)L/h, 1.803 (1.16+0.643)L/h, and 1.636 (1.16+0.476)L/h, respectively, which was 117, 87, 55, and 41% higher, respectively, than in patients without co-medication.. The apparent clearance of topiramate increased with co-medication of PHT, CBZ, OXC, and PB. This population PK model can be applied for optimizing topiramate dosage regimens in actual clinical practice.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Carbamazepine; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Models, Biological; Oxcarbazepine; Phenobarbital; Phenytoin; Topiramate; Valproic Acid; Young Adult

Generic substitution of antiepileptic drugs (AEDs) is still a matter of controversy and concern among clinicians and patients. We aimed to assess intrasubject variation in plasma concentrations of lamotrigine (LTG), levetiracetam (LEV) and topiramate (TPM) after generic substitution compared with a stable brand-name drug regimen in a population of patients with epilepsy. A retrospective analysis was performed on prospectively collected and stored data from our therapeutic drug monitoring (TDM) database for the years 2009-2014. The main outcome variable was the proportion of patients who, after switching from branded to generic formulations, showed a greater than ±20% change in AED plasma concentrations compared to the proportion of control patients showing a change in AED plasma concentrations of the same extent while receiving stable branded formulations over repeated TDM tests. Fifty patients on LTG, 27 on LEV and 16 on TPM showing at least one TDM test while receiving generic products fulfilled the inclusion/exclusion criteria for the analysis and were compared with 200 control patients for LTG, 120 for LEV and 80 for TPM. The proportion of patients showing an intrasubject change greater than ±20% in AED plasma concentrations was similar in the brand name vs generic group compared with the control one for LTG (22% vs 33%) and LEV (44% vs 38%), while it was higher in the control group for TPM (41% vs 6%, p<0.01). These are the first data in the literature about the within-patient variation in steady-state plasma concentrations of a series of stable treatments with brand-name AEDs in a real clinical setting. In conclusion, a significant interday variability in intrapatient LTG, LEV and TPM plasma concentrations can be observed even in patients stabilized with the same brand name product over time. This suggests that any change in plasma AED concentration and possible related clinical effects after generic substitution may be not necessarily related to the switch. Our results should be confirmed by large, prospective, blinded, randomized controlled studies in people with epilepsy.

Topics: Adult; Anticonvulsants; Blood Chemical Analysis; Databases, Pharmaceutical; Drug Substitution; Drugs, Generic; Epilepsy; Female; Follow-Up Studies; Fructose; Humans; Inpatients; Lamotrigine; Levetiracetam; Male; Middle Aged; Piracetam; Prospective Studies; Retrospective Studies; Topiramate; Triazines

Topiramate (TPM) is well recognized for its negative effects on language in healthy volunteers and patients with epilepsy. The aim of this study was to investigate the brain activation and deactivation patterns in TPM-treated patients with epilepsy with language impairment and their dynamic alteration during TPM withdrawal using functional magnetic resonance imaging (fMRI) with the verb generation task (VGT).. Twelve patients with epilepsy experiencing subjective language disfluency after TPM add-on treatment (TPM-on) and thirty sex- and age-matched healthy controls (HCs) were recruited. All subjects received a battery of neuropsychological tests and an fMRI scan with the VGT. Withdrawal of TPM was attempted in all patients. Only six patients reached complete withdrawal without seizure relapses (TPM-off), and these patients underwent a reassessment of neuropsychological and neuroimaging tests.. The neuropsychological tests demonstrated objective language impairments in TPM-on patients. Compared with the HCs, the bilateral medial prefrontal cortex and the posterior midline and lateral parts of the default mode network (DMN) (including the bilateral posterior cingulate cortex (PCC), the right medial prefrontal cortex, the right angular gyrus, the right inferior temporal gyrus, and the bilateral supramarginal gyrus) in TPM-on patients failed to deactivate during the VGT. Their task-induced activation patterns were largely similar to those of the HCs. After TPM withdrawal, partial improvement of both task-induced deactivation of the DMN (the left parahippocampal gyrus and the bilateral PCC) and task-related activation of the language network (the right middle frontal gyrus and the left superior occipital gyrus) was identified along with partial improvement of neuropsychological tests.. Task-induced deactivation is a more sensitive neuroimaging biomarker for the impaired language performance in patients administered TPM than task-induced activation. Disruption and reorganization of the balance between the DMN and the cortical language networks are found along with reversible TPM-related language impairment. These results may suggest an underlying brain mechanism by which TPM affects cognitive function.

Topics: Adult; Anticonvulsants; Brain Mapping; Cognition; Epilepsy; Female; Frontal Lobe; Fructose; Gyrus Cinguli; Humans; Language Disorders; Longitudinal Studies; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Topiramate; Withholding Treatment; Young Adult

To investigate the relationship between antiepileptic drug (AED) polytherapy in pregnant women and the risk of fetal malformations as prescribing practice changed, with valproate being used less often and at lower doses. Specifically, the risks associated with two of the most common AEDs included in polytherapy over recent years, levetiracetam and topiramate, were examined.. An observational cohort study in which malformation rates were analyzed in 1,461 pregnancies exposed to AED monotherapy, and in 484 exposed to antiepileptic drug combinations, from the Australian Register of Antiepileptic Drugs in Pregnancy over a 15-year period (1999-2014).. Fetal malformation rates had fallen over time in monotherapy pregnancies, but increased in polytherapy pregnancies, despite decreasing use and lower dosages of valproate. The rise in polytherapy malformation rates began around 2005 when levetiracetam and topiramate use began to increase. Excluding pregnancies involving valproate exposure, malformation rates were higher in the remaining polytherapy pregnancies as compared with the monotherapy ones (6.90% vs. 3.64%; odds ratio [OR] 1.96, 95% confidence interval [CI] 1.14-3.39). Malformation rates were similar in polytherapy pregnancies whether or not levetiracetam was included (7.14% vs. 8.38%), but were higher in polytherapy pregnancies involving topiramate (14.94% vs. 6.55%: OR 2.507, 95% CI 1.23-5.10). Logistic regression showed that topiramate in polytherapy had a positive dose relationship with teratogenicity risk (p = 0.025).. The malformation risk associated with AED polytherapy depends on the specific drugs involved. Topiramate, when used as part of AED polytherapy that did not include valproate, was associated with a dose-related increased risk of fetal malformations.

Topics: Abnormalities, Drug-Induced; Anticonvulsants; Cohort Studies; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Male; Pregnancy; Prenatal Exposure Delayed Effects; Regression Analysis; Risk Factors; Topiramate; Valproic Acid

To determine prescribing patterns of antiepileptic drugs (AEDs) in pediatric patients with confirmed diagnosis of epilepsy, and to provide knowledge of general practice of physicians.. The study was a multi-center crosssectional observational study, in specialized clinics for management of epilepsy in north, central and south Jordan. This study was conducted from January 2014 to July 2014. These were 3 from university tertiary care hospitals and 4 from governmental tertiary care hospitals.. A total of 694 pediatric patients were included. Monotherapy AED use had the highest frequency 465 (67.0%), followed by dual therapy 162 (23.3%). The frequency of monotherapy in university hospitals was lower than governmental hospitals (p<0.05); however, Polytherapy was more frequent in younger children. Two old AEDs were most frequently prescribed as a monotherapy; Valproic acid 235 (50.5%) and carbamazepine 155 (33.3%). The most common combination in dual therapy was valproic acid with carbamazepine 28 (17.3%). The second most common combinations were carbamazepine with levetiracetam 21 (13.0%) or valproic acid with levetiracetam 20 (12.3%).. Older AED remain first line drugs for use in both monotherapy and combination therapy for epileptic disorders. Polytherapy is associated with younger kids and being treated in a university hospital.

Topics: Adolescent; Anticonvulsants; Carbamazepine; Child; Child, Preschool; Cross-Sectional Studies; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Jordan; Levetiracetam; Male; Phenobarbital; Piracetam; Practice Patterns, Physicians'; Topiramate; Valproic Acid

The relative contribution of interictal epileptiform discharges (IEDs) to cognitive dysfunction in comparison with the underlying brain pathology is not yet understood in children with lesional focal epilepsy.. The current study investigated the association of IEDs with intellectual functioning in 103 children with medication-resistant focal epilepsy. Hierarchical multiple regression analyses were used to determine the independent contribution of IED features on intellectual functioning, after controlling for effects of lesional pathology, epilepsy duration, and medication. Exploratory analyses were conducted for language and memory scores as well as academic skills available in a subset of participants.. The results reveal that IEDs have a negative association with IQ with independent, additive effects documented for frequent and bilaterally distributed IEDs as well as discharge enhancement in sleep. Left-lateralized IEDs had a prominent effect on verbal intelligence, in excess of the influence of left-sided brain pathology. These effects extended to other cognitive functions, most prominently for sleep-enhanced IEDs to be associated with deficits in expressive and receptive language, reading, spelling and numerical skills.. Overall, IED effects on cognition were of a magnitude similar to lesional influences or drug effects (topiramate use). This study demonstrates an association between IEDs and cognitive dysfunction, independent of the underlying focal brain pathology.

Topics: Adolescent; Anticonvulsants; Brain; Brain Waves; Child; Cognition Disorders; Electroencephalography; Epilepsy; Female; Fructose; Humans; Intelligence; Male; Neuroimaging; Neuropsychological Tests; Regression Analysis; Retrospective Studies; Sleep; Statistics, Nonparametric; Topiramate; Wakefulness

To investigate the effects of prenatal exposure to monotherapy levetiracetam, topiramate, and valproate on child cognitive functioning.. This was a cross-sectional observational study. Children exposed to monotherapy levetiracetam (n = 42), topiramate (n = 27), or valproate (n = 47) and a group of children born to women who had untreated epilepsy (n = 55) were enrolled retrospectively from the UK Epilepsy and Pregnancy Register. Assessor-blinded neuropsychological assessments were conducted between 5 and 9 years of age. Information was collected on demographic and health variables and adjusted for in multiple regression analyses.. In the adjusted analyses, prenatal exposure to levetiracetam and topiramate were not found to be associated with reductions in child cognitive abilities, and adverse outcomes were not associated with increasing dose. Increasing dose of valproate, however, was associated with poorer full-scale IQ (-10.6, 95% confidence interval [CI] -16.3 to -5.0, p < 0.001), verbal abilities (-11.2, 95% CI -16.8 to -5.5, p < 0.001), nonverbal abilities (-11.1, 95% CI -17.3 to -4.9, p < 0.001), and expressive language ability (-2.3, 95% CI -3.4 to -1.6, p < 0.001). Comparisons across medications revealed poorer performance for children exposed to higher doses of valproate in comparison to children exposed to higher doses of levetiracetam or topiramate.. Preconception counseling should include discussion of neurodevelopmental outcomes for specific treatments and their doses and women should be made aware of the limited nature of the evidence base for newer antiepileptic drugs.

Topics: Adult; Anticonvulsants; Child; Cognition Disorders; Cross-Sectional Studies; Epilepsy; Female; Follow-Up Studies; Fructose; Humans; Levetiracetam; Male; Piracetam; Pregnancy; Prenatal Exposure Delayed Effects; Topiramate; Valproic Acid; Young Adult

We compared persistence of antiepileptic drugs (AEDs) including carbamazepine, oxcarbazepine, gabapentin, lamotrigine, topiramate, valproic acid, and phenytoin in an Asian population with epilepsy.A retrospective cohort study was conducted by analyzing Taiwan's National Health Insurance Research Database (NHIRD). Adult epilepsy patients newly prescribed with AEDs between 2005 and 2009 were included. The primary outcome was persistence, defined as the treatment duration from the date of AED initiation to the date of AED discontinuation, switching, hospitalization due to seizure or disenrollment from databases, whichever came first. Cox proportional hazard models were used to estimate the risk of non-persistence with AEDs.Among the 13,061 new users of AED monotherapy (mean age: 58 years; 60% men), the persistence ranged from 218.8 (gabapentin) to 275.9 (oxcarbazepine) days in the first treatment year. The risks of non-persistence in patients receiving oxcarbazepine (adjusted hazard ratio [HR], 0.78; 95% CI, 0.74-0.83), valproic acid (0.88; 0.85-0.92), lamotrigine (0.72; 0.65-0.81), and topiramate (0.90; 0.82-0.98) were significantly lower than in the carbamazepine group. Compared with carbamazepine users, the non-persistence risk was higher in phenytoin users (1.10; 1.06-1.13), while gabapentin users (1.03; 0.98-1.09) had similar risk. For risk of hospitalization due to seizure and in comparison with carbamazepine users, oxcarbazepine (0.66; 0.58-0.74) and lamotrigine (0.46; 0.35-0.62) users had lower risk, while phenytoin (1.35; 1.26-1.44) users had higher risk. The results remained consistent throughout series of sensitivity and stratification analyses.The persistence varied among AEDs and was better for oxcarbazepine, valproic acid, lamotrigine, and topiramate, but worse for phenytoin when compared with carbamazepine.

Topics: Adolescent; Adult; Aged; Amines; Anticonvulsants; Carbamazepine; Cyclohexanecarboxylic Acids; Epilepsy; Female; Fructose; Gabapentin; gamma-Aminobutyric Acid; Hospitalization; Humans; Lamotrigine; Male; Medication Adherence; Middle Aged; Oxcarbazepine; Phenytoin; Proportional Hazards Models; Retrospective Studies; Risk Factors; Taiwan; Topiramate; Triazines; Valproic Acid; Young Adult

The present study aimed to establish population pharmacokinetic model for phenobarbital (PB), examining and quantifying the magnitude of PB interactions with other antiepileptic drugs concomitantly used and to demonstrate its use for individualization of PB dosing regimen in adult epileptic patients.. In total 205 PB concentrations were obtained during routine clinical monitoring of 136 adult epilepsy patients. PB steady state concentrations were measured by homogeneous enzyme immunoassay. Nonlinear mixed effects modelling (NONMEM) was applied for data analyses and evaluation of the final model.. According to the final population model, significant determinant of apparent PB clearance (CL/F) was daily dose of concomitantly given valproic acid (VPA). Typical value of PB CL/F for final model was estimated at 0.314 l/h. Based on the final model, co-therapy with usual VPA dose of 1000 mg/day, resulted in PB CL/F average decrease of about 25 %, while 2000 mg/day leads to an average 50 % decrease in PB CL/F.. Developed population PB model may be used in estimating individual CL/F for adult epileptic patients and could be applied for individualizing dosing regimen taking into account dose-dependent effect of concomitantly given VPA.

Topics: Adult; Anticonvulsants; Carbamazepine; Drug Interactions; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Lamotrigine; Male; Middle Aged; Models, Biological; Nonlinear Dynamics; Phenobarbital; Topiramate; Triazines; Valproic Acid

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Anticonvulsants; Drug Therapy, Combination; Epilepsy; Fructose; Headache; Humans; Indomethacin; Male; Photic Stimulation; Topiramate

To determine the frequency of metabolic acidosis and its related factors in outpatients taking topiramate in monotherapy or as an adjuvant for the treatment of epilepsy.. Cross-sectional analysis of arterial blood gas test of epileptic patients who received topiramate during 2010 in the Epilepsy Clinic at the National Medical Center '20 de Noviembre' in Mexico. Clinical data regarding epilepsy history and management and the common symptoms of metabolic acidosis were recorded.. We studied 32 adults with epilepsy at an outpatient epilepsy clinic who were treated with topiramate in monotherapy or in combination for at least one month. Metabolic acidosis was found in all patients (HCO3<22 Eq/L); nine were taking topiramate in monotherapy, and 23 were taking at least two antiepileptic drugs (AEDs). All of the patients were asymptomatic. We found no correlation between bicarbonate levels and the dose of the drug or the duration of treatment. The dose was significantly higher in the monotherapy group, and the bicarbonate level was lower in the patients taking more than one AEDs.. The use of concomitant AEDs increases the known effects of topiramate on serum bicarbonate levels and the presence of metabolic acidosis, and these effects appear to be independent of the number of AEDs used.. Topiramato en monoterapia o en combinacion como causa de acidosis metabolica en adultos con epilepsia.. Objetivo. Determinar la frecuencia de acidosis metabolica y sus factores relacionados en pacientes tratados con topiramato solo o como adyuvante para el tratamiento de epilepsia. Pacientes y metodos. Analisis transversal de la gasometria arterial de pacientes epilepticos que recibieron topiramato durante 2010 en la clinica de epilepsia del Centro Medico Nacional 20 de Noviembre en Mexico. Se registraron datos clinicos concernientes a la epilepsia y su tratamiento, asi como de los sintomas comunes de acidosis metabolica. Resultados. Se estudiaron 32 adultos con epilepsia, quienes recibieron topiramato en monoterapia o en combinacion por lo menos durante un mes. Se encontro acidosis metabolica en todos los pacientes (HCO3 < 22 Eq/L); nueve tomaron solo topiramato y 23 tomaron por lo menos dos farmacos antiepilepticos (FAE). Todos los pacientes fueron asintomaticos. No se encontro correlacion entre los niveles de bicarbonato y la dosis del medicamento o la duracion del tratamiento. La dosis fue significativamente mayor en el grupo de monoterapia y el nivel de bicarbonato fue mas bajo en los pacientes que tomaban mas de un FAE. Conclusiones. El uso concomitante de FAE incrementa los efectos conocidos del topiramato sobre los niveles sericos de bicarbonato y la presencia de acidosis metabolica; estos efectos parecen ser independientes del numero de FAE utilizados.

Topics: Acidosis; Adult; Anticonvulsants; Cross-Sectional Studies; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Male; Prospective Studies; Topiramate

The purpose of the present study was to evaluate the efficacy and safety of topiramate (TPM) on inter-ictal headache in children with epilepsy.. Patients were interviewed regarding whether they suffered from headaches. Data obtained from each patient included seizure frequency. Inter-ictal headache was defined as a headache beginning outside an hour before or after the seizure. The study group included 85 outpatients (42 valproate-treated, 34 carbamazepine-treated, 6 combination therapy, 3 other) between 5 and 15 years old. For children with headache, TPM was administered twice daily at a total initial dose of 0.5 mg/kg/day, up to 3.0 mg/kg/day in accordance with symptoms.. Of 85 patients, 18 (21.2%) patients (8 valproate-treated, 6 carbamazepine-treated, 3 combination therapy, and 1 other) complained of inter-ictal headache. Seizure frequency was significantly higher in children with headache (2.6 times/year) than in children without headache (0.9 times/year; p < 0.0001). The responder rate (rate of patients with a > 50% reduction in headache frequency or degree) was 13/18 (72%). Six children (33.3%) achieved complete cessation for the entire 6 months. Mean dose of TPM was significantly lower in responders (1.1 mg/kg/day) than in non-responders (2.7 mg/kg/day; p < 0.001).. Headache is encountered more frequently in patients with frequent seizures. In addition, TPM represents a useful addition to the treatments available for headache in children with epilepsy. The effective dose of TPM for headache may be lower than that for seizure.

Topics: Adolescent; Anticonvulsants; Carbamazepine; Child; Child, Preschool; Epilepsy; Female; Fructose; Headache; Humans; Male; Topiramate; Treatment Outcome

Topiramate (TPM) is an effective antiepileptic drug (AED). A high proportion of patients, however, experiences cognitive adverse events (CAEs), especially in verbal fluency, memory spans, and working memory. To our knowledge, CAEs of TPM have not been studied systematically in patients with intellectual disability (ID). This may be due to the fact that many of those patients are not able to follow test instructions properly and that neuropsychological instruments are not validated for that group. Cognitive deterioration in patients with ID may thus easily be overlooked. Topiramate is in frequent use in persons with ID. We included 26 consecutive patients with epilepsy and ID in this observational study who had undergone neuropsychological examinations as part of clinical routine before and after the introduction of TPM into the therapeutic regimen (n=4) or before and after the withdrawal of TPM (n=22). Examinations under TPM showed reduced cognitive speed, reduced verbal memory, reduced verbal fluency, and reduced flexibility compared to examinations without TPM. Despite some limitations (especially small sample size, high interindividual variation of the results dependent on the degree of ID, effects of other - limited - changes in the therapeutic regimen), our study indicates that TPM in persons with epilepsy and ID may lead to CAEs comparable to those in persons with normal intelligence. Neuropsychological testing is mandatory in order not to miss CAEs that might severely impair quality of life.

Topics: Adult; Aged; Anticonvulsants; Cognition Disorders; Epilepsy; Female; Fructose; Humans; Intellectual Disability; Male; Memory, Short-Term; Middle Aged; Neuropsychological Tests; Topiramate; Young Adult

As new research has increased our understanding of epilepsy and the challenges patients with epilepsy face, the role of the nurse as an educator and advocate has grown. This article, the second in a two-part series, addresses the most important aspects of assessing and caring for patients with epilepsy-highlighting the seizure first-aid instructions that all family members of a patient with epilepsy should have; the teaching points to share with parents of young children with epilepsy; and online epilepsy resources for patients, family members, and health care professionals. The authors also discuss current medical, surgical, neurostimulatory, and dietary approaches to epilepsy treatment.

Topics: Anticonvulsants; Brain; Cognition Disorders; Consumer Health Information; Diet, Ketogenic; Drug Resistance; Epilepsy; Evidence-Based Nursing; Fructose; Humans; Internet; Levetiracetam; Medical Marijuana; Parents; Piracetam; Topiramate

Treatment decisions should be informed by high quality evidence of both the potential benefit and harms of treatment alternatives. Randomised controlled trials (RCTs) provide the best evidence regarding benefits; however information relating to serious, rare and long-term harms is usually available only from non-randomised studies (NRSs). The aim of this study was to use a checklist based on the CONSORT (Consolidating Standards for Reporting Trials) extension for harms recommendations to assess the quality of reporting of harms data in both NRSs and RCTs of antiepileptic drugs, using studies of topiramate as an example.. Seventy-eight studies were included from an online search of seven databases. Harms data was extracted from each study using a 25-point checklist. The mean number of items met was 11.5 (SD 2.96) per study. Commercially funded studies met on average 12.7 items and non-commercially funded studies met 10.08 (p value < 0.001). RCTs met on average 13.0 items and NRSs met 10.8 (p = 0.001). Multi-centre studies and commercially funded studies met significantly more items than single centre and non-commercially funded studies respectively. There was no significant difference in the mean number of items met by studies that had included adult vs. child participants, or studies published pre- vs. post-CONSORT extension for harms in 2004.. Reporting of harms is significantly better in RCTs than in NRSs of TPM, but is suboptimal overall and has not improved since the publication of CONSORT extension for harms in 2004. There is a need to improve the reporting of harms in order to better inform treatment decisions.

Topics: Adult; Aging; Anticonvulsants; Checklist; Child; Clinical Trials as Topic; Databases, Factual; Epilepsy; Fructose; Humans; Multicenter Studies as Topic; Observer Variation; Randomized Controlled Trials as Topic; Research Design; Research Support as Topic; Topiramate

Topics: Anticonvulsants; Child; Child, Preschool; Epilepsy; Female; Fructose; Humans; Infant; Male; Spasm; Topiramate

The application of artificial neural networks in the pharmaceutical sciences is broad, ranging from drug discovery to clinical pharmacy. In this study, we explored the applicability of counter-propagation artificial neural networks (CPANNs), combined with genetic algorithm (GA) for prediction of topiramate (TPM) serum levels based on identified factors important for its prediction.. The study was performed on 118 TPM measurements obtained from 78 adult epileptic patients. Patients were on stable TPM dosing regimen for at least 7 days; therefore, steady-state was assumed. TPM serum concentration was determined by high performance liquid chromatography with fluorescence detection. The influence of demographic, biochemical parameters and therapy characteristics of the patients on TPM levels were tested. Data analysis was performed by CPANNs. GA was used for optimal CPANN parameters, variable selection and adjustment of relative importance.. Data for training included 88 measured TPM concentrations, while remaining were used for validation. Among all factors tested, TPM dose, renal function (eGFR) and carbamazepine dose significantly influenced TPM level and their relative importance were 0.7500, 0.2813, 0.0625, respectively. Relative error and root mean squared relative error (%) and their corresponding 95% confidence intervals for training set were 2.14 [(-2.41) - 6.70] and 21.5 [18.5 - 24.1]; and for test set were -6.21 [(-21.2) - 8.77] and 39.9 [31.7 - 46.7], respectively.. Statistical parameters showed acceptable predictive performance. Results indicate the feasibility of CPANNs combined with GA to predict TPM concentrations and to adjust relative importance of identified variability factors in population of adult epileptic patients.

Topics: Adult; Algorithms; Anticonvulsants; Carbamazepine; Chromatography, High Pressure Liquid; Drug Interactions; Epilepsy; Female; Fructose; Glomerular Filtration Rate; Humans; Machine Learning; Male; Middle Aged; Neural Networks, Computer; Topiramate

To investigate the relationships between demographic data, seizure-related factors, anti-epileptic drugs (AEDs) taking, and depressive symptoms in patients with epilepsy (PWE), determining the major clinical risk factors of depression.. Patients with epilepsy who visited our epilepsy clinic from 2010 to 2012 were included. The clinical data were collected, and Hamilton Depression Rating Scale (HAMD), National Hospital Seizure Severity Scale (NHS3) and Pittsburgh Sleep Quality Index (PSQI) were evaluated.. A total of 116 PWE were recruited. They were divided into three groups. Age, duration of epilepsy, percentages of patients with partial seizures, history of status epilepticus (SE), using topiramate (TPM) or clonazepam (CZP), and using greater than or equal to 2 types of AEDs were all significantly higher in patients with moderate depressive symptoms than patients without depression. HAMD scores were positively correlated with age, duration of epilepsy, and the number of AEDs taking, respectively. PSQI scores were positively correlated with HAMD scores in patients with depressive symptoms. Age greater than 35 years, females, having partial seizures, history of SE, and using TPM were independent predictors of depressive symptoms in PWE by regression analysis.. Age greater than 35 years, females, having partial seizures, history of SE, and using TPM might become risk factors for depressive symptoms in PWE.

Topics: Adolescent; Adult; Age Factors; Anticonvulsants; Depression; Epilepsies, Partial; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Prospective Studies; Risk Factors; Sex Factors; Status Epilepticus; Time Factors; Topiramate; Young Adult

The primary aim of this study was to assess the risks of fetal growth restriction and birth defects in children exposed prenatally to newer and older antiepileptic drugs, using an unselected epilepsy cohort. Deliveries recorded in the compulsory Medical Birth Registry of Norway 1999-2011 formed the study population. All 2,600 children exposed to antiepileptic drugs during pregnancy were compared to all 771,412 unexposed children born to women without epilepsy. Children of untreated mothers with epilepsy served as an internal control group. The main outcomes were small for gestational age birth weight and head circumference, and major congenital malformations. Children exposed to antiepileptic drugs had a moderate risk of growth restriction. Infants exposed to topiramate had a considerable risk of microcephaly (11.4 vs. 2.4 %; OR 4.8; CI 2.5-9.3) and small for gestational age birth weight (24.4 vs. 8.9 %; OR 3.1; 95 % CI 1.9-5.3). Carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, gabapentin, and pregabalin had low malformation rates, whereas topiramate tended to have an elevated malformation rate. Valproate monotherapy was associated with a significant risk of birth defects (6.3 vs. 2.9 %; OR 2.5; CI 1.6-3.8), and specifically with septal heart defects and hypospadias. For mothers using valproate, the presence of major birth defect in one child was associated with a markedly increased risk for the siblings (42.9 vs. 6.7 %; OR 10.4; CI 2.3-46.7). Children of untreated mothers with epilepsy had malformation risk similar to the reference group. In conclusion, topiramate was associated with a substantial risk of fetal growth restriction, and possibly an increased malformation rate. Other newer-generation antiepileptic drugs had a low malformation rate. Valproate monotherapy had a significant malformation risk, especially in repeated pregnancies.

Topics: Abnormalities, Drug-Induced; Adult; Anticonvulsants; Birth Weight; Cohort Studies; Epilepsy; Female; Fetal Growth Retardation; Fructose; Humans; Infant, Newborn; Infant, Small for Gestational Age; Norway; Pregnancy; Pregnancy Complications; Registries; Risk; Topiramate; Valproic Acid

To evaluate fetal or neonatal outcomes (with a focus on major congenital anomalies) with use of topiramate monotherapy and to examine whether differences occurred in the reporting and patterns of these outcomes for pregnant women with and without epilepsy.. Spontaneous, postmarketing reports involving women who used topiramate monotherapy during pregnancy from 18 July 1995 (International Birth Date of topiramate) through 30 April 2011 were retrieved from the sponsor's (Janssen Research & Development, LLC) Global Medical Safety database. All formulations for topiramate, used as monotherapy, were selected for the analysis. Monotherapy was defined as any situation where no other AED was listed in the pregnancy case report, either as a suspect or concomitant medication, regardless of indication. Results were summarized descriptively.. A total of 1163 cases of women who used topiramate monotherapy during pregnancy (for any indication) were retrieved from the Global Medical Safety database. Since some women used topiramate for more than one indication, there were a total of 1199 reported indications for topiramate monotherapy, which were primarily for treatment of epilepsy (n=599), accounting for half of the indications, and migraine prophylaxis (n=240, 20.0%). Out of 1163 cases, pregnancy outcome was reported in 50.6% (n=589). Live birth was the most frequently reported outcome, regardless of indication (epilepsy, 78.8% [312/396]; prophylaxis of migraine, 59. 3% [48/81]; other indication, 64.4% [85/132]). Cleft lip or palate anomalies (epilepsy, n=15; migraine, n=2; other indication, n=4; and indication not reported, n=2), limb, hand, or other skeletal anomalies (epilepsy, n=13; migraine, n=2; other indication, n=0; and indication not reported, n=1), and respiratory or cardiovascular anomalies (epilepsy, n=12; migraine, n=1; other indication, n=1; and indication not reported, n=2) were the most often reported major fetal or neonatal anomalies. More reported major fetal or neonatal anomalies occurred in patients being treated for epilepsy (53/79 anomaly-indication pairs) compared with patients being treated for migraine prophylaxis (10/79 anomaly-indication pairs).. Although incidence rates cannot be calculated based on spontaneous adverse event reporting, this summary of reported pregnancy and neonatal outcomes with use of topiramate monotherapy suggests that the risk for major fetal or neonatal anomalies may differ based on the indication for topiramate.

Topics: Abnormalities, Drug-Induced; Adult; Adverse Drug Reaction Reporting Systems; Anticonvulsants; Epilepsy; Female; Fructose; Humans; Infant, Newborn; Migraine Disorders; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Topiramate

Topics: Child; Epilepsy; Fructose; Glaucoma; Humans; Male; Sturge-Weber Syndrome; Topiramate

The aim of this study was to characterize the effects of topiramate on language functions in newly diagnosed pediatric epileptic patients.. Thirty-eight newly diagnosed epileptic patients were assessed using standard language tests. Data were collected before and after beginning topiramate during which time a monotherapy treatment regimen was maintained. Language tests included the Test of Language Problem Solving Abilities, a Korean version of the Peabody Picture Vocabulary Test. We used language tests in the Korean version because all the patients were spoken Korean exclusively in their families.. All the language parameters of Test of Language Problem Solving Abilities worsened after initiation of topiramate (determine cause, 13.2 ± 4.8 to 11.2 ± 4.3; problem solving, 14.8 ± 6.0 to 12.8 ± 5.0; predicting, 9.8 ± 3.6 to 8.8 ± 4.6). Patients given topiramate exhibited a shortened mean length of utterance in words during response (determine cause, 4.8 ± 0.9 to 4.3 ± 0.7; making inference, 4.5 ± 0.8 to 4.1 ± 1.1; predicting, 5.2 ± 1.0 to 4.7 ± 0.6; P < 0.05), provided ambiguous answers during the testing, exhibited difficulty in selecting appropriate words, took more time to provide answers, and used incorrect grammar. However, there were no statistically significant changes in the receptive language of patients after taking topiramate (95.4 ± 20.4 to 100.8 ± 19.1).. Our data suggest that topiramate may have negative effects on problem-solving abilities in children. We recommend performing language tests should be considered in children being treated with topiramate.

Topics: Anticonvulsants; Child; Epilepsy; Female; Fructose; Humans; Korea; Language; Language Tests; Male; Problem Solving; Topiramate

To assess the risk of teratogenicity from maternal intake of the more widely used newer antiepileptic drugs, especially lamotrigine, levetiracetam and topiramate.. Use of confidence interval and regression methods to compare risks of foetal malformation in pregnancies in women exposed (n = 1572) and in women with epilepsy not exposed (n = 153) to antiepileptic drugs in the first trimester.. Compared with the foetal malformation rate in women with epilepsy who were untreated in the first trimester (3.3%), the malformation rates for lamotrigine (4.6%), levetiracetam (2.4%) and topiramate (2.4%), all in monotherapy, were not statistically significantly different. However, the malformation rates for topiramate as part of polytherapy (14.1%) and for valproate in both monotherapy (13.8%) and polytherapy (10.2%) were statistically significantly higher. Regression analysis of combined monotherapy and polytherapy data showed no statistically significant increased risk of teratogenesis associated with lamotrigine or levetiracetam, but a statistically significant and dose-related risk for first trimester topiramate (P = 0.01) and valproate (P < 0.0001) exposure.. Evidence from this and other studies suggests that lamotrigine and levetiracetam have low risk for teratogenesis, but that topiramate exposure early in pregnancy may be associated with dose-related anatomical teratogenesis, as valproate is already known to be.

Topics: Abnormalities, Drug-Induced; Adult; Anticonvulsants; Epilepsy; Female; Fetus; Fructose; Humans; Lamotrigine; Levetiracetam; Piracetam; Pregnancy; Registries; Risk; Topiramate; Triazines; Valproic Acid

Weight loss is one of the most frequent side effects of topiramate treatment. The aim of our study was to investigate the effect of topiramate on body mass index, serum glucose, insulin, cortisol, leptin, and neuropeptide-Y levels and the role of these variables on the pathogenesis of weight loss in prepubertal children with epilepsy.. Twenty prepubertal children with epilepsy who were treated with topiramate were enrolled in the study. Topiramate was used at a daily dose of 5 mg/kg. Body mass index and fasting insulin-to-glucose ratio were calculated. Serum glucose, insulin, leptin, neuropeptide-Y, ghrelin, and cortisol levels were measured for all patients before the treatment and at the third and sixth months of the treatment.. There were significant decreases in mean body mass index, fasting insulin-to-glucose ratio, and serum cortisol and leptin levels at the third and sixth months of the treatment compared with pretreatment levels. No significant changes were observed in serum glucose, ghrelin, neuropeptide-Y, or insulin levels.. The exact mechanism of topiramate on energy balance regulation is not clearly understood. Topiramate affects body mass index, fasting insulin-to-glucose ratio, and serum leptin and cortisol levels in prepubertal children. These changes may be key factors in weight loss due to topiramate.

Topics: Anticonvulsants; Blood Glucose; Body Mass Index; Body Weight; Child; Child, Preschool; Epilepsy; Female; Fructose; Ghrelin; Humans; Hydrocortisone; Insulin; Leptin; Male; Neuropeptide Y; Topiramate

Broad-spectrum anticonvulsants are of considerable interest as antiepileptic drugs, especially because of their potential for treating refractory patients. Such "neurostabilizers" have also been used to treat other neurological disorders, including migraine, bipolar disorder, and neuropathic pain. We synthesized a series of sulfamide derivatives (4-9, 10a-i, 11a, 11b, 12) and evaluated their anticonvulsant activity. Thus, we identified promising sulfamide 4 (JNJ-26489112) and explored its pharmacological properties. Compound 4 exhibited excellent anticonvulsant activity in rodents against audiogenic, electrically induced, and chemically induced seizures. Mechanistically, 4 inhibited voltage-gated Na(+) channels and N-type Ca(2+) channels and was effective as a K(+) channel opener. The anticonvulsant profile of 4 suggests that it may be useful for treating multiple forms of epilepsy (generalized tonic-clonic, complex partial, absence seizures), including refractory (or pharmacoresistant) epilepsy, at dose levels that confer a good safety margin. On the basis of its pharmacology and other favorable characteristics, 4 was advanced into human clinical studies.

Topics: Absorption; Amides; Animals; Anticonvulsants; Dioxanes; Dogs; Drug Evaluation, Preclinical; Drug Resistance; Epilepsy; Female; Humans; Male; Mice; Rats; Sulfonamides

To identify risk factors for hyperammonemia in pediatric patients with epilepsy.. A total of 2,944 pediatric patients (ages 0-15 years) were classified into the following three groups: a group without drug treatment (n = 445, group I), a group receiving antiepileptic drugs other than valproic acid (VPA) (n = 673, group II), and a VPA-treated group (n = 1,826, group III). Hyperammonemia was defined as a plasma ammonia level exceeding 100 μg/dl with reference to the standard range and previous reports.. The mean ammonia level of groups I, II, and III was 36.0, 56.0, and 86.8 μg/dl, respectively, and the incidence of hyperammonemia was 1.6%, 7.7%, and 31.7%, respectively. In each group, the mean ammonia level of patients aged 3 years or younger was significantly higher than that of patients aged 4-15 years. In group II, concomitant use of topiramate and zonisamide were risk factors for hyperammonemia (adjusted odds ratio [OR] 3.9, 95% confidence interval [CI] 1.7-9.2, and OR 3.5, 95% CI 1.9-6.5, respectively). In group III, the ammonia level increased in a VPA dose-dependent manner. At a VPA dose of 30 mg/kg, there was 4.3-fold increase in the incidence of hyperammonemia. The other significant risk factors identified were female gender (OR 1.3, 95% CI 1.0-1.6), symptomatic generalized epilepsy (OR 1.4, 95% CI 1.1-1.8), and the concomitant use of phenytoin (OR 4.7, 95% CI 3.3-6.9), phenobarbital (OR 2.2. 95% CI 1.6-3.2), acetazolamide (OR 6.6, 95% CI 2.5-17.2), topiramate, or zonisamide.. A young age and concomitant use of carbonic anhydrase inhibitors are associated with an increased risk of hyperammonemia regardless of whether the patient is taking VPA. In patients receiving VPA, concomitant use of phenytoin and/or phenobarbital enhances the risk of hyperammonemia. An increase in ammonia can be caused by multiple factors. Our results may help clinicians to avoid problems of hyperammonemia.

Topics: Acetazolamide; Adolescent; Age Factors; Anticonvulsants; Child; Child, Preschool; Dose-Response Relationship, Drug; Epilepsy; Female; Fructose; Humans; Hyperammonemia; Infant; Isoxazoles; Male; Phenobarbital; Phenytoin; Retrospective Studies; Risk Factors; Sex Factors; Topiramate; Valproic Acid; Zonisamide

Topics: Adult; Anticonvulsants; Coma; Diffusion Magnetic Resonance Imaging; Epilepsy; Fructose; Glasgow Coma Scale; Heat Stroke; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Tomography, X-Ray Computed; Topiramate

To study associations between patterns of fetal malformation and individual antiepileptic drugs taken during pregnancy.. Multiple variable logistic regression and other statistical analyses of data relating to 1733 fetuses from 1703 pregnancies (147 of which were not exposed to antiepileptic drugs during pregnancy).. There were statistically significant (P < 0.05) associations between (i) valproate exposure and spina bifida, malformations of the heart and great vessels, digits, skull bones, and brain, but not hypospadias, cleft palate/lip and mouth abnormalities, (ii) topiramate exposure and hypospadias and brain maldevelopments, and (iii) carbamazepine (CBZ) exposure and renal tract abnormalities.. The valproate findings are mostly in keeping with the published literature, but the topiramate finding regarding hypospadias and the association between CBZ exposure and various renal tract abnormalities raise questions of organ specific teratogenesis. More extensive data are desirable, particularly in relation to topiramate, which is being used increasingly as a migraine prophylactic in women of childbearing potential.

Topics: Abnormalities, Drug-Induced; Anticonvulsants; Australia; Epilepsy; Female; Fetal Diseases; Fructose; Humans; Male; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Regression Analysis; Risk Factors; Topiramate; Valproic Acid

Topiramate (TPM) is a broad-spectrum anticonvulsant used both as an adjunctive treatment and as monotherapy. In this study, the results from a routine therapeutic drug monitoring (TDM) service for TPM are summarized. In addition, factors influencing the variability in serum concentration of TPM and the effects of comedication on serum TPM concentration were investigated.. Serum measurements of TPM from a routine TDM database were analyzed retrospectively. Concentration-to-dose ratio (CDR) was calculated to assess pharmacokinetic variability. We compared CDRs for patients receiving TPM monotherapy and patients receiving TPM with other antiepileptic drugs, together with the effects of each comedication on TPM concentration were studied.. There were 510 samples from 476 adult patients. Serum TPM was below 2.0 mg/L or above 10.0 mg/L in 28.2% and 5.9% of samples, respectively. Although serum TPM was broadly related to prescribed dose, there was wide variation. Most patients using TPM were treated in combination with other anticonvulsants (90.8%). TPM-CDR in patients receiving TPM monotherapy was not significantly different from those receiving TPM in combination with nonenzyme inducers, but TPM-CDR was lower in patients who were taking inducers (P < 0.0001, Kruskal-Wallis test, Dunnett method).. A large interindividual variability in TPM serum concentrations was observed in this cohort of patients. TDM of TPM is useful in selected patients such as those suspected of poor compliance/absorption and those who may experience pharmacokinetic changes because of comedication or physiological changes.

Topics: Adult; Anticonvulsants; Drug Monitoring; Epilepsy; Female; Follow-Up Studies; Fructose; Humans; Male; Republic of Korea; Retrospective Studies; Topiramate

Topics: Anticonvulsants; Epilepsy; Female; Fructose; Humans; Male; Sexual Dysfunction, Physiological; Topiramate

Seven hundreds and twenty-two epileptic patients receiving topiramate (374 males, 348 females), aged from 3 month to 57 years, were followed with video-EEG control during the period of 2002-2012. Topiramate was effective in 465 (64.4%) patients, and among them the efficacy of monotherapy (72.2%) was higher compared to combined therapy (61.9%). The low efficacy was seen in 198 (27.4%) patients. The aggravation effect was noted in 59 (8.2%) of patients. Drug compliance (for >1 year) was 60.7%. In the group <1 year, the high efficacy was observed in 55.2%, low efficacy - in 34.5%, aggravation - in 10.3%. In the group 1-3 years, these indicators were 54.8%, 31.8% and 13.4%, respectively. In the pediatric population (>3 years), they were 67.3%, 26.2% and 6.5% as well as in the adult population (>18 years) - 82.1%, 16.6% and 1.3%, respectively. Thus, topiramate is a highly effective medication in the therapy of idiopathic generalized epilepsies without absences and in symptomatic/cryptogenic focal forms of epilepsy. The efficacy of topiramate raised with increasing of age while the aggravation risk decreased significantly.

Topics: Adolescent; Adult; Age Factors; Anticonvulsants; Child; Child, Preschool; Dose-Response Relationship, Drug; Electroencephalography; Epilepsy; Female; Fructose; Humans; Infant; Male; Middle Aged; Topiramate; Treatment Outcome; Young Adult

Topics: Adolescent; Adult; Aged; Anticonvulsants; Brain Injuries; Dose-Response Relationship, Drug; Epilepsy; Female; Follow-Up Studies; Fructose; Humans; Male; Middle Aged; Retrospective Studies; Time Factors; Topiramate; Treatment Outcome; Young Adult

Early treatment of epilepsy is warranted to avoid possible severe consequences. This study aimed to assess the value of treatment in a patient who developed epilepsy after major brain surgery.. Case description. A 51 years-old man had a history of putative petit mal seizures since adolescence and left frontotemporal lobectomy after a major traffic accident at age 17. He subsequently developed quickly generalizing partial complex seizures, associated with severe behavioural alterations and personality changes; the condition was left untreated. A further seizure-related loss of consciousness led to another traffic accident at age 47.. The patient was administered 200 mg/day topiramate, 600 mg/day quetiapine, 1000 mg/day valproate, 1200 mg/day gabapentin and 800 mg/day carbamazepine.. The instituted anti-epileptic treatment reduced seizure frequency and severity, but did not affect psychiatric symptomatology, which even worsened. An association between anti-epileptic drugs with mood stabilizing properties and an atypical anti-psychotic dramatically improved psychiatric symptoms, but did not prevent the patient from needing long-term healthcare.. Long-term untreated epilepsy may expose to accident proneness and further psychiatric deterioration. Early diagnosis and treatment of epilepsy may help in avoiding a potentially lethal vicious circle.

Topics: Accidents, Traffic; Aggression; Amines; Anterior Temporal Lobectomy; Anticonvulsants; Brain Injuries; Carbamazepine; Cyclohexanecarboxylic Acids; Dibenzothiazepines; Disease Progression; Early Diagnosis; Epilepsy; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Italy; Male; Middle Aged; Personality Disorders; Quetiapine Fumarate; Time Factors; Topiramate; Treatment Outcome; Valproic Acid

Antiepileptic drugs may affect the endocrine system. We investigated the effects of valproic acid and topiramate on the levels of insulin, c-peptide and adipocytokines in pre-pubertal patients with idiopathic partial and generalized epilepsy.. Forty-one children with epilepsy were included. The patients were divided into two groups (valproic acid; n = 21, topiramate; n = 20). The weight, height, body mass index and homeostasis model assessment of insulin resistance (HOMA-IR) were recorded and insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin and resistin levels were determined at 0, 6 and 12 months of therapy.. In the valproate group, weight and height increased significantly. Seven of 21 patients were overweight at the end of one year. Leptin was higher in the overweight subgroup. Although insulin and HOMA-IR increased (p < 0.05), none of the patients showed hyperinsulinism or IR. Resistin had decreased at the 6th and 12th months (p < 0.05). In the topiramate group, some statistically nonsignificant changes were demonstrated.. The mechanisms behind valproate and topiramate-related weight control are still unclear, especially in children. Valproate and topiramate affect the weight, BMI, and insulin, leptin and adipocytokine levels in prepubertal children. We suggest that further studies including more patients with a long follow-up period are necessary to draw a firm conclusion regarding an association between the treatment with these drugs and the levels of leptin, insulin and adipocytokines.

Topics: Adiponectin; Anticonvulsants; Body Mass Index; Body Weight; C-Peptide; Child; Epilepsy; Female; Fructose; Humans; Insulin; Leptin; Male; Neuropeptide Y; Nicotinamide Phosphoribosyltransferase; Resistin; Topiramate; Valproic Acid

Although it is well documented that long-term therapy with older antiepileptic drugs (AEDs) leads to an increase in risk for atherosclerosis, there has been only limited information regarding the vascular risk in patients who are treated with new AEDs. We therefore conducted a prospective longitudinal study to assess the potential effects of new AEDs on the circulatory markers for vascular risk in patients with newly diagnosed epilepsy. We recruited adult patients with epilepsy who began to receive monotherapy with one of the new AEDs, including levetiracetam (LEV), oxcarbazepine (OXC), and topiramate (TPM). Circulatory markers of vascular risk were measured twice before and after 6 months of AED monotherapy. A total of 109 patients completed the study (LEV, n = 40; OXC, n = 40; TPM, n = 29). Six months of monotherapy resulted in significant increases in low-density lipoprotein cholesterol (LEV, from 90.2 to 98.5 mg/dl, 9.2% increase, p = 0.025; OXC, from 96.5 to 103.2 mg/dl, 7.0% increase, p = 0.049), homocysteine (LEV, from 7.9 to 10.4 μm, 31.6% increase, p = 0.001; OXC, from 8.7 to 11.5 μm, 32.2% increase, p < 0.001; TPM, from 8.3 to 12.3 μm, 48.2% increase, p < 0.001), apolipoprotein B (LEV, from 63.6 to 77.4 mg/dl, 21.7% increase; OXC, from 67.0 to 83.2 mg/dl, 24.2% increase; TPM, from 66.7 to 84.4 mg/dl, 26.5% increase; all p < 0.001), and apolipoprotein B/apolipoprotein A1 ratio (LEV, from 0.51 to 0.61, 19.6% increase; OXC, from 0.52 to 0.67, 28.8% increase; TPM, from 0.50 to 0.67, 34.0% increase; all p < 0.001). Serum apolipoprotein A1 and folate were significantly decreased in TPM (from 139.1 to 132.1 mg/dl, 5.0% decrease, p = 0.014) and OXC (from 8.1 to 6.4 ng/ml, 21.0% decrease, p = 0.046) groups, respectively. There were no significant changes in total cholesterol, triglyceride, high-density lipoprotein cholesterol, lipoprotein(a), and vitamin B12 in all three groups. Our findings suggest that treatment with some new AEDs might be associated with alterations in circulatory markers of vascular risk, which could contribute to the acceleration of atherosclerosis and increased risk of vascular diseases.

Topics: Adult; Anticonvulsants; Apolipoprotein A-I; Apolipoproteins B; Atherosclerosis; Biomarkers; Carbamazepine; Cholesterol, LDL; Epilepsy; Female; Fructose; Homocysteine; Humans; Levetiracetam; Male; Oxcarbazepine; Piracetam; Prospective Studies; Risk Factors; Topiramate

A 40-year-old man with diabetes and seizure disorder was found at home unresponsive and "very hot to touch" by his father 40 minutes before emergency medical services arrival. His usual medications included topiramate, divalproex sodium, and rosiglitazone/metformin. Paramedics administered oxygen, intravenous fluids, and naloxone. They did not witness or report seizure activity. Upon emergency department arrival, the patient was unresponsive (Glasgow Coma Scale 3), hypotensive (94/50 mm Hg), and tachypneic (32 breaths per minute), with a heart rate of 60 beats per minute and elevated rectal temperature peaking at 43.2°C. His skin was hot and dry, without rash; physical examination was otherwise normal. Laboratory studies revealed severe metabolic acidosis with acute renal failure and rhabdomyolysis. In spite of sedation, intubation, and aggressive cooling measures, the patient had cardiac arrest and died approximately 2 hours after arrival. Serum topiramate and valproate concentrations were within therapeutic ranges at 8.8 μg/mL (therapeutic 2-12) and 97 μg/mL (therapeutic 50-100), respectively.

Topics: Adult; Anticonvulsants; Epilepsy; Fatal Outcome; Fructose; Heat Stroke; Humans; Male; Topiramate

Topics: Age Factors; Anticonvulsants; Delayed-Action Preparations; Drug Interactions; Epilepsy; Fructose; Humans; Topiramate

This study investigated whether long-term treatment with antiepileptic drugs (AEDs) had negative effects on statural growth and serum calcium levels in children with epilepsy in Taiwan.. Children with epilepsy treated with one prescription of AEDs (monotherapy) for at least 1 year were selected. The AEDs included valproic acid (VPA; Deparkin) in 27 children (11 boys and 16 girls) aged 4-18 years, oxcarbazepine (Trileptal) in 30 children (15 boys and 15 girls) aged 5-18 years, topiramate (Topamax) in 19 children (10 boys and 9 girls) aged 6-18 years, and lamotrigine (Lamicta) in eight children (5 boys and 3 girls) aged 5-13 years. Patients with a history of febrile convulsions were selected as the controls.. One year of VPA treatment significantly impaired the statural growth of pediatric patients with epilepsy (p < 0.005) compared with the control group. The underlying mechanism may have been due to the direct effect of VPA on the proliferation of growth plate chondrocytes rather than alterations of serum calcium.. These results raise serious concerns about the growth of pediatric epilepsy patients who use AEDs, and potentially the need to closely monitor growth in children with epilepsy and adolescents under AED treatment, especially VPA.

Topics: Adolescent; Anticonvulsants; Body Height; Bone Diseases, Developmental; Calcium; Carbamazepine; Cell Size; Cells, Cultured; Child; Child, Preschool; Chondrocytes; Epilepsy; Female; Fructose; Growth Plate; Humans; Lamotrigine; Male; Oxcarbazepine; Topiramate; Triazines; Valproic Acid

Treatment with topiramate (TPM) is known to negatively affect executive functions and verbal fluency in particular. However, judgments of cognitive side effects under TPM rarely consider clinical conditions and possible effects of epilepsy, treatment, and drug load.. This retrospective cross-sectional study in large cohorts of patients with epilepsy evaluated the impact of TPM mono- and polytherapy on verbal fluency. To isolate TPM-induced effects from those of epilepsy and antiepileptic medication in general, verbal fluency under TPM (N = 421) was compared to the performance of a matched sample of patients with an antiepileptic medication other than TPM (N = 351), untreated patients (N = 108), and healthy controls (N = 100).. Impaired verbal fluency performance was seen in 77% of the patients treated with TPM. Compared to healthy controls, verbal fluency in untreated patients was reduced by 22%, under monotherapy without TPM by 31% and under TPM monotherapy by 45%. With and without TPM, verbal fluency performance linearly decreased with each additional drug in polytherapy. On each level, performance under TPM was 21-28% worse than in the respective condition without TPM. Unimpaired performance under TPM was primarily associated with lower dose, higher education, and a later onset of epilepsy.. The majority of patients under TPM shows reduced verbal fluency. However, when taking the cumulative negative effects of epilepsy, and the concomitant drug regimen into account, TPM is associated with a 21-28% poorer performance as compared with other drugs. Additionally, the data indicate an impact of dose and reserve capacity on the occurrence of impairments.

Topics: Adolescent; Adult; Aged; Analysis of Variance; Anticonvulsants; Cohort Studies; Cross-Sectional Studies; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Neuropsychological Tests; Speech Disorders; Topiramate; Young Adult

Topics: Adult; Epilepsy; Female; Fructose; Humans; Migraine with Aura; Topiramate

The earliest records of traditional Chinese medicine (TCM) prevention and treatment of epilepsy dated back to famous "Huang Di Nei Jing." TCM "spasmolytic powder" (equal-ratio compatibility of scorpion and centipede) is a famous prescription which was recognized as a useful add-on drug for refractory epilepsy in clinical observations. Multidrug resistance gene (mdr1) product Pgp overexpression in blood-brain barrier and blood-cerebrospinal fluid barrier is well recognized as the drug resistance mechanism of refractory epilepsy. Here, we established the drug-resistant epilepsy Sprague-Dawley rat model induced by Coriaria Lactone and treated these rats with topiramate and verapamil and low dose, middle dose, and high dose of spasmolytic powder by intragastric administration for 1 week. Electroencephalogram, real-time PCR, and immunohistochemistry were respectively used to detect epileptic discharge frequencies and amplitudes and expression of mdrl mRNA and Pgp on hippocampus and temporal lobe of rats. The results showed that the seizure decreases significantly in the high- and middle-dose groups of spasmolytic powder and topiramate group; in addition, mdr1 mRNA and Pgp expressions on hippocampus and temporal lobe of these drug intervention groups were significantly less than the model group (P < 0.05). These findings indicate that inhibition of intracephalic Pgp expression is possibly one of mechanisms of spasmolytic powder treating refractory epilepsy.

Topics: Animals; Anticonvulsants; Arthropods; ATP Binding Cassette Transporter, Subfamily B, Member 1; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Electroencephalography; Epilepsy; Fructose; Hippocampus; Kindling, Neurologic; Lactones; Male; Medicine, Chinese Traditional; Rats; Rats, Sprague-Dawley; Temporal Lobe; Tissue Extracts; Topiramate; Verapamil

In this retrospective controlled study, the impact of adjunctive lacosamide (LCM) on cognition in patients with epilepsy was evaluated and compared with that of topiramate (TPM) and lamotrigine (LTG) in a naturalistic outpatient setting. Cognition was investigated by means of objective assessment of executive functions (EpiTrack®) and verbal memory and by subjective ratings of self-perceived side effects (cognition, mood, and vegetative). Quality of life was assessed using the QOLIE-10 questionnaire. Patients underwent assessment at baseline and after a median follow-up interval of 32 weeks. Forty-four patients were treated with LCM, 11 with LTG, and 15 with TPM. Treatment arms differed with regard to the age at onset of epilepsy (LTG>TPM) and to seizure control from baseline to follow-up, which was best in patients whose seizures were treated with LTG (55% vs. 16% in patients whose seizures were treated with LCM and 13% in patients whose seizures were treated with TPM). Groups did not differ in the type of epilepsy, daily drug load or drug load change, nor in baseline seizure frequency. Repeated measures statistics controlling for epilepsy onset and seizure outcome showed deteriorated executive functions with TPM (F=7.5, p=0.001). On an individual level (reliable change indices), 53% of the patients whose seizures were treated with TPM showed losses in this domain (LCM 14%, LTG 27%) and none of the patients showed improvement (LCM 23%, LTG 27%; χ(2)=11.8, p=0.019). No differences in memory, quality of life, or mood were noted among patients in the three treatment arms. Subjective cognitive complaints increased in 5 of the 9 patients whose seizures were treated with TPM (LCM 1/9, LTG 0/9; χ(2)=11.9, p=0.025). The findings of this study demonstrate for the first time that the cognitive side effect profile of LCM is comparable to that of LTG and superior to that of TPM. This is indicated by both subjective and objective measures. Given the naturalistic setting and the retrospective nature of the study, a follow-up prospective, randomized trial with larger sample sizes is required to confirm these findings.

Topics: Acetamides; Adolescent; Adult; Anticonvulsants; Cognition; Epilepsy; Executive Function; Female; Fructose; Humans; Lacosamide; Lamotrigine; Male; Memory; Middle Aged; Neuropsychological Tests; Outpatients; Quality of Life; Retrospective Studies; Topiramate; Treatment Outcome; Triazines

Topiramate (TPM), an anti-epileptic drug with >4 million users, increases renal stones in adults. We screened outpatient TPM-treated children without history of stones to estimate the prevalence of renal stones and to characterize urine stone-risk profiles.. Children taking TPM ≥1 month underwent an interview, renal ultrasound, and spot urine testing in this prospective study. Normal spot urine values were defined as: calcium/creatinine ratio ≤0.20 mg/mg (>12 months) or ≤0.60 mg/mg (≤12 months), citrate/creatinine ratio >0.50 mg/mg, and pH ≤ 6.7.. Of 41 patients with average age of 9.2 years (range 0.5-18.7), mean TPM dose of 8.0 mg/kg/day (range 1.4-23.6), and mean treatment duration of 27 months (range 1-112), two (4.9%) had renal stones. The majority of children taking TPM had lithogenic abnormalities on spot urine testing, including 21 (51%) with hypercalciuria, 38 (93%) with hypocitraturia, and 28 (68%) with pH ≥ 6.7. Hypercalciuria and hypocitraturia were independent of TPM dose and duration; urine pH increased with dose. 24-h urine parameters improved in 1 stone-former once TPM was weaned.. Asymptomatic stones were found in 2/41 (4.8%) children taking TPM. Risk factors for stones were present in the spot urine of most children, including hypocitraturia (93%) and hypercalciuria (51%), independent of TPM dose and duration. High urine pH, found in 68%, correlated with TPM dose. Pediatric specialists should be aware of increased risks for stones, hypercalciuria, hypocitraturia, and alkaline urine in children taking TPM.

Topics: Adolescent; Alkalies; Anticonvulsants; Calcium; Child; Child, Preschool; Citric Acid; Creatinine; Epilepsy; Female; Fructose; Humans; Hypercalciuria; Infant; Kidney Calculi; Male; Prevalence; Prospective Studies; Risk Factors; Topiramate

It is well known that oxidative stress plays an important role in the etiology of epilepsy. We investigated effects of selenium (Se) and topiramate (TPM) combination supplementation on antioxidant and oxidant values in control and patients with epilepsy and refractory epilepsy. For the aim, we used control (n = 19), epilepsy + TPM (n = 19), epilepsy + TPM + Se (n = 15) groups. We also used control (n = 15), refractory epilepsy (n = 15), and refractory epilepsy + Se (n = 8) groups. TPM (0.2 mg/daily) and Se, as sodium selenite (twice daily with 0.1 mg doses), were orally supplemented to the patients for 45 days. Erythrocyte lipid peroxidation levels were higher in refractory epilepsy groups than in control although its level and seizure numbers were decreased in TPM and TPM + Se supplemented groups of the patients. The erythrocyte reduced glutathione (GSH), glutathione peroxidase (GSH-Px), plasma total antioxidant status (TAS), and vitamin E concentration in refractory epilepsy group were lower than in control. However, the erythrocyte and plasma TAS, erythrocyte GSH and GSH-Px, and plasma vitamins A and C values were increased either by Se or Se + TPM in epilepsy and refractory epilepsy groups. There were no effects of TPM and Se on plasma β-carotene values in the groups. In conclusion, TPM and selenium caused protective effects on the epilepsy and refractory epilepsy-induced oxidative injury by inhibiting free radical production and supporting antioxidant redox system.

Topics: Adult; Antioxidants; Ascorbic Acid; beta Carotene; Case-Control Studies; Epilepsy; Female; Fructose; Glutathione; Glutathione Peroxidase; Humans; Lipid Peroxidation; Male; Oxidative Stress; Pilot Projects; Selenium; Topiramate; Vitamin A; Vitamin E; Young Adult

We describe a 43-year-old patient who experienced visual loss 4 years after beginning antiepileptic therapy with topiramate. Ophthalmological and neurological examinations led to a preliminary diagnosis of bilateral toxic optic neuritis. Mitochondrial genome sequence analysis detected a Leber hereditary optic neuropathy 11778G>A mutation. The possibility that topiramate might favor a conversion disease, alerts physicians to seek a history of blindness in patients undergoing chronic antiepileptic therapy.

Topics: Adult; Anticonvulsants; Blindness; Epilepsy; Fructose; Humans; Male; Mutation; Optic Atrophy, Hereditary, Leber; Topiramate; Visual Fields

Topiramate is an antiepileptic drug that has marked treatment-limiting side effects on specific aspects of cognitive performance in both patients and healthy volunteers. Because these severe side effects occur only in certain individuals, identifying genetic or environmental variables that influence cognitive response would be of great utility in determining whether to administer this drug to a patient. We gave an acute 100 mg oral dose of topiramate to 158 healthy volunteers and measured how the drug changed their performance on a diverse battery of cognitive tests. We found a wide range of responses to topiramate, and we demonstrated that not all tests in the battery were equally affected. There was no correlation between the effect of topiramate and either education level or baseline cognitive performance. Of interest, there was an up to 55-fold variation in the topiramate plasma levels of the participants. Our genome-wide association study (GWAS) of cognitive response did not reveal any genome-wide significant associations; the study was powered to find variants explaining at least 25% of the variation in cognitive response. Combining the results of this GWAS with a retrospective study of cognitive complaints in 290 epilepsy patients who received topiramate as part of their treatment also did not result in a significant association. Our results support the need for additional genetic studies of topiramate that use larger sample sizes.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Cognition; Cognition Disorders; Educational Status; Epilepsy; Female; Fructose; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Male; Middle Aged; Neuropsychological Tests; Topiramate; Young Adult

We previously demonstrated that converting patients from the enzyme-inducers phenytoin or carbamazepine to the non-inducers levetiracetam or lamotrigine reduces serum lipids and C-reactive protein (CRP). We sought to determine if the same changes would occur when patients were switched to topiramate, which has shown some evidence of enzyme induction at high doses. We also examined the effects of drug switch on low-density lipoprotein (LDL) particle concentration.. We converted 13 patients from phenytoin or carbamazepine monotherapy to topiramate monotherapy (most at doses of 100-150 mg/day). Fasting lipids, including LDL particle concentration, and CRP were obtained before and ≥6 weeks after the switch. A group of normal subjects had the same serial serologic measurements to serve as controls.. Conversion from inducers to topiramate resulted in a -35 mg/dL decline in total cholesterol (p=0.033), with significant decreases in all cholesterol fractions, triglycerides, and LDL particle concentration (p≤0.03 for all), as well as a decrease of over 50% in serum CRP (p<0.001). Alterations in cholesterol fractions and CRP remained significant when compared to those seen in normal controls.. Changes seen when inducer-treated patients are converted to TPM closely mimic those seen when inducer-treated patients are converted to lamotrigine or levetiracetam. These findings provide evidence that CYP450 induction elevates CRP and serum lipids, including LDL particles, and that these effects are reversible upon deinduction. Low-dose TPM appears not to induce the enzymes involved in cholesterol synthesis.

Topics: Adult; Aged; Aged, 80 and over; Anticonvulsants; C-Reactive Protein; Carbamazepine; Epilepsy; Female; Fructose; Humans; Lipids; Lipoproteins, LDL; Male; Middle Aged; Phenytoin; Topiramate

Topiramate, an antiepileptic drug, was synthesized with an improved protocol and identified by (1)H NMR, (13)C NMR, (1)H-(1)H COSY, HMQC and HMBC spectrum. In parallel, density functional theory (DFT) using B3LYP functional and split-valance 6-311++G** basis set has been used to optimize the structures and conformers of Topiramate. Also experimental and theoretical methods have been used to correlate the dependencies of (1)J and (2)J involving (1)H and (13)C on the C1-C2 (ω) and C1-O1 (θ) torsion angles in the glycosidic part of Topiramate. New Karplus equations are proposed to assist in the structural interpretation of these couplings. Importantly, due to the sensitivity of some couplings, most notably (2)J(H1R,H1S), (2)J(C2,H1R) and (2)J(C2,H1S) values depend on both C-C (ω) and C-O (θ) torsion angles. Analyses of experimental coupling constants for protons on the pyranose ring of Topiramate indicate a twist boat structure for Topiramate in solution. In all calculations solvent effects were considered using a polarized continuum model (PCM).

Topics: Anticonvulsants; Computer Simulation; Epilepsy; Fructose; Humans; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Solutions; Solvents; Stereoisomerism; Topiramate

To examine the possible link of acute-onset glaucoma with topiramate.. Case-control study.. A case-control study was conducted among a cohort of subjects who had visited an ophthalmologist in the Province of British Columbia, Canada from 2000 to 2007. Cases were identified as those newly diagnosed with glaucoma (ICD-9 360). For each case, 5 controls were selected and matched to the cases by age and calendar time using density-based sampling. Crude and adjusted rate ratios (RRs) for current and past use of topiramate were computed. As a sensitivity analysis, the risk of glaucoma with a positive control drug (an oral steroid) and a negative control drug (inhaled albuterol) was also assessed.. From the initial cohort of 989 591 subjects, 178 264 cases of glaucoma and 891 320 controls were identified. There was a slight increase in the risk of glaucoma among current users of topiramate (RR = 1.23 [95% confidence interval (CI), 1.09-1.40]). This risk was further elevated among new users of the drug (RR = 1.54 [95% CI, 1.09-2.17]). No increase in the risk of glaucoma requiring drug therapy was observed among current topiramate users (RR = 1.09 [95% CI, 0.80-1.61]).. We found an increase in the risk of glaucoma with first-time users of topiramate. Future studies are needed to confirm these findings.

Topics: Acute Disease; Aged; Anticonvulsants; British Columbia; Case-Control Studies; Databases, Factual; Epilepsy; Female; Fructose; Glaucoma, Angle-Closure; Humans; Incidence; Intraocular Pressure; Male; Risk Factors; Topiramate

Antiepileptic drugs are generally used to control the cortical hyperexcitable states. But some of them are also effective on the peripheral nervous system, so they may be used in some states like neuropathic pain. Several recent reports suggest the possible effects of antiepileptic drugs on peripheral nerve excitability. Strength duration time properties gives an indirect idea about the persistent, paranodal sodium (Na) channels and may indirectly reflect the peripheral nerve excitability. Topiramate suppresses the cortical hyperexcitability, but previous studies could not prove a significant effect of topiramate on peripheral nerves. The aim of this study is to investigate the probable nerve excitability changes caused by topiramate.. Forty migraine patients and 40 controls were included in the study. Median motor and sensory conduction parameters were recorded. Strength duration properties were also recorded from abductor pollicis longus muscle, with the stimulation of median nerve. The electrophysiological studies were repeated 4 weeks after the initiation of topiramate in the treatment group.. Nerve conduction parameters were not significantly affected by 4-week topiramate treatment. But the strength duration time constant decreased significantly, reflecting a reduction in the excitability. This decrement seemed to be more obvious in those in whom topiramate was also clinically useful.. The method used demonstrated a probable effect of topiramate on the peripheral nerve excitability.

Topics: Action Potentials; Adult; Anticonvulsants; Electromyography; Epilepsy; Evoked Potentials, Motor; Evoked Potentials, Somatosensory; Female; Fructose; Humans; Neural Conduction; Peripheral Nerves; Topiramate; Wrist

Epileptic spasms (ES) beyond infancy are a highly refractory type of seizures that require the development of an effective treatment. We therefore studied the efficacy and safety of topiramate (TPM), which is a drug that is indicated to be effective for intractable childhood epilepsy, for ES.. Out of 58 children with ES, we enrolled 33 patients treated with TPM at ≤ 12 years of age. The administration of TPM was limited to cases of epilepsies that were resistant to any other potent treatment. We retrospectively investigated the efficacy of TPM for seizures and changes in electroencephalogram (EEG) findings.. The median age at the start of TPM treatment was 5 years, 8 months. All patients had ES and 28 also had tonic seizures. As for the efficacy of TPM for all seizures, five patients became seizure-free and two had a ≥ 50% reduction in seizures. Seizure aggravation was observed in six patients. Of 29 patients whose EEG findings were compared before and during TPM treatment, nine showed EEG improvement with reduced epileptic discharges. Adverse effects were observed in 13 patients and included somnolence, anorexia, and irritability. In general, TPM was well tolerated.. TPM can be effective at suppressing very intractable ES in a proportion of patients who do not respond to any other treatment. The efficacy of TPM may be predictable based on EEG changes observed early in the course of treatment. TPM is promising for the treatment of extremely intractable childhood epilepsy and it has largely tolerable adverse effects.

Topics: Anticonvulsants; Child; Child, Preschool; Electroencephalography; Epilepsy; Female; Fructose; Humans; Infant; Infant, Newborn; Male; Retrospective Studies; Topiramate; Treatment Outcome

Newer antiepileptic drugs (AEDs) are widely used in patients with epilepsy. There is still insufficient documentation regarding pharmacokinetic variability of these AEDs in different patient groups.. The purpose of this study was to compare age and comedication as factors contributing to pharmacokinetic variability between 4 newer AEDs (lamotrigine, levetiracetam, oxcarbazepine, and topiramate) among patients with refractory epilepsy.. Data regarding age, gender, use of AEDs, daily doses, and serum concentration measurements were retrieved from a therapeutic drug monitoring database, from patients admitted to the National Center for Epilepsy, Norway, 2007-2008.. In total, 1050 patients were included, 111 younger children (2-9 years), 137 older children (10-17 years), 720 adults (18-64 years), 82 elderly (65-93 years). Fifty percent of the patients were prescribed polytherapy, in 88 different combinations. The interindividual pharmacokinetic variability was extensive, as illustrated by a 10-fold variability in serum concentration compared with dose. Age affected the apparent clearance of levetiracetam to the largest extent, as shown by a 60% increase in younger children and a 40% reduction in the elderly, respectively, compared with adults. Comedication altered the clearance of lamotrigine to the greatest extent ±70% because it is affected by both enzyme inducers and inhibitors. Hepatic enzyme inducers increased the clearance of levetiracetam and topiramate by 25% and oxcarbazepine by 75%. Valproic acid reduced the clearance of topiramate by 25%.. Age and comedication are important contributors to pharmacokinetic variability. Age had the greatest impact on levetiracetam, and comedication affected the clearance of each of the 4 AEDs investigated in this study. Pharmacokinetic drug interactions must be carefully considered when multidrug therapies are prescribed. Therapeutic drug monitoring is a valuable tool for individualizing AED therapy.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Anticonvulsants; Carbamazepine; Child; Child, Preschool; Drug Monitoring; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Lamotrigine; Levetiracetam; Male; Middle Aged; Oxcarbazepine; Piracetam; Topiramate; Triazines; Young Adult

The objective of this study was to evaluate the association between the use of monotherapy topiramate in pregnancy and cleft lip with or without cleft palate (CL/P) in the offspring.. Data from the Slone Epidemiology Center Birth Defects Study (BDS) from 1997 to 2009 and the National Birth Defects Prevention Study (NBDPS) from 1997 to 2007 were analyzed. Conditional logistic regression was used to compare the first-trimester use of topiramate monotherapy to no antiepileptic drug use during the periconceptional period between the mothers of infants with CL/P and the mothers of controls for each study separately and in pooled data.. The BDS contained 785 CL/P cases and 6986 controls; the NBDPS contained 2283 CL/P cases and 8494 controls. The odds ratios (exact 95% confidence intervals) for the association between topiramate use and CL/P were 10.1 (1.1-129.2) in the BDS, 3.6 (0.7-20.0) in the NBDPS, and 5.4 (1.5-20.1) in the pooled data.. First-trimester use of topiramate may be associated with CL/P.

Topics: Adult; Anticonvulsants; Case-Control Studies; Cleft Lip; Cleft Palate; Epilepsy; Female; Fructose; Humans; Incidence; Pregnancy; Pregnancy Trimester, First; Prenatal Exposure Delayed Effects; Prevalence; Risk; Topiramate; Young Adult

Topiramate (topamax) is an antiepileptic drug of the new generation that was first registered and introduced in clinical practice in 1995. Due to its effective clinical properties, the drug is used widely all over the world including Russia where it has been using since 1999. Topamax is a principally new antiepileptic drug (AED) with the unique mechanism of action, favorable pharmacokinetics, high efficacy and safety. During its existence, it is widely accepted as an AED of first choice for additional and initial treatment of many forms of epilepsy in children over 2 years old and adults including old patients of both sexes. The drug can be successfully used as monotherapy and as well as polytherapy in treatment of most severe and "catastrophic" epilepsies resistant to any previous treatment.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Child; Child, Preschool; Drug Interactions; Drug Therapy, Combination; Epilepsy; Fructose; Humans; Middle Aged; Russia; Topiramate; Treatment Outcome; Young Adult

We investigated the mechanism of topiramate-related appetite loss and exposed its relationship to body weight, body mass index, body fat index, and serum insulin, lipid, leptin, neuropeptide-Y, cortisol, ghrelin, and adiponectin levels. Twenty children with epilepsy were evaluated at baseline and months 3 and 6 of treatment. Their body fat index, leptin, and neuropeptide-Y levels significantly decreased at month 3, whereas significant decreases occurred in body weight, body mass index, body fat index, neuropeptide-Y, cholesterol, and cortisol levels of patients at month 6 compared with baseline. Weight loss during topiramate treatment was attributed to loss of appetite and reduced food intake caused by reductions in neuropeptide-Y. To the best of our knowledge, this study is the first to describe reductions in neuropeptide-Y with topiramate use in humans.

Topics: Adiponectin; Adiposity; Anticonvulsants; Appetite; Body Mass Index; Body Weight; Child; Epilepsy; Female; Fructose; Ghrelin; Humans; Insulin; Leptin; Male; Neuropeptide Y; Topiramate

Newer anti-epileptic drugs (nAEDs) have been introduced in Japan, including zonisamide (ZNS), gabapentine (GBP), topiramate (TPM), lamotrigine (LTG), and levetiracetam (LEV). Because nAEDs have different properties from older AEDs, they may provide a better control of the seizures and a more favorable safety and tolerability profile. Indeed, the systematic meta-analyses of randomized control trials demonstrated that the odds ratios for 50% responder rate were ZNS 2.7-2.99, GBP 2.02-2.29, TPM 4.07-5.22, LTG 2.32-2.87, and LEV 3.75-5.33, indicating their clinical efficacy. These studies also showed that the odds ratios for discontinuation were ZNS 1.78-4.23, GBP 0.99-1.36, TPM 2.38-2.56, LTG 1.16-1.19, and LEV 0.97-1.26, indicating their good tolerability. In the guidelines and the expert opinions, it was demonstrated that nAEDs can be used as the second-line drugs for both partial and generalized seizures. Furthermore, because nAEDs may have fewer drug-interactions, fewer adverse effects, and different mechanisms, it was also demonstrated that nAEDs are rather ideal as an add-on drug. It was also reported that nAEDs are less harmful for females of reproductive age.

Topics: Amines; Anticonvulsants; Cyclohexanecarboxylic Acids; Epilepsy; Female; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Isoxazoles; Lamotrigine; Levetiracetam; Piracetam; Pregnancy; Pregnancy Complications; Topiramate; Triazines; Zonisamide

An open pilot study to evaluate the effect of pregabalin (PGB) as add-on therapy on seizure control, quality of life, and anxiety in patients with brain tumour-related epilepsy (BTRE).. We recruited 25 consecutive patients with BTRE and uncontrolled seizures. At baseline and during follow-up, patients underwent a complete physical and neurological examination and were evaluated using the QOLIE 31P (V2), EORTC QLQ C30, Adverse Events Profile, and Hamilton Anxiety Rating Scale (HAM-A). At baseline, a seizure diary was given.. During follow-up, 17 patients underwent chemotherapy, none underwent radiotherapy, 9 had disease progression, and 3 died. Mean duration of follow-up was 4.1 months. Mean PGB dosage was 279 mg/day. At baseline, mean weekly seizure frequency was 5.3 (±10) and at last available follow-up visit was 2.8±5. This difference was statistically significant (p=0.016). The responder rate was 76%. Ten patients dropped out; 4 as a result of seizure worsening, 1 as a result of unchanged seizure frequency, 3 as a result of a lack of compliance, and 2 as a result of side effects. Based on the QOLIE-31-P, a significant improvement of the subscale "seizure worry" (p=0.004) and a significant decrease in distress scores related to AEDs and social life (p=0.009 and p=0.008, respectively) were observed. A significant decrease in HAM-A score (p=0.002) was documented. CONCLUSIONS; These data indicate that PGB may represent a valid alternative as add-on treatment in this patient population, based on its efficacy on seizure control and anxiety.

Topics: Adult; Aged; Anticonvulsants; Anxiety; Benzodiazepines; Brain Neoplasms; Carbamazepine; Clobazam; Drug Therapy, Combination; Epilepsy; Female; Fructose; gamma-Aminobutyric Acid; Humans; Lamotrigine; Levetiracetam; Male; Middle Aged; Oxcarbazepine; Phenobarbital; Pilot Projects; Piracetam; Pregabalin; Quality of Life; Topiramate; Treatment Outcome; Triazines; Valproic Acid; Young Adult

Aromatic amides comprising branched aliphatic carboxylic acids and 4-aminobenzenesulfonamide were evaluated for their inhibition of carbonic anhydrase (CA) isoforms. Of the most anticonvulsant-active compounds (2, 4, 13, 16, and 17), only 13, 16, and 17 were potent inhibitors of CAs VII and XIV. Compounds 9, 14, and 19 inhibited CA II, while 10 and 12 inhibited all isoforms. Structural studies suggest that differences in the active sites' hydrophobicity modulate the affinity of the inhibitors.

Topics: Anticonvulsants; Binding Sites; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Crystallography, X-Ray; Epilepsy; Humans; Hydrophobic and Hydrophilic Interactions; Protein Isoforms; Structure-Activity Relationship; Sulfonamides

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

Carbonic anhydrase (CA) inhibitors topiramate and zonisamide can induce metabolic acidosis in some patients. Our aims were to assess the prevalence and severity of this acidosis and to determine its predictors.. For 70 patients established on treatment with topiramate (n=55) or zonisamide (n=14) or both (n=1), we measured electrolytes, and genotyped single nucleotide polymorphisms (SNPs) in the main renal CA isoenzymes (II, IV and XII).. Twenty-six percent of patients had a metabolic acidosis (serum bicarbonate <20 mmol/l). The mean serum bicarbonate of patients taking topiramate was significantly lower than those taking zonisamide (P=0.002). We found no association between serum bicarbonate and the dose of drug or the duration of treatment. Serum bicarbonate levels were associated with the CA type XII SNPs rs2306719 (P=0.006 by one-way analysis of variance) and rs4984241 (P=0.015), but this association was not strong enough to survive correction for multiple testing.. The development of acidosis with topiramate and zonisamide is not determined by drug dose or by treatment duration, but may be influenced by polymorphisms in the gene for CA type XII. The aforementioned SNPs lie 9.8 kb apart in intron 1 of the CA type XII gene, and deserve further study in a larger cohort of patients.

Topics: Acid-Base Equilibrium; Acidosis, Renal Tubular; Adult; Aged; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Epilepsy; Female; Fructose; Genome-Wide Association Study; Humans; Isoxazoles; Male; Middle Aged; Polymorphism, Single Nucleotide; Prevalence; Severity of Illness Index; Topiramate; Young Adult; Zonisamide

Increase in neuronal Ca(2+), activation of hippocampus N-methyl-D-aspartate receptor (NMDAR) and defects in enzymes such as brain cortex microsomal membrane Ca(2+)-ATPase (MMCA) are thought to play a role in epilepsy. Topiramate (TOP) is a novel drug with broad antiepileptic effect, and its effect on brain cortex MMCA is not known. We investigated effects of TOP on pentylentetrazol (PTZ)-induced MMCA activity and NMDAR subunits in rat brain.. Thirty-two rats were randomly divided into four equal groups. The first group and second groups were used for the control and PTZ groups, respectively. 50 and 100 mg TOP were administered to rats constituting the third (TOP50) and fourth (TOP100) groups for 7 days, respectively. At the end of 7 days, all groups except the first received a single dose PTZ. Brain and hippocampus samples were taken at 3 hrs after PTZ administration.. The microsomal MMCA activity was lower in the PTZ group than in control although the MMCA activities were higher in the treatment group than in PTZ group. Brain cortex total calcium levels, the hippocampus NMDAR 2A and 2B subunit concentrations were higher in the PTZ group than in control although their concentrations were decreased by TOP50 and TOP100 administration. Total brain cortex calcium and hippocampus NMDAR 2A and 2B subunit concentrations were higher in TOP100 group than in TOP50 group.. The two doses of TOP modulated MMCA activity, total brain cortex calcium and hippocampus NMDAR 2A and 2B subunit concentrations in the epileptic rats.

Topics: Animals; Calcium; Calcium-Transporting ATPases; Epilepsy; Fructose; Hippocampus; Homeostasis; Intracellular Membranes; Male; Microsomes; Pentylenetetrazole; Protein Subunits; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Topiramate

Clobazam (CLB), Topiramate (TOP) and Lamotrigine (LAM) are newer second-line antiepileptic drugs (AEDs) used in children. This is a single-centre retrospective observational study of the efficacy, tolerability and retention rate in 224 separate treatment episodes in 194 children, aged 0.1-16.7 years (median 9.4) over an 8 year period. The median age of epilepsy onset was 3.3 years (range 0-15.1). 79% started CLB, TOP or LAM as at least the 3rd AED, with 39% having been withdrawn from at least 2 AEDs. 53% had generalised and 37% idiopathic epilepsies. The maintenance doses for CLB ranged 0.12-3.50 mg/kg/day (mean 0.7); for TOP 0.45-32.0 mg/kg/day (mean 7.1) and for LAM 1.13-16.0 mg/kg/day (mean 5.6). The study comprised 75 person-treatment years for CLB, 56 for TOP, 124 for LAM.. CLB, TOP and LAM were well tolerated with 51%, 37% and 69% remaining on treatment beyond 1 year respectfully. 1 serious adverse event for CLB (inducing seizures) and 2 for LAM (rashes) were reported, and 60%, 47% and 39% had possibly and probably related adverse events for CLB, TOP and LAM respectively. Beyond 12 months seizure improvement (< 50% seizure frequency compared to baseline) was reported in 43%, 35% and 44% on CLB, TOP and LAM, including 5% and 8% remaining seizure free on CLB and LAM respectively.. Our results demonstrate the efficacy and tolerability of CLB, TOP and LAM in children with difficult to treat epilepsies and a good response in CLB and LAM, and a reasonable response in TOP beyond 12 months.

Topics: Adolescent; Benzodiazepines; Child; Child, Preschool; Clobazam; Epilepsy; Exanthema; Female; Fructose; Humans; Infant; Lamotrigine; Male; Patient Compliance; Retrospective Studies; Sleep Wake Disorders; Topiramate; Treatment Outcome; Triazines

Causes of losing the pharmacological remission with duration of more than one year have been analyzed in 220 patients with epilepsy. The most often cause of losing control of seizures was switching from brand antiepileptic drugs to generic analogue (60,4% of patients) with 28,2% of them being switched to topiramate generics. The results of switching of 160 patients from the brand form of topiramate (topamax) to its generics were compared to those in the control group of 52 patients who continued to receive the original form. As a result of switching the remission was lost in 75,6% of patients, epileptic status in 3,75%; 51,9% of patients needed emergency care and hospitalization. Switching back to original medication was done in 86,2% of patients with the following increasing of initial doses of topamax in 58,0% and transition from mono- to polytherapy in 60,0%. The baseline level of seizure control has been achieved only in 32,9% of patients.

Topics: Adolescent; Adult; Anticonvulsants; Drug Substitution; Drugs, Generic; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Recurrence; Topiramate; Treatment Failure; Young Adult

Topiramate is an antiepileptic medicine that has been used adjunctively in the treatment of refractory seizures in Japan since 2007. Topiramate has been shown to inhibit specific carbonic anhydrase activity in the kidney and may induce a distal type of renal tubular acidosis. Case 1 : A 22-year-old male was referred to our hospital after complaining of left flank pain. He developed a seizure disorder and had been using topiramate for 4 months. Drip infusion pyelography showed a left ureteral stone. Case 2 : A 7-year-old boy presented with gross hematuria. He developed West syndrome and had been using topiramate for 6 months. A computed tomographic scan showed a right kidney stone.

Topics: Anticonvulsants; Child; Epilepsy; Fructose; Humans; Infant; Kidney Calculi; Male; Spasms, Infantile; Topiramate; Urolithiasis; Young Adult

We present a woman with epilepsy secondary to a lesion in the left frontal lobe. She developed episodes of disorientation and behavioral changes. She was taking valproic acid (1500 mg/day), topiramate (200 mg/day), and phenobarbital (100 mg/day). During an episode, the EEG revealed moderate encephalopathy and ammonia levels were increased (195 μg/dL, reference range: 11-60 μg/dL). Episodes ceased after withdrawal of valproic acid.

Topics: Drug Synergism; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Hyperammonemia; Middle Aged; Neurotoxicity Syndromes; Phenobarbital; Topiramate; Valproic Acid

4-Aminopyridine (4-AP) is a convulsing agent that in vivo preferentially releases Glu, the most important excitatory amino acid neurotransmitter in the brain. Here the ionic dependence of 4-AP-induced Glu release and the effects of several of the most common antiepileptic drugs (AEDs) and of the new potential AED, vinpocetine on 4-AP-induced Glu release were characterized in hippocampus isolated nerve endings pre-loaded with labelled Glu ([3H]Glu). 4-AP-induced [3H]Glu release was composed by a tetrodotoxin (TTX) sensitive and external Ca2+ dependent fraction and a TTX insensitive fraction that was sensitive to the excitatory amino acid transporter inhibitor, TBOA. The AEDs: carbamazepine, phenytoin, lamotrigine and oxcarbazepine at the highest dose tested only reduced [3H]Glu release to 4-AP between 50-60%, and topiramate was ineffective. Vinpocetine at a much lower concentration than the above AEDs, abolished [3H]Glu release to 4-AP. We conclude that the decrease in [3H]Glu release linked to the direct blockade of presynaptic Na+ channels, may importantly contribute to the anticonvulsant actions of all the drugs tested here (except topiramate); and that the significantly greater vinpocetine effect in magnitude and potency on [3H]Glu release when excitability is exacerbated like during seizures, may involve the increase additionally exerted by vinpocetine in some K+ channels permeability.

Topics: 4-Aminopyridine; Animals; Anticonvulsants; Calcium; Carbamazepine; Drug Interactions; Epilepsy; Fructose; gamma-Aminobutyric Acid; Glutamic Acid; Hippocampus; In Vitro Techniques; Lamotrigine; Male; Nerve Endings; Oxcarbazepine; Phenytoin; Potassium Channel Blockers; Rats; Rats, Wistar; Sodium; Sodium Channel Blockers; Tetrodotoxin; Topiramate; Triazines; Tritium; Vinca Alkaloids

We ran this study to assess the incidence of nephrolithiasis in a group of children on topiramate (TPM) therapy for at least 1 year.. In this retrospective observational surveillance study, we reviewed the medical charts of children on TPM for at least 1 year seen at the pediatric neurology department during the period from 2005 to 2010 at King Fahad Medical City. Children with a normal baseline ultrasound report were included. Follow-up ultrasound reports after at least 1 year were collected. However, patients with any evidence of chronic illness or medications that may affect the kidney functions in addition to those who are not compliant with the prescribed dose were excluded. Family history of renal stones, symptoms suggestive of urologic disorders, and comorbidities were recorded.. Medical charts of 96 children on TPM with a mean age of 6.9 (±3.8) years were reviewed; 52 (54.2%) of the children were male. The follow-up ultrasound showed that five children (5.2%) had developed kidney stones. The occurrence of kidney stones was found in four female patients (80%) versus one male (20%) (p > 0.05).. Long-term use of TPM may result in increased incidence of asymptomatic kidney stones in the pediatric population. Hence, routine baseline and follow-up ultrasound of the urinary system should be recommended during the use of TPM in children.

Topics: Age Factors; Anticonvulsants; Child; Epilepsy; Female; Fructose; Humans; Incidence; Kaplan-Meier Estimate; Kidney Calculi; Male; Retrospective Studies; Sex Factors; Topiramate

Seventy-two elderly patients with a possible diagnosis of epilepsy were studied. A study included the evaluation of anamnesis, clinical and neurological examination, EEG and/or video-EEG-monitoring, MRI of the brain. The follow-up period was 1-5 years (on average 3 years). Epilepsy was confirmed in 58 cases. Symptomatic partial epilepsy was diagnosed in 43,1% patients, cryptogenic - in 55,2%. Cerebrovascular accidents were the most frequent cause of symptomatic epilepsy. The distinct feature of the cohort studied was the non-compliance recorded in a half of all patients. In the end of the study, 46,6% patients received carbamazepine, 34,5% - valproate, 24,1% - phenobarbital, 13,8% - topiramate, 3,4% - phenytoin, 1,7% - lamotrigine and 12,1% of patients did not use antiepileptic drugs. Clinical features, efficacy of diagnosis and treatment as well as reasons of non-compliance in elderly epileptic patients were described and analyzed.

Topics: Aged; Aged, 80 and over; Aging; Anticonvulsants; Carbamazepine; Electroencephalography; Epilepsies, Partial; Epilepsy; Female; Fructose; Humans; Lamotrigine; Magnetic Resonance Imaging; Male; Middle Aged; Patient Compliance; Phenobarbital; Phenytoin; Topiramate; Triazines; Valproic Acid

The use of topiramate therapy to control the neuropsychiatric and behavioral disturbances in individuals with mental and/or developmental disabilities with co-occurring psychiatric disturbances has become a standard of practice in many long-term care assisted living facilities. With increased utilization of this anticonvulsant, there has been a rise in the number documented cases of agitation and/or aggressive behavior associated with topiramate therapy. It is the purpose of this article to explore the current literature documenting the connection between topiramate utilization and the development of aggressive and/or agitated behavior.

Topics: Adult; Aggression; Anticonvulsants; Epilepsy; Fructose; Humans; Male; Mental Disorders; Psychomotor Agitation; Topiramate

The authors report on the case of a 6-week-old boy who presented with infantile spasms. At 2.5 months of age, the patient underwent a right hemispherectomy. Approximately 3 months postoperatively, the patient presented with left coronal craniosynostosis. Subsequent cranial vault remodeling resulted in satisfactory cosmesis. Four years after surgery, the patient remains seizure free without the need for anticonvulsant medications. The authors believe this to be the first reported case of iatrogenic craniosynostosis due to hemispherectomy, and they describe 2 potential mechanisms for its development. This case suggests that, in the surgical treatment of infants with intractable epilepsy, minimization of brain volume loss through disconnection techniques should be considered, among other factors, when determining the best course of action.

Topics: Adrenocorticotropic Hormone; Anticonvulsants; Clonazepam; Craniosynostoses; Craniotomy; Electroencephalography; Epilepsy; Fructose; Hemispherectomy; Humans; Infant; Male; Postoperative Complications; Spasms, Infantile; Tomography, X-Ray Computed; Topiramate

Topiramate (TPM) has been shown to be effective for epileptic spasms (ES) in children, but there is little clinical experience with TPM use in Japan. We report three tuberous sclerosis (TS) patients with relapsed ES, who became spasm-free while receiving TPM treatment. All three patients were treated with a starting dose of 0.5 mg/kg/day. The dosage was increased by 0.5 mg/kg/day every 2 weeks. Although the dose of TPM and the period until the relapsed ES subsided differed among these patients, spasm frequency was clearly reduced by a 1 mg/kg/day dose of TPM. Therefore, efficacy against relapsed ES appeared within one month in all three patients. All three became spasm-free, and there have been no ES relapses for more than 5 months to date. In case 2, seizures were well controlled by TPM alone. Cases 2 and 3 were able to discontinue zonisamide treatment. No adverse effects occurred in any of these patients.

Topics: Adolescent; Anticonvulsants; Drug Administration Schedule; Epilepsy; Female; Fructose; Humans; Infant; Male; Recurrence; Topiramate; Treatment Outcome; Tuberous Sclerosis

Topics: Anticonvulsants; Epilepsy; Expert Testimony; Fructose; Humans; Teratogens; Topiramate

Older enzyme-inducing antiepileptic drugs (AEDs) may induce supraphysiologic plasma concentrations of total (t) homocysteine (Hcy). The aim of the present study was to investigate the effect of new AEDs on plasma tHcy levels.. Patients 18-50 years of age, on AEDs monotherapy, with no other known cause of hyper-tHcy were enrolled. Plasma tHcy, folate, vitamin B(12), and AEDs levels were determined by standard high-performance liquid chromatography (HPLC) methods. Methylenetetrahydrofolate-reductase (MTHFR) polymorphisms were checked using Puregene genomic DNA purification system (Gentra, Celbio, Italy). A group of healthy volunteers matched for age and sex was taken as control.. Two hundred fifty-nine patients (151 on newer and 108 on older AEDs) and 231 controls were enrolled. Plasma tHcy levels were significantly higher [mean values, standard error (SE) 16.8, 0.4 vs. 9.1, 0.2 microm; physiologic range 5-13 microm] and folate lower (6.3, 0.1 vs. 9.3, 0.1 nm; normal > 6.8 nm) in patients compared to controls. Patients treated with oxcarbazepine, topiramate, carbamazepine, and phenobarbital exhibited mean plasma tHcy levels above the physiologic range [mean values (SE) 16 (0.8), 19.1 (0.8), 20.5 (1.0), and 18.5 (1.5) microm, respectively]. Conversely, normal tHcy concentrations were observed in the lamotrigine and levetiracetam groups [both 11.1 (0.5) microm].. Oxcarbazepine and topiramate might cause hyper-tHcy, most likely because of the capacity of these agents to induce the hepatic enzymes. Because literature data suggest that hyper-tHcy may contribute to the development of cerebrovascular diseases and brain atrophy, a supplement of folate can be considered in these patients to normalize plasma tHcy.

Topics: Adolescent; Adult; Anticonvulsants; Carbamazepine; Enzyme Induction; Epilepsy; Female; Folic Acid; Fructose; Genotype; Humans; Hyperhomocysteinemia; Lamotrigine; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Oxcarbazepine; Phenobarbital; Polymorphism, Genetic; Topiramate; Triazines; Vitamin B 12

Antiepileptic drug (AED) use in young people is increasing. However, evidence of its use at a multinational level is limited. This study aims to characterize AED prescribing in the young in three European countries and to assess the capacity of drug safety surveillance.. A retrospective cohort study was conducted in 2001-2005 using primary care databases: PEDIANET (Italy, 0-11 years), IPCI (The Netherlands, 0-18 years), and IMS Disease Analyzer (United Kingdom, 0-18 years). Prescribing prevalence was calculated by country, patient age, and drug type.. In 2005, AED prevalence in children (0-11 years) was highest in Italy [3.9 subjects/1,000 person-years (PY)] followed by the United Kingdom (3.0 subjects/1,000 PY) and The Netherlands (2.2 subjects/1,000 PY). Over the study period, prescribing prevalence in 0-11 year olds was stable in all countries. In contrast, a steady rise of AED prevalence was observed in adolescents (12-18 years) in the United Kingdom (p = 0.0003) but not in The Netherlands (p = 0.88). All countries showed a slight increase in prevalence for newer AEDs. Simultaneously, the prevalence of conventional AEDs decreased in The Netherlands and Italy, but not in the United Kingdom. In 2005, lamotrigine use was highest in The Netherlands and the United Kingdom, whereas topiramate was favored in Italy.. In Europe, conventional AEDs are still the main treatment choice for children with epilepsy, and the use of newer AEDs remains low. Our study highlights a lack of research capacity to conduct multinational AED safety studies in children. Further work should explore large databases and other health care settings to meet these research needs.

Topics: Adolescent; Age Factors; Anticonvulsants; Child; Cohort Studies; Drug Prescriptions; Drug Utilization; Epilepsy; Female; Fructose; Health Care Surveys; Humans; Italy; Lamotrigine; Male; Netherlands; Practice Patterns, Physicians'; Retrospective Studies; Topiramate; Triazines; United Kingdom

To estimate the cost-effectiveness of rufinamide relative to topiramate and lamotrigine as adjunctive treatment for children with Lennox-Gastaut Syndrome (LGS).. A Markov decision analytic model was developed to estimate the incremental cost-effectiveness ratio over a three-year time horizon in patients with LGS uncontrolled by up to three antiepileptic drugs. Utilities were assigned to health states, defined according to a patient's response to treatment (> or =75%, > or =50% and <75%, and <50% reduction in tonic-atonic [drop attack] seizure frequency and death). Efficacy and safety estimates were made using indirect/mixed-treatment comparisons of data obtained from published literature. Outcomes included costs and quality-adjusted life-years (QALYs), allowing the incremental cost-effectiveness ratio to be estimated as cost per QALY gained.. Over three years, the total cumulative costs for rufinamide, topiramate, and lamotrigine were pound24,992, pound23,360, and pound21,783, respectively. Rufinamide resulted in an incremental QALY gain of 0.079 relative to topiramate and 0.021 relative to lamotrigine. The incremental costs of rufinamide were pound1632 and pound3209, relative to topiramate and lamotrigine, resulting in an incremental cost per QALY gained of pound20,538 and pound154,831, respectively.. Considering the underlying assumptions, this current economic evaluation demonstrates that rufinamide is likely to be a cost-effective alternative to topiramate as adjunctive treatment for children with LGS in the UK. In addition, when compared to lamotrigine, which is an inexpensive treatment, rufinamide should be considered as a cost-effective alternative due to the importance of patient choice and equity of access in such a rare and devastating condition.

Topics: Anticonvulsants; Child; Confidence Intervals; Cost-Benefit Analysis; Drug Utilization; Epilepsy; Follow-Up Studies; Fructose; Health Status; Humans; Lamotrigine; Markov Chains; Quality of Life; Sensitivity and Specificity; Topiramate; Triazines; Triazoles; United Kingdom

Topiramate, which is commonly prescribed for seizure disorders and migraine prophylaxis, sometimes causes metabolic acidosis and hypokalemia. Since the effects of topiramate on acid-base balance and potassium levels have not been well explored in children, acid-base balance, anion gap and potassium were assessed in 24 patients (8 females and 16 males) aged between 4.6 and 19 years on topiramate for more than 12 months and in an age-matched control group. Plasma bicarbonate (21.7 versus 23.4 mmol/L; P<0.03), carbon dioxide pressure (39.7 versus 43.2mm Hg; P<0.05), and potassium (3.7 versus 4.0 mmol/L; P<0.03) were on the average lower and chloride (109 versus 107 mmol/L; P<0.03) higher in patients treated with topiramate than in controls. Blood pH, plasma sodium and the anion gap were similar in patients on topiramate and in controls. In patients on topiramate no significant correlation was observed between the dosage of this agent and plasma bicarbonate or potassium as well as between topiramate blood level and the mentioned electrolytes. In conclusion long-term topiramate treatment is associated with a mild, statistically significant tendency towards compensated normal anion gap metabolic acidosis and hypokalemia.

Topics: Acid-Base Equilibrium; Acidosis; Adolescent; Anticonvulsants; Bicarbonates; Child; Child, Preschool; Chlorides; Dose-Response Relationship, Drug; Electrolytes; Epilepsy; Female; Fructose; Humans; Hypokalemia; Male; Potassium; Topiramate; Young Adult

We aimed to compare the effects of antiepileptic drugs and provide findings of peripheral nerve impairment using standard electrophysiological techniques.. Young adult outpatients with epilepsy on monotherapy for no less than 6 months with carbamazepine (CBZ), valproic acid (VPA), oxcarbazepine (OXC) and topiramate (TPM) were examined. Patients who had any other disease that could effect nerve conduction studies and who had neuropathic symptoms were excluded.. Each group contained 15 patients and 20 healthy subjects were examined as the control group. Prolonged latency of median sensory nerve (P = 0.004), ulnar sensory nerve (P = 0.01) and sural nerve (P = 0.003) with a diminished nerve conduction velocity was observed in the CBZ group (P = 0.014, P = 0.002, P = 0.025, respectively). No correlation was found between VPA, OXC and TPM and the nerve conduction studies (P > 0.05).. Valproic acid, oxcarbazepine and topiramate don't have effects on nerve conduction studies. Mild electrophysiological changes contribute to carbamazepine therapy.

Topics: Anticonvulsants; Carbamazepine; Epilepsy; Female; Fructose; Humans; Male; Median Nerve; Neural Conduction; Oxcarbazepine; Peripheral Nerves; Peripheral Nervous System Diseases; Severity of Illness Index; Sural Nerve; Topiramate; Ulnar Nerve; Valproic Acid; Young Adult

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

Topiramate (TPM) is a new antiepileptic drug (AED) used worldwide in patients with various types of epilepsies and also for prophylaxis of migraine. A rapid, selective, reliable, precise, accurate, and reproducible tandem mass spectrometric (MS/MS) method for quantification of TPM in human plasma using topiramate-d12 as an internal standard (IS) has been developed and validated to be used routinely for TDM of TPM.. The drug and IS were extracted by ether and analyzed on Symmetry C18 column. Quantitation was achieved using ESI-interface employing MRM mode.. The method was validated over the concentration range of 0.5-30 microg/ml (r>0.99). Intra- and inter-run precisions of TPM assay at three concentrations ranged from 0.7 to 7.8% with accuracy (bias) varied from -10.0 to 2.1% indicating good precision and accuracy. Analytical recoveries of TPM and IS from spiked human plasma were in the range of 84.1 to 90.0% and 90.0 to 111.0%, respectively. Stability of TPM in human plasma samples at different conditions showed that the drug was stable under the studied conditions. Matrix effect study showed a lack of matrix effect on mass ions of TPM and IS.. The described method compared well when assessed by Heathcontrol TDM theme program (r>0.99). The suitability of the developed method for TDM was demonstrated by measuring TPM in human plasma samples of epileptic patients treated with TPM. The proposed method is appropriate for routine TDM of TPM.

Topics: Anticonvulsants; Chromatography, Liquid; Drug Monitoring; Drug Stability; Epilepsy; Fructose; Humans; Quality Control; Reproducibility of Results; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Topiramate

Persistent Genital Arousal Disorder (PGAD) refers to the experience of persistent sensations of genital arousal that are felt to be unprovoked, intrusive and unrelieved by one or several orgasms. It is often mistaken for hypersexuality since PGAD often results in a high frequency of sexual behaviour. At present little is known with certainty about the etiology of this condition. We described a woman with typical PGAD symptoms and orgasmic seizures that we found to be related to a specific epileptic focus. We performed a EEG/MEG and fMRI spontaneous activity study during genital arousal symptoms and after the chronic administration of 300 mg/day of topiramate. From MEG data an epileptic focus was localized in the left posterior insular gyrus (LPIG). FMRI data evidenced that sexual excitation symptoms with PGAD could be correlated with an increased functional connectivity (FC) between different brain areas: LPIG (epileptic focus), left middle frontal gyrus, left inferior and superior temporal gyrus and left inferior parietal lobe. The reduction of the FC observed after antiepileptic therapy was more marked in the left than in the right hemisphere in agreement with the lateralization identified by MEG results. Treatment completely abolished PGAD symptoms and functional hyperconnectivity. The functional hyperconnectivity found in the neuronal network including the epileptic focus could suggest a possible central mechanism for PGAD.

Topics: Adult; Anticonvulsants; Brain; Brain Mapping; Electroencephalography; Epilepsy; Female; Follow-Up Studies; Fructose; Functional Laterality; Genital Diseases, Female; Humans; Magnetic Resonance Imaging; Magnetoencephalography; Neural Pathways; Topiramate; Treatment Outcome

To assess bone health in epileptic children who have been treated with topiramate (TPM) or carbamazepine (CBZ).. Sixty-three epileptic children who received TPM or CBZ treatment and 36 eileptic children who did not receive any drug treatment (control group) were enrolled. Bone mineral density (BMD) at lumbar vertebrae (L1-L4) and radius-ulna was evaluated by the dual-energy X-ray absorptiometry method. Biochemical indices of bone metabolism, including serum calcium, phosphorus and alkaline phosphatase contents were measured.. The serum calcium content was higher in the TPM group (2.41+/-0.17 mmol/L), but it was lower in the CBZ group (2.15+/-0.26 mmol/L) than that (2.26+/-0.11 mmol/L) in the control group (p<0.05). The serum phosphorus content in both the TPM (1.55+/-0.17 mmol/L) and the CBZ groups (1.52+/-0.26 mmol/L) was significantly lower than that in the control group (1.70+/-0.30 mmol/L) (p<0.05). There were no significant differences in the serum content of alkaline phosphatase between three groups. BMD was significantly reduced in both the TPM and the CBZ groups when compared to the control group (p<0.05).. TPM and CBZ may result in alterations in serum contents of calcium, phosphorus and alkaline phosphatase as well as BMD reduction.

Topics: Adolescent; Alkaline Phosphatase; Anticonvulsants; Bone and Bones; Bone Density; Calcium; Carbamazepine; Child; Child, Preschool; Epilepsy; Female; Fructose; Humans; Male; Phosphorus; Topiramate

To compare the effectiveness of antiepileptic drugs (AEDs) for use in older adults with epilepsy.. Retrospective review.. Columbia Comprehensive Epilepsy Center, New York, New York.. Four hundred seventeen outpatients 55 years and older newly taking any of the 10 most commonly prescribed AEDs between 2000 and 2005.. The percentage of patients who remained taking the AED for 12 or more months (12-month "retention"). We also measured efficacy (12-month seizure freedom) and adverse effects leading to dose change. Retention and seizure-freedom rates were analyzed by pairwise comparisons using chi(2) for the overall group and patients with refractory and nonrefractory disease as well as patients newly taking their first AED.. The 10 AEDs newly taken by 10 or more patients were analyzed. There were no significant non-AED predictors of retention. Without controlling for severity, lamotrigine had the highest 12-month retention rate (79%), significantly higher than carbamazepine (48%), gabapentin (59%), oxcarbazepine (24%), phenytoin (59%), and topiramate (56%). The retention rate for levetiracetam (73%) was second highest and significantly higher than carbamazepine and oxcarbazepine. Oxcarbazepine had the lowest retention rate, significantly lower than all other AEDs. Lamotrigine had the highest 12-month seizure-freedom rate (54%), followed by levetiracetam (43%). When stratified into patients with nonrefractory and refractory disease, relative rates of seizure freedom and retention remained comparable with the overall group. Imbalance, drowsiness, and gastrointestinal symptoms were the most common intolerable adverse effects.. In this study of older adults with epilepsy, lamotrigine was the most effective AED as measured by 12-month retention and seizure freedom, with levetiracetam a close second. Oxcarbazepine was consistently less effective than most other AEDs.

Topics: Adult; Aged; Amines; Anticonvulsants; Carbamazepine; Cyclohexanecarboxylic Acids; Dose-Response Relationship, Drug; Drug Resistance; Epilepsy; Female; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Lamotrigine; Levetiracetam; Male; Middle Aged; Oxcarbazepine; Phenytoin; Piracetam; Retrospective Studies; Topiramate; Treatment Outcome; Triazines

Phenylketonuria (PKU) is one of the most common inherited metabolic disorders, which is characterized by excessive accumulation of phenylalanine (Phe) in tissues. Generalized seizures occur in 25% of the patients. Little is known about seizures and their treatment in adult PKU patients, and information with newer antiepileptic drugs is lacking. Here we report an adult patient who developed generalized seizures later in life, despite strict dietary control, and whose seizures were aggravated by levetiracetam (LEV). Convulsions ceased after discontinuation of LEV and the patient has been seizure free on topiramate 125 mg/day.

Topics: Anticonvulsants; Dose-Response Relationship, Drug; Electroencephalography; Epilepsy; Female; Fructose; Humans; Levetiracetam; Phenylalanine; Phenylketonurias; Piracetam; Topiramate; Treatment Outcome; Young Adult

Children with refractory epilepsy who are co-treated with the ketogenic diet (KD) and carbonic anhydrase inhibitor (CA-I) anti-epileptic medications including topiramate (TPM) and zonisamide (ZNS) are at risk for urolithiasis. Retrospective chart review of all children treated with ketogenic therapy at our institution was performed in order to estimate the minimal risk of developing signs or symptoms of stone disease. Children (N=93) were classified into groups according to KD+/-CA-I co-therapy. Fourteen patients had occult hematuria or worse, including 6 with radiologically confirmed stones. Three of 6 calculi developed in the KD+ZNS group of 17 patients who were co-treated for a cumulative total of 97 months (3.1 stones per 100 patient months). One confirmed stone was in the KD+TPM group of 22 children who were co-treated for a cumulative total of 263 months (0.4 stones per 100 patient months). All six patients had at least three of five biochemical risk factors including metabolic acidosis, concentrated urine, acid urine, hypercalciuria and hypocitraturia. Standard of care interventions to minimize hypercalciuria, crystalluria and stone formation used routinely by pediatric nephrologists should also be prescribed by neurologists treating patients with combination anti-epileptic therapy. Non-fasting KD initiation, fluid liberalization, potassium citrate prophylaxis as well as regular laboratory surveillance are indicated in this high risk population.

Topics: Anticonvulsants; Child; Child, Preschool; Combined Modality Therapy; Diet, Ketogenic; Epilepsy; Female; Fructose; Humans; Infant; Isoxazoles; Male; Retrospective Studies; Risk Factors; Topiramate; Urolithiasis; Zonisamide

We aimed to investigate the effects of topiramate monotherapy on anthropometric indexes, insulin resistance, and serum leptin and lipid levels in 33 premenopausal women (mean age+/-standard deviation: 26.7+/-7.1years) with cryptogenic epilepsy. Body mass index (BMI), waist circumference and serum leptin, insulin and lipid levels were measured at baseline and at 6months after initiation of topiramate. We found reductions in BMI (p<0.001), waist circumference (p<0.001) and serum high-density lipoprotein (HDL) cholesterol levels (p=0.011). We also found significant improvements in insulin resistance (p=0.023), but not in serum leptin levels (p=0.45). Our results suggest that topiramate treatment in women with epilepsy is associated with reduced BMI and waist circumference and improvement in insulin resistance; however, according to our data, topiramate treatment is also associated with lower HDL cholesterol levels, which may substantially increase vascular disease.

Topics: Adolescent; Adult; Anthropometry; Anticonvulsants; Body Mass Index; Body Weight; Enzyme-Linked Immunosorbent Assay; Epilepsy; Female; Fructose; Humans; Insulin Resistance; Leptin; Lipid Metabolism; Topiramate; Young Adult

This is a large-sample, prospective, long-term observational study to assess the retention rate of topiramate as initial monotherapy in Chinese patients with newly diagnosed epilepsy. The retention rate was calculated by Kaplan-Meier method using intention-to-treatment analysis. Cox proportional hazard models were used to analyze the risk factors for retention rate. A total of 229 patients were enrolled into this study. The retention rate was 75.5% at 1 year, 47% at 6 years. Three risk factors for treatment failure were female gender, rural residence, and frequent seizures before treatment. Four predominant causes leading to treatment failure were: lack of efficacy (7.4%), adverse effects (10.9%), follow-up loss (15.7%), and subjective misunderstanding (8.3%). Adverse effects occurred in 129 (56.3%) patients, with 7 (3.1%) patients suffered from renal calculus. This study suggests the long-term retention rate of topiramate as initial monotherapy is high in Chinese patients. Lower initial dose, lower target dose and slower titration contribute to better tolerability. Frequent abdominal ultrasound for detecting renal calculus is necessary. Rural patients and patients with poor education level should be paid more attention by physicians to ensure continued therapy.

Topics: Adolescent; Adult; Anticonvulsants; Asian People; Child; Epilepsy; Female; Fructose; Humans; Intention to Treat Analysis; Kaplan-Meier Estimate; Male; Patient Satisfaction; Proportional Hazards Models; Prospective Studies; Topiramate; Treatment Outcome

Topiramate pharmacokinetics is influenced by individual factors such as patient age, renal function and co-treatment. The aim of this study was to develop a population pharmacokinetic model of topiramate to assist dosage adjustments in individual patients. Steady-state topiramate plasma concentrations in patients with epilepsy were determined by HPLC using fluorescent labelling. Demographic, biochemical data and dosing history including concomitant drug therapy were collected from patients' charts. Nonlinear mixed effects modelling was used to fit a one-compartment pharmacokinetic model. The influence of patient weight and gender, body surface area, age, creatinine clearance, serum transaminases, topiramate daily dose and co-treatment with carbamazepine, valproic acid, benzodiazepines, and risperidone on topiramate pharmacokinetics was evaluated. Additionally, the relationship between topiramate plasma concentration and clinical response was investigated. Volume of distribution of topiramate was 0.518 l/kg. For a typical patient oral clearance was estimated at 1.47 l/h, with interindividual variability of 39.2%. Clearance was 70% higher in patients co-treated with carbamazepine and was found to increase with patient age. Somnolence was the most frequently observed adverse event. Incidence of headache was associated with topiramate plasma concentration. Somnolence, ataxia, tremor, speech disorders and fatigue were associated with adjunctive therapy with carbamazepine, valproic acid, benzodiazepines, risperidone, and clozapine. No association of topiramate plasma concentration with frequency of seizures or patient quality of life was observed. The developed model can be used for Bayesian estimation of pharmacokinetic parameters based on sparse plasma samples and for selection of optimum dosing in routine patient care.

Topics: Adolescent; Adult; Anticonvulsants; Bayes Theorem; Child; Chromatography, High Pressure Liquid; Drug Monitoring; Epilepsy; Female; Fructose; Half-Life; Humans; Male; Middle Aged; Topiramate; Young Adult

To evaluate the efficacy of topiramate (TPM) for the treatment of children with epilepsies, we introduced TPM to 45 patients whose epilepsy began in childhood and whose ages ranged from 4 months to 30 years old (mean age: 11 years 7 months). Thirteen of these patients had been diagnosed with generalized epilepsy (GE) (1 cryptogenic, 12 symptomatic), 30 with localization-related epilepsy (LRE) (7 idiopathic, 23 symptomatic), and 2 with unclassified epilepsy [1 case of severe myoclonic epilepsy in infancy (SMEI), 1 case of epilepsy with continuous spikes and waves during slow sleep (CSWS)]. The initial dose of TPM was 1.97 +/- 0.45 mg/kg/day, followed by a slow titration to the maximum dose of 7.32 +/- 1.32 mg/kg/day. After a mean treatment period of 13.5 months (range 4-20 months), the rate of reduction in seizure frequency by more than 50% [50% responder rate (50% RR)] and the rate of complete remission (seizure-free) were 53.8% and 23.1%, respectively, in patients with GE, and 73.3% and 23.3%, respectively, in patients with LRE. TPM was significantly effective against many seizure types including tonic, clonic, complex partial, myoclonic, and atypical absence seizures. Adverse effects included sleepiness in 13 cases (28.9%), weight loss in 6 cases (13.3%), and metabolic acidosis in 2 cases (4.4%); all of these effects were both mild and transient. In conclusion, TPM is effective and safe for the treatment of pediatric epilepsies.

Topics: Adolescent; Adult; Age Factors; Anticonvulsants; Child; Child, Preschool; Drug Therapy, Combination; Drug Tolerance; Epilepsy; Female; Fructose; Humans; Infant; Male; Topiramate; Treatment Outcome; Young Adult

To identify and validate the efficacious monotherapy dosing regimen for topiramate in children aged 2 to <10 years with newly diagnosed epilepsy using pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation bridging.. Several models were developed in pediatric and adult populations to relate steady-state trough plasma concentrations (C(min)) of topiramate to the magnitude of clinical effect in monotherapy and adjunctive settings. These models were integrated to derive and support the monotherapy dosing regimen for pediatric patients.. A two-compartmental population PK model with first-order absorption described the time course of topiramate C(min) as a function of dosing regimen. Disposition of topiramate was related to age, body weight, and use of various concomitant antiepileptic drugs. The PK-PD model for monotherapy indicated that the hazard of time to first seizure decreased with increasing C(min) and time since randomization. Higher baseline seizure frequency increased risk for seizures. Age did not significantly influence hazard of time to first seizure after randomization to monotherapy. For adjunctive therapy, the distribution of drug and placebo responses was not significantly different among age groups. Based on the available PK-PD modeling data, the dosing regimen expected to achieve a 65-75% seizure freedom rate after 1 year for pediatric patients age 2-10 years is approximately 6-9 mg/kg per day.. This analysis indicated no difference in PK-PD of topiramate between adult and pediatric patients. Effects of indication and body weight on PK were adequately integrated into the model, and monotherapy dosing regimens were identified for children 2-10 years of age.

Topics: Adolescent; Adult; Age Distribution; Age Factors; Aged; Aged, 80 and over; Anticonvulsants; Body Weight; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Randomized Controlled Trials as Topic; Topiramate; Treatment Outcome

Topics: Anticonvulsants; Epilepsy; Fructose; Humans; Topiramate

We evaluated long-term retention rates of newer antiepileptic drugs (AED) in adults with localization-related epilepsy retrospectively.. We estimated retention rates by Kaplan-Meier method in all 222 patients (age > or = 16) with localization-related epilepsy exposed to new AED at the Tampere University Hospital.. There were 141 patients exposed to lamotrigine, 78 to levetiracetam, 97 to topiramate, 68 to gabapentin, and 69 to tiagabine. Three-year retention rate for lamotrigine was 73.5%, levetiracetam 65.4%, topiramate 64.2%, gabapentin 41.7%, and tiagabine 38.2%. The most common cause for withdrawal of these AED was lack of efficacy.. Our study suggests that there are clinically significant differences among gabapentin, lamotrigine, levetiracetam, tiagabine, and topiramate as treatment for focal epilepsy in everyday practice. Gabapentin and tiagabine seem to be less useful than the other three AED. Furthermore, our study supports the value of retention rate studies in assessing outcome of the drugs in clinical practice.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amines; Anticonvulsants; Child; Cyclohexanecarboxylic Acids; Epilepsy; Female; Finland; Fructose; Gabapentin; gamma-Aminobutyric Acid; Half-Life; Humans; Lamotrigine; Levetiracetam; Licensure, Pharmacy; Male; Middle Aged; Nipecotic Acids; Piracetam; Retrospective Studies; Tiagabine; Topiramate; Treatment Outcome; Triazines; Young Adult

To assess the long-term usefulness of 'new anti-epileptic drugs (AEDs)' (lamotrigine, topiramate, levetiracetam, gabapentin and pregabalin) in institutionalized intellectually disabled patients. Information from RCTs is lacking in this population with severe intellectual and behavioural disabilities.. Retrospective study. Data from the medical files and the pharmacy databases of 118 institutionalized intellectually disabled patients who had ever used at least one of the new AEDs were analyzed. The main evaluation parameters were the duration of use (using Kaplan-Meier survival estimates) and the reason for discontinuation (lack of efficacy, occurrence of adverse events, or both) of the new AEDs. Drug continuation was based on the evaluation of treatment results by experienced epileptologists, and not on fixed criteria.. New AEDs were generally tried only after a substantial number of other regimens (with classic AEDs) had failed. The most frequently used new AEDs were lamotrigine (68%) and levetiracetam (58%), followed by topiramate (28%) and gabapentin (8%). The 3-year retention rates were 70% (lamotrigine), 52% (levetiracetam), 51% (topiramate) and 33% (gabapentin). Discontinuation due to "lack of efficacy" occurred in 61% (topiramate), 60% (lamotrigine) and 42% (levetiracetam) of the cases. Discontinuation due to adverse events occurred in 42% (levetiracetam), 33% (topiramate) and 28% (lamotrigine).. Treatment of epilepsy with new AEDs was quite often successful in this very therapy-resistant population.

Topics: Adolescent; Adult; Amines; Anticonvulsants; Child; Cyclohexanecarboxylic Acids; Drug Utilization Review; Epilepsy; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Institutionalization; Intellectual Disability; Lamotrigine; Levetiracetam; Middle Aged; Piracetam; Retrospective Studies; Topiramate; Triazines

Free radicals and selenium (Se) deficiency are involved in pathogenesis of epilepsy. Topiramate (TPM), a new anticonvulsant, was reported to possess neuroprotective effect via inhibition of free radicals. We investigated the effects of Se and TPM on pentylentetrazol (PTZ)-induced blood toxicity in rats. Forty male Wistar rats were equally divided into five groups. First and second groups were used as control and PTZ group, respectively. TPM and Se were administrated to rats constituting third and forth groups for 7 days, respectively. The TPM and Se combination were given to animals in fifth group for 7 days. At the end of 7 days all groups except the first group received single dose PTZ. The brain cortex samples were taken at 3 h of PTZ administration. PTZ resulted in significant increase in plasma and erythrocytes lipid peroxidation (LP) levels although plasma vitamin E concentrations and erythrocytes glutathione peroxidase (GSH-Px) activities were reduced by PTZ. The plasma and erythrocytes LP levels in third, fourth, and fifth groups were decreased as compared to second group although GSH-Px and reduced glutathione values increased in the groups. Vitamin C and E concentrations were increased through fourth and fifth group only. Vitamin A concentrations were not changed by PTZ. In conclusion, Se and TPM seem to have protective effects on the PTZ-induced blood toxicity by inhibiting free radical supporting antioxidant redox system.

Topics: Animal Feed; Animals; Antioxidants; Epilepsy; Erythrocytes; Fructose; Glutathione; Glutathione Peroxidase; Lipid Peroxidation; Male; Pentylenetetrazole; Rats; Rats, Wistar; Selenium; Topiramate; Vitamin E

Recent information suggests that use of the antiepileptic drug topiramate in pregnancy may raise some concerns, especially if used in polytherapy. Moreover, data on the safety of this antiepileptic drug for the breastfed infant are very limited. However, use of topiramate may be unavoidable in women who wish to become pregnant but who have already experienced severe adverse reactions to antiepileptic medications considered relatively safe in this female condition. Hence, we describe the healthy outcome of a male infant exposed to topiramate through the placenta and maternal milk and who was conceived while the mother was undergoing folic acid supplementation.

Topics: Abnormalities, Drug-Induced; Anticonvulsants; Breast Feeding; Dietary Supplements; Epilepsy; Female; Folic Acid; Fructose; Humans; Infant, Newborn; Maternal-Fetal Exchange; Milk, Human; Pregnancy; Risk Assessment; Topiramate; Vitamins; Young Adult

Caspase-3 expression was determined in the hippocampus of electrically kindled rats with and without topiramate treatment. Bipolar electrotrodes were implanted for chronic stimulation of the basolateral amygdala (BLA) to achieve a kindled state. Seizure and behavioral responses were observed, and video-electroencephalograms were recorded during and after kindling. After topiramate treatment (80 mg/kg, p.o.), the hippocampi were extracted and caspase-3 mRNA analyzed by semiquantitative RT-PCR. Caspase-3 immunoreactivity was determined with immunohistochemical staining. Topiramate treatment resulted in a significant decrease in the mean duration of seizures from 52 s in kindled rats to 13 s. The after-discharge duration was significantly decreased by 70% after topiramate treatment. Significant upregulations of both caspase-3 mRNA and caspase-3 immunoreactivity were observed in the kindled rats. These kindling-mediated increases in caspase-3 were prevented by topiramate treatment, and these levels were not different from those of sham-operated controls. In BLA-kindled rats, mRNA and immunoreactivity for caspase-3 were increased. Treatment with topiramate prevented the kindling-associated increases in caspase-3 as well as the increases in seizure duration and after-discharge duration. These data suggest that topiramate may have a neuroprotective role in addition to its action as an anticonvulsant.

Topics: Amygdala; Animals; Anticonvulsants; Caspase 3; Electric Stimulation; Epilepsy; Fructose; Hippocampus; Kindling, Neurologic; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Topiramate

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

To study the impact of pregnancy on the serum concentration/dose ratio (C/D-ratio) of topiramate (TPM).. Twelve women with epilepsy using TPM during pregnancy, and 15 pregnancies were studied. The main target variable was the C/D-ratio at baseline and during pregnancy. Additional variables were changes in TPM dose, concomitant use of other antiepileptic drugs, seizure frequency, and pregnancy outcome. Clinical and pharmacological data were obtained from the women's medical records.. The average C/D-ratios in the second and third trimester were 30% (p = 0.002, n = 11) and 34% (p = 0.001, n = 8) lower than the baseline values, respectively. The interindividual variability was pronounced. Increased seizure frequency was common in pregnant women using TPM, but a correlation to the decline in TPM C/D-ratio could not be established from our data.. Dose-corrected serum concentrations of TPM appear to decline gradually throughout pregnancy. The underlying mechanisms are not known. Increased glomerular filtration may play a major role. During pregnancy, therapeutic drug monitoring of TPM may be useful.

Topics: Abnormalities, Drug-Induced; Anticonvulsants; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epilepsies, Myoclonic; Epilepsies, Partial; Epilepsy; Epilepsy, Absence; Epilepsy, Tonic-Clonic; Female; Fructose; Humans; Infant, Newborn; Metabolic Clearance Rate; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnancy Trimester, First; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Topiramate; Treatment Outcome

To determine whether a fast titration schedule of topiramate (TPM) has different effects on the occurrence of depression, in relation to other risk factors for TPM-induced depression, including history of depression (HxDEP), febrile seizures (FS), and hippocampal sclerosis (HS).. Using data from a large case registry of patients prescribed TPM, two models were constructed: Model 1 examined the independent effect of rapid TPM titration after separate adjustment for FS, HxDEP, and HS. Model 2 examined effect of the cooccurrence of rapid titration on the development of depression with each of these risk factors.. A total of 423 patients were included (51.8% females), mean age (SD) 35.5 (11.8) years, mean duration of epilepsy of 22.2 (11.5) years. Forty-four patients (10.4%) developed depression during TPM therapy. A rapid TPM titration was associated with 5-fold increased risk of depression that increased to 12.7-fold in the presence of both FS and rapid TPM titration, 23.3-fold in the presence of both HxDEP and rapid TPM titration, and 7.6-fold in the presence of both HS and rapid TPM titration schedule.. Our study suggests that a rapid titration schedule is associated with an increased risk of developing depression during TPM therapy. HxDEP and FS are major contraindications to the use of a rapid titration, with a 23.3-fold and 12.7 fold increased risk, respectively.

Topics: Adult; Anticonvulsants; Depression; Drug Administration Schedule; Epilepsy; Fructose; Humans; Logistic Models; Middle Aged; Models, Statistical; Titrimetry; Topiramate

Dyke-Davidoff-Masson syndrome is a disorder involving hemiatrophy or hypoplasia of 1 cerebral hemisphere secondary to an insult in the developing brain. Often this will manifest with seizures, hemiparesis, mental retardation, and facial changes. Associated with this pathology are the radiologically evident changes, such as thickening of the calvarium, hyperpneumatization of the sinuses, and dilation of the ipsilateral lateral ventricle among others. The following is a case presentation of an 18-year-old female emigrating from Ghana who presented to the emergency department with complaints of seizures diagnosed as being caused by cerebral malaria at 13 years of age. We hypothesize that the cerebral malaria and related vascular occlusion are the causes of her acquired cerebral changes. Included are computed tomography images.

Topics: Adolescent; Anticonvulsants; Atrophy; Cerebral Cortex; Epilepsy; Female; Frontal Sinus; Fructose; Ghana; Humans; Hyperostosis; Lateral Ventricles; Malaria, Cerebral; Skull; Syndrome; Tomography, X-Ray Computed; Topiramate; Treatment Outcome

With an apparently first epileptic seizure in a young female patient, we propose a diagnostic and therapeutic discussion on a common clinical problem. Due to the large number of available antiepileptic drugs, choosing the best treatment is not an easy task. One must take into consideration the type of epilepsy, the pharmacological properties of the antiepileptic drug, and the clinical profile of the patient. Besides drug prescription, specific recommendations must also be made.

Topics: Adult; Anticonvulsants; Carbamazepine; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Lamotrigine; Levetiracetam; Piracetam; Topiramate; Treatment Outcome; Triazines; Valproic Acid

Thirty patients with different forms of epilepsy were treated with toreal in dosage 200 mg per day. The clinical efficacy was assessed after 8 and 12 weeks. Side-effects and changes of laboratory parameters were assessed taking into account their intensity, duration and possible relation to the drug. Toreal was most effective in symptomatic local forms of epilepsy (76-95%) and less effective in idiopathic forms (up to 70%). In the period of dose titration, higher fatigue (70%), sleepiness (53.33%) were recorded more often than dizziness, paresthesias, dry mouth, diplopia, dyspepsia, ataxia and others side-effects. Higher fatigue remained in 70% of patients to the end of 12th week while the frequency of other side- effects has decreased. Overall, the severity of side-effects was mild that did not lead to changing of dose or drug's withdrawal.

Topics: Adolescent; Adult; Anticonvulsants; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Topiramate; Treatment Outcome; Young Adult

To compare rapid vs regular titration of topiramate concerning efficacy and safety.. Open-label, prospective, single-center study exploring efficacy and tolerability of two adjunctive dosing regimens of topiramate (TPM) in adult patients with difficult-to-treat epilepsy. Based on investigator judgment, 21 of 50 consecutive patients received a rapid titration (starting dose 50 mg/day, stepwise increase with 50 mg/day after 3 days each until reaching the target dose), while the other 29 patients received titration according to the German prescribing information (starting dose 25 mg/day, stepwise increase with 25-50 mg/day every 7 days). Patients were observed until the target dose was reached and 3 months thereafter.. Mean final dosages were 136 mg/day (regular titration) and 213 mg/day (rapid titration). Efficacy and tolerability measures did not differ significantly. Forty-six percent of all patients experienced a seizure reduction of > or = 50%; 14% became seizure free. No serious adverse events occurred. The most common adverse effects were tiredness (20%), memory and language difficulties (18% each), slowness in thinking and speech (10%), psychomotor disturbance (8%) and paresthesia (8%).. This study suggests that rapid and conventional titration generate similar tolerability, safety and effectiveness in selected patients.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Chemotherapy, Adjuvant; Dose-Response Relationship, Drug; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Prospective Studies; Topiramate; Treatment Outcome

To explore the mechanism of topiramate-induced weight loss in epilepsy children by monitoring metabolism indices.. Children with epilepsy were treated with topiramate at their first clinical visit. Metabolism indices including body mass index (BMI) and its SD scores, leptin, adiponectin, leptin/adiponectin (L/A), lipid profile-insulin and Homeostasis Model Assessments (HOMA) index were collected before and after treatment.. Topiramate treatment significantly reduced L/A (t = 2.156, p = 0.031), and markedly increased the serum level of adiponectin (t = 3.124, p = 0.002). Moreover, there were no relationships between the metabolism indices and dosages of topiramate (p > 0.05).. Our studies find that topiramate treatment in epilepsy children increases energy metabolism, resulting in weight loss. It has been demonstrated that adiponectin play a significant role in metabolic regulations.

Topics: Adiponectin; Anti-Obesity Agents; Blood Glucose; Body Mass Index; Body Weight; Case-Control Studies; Child; Epilepsy; Female; Fructose; Homeostasis; Humans; Insulin; Insulin Resistance; Leptin; Lipids; Male; Metabolism; Statistics, Nonparametric; Topiramate

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

To investigate clinical and economic consequences following generic substitution of one vs multiple generics of topiramate (Topamax; Ortho-McNeil Neurologics, Titusville, NJ).. Medical and pharmacy claims data of Régie de l'Assurance-Maladie du Québec from January 2006 to October 2007 were used. Patients with epilepsy treated with topiramate were selected. An open-cohort design was used to classify the observation period into periods of brand, single-generic, and multiple-generic use. One-year generic-switch and switchback-to-brand rates were estimated using Kaplan-Meier methodology. Medical resource utilization and costs were compared among the three periods using multivariate regression analysis.. In total, 948 patients were observed during 1,105 person-years of brand use, 233 person-years of single-generic use, and 92 person-years of multiple-generic use. A total of 23% of generic users received at least two different generic versions. Compared to brand use, multiple-generic use was associated with higher utilization of other prescription drugs (incidence rate ratio [IRR] = 1.27, 95% confidence interval [CI] = 1.24-1.31), higher hospitalization rates (0.48 vs 0.83 visit/person-year, IRR = 1.65, 95% CI = 1.28-2.13), and longer hospital stays (2.6 vs 3.9 days/person-year, IRR = 1.43, 95% CI = 1.27-1.60), but the effect was less pronounced in single-generic use (hospitalization: IRR = 1.08, 95% CI = 0.88-1.34, length of stay: IRR = 1.12, 95% CI = 1.03-1.23). The risk of head injury or fracture was nearly three times higher (hazard ratio = 2.84, 95% CI = 1.24-6.48) following a generic-to-generic switch compared to brand use. The total annualized health care cost per patient was higher in the multiple-generic than brand periods by C$1,716 (cost ratio = 1.21, p = 0.0420).. Multiple-generic substitution of topiramate was significantly associated with negative outcomes, such as hospitalizations and injuries, and increased health care costs.

Topics: Adult; Anticonvulsants; Chronic Disease; Cohort Studies; Comorbidity; Craniocerebral Trauma; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Costs; Drug Utilization; Drugs, Generic; Epilepsy; Female; Fractures, Bone; Fructose; Health Benefit Plans, Employee; Health Care Costs; Hospitalization; Humans; Insurance, Health, Reimbursement; Male; Patient Acceptance of Health Care; Proportional Hazards Models; Quebec; Retrospective Studies; Risk Factors; Topiramate

To determine the prevalence and describe clinical characteristics of seizure disorders and epilepsy as causes of apparent life- threatening event (ALTE) in children admitted at the emergency and followed in a tertiary hospital.. Cross-sectional study with prospective data collection using specific guidelines to determine the etiology of ALTE.. During the study, 30 (4.2%) children admitted to the hospital had a diagnosis of ALTE. There was a predominance of males (73%) and term infants (70%). Neonatal neurological disorders and neuropsychomotor development delay were found respectively in 13.4% and 10% of the cases. Etiological investigation revealed that 50% of the cases were idiopathic, and 13.4% were caused by epilepsy or seizure disorders. Although all patients had recurrent ALTE events, epilepsy had not been previously suspected.. Epilepsy should be included in the differential diagnosis of ALTE, particularly when events are recurrent.

Topics: Anticonvulsants; Carbamazepine; Cross-Sectional Studies; Emergency Service, Hospital; Epilepsy; Female; Fructose; Humans; Infant; Infant, Newborn; Male; Prevalence; Prospective Studies; Recurrence; Topiramate

Resistance to antiepileptic drugs (AEDs) is the major problem in the treatment of epilepsy. One of the candidate mechanisms of pharmacoresistance is the limitation of AED access to the seizure focus by overexpression of efflux transporters, including P-glycoprotein (Pgp) and multidrug resistance proteins (MRPs).In this respect, it is important to know which AEDs are substrates for such drug transporters in humans.. In the present study, we used polarized kidney cell lines (LLC, MDCK) transfected with human drug transporters (Pgp, MRP1, MRP2 or MRP5) to evaluate whether the AED topiramate is a substrate for any of these transporters. Known Pgp and MRP substrates were used for comparison.. Basolateral-to-apical transport of topiramate, which could be counteracted with the Pgp inhibitor, tariquidar, was determined in Pgp overexpressing LLC cells, whereas topiramate was not transported by any of the MRPs. A comparison with previous experiments in the same transport assay showed that topiramate exhibited the most pronounced Pgp-mediated efflux transport among the AEDS that have been studied as yet.. Thus, these data indicate that brain levels of topiramate may be affected by overexpression of Pgp as determined in patients with intractable epilepsy.

Topics: Animals; Anticonvulsants; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Line; Epilepsy; Fructose; Humans; Multidrug Resistance-Associated Proteins; Recombinant Proteins; Swine; Topiramate

To study the effects of pregnancy on plasma concentrations of topiramate (TPM).. An established routine fluorescence polarization immunoassay (FPIA) method was used to determine TPM concentrations in 15 women with epilepsy treated with TPM during altogether 17 pregnancies.. In 10 pregnancies, where samples were available from all three trimesters, the mean TPM dose/concentration ratio (D/C-ratio) was significantly higher than outside pregnancy baseline value 37.3 L/day (+/-15.9), during the 2nd, 67.5L/day (+/-23.4), and the 3rd trimester, 65.1L/day (+/-30.4), but not during the 1st, 49.4 L/day (+/-29.4). Including seven additional pregnancies enrolled late with data only from the 3rd trimester, the mean D/C-ratio during the 3rd trimester was 67.4 L/day (+/-27.5) compared to baseline, 38.8L/day (+/-18.0), an average increase by 71.8%. There was a pronounced intra-individual variability in alterations in D/C-ratios during pregnancies.. Our data show a significant pregnancy-related increase in D/C-ratios of TPM suggesting that therapeutic drug monitoring might be of value.

Topics: Adult; Analysis of Variance; Anticonvulsants; Dose-Response Relationship, Drug; Drug Monitoring; Epilepsy; Female; Fluorescence Polarization Immunoassay; Fructose; Humans; Pregnancy; Pregnancy Trimester, Third; Topiramate

Topiramate is licensed for the treatment of epilepsy and for migraine prophylaxis, but is also used off-licence for a wide range of indications. With the increasing use of topiramate, reports have emerged that topiramate can cause metabolic acidosis in some patients. It does this by impairing both the normal reabsorption of filtered HCO(3)(-) by the proximal renal tubule and the excretion of H(+) by the distal renal tubule. This combination of defects is termed mixed renal tubular acidosis (RTA). The mechanism involves the inhibition of the enzyme carbonic anhydrase, which is consistent with the fact that genetic deficiency of carbonic anhydrase is associated with mixed RTA. Topiramate-induced RTA can make patients acutely ill, and chronically, can lead to nephrolithiasis, osteoporosis and, in children, growth retardation. There is no proven method for predicting or preventing the effect of topiramate on acid-base balance, but patients with a history of renal calculi or known RTA should not receive topiramate. The utility of regular monitoring of HCO(3)(-) levels has not been proven and is not routine practice currently. For patients with persistent RTA, topiramate should usually be discontinued as alternative agents are available.

Topics: Acid-Base Equilibrium; Acidosis, Renal Tubular; Adult; Anticonvulsants; Carbonic Anhydrase II; Child; Epilepsy; Fructose; Genetic Predisposition to Disease; Humans; Kidney Tubules, Distal; Middle Aged; Topiramate; Young Adult

This is a long-term, open label, observational study aimed to broaden our clinical experiences in managing infants and toddlers with epilepsy. The long-term retention rate and side effects of topiramate (TPM) in them were evaluated and compared with carbamazepine (CBZ). A total of 146 children were involved in the study (TPM=41, CBZ=105). The retention rates at 24 , 36, and 48 months were 46.3%, 34.1%, 26.8% for TPM and 36.2%, 23.8%, 13.3% for CBZ, respectively. At 6 months after starting antiepileptic drugs (AED), the seizure freedom or clinical efficacy (seizure reduction rate more than 50 percent) were 73.2% for TPM and 62.9% for CBZ. The major side effects led to discontinuation included psychomotor slowing, poor oral intake from TPM and sleepiness and skin rash from CBZ. TPM was discontinued due to side effects in one case (2.4%) and lack of efficacy in five cases (12.2%), whereas CBZ was discontinued due to lack of efficacy (22.9%) and side effects (6.7%). As compared with CBZ, TPM showed the same long-term retention rate in children under the age of 2 yr, and no serious side effects. It is therefore concluded that TPM can be considered as a major AED for treating children with epilepsy under the age of 2 yr.

Topics: Anticonvulsants; Carbamazepine; Child; Child, Preschool; Epilepsy; Female; Follow-Up Studies; Fructose; Humans; Infant; Male; Topiramate; Treatment Outcome

(1) Numerous follow-up studies of pregnancies in women with epilepsy show that valproic acid is more teratogenic than other antiepileptics. The risk of malformations increases with doses above 1000 mg/day; (2) Malformations associated with valproic acid include neural tube defects in 1-2% of exposed children, as well as urogenital, craniofacial and digital abnormalities. Cardiac disorders and limb defects have also been reported; (3) Convergent results of several cohort studies show that exposure to valproic acid in utero has detrimental effects on intelligence, language and behavior, which appear in school-age children; (4) In practice, the use of valproic acid should be avoided throughout pregnancy, as well as by women of childbearing age not using effective contraception. If a woman is planning pregnancy, the choice of valproic acid should be reassessed with the patient. If valproic acid therapy is maintained, the minimum effective daily dose should be determined and folic acid supplementation initiated.

Topics: Abnormalities, Drug-Induced; Anticonvulsants; Carbamazepine; Cohort Studies; Contraindications; Dose-Response Relationship, Drug; Epilepsy; Female; Fructose; Humans; Intelligence; Lamotrigine; Language Development Disorders; Phenytoin; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prenatal Exposure Delayed Effects; Psychomotor Disorders; Topiramate; Triazines; Valproic Acid

Topiramate (Topamax) is licensed to be used, either in monotherapy or as adjunctive treatment, for generalized tonic clonic seizures or partial seizures with or without secondary generalization and for prevention of migraine. The safety of topiramate in human pregnancy is largely unknown. Here we report on our experience of pregnancies exposed to topiramate.. This study is part of a prospective, observational, registration and follow-up study. Suitable cases are women with epilepsy who become pregnant while taking topiramate either singly or along with other antiepileptic drugs (AEDs), and who are referred before outcome of the pregnancy is known. The main outcome measure is the major congenital malformation (MCM) rate. Secondary outcomes include risk of specific MCM, minor malformation rate, birthweight, and gestational age at delivery.. Full outcome data are available on 203 pregnancies. Of these, 178 resulted in live birth; 16 had an MCM (9.0%; 95% CI 5.6% to 14.1%). Three MCMs were observed in 70 monotherapy exposures (4.8%; 95% CI 1.7% to 13.3%) and 13 in cases exposed to topiramate as part of a polytherapy regimen (11.2%; 95% CI 6.7% to 18.2%). Four of the MCMs were oral clefts (2.2%; 95% CI 0.9% to 5.6%). Four cases of hypospadias were reported (5.1%; 95% CI 0.2% to 10.1%) among 78 known live male births of which two were classified as major malformations.. The number of outcomes of human pregnancies exposed to topiramate is low, but the major congenital malformation rate for topiramate polytherapy raises some concerns. Overall, the rate of oral clefts observed was 11 times the background rate. Although the present data provide new information, they should be interpreted with caution due to the sample size and wide confidence intervals.

Topics: Abnormalities, Drug-Induced; Adult; Anticonvulsants; Cleft Palate; Confidence Intervals; Drug Therapy, Combination; Epilepsy; Female; Follow-Up Studies; Fructose; Gestational Age; Humans; Hypospadias; Incidence; Infant, Newborn; Male; Pregnancy; Prospective Studies; Registries; Sample Size; Topiramate; United Kingdom

The highest incidence of seizures during lifetime is found in the neonatal period and neonatal seizures lead to a propensity for epilepsy and long-term cognitive deficits. Here, we identify potential mechanisms that elucidate a critical role for AMPA receptors (AMPARs) in epileptogenesis during this critical period in the developing brain. In a rodent model of neonatal seizures, we have shown previously that administration of antagonists of the AMPARs during the 48 h after seizures prevents long-term increases in seizure susceptibility and seizure-induced neuronal injury. Hypoxia-induced seizures in postnatal day 10 rats induce rapid and reversible alterations in AMPAR signaling resembling changes implicated previously in models of synaptic potentiation in vitro. Hippocampal slices removed after hypoxic seizures exhibited potentiation of AMPAR-mediated synaptic currents, including an increase in the amplitude and frequency of spontaneous and miniature EPSCs as well as increased synaptic potency. This increased excitability was temporally associated with a rapid increase in phosphorylation at GluR1 S845/S831 and GluR2 S880 sites and increased activity of the protein kinases CaMKII (calcium/calmodulin-dependent protein kinase II), PKA, and PKC, which mediate the phosphorylation of these AMPAR subunits. Postseizure administration of AMPAR antagonists NBQX (2,3-dihydroxy-6-nitro-7-sulfonyl-benzo[f]quinoxaline), topiramate, or GYKI-53773 [(1)-1-(4-aminophenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine] attenuated the AMPAR potentiation, phosphorylation, and kinase activation and prevented the concurrent increase in in vivo seizure susceptibility. Thus, the potentiation of AMPAR-containing synapses is a reversible, early step in epileptogenesis that offers a novel therapeutic target in the highly seizure-prone developing brain.

Topics: Animals; Animals, Newborn; Anticonvulsants; Benzodiazepines; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cyclic AMP-Dependent Protein Kinases; Disease Susceptibility; Enzyme Activation; Epilepsy; Excitatory Postsynaptic Potentials; Fructose; Hypoxia; Male; Phosphorylation; Protein Kinase C; Quinoxalines; Rats; Rats, Long-Evans; Receptors, AMPA; Synapses; Topiramate

Previous studies have shown that generation of free radicals is increased following pentylenetetrazol kindling, due to increased cytosolic Ca2+ concentrations. Topiramate, a voltage-gated calcium channel inhibitor, has an evident effect in the treatment of childhood epilepsy; however, topiramate may cause nephrotoxicity. We investigated the effects of topiramate and vitamin E administration on pentylenetetrazol-induced nephrotoxicity in rats by evaluation of lipid peroxidation, nitric oxide, glutathione peroxidase, catalase and superoxide dismutase values. Forty male Wistar rats were randomly divided into five equal groups. Group 1 was used as control and group II received a single dose of pentylenetetrazol. Fifty and 100 mg/kg topiramate daily were intragastrically administered to rats in groups III and IV for 7 days, respectively. Intragastric 100 mg topiramate (daily for 7 days) and intraperitoneal vitamin E (150 mg/kg, daily for 3 days) combination were given to animals in group V before a single-dose pentylenetetrazol administration. Serum and kidney samples were taken after 3 hr of pentylenetetrazol administration. Pentylenetetrazol resulted in a significant increase in nitric oxide levels of serum and kidney, and lipid peroxidation levels of kidney although superoxide dismutase and catalase activities in the kidney was reduced by pentylenetetrazol administration. The lipid peroxidation levels in serum and kidneys and the nitric oxide levels in kidneys of groups III, IV and V were decreased by topiramate although the superoxide dismutase and catalase activities in the kidneys were increased. Lipid peroxidation and nitric oxide levels were reduced by the topiramate and vitamin E combination compared to only topiramate. Glutathione peroxidase activity was not affect by pentylenetetrazol, topiramate and vitamin E administrations. In conclusion, topiramate and vitamin E have protective effects on pentylenetetrazol-induced nephrotoxicity by inhibition of free radicals and by support of the antioxidant redox system.

Topics: Animals; Anticonvulsants; Antioxidants; Catalase; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epilepsy; Fructose; Glutathione Peroxidase; Kidney; Kidney Diseases; Lipid Peroxidation; Male; Nitric Oxide; Pentylenetetrazole; Rats; Rats, Wistar; Superoxide Dismutase; Topiramate; Vitamin E

The event related potential (ERP-P300) is useful to determine cognitive disturbances. This study examined the changes of ERP-P300 following different dosages of topiramate (TPM) treatment in children with epilepsy in order to investigate the effect of different dosages of TPM on cognitive function.. Thirty cases of benign childhood epilepsy with centrotemporal spikes (BECTS) were first administered with TPM at a dosage of 2 mg/kg/d for 6 months. Afterwards they received another 6 months of TPM treatment at a dosage of 5 mg/kg/d. ERP-P300 was tested before and after different dosages of TPM treatment.. There were no significant differences in the latency and amplitude of ERP-P300 before and after 6 months low dosages of TPM treatment. However, the latency was more prolonged and the amplitude was reduced in the ERP-P300 testing after 6 months high dosage of TMP treatment (P<0.01).. The effect of TPM on cognitive function is related to its dosage in children with epilepsy.

Topics: Adolescent; Anticonvulsants; Child; Cognition; Epilepsy; Event-Related Potentials, P300; Female; Fructose; Humans; Male; Reaction Time; Topiramate

Topiramate (TPM) is a new antiepiletic drug with efficacy in several types of seizures. Therapeutic drug monitoring of TPM is essential for effective patient management. The aim of this study was to evaluate the use of dried blood spot (DBS) specimens to determinate the TPM levels during the treatment. Advantages of DBS include short collection time, low invasiveness, ease and low cost of sample collection, transport and storage. Performance comparison between this method and the commercially available fluorescence-polarization immunoassay (FPIA) was made. The analysis was performed in selected reaction monitoring (SRM) mode. The calibration curve in matrix using D(12)-topiramate was linear in the concentration range of 0.0166-1.66mg/L (0.5-50mg/L in DBS) of topiramate with correlation coefficient value of 0.9985. In the concentration range of 0.5-50mg/L, the coefficients of variation in DBS were in the range 2.13-11.85% and the accuracy ranged from 93.93% to 110.67%. There was no significant differences between the concentrations (ranging 0.5-50mg/L) measured both FPIA on venous samples and LC-MS/MS assay on simultaneous DBS samples. The sensitivity and specificity of tandem mass spectrometry allow now high throughput topiramate analysis (the improvement was three times in comparison with FPIA). This new assay has favourable characteristics being highly precise and accurate. FPIA also proved to be precise and accurate, but is not always suitable for the sample collection in neonates in whom obtaining larger blood samples is not convenient or possible.

Topics: Anticonvulsants; Biological Assay; Blood Specimen Collection; Calibration; Case-Control Studies; Chromatography, Liquid; Desiccation; Epilepsy; Fluorescence Polarization; Fructose; Humans; Immunoassay; Molecular Structure; Reference Standards; Sensitivity and Specificity; Tandem Mass Spectrometry; Time Factors; Topiramate

Two of the most commonly prescribed new antiepileptic drugs as add-on therapy for patients with chronic refractory epilepsies are topiramate and levetiracetam. In regulatory trials, both drugs were characterized as very promising new antiepileptic drugs. However, results from these highly controlled short-term clinical trials cannot simply be extrapolated to everyday clinical practice, also because head-to-head comparisons are lacking. Therefore, results from long-term open label observational studies that compare two or more new AEDs are crucial to determine the long-term performance of competing new antiepileptic drugs in clinical practice.. We analyzed all patients referred to a tertiary epilepsy centre who had been treated with topiramate from the introduction of the drug in spring 1993 up to a final assessment point mid-2002 and all patients who had been treated with LEV in the same centre from the introduction of the drug in early 2001 up to a final assessment point end-2003 using a medical information system.. Three hundred and one patients were included for levetiracetam and 429 patients for TPM. Retention rate after 1 year was 65.6% for LEV-treated patients and 51.7% for TPM-treated patients (p=0.0015). Similarly, retention rates for LEV were higher at the 24-month mark: 45.8% of LEV-treated patients and 38.3% of TPM-treated patients were still continuing treatment (p=0.0046). Adverse events led to drug discontinuation in 21.9% of TPM-treated patients compared to 6.0% of LEV-treated patients (p<0.001). The number of patients discontinuing treatment because of lack of efficacy was similar for both groups. Seizure freedom rates varied between 11.6 and 20.0% for TPM and between 11.1 and 14.3% for LEV per 6-months interval. Several important AED specific adverse events leading to drug discontinuation were identified, including neurocognitive side effects from TPM and mood disorders from LEV.. The retention rate for LEV is significantly higher than for TPM. LEV had a more favourable side effect profile than TPM with comparable efficacy. Patients on TPM discontinued treatment mainly because of neurocognitive side effects. In the treatment with LEV, the effects on mood must not be underestimated.

Topics: Adolescent; Adult; Age of Onset; Aged; Anticonvulsants; Child; Child, Preschool; Cognition; Epilepsy; Female; Fructose; Humans; Infant; Levetiracetam; Long-Term Care; Magnetic Resonance Imaging; Male; Middle Aged; Piracetam; Tomography, X-Ray Computed; Topiramate

Analysis of factors influencing seizure outcome in antiepileptic drug treatment of epilepsy.. Retrospective analysis of 500 patients with complete seizure control and 321 patients with refractory epilepsy (mean ages 33.3 and 32.1 years respectively).. The seizure-free group consisted of 377 patients with symptomatic/cryptogenic epilepsy (SCE; mean seizure control 45 months) and 123 patients with idiopathic generalized epilepsy (IGE; mean seizure control 61 months) (P = 0.02). Of the patients with SCE, 35.7% had achieved seizure control with monotherapy (MT), 29.6% with >or=2 AEDs. No single AED was superior in MT. Of the patients with IGE, 35.9% had become seizure free with MT, 15.6% on combination therapy (CT). Valproate MT was more commonly associated with seizure freedom than lamotrigine (P < 0.05).. The results indicate that, in SCE, seizures can be controlled with carefully selected CT more commonly than suggested by previous studies. The seizure prognosis of patients with IGE presenting to a specialist in epilepsy may be worse than previously thought.

Topics: Adult; Anticonvulsants; Carbamazepine; Cohort Studies; Drug Resistance; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Lamotrigine; Male; Middle Aged; Prognosis; Retrospective Studies; Secondary Prevention; Topiramate; Treatment Outcome; Triazines; Valproic Acid

To evaluate prospectively the relationship between appetite, food composition, nutritional habits and weight loss following administration of topiramate (TPM) and to identify predictors for TPM induced weight loss.. 22 patients with epilepsy who were started on TPM were prospectively followed for 6 months and contacted again after a mean follow-up time of 37.1 months.. Body mass index (BMI) loss occurred in 59% of patients, with a mean weight loss of 9.5 kg after 6 months while receiving TPM without further weight loss at the long term follow-up. Weight loss was associated with reduction in appetite without affecting food composition. Predictors for BMI loss after 6 months were high initial BMI and body fat. After 3 weeks of treatment with TPM, the recorded parameters did not predict BMI loss but at 3 months, weight loss, reduction of appetite and amount of food intake were predictive for the amount of BMI loss after 6 months.

Topics: Adult; Anticonvulsants; Appetite; Body Mass Index; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epilepsy; Feeding Behavior; Female; Follow-Up Studies; Fructose; Humans; Male; Middle Aged; Nutritional Status; Prospective Studies; Topiramate; Weight Loss

To study the neuroprotective effects of topiramate (TPM) alone or together with folic acid (FA) on young rats with kindling-induced epilepsy.. Rat models of epilepsy were prepared by pentylenetetrazol (PTZ)-induced kindling. Seventy-two 3-week-old male Wistar rats were randomly divided into 6 groups: four TPM-treated epilepsy groups (TPM 20, 40 or 80 mg/kg/d and TPM 40 mg/kg/d + FA 5 mg/kg/d), a positive control group (untreated epilepsy group) and a negative control group (normal control group). After two months of administration, behaviors of the rats were recorded; serum levels of neuron-specific enolase (NSE) were measured using ELISA; pathological changes in the hippocampus were observed.. The frequency of convulsion seizures in the 20, 40 and 80 mg TPM treatment and TPM+FA groups was 44.7 +/- 2.9, 44.3 +/- 3.1, 42.7 +/- 3.2, and 40.8 +/- 3.7 respectively, which were significantly lower than that in the positive control group (48.4 +/- 3.7) (P <0.01). Twenty, forty and eighty mg TPM treatment and TPM+FA treatment significantly reduced NSE levels from 35.71 +/- 5.97 microg/L of the control group to 27.40+/- 6.40, 24.79 +/- 6.22, 21.47 +/- 6.87 and 22.55 +/- 7.02 microg/L respectively (P <0.05). Neuronal apoptosis in the CA3 and CA1 regions were alleviated in the four TPM treatment groups compared with positive control. The number of necrotic neurons was progressively reduced with the increased dose of TPM. The 40 mg TPM+FA treatment group showed less necrotic neurons in the CA3 and CA1 regions than the 40 mg TPM alone treatment group.. TPM has protective effects against epilepsy-induced neuronal damage. The effect is dose-dependent. A combination of TPM and FA can produce a synergistic effect.

Topics: Animals; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Epilepsy; Folic Acid; Fructose; Hippocampus; Kindling, Neurologic; Male; Neuroprotective Agents; Phosphopyruvate Hydratase; Rats; Rats, Wistar; Topiramate

The cerebellar cognitive affective syndrome (CCAS) represents a spectrum of cerebellar-induced neurocognitive and affective disturbances. In this report a patient is described who developed CCAS under a treatment with standard daily dose of the anti-epileptic drug topiramate (TPM). Cognitive disturbances consisted of impaired visuo-spatial memory, concentration deficits and executive dysfunctions. Behavior and affect were characterized by marked mood-swings and several disinhibited symptoms. After a gradual discontinuation of treatment with topiramate, a complete remission of the cognitive and affective symptoms was observed within 6 weeks. Functional neuroimaging studies by means of SPECT were conducted 2 weeks and 8 months following TPM discontinuation. This case report seems to suggest that functional disruption of the cerebello-cerebral circuitry, leading to CCAS, can follow treatment with topiramate.

Topics: Amines; Anticonvulsants; Carbamazepine; Cerebellar Diseases; Cerebellum; Cognition Disorders; Cyclohexanecarboxylic Acids; Drug Therapy, Combination; Epilepsy; Female; Follow-Up Studies; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Middle Aged; Mood Disorders; Neuropsychological Tests; Oxcarbazepine; Syndrome; Topiramate; Treatment Outcome

New antiepileptic drugs (AEDs), introduced since 1993, provide more diverse options in the treatment of epilepsy. Despite the equivalent efficacy and better tolerability of these drugs, more than 25% of patients remain refractory to treatment. Moreover, the issues for pediatric patients are different from those for adults, and have not been addressed in the development and application of the new AEDs. Recently published evidence-based treatment guidelines have helped physicians to choose the most reasonable AED, although they cannot fully endorse new AEDs because of the lack of well-designed, randomized controlled trials. We review the mechanisms of action, pharmacokinetic properties, adverse reactions, efficacy, and tolerability of eight new AEDs (felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, topiramate, vigabatrin, and zonisamide), focusing on currently available treatment guidelines and expert opinions regarding pediatric epilepsy.

Topics: Amines; Anticonvulsants; Carbamazepine; Child; Child, Preschool; Cyclohexanecarboxylic Acids; Epilepsy; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Lamotrigine; Levetiracetam; Pediatrics; Phenylcarbamates; Piracetam; Practice Guidelines as Topic; Propylene Glycols; Topiramate; Triazines; Vigabatrin

Heatstroke, which is a major disorder related to environmental hyperthermia, is a rare event in children. The risk is increased with predisposing medical conditions and specific medications. We report the case of a 10-year-old epileptic patient, who received topiramate. Topiramate causes hypohydrosis and hyperthermia. We suggest that topiramate treatment may be a risk factor for heatstroke.

Topics: Child; Epilepsy; Fructose; Heat Stroke; Humans; Male; Neuroprotective Agents; Risk Factors; 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

Topics: Adult; Aged; Ambulatory Care Facilities; Anticonvulsants; Dose-Response Relationship, Drug; Drug Resistance; Epilepsy; Follow-Up Studies; Fructose; Humans; Middle Aged; Neuroprotective Agents; Outpatients; Topiramate; Treatment Outcome

To search for association between the 163G>A polymorphism of the fatty acid binding protein 2 (FABP2) gene and intracellular transport of the valproic acid in the small intestines, 168 patients with different forms of epilepsy, aged from 1 to 89 years, and different illness duration have been studied. The patients received valproates (127 patients) and topiramate (41 patients) as a monotherapy. It has been shown that the 163G>A (Ala54Thr) polymorphism exerts an influence on effective dose of the valproic acid but not of topiramate.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alleles; Anticonvulsants; Biological Transport, Active; Child; Child, Preschool; DNA; Epilepsy; Fatty Acid-Binding Proteins; Fructose; Gene Frequency; Humans; Infant; Intestine, Small; Middle Aged; Polymerase Chain Reaction; Polymorphism, Genetic; Topiramate; Treatment Outcome; Valproic Acid

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

Levetiracetam (LEV) and topiramate (TPM) are considered highly effective novel antiepileptic drugs (AEDs) in the treatment of focal epilepsies. To explore potential side effects, this study investigated their influence on cognitive functions comparatively by means of a standardized neuropsychological test battery assessing several cognitive domains. In this observational study, cognitive changes were explored in 30 consecutively recruited patients with focal epilepsy treated with LEV and in 21 patients treated with TPM, comparing functions assessed prior to gradual initiation and after reaching steady state of the individual target dosage. Before titration, patient groups did not differ significantly with respect to cognitive performance. Whereas the LEV group manifested no change in cognitive performance after AED titration, the TPM group worsened in the cognitive domains of cognitive speed and verbal fluency, as well as short-term memory. These findings suggest that TPM, unlike LEV, may impair frontal lobe functions. The lack of cognitive side effects related to LEV treatment may be relevant for treatment decisions.

Topics: Adult; Anticonvulsants; Case-Control Studies; Cognition; Electroencephalography; Epilepsy; Female; Fructose; Humans; Intelligence; Levetiracetam; Male; Memory, Short-Term; Middle Aged; Multivariate Analysis; Neuropsychological Tests; Piracetam; Topiramate; Visual Perception

We describe two siblings with neonatal hypocalcemic seizures whose mother took topiramate during both pregnancies. Apart from hypocalcemia, the patients had no identifiable etiology for their seizures. Although biochemical data suggested that the hypocalcemia was caused by hypoparathyroidism, no disorders typically associated with this condition were identified in the patients. We propose that topiramate exposure in utero led to hypoparathyroidism and subsequent hypocalcemia via effects on protein kinase A signaling, resulting in hypocalcemic seizures. Neonates exposed to topiramate in utero should be monitored for hypocalcemic seizures.

Topics: Anticonvulsants; Epilepsy; Female; Fructose; Humans; Hypocalcemia; Hypoparathyroidism; Infant, Newborn; Male; Pregnancy; Prenatal Exposure Delayed Effects; Siblings; Topiramate

Topiramate is a new broad-spectrum anti-epileptic drug. Decreased body weight and appetite are common side effects of topiramate. The side effect affects the growth and development in children greatly. Little is known about the mechanisms of topiramate-induced weight loss and decreased appetite in children with epilepsy in China and abroad. galanin is one of factors that affect appetite. It is a neuroendocrine peptide and play an important role in the control of appetite and body weight in the mechanism of hormone release. The purpose of this study was to explore the mechanism of topiramate-induced weight loss in children with epilepsy and the relation of weight loss with change of galanin, thereby to provide evidences for improvement of quality of life, compliance to treatment and reduce side effects of growth and development in children with epilepsy.. Totally 61 patients with especial epilepsy were enrolled into this study and the disease was defined by clinical manifestations and electroencephalography (EEG). Among them 32 cases had generalized seizures and 29 had local seizures. Sixteen normal children were enrolled as control group. The patients' age ranged from 0.5 to 14 (4.76 +/- 4.05) years and the patients were instructed to take 0.5 - 1 mg/kg of topiramate per day, with 0.5 - 1 mg/kg every 3 - 5 d increased to maximum of 3 - 8 mg/kg per day. Patients continued receiving the doses for 4 months. All patients' serum galanin levels and body height and weight and hepatic function were detected before and after antiepileptic drugs treatment. The galanin was detected by using radioimmunoassay.. After treatment with topiramate (61 cases) for 4 months, plasma galanin [(22.01 +/- 8.12) pg/ml] declined as compared with baseline [(26.56 +/- 9.35) pg/ml, t = 2.85, P < 0.01] in children with epilepsy. Twenty-two of 61 patients lost weight, their plasma galanin concentration was significantly lower [(26.51 +/- 10.00) pg/ml vs. (20.45 +/- 8.09) pg/ml, t = 2.91, P < 0.01], but there was no significant change in the weight-gained patients (39/61) and control group (n = 16). In children with epilepsy, the mean value of body weight decreased as compared with the pre-treatment values, but the difference was not significant; however, the body-mass index (BMI) was significantly lower than that obtained before treatment (t = 8.628, P < 0.01). Eighteen of 22 patients who lost weight had decreased appetite, but only five of 39 patients who gained weight showed decreased appetite (chi(2) = 28.50, P < 0.001). The mean value of plasma galanin declined after treatment in patients (23 cases) with decreased appetite [(18.35 +/- 7.80) pg/ml vs. (27.28 +/- 6.90) pg/ml, t = 4.84, P < 0.001]; while plasma galanin did not change significantly after treatment in patients (38 cases) without decreased appetite [(24.23 +/- 7.66) pg/ml vs. (26.12 +/- 5.49) pg/ml, t = 1.04, P > 0.05].. Topiramate treatment may lower the body weight and reduce appetite in part of children with epilepsy which may be mediated by the reduced plasma galanin level.

Topics: Adolescent; Anticonvulsants; Appetite; Case-Control Studies; Child; Child, Preschool; Epilepsy; Female; Fructose; Galanin; Humans; Infant; Male; Topiramate; Weight Loss

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

Routine clinical practice data are useful for payers and formulary decision makers to make sound decisions regarding coverage policy. Based on a literature search, there has been scant research into topiramate prescribing patterns among Medicaid patients.. The aim of this study was to describe diagnoses, demographic characteristics, additional co-existing diagnoses, and dosing among Medicaid patients prescribed topiramate.. This descriptive, retrospective database analysis used data from South Carolina (SC) and Texas (TX) ambulatory Medicaid claims dated October 1, 2003, to December 31, 2004. Patients whose data were eligible for inclusion in the study were enrolled in Medicaid during the study period, had >or=2 topiramate prescriptions, were aged <65 years, and had evidence of a topiramate treatment-related diagnosis (possible diagnoses were identified through literature search and drug compendiums). Four cohorts were defined: (1) epilepsy only; (2) migraine only; (3) epilepsy and migraine; and (4) nonepilepsy/nonmigraine. Demographic characteristics, diagnoses, comorbidities, and daily dose of topiramate were summarized using descriptive statistics. The initial study analysis (period 1) was a 180-day window comprising the 90 days before and after the first available topiramate prescription claim was filed. A second, 360-day analysis (period 2) was completed comprising the 180 days before and after the index topiramate prescription date.. In the 180-day analysis, 2216 SC and 4766 TX Medicaid patients met the selection criteria. Cohort classification percentages were 32.3% and 39.6% (epilepsy only), 29.7% and 16.4% (migraine only), 10.7% and 9.2% (epilepsy and migraine), and 27.3% and 34.9% (nonepilepsy/nonmigraine) for SC and TX, respectively. Mean (SD) ages were 29.9 (15.9) (SC) and 27.1 (16.1) (TX) years. In the nonepilepsy/nonmigraine cohort, the most common diagnoses were bipolar disorder and depression. The median daily doses in the epilepsy-only cohort were 175 mg/d in the SC group and 200 mg/d in the TX group. In the migraine-only cohort, the median daily dose was 100 mg/d in SC and TX. Results for the 360-day analysis were similar.. In this descriptive study using data from 2 Medicaid populations, the majority of patients using topiramate had a diagnosis of epilepsy and/or migraine. Median dosages ranged from 175 to 200 mg/d in patients with epilepsy and 100 mg/d in those with migraine. Depression was a common comorbidity in the migraine cohort and the nonepilepsy/nonmigraine cohort.

Topics: Adolescent; Adult; Child; Comorbidity; Databases as Topic; Drug Utilization; Epilepsy; Female; Fructose; Humans; Male; Medicaid; Middle Aged; Migraine Disorders; Retrospective Studies; South Carolina; Texas; Topiramate

To investigate the hypothesis that some patients with epilepsy are generally prone to develop psychiatric adverse events (PAEs) during antiepileptic drug (AED) therapy irrespective of the mechanism of action of the drugs.. From a large case registry of patients prescribed topiramate (TPM) and levetiracetam (LEV), data of patients who had a trial with both drugs were analyzed. Demographic and clinical variables of those who developed PAEs with both drugs (group 1) were compared with those who did not (group 2). Subsequently, from the whole case registry, psychopathological features, demographic, and clinical variables of patients developing PAEs with TPM were compared with those of patients developing PAEs with LEV.. The case registry included over 800 patients. Among 108 patients having a trial with both drugs, we identified 9 patients in group 1 and 71 in group 2. Previous psychiatric history, family psychiatric history and history of febrile convulsions showed to be significant clinical correlates. Comparing patients who developed PAEs with LEV with those who developed PAEs with TPM, there were no differences in epilepsy related variables. Well-defined DSM-IV disorders were more frequent with TPM than with LEV. Seizure freedom was associated with psychosis.. This study suggests that a subgroup of patients is generally prone to develop PAEs during AED therapy, despite different pharmacological properties of the AEDs. A particular clinical profile and relevant variables have been identified.

Topics: Adult; Anticonvulsants; Comorbidity; Diagnostic and Statistical Manual of Mental Disorders; Epilepsy; Female; Fructose; Humans; Levetiracetam; Male; Mental Disorders; Netherlands; Piracetam; Psychiatric Status Rating Scales; Psychoses, Substance-Induced; Registries; Retrospective Studies; Seizures, Febrile; Topiramate

Insulinoma is a common cause of seizures due to recurrent hypoglycemic crises. Surgical treatment usually results in disappearance of such seizures. We describe a previously healthy 17 year-old girl who became epileptic after the onset of insulinoma with persistent seizures after surgical removal of the tumour. Insulinoma must be taken into account for differential diagnosis with convulsions of unknown origin, and even after metabolic normalization it may cause epilepsy.

Topics: Adolescent; Anticonvulsants; Electroencephalography; Epilepsy; Female; Fructose; Humans; Insulinoma; Pancreatic Neoplasms; Topiramate

Topics: Adult; Anticonvulsants; Electroencephalography; Epilepsy; Facial Muscles; Female; Fructose; Functional Laterality; Humans; Male; Middle Aged; Myoclonus; Topiramate

To report the role of choroidal drainage in patient with acute bilateral angle closure secondary to cilio-choroidal effusion with Topiramate.. Interventional case report.. Two weeks after commencing tablet Topiramate (Sulfamate derivative) for management of epilepsy, a patient developed bilateral acute angle closure secondary to cilio-choroidal effusion with lenticulo-corneal touches for which choroidal drainage was performed in 1 eye.. After choroidal drainage, anterior chamber deepened, corneal edema resolved, choroidals started resolving, and intraocular pressure was controlled without medication.. In patients presenting with acute angle closure secondary to Topiramate toxicity, choroidal drainage if indicated, is a safe and effective interventional procedure.

Topics: Anticonvulsants; Choroid Diseases; Corneal Edema; Drainage; Epilepsy; Fructose; Glaucoma, Angle-Closure; Humans; Intraocular Pressure; Male; Microscopy, Acoustic; Middle Aged; Topiramate; Treatment Outcome; Ultrasonography

A comparative analysis of treatment with keppra and topamax of various types of epilepsy has been carried out in 37 patients aged from 1 to 35 years. Symptomatic temporal-frontal-lobe epilepsy was diagnosed in 22 patients, symptomatic temporal lobe epilepsy in 15 including "urgent aid" cases with previous antiepileptic therapy being ineffective. Effect of the drugs on the cerebral blood flow was studied with the single proton emission CT. Keppra treatment was assigned to 20 patients in dosages varying from 500 to 2,500 mg (30-50 mg/kg/daily) for single intake. Then the patients received the drug two times daily under the clinical and EEG control. The drug was tested for using in the "urgent care mode". The clinical effect by 43% decreasing (p<0,001) of seizures was observed in the first 12 h. The "stability state" was 80% after 8 months of the treatment. Topamax was administered to 17 patients in two dosages depending on patient's age and weight starting with 25-50 mg (from 3 to 12,5 mg/kg/daily) with the dose adjustment during 2 days. The latter was depended on the dynamics of clinical data and EEG. For the first 2 days, patients revealed changes in seizures quality: the seizure structure became less complex, without generalized seizures, and period of a seizure was shorter. Reduction of seizures frequency was observed on the 7-10th day and made up on average 73,9% (p<0,01). Comparing to keppra, topamax did not cause signs of autonomic and psychological discomfort. Generalized seizures became less frequent by the 3rd day.

Topics: Adolescent; Adult; Anticonvulsants; Blood Flow Velocity; Cerebrovascular Circulation; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Therapy, Combination; Electroencephalography; Epilepsy; Female; Follow-Up Studies; Fructose; Humans; Infant; Levetiracetam; Male; Neuroprotective Agents; Piracetam; Tomography, Emission-Computed, Single-Photon; Topiramate; Treatment Outcome

The results of an open prospective naturalistic study on the use of topiramate (topamax) in 92 patients with focal epilepsy are presented. The pharmacological remission with duration over one year was achieved in 47,8% of patients. In total, the percentage of remission and clinical improvement made up 68,5%. The positive changes were observed in drug-naive patients (during first monotherapy) and in patients who previously received ineffective therapy. In some cases of patients with resistant forms of epilepsy, pharmacological remission or significant improvement of the control over seizures was found. The topamax therapy substantially increased the quality of life of the patients. The cost of therapy was 3100-5200 rubles per month, mean costs for a one patient during one year--416,000 rubles. The marginal utility 237,000 rubles per each additional QALY was significantly lower than $20,000, the minimal threshold of cost-effectiveness for European countries.

Topics: Adult; Anticonvulsants; Drug Costs; Economics, Pharmaceutical; Epilepsy; Female; Follow-Up Studies; Fructose; Humans; Male; Prospective Studies; Quality of Life; Remission Induction; Topiramate; Treatment Outcome

To investigate the relevance of serum topiramate (TPM) levels (SL) monitoring in the clinical management of epileptic patients.. Twenty-seven patients with different epileptic syndromes on TPM therapy were studied. TPM was used as add-on in 26 patients, only in one as monotherapy de novo; one case changed from TPM as add-on to TPM monotherapy. The mean follow-up time was 11 months. TPM SL were measured by fluorescence polarization immunoassay.. We analyzed the TPM SL in 43 samples from 27 patients. Mean TPM dose was 3.9mg/kg, mean TPM SL 13.43mumol/l. The mean level to dose ratio (LDR) was 3.63mumol/l/mg/kg. Four patients became seizure-free, all with TPM dosages lower than the mean. Eleven patients had at least 50% seizure reduction. The comedication with enzyme-inducing AED significantly reduced TPM SL and LDR. On the other hand, the influence of valproic acid (VPA) on TPM LDR was not univocal. Indeed, patients younger than 15 years showed SL values lower than the adults did, although not significant.. We could not detect a direct relationship between high TPM SL and efficacy neither between high TPM SL and tolerability. However, the data we collected seem to favour the hypothesis that high TPM dosage and SL might be associated to a greater probability to reduce seizure severity.

Topics: Adolescent; Adult; Anticonvulsants; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Infant; Male; Middle Aged; Prospective Studies; Regression Analysis; Topiramate

Functional magnetic resonance imaging of covert word generation was used to examine brain activation abnormalities associated with topiramate-induced cognitive language impairment in patients with epilepsy. Compared with a control epilepsy group, in the topiramate-treated group, there was significantly less activation in the language-mediating regions of the prefrontal cortex; the topiramate group also had significantly lower neuropsychological language scores. These findings suggest that topiramate has a critical effect on the cerebral neural systems that mediate expressive language.

Topics: Adult; Anticonvulsants; Cognition; Epilepsy; Female; Fructose; Humans; Language Disorders; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Prefrontal Cortex; Topiramate

The aim of the study was to evaluate efficacy and tolerability of topamax in patients of different age with various types of epilepsy. The drug was prescribed as monotherapy and combined therapy to 114 patients (53 men, 61 women) who were divided into age groups as follows: early age children--16 patients, preschool and school children--20, pubertal children--16, adolescent--23, middle-age patients--38, elderly--1. During topamax treatment, a complete remission was achieved in 48% patients, reduction of seizures frequency (more than by 50%)--in 44% patients. Topamax was more effective by remission index in the pubertal children, adolescent and adults as compared to early age children. The same peculiarity was characteristic of topamax in the treatment of symptomatic epilepsy. This drug was well-tolerable in all the groups studied, with isolated cases of moderate side-effects (body mass reduction, irritability, allergic skin reactions, paresthesias).

Topics: Adolescent; Adult; Age Distribution; Age Factors; Aged; Anticonvulsants; Child; Child, Preschool; Epilepsy; Female; Follow-Up Studies; Fructose; Humans; Infant; Male; Middle Aged; Retrospective Studies; Topiramate; Treatment Outcome

Neurocognitive complaints may interfere with long-term antiepileptic drug (AED) treatment and are an important issue in clinical practice. Most data about drug-induced cognitive problems are derived from highly controlled short-term clinical trials. We analyzed such cognitive complaints for the two most commonly used AEDs in a clinical setting using patient perceived problems as primary outcome measure.. All patients of the epilepsy center Kempenhaeghe that received topiramate (TPM) or levetiracetam (LEV) from the introduction to mid 2004 were analyzed using a medical information system, an automated medical file. Patients were analyzed after 6, 12, and 18 months of treatment.. Four hundred and two patients used either TPM (n = 260) or LEV (n = 142); 18 months retention showed a statistically significant difference, revealing 15% more patients that continued LEV compared to TPM: 18 months retention 46% for TPM and 61% for LEV [F (1.400) = 3.313, p = 0.043]. Neurocognitive complaints accounted for a significant number of drug discontinuations and especially the high frequency of neurocognitive complaints in the first period of TPM treatment appeared to be significant different from LEV [F(2,547) = 3.192, p = 0.042]. In the remaining patients, the difference in neurocognitive complaints was not statistically significant.. cognitive complaints are common in TPM treatment and frequently lead to drug withdrawal. The impact of LEV on cognitive function is only mild. This leads to a much higher (15%) drug discontinuation rate for TPM compared to LEV.

Topics: Adult; Anticonvulsants; Attitude to Health; Child; Cognition Disorders; Drug Utilization; Epilepsy; Female; Follow-Up Studies; Fructose; Humans; Levetiracetam; Male; Patient Dropouts; Piracetam; Topiramate

Topics: Anticonvulsants; Antipsychotic Agents; Autistic Disorder; Caregivers; Child; Developmental Disabilities; Epilepsy; Female; Foster Home Care; Fructose; Humans; Impulsive Behavior; Mental Status Schedule; Psychological Tests; Risperidone; Status Epilepticus; Topiramate; Valproic Acid

It is known that current antiepileptic drugs cannot control seizures in 20-30% of patients. The aim of this study was to evaluate the efficacy and safety of topiramate (TPM) as add-on therapy in intractable epileptic children in Iran.. As a quasi- experimental (before and after) study, 42 iranian children aged 1-15 years, 28 boys and 14 girls with refractory seizures seeking treatment were recruited to be subjects of this study.. Type of seizures of those 42 epileptic children were as follows: L.G.S (n=14), idiopathic epilepsy (n=8), symptomatic epilepsy (n=16) and progressive myoclonic epilepsy (n=4). At the end of three months of treatment in which topiramate was used concomitantly with previous AED, 17% became seizure free, 26% had more than 50% reduction of seizure frequency and 5% of them had increasing seizures. Therefore, the drug is statistically significant in seizures reduction. The efficacy of the drug was statistically significant in idiopathic and symptomatic epilepsy. The author's did not notice any serious side effects such as: hematologic abnormality, hepatotoxicity and nephrotoxicity.. This study supports efficacy and safety of TPM in controlling of intractable epilepsy in children and indicates the drug should be considered as an add-on therapy in the management of refractory epileptic syndromes.

Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Epilepsy; Female; Fructose; Humans; Infant; Iran; Male; Topiramate; Treatment Outcome

Topiramate is an antiepileptic drug known to have effects on weight. In order to use this as a tool to treat eating disorders, it is useful to examine whether these effects can be predicted in certain patients.. To report the effects of topiramate, initiated for the treatment of epilepsy, on top of ongoing treatment, on eating patterns and weight of 17 patients with traumatic brain injury (TBI) with post-traumatic epilepsy and weight gain of various etiologies.. Patients were followed up according to their usual treatment plan. Topiramate was added on top of current and stable treatment. Dose was titrated based on the patients' neurological status. Patients were asked to report side effects. No other changes were made.. Of the 17 patients included, one patient dropped out. Six patients with binge eating disorder (BED) demonstrated the most pronounced effects, with marked attenuation of binges and normalizing body mass index. Less noticeable were the effects in patients with mood disorders. Topiramate was ineffective in patients whose overweight was a side effect of their medication. Side effects were rated as mild and included somnolence, paresthesias, mild cognitive disturbances and some gastrointestinal disturbances.. In this report of the actual effects of topiramate in a clinical setting on weight and eating habits of 17 patients with TBI and obesity of various etiologies, topiramate seemed to be a safe intervention. Topiramate appeared to be differentially effective, with particular effects on primary pathological eating patterns.

Topics: Adult; Anticonvulsants; Body Weight; Brain Injuries; Bulimia; Dose-Response Relationship, Drug; Electroencephalography; Epilepsy; Feeding Behavior; Female; Fructose; Humans; Male; Middle Aged; Neuroprotective Agents; Obesity; Psychiatric Status Rating Scales; Psychotic Disorders; Topiramate

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

Potential antiepileptic drugs (AEDs) are typically screened on acute seizures in normal animals, such as those induced in the maximal electroshock and pentylenetet-razole models. As a proof-of-principle test, the present experiments used spontaneous epileptic seizures in kainate-treated rats to examine the efficacy of topiramate (TPM) with a repeated-measures, crossover protocol.. Kainic acid was administered in repeated low doses (5 mg/kg) every hour until each Sprague-Dawley rat experienced convulsive status epilepticus for >3 h. Six 1-month trials (n = 6-10 rats) assessed the effects of 0.3-100 mg/kg TPM on spontaneous seizures. Each trial involved six pairs of TPM and saline-control treatments administered as intraperitoneal injections on alternate days with a recovery day between each treatment day. Data analysis included a log transformation to compensate for the asymmetric distribution of values and the heterogeneous variances, which appeared to arise from clustering of seizures.. A significant effect of TPM was observed for 12 h (i.e., two 6-h periods) after a 30-mg/kg injection, and full recovery from the drug effect was complete within 43 h. TPM exerted a significant effect at doses of 10, 30, and 100 mg/kg, and the effects of TPM (0.3-100 mg/kg) were dose dependent.. These data suggest that animal models with spontaneous seizures, such as kainate- and pilocarpine-treated rats, can be used efficiently for rapid testing of AEDs with a repeated-measures, crossover protocol. Furthermore, the results indicate that this design allows both dose-effect and time-course-of-recovery studies.

Topics: Animals; Anticonvulsants; Chronic Disease; Cross-Over Studies; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Epilepsy; Fructose; Injections, Intraperitoneal; Kainic Acid; Pilocarpine; Rats; Rats, Sprague-Dawley; Research Design; Sodium Chloride; Status Epilepticus; Topiramate

Topics: Adult; Anticonvulsants; Epilepsy; Epilepsy, Frontal Lobe; Epilepsy, Temporal Lobe; Erectile Dysfunction; Fructose; Humans; Male; Topiramate

Topiramate is a new anticonvulsant drug recommended for treatment of partial and generalized seizures in children and adults. It has been found to cause a nonanion gap metabolic acidosis in some patients, which is related to carbonic anhydrase inhibition. This adverse reaction is more common in children than adults and is rarely symptomatic. Clinicians need to be aware of this potential side effect especially in children undergoing major surgery. Children who are treated with topiramate should have a careful history taken preoperatively looking for signs of a metabolic acidosis and baseline blood chemistries should be measured prior to surgery to detect an asymptomatic metabolic acidosis.

Topics: Acidosis; Adolescent; Anticonvulsants; Blood Gas Analysis; Child; Child, Preschool; Electrodiagnosis; Epilepsy; Female; Fructose; Humans; Male; Retrospective Studies; Spinal Fusion; Topiramate

Topiramate is an antiepileptic medication with multiple pharmacologic effects, including inhibition of carbonic anhydrase activity. It is associated with metabolic acidosis in both children and adults.. To evaluate the incidence and magnitude of the effect of topiramate on serum bicarbonate concentrations in an adult population.. This was a retrospective cohort study. Data were evaluated to assess the relationship between serum bicarbonate concentrations before and during topiramate therapy.. Fifty-four patients (40 females) with a mean age of 47.6 years (range 19-89) were included in the study. Mean +/- SD serum bicarbonate concentrations before and during topiramate therapy were 26.8 +/- 2.9 mEq/L (range 21-36) and 21.7 +/- 3.6 mEq/L (range 13-29), respectively, with a mean difference of 5.1 (95% CI 3.7 to 6.5; p < 0.001). Twenty-six patients (48%) had low serum bicarbonate concentrations while on topiramate, with a mean concentration of 18.8 mEq/L (range 13-21).. Topiramate was associated with metabolic acidosis in 48% of the patients studied, which did not result in clinically significant problems.

Topics: Acidosis; Adult; Aged; Aged, 80 and over; Anticonvulsants; Bicarbonates; Cohort Studies; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Retrospective Studies; Topiramate

Topics: Adolescent; Adult; Aged; Ambulatory Care Facilities; Anticonvulsants; Child; Data Interpretation, Statistical; Epilepsy; Epilepsy, Generalized; Female; Fructose; Humans; Male; Middle Aged; Remission Induction; Time Factors; Topiramate; Treatment Outcome

A 15-year-old boy with inverted duplication of chromosome 15 was admitted for acute onset of irritability, increasing sleepiness, and worsening of seizures. He had been on valproate and other anti-convulsants. However, he was found to have hyperammonemia within 2 weeks after the addition of low-dose topiramate to valproate. He recovered within 7 days after discontinuation of valproate. Topiramate was tailed off. The reintroduction of valproate monotherapy caused hyperammonemia again without clinical features of encephalopathy. He also developed anticonvulsant hypersensitivity syndrome following the use of phenytoin. We propose the term topiramate-valproate-induced hyperammonemic encephalopathy syndrome to include the following features: excessive sleepiness or somnolence, aggravation of seizures, hyperammonemia, and absence of triphasic waves on electroencephalography in any individual on simultaneous topiramate-valproate therapy. The ammonia level ranged from 1.5 to 2 times normal. The serum valproate level might be within the therapeutic range. The possible mechanism is topiramate-induced aggravation of all the known complications of valproate monotherapy. This condition is reversible with cessation of either valproate or topiramate.

Topics: Adolescent; Anticonvulsants; Brain Diseases; Chromosome Inversion; Chromosomes, Human, Pair 15; Drug Therapy, Combination; Epilepsy; Fructose; Humans; Hyperammonemia; Male; Syndrome; Topiramate; Valproic Acid

To compare the steady-state pharmacokinetics of topiramate in a large population of children and adults with epilepsy in a therapeutic drug monitoring setting.. Retrospective, case-matched pharmacokinetic evaluation.. Seventy children (aged 1-17 years) with epilepsy and 70 adult controls (aged 18-65 years) with epilepsy, matched for sex and comedication.. Topiramate apparent oral clearance (CL/F) values were calculated from steady-state serum concentrations in children and compared with those determined in controls. Comparisons were made by means of the Mann-Whitney's U-test, or the Kruskal-Wallis test in the case of multiple comparisons. A linear regression model was used to assess potential correlation of CL/F values with age. To investigate the influence of different variables on the variability in topiramate CL/F values, a multiple regression model was developed.. In the absence of enzyme-inducing comedication, mean topiramate CL/F was 42% higher in children than in adults (40.3 +/- 21.0 vs 28.4 +/- 15.3 mL/h/kg; p < 0.01). In children and adults comedicated with enzyme-inducing antiepileptic drugs (AEDs), topiramate CL/F values were approximately 1.5- to 2-fold higher than those observed in the absence of enzyme inducers, and the elevation in topiramate CL/F in children compared with adults was also present in the subgroups receiving enzyme inducers (66%; 76.6 +/- 35.1 vs 46.1 +/- 16.7 mL/h/kg; p < 0.0001). In the paediatric population, a negative correlation between CL/F and age was demonstrated, both in the absence (p < 0.01) and in the presence (p < 0.001) of enzyme induction. The independent influence of age and enzyme-inducing AEDs on topiramate CL/F was confirmed by multiple regression analysis.. Topiramate CL/F is highest in young children and decreases progressively with age until puberty, presumably due to age-dependent changes in the rate of drug metabolism. As a result of this, younger patients require higher dosages to achieve serum topiramate concentrations comparable with those found in older children and adults. Enzyme-inducing comedication decreases serum topiramate concentration by approximately one-half and one-third in children and adults, respectively.

Topics: Administration, Oral; Adolescent; Adult; Age Factors; Aged; Anticonvulsants; Child; Child, Preschool; Drug Interactions; Drug Monitoring; Enzyme Induction; Epilepsy; Female; Fructose; Humans; Infant; Male; Metabolic Clearance Rate; Middle Aged; Retrospective Studies; Topiramate

Topics: Adult; Anticonvulsants; Epilepsy; Female; Fructose; Humans; Male; Topiramate; Weight Loss

Topics: Anticonvulsants; Body Weight; Epilepsy; Female; Fructose; Humans; Infant; Male; Topiramate

To specify efficacy of topamax in different types of epileptic seizures and its influence on patient's quality of life (QL), the drug was assigned to 38 patients, aged 18-69 years, as mono- and polytherapy (in combination with other anticonvulsive medications). Topamax dosages ranged from 25-50 mg at a base-line to 600 mg. Treatment duration was 6-18 months. Positive effect of different extent was achieved in 95.7% patients. A seizures frequency decreased by 25% in 17.4% patients; by 50%--in 8.7%; by 75%--in 43.5%; a complete disappearance of seizures was detected in 30.4%. The results confirmed the earlier data received by the authors that topamax was most effective in generalized convulsive, partial and secondary generalized seizures. It exerts a less pronounced effect in myoclonic seizures and absences. After topamax treatment, a total QL index measured by WHO questionnaire increased by 5.2%. The drug is well tolerated and does not affect cognitive functions of the patients. It is concluded that currently topamax is one of the most effective antiepileptic medications.

Topics: Adolescent; Adult; Anticonvulsants; Cognition Disorders; Drug Administration Schedule; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Neuropsychological Tests; Quality of Life; Topiramate

The aims of this project were to evaluate the impact of adjunctive treatment with an anti-epileptic drug (AED) on the health status of people with epilepsy and to investigate how seizure frequency affects their health status.. Adult epilepsy patients, refractory to current treatment, were included in this prospective observational study. Patients commencing adjunctive therapy with one of five AEDs (topiramate, lamotrigine, gabapentin, clobazam, vigabatrin) were eligible for inclusion. The study took place at the outpatient clinics of the National Hospital for Neurology and Neurosurgery, Queen Square, London. Patients completed the EQ-5D, a generic health status measure, at baseline and again after 3 and 6 months. Information was also collected on medications and seizure frequency.. In total, 125 patients entered the study and were followed up for 6 months. Patients treated with topiramate had a significant increase (p < 0.05) in EQ-5D score from baseline, indicating an improvement in their health status whereas scores for lamotrigine, clobazam and gabapentin all showed a non-significant decline. When the data were analysed according to seizure frequency, only patients who became seizure-free on adjunctive treatment had a significant increase in their health status. The group who had a 50% reduction in seizure frequency did not have increased health status.. In summary, adjunctive treatment with topiramate significantly increased health status as measured by the EQ-5D. These data also suggest that achievement of seizure-freedom is the key to improving health status in this patient group.

Topics: Adult; Amines; Anticonvulsants; Cyclohexanecarboxylic Acids; Epilepsy; Female; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Lamotrigine; Male; Prospective Studies; Secondary Prevention; Sickness Impact Profile; Surveys and Questionnaires; Topiramate; Triazines; Vigabatrin

Topics: Aged; Anti-Obesity Agents; Blood Glucose; Diabetes Complications; Epilepsy; Female; Fructose; Humans; Neuroprotective Agents; Topiramate

To compare the influence of enzyme-inducing comedication and valproic acid (VPA) on topiramate (TPM) pharmacokinetics and metabolism at steady state.. Three groups were assessed: (a) patients receiving TPM mostly alone (control group, n =13); (b) patients receiving TPM with carbamazepine (CBZ; n = 13); and (c) patients receiving TPM with VPA (n = 12). TPM and its metabolites were assayed in plasma and urine by liquid chromatography-mass spectrometry (LC-MS).. No significant differences were found in TPM oral (CL/F) and renal (CL(r)) clearance between the VPA group and the control group. Mean TPM CL/F and CL(r) were higher in the CBZ group than in controls (2.1 vs. 1.2 L/h and 1.1 vs. 0.6L/h, respectively; p < 0.05). In all groups, the urinary recovery of unchanged TPM was extensive and accounted for 42-52% of the dose (p > 0.05). Urinary recovery of 2,3-O-des-isopropylidene-TPM (2,3-diol-TPM) accounted for 3.5% of the dose in controls, 2.2% in the VPA group (p > 0.05), and 13% in the CBZ group (p < 0.05). The recovery of 10-hydroxy-TPM (10-OH-TPM) was twofold higher in the CBZ group than in controls, but it accounted for only <2% of the dose. The plasma concentrations of TPM metabolites were severalfold lower than those of the parent drug.. Renal excretion remains a major route of TPM elimination, even in the presence of enzyme induction. The twofold increase in TPM-CL/F in patients taking CBZ can be ascribed, at least in part, to stimulation of the oxidative pathways leading to formation of 2,3-diol-TPM and 10-OH-TPM. VPA was not found to have any clinically significant influence on TPM pharmacokinetic and metabolic profiles.

Topics: Adult; Anticonvulsants; Biological Availability; Carbamazepine; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Enzyme Induction; Epilepsy; Female; Fructose; Humans; Male; Topiramate; Valproic Acid

Seizures arising from acetylcholinesterase inhibition are a feature of organophosphate anticholinesterase intoxication. Although benzodiazepines are effective against these seizures, alternative anticonvulsant drugs may possess greater efficacy and fewer side-effects. We have investigated in the guinea-pig hippocampal slice preparation the ability of a series of anticonvulsants to suppress epileptiform bursting induced by the irreversible organophosphate anticholinesterase, soman (100 nM). Carbamazepine (300 microM), phenytoin (100 microM), topiramate (100-300 microM) and retigabine (1-30 microM) reduced the frequency of bursting but only carbamazepine and phenytoin induced a concurrent reduction in burst duration. Felbamate (100-500 microM) and clomethiazole (100-300 microM) had no effect on burst frequency but decreased burst duration. Clozapine (3-30 microM) reduced the frequency but did not influence burst duration. Levetiracetam (100-300 microM) and gabapentin (100-300 microM) were without effect. These data suggest that several compounds, in particular clomethiazole, clozapine, felbamate, topiramate and retigabine, merit further evaluation as possible treatments for organophosphate poisoning.

Topics: Amines; Animals; Anticonvulsants; Carbamates; Carbamazepine; Chlormethiazole; Clozapine; Cyclohexanecarboxylic Acids; Dose-Response Relationship, Drug; Epilepsy; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Guinea Pigs; Hippocampus; In Vitro Techniques; Levetiracetam; Male; Phenylcarbamates; Phenylenediamines; Piracetam; Propylene Glycols; Soman; Topiramate

The aim of this audit was to ascertain outcomes for people who had taken or who were still taking three "new generation" broad-spectrum antiepileptic drugs (AEDs), namely lamotrigine, levetiracetam and topiramate. Thirteen percent of people became seizure free and approximately, one-third had a reduction of greater than 50% in their seizures. Two-thirds of people were still taking their audit AED. In addition, approximately one-third of people with a learning disability derived substantial benefit, although the rate of seizure freedom was lower. All three AEDs were most successful at treating primary generalised epilepsy and least successful with symptomatic generalised epilepsy. With some reservations the data suggests that levetiracetam and topiramate are the most efficacious AEDs, but topiramate is the least well tolerated. These results mean consideration of a "general prescribing policy" is important when using and choosing these AEDs. We conclude that lamotrigine, levetiracetam and topiramate are useful additions to the armamentarium of AEDs.

Topics: Adult; Aged; Anticonvulsants; Cohort Studies; Drug Utilization; Epilepsy; Epilepsy, Generalized; Female; Fructose; Hospitals, General; Humans; Knowledge Bases; Lamotrigine; Learning Disabilities; Levetiracetam; Male; Medical Audit; Middle Aged; Patient Dropouts; Piracetam; Topiramate; Triazines; United Kingdom

The aim of the study was to obtain pharmacokinetic data for carbamazepine (CBZ) and its fractions not bound with proteins in bitherapy with lamotrigine (LTG), topiramate (TPM), vigabatrin (VGB) or valproic acid (VPA) in children and adolescents treated for epilepsy.. The participants of the presented investigations were fifty-five patients with epilepsy who were under control of The Department of Developmental Neurology, University of Medical Sciences in Poznaf. All of patients were treated with CBZ in bitherapy with LTG, TPM, VGB or VPA. The blood samples were taken under steady-state conditions, before the morning dose and subsequently every 3 or 2 for 24 h. The plasma levels of CBZ were determined using TDX analyzer (Abbott Diagnostic Division, USA). Free CBZ fraction was isolated with the use of ultrafiltration system (Amicon, USA). For pharmacokinetic calculations of total and free CBZ, one-compartment model was used according to standardized procedure.. No significant differences in pharmacokinetic parameters of unbound CBZ in four groups of patients on bitherapy with CBZ and LTG, TPM, VGB or VPA were found. The changes in pharmacokinetics of total CBZ were related with difference in CBZ concentrations, area under curve (AUC), L/D/kg ratios and clearance (Cl)/kg. CBZ+VGB bitherapy led to higher total CBZ concentrations. In the group on bitherapy with CBZ+VPA, no increase in unbound CBZ was detected.. Pharmacokinetic interactions of CBZ with LTG, TPM, VGB or VPA in children are associated only with the changes in total CBZ parameters.

Topics: Adolescent; Anticonvulsants; Carbamazepine; Child; Drug Interactions; Epilepsy; Female; Fructose; Humans; Lamotrigine; Male; Protein Binding; Topiramate; Triazines; Valproic Acid; Vigabatrin

Topics: Adolescent; Ambulatory Care Facilities; Anticonvulsants; Child; Child, Preschool; Epilepsy; Female; Follow-Up Studies; Fructose; Humans; Infant; Male; Outpatients; Russia; Severity of Illness Index; Topiramate; Treatment Outcome; Urban Population

According to the best of our knowledge this is the first case of intoxication with topiramate in Polish medical literature. A case of a 15-year-old female who tried to commit suicide with 450 mg of Topamax was described. There were no significant changes in the medical examination as well as biochemical results. An agitation which transformed into bradykinesia and bradyphasia and lasted for about 24 hours were the only complaints of the patient.

Topics: Acute Disease; Adolescent; Anticonvulsants; Depression; Drug Overdose; Epilepsy; Female; Fructose; Humans; Poisoning; Suicide, Attempted; Time Factors; Topiramate; Treatment Outcome

Most large-scale clinical trials of antiepileptic drugs (AEDs) are undertaken for regulatory purposes and generate basic data supporting the efficacy and safety of a new treatment. They do not, however, provide all the information required for physicians to know how well the drug will work in clinical practice. One valuable approach to generating more clinically meaningful information is to assess AED treatment retention rates, which reflect the combination of efficacy and tolerability in the real world, and have historically been low. Long-term retention rate data are available for levetiracetam (LEV), topiramate, gabapentin, and lamotrigine, and these data suggest that LEV is more likely to retain patients than other new AEDs. In a recent tertiary care study involving mainly refractory patients, 11% of participants became seizure-free on LEV and nearly two-thirds were retained on long-term treatment. High seizure freedom rates and good tolerability reported with LEV in clinical trials thus appear to translate into improved treatment retention rates in clinical practice.

Topics: Amines; Anticonvulsants; Controlled Clinical Trials as Topic; Cyclohexanecarboxylic Acids; Epilepsy; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Lamotrigine; Levetiracetam; Long-Term Care; Patient Dropouts; Piracetam; Topiramate; Treatment Outcome; Triazines

Topics: Anticonvulsants; Carbamazepine; Child; Drug Therapy, Combination; Electroencephalography; Epilepsy; Epilepsy, Generalized; Epilepsy, Tonic-Clonic; Fructose; Humans; Magnetic Resonance Imaging; Phenobarbital; Phenytoin; Topiramate; Valproic Acid

Topics: Anti-Obesity Agents; Anticonvulsants; Cognition Disorders; Epilepsy; Fructose; Humans; Neuroprotective Agents; Obesity; Practice Guidelines as Topic; Practice Patterns, Physicians'; Topiramate

Authors presented the data on the efficacy and tolerability of the new anticonvulsant drug topiramate (topamax) in the treatment of 110 children aged from 6 months to 16 years with pharmacoresistant types of epilepsy including 42 patients with tuberous sclerosis. The medication dosage varied from 1 to 20 mg/kg daily. As a monotherapy the drug was used in 28 children, in the other cases it was combined with different anticonvulsant medications. Topiramate was effective in 78% patients; complete remission has been achieved in 35% cases. Side-effects were observed in 17% patients but they were transient and did not result in the drug withdrawal. The results of the study allowed to recommend the drug as an add-on and monotherapy in the treatment of resistant epilepsy.

Topics: Adolescent; Anticonvulsants; Carbamazepine; Child; Child, Preschool; Drug Resistance; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Infant; Lamotrigine; Male; Topiramate; Treatment Outcome; Triazines; Valproic Acid; Vigabatrin

Interventional case report.. In an institutional practice setting, two women, aged 25 and 45, developed acute myopia after starting topiramate for epilepsy. One patient also developed bilateral angle closure glaucoma.. Topiramate was discontinued. Anterior chamber shallowing was noted in both patients at presentation. Ultrasonography showed ciliochoroidal effusion. Baseline measurements of anterior chamber depth and lens thickness were obtained.. Topiramate may be associated with ciliochoroidal effusion with forward displacement of the lens-iris diaphragm and anterior chamber shallowing, resulting in acute myopia and angle-closure glaucoma. Increased lens thickness contributes only minimally (9%-16%) to anterior chamber shallowing.

Topics: Acute Disease; Adult; Anterior Chamber; Anticonvulsants; Epilepsy; Female; Fructose; Glaucoma, Angle-Closure; Humans; Intraocular Pressure; Middle Aged; Myopia; Topiramate; Ultrasonography

To examine a large population with idiopathic generalised epilepsy (IGE), and estimate the overall remission rates for the IGEs and subsyndromes in a clinic based sample. Remission rates on valproate, lamotrigine, topiramate, and combinations of these antiepileptic drugs were estimated and factors predicting outcome examined.. All patients with IGE were identified from a computerised database and EEG records at large adult and paediatric epilepsy clinics. Data were recorded retrospectively on demographics and clinical information, seizure types and syndrome diagnosis, antiepileptic drug treatment details, and remission rates.. 54.3% of 962 patients had achieved a one year period of remission; this was most likely with valproate monotherapy (52.1%), with lower rates for lamotrigine and topiramate (16.7% and 34.6%, respectively). The combination of valproate and lamotrigine achieved a remission rate of 15.3%. The factor most predictive of a response to a particular antiepileptic drug regimen was the rank order in which it was given. Relapse rate was high (79.9%) after antiepileptic drug withdrawal in remission, particularly with juvenile myoclonic epilepsy (93.6%).. Valproate may be the most effective antiepileptic drug in the treatment of the IGEs. Combination therapy should be initiated if an adequate trial of valproate monotherapy is not effective, rather than switching to alternative monotherapy. Antiepileptic drug treatment needs to be lifelong in many adult patients with IGE.

Topics: Adolescent; Adult; Anticonvulsants; Child; Child, Preschool; Databases, Factual; Electroencephalography; Epilepsy; Female; Fructose; Humans; Lamotrigine; Male; Retrospective Studies; Topiramate; Treatment Outcome; Triazines; Valproic Acid

To examine the inhibitory effect of anticonvulsants (AEDs) on carnitine transport by the human placental carnitine transporter.. Uptake of radiolabeled carnitine by human placental brush-border membrane vesicles was measured in the absence and presence of tiagabine (TGB), vigabatrin (VGB), gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), valproic acid (VPA), and phenytoin (PHT). The mechanism of the inhibitory action of TGB was determined.. Most of the AEDs inhibited placental carnitine transport. Kinetic analyses showed that TGB had the greatest inhibitory effect [50% inhibitory concentration (IC50, 190 microM)], and the order of inhibitory potency was TGB > PHT > GBP > VPA > VGB, TPM > LTG. Further studies showed that TGB competitively inhibited carnitine uptake by the human placental carnitine transporter, suggesting that it may be a substrate for this carrier.. Although the involvement of carnitine deficiency in fetal anticonvulsant syndrome requires further evaluation, potential interference with placental carnitine transport by several AEDs was demonstrated. Despite the higher inhibitory potency of TGB, given the therapeutic unbound concentrations, the results for VPA and PHT are probably more clinically significant.

Topics: Acetates; Amines; Aminoisobutyric Acids; Anticonvulsants; Carnitine; Carrier Proteins; Culture Techniques; Cyclohexanecarboxylic Acids; Dose-Response Relationship, Drug; Drug Administration Schedule; Epilepsy; Female; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Lamotrigine; Models, Biological; Nipecotic Acids; Organic Cation Transport Proteins; Phenytoin; Placenta; Pregnancy; Pregnancy Complications; Pregnancy Proteins; Solute Carrier Family 22 Member 5; Tiagabine; Topiramate; Triazines; Valproic Acid; Vigabatrin

Limited research has focused to date on objective neurophysiological evaluation of daytime sleepiness in patients treated with newer antiepileptic drugs (AEDs), especially when used as monotherapy. This study was aimed at assessing occurrence of daytime sleepiness in newly diagnosed, drug-naïve patients with partial epilepsy receiving initial topiramate (TPM) monotherapy.. Daytime vigilance was assessed in 14 consecutive, newly diagnosed and never medicated adult patients with focal epilepsy, receiving monotherapy with TPM. At baseline and 2 months after slowly titrated therapy with TPM, 200 mg/day, patients underwent the Multiple Sleep Latency Test (MSLT), visual simple and choice reaction times (VRT), and self-rated their own degree of sleepiness with the Epworth Sleepiness Scale. A group of 14 age- and gender-matched healthy volunteers served as controls.. At baseline, mean daytime sleep latencies on the MSLT were comparable in patients and in controls. Two months after TPM monotherapy, MSLT scores did not significantly change in patients as compared with pretreatment values. Accordingly, subjective daytime sleepiness and VRTs, which were comparable in controls and in untreated patients at baseline, did not change in patients after TPM monotherapy.. Study results suggest that an initial short-course monotherapy with TPM, 200 mg/day, does not impair daytime vigilance in newly diagnosed adult patients with partial seizures.

Topics: Adult; Aged; Arousal; Circadian Rhythm; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Psychomotor Performance; Reaction Time; Sleep Stages; Statistics, Nonparametric; Topiramate

Topiramate (TPM), a new generation antiepileptic drug was investigated for its anticonvulsant effects in various models of genetically determined and chemically induced epilepsy in rodents. In addition, based on recent electrophysiological data suggesting that TPM may interact with L-type Ca(2+) channels, we evaluated the effects of a concomitant administration of L-type Ca(2+) channel modulators on TPM's antiepileptic properties. TPM, dose-dependently, protected against audiogenic seizures in DBA/2 mice. Concomitant treatment with TPM and a low dose of L-type Ca(2+) channel antagonists nifedipine or verapamil or with the L-type Ca(2+) channel agonist, S(-)-1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-3-pyridinecarboxylic acid methyl ester (Bay k 8644) was able to increase the ED(50) for this drug. TPM also protected against seizures induced by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), 4-aminopyridine (4-AP) and pentylenetetrazole (PTZ), but this activity was not significantly modified by nifedipine. TPM, dose-dependently, reduced the number and duration of epileptic spike-wave discharges (SWDs) both in WAG/Rij rats and lethargic (lh/lh) mice, two genetic models of absence epilepsy. Nifedipine decreased TPM's activity in WAG/Rij rats but paradoxically enhanced it in lh/lh mice, whereas Bay k 8644 displayed opposite effects in both absence models. These results confirm TPM's broad spectrum of anticonvulsant activity and support the proposal that a modulation of neuronal L-type Ca(2+) channel activity plays an important role in its antiepileptic activity.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Drug Synergism; Epilepsy; Female; Fructose; Male; Mice; Mice, Inbred DBA; Mice, Inbred ICR; Mice, Transgenic; Nifedipine; Rats; Topiramate

Six severe epileptic patients developed stuporous encephalopathy with marked cognitive impairment when topiramate (TPM) and sodium valproate (VPA) were coprescribed for five patients, and when monotherapy with TPM was introduced for one patient. In four patients, ammonaemia increased and then returned to normal after TPM or VPA withdrawal. This severe potential side effect must be recognized. Moreover two distinct mechanisms might explain this toxicity: (1). a pharmacokinetic interaction between VPA and TPM, leading to hyperammonaemia, (2). a pharmacodynamic mechanism due to a direct toxicity of TPM in at-risk epileptic patients.

Topics: Adolescent; Adult; Ammonia; Anticonvulsants; Drug Interactions; Drug Therapy, Combination; Electroencephalography; Epilepsy; Female; Fructose; Humans; Male; Neurotoxicity Syndromes; Topiramate; Valproic Acid

It has been reported that vagus nerve stimulation (VNS) improves behavior in children, whereas topiramate has a less clear effect. Three boys, aged 5-12 years, with generalized slow spike-wave discharges and refractory epilepsy, were treated with combination therapy of topiramate and VNS. All three had a significant reduction in seizures, but even more dramatic improvement in aggression, social interaction, and ambulation. The Cyberonics Patient Outcome Registry was subsequently queried and a beneficial effect of this combination therapy on behavior (specifically alertness) beyond that of VNS and other anticonvulsants was noted. This did not appear to be due solely to seizure reduction, which was observed only differentially at 12 months.

Topics: Anticonvulsants; Arousal; Child; Child Behavior Disorders; Child, Preschool; Combined Modality Therapy; Educational Status; Electric Stimulation Therapy; Electroencephalography; Epilepsy; Evoked Potentials; Fructose; Humans; Male; Memory; Quality of Life; Registries; Social Behavior; Topiramate; Treatment Outcome; Vagus Nerve; Verbal Behavior

Topiramate (TPM) is an anticonvulsant whose impact on firing activity and intracellular pH (pHi) regulation of CA3 neurons was investigated. Using the 4-aminopyridine-treated hippocampal slice model bathed in bicarbonate-buffered solution, TPM (25-50 microm) reduced the frequency of epileptiform bursts and action potentials without affecting membrane potential or input resistance. Inhibitory effects of TPM were reversed by trimethylamine-induced alkalinization. TPM also lowered the steady-state pHi of BCECF-AM-loaded neuronal somata by 0.18+/-0.07 pH units in CO(2)/HCO(3)(-)-buffered solution. Subsequent to an ammonium prepulse, TPM reduced the acidotic peak but clearly slowed pHi recovery. These complex changes were mimicked by the protein phosphatase inhibitor okadaic acid. Alkalosis upon withdrawal of extracellular Cl(-) was augmented by TPM. Furthermore, at decreased pHi due to the absence of extracellular Na(+), TPM reversibly increased pHi. These findings demonstrate that TPM modulates Na(+)-independent Cl(-)/HCO(3)(-) exchange. In the nominal absence of extracellular CO(2)/HCO(3)(-) buffer, both steady-state pHi and firing of epileptiform bursts remained unchanged upon adding TPM. However, pHi recovery subsequent to an ammonium prepulse was slightly increased, as was the case in the presence of the carbonic anhydrase (CA) inhibitor acetazolamide. Thus, a slight reduction of intracellular buffer capacity by TPM may be due to an inhibitory effect on intracellular CA. Together, these findings show that TPM lowers neuronal pHi most likely due to a combined effect on Na(+)-independent Cl(-)/HCO(3)(-) exchange and CA. The apparent decrease of steady-state pHi may contribute to the anticonvulsive property of TPM.

Topics: Action Potentials; Ammonium Chloride; Animals; Anticonvulsants; Bicarbonates; Carbon Dioxide; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Chloride-Bicarbonate Antiporters; Chlorides; Electrophysiology; Enzyme Inhibitors; Epilepsy; Fructose; Guinea Pigs; Hippocampus; Hydrogen-Ion Concentration; In Vitro Techniques; Membrane Potentials; Microelectrodes; Neurons; Okadaic Acid; Phosphoric Monoester Hydrolases; Sodium; Sodium-Hydrogen Exchangers; 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

To assess the effect of topiramate (TPM) on body mass index (BMI) in paediatric epilepsy patients and to examine predictors of weight loss.. Retrospective, observational study.. University clinic epilepsy outpatient department.. Patients below age 18 years who received TPM for at least 12 months.. Changes in BMI (kg/m2) standard deviation scores (S.D.S.) from baseline to the follow-up periods of 12, 24 and 36 months were evaluated. The repeated measures t-test for paired samples, revealed significant decreases for BMI S.D.S. at 12 months (P = 0.004; n = 53) and 24 months (P = 0.044; n = 35), but no significant decrease at 36 months (n = 21). Analysis of variance revealed a predictor value of sex for BMI S.D.S. at 12 months (females more likely to lose weight; P = 0.037) and a predictor value of baseline BMI for BMI S.D.S. at 24 months (patients with a higher baseline BMI were more likely to lose weight; P = 0.047).. Weight loss is common in paediatric epilepsy patients who receive TPM and is sustained for at least one year. The pattern of weight loss differs according to sex and baseline BMI.

Topics: Adolescent; Analysis of Variance; Anticonvulsants; Body Mass Index; Body Weight; Child; Child, Preschool; Epilepsy; Female; Follow-Up Studies; Fructose; Humans; Male; Retrospective Studies; Sex Factors; Time Factors; Topiramate

This retrospective study was conducted to identify cognitive domains affected by topiramate (TPM), and to evaluate the role of blood serum levels of TPM and comedication in the etiology of TPM-induced cognitive impairment.. Forty-two patients on AED polytherapy containing topiramate and a random sample of 42 patients with lamotrigine as the corresponding agent underwent extensive neuropsychological testing. Current blood serum levels of TPM were correlated with test scores.. Patients on TPM scored significantly worse in phonematic verbal fluency, memory spans, and working memory; language and memory function were not affected per se. In few cognitive domains, serum levels of TPM and performance were correlated before correction for multiple testing. Drug load of additional medication did not account for differences between or within groups.. Consistent with previous reports, patients on AED polytherapy including TPM display a cognitive pattern with specific impairment in executive functions. The severity of the cognitive side effects of TPM may be related to dosing to a certain extent, but this relationship may be disclosed only with larger sample sizes. Accordingly, TPM dosage does not appear to be a good indicator of TPM-related cognitive side effects in the individual patient.

Topics: Adult; Anticonvulsants; Cognition; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Lamotrigine; Language; Male; Memory; Neuropsychological Tests; Retrospective Studies; Topiramate; Triazines; Valproic Acid

The influence of age and comedication on the dose-to-level ratio of topiramate was examined in 91 children with epilepsy treated with topiramate. The topiramate dosing and plasma concentrations, as well as those of their concomitant antiepileptic drugs were examined retrospectively. The dose-to-level ratio was used as a measure of clearance and was calculated as the weight-normalized topiramate dose (mg/kg/day) divided by the steady-state trough plasma drug level in the child. The children were classified in age groups and treatment groups; topiramate was administered with an enzyme inducer (n = 32), with a nonenzyme inducer (n = 49), or as monotherapy (n = 10). The topiramate clearance in children aged 0-8 years compared with those aged 9-17 years was more than twofold higher if treated with an enzyme-inducing antiepileptic drug and 1.5-fold higher if treated with a nonenzyme inducer. Children receiving enzyme inducers had a more than twofold higher clearance compared with those who did not. Within all age groups, significant differences in topiramate clearance were observed between those receiving enzyme inducers and those receiving nonenzyme inducers or monotherapy. Thus younger age and concomitant enzyme inducers, both acting independently, significantly increased the clearance of topiramate in children. This effect has to be considered to optimize treatment in the individual patient.

Topics: Adolescent; Age Factors; Anticonvulsants; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Enzyme Induction; Epilepsy; Female; Fructose; Humans; Infant; Male; Retrospective Studies; Topiramate

Thirty-three patients, aged 3-29 years, with the following epileptic types: symptomatic forehead (15), symptomatic temporal (6), symptomatic occipital (2), juvenile myoclonic, in combination with eyelid myoclonus syndrome with absences, (5), epilepsy with isolated generalized seizures (3) and rolandic epilepsy (2), were treated with topamax. A medication dose was 50-200 mg per day in children younger 12 years and 100-550 mg per day in those older 12 years and in adults. The results obtained suggest the high efficacy and well tolerability of topamax in monotherapy of epilepsy. Therapeutic effect was achieved in 28 out of 33 patients (84.8%), i.e. seizures stopping--in 18 patients (54.5%). Monotherapy was mostly effective in symptomatic forehead epilepsy: seizures stopped in 53.3% patients and a frequency of seizures reduced in 33.3%. Side-effects were detected only in 18% cases, they were mostly transient and resulted in treatment withdrawal in 6% patients only.

Topics: Adolescent; Adult; Age Factors; Anticonvulsants; Child; Child, Preschool; Electroencephalography; Epilepsy; Follow-Up Studies; Fructose; Humans; Magnetic Resonance Imaging; Male; Time Factors; Topiramate; Treatment Outcome

For the antiepileptic drug (AED) topiramate (TPM), neuroprotective effects have been reported in models of focal cerebral ischemia and experimental status epilepticus, but the putative mechanism of action has remained elusive.. We studied the effects of TPM on mitochondrial function in the pilocarpine rat model of chronic epilepsy and in isolated mitochondria from rat brain.. TPM treatment in status epilepticus at doses ranging from 20 to 100 mg/kg considerably improved the survival of rats and improved CA1 and CA3 pyramidal cell survival in a dose-dependent manner. This treatment increased the activity of mitochondrial respiratory chain complex I in the CA1 and CA3 pyramidal subfields and resulted in lower seizure frequencies in chronic epileptic rats. In vitro investigations of the action of TPM on isolated rat brain mitochondria ruled out any direct effects of the drug on mitochondrial oxidative phosphorylation but revealed a protective effect on hippocampal mitochondria against an external calcium challenge. This can explain its observed neuroprotective action in the concentration range tested. The in vitro effects of TPM on the calcium handling of isolated brain mitochondria was found to be comparable to the action of cyclosporin A.. The neuroprotective action of TPM seems to be directly related to its inhibitory effect on the mitochondrial permeability transition pore.

Topics: Animals; Brain; Cell Survival; Cyclosporine; Disease Models, Animal; Dose-Response Relationship, Drug; Epilepsy; Fructose; Hippocampus; In Vitro Techniques; Ion Channels; Kindling, Neurologic; Male; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Neuroprotective Agents; Oxidative Phosphorylation; Pilocarpine; Pyramidal Cells; Rats; Rats, Wistar; Status Epilepticus; Topiramate

We investigated possible cognitive effects of topiramate (TPM) in polypharmacy on patients with intractable epilepsy.. Study 1 evaluated 22 consecutively admitted patients whose antiepileptic drugs (AEDs) on admission to the Montreal Neurological Hospital included TPM. Performance on neuropsychological tests administered on and subsequently off TPM was analyzed. Four patients also were tested before taking TPM, allowing comparisons off, then on, and then off the drug again. Measures included intellectual function, verbal and nonverbal memory, language, word and design fluency, somatosensory sensitivity, and motor skills. In Study 2, 16 patients at the Minnesota Epilepsy Group were tested first off, then on TPM with nine cognitive tasks that measured concentration, verbal fluency, language, and psychomotor speed.. In Study 1, significant (p < or = 0.01) improvements were observed off TPM on 13 measures including verbal and nonverbal fluency and certain verbal and perceptual tasks. Notably, verbal learning and memory were unaffected; a limited effect was observed on nonverbal memory. Patients tested 3 times scored better in both tests off TPM compared with on this drug. In Study 2, declines on TPM were observed on all measures, significantly (p < or = 0.05) for tests of fluency, sustained concentration, and visual motor processing speed.. TPM was associated with declines in fluency, attention/concentration, processing speed, language skills, and perception; working memory but not retention was affected. As the two studies used an opposite order of testing on versus off TPM, our results clearly show a performance decrement while patients are taking TPM, without respect to which condition is tested first.

Topics: Adolescent; Adult; Anticonvulsants; Cognition; Cognition Disorders; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Male; Memory; Middle Aged; Neuropsychological Tests; Psychomotor Performance; Topiramate; Verbal Learning

Topics: Anticonvulsants; Epilepsy; Fructose; Humans; Psychoses, Substance-Induced; Topiramate

A number of new antiepileptic agents have been introduced within a short period of time. Direct comparisons are not available, and information about the balance between costs and effects for these new therapies is lacking.. To introduce a first approximation of the cost effectiveness of the new therapeutic agents (topiramate and lamotrigine) for epilepsy that have been assessed in clinical trials against placebo.. Without head to head comparative data no formal methods are available to assess the relative cost effectiveness of two products; therefore, a Bayesian approach was developed. The approach starts with the 'proportionality assumption' saying that the differences in healthcare expenditure (less the direct cost of therapy) are directly proportional to the differences in effectiveness. Given this assumption, a therapy that is x times as expensive as an alternative therapy has an equivalent cost-effectiveness profile if the acquisition cost is x times as high. Moreover, simple formulas can be derived to calculate the probabilities that a therapy is dominant (more effective and less expensive) and that it is weakly dominant (more effective and a better cost-effectiveness profile). The approach is applied to data from published fixed dosage, parallel-design studies comparing both topiramate and lamotrigine with placebo.. Assuming that the 'proportionality assumption' holds for the medical treatment of epilepsy, and disregarding uncertainties, it is estimated that topiramate may be priced more than 2.2 times its current acquisition cost and still be more cost effective than lamotrigine. Taking uncertainties into account, it is estimated that lamotrigine 500 mg/day is dominated by topiramate 200 mg/day with a probability of 0.875 and by topiramate 400 mg/day with a probability of 0.986.. A simple method can be applied to assess the relative cost effectiveness of two therapies in the absence of direct comparative data. Applying this method to compare topiramate and lamotrigine leads to a strong preference for topiramate. However, to be able to draw this conclusion, some heroic assumptions need to be made. As such the method as developed here only reflects a first approximation. It needs to be used with care and is not intended to replace good comparative research.

Topics: Anticonvulsants; Bayes Theorem; Clinical Trials as Topic; Cost-Benefit Analysis; Epilepsy; Fructose; Humans; Lamotrigine; Models, Economic; Topiramate; Triazines

Topics: Adult; Anticonvulsants; Epilepsy; Female; Fructose; Humans; Self-Injurious Behavior; Suicide, Attempted; Topiramate

To evaluate the prevalence of word-finding difficulties as a treatment-emergent adverse event in patients with epilepsy taking topiramate and to identify a clinical phenotype at risk.. The authors investigated the relationship of word-finding difficulties to topiramate titration schedule, seizure frequency and pattern, and EEG and neuroradiologic findings in 431 consecutively and prospectively collected patients taking topiramate.. Thirty-one patients (7.2%) developed word-finding difficulties. Presence of simple partial seizures (OR = 6.7 p = 0.007) and a left temporal EEG epileptic focus (OR = 5.2 p = 0.021) were significantly associated with word-finding difficulties.. The presence of word-finding difficulties seems to be a titration schedule independent phenomenon that occurs in a subgroup of patients with a specific biologic vulnerability.

Topics: Adult; Anticonvulsants; Aphasia; Causality; Comorbidity; Dose-Response Relationship, Drug; Electroencephalography; Epilepsy; Female; Fructose; Humans; Logistic Models; Male; Neuropsychological Tests; Odds Ratio; Prevalence; Prospective Studies; Risk Assessment; Risk Factors; Topiramate; United Kingdom; Verbal Behavior

Topics: Anticonvulsants; Clinical Trials, Phase IV as Topic; Drug Industry; Epilepsy; Fructose; Humans; Topiramate

Clinical pharmacologists, neurologists, internists, and all health care givers must consider the efficacy, safety, and side effect profile of a given antiepileptic drug (AED) when determining which drug is best for a given patient. The first purpose of this paper is to address whether the "new" AEDs have advantages over the "old" drugs. The second purpose is to teach those interested in clinical pharmacology about the use of Web-based information access to answer a neurology/clinical pharmacology problem: to compare the efficacy and side effects of topiramate versus lamotrigine versus phenobarbital using odds ratios. Cost of all three AEDs was also compared. A number of new AEDs, including topiramate and lamotrigine, have been developed for chronic focal and secondarily generalized epileptic seizures. Efficacy of these drugs as anticonvulsants does not seem to be superior to that of traditional anticonvulsants such as phenobarbital. However, the advantage of the new drugs is a different spectrum of possible adverse events. Newer AEDs may or may not induce sedation and may minimize noncompliance by reducing side effects of lethargy and cognitive impairment. The difficulty in achieving therapeutic dosage because of side effects makes one consider whether these agents are "better" than the oldest and most side effect-prone AED, phenobarbital. The new AEDs have less frequent interactions, leading to improved tolerability with comedication. This exercise compares two "new" AEDs, topiramate and lamotrigine, with phenobarbital by evaluating efficacies and side effects using relative odds ratios, a method commonly used in drug development research. Development of new algorithms and/or new knowledge will bring beneficial tools to all clinical pharmacologists.

Topics: Anticonvulsants; Costs and Cost Analysis; Dose-Response Relationship, Drug; Epilepsy; Fructose; Humans; Lamotrigine; Odds Ratio; Phenobarbital; Topiramate; Triazines

The aim of this study was to determine the prevalence of psychiatric adverse events (PAEs) in patients with epilepsy treated with topiramate (TPM). Classification, relation to TPM dosing, and outcome were evaluated to identify a patient profile at risk of developing PAEs.. We evaluated the data of the first consecutive and prospectively collected patients in therapy with TPM.. Follow-up information was available for 431 patients. PAEs occurred in 103 (23.9%) patients; M/F ratio, 55:48; mean age (+/-SD), 36.5 +/- 11.2. In 46 (10.7%) patients, an affective disorder developed; in 16 (3.7%), a psychotic disorder; in 24 (5.6%), aggressive behavior with or without irritability; in 17 (3.9%), other behavior abnormalities such as agitated behavior, anger/hostility behavior, or anxiety. High starting dose and rapid titration schedule were relevant for the development of PAEs. Family psychiatric history and family history of epilepsy, personal history of febrile convulsions, psychiatric history, and presence of tonic-atonic seizures were found to be significant risk factors. Low seizure frequency before starting TPM and TPM/lamotrigine coadministration had a protective effect for PAEs.. We found that PAEs associated with TPM were related to the titration schedule of the drug and that a unique patient profile is suggested by the clinical history.

Topics: Adult; Affective Symptoms; Anticonvulsants; Dose-Response Relationship, Drug; Drug Administration Schedule; Epilepsy; Epilepsy, Complex Partial; Female; Fructose; Genetic Predisposition to Disease; Humans; Male; Mental Disorders; Middle Aged; Product Surveillance, Postmarketing; Prospective Studies; Psychoses, Substance-Induced; Risk Factors; Topiramate

To assess the efficacy, safety, and tolerability of topiramate in infants younger than 24 months of age, we conducted an open-label, multicenter chart review study of infants who received topiramate. Twenty-eight patients were evaluated. All had refractory epilepsy. The mean age of seizure onset was 3.8 months (range 0-10 months). Refractory infantile spasms were the most common epilepsy syndrome. Among infants without infantile spasms, complex partial seizures were the prominent seizure type in eight, followed by simple partial seizures in six. Topiramate was prescribed as add-on therapy in 25 cases and a s monotherapy in 3 cases. Seven of the eight infantile spasms cases improved on topiramate therapy, attaining topiramate monotherapy in three infants. Half of the infants with other seizure types responded to topiramate. The average treatment duration among topiramate responders was 11 months. Topiramate was prescribed after a mean of 3.3 antiepilepsy drugs had been used in these infants. In no case was topiramate the first prescribed antiepilepsy drug. Adverse effects occurred only in five patients, leading to topiramate discontinuation in two patients. Topiramate was efficacious and well tolerated in infants younger than 24 months of age with refractory epilepsy. Prospective data are needed to corroborate this observation.

Topics: Age Factors; Age of Onset; Anticonvulsants; Dose-Response Relationship, Drug; Epilepsy; Female; Fructose; Humans; Infant; Male; Retrospective Studies; Severity of Illness Index; Topiramate; Treatment Outcome

A novel liquid chromatography-mass spectrometry (LC-MS) method was developed and validated for quantification of topiramate (TPM) and its metabolites 10-hydroxy topiramate (10-OH-TPM), 9-hydroxy topiramate (9-OH-TPM), and 4,5-O-desisopropylidene topiramate (4,5-diol-TPM) in plasma and urine. The method uses 0.5 mL of plasma or 1 mL of urine that is extracted with diethyl ether and analyzed by LC-MS. Positive ion mode detection enables tandem mass spectrometric (MS/MS) identification of the aforementioned four compounds. Calibration curves of TPM, 4,5-diol-TPM, 9-OH-TPM, and 10-OH-TPM in plasma and urine were prepared and validated over the concentration range of 0.625 to 40 microg/mL using TPM-d(12) as an internal standard. Calibration curves were linear over this concentration range for TPM and its metabolites. Accuracy and precision ranged in urine from 83% to 114% and 4% to 13% (%CV), respectively, and in plasma from 82% to 108% and 6% to 13%, respectively. The applicability of the assay was evaluated by analyzing plasma samples from a healthy subject who received a single oral dose of TPM (200 mg) and urine samples from 11 patients with epilepsy treated with TPM (daily dose between 100 to 600 mg) alone or with other antiepileptic drugs. Only TPM was detected and quantified in the plasma samples, and its concentration ranged between 0.7 and 4.3 microg/mL. The concentrations of TPM and 10-OH TPM were quantifiable in all urine samples and ranged from 20 to 300 microg/mL for TPM and from 1 to 50 microg/mL for 10-OH-TPM. The metabolites 4,5-diol-TPM and 9-OH-TPM were also detected in all urine samples, but their concentrations were quantifiable only in 4 patients. An unidentified peak in the chromatograms obtained from patients' urine was attributed to 2,3-O-desisopropylidene topiramate (2,3-diol-TPM). Due to a lack of reference material of 2,3-diol TPM and the similar MS/MS spectrum with 4,5-diol-TPM, the calibration curves of 4,5-diol-TPM were used for the quantification of its isomer 2,3-diol-TPM. Based on these determinations, the apparent 2,3-diol-TPM-to-TPM concentration ratio in patients' urine ranged from 0.05 to 0.51 and the 10-OH-TPM-to-TPM ratio ranged from 0.02 to 0.17. In conclusion, a novel LC-MS method for the assay of TPM and four of its metabolites in plasma and urine was developed. Its utilization for analysis of urine samples from patients with epilepsy showed that the method was suitable for analysis of TPM and its metabolites in clinic

Topics: Adult; Epilepsy; Female; Fructose; Gas Chromatography-Mass Spectrometry; Humans; Male; Middle Aged; Topiramate

The study is to invesigate the effect of topiramate (TPM) on EEG by means of quantitative pharmacoelectroencephalography (QPEEG).. One dose of TPM was administrated to epileptics and healthy adults. The EEG samples were obtained prior to and at regular intervals within the 24 hours following the administration of TPM. The EEG activity was processed with power spectral analysis.. The power of slow wave, alpha 1 bands and total power increased after the administration of TPM, the power or slow wave in both occipital areas, and the total power of all scalp areas also increased. The percent of power increased at the theta band and alpha 1 band (healthy adults) or delta band, theta band (patients).. TPM can change the EEG background activity. These changes are different from other antiepileptic drugs.

Topics: Adult; Anticonvulsants; Electroencephalography; Epilepsy; Female; Fructose; Humans; Male; Topiramate

Topiramate (TPM) is a highly effective anticonvulsant drug, but a comparably high rate of cognitive adverse effects have been reported. In this study, we investigated changes in frontal lobe associated cognitive measures after TPM withdrawal in epilepsy patients hospitalized for presurgical evaluation.. Twenty epilepsy patients were administered a brief neuropsychological test battery before and after withdrawal of TPM. Neuropsychological evaluation included a verbal fluency task, verbal (Wechsler's digits) and spatial spans (Corsi block-tapping) and Trail Making Test (TMT, parts A and B). Median baseline dosage of TPM was 237.5mg/d, the median retest-interval was 8 days. Results were compared to a matched group of patients, who had been tested and retested before and after reduction of AEDs other than TPM at comparable time intervals.. After TPM withdrawal, group performance appeared significantly improved in five of six tests administered. The scores of the control patients remained largely unchanged after drug reduction. After withdrawal, the scores of the TPM group did not differ significantly from the results of the control group whereas pronounced differences had been observed before. Individual improvement became apparent in the majority of patients. Cognitive performance was not correlated to current daily dosages/current blood serum levels of TPM.. Withdrawal of TPM causes significant improvement in frontal lobe associated measures like verbal fluency and working memory. As withdrawal was part of the preoperative work-up, and not initiated because of patients' complaints or hints of intoxication, cognitive impairment due to TPM appears to be easily overlooked and underestimated.

Topics: Adult; Chi-Square Distribution; Cognition; Cognition Disorders; Epilepsy; Female; Frontal Lobe; Fructose; Humans; Male; Middle Aged; Neuropsychological Tests; Preoperative Care; Statistics, Nonparametric; Topiramate

The study investigated the types of interactions between lamotrigine (LTG) and first-generation antiepileptic drugs (AEDs) or topiramate (TPM) with isobolographic analysis.. Anticonvulsant and adverse-effect profiles of combinations of LTG with other AEDs, at fixed ratios of 1:3, 1:1, and 3:1, were evaluated in the maximal electroshock (MES)-induced seizures and the chimney test (motor performance) in mice, which allowed the determination of benefit indices (BIs) for individual combinations.. Combinations of LTG with TPM or valproate (VPA), at fixed ratios of 1:1, were significantly supraadditive (synergistic) in the MES test and, simultaneously, subadditive (antagonistic) in the chimney test, showing the best profile for AED combinations. In contrast, combinations between LTG and carbamazepine (CBZ), in terms of antiseizure protection against MES, were subadditive (antagonistic) and additive in the chimney test, resulting in unfavorable AED combinations. Moreover, the combination of LTG with phenobarbital (PB), at a fixed ratio of 1:1, despite synergy in the MES test, also was synergistic in the chimney test, resulting in a modest BI for AED combination. LTG combined with phenytoin was additive in both the MES and chimney tests in mice. The remaining combinations, at fixed ratios not mentioned earlier, also showed an average BI for AED combinations. Furthermore, LTG combined with all studied AEDs did not affect long-term memory in mice. None of the AEDs influenced the free plasma level of LTG, whereas LTG slightly reduced the free plasma concentration of PB.. Interactions between LTG and TPM or LTG and VPA at a fixed ratio of 1:1 might be profitable from a preclinical point of view, displaying the most optimal BI.

Topics: Animals; Anticonvulsants; Dose-Response Relationship, Drug; Drug Interactions; Electroshock; Epilepsy; Fructose; Lamotrigine; Male; Mice; Motor Skills; Topiramate; Triazines

The aim of this study was to analyze in detail psychopathology associated with topiramate (TPM) prescription and to analyze the relationship between psychopathology and seizure freedom. We analyzed the data on 103 patients who developed psychiatric disorders during TPM therapy. Forty-six patients developed an affective disorder, 22 aggressive behavior, 16 psychosis, 11 anxiety, and 8 personality changes such as anger, agitation, and hostile behavior. Patients with psychosis were more likely to be seizure-free during psychopathology, to receive psychotropic drug prescription, and to be admitted to hospital. In general, patients seizure-free during psychopathology were more likely to have a diagnosis of idiopathic generalized epilepsy, to be in co-therapy with vigabatrin, and to remit after drug reduction. We observed that psychopathology was related to seizure control in a subgroup of patients. The role of forced normalization, interlinked with interactions with other antiepileptic drugs, could be relevant.

Topics: Adult; Aggression; Anticonvulsants; Epilepsy; Female; Fructose; Humans; Male; Mood Disorders; Personality; Psychopathology; Psychoses, Substance-Induced; Quality of Life; Topiramate; Treatment Outcome

Topics: Anticonvulsants; Child; Epilepsy; Fructose; Humans; Topiramate

To examine the tolerability of topiramate (TPM) in paediatric practice.. A retrospective cohort study of patients aged less than 18 years commenced on TPM by paediatric neurologists. Patients were identified from the dispensing databases of two paediatric tertiary referral hospitals and from the authority prescription records of four paediatric neurologists. The clinical data were obtained from the patients' medical records.. There were 159 patients who were identified as having been commenced on TPM and follow-up data were available for 127 (80%) patients. The median (range) age at commencement of TPM was 8.1 (0.5-17.9) years, with 12 patients aged less than 2 years. After 4 years, 60% of patients had ceased the medication. Treatment limiting adverse effects included aggression/psychosis (n = 10), cognitive impairment/sedation (n = 6), anorexia/weight loss (n = 4) and desquamation (n = 1). Prior aggression (hazard ratio 5.91 (2.12-16.44)) and female gender (hazard ratio 2.94 (1.02-8.41)) were risk factors for ceasing TPM because of an adverse event. Thirty percent of children commenced on TPM experienced a treatment limiting adverse effect within 2 years of commencement.. The frequency of treatment limiting adverse events in children receiving topiramate is higher than previously reported.

Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Cohort Studies; Epilepsy; Follow-Up Studies; Fructose; Humans; Infant; Retrospective Studies; 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

Case series report of presence of pruritus in five patients taking topiramate for treatment of epilepsy. This is a benign side effect of topiramate not previously reported that interfered with seizure treatment. Four out of five patients have previous history of antiepileptic drug (AED) allergy. Only one patient improved with a very slow titration, three of them discontinued treatment and one remained on a sub-therapeutic dose.

Topics: Adult; Aged; Anticonvulsants; Dose-Response Relationship, Drug; Drug Interactions; Epilepsy; Female; Fructose; Humans; Hypersensitivity; Male; Middle Aged; Pruritus; Topiramate

Topics: Epilepsy; Fructose; Humans; Topiramate

Topics: Clinical Trials as Topic; Epilepsy; Fructose; Humans; Topiramate

Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Double-Blind Method; Epilepsy; Fructose; Humans; Randomized Controlled Trials as Topic; Time Factors; Topiramate

This study examines the relationship between serum and saliva topiramate concentrations, and attempts to determine if saliva may be a useful alternative to serum for therapeutic monitoring. Saliva and blood specimens were collected from 31 epilepsy patients (mean age 10.5 +/- 6.0 years; range 2.5 years to 24.8 years), and topiramate concentrations were determined by fluorescence polarization immunoassay. One patient's results were omitted because the saliva concentration was below the limit of quantitation of the assay. A strong correlation exists between serum and saliva topiramate concentrations (adjusted r(2) = 0.97, n = 30, P < 0.0001). The mean fraction of saliva to serum concentration is 89.8% +/- 12.1% (range 62.9% to 112.7%). The results of this study support the use of saliva as a viable alternative to serum for monitoring topiramate therapy. Topiramate concentration in saliva: an alternative to serum monitoring.

Topics: Adolescent; Adult; Anticonvulsants; Child; Child, Preschool; Epilepsy; Female; Fructose; Humans; Male; Saliva; Topiramate

The influence of dosage, age, and co-medication on plasma topiramate (TPM) concentrations at steady state was investigated in 51 patients aged 3 to 30 years. All patients had chronic active epilepsy, and most were receiving concomitant medication with enzyme-inducing anticonvulsants (carbamazepine and phenobarbital). Plasma TPM concentrations were determined by a specific immunoassay in samples obtained before the morning dose. Thirty-five patients could be evaluated prospectively at different dose levels, and the relationship between plasma TPM concentration and dosage was linear over the assessed dose range (1.8 to 10.0 mg/kg) both in adults and in children. The influence of age on pharmacokinetic parameters could be assessed only for the 42 patients co-medicated with enzyme inducers. In these patients dose-normalized plasma TPM concentrations correlated positively with age (r = 0.59, P < 0.0001), where apparent oral clearance values (CL/F) were inversely related to age (r = 0.73, P < 0.0001). In particular, CL/F values in children aged less than 10 years (112 +/- 82 mL/kg/h, mean +/- SD, n = 14) were almost three times as high as those observed in patients aged >15 to 30 years (42 +/- 16 mL/kg/h, n = 17), whereas the CL/F value in children aged 10 to 15 years (66 +/- 22 mL/kg/h, n = 11) was intermediate between those found in the two other age groups. Patients not receiving enzyme-inducing AEDs showed lower CL/F values than did age- and gender-matched patients on enzyme-inducing co-medication. A preliminary evaluation of the relationship between plasma TPM concentration and therapeutic response could be made in 41 patients. No significant difference in drug concentration was detected between patients showing a greater than 50% reduction in seizure frequency compared with baseline (5.9 +/- 2.2 micrograms/mL, n = 30) and those having no clinical improvement (5.2 +/- 2.2 micrograms/mL, n = 11). Likewise, there was no consistent relationship between plasma TPM concentration and appearance of adverse effects. These results indicate that plasma TPM concentrations are linearly related to dosage both in adults and in children and that children aged <10 years require much greater body weight-adjusted dosage to achieve drug levels comparable to those observed in young adults. The marked increase in TPM clearance caused by enzyme-inducing co-medication was confirmed.

Topics: Adolescent; Adult; Age Factors; Anticonvulsants; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Monitoring; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Male; Topiramate

We conducted a prospective, long-term audit of lamotrigine and topiramate as add-on treatment for refractory epilepsy. A total of 55 patients participated in the study. Five years after starting the drug 7/20 patients remained on lamotrigine and 13/35 on topiramate. The patients still on the study drugs showed an improvement in seizure frequency, with 5/7 patients being seizure free on lamotrigine and 4/13 on topiramate. Furthermore, we assessed quality of life using the quality of life assessment schedule and found a significant improvement for the patients still on the study drugs. These data suggest that about one third of the patients on lamotrigine or topiramate as add-on therapy stay on the drug in the long term. These patients are likely to benefit with respect to objective and subjective outcome measures.

Topics: Antidepressive Agents; Electroencephalography; Epilepsy; Follow-Up Studies; Fructose; Humans; Lamotrigine; Prospective Studies; Quality of Life; Severity of Illness Index; Time; Topiramate; Triazines

Pharmacokinetic interactions between the older antiepileptic drugs (AEDs) and topiramate (TPM) were assessed during the clinical development of this drug. Lamotrigine (LTG) has become established as an important new drug in treating a wide spectrum of seizure types, but there are no published data on whether LTG serum concentrations change when TPM is added to treatment.. Escalating doses of TPM were added to stable LTG treatment in 24 young patients (8-21 years) with epilepsy. Blood samples taken before the morning dose were collected for drug-concentration measurement in all patients before starting treatment with TPM and after stabilisation at each dose escalation. Several patients had been maintained on unchanged therapy with drug-concentration monitoring for many months before introducing TPM, and a sequence of baseline LTG serum concentrations were available on these patients.. The mean of all baseline LTG concentrations for the group as a whole was 10.4 +/- 4.4 mg/L compared with 9.7 +/- 4.3 mg/L after addition of TPM. A comparison of last baseline LTG concentration with first test LTG concentration (i.e., after 2 weeks' TPM treatment) gave mean values of 10.7 +/- 4.7 and 10.8 +/- 4.6 mg/L, respectively. The mean LTG concentration for patients while taking their highest TPM dose was 9.5 +/- 4.3 mg/L. The analysis-of-variance modeling for the effect of TPM on LTG concentration yielded a mean LTG concentration ratio (with TPM vs. without TPM) of 94.2%, with a 90% confidence interval of 89.5-99.1%.. TPM did not cause a significant change in LTG serum concentration in this group of patients.

Topics: Adolescent; Adult; Anticonvulsants; Child; Drug Interactions; Epilepsy; Female; Fructose; Humans; Lamotrigine; Male; Osmolar Concentration; Topiramate; Triazines

Topiramate (TPM) is widely used as add-on therapy for epilepsy. TPM inhibits carbonic anhydrase, which may result in metabolic acidosis from decreased serum bicarbonate. The ketogenic diet (KGD) predisposes patients to metabolic acidosis, especially during induction. In children with refractory epilepsy, cotreatment with TPM and KGD may be considered, but special attention should be paid to the combined risks for metabolic acidosis and nephrolithiasis. We report our experience in 14 children cotreated with TPM and the KGD.. Medical records of 14 children cotreated with the KGD and TPM for medically refractory epilepsy were reviewed retrospectively. Bicarbonate levels were analyzed and correlated with clinical profiles, including duration of cotreatment, TPM dose, KGD ratio, and seizure control.. Nine children had a <20% decrease in bicarbonate levels, from 5.3 to 12.3 mEq/L (mean, 7.6 mEq/L). Cotreatment was continued in all patients for duration of 33 to 544 days (seven had remained on cotreatment at the end of the study period), although two children required bicarbonate supplements to continue the KGD. No patient had nephrolithiasis.. Although a large decrease in bicarbonate level occurred in the majority of children, the decrease appeared mostly at the time of KGD induction when added to prior TPM therapy. Bicarbonate levels should be monitored carefully with TPM and KGD cotreatment, and bicarbonate supplements given when symptomatic.

Topics: Acidosis; Adolescent; Age Factors; Anticonvulsants; Bicarbonates; Child; Child, Preschool; Combined Modality Therapy; Epilepsy; Female; Fructose; Humans; Infant; Ketosis; Male; Retrospective Studies; Topiramate; Treatment Outcome; Urinary Calculi

We report a case of a 5-year-old boy with intractable partial seizures who developed a transient hemiparesis, worsening of the electroencephalogram (EEG) and a change in his seizure pattern with increased seizure frequency after receiving topiramate (TPM). Symptoms resolved within a month after TPM was discontinued. Clinicians need to be aware that TPM use may occasionally be associated with focal motor weakness and exacerbation of seizures.

Topics: Anticonvulsants; Child, Preschool; Electroencephalography; Epilepsy; Fructose; Humans; Male; Paresis; Severity of Illness Index; Topiramate

We describe a possible clinical interaction between topiramate (TPM) and carbamazepine modified release (CBZ-MR) in patients taking maximum tolerated doses of carbamazepine. Data are presented on 25 patients who contacted the epilepsy nurse specialist telephone helpline for advice after starting treatment with TPM. Thirteen male and 12 female patients, mean age 41 years (range 25-69 years), with localization-related epilepsy contacted the helplines, between November 1999 and March 2001, complaining of symptoms of antiepileptic drug intoxication after starting treatment with TPM. All were taking maximum tolerated doses of CBZ-MR before starting TPM. Sixteen of the patients were taking other antiepileptic drugs concomitantly with CBZ-MR and TPM. Symptoms of intoxication were similar to those previously experienced when maximum tolerated doses of CBZ-MR were exceeded. Symptoms resolved when concomitant CBZ-MR doses were reduced, enabling further dose escalation of TPM. To our knowledge, neither clinical nor pharmacological interactions between CBZ and TPM have been described previously in man. These data suggest that such an interaction may be of clinical importance, and that reduction of the CBZ dose may enable optimization of the dose of TPM, improving seizure control.

Topics: Adult; Aged; Anticonvulsants; Carbamazepine; Drug Synergism; Drug Therapy, Combination; Epilepsy; Fructose; Humans; Male; Middle Aged; Topiramate

There is little knowledge about the effects of topiramate in intellectually impaired epileptic patients. This open prospective study compares seizure frequencies during a 3-month period of topiramate add-on therapy (after 3 months of titration) compared with a 3-month baseline period. An intention-to-treat analysis was made on the first 24 consecutive topiramate-treated adult patients (residents of the Bethel epilepsy centre, therapy-resistant epilepsy, intellectual impairment of different degrees, one half with neurological deficits). The responder rate (at least a 50% reduction in seizure frequency) was 37.5%. One patient became completely seizure-free during post-evaluation (up to 24 months). Efficacy was not different between different epileptic syndromes or seizure types (case number too small). Responders had topiramate dosages above 200 mg/day and serum concentrations above 2.2 micrograms/ml. Six patients (25%) experienced serious neuropsychiatric complications such as confusion and severe deceleration of thinking and acting, up to complete helplessness (at topiramate dosages from 50 mg/day to 900 mg/day and serum concentrations from 2.2 micrograms/ml to 8.0 micrograms/ml). Preexisting brain damage may enhance the risk of unwanted central nervous effects.

Topics: Adult; Anticonvulsants; Dose-Response Relationship, Drug; Drug Therapy, Combination; Electroencephalography; Epilepsy; Female; Follow-Up Studies; Fructose; Humans; Intellectual Disability; Male; Middle Aged; Neuropsychological Tests; Topiramate; Treatment Outcome

Topiramate (TPM) is a novel drug with broad antiepileptic effect in children and adults. In vitro studies suggest activity as sodium-channel blocker, as gamma-aminobutyric acid type A (GABAA)-receptor agonist and as non-N-methyl-D-aspartate (NMDA)-glutamate receptor antagonist.. With transcranial magnetic stimulation (TMS), we evaluated which of the mechanisms of action of TPM detected in vitro are relevant for the modulation of human motor cortex excitability. In a double-blind, placebo-controlled, crossover study design, we investigated the effect of single oral doses of 50 mg and 200 mg TPM on motor thresholds, cortical silent period (CSP), and on intracortical inhibition (ICI) and intracortical facilitation (ICF) in 20 healthy subjects.. A significant dose-dependent increase of ICI was noticed after 200 mg TPM as compared with placebo at short interstimulus intervals of 2 to 4 ms. TPM had no effect on motor thresholds or the CSP.. We conclude that a single dose of TPM selectively increases ICI by GABAAergic and/or glutamatergic mechanisms without a relevant influence on measures, depending on ion-channel blockade or GABAB-receptor activity. The decrease of intracortical excitability (as measured by ICI and ICF) caused by TPM may correlate with its lack of proconvulsive potential in idiopathic generalized epilepsy, because drugs without this action or with less pronounced action may exacerbate seizures in this condition.

Topics: Adult; Brain; Electromyography; Epilepsy; Evoked Potentials, Motor; Excitatory Amino Acid Antagonists; Female; Fructose; GABA Agonists; Humans; Ion Channels; Magnetics; Male; Middle Aged; Models, Statistical; Motor Cortex; Neural Inhibition; Placebos; Topiramate

To study the pharmacokinetics of topiramate (TPM) during delivery, lactation, and in the neonate.. TPM concentrations in plasma and breast milk were measured with fluorescence polarization immunoassay (FPIA) in five women with epilepsy treated with TPM during pregnancy and lactation. Blood samples were obtained at delivery from mothers, from the umbilical cord, and from the newborns on three occasions (24, 48, and 72 h) after delivery. Blood and breast milk also were collected from mothers 2 weeks, and 1 and 3 months postpartum. Blood samples also were drawn from the infants during breast-feeding. Three of the mother-infant pairs were studied both at delivery and during lactation; two contributed with data from delivery only.. The umbilical cord plasma/maternal plasma ratios were close to unity, suggesting extensive transplacental transfer of TPM. The mean milk/maternal plasma concentration ratio was 0.86 (range, 0.67-1.1) at 2-3 weeks after delivery. The milk/maternal plasma concentration ratios at sampling 1 and 3 months after delivery were similar (0.86 and 0.69, respectively). Two to 3 weeks after delivery, two of the breast-fed infants had detectable (>0.9 microM) concentrations of TPM, although below the limit of quantification (2.8 microM), and one had an undetectable concentration.. Our limited data suggest free passage of TPM over the placenta and an extensive transfer into breast milk. Breast-fed infants had very low TPM concentrations, and no adverse effects were observed in the infants.

Topics: Anticonvulsants; Breast Feeding; Delivery, Obstetric; Epilepsy; Female; Fetal Blood; Fluorescence Polarization Immunoassay; Fructose; Humans; Infant, Newborn; Lactation; Maternal-Fetal Exchange; Milk, Human; Pregnancy; Pregnancy Complications; Topiramate

Topiramate, an antiepileptic drug with a number of mechanisms of action including inhibition of glutamate activity at the AMPA and KA receptors, was assessed as a neuroprotective agent following seizures. We administered topiramate, 80 mg/kg, or saline for 4 weeks following a series of 25 neonatal seizures or status epilepticus (SE) induced by lithium-pilocarpine in postnatal day 20 rats. Age-matched control rats without a history of seizures were administered topiramate or saline. Following completion of the topiramate injections, animals were tested in the water maze for spatial learning and the brains examined for cell loss and sprouting of mossy fibers. While there was a trend for improved visual-spatial performance in the water maze following topiramate therapy in rats with neonatal seizures, no differences were found in the histological examination of the hippocampus. Neonatal rats exposed to 4 weeks of topiramate did not differ from non-treated controls in water maze performance or histological examination. In weanling rats subjected to SE, topiramate provided a moderate degree of neuroprotection, with topiramate-treated rats performing better in the water maze than rats receiving saline. However, no differences in cell loss or mossy fiber sprouting were found in the histological examination of the brains. These findings demonstrate that chronic treatment with topiramate following SE improves cognitive function. In addition, long-term administration of high-dose topiramate in the normal developing rat brain does not appear to impair cognitive performance.

Topics: Animals; Animals, Newborn; Anticonvulsants; Body Weight; Cell Death; Cognition; Convulsants; Disease Models, Animal; Epilepsy; Flurothyl; Fructose; Hippocampus; Lithium; Maze Learning; Mossy Fibers, Hippocampal; Muscarinic Agonists; Nerve Degeneration; Pilocarpine; Rats; Rats, Sprague-Dawley; Reaction Time; Recurrence; Research Design; Topiramate

Monotherapy is recommended preferentially among newly diagnosed epileptic patients. In monotherapy-resistant patients polytherapy may be necessary. Two antiepileptic drugs may produce antagonistic, additive, and supra-additive (synergistic) anticonvulsant effects. The drug combination providing the supra-additive effect seems of clinical significance. However, when the supra-additive anticonvulsant efficacy is also associated by a distinct increase in toxicity, the protective index may be not affected or even lowered. Synergistic interactions have been shown for the combinations of valproate-phenytoin/ethosuximide, topiramate-carbamazepine/phenobarbital and felbamate-all major conventional antiepileptics. In contrast, the protective action of conventional antiepileptics has not been affected by felbamate at subprotective doses against maximal electroshock in mice. This is indicative that synergism is evident at only some drug ratios. Potential antiepileptic drugs, excitatory amino acid antagonists and calcium channel inhibitors, generally enhanced the protection offered by antiepileptic drugs. The experimental data may be helpful for predicting which drug combinations may prove effective in epileptic patients.

Topics: Animals; Anticonvulsants; Calcium Channel Blockers; Drug Synergism; Drug Therapy, Combination; Electroshock; Epilepsy; Excitatory Amino Acid Antagonists; Fructose; Humans; Lamotrigine; Topiramate; Triazines

In three patients, two men aged 33 and 43 years receiving treatment for epilepsy, and one woman aged 31 years with mild mental retardation and psychotic episodes, psychotic symptoms emerged soon after the introduction of topiramate. These symptoms were associated with agitation/aggressive behaviour and significant weight loss. Psychotic symptomatology gradually disappeared after discontinuation of topiramate without the administration of an antipsychotic. Over the past years several novel anticonvulsants, including topiramate, have become available for the treatment of refractory partial seizures, with or without secondary generalisation. Some of them have been demonstrated to be effective in bipolar affective disorders as well. Treatment with topiramate can be associated with neuropsychiatric side-effects such as cognitive impairments, deficits in word finding, and incidental psychotic decompensation. Significant weight loss is often noted as well. Since psychiatric and cognitive side-effects may occur during treatment with topiramate, careful evaluation is mandatory especially in patients with a psychiatric history.

Topics: Adult; Anticonvulsants; Epilepsy; Female; Fructose; Humans; Male; Psychoses, Substance-Induced; Topiramate

Although reduction in seizure frequency is the most common endpoint used to assess the antiepileptic efficacy, seizure frequency alone does not provide a complete picture of effectiveness, particularly in patients with refractory epilepsy. The aim of our study was to assess the effects of topiramate on seizure severity and health-related quality of life (HRQL), in addition to standard efficacy measures, in an open, multicentre, 6-month trial of patients with epilepsy uncontrolled on antiepileptic drugs other than topiramate. Two hundred and nine patients were enrolled and received topiramate for up to 6 months (initiated at 50 mg/day and titrated to a recommended dose of 200-400 mg/day) in addition to existing medication. The median reduction in seizure frequency from baseline to the post-titration period was 40.9% ( P< 0.0001). Patients also demonstrated a mean reduction in the Liverpool Seizure Severity Scale (LSSS) of 5.3 ( P< 0.0001), which was considered clinically significant. Statistically significant changes in HRQL were not observed with the SF-36, a generic measure. Tolerability of antiepileptic medication was good, with a low incidence of cognitive adverse events. The results indicate that topiramate significantly reduces seizure severity---an important aspect of HRQL---when administered as adjunctive therapy to anticonvulsant therapy.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Canada; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Electroencephalography; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Quality of Life; Topiramate; Treatment Outcome

The efficacy and safety of topiramate in patients with intractable mixed seizures, mental retardation (MR), and developmental disabilities (DD) were investigated. Twenty patients (eight females and 12 males) aged 21-57 years old with intractable epilepsy with mixed seizures, MR [profound (five), severe (three), moderate (two), mild (eight) and borderline (two)], and DD were treated with adjunctive topiramate 25 mg per day for 1 week followed by titration to clinical response (range 50-350 mg per day). Other antiepileptic drugs (AEDs) were decreased simultaneously. Topiramate therapy was discontinued in four patients for adverse events consisting of disorientation, unsteadiness, and pneumonia (one patient); anaphylactic shock from a tuna fish allergy (one); patient choice (one); and loss to follow-up (one). Seizures improved by gt-or-equal, slanted 50% in 11 of 16 patients (69%). Two patients (13%) were seizure free, including one patient who prior to topiramate therapy was seizure free but experiencing an intolerable adverse effect during therapy with another AED. Seizure duration and/or severity decreased in seven patients (44%). An increase in alertness was observed in 11 patients (59%). Topiramate was associated with improvement in seizure severity and alertness in this series and may be useful as adjunctive therapy in patients with mixed seizures, MR, and DD.

Topics: Adult; Adverse Drug Reaction Reporting Systems; Anticonvulsants; Child; Comorbidity; Developmental Disabilities; Dose-Response Relationship, Drug; Electroencephalography; Epilepsy; Female; Fructose; Humans; Intellectual Disability; Male; Middle Aged; New York; Topiramate; Treatment Outcome

We present three children with severe therapy-refractory epilepsy who tolerated valproate (VPA) well in various combinations with other antiepileptic drugs (AEDs) but developed typical VPA side effects in combination with topiramate (TPM).. The clinical symptoms began with apathy in all three children; two of them also had hypothermia. Furthermore all children had elevated blood ammonia levels, one child in combination with increased liver transaminases and one with thrombocytopenia.. All children recovered completely after discontinuation of VPA or TPM.. TPM seems likely to enhance the risk of side effects usually attributed to VPA and not described in TPM monotherapy. Our case reports suggest that possible adverse effects of VPA should be given particular attention when VPA is combined with TPM.

Topics: Affective Symptoms; Anticonvulsants; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Hyperammonemia; Hypothermia; Infant; Liver; Liver Diseases; Male; Risk Factors; Thrombocytopenia; Topiramate; Transaminases; Valproic Acid

Topiramate is a new antiepileptic drug (AED) approved as add-on therapy. Previous studies have shown that topiramate has only a limited effect on other AEDs, but its own metabolism can be induced by enzyme-inducing drugs. The aim of this study was to investigate the influence of topiramate dose, age, and comedication, especially of carbamazepine, phenytoin, phenobarbital, oxcarbazepine, lamotrigine, and valproic acid (VPA) on topiramate serum concentrations in patients with epilepsy. In total, 480 samples of 344 inpatients who fulfilled the inclusion criteria (e.g., trough concentration, body weight available) were investigated. The topiramate serum concentration in relation to topiramate dose per body weight (level-to-dose ratio) was calculated and compared for patients receiving topiramate monotherapy and for patients receiving topiramate plus one other AED. Analysis of covariance (using age as covariate) showed that comedication had a highly significant influence on the topiramate serum concentrations. Regression analysis including all 480 samples confirmed that in combinations with phenytoin, carbamazepine, phenobarbital, and oxcarbazepine, the topiramate concentrations were significantly lower compared with topiramate monotherapy, whereas VPA and lamotrigine had no significant influence. Moreover, regression analysis indicated that primidone and methsuximide lowered topiramate concentrations, whereas gabapentin, bromide, and sulthiame did not. In addition to comedication, the patient's age was significantly correlated with topiramate clearance. In accordance with the results of previous studies, these results indicated that infants and children had lower topiramate concentrations than adults receiving the same topiramate dose per body weight. Comedication and age should be considered in adjusting topiramate dosage. Determination of topiramate serum concentrations may be useful, especially when enzyme-inducing drugs are withdrawn or added.

Topics: Adolescent; Adult; Age Factors; Anticonvulsants; Body Weight; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Infant; Infant, Newborn; Male; Middle Aged; Regression Analysis; Topiramate

We report on two epileptic patients who developed acute psychosis after the use of topiramate (TPM). One patient exhibited severe psychomotor agitation, heteroaggressiveness, auditory and visual hallucinations as well as severe paranoid and mystic delusions. The other patient had psychomotor agitation, depersonalization, derealization, severe anxiety and deluded that he was losing his memory. Both patients had to be taken to the casualty room. After interruption of TPM in one patient and reduction of dose in the other, a full remission of the psychotic symptoms was obtained without the need of antipsychotic drugs. Clinicians should be aware of the possibility of development of acute psychotic symptoms in patients undergoing TPM treatment.

Topics: Acute Disease; Adult; Anticonvulsants; Epilepsy; Female; Fructose; Humans; Male; Psychoses, Substance-Induced; Topiramate

To evaluate the potential pharmacokinetic interactions between topiramate (TPM) and phenytoin (PHT) in patients with epilepsy by studying their pharmacokinetics (PK) after monotherapy and concomitant TPM/PHT treatment.. Twelve patients with epilepsy stabilized on PHT monotherapy were enrolled in this study, with 10 and seven patients completing the phases with 400 and 800 mg TPM daily doses, respectively. TPM was added at escalating doses, and after stabilization at the highest tolerated TPM dose, PHT doses were tapered. Serial blood and urine samples were collected for PK analysis during the monotherapy phase or the lowest PHT dose after taper and the concomitant TPM/PHT phase. Potential metabolic interaction between PHT and TPM also was studied in vitro in human liver microsomal preparations.. In nine of the 12 patients, PHT plasma concentrations remained stable, with a mean (+/-SD) area under the curve (AUC) ratio (combination therapy/monotherapy) of 1.13 +/- 0.17 (range, 0.89-1.23). Three patients had AUC ratios of 1.25, 1.39, and 1.55, respectively, and with the addition of TPM (800, 400, and 400 mg daily, respectively), their peak PHT plasma concentrations increased from 15 to 21 mg/L, 28 to 36 mg/L, and 27 to 41 mg/L, respectively. Human liver microsomal studies with S-mephenytoin showed that TPM partially inhibited CYP2C19 at very high concentrations of 300 microM (11% inhibition) and 900 microM (29% inhibition). Such high plasma concentrations would correspond to doses in humans that are 5 to 15 times higher than the recommended dose (200-400 mg). TPM clearance was approximately twofold higher during concomitant TPM/PHT therapy. This study provides evidence that the addition of TPM to PHT generally does not cause clinically significant PK interaction. PHT induces the metabolism of TPM, causing increased TPM clearance, which may require TPM dose adjustments when PHT therapy is added or is discontinued. TPM may affect PHT concentrations in a few patients because of inhibition by TPM of the CYP2C19-mediated minor metabolic pathway of PHT.

Topics: Adolescent; Adult; Anticonvulsants; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP2C19; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Mixed Function Oxygenases; Phenytoin; Topiramate

Topiramate (TPM) inhibits carbonic anhydrase, with metabolic acidosis as a possible side effect, although this has been reported in only two adult cases. We investigated the acid-base metabolism in infants and toddlers treated with TPM.. Nine infants and toddlers aged 5 months to 2.3 years (median, 6 months) were treated with TPM at maximal doses of 8.2-26 mg/kg/day (median, 11 mg/kg/day). The maximal TPM dose was achieved after 8-35 days (median, 17 days). TPM was given in addition to other antiepileptic drugs (AEDs) in five cases and as a sole AED in four patients with refractory epilepsy resistant to multiple AEDs. The diagnoses were infantile spasms (n = 5), epilepsia partialis continua (n = 1), infantile epileptic encephalopathy (n = 1), and Lennox-Gastaut syndrome (n = 2).. The blood gases were normal before treatment with TPM in all nine children. Metabolic acidosis developed in eight children after 8-26 days (median, 14 days) of TPM treatment with a minimum of serum bicarbonate between 15 to 18 mM (median, 17 mM), a minimal base excess between -6.2 and -11.2 mM (median, -7.9 mM), and pH between 7.22 and 7.40 (median, 7.35). Four of nine children showed clinical signs of hyperventilation and received oral sodium bicarbonate (1-2 mmol/kg), while TPM was still effective.. Because metabolic acidosis developed in eight of the nine infants and toddlers taking TPM, we would suggest that the acid-base metabolism be monitored in young children who receive TPM.

Topics: Acid-Base Equilibrium; Acidosis; Age Factors; Anticonvulsants; Bicarbonates; Blood Gas Analysis; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Epilepsy; Follow-Up Studies; Fructose; Humans; Hydrogen-Ion Concentration; Infant; Topiramate; Treatment Outcome

Topics: Anticonvulsants; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Epilepsy; Fructose; Humans; Patient Dropouts; Prognosis; Research Design; Retrospective Studies; Topiramate; Treatment Refusal

Topics: Acetates; Amines; Anticonvulsants; Carbamazepine; Cognition; Cognition Disorders; Cyclohexanecarboxylic Acids; Epilepsy; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Lamotrigine; Levetiracetam; Nipecotic Acids; Oxcarbazepine; Piracetam; Tiagabine; Topiramate; Triazines; Triazoles; Vigabatrin

Topics: Adolescent; Adult; Anticonvulsants; Cognition; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Neuropsychological Tests; Topiramate

Topiramate (TPM) has been widely used as an adjunctive therapy for treating epilepsy. TPM is reported to have multiple mechanisms of action, including inhibition of carbonic anhydrase, which may result in metabolic acidosis from decreased serum bicarbonate (HCO3-).. Clinical data from 30 children who received TPM as adjunctive therapy for medically refractory epilepsy were reviewed at Children's Hospital, Boston. Serum HCO3- levels were assessed before, during, and after discontinuing TPM (n = 9). When multiple data were available, mean values were used for analysis.. Of the 30 patients, 21 had a >10% decrease in HCO3- levels. The mean decrease in HCO3- among the 21 patients was 4.7 mEq/L, and maximum was 10 mEq/L. No clinical symptoms occurred, and HCO3- supplement was not needed, except for one patient who developed tachypnea from worsened acidosis after prolonged status epilepticus during a suspected viral illness. Among the 21 patients, TPM was discontinued in seven children because of a lack of efficacy, and in two because of anorexia. After discontinuing TPM, the serum HCO3- returned to the previous level before starting TPM in all nine.. Decreased HCO3- levels occurred in the majority of patients reviewed, usually only to a small to moderate extent, but by 8 and 10 mEq/L in two cases. In patients at risk for acidosis, the decrease in HCO3- may cause significant consequences, such as severe acidosis or renal calculi. Monitoring HCO3- levels before and during TPM therapy may be indicated, especially with conditions that predispose to acidosis.

Topics: Acidosis; Adolescent; Adult; Age Factors; Anticonvulsants; Bicarbonates; Carbonic Anhydrase Inhibitors; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Epilepsy; Fructose; Humans; Infant; Topiramate

Ideal antiepileptic drugs (AEDs) are designed to stop seizures with limited central nervous system (CNS) side effects. However, CNS-related treatment-emergent adverse events (TEAEs) often occur in patients receiving AEDs. Topiramate (TPM) is an AED proven to be safe and effective as adjunctive treatment for epilepsy patients with partial seizures. Double-blind, placebo-controlled, multicenter trials demonstrated potential effects on cognition. The P.A.D.S. (post-marketing antiepileptic drug survey) group, a cooperative group of 14 epilepsy centers that collaborate on obtaining data about new AEDs and devices, prospectively collected standardized data forms before and during treatment with TPM for epilepsy, and analyzed the postmarketing experience of CNS TEAEs with TPM. Our results from 701 treated patients show that cognitive complaints were the most common reason to discontinue TPM. The presence of complaints did have predictive value if the patient would discontinue TPM, although was not specific as to when discontinuation would occur. The spectrum of complaints in our open-label prospective multicenter postmarketing study was similar to those observed in controlled clinical trials. We were unable to demonstrate a specific population, dose titration, or concomitant AED that was at risk to discontinue treatment. We conclude that most patients treated with TPM will continue therapy beyond 6 months. Cognitive complaints and not efficacy reflect the primary reason for discontinuing therapy. Psychomotor slowing was the most common complaint, yet most patients elect to continue treatment, with "better" or "much better" ratings of both seizure and global improvement during treatment.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Child; Child, Preschool; Clinical Trials as Topic; Cognition; Cognition Disorders; Double-Blind Method; Drug Therapy, Combination; Epilepsy; Female; Follow-Up Studies; Fructose; Humans; Infant; Male; Middle Aged; Multicenter Studies as Topic; Product Surveillance, Postmarketing; Prospective Studies; Psychomotor Disorders; Risk Factors; Topiramate

The authors examined the ratio between the plasma and the cerebrospinal fluid (CSF) concentration of topiramate in 14 adults with epilepsy. Simultaneous trough samples of venous blood and CSF were collected and analyzed as total and unbound concentrations. Concomitant levels were also analyzed of lamotrigine (n = 5) and the relevant oxcarbazepine metabolite, 10-hydroxycarbazepine (n = 3). There was a close correlation between the plasma and the CSF concentration for both the total and unbound concentration of topiramate. The median CSF/plasma ratio of total topiramate was 0.85. The free topiramate concentration in plasma was not different from the free topiramate concentration in CSF. The CSF/plasma ratios showed little variation and were independent of the plasma level for both the total and the unbound levels. The unbound fraction of topiramate was 84% in plasma and 97% in CSF. The CSF concentrations of lamotrigine and 10-hydroxycarbazepine were 50% and 61% of the plasma concentrations, respectively. For topiramate, there is a close correlation between the plasma concentration and the CSF concentration. There does not seem to be a saturable carrier mechanism restricting topiramate transport across the blood-brain barrier. The concentration of topiramate in CSF is equal to the unbound proportion of topiramate in plasma, implying that the delivery of topiramate to the brain occurs via transfer from the unbound plasma pool. Plasma is thus a relevant matrix for therapeutic drug monitoring of topiramate.

Topics: Adolescent; Adult; Anticonvulsants; Blood-Brain Barrier; Brain; Carbamazepine; Drug Monitoring; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Lamotrigine; Male; Middle Aged; Oxcarbazepine; Prospective Studies; Topiramate; Triazines

Two children who presented with symptomatic metabolic acidosis after being put on topiramate (TPM) are reported. The first patient was an 11-year-old male with refractory complex partial epilepsy who was put on TPM for 13 months. He developed hyperventilation 1 week after increasing the dose to 300 mg/day. Arterial blood gas revealed hyperchloraemic metabolic acidosis with partial respiratory compensation: pH 7.36, PCO2 27.2 mmHg, bicarbonate 14.9 mEq/L, base excess -8.9 mmol/L. Hyperventilation and acidosis resolved after administration of sodium bicarbonate and reduction of the dose of TPM. The second patient was a female who developed increasing irritability at age 16 months and 21 months, each time associated with introduction of TPM and resolved promptly upon withdrawal of the drug. Venous blood gas taken during the second episode revealed pH 7.34, PCO2 37.4 mmHg, bicarbonate 20.4 mEq/L, base excess -4.2 mmol/L. The predominant mechanism of TPM-induced hyperventilation involves inhibition of carbonic anhydrase at the proximal renal tubule, resulting in impaired proximal bicarbonate reabsorption. The occurrence of hyperpnoea or mental status change in any patient who is on TPM should prompt an urgent blood gas sampling, with correction of the acid-base disturbances accordingly.

Topics: Acidosis; Anticonvulsants; Bicarbonates; Blood Gas Analysis; Child; Dose-Response Relationship, Drug; Epilepsy; Female; Fructose; Humans; Hyperventilation; Infant; Male; Topiramate

Topics: Adult; Anticonvulsants; Epilepsy; Fructose; Humans; Intellectual Disability; Male; Topiramate; Vomiting

Topiramate (TPM) is an antiepileptic agent, first licensed in the United Kingdom in 1994, that is used in the treatment of patients with refractory seizure disorders. TPM is a monosaccharide d-fructose derivate, with sulfamate function, and so far, few adverse side effects have been reported.. We describe three patients with epilepsy who were treated with TPM and developed hypohidrosis, heat and exercise intolerance, as well as fever. The sudomotor function was assessed after peripheral stimulation with pilocarpine iontophoresis.. Sweat response was reduced in all three patients. Signs and symptoms ceased after drug suppression.. This side effect associated with TPM, which has not been described previously, can be clinically significant during heat stress and exercise challenge.

Topics: Adolescent; Anticonvulsants; Child; Epilepsies, Partial; Epilepsy; Fever; Fructose; Humans; Hypohidrosis; Infant; Male; Spasms, Infantile; Sweating; Topiramate

Two adult patients with focal epilepsy who tolerated valproate (VPA) well in different combinations of anticonvulsants developed hyperammonemic encephalopathy when treated with VPA in combination with topiramate (TPM). Topiramate may contribute to the increased ammonia level by its inhibition of carbonic anhydrase and cerebral glutamine synthetase, thereby facilitating VPA/TPM hyperammonemic encephalopathy. Recovery occurred after withdrawal of VPA or TPM.

Topics: Adult; Ammonia; Anticonvulsants; Brain Diseases; Drug Therapy, Combination; Electroencephalography; Epilepsy; Female; Fructose; Humans; Male; Topiramate; Valproic Acid

Five antiepileptic drugs have been marketed in the last decade. We report here a retrospective study of patients attending our unit who were prescribed one of the new antiepileptic drugs. All these patients had refractory localization related epilepsy and had failed to respond to a first-line drug. The drugs had a different profile of side-effects but topiramate (42%) was the most common drug to be withdrawn due to side-effects as compared with tiagabine (26%), vigabatrin (16%), gabapentin (16%), and lamotrigine (15%). With regard to efficacy, 31% of the patients receiving gabapentin had a greater than 50% reduction in seizures compared with lamotrigine (25%), topiramate (20%), vigabatrin (19%) and tiagabine (11%). The number of patients remaining seizure free with gabapentin was 8% whilst for lamotrigine this was 5%, vigabatrin 5%, topiramate 1% and tiagabine 4%. In conclusion, all these five antiepileptic drugs are useful in treating refractory localization related epilepsy.

Topics: Acetates; Adolescent; Adult; Aged; Amines; Anticonvulsants; Cyclohexanecarboxylic Acids; Drug Resistance; Drug Therapy, Combination; Epilepsy; Female; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Lamotrigine; Male; Middle Aged; Nipecotic Acids; Patient Dropouts; Retrospective Studies; Tiagabine; Topiramate; Treatment Outcome; Triazines; Vigabatrin

To determine the long-term retention rate of topiramate (TPM) therapy in patients with chronic epilepsy and to identify the relevant prognostic factors that influence retention.. All patients with chronic epilepsy (n = 393) prescribed TPM between October 1, 1995, and December 31, 1998, at a tertiary referral centre for epilepsy were analysed. The retention rate for TPM was calculated by using Kaplan-Meier survival analysis, and the prognostic factors influencing retention were analysed by using Cox regression.. Of patients prescribed TPM, 30% continued taking the drug beyond 3 years. Discontinuation was mainly due to adverse events and lack of efficacy. Use of more than one new concurrent antiepileptic drug (AED) and lower maximal daily doses were more likely to result in treatment discontinuation due to adverse events. Older age at onset of epilepsy, a history of having previously taken more than one new AED [lamotrigine (LTG), gabapentin (GBP), or vigabatrin (VGB)], and lower maximal daily doses were more likely to lead to discontinuation due to lack of efficacy.. A third of patients with chronic epilepsy started on TPM therapy will continue on treatment for >3 years. Absence of learning disabilities, late age at onset of seizures, previous use of more than one new AED, two or more concurrent AED use, and low maximal daily doses of TPM are more likely to result in discontinuation of medication. These factors should be taken into account when considering the use of TPM for the treatment of chronic epilepsy.

Topics: Adolescent; Adult; Age of Onset; Aged; Anticonvulsants; Chronic Disease; Comorbidity; Drug Administration Schedule; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Learning Disabilities; Male; Middle Aged; Prognosis; Proportional Hazards Models; Survival Analysis; Topiramate

Angelman's syndrome, a genetic disorder involving a defect in the DNA coding for subunits of the gamma-aminobutyric acid (GABA) type A receptor, often is associated with intractable epilepsy. Topiramate is a novel anticonvulsant that enhances GABAergic neurotransmission. Five children with Angelman's syndrome and epilepsy were treated with topiramate for clinical indications. The drug was effective and well tolerated, possibly because of its GABAergic properties. Further studies are necessary to confirm and elucidate this observation.

Topics: Angelman Syndrome; Anticonvulsants; Child; Child, Preschool; Epilepsy; Female; Fructose; Humans; Male; Topiramate

The objective of this study was to examine the factors associated with the occurrence of behavioral and cognitive abnormalities in children treated with topiramate. A retrospective chart review of patients up to 18 years of age who had been treated with topiramate at a tertiary epilepsy center was performed. Behavioral or cognitive abnormalities were observed in 11 (14.6%) of 75 children between 2 weeks and 4 months after initiation of therapy. The mean dosage (4.6 mg/kg daily) at which these abnormalities were observed was similar to the mean final dose (5.8 mg/kg daily) in children without abnormalities. The mean rate of dosage increase was 0.72 mg/kg weekly and 0.7 mg/kg weekly in those with and without abnormalities, respectively. Five of the 11 children with behavioral or cognitive abnormalities had a previous history of behavioral or cognitive abnormalities, but only nine of the 64 children without abnormalities had a previous history of behavioral or cognitive abnormalities (P = 0.03). Lamotrigine was used concurrently in four of the 11 children with behavioral or cognitive abnormalities but in only seven of the 64 children without abnormalities (P = 0.05). Behavioral and cognitive abnormalities in children treated with topiramate do not appear to be related to the rate of dosage increase. A previous history of behavioral problems and the concurrent use of lamotrigine may be predisposing factors.

Topics: Adolescent; Anticonvulsants; Child; Child Behavior Disorders; Child, Preschool; Cognition Disorders; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Infant; Lamotrigine; Male; Medical Records; Retrospective Studies; Risk Factors; Topiramate; Treatment Outcome; Triazines

We evaluated the anticonvulsant efficacy of topiramate (TPM), a structurally novel antiepileptic drug (AED), in amygdala kindled rats that had been preselected with respect to their response to phenytoin (PHT).. Anticonvulsant response was tested by determining the afterdischarge threshold (ADT; i.e., a sensitive measure for drug effects on focal seizure activity). By repeated testing with the PHT prodrug fosphenytoin (FOS) three groups of kindled rats were separated: rats in which consistent anticonvulsant effects were obtained (PHT responders), rats that showed no anticonvulsant response (PHT nonresponders), and rats with variable responses (variable PHT responders). The latter, largest group was used to evaluate at which doses and pretreatment times TPM exerted significant anticonvulsant effects on ADT. For this purpose, TPM was tested at four doses (20, 40, 80, 160 mg/kg i.p.) and two pretreatment times (1 and 4 h). The most effective treatment protocol was then used for TPM testing in PHT responders and nonresponders.. TPM proved to be an effective AED in the kindling model. At 40 mg/kg, significant ADT increases were obtained after both 1 and 4 h after administration. In addition to the effect on focal seizure threshold, seizure severity and duration recorded at ADT were decreased by TPM, indicating that this drug acts on both seizure threshold and seizure spread. In PHT nonresponders, TPM significantly increased ADT, which is in line with its proven efficacy in patients with refractory partial epilepsy in whom phenytoin has failed. However, TPM was more efficacious in increasing ADT in PHT responders than in nonresponders, substantiating that the difference between these groups of kindled rats extends to other AEDs. Repeated testing of kindled rats with TPM indicated that, similar to PHT, there are individual kindled rats without anticonvulsant response to TPM (i.e., TPM nonresponders).. The data of this study substantiate that PHT nonresponders are a unique model for the search of new AEDs with improved efficacy in refractory partial epilepsy.

Topics: Amygdala; Animals; Anticonvulsants; Disease Models, Animal; Drug Resistance; Electric Stimulation; Epilepsy; Female; Fructose; Kindling, Neurologic; Phenytoin; Prodrugs; Rats; Rats, Wistar; Topiramate

In this study, we examined the effects of topiramate (TPM) on the electrophysiologic properties of cultured rat hippocampal pyramidal neurons.. Whole-cell current-clamp recording techniques were used to determine the effects of TPM on sustained repetitive firing (SRF), spontaneous epileptiform-burst firing, and spontaneous recurrent seizures (SRS).. Topiramate at therapeutic concentrations (10-100 microM) significantly decreased or abolished SRF in a dose-dependent and partially reversible manner. When transiently exposed to a medium in which Mg2+ is omitted, hippocampal neurons in culture develop SRS ("epilepsy") and epileptiform discharges. Application of TPM at concentrations ranging from 10 to 100 microM to cells displaying seizure activity caused a concentration-dependent decrease in the number of action potentials within a burst and in the average duration of epileptiform activity. Both effects were partially reversed during a 5- to 30-min drug washout period.. These effects on the electrophysiologic properties of cultured neurons are consistent with the concept that TPM exerts modulatory effects on voltage-dependent Na+ and/or Ca2+ conductances responsible for the generation and propagation of action potentials. Topiramate also may inhibit synaptic conductances responsible for transmission of epileptiform discharges.

Topics: Action Potentials; Animals; Anticonvulsants; Calcium Channels; Cells, Cultured; Dose-Response Relationship, Drug; Epilepsy; Fructose; Hippocampus; Models, Neurological; Patch-Clamp Techniques; Phenytoin; Pyramidal Cells; Rats; Sodium Channels; Synaptic Transmission; Topiramate

Clinical success with an antiepileptic drug (AED) depends primarily on its efficacy and tolerability. Clinicians also need to have a basic understanding of an AED's pharmacokinetic characteristics, particularly those affecting the potential for drug interactions such as hepatic enzyme inhibition or induction and protein-binding displacement. Successful treatment may be complicated by pharmacokinetic characteristics such as a short half-life, nonlinear kinetics, and active metabolites. Pharmacokinetic characteristics that make a drug easy to use may affect patient adherence. In general, newer AEDs such as topiramate (TPM) are simpler to use than traditional AEDs because they have more favorable pharmacokinetic characteristics and fewer drug interactions.

Topics: Adolescent; Age Factors; Aged; Anticonvulsants; Biological Availability; Child; Child, Preschool; Drug Interactions; Epilepsy; Food-Drug Interactions; Fructose; Half-Life; Humans; Intestinal Absorption; Patient Compliance; Pharmacokinetics; Tissue Distribution; Topiramate

Topiramate is a new antiepileptic drug that has now become available for prescription in Belgium. In vitro and in vivo preclinical studies have indicated that topiramate has several mechanisms of action that may contribute to its anticonvulsivant activity. A broad antiepileptic spectrum could be suspected that has been confirmed on a clinical basis. Topiramate has favorable pharmacokinetic properties: rapid absorption, long half-life and little interaction with other AED. Several meta-analysis have confirmed its efficacy, particularly as adjunctive therapy for partial onset seizures, refractory to other AED. It is actually reimbursed only for these patients but its indications will probably be widened in the future.

Topics: Anticonvulsants; Belgium; Drug Interactions; Epilepsy; Fructose; Half-Life; Humans; Topiramate

Topiramate is a recently released antiepileptic agent used in the treatment of patients with refractory seizure disorders. In addition to its antiepileptogenic activities, it results in inhibition of carbonic anhydrase isoenzymes II and IV, which are present in the central nervous system. A 15-year-old female who presented with hyperpnea and primary respiratory alkalosis is reported. Other possible etiologies of the central hyperventilation syndrome were excluded. The problem resolved within 24 hours after discontinuing topiramate.

Topics: Adolescent; Anticonvulsants; Bicarbonates; Chlorides; Epilepsy; Female; Fructose; Humans; Hyperventilation; Sodium; Topiramate

A 3-year retrospective review was undertaken of the use of topiramate in 51 children aged 3-16 years with partial and generalized epilepsies who attended a tertiary referral epilepsy centre in a large children's hospital. The mean follow-up period was 19 months (range 6-33 months). Twenty-six children (51%) were still receiving topiramate at the time of their last review. Fifteen children (29%) showed a greater than 50% reduction in their seizure frequency and four children (8%) became seizure free, three on topiramate monotherapy. The drug appeared to be most effective in children with moderate learning difficulties with 75% showing an improvement in seizure control compared with 25% of children with normal educational functioning. Topiramate was withdrawn in 25 patients. The reasons for withdrawal included adverse effects in 20, lack of effect in three and worsening of seizures in two patients. Adverse side effects were reported in 57% of the 51 patients. The majority of the side effects were related to behavioural and cognitive difficulties, with less-common side effects including anorexia, weight loss and headaches.

Topics: Adolescent; Anticonvulsants; Child; Child Behavior Disorders; Child, Preschool; Cognition Disorders; Drug Tolerance; Epilepsy; Female; Follow-Up Studies; Fructose; Humans; Male; Medical Audit; Retrospective Studies; Topiramate; Treatment Outcome

The purpose of this paper is to understand the association between antiepileptic drugs (AEDs), patient characteristics, changes in seizure pattern and emergent psychiatric disorder, i.e. psychosis or affective disorder. To this end we carried out a retrospective casenote study on 89 patients who developed psychiatric symptoms during treatment with topiramate, vigabatrin or tiagabine. The psychiatric problem was either an affective or a psychotic disorder (not including affective psychoses). It was discovered that 99% of the patients suffered from complex partial seizures with or without secondary generalization. More than half were on polytherapy with two or more other AEDs. Nearly two-thirds had a previous psychiatric history. There was a strong association between the type of previous psychiatric illness and the type of emerging psychiatric problem, both for psychoses and for affective disorders. Patients on vigabatrin had an earlier onset of epilepsy and more neurological abnormalities than those on topiramate. Those patients on lower doses had a shorter interval between the start of the AED therapy and the onset of the psychiatric problem. A seizure-free period was observed in more than half of the patients before they developed the psychiatric symptoms, and of these more were likely to develop a psychosis rather than an affective disorder. There seemed to be an association of suppression of right-sided seizures and the onset of the psychiatric problem. The conclusions drawn were that patients with a previous history of psychosis or affective disorder tended to develop the same psychiatric problem with new AEDs. Those with a seizure-free period before the onset of the psychiatric problem were more likely to develop a psychosis than an affective disorder.

Topics: Adolescent; Adult; Anticonvulsants; Dominance, Cerebral; Dose-Response Relationship, Drug; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Mood Disorders; Nipecotic Acids; Psychoses, Substance-Induced; Recurrence; Retrospective Studies; Tiagabine; Topiramate; United Kingdom; Vigabatrin

Topics: Anticonvulsants; Epilepsy; Female; Fructose; Humans; Kidney Calculi; Middle Aged; Topiramate

Topiramate is a novel antiepileptic drug that was licensed in Norway in 1997 as adjunctive treatment for patients with partial seizures. Metaanalysis of randomized controlled studies suggest that topiramate may be the most potent of the new antiepileptic drugs and have a favourable pharmacokinetic profile. At the National Center for Epilepsy we have used topiramate since 1990. We present our clinical experience with the drug.. We have, retrospectively, assessed 114 adult patients, mainly with intractable partial seizures, who received topiramate as add-on treatment. Average follow-up was 2.3 years.. Four patients (3.5%) became seizure free. The overall seizure frequency was reduced by > 50% in 56 patients (49%). Adverse effects were observed in 82 patients (72%); in 54 patients (47%) the drug had to be withdrawn due to unacceptable side effects and/or lack of clinical effect. The most frequent side effects were weight loss, fatigue, behavioural and cognitive problems.. Our results corroborate an impression of topiramate being an effective drug used as adjuntive therapy in patients with refractory epilepsy. Side effects can be a problem, but a low starting dose, a slow dose escalation, and topiramate used alone may reduce this problem.

Topics: Adolescent; Adult; Anticonvulsants; Epilepsy; Epilepsy, Complex Partial; Epilepsy, Generalized; Female; Follow-Up Studies; Fructose; Humans; Male; Middle Aged; Myoclonic Epilepsy, Juvenile; Retrospective Studies; Topiramate

To explore the impact of topiramate on tests of intellect and other cognitive processes.. This was a retrospective study. The neuropsychological test scores of 18 patients obtained before and after the introduction of treatment with topiramate (median dose 300 mg) were compared with changes in test performance of 18 patients who had undergone repeat neuropsychological assessments at the same time intervals. Complaints of cognitive decline precipitated referral for reassessment in five cases in the topiramate treated group. The groups were matched for age and intellectual level at the time of the first assessment. Patients were assessed using the WAIS-R, tests of verbal and non-verbal memory, language, and perceptual processing. A subgroup of patients underwent a brief reassessment after the withdrawal or substantial reduction of topiramate.. Repeat assessments in those taking topiramate were associated with a significant deterioration in many domains, which were not seen in the comparison group. The greatest changes were for verbal IQ, verbal fluency, and verbal learning (p<0. 001). Improvements in verbal fluency (p<0.05), verbal learning (p<0. 01), and digit span (p<0.001) were recorded in those patients who had topiramate withdrawn or reduced.. In our patient group topiramate had a negative impact on cognition which was consistent with subjective complaints of patients. Tests requiring verbal processing seemed especially sensitive to the drug. A decline in verbal intellect (VIQ), a measure which has been considered by some to be insensitive to antiepileptic drug effects, was particularly striking. Caution is warranted in the interpretation of the findings due to methodological limitations of the study design. Further investigation of mediating factors such as serum concentrations, comedication, and other potential risk factors, however, is needed to enable appropriate targeting of treatment with this effective antiepileptic agent.

Topics: Adolescent; Adult; Anticonvulsants; Cognition; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Neuropsychological Tests; Topiramate

Since the beginning of the 1990's, a dozen of new anti-epileptic drugs have been on the market or will be soon. This article reviews the daily clinical utilisation of new anti-epileptic drugs. It considers, without being complete, the current opinions and tendencies. The new anti-epileptic substances are generally as efficient as conventional medications. However, they are better tolerated and are more easily used in combination with conventional anti-epileptic drugs. Polytherapy is certainly the form of treatment, which is used in the most cases of resistant epilepsies. The surgical treatment can be used in only a very limited number of cases. The objective of treatment is the complete control of seizures, with minimum secondary effects. Though this objective is rarely reached, the NAE significantly improves the quality of life of patients suffering from severe epilepsy. The utilisation of NAE is not without risk. Increase in the frequency and severity of seizures may occur; we should remember that severe adverse effects appeared in the post-marketing period of the use of Vigabatrine and Felbamate. Therefore, we must remain vigilant in the clinical use of the anti-epileptic drugs.

Topics: Acetates; Amines; Anemia, Aplastic; Anticonvulsants; Carbamazepine; Cyclohexanecarboxylic Acids; Drug Therapy, Combination; Drug Tolerance; Epilepsy; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Lamotrigine; Levetiracetam; Nipecotic Acids; Oxcarbazepine; Phenylcarbamates; Piracetam; Propylene Glycols; Tiagabine; Topiramate; Triazines; Vigabatrin; Visual Fields

Metabolic acidosis induced by topiramate is a well documented but infrequent adverse event. The objective was to demonstrate the lowering of carbon dioxide serum levels, which is usually asymptomatic but may facilitate the occurrence of metabolic acidosis in patients using topiramate.. We evaluated, prospectively, the carbon dioxide serum levels of 18 patients seen at the epilepsy clinic of our university hospital, before and 3 months after introducing topiramate.. Five patients were female and 13 were male, age ranging from 2 to 16 years old (mean=9. 3). Carbon dioxide mean serum levels were 25 and 21.2 mmol/L (normal = 22 to 30), before and 3 months after introducing topiramate, respectively. Dose ranged from 2.08 to 11.76 mg/kg/day (mean=6. 7mg/kg/day). Adverse events were anorexia, nausea and somnolence.. We conclude that the lowering of carbon dioxide serum levels induced by topiramate is mostly asymptomatic, but may facilitate the occurrence of metabolic acidosis. Since patients in use of topiramate have refractory epilepsy, they may need epilepsy surgery, and must be carefully monitored for the risk of metabolic acidosis during surgery.

Topics: Acidosis; Adolescent; Anticonvulsants; Carbon Dioxide; Child; Child, Preschool; Disease Susceptibility; Epilepsy; Female; Fructose; Humans; Infant; Male; Prospective Studies; Topiramate

We sought to determine the long-term retention rates of lamotrigine (LTG), gabapentin (GBP), and topiramate (TPM) therapy for patients at a tertiary referral clinic for chronic, refractory epilepsy.. We analyzed 424 consecutive patients with chronic, refractory partial and/or generalized epilepsy who were started on LTG, 158 patients who were started on GBP, and 393 patients who were started on TPM. The percentages of patients who continued therapy with LTG, GBP, and TPM were estimated with the use of Kaplan-Meier survival analysis. Factors that influence retention were analyzed with the use of Cox regression analysis.. Kaplan-Meier survival analysis showed that at 3 years, 30% continued therapy on TPM compared with 29% on LTG and fewer than 10% on GBP. Adverse events resulted in therapy withdrawal in 40% of patients on TPM compared with GBP (37%) and LTG (22%). Perceived lack of efficacy led to treatment withdrawal in 39% of patients on GBP compared with 34% on LTG and 19% on TPM. Cox regression estimated that a fourth or fewer of patients with chronic partial epilepsy are likely to continue therapy with a new antiepileptic drug beyond 5 years.. The impact of these new antiepileptic drugs on the long-term course of chronic partial epilepsy is likely to be small, as approximately three of four patients will discontinue therapy. More patients appear to continue on TPM compared with LTG or GBP, with a possible reason being better perceived efficacy of TPM, despite having the highest incidence of adverse events.

Topics: Acetates; Adolescent; Adult; Age of Onset; Aged; Amines; Anticonvulsants; Chronic Disease; Cyclohexanecarboxylic Acids; Epilepsy; Female; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Lamotrigine; Male; Middle Aged; Patient Compliance; Patient Dropouts; Proportional Hazards Models; Survival Analysis; Topiramate; Triazines

Topics: Anticonvulsants; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Therapy; Epilepsy; Fructose; Humans; Topiramate

Several epileptic syndromes that occur during childhood are characterized by severe treatment-resistant seizures, progressive loss of higher intellectual functions, and characteristic electroencephalographic abnormalities. These catastrophic epileptic syndromes include epileptic encephalopathy with diffuse slow spike waves (Lennox-Gastaut syndrome), West syndrome, progressive myoclonic epilepsies, and electrical status epilepticus during sleep. This article summarizes each syndrome and reviews the most recent information concerning the effectiveness of topiramate with respect to each condition. Suggestions are offered to help clinicians maximize topiramate's efficacy and tolerability in patients suffering with these syndromes. Overall, topiramate is a valuable antiepileptic medication in the treatment of catastrophic pediatric epileptic syndromes.

Topics: Anticonvulsants; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Epilepsy; Fructose; Humans; Randomized Controlled Trials as Topic; Syndrome; Topiramate; Treatment Outcome

Three double-blind, randomized, placebo-controlled studies of topiramate that include children have been published and prospective but unblinded and retrospective reviews have been reported providing information regarding topiramate's safety and tolerability. These studies indicate that side effects tend to occur early in treatment with topiramate, especially in children receiving polypharmacy. Two classes of adverse events are commonly reported: central nervous system and anorexia/weight loss. Central nervous system effects include somnolence, difficulties with concentration, and behavior changes. Tolerance to these effects seems to develop in most children. When it occurs, weight loss has been noted in the first 12 to 18 months, after which normal weight gain resumes, without long-term impact on growth. As opposed to the experience in adults, aphasia and word-finding difficulties are not commonly seen, and parasthesiae are not reported by children. Renal calculi are rare. Life-threatening idiosyncratic reactions have not been attributed to topiramate. While metabolic acidosis has been reported, no other clinically significant laboratory abnormalities have been associated with the use of topiramate in children.

Topics: Anticonvulsants; Child; Child, Preschool; Drug Tolerance; Epilepsy; Fructose; Humans; Prospective Studies; Randomized Controlled Trials as Topic; Retrospective Studies; Topiramate

In the treatment of children with epilepsy, the role of topiramate has been expanding gradually. The main factor that has contributed to this trend is the relatively large body of information that has accumulated on the clinical pharmacology of topiramate in children, including its broad-spectrum efficacy, pediatric pharmacokinetics, side-effect profile, and safety. It has also become increasingly apparent with time that topiramate, in contrast to other broad-spectrum antiepileptic drugs used in children, does not seem to be associated with a significant risk of any serious or life-threatening adverse effects. The present review summarizes the available evidence related to the clinical pharmacology of topiramate in children and provides an update on its known mechanisms of action. Finally, available experimental data on the neuroprotective effect of topiramate are reviewed because of their considerable clinical potential in the treatment of children and newborns.

Topics: Adolescent; Anticonvulsants; Calcium Channels; Carbonic Anhydrases; Child; Child, Preschool; Epilepsy; Fructose; gamma-Aminobutyric Acid; Humans; Kainic Acid; Sodium Channels; Topiramate

To measure the effects of topiramate on brain gamma-aminobutyric acid (GABA) in patients with epilepsy.. Topiramate is a new antiepileptic medication with multiple putative mechanisms of action. In a recent meta-analysis of the newer antiepileptic drugs, topiramate was the most potent. Homocarnosine and pyrrolidinone are important metabolites of GABA with antiepileptic actions.. In vivo measurements of GABA, homocarnosine, and pyrrolidinone were made of a 14-cm3 volume in the occipital cortex using 1H spectroscopy with a 2.1-Tesla magnetic resonance spectrometer and an 8-cm surface coil. Twelve patients (eight women) with refractory complex partial seizures were studied while using topiramate. Nine epilepsy-free, drug-free volunteers served as control subjects.. Topiramate increased mean brain GABA, homocarnosine, and pyrrolidinone concentrations in all patients. In paired measurements, brain GABA increased by 0.7 micromol/g (SD 0.3, n 7, 95% CI 0.4 to 1.0, p < 0.01). Homocarnosine increased by 0.5 micromol/g (SD 0.2, n 7, 95% CI 0.3 to 0.7, p < 0.001). Pyrrolidinone increased by 0.21 micromol/g (SD 0.06, n 7, 95% CI 0.16 to 0.27, p < 0.01). In two additional patients, GABA, homocarnosine, and pyrrolidinone increased after they were switched from vigabatrin to topiramate.. Topiramate increased brain GABA, homocarnosine, and pyrrolidinone to levels that could contribute to its potent antiepileptic action in patients with complex partial seizures.

Topics: Adolescent; Adult; Anticonvulsants; Brain; Carnosine; Epilepsy; Female; Fructose; gamma-Aminobutyric Acid; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Pyrrolidinones; Topiramate

The objective of this study was to compare the relative cost-effectiveness of two AEDs by a prospective clinical audit. Patients starting on the adjunctive therapies lamotrigine and topiramate were recruited from the out-patient epilepsy clinics at Queen Square. Three interview were scheduled: baseline; three months follow-up and six months from baseline. Of the 81 patients recruited, a total of 73 patients completed all three interviews. An intention to treat analysis was performed on the data. Seizure severity and frequency were assessed using the National Hospital Seizure Severity Scale. Side-effects, adverse events and reasons for stopping medication were also recorded. At the third interview, a total of 47/73 (64%) were still on the prescribed adjunctive drug. Outcome was assessed by two methods: the > 50% seizure reduction cited in the literature and a more stringent assessment of patient 'satisfaction' which we defined operationally on clinical criteria. Using this definition, a total of 10/73 (14%) patients were 'satisfied'. The relative costs of starting patients on each of the two AEDs were calculated, both drug costs and the costs of adverse events (the latter were defined as events requiring urgent medical attention). The costs of the two drugs were compared. A number of methodological issues relating to cost comparison are discussed. Outcome and pharmaco-economic studies need to assess more than reduction in number of seizures. They should take into account variables important for quality of life including side-effects and adverse events.

Topics: Adult; Anticonvulsants; Cost-Benefit Analysis; Epilepsy; Female; Follow-Up Studies; Fructose; Humans; Lamotrigine; Male; Medical Audit; Middle Aged; Patient Satisfaction; Prospective Studies; Quality of Life; Severity of Illness Index; Time Factors; Topiramate; Treatment Outcome; Triazines

Topiramate became available for use in October 1995. Meta-analysis of its randomised controlled data suggested that it may be the most potent of the new antiepileptic drugs. The aim of this study was to assess the first year's postlicensing experience in a specialist regional epilepsy clinic.. The case notes of 174 of 178 patients who were prescribed topiramate in the 12 months between November 1995 and October 1996 were retrospectively reviewed. Data were collected on seizure type, classification of epilepsy, presence or absence of learning difficulties, depression, or behavioural problems, co-medication, dosage escalation, efficacy, adverse events, whether or not the patient was still on topiramate and, if not, the reason for withdrawal. Kaplan-Meier survival analysis was used to estimate the overall retention rate and log rank tests were used to determine factors associated with stopping topiramate.. Overall 90 of 174 patients had ceased taking topiramate at the end of the study. The median "survival time" was 427 days (95% CI 362.9-491.1). The cumulative probability for remaining on topiramate at 1 year was 0.549 (95% CI 0.475-0.623). The retention rate in patients in whom topiramate was substituted for another drug was significantly higher than in those in whom it was added to current therapy. Adverse events (CNS related) were the most common reason for stopping topiramate. Eight patients with partial and one patient with juvenile myoclonic epilepsy became seizure free.. There is a significant (20-25%) chance of being intolerant to topiramate at relatively low doses. Substituting topiramate for another antiepileptic drug may reduce the chances of drug withdrawal. If topiramate is tolerated there is a good chance of worthwhile improvement in seizure control. These data, although not derived from randomised controlled trials, represent pragmatic use of novel antiepileptic drugs in "real life" and may be helpful to non-specialists when prescribing topiramate.

Topics: Anticonvulsants; Epilepsy; Female; Fructose; Humans; Male; Practice Patterns, Physicians'; Time Factors; Topiramate

Topiramate (TPM) is a novel antiepileptic medication (AED) with at least three mechanisms of action. A possible fourth mechanism, that of a carbonic anhydrase inhibitor, also may contribute to its antiepileptic properties. We report a patient with intractable epilepsy and normal renal function who developed a normal anion gap metabolic acidosis, which worsened during elective surgery for temporal lobectomy. We believe this side effect of TPM can become clinically significant during surgery, concomitant use of another carbonic anhydrase inhibitor, and potentially with the ketogenic diet.

Topics: Acidosis; Anticonvulsants; Carbonic Anhydrase Inhibitors; Epilepsy; Epilepsy, Temporal Lobe; Fructose; Humans; Male; Middle Aged; Temporal Lobe; Topiramate

Topics: Anticonvulsants; Epilepsy; Fructose; Humans; Topiramate

To study the effectiveness and safety of topiramate in clinical practice, for a group of patients with childhood onset epilepsy.. All patients treated with topiramate at the three study centers between November 1995 and December 31, 1997 were analyzed retrospectively, using a standardized study protocol. Data were gathered on demographic features, seizures response and medication related adverse events.. Eighty-seven patients were treated with topiramate. Over 90% seizure reduction was achieved in 8 (9%) patients, 50%-90% in 21 (24%), < 50% in 54 (62%) patients. Four patients (5%) had a deterioration in seizure control. Adverse events required topiramate discontinuation in 36 (41%). Of these 27 (31%) complained of unacceptable cognitive dulling. The rate of dose escalation and final dose in mg/kg were similar in those who remained on topiramate and those who were intolerant because of cognitive side effects.. Although topiramate resulted in > 50% seizure reduction in 29 (33%) of this group of patients with difficult epilepsy, its usefulness was limited by a high incidence of adverse effects. Adverse events prevented ongoing therapy for 36 (41%) and cognitive dulling resulted in topiramate discontinuation by 27 (31%) of the group.

Topics: Adolescent; Age of Onset; Anticonvulsants; Child; Child, Preschool; Epilepsies, Myoclonic; Epilepsy; Epilepsy, Absence; Epilepsy, Complex Partial; Epilepsy, Generalized; Fructose; Humans; Infant; Retrospective Studies; Topiramate

Topics: Anticonvulsants; Epilepsy; Female; Fructose; Germany; Humans; Male; Topiramate

Topiramate, a novel antiepileptic drug, inhibits the seizures of spontaneously epileptic rat (SER), a double mutant (zi/zi, tm/tm) which exhibits both tonic convulsion and absence-like seizures from the age of 8-weeks. Hippocampal CA3 pyramidal neurons in SER show a long-lasting depolarization shift with accompanying repetitive firing when a single electrostimulation is delivered to the mossy fibers in vitro. The effects of topiramate on the excitability of CA3 pyramidal neurons in SER were examined to elucidate the mechanism underlying the antiepileptic action. Intracellular recordings were performed in 23 hippocampal slice preparations of 16 SER aged 8-17 weeks. Topiramate (10-100 microM) dose-dependently inhibited the depolarizing shifts with repetitive firing induced by mossy fiber stimulation without affecting the first spike and resting membrane potentials in hippocampal CA3 neurons of SER. Higher dose of topiramate (100 microM) sometimes inhibited the first spike, and decreased excitatory postsynaptic potentials in the SER CA3 neurons. However, topiramate up to 100 microM did not affect the single action potential elicited by the stimulation in the hippocampal CA3 neurons of age-matched Wistar rat devoid of the seizure. Application of topiramate (100 microM) did not significantly affect the firing induced by depolarizing pulse applied in the CA3 neurons of the SER. In addition, topiramate (100 microM) had no effects on the Ca2+ spike induced by intracellularly applied depolarizing pulse in the presence of tetrodotoxin and tetraethylammonium. In contrast, a dose-dependent inhibition of depolarization and repetitive firing induced by bath application of glutamate in CA3 pyramidal neurons was obtained with topiramate (10-100 microM). Furthermore, topiramate (100 microM) decreased the number of miniature postsynaptic potential of CA3 pyramidal neurons of SER. In patch clamp whole cell recording using acutely dissociated hippocampal CA3 neurons from SER aged 8-weeks and age-matched normal Wistar rats, there were no remarkable effects on voltage dependent Ca2+ current with topiramate up to 300 microM in either animal; the current was completely blocked by Cd2+ at a concentration of 1 mM. These findings suggest that topiramate inhibits release of glutamate from the nerve terminals and/or abnormal firing of the CA3 pyramidal neurons of SER by mainly blocking glutamate receptors in the neurons.

Topics: Action Potentials; Animals; Anticonvulsants; Calcium; Electrophysiology; Epilepsy; Female; Fructose; Glutamic Acid; Hippocampus; Male; Neurons; Patch-Clamp Techniques; Pyramidal Cells; Rats; Rats, Mutant Strains; Synaptic Transmission; Topiramate

Topics: Adult; Anticonvulsants; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Myopia; Topiramate

The purpose of this study was to look at the efficacy and side effect profile of topiramate in a neurology unit. Using case notes, 94 patients who had been treated with topiramate were identified: 48 patients had taken part in clinical trials of topiramate, 46 received topiramate once licensed. Of these patients 24% had a greater than 50% decrease in seizure frequency. Patients with primary generalized epilepsy (n = 12) had a greater reduction in seizures compared with those with partial epilepsies (n = 70) P > 0.03. There was a high incidence (41%) of side effects, particularly psychiatric problems, leading to withdrawal of therpay in 41% of patients. Seven patients were admitted to hospital as a result of psychotic symptoms or depression. The incidence of psychotic symptoms (12%) was significantly higher for patients receiving topiramate compared with 191 patients attending the department on gabapentin (0.5%) and 270 patients attending the department on lamotrigine (0.7%) P < 0.001. 'Abnormal thinking', consisting of mental slowing and word-finding difficulties, occurred in 31%. The incidence could be significantly reduced by using 25 mg dose increments fortnightly as opposed to 100 mg weekly (P > 0.03). Although topiramate is an effective antiepileptic drug, its use is accompanied by a high incidence of particularly psychiatric side effects.

Topics: Adolescent; Adult; Aged; Ambulatory Care; Anticonvulsants; Child; Cognition; Depression; Epilepsy; Female; Fructose; Hallucinations; Humans; Male; Medical Audit; Memory; Middle Aged; Neurology; Psychoses, Substance-Induced; Retrospective Studies; Topiramate; United Kingdom

Topics: Adolescent; Adult; Animals; Anticonvulsants; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Lamotrigine; Male; Mice; Mice, Inbred ICR; Topiramate; Triazines

A survey of the prescription of the novel anticonvulsants lamotrigine, vigabatrin, gabapentin and topiramate was carried out in an outpatient setting to investigate the outcome of prescription and factors affecting response. One hundred and fifty randomly selected patient notes were analysed retrospectively. Drug continuation and seizure freedom were used as measures of response. Twenty-nine percent of patients had a brain lesion, 14% a psychiatric disorder, 7% neonatal seizures, 21% a family history of epilepsy and 15% a learning disability. On average at the moment of initiation of the novel anticonvulsant the patients had had a diagnosis of epilepsy for 18 years, were 33 years old, had 19 seizures per month and had previously used two drugs which failed to control their epilepsy. The first novel anticonvulsant was in 55% of cases lamotrigine, in 43% vigabatrin and in 1 % gabapentin. The overall percentage of patients who stayed on their first novel anticonvulsant was 55%, and 17% became seizure-free. No factors were found to influence the response in terms of drug continuation. For seizure freedom, the presence of a psychiatric disorder and partial seizures predicted a significantly poorer response. Length of seizure disorder, seizure frequency at initiation, the number of previously used failed drugs and the total number of drugs previously used were all significantly lower in the seizure-free group.

Topics: Acetates; Adolescent; Adult; Ambulatory Care; Amines; Anticonvulsants; Chi-Square Distribution; Cyclohexanecarboxylic Acids; Drug Prescriptions; Epilepsy; Female; Follow-Up Studies; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Lamotrigine; Male; Middle Aged; Patient Compliance; Retrospective Studies; Topiramate; Treatment Outcome; Triazines; Vigabatrin; Wales

Topics: Acetates; Amines; Anticonvulsants; Cyclohexanecarboxylic Acids; Epilepsy; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Lamotrigine; Phenylcarbamates; Propylene Glycols; Topiramate; Triazines

Because enzyme-inducing antiepileptic drugs (AEDs) can affect pharmacokinetics of oral contraceptives and thereby cause contraceptive failure, the potential effect of topiramate, a new AED, on the pharmacokinetics of the combination oral contraceptive norethindrone/ethinyl estradiol was evaluated.. Twelve women receiving stable valproic acid (VPA) monotherapy for epilepsy received a combination norethindrone 1.0 mg/ethinyl estradiol 35-microg tablet daily for 21 days followed by seven daily doses of inert tablets for four 28-day cycles. After a baseline cycle (cycle 1), topiramate 100, 200, and 400 mg every 12 h was administered in cycles 2 through 4, respectively. Serial blood samples were obtained on day 20 of each cycle and were analyzed for norethindrone, ethinyl estradiol, and progesterone by using validated radioimmunoassay methods.. Compared with cycle 1, none of the norethindrone pharmacokinetic parameters changed significantly in the presence of topiramate, 100-400 mg every 12 h. Individual patient serum progesterone concentrations measured during each cycle were at or close to the limit of quantification with no apparent differences among cycles. However, mean area under the concentration-versus-time curve over the 24-h period (AUC(0-24)) values for ethinyl estradiol were 18-30% lower in cycles 2 through 4 compared with cycle 1 (p < or = 0.05 for all pairs), whereas mean oral serum clearance (CL/F) values were 14.7-33.0% higher (p < or = 0.05 for cycles 2 and 4 vs. cycle 1). Mean time of peak concentration (T(max)) values determined during topiramate therapy were not significantly different from those at baseline.. When prescribing an oral contraceptive for patients receiving topiramate, clinicians should consider initial therapy with an agent containing > or = 35 microg of ethinyl estradiol.. The efficacy of combined oral contraceptives (OCs) is diminished in women taking enzyme-inducing anti-epileptic drugs such as phenytoin, phenobarbital, and carbamazepine. In preliminary in vitro studies, a new anti-epileptic drug derived from D-fructose, topiramate, produced no clinically relevant inhibitory effects on the metabolism of such drugs as barbiturates, classic neuroleptics, and tricyclic antidepressants. To assess this new drug, 12 women with documented histories of epilepsy took an OC containing 1 mg norethindrone and 35 mcg ethinyl estradiol as well as topiramate (100-400 mg every 12 hours) for 4 menstrual cycles. Serial blood samples were obtained on day 20 of the 4 cycles. None of the norethindrone pharmacokinetic parameters changed significantly in the presence of topiramate. Ethinyl estradiol serum levels were reduced by an average of 30% from baseline. The mean area under the concentration-versus-time curve over the 24-hour period values for ethinyl estradiol were 18-30% lower in cycles 2-4 than the baseline cycle and mean oral serum clearance values were 14.7-33.0% higher. This compares favorably with the 40-72% reductions in progestin and estrogen levels recorded in women taking a levonorgestrel-containing OC and enzyme-inducing anti-epileptics. Although topiramate's modest interaction with OCs is not likely to interfere with contraceptive efficacy, the reduction in serum estrogen concentrations has the potential to increase the incidence of breakthrough bleeding, indicating the OC should contain at least 35 mcg of estrogen.

Topics: Adult; Anticonvulsants; Contraception; Contraceptives, Oral, Combined; Contraceptives, Oral, Synthetic; Epilepsy; Estradiol Congeners; Ethinyl Estradiol; Female; Fructose; Humans; Norethindrone; Progesterone; Topiramate; Valproic Acid

Topics: Acetates; Amines; Anticonvulsants; Child, Preschool; Cyclohexanecarboxylic Acids; Drug Resistance; Electroencephalography; Epilepsies, Partial; Epilepsy; Female; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Infant; Lamotrigine; Male; Topiramate; Triazines

Topics: Anticonvulsants; Epilepsy; Fructose; Humans; Topiramate

Topics: Anticonvulsants; Carbamazepine; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Interactions; Epilepsy; Fructose; Humans; Phenytoin; Topiramate; Valproic Acid

Topiramate, a structurally novel anticonvulsant, and phenytoin were evaluated in a rat model of ischemia-induced epilepsy. In this model a transient global cerebral ischemia is induced by cardiac compression. By precisely controlling the experimental conditions the procedure causes reproducible neurological deficits that include audiogenic epileptic seizures. The seizures can be broadly separated into three types reflecting the degree of severity: wild running, clonic seizures, and tonic extension seizures of the forelimbs and hindlimbs. Topiramate and phenytoin blocked all three types of seizures. Calculated ED50 values for topiramate 1 hr after oral administration were 8.2, 13.0 and 36.1 mg/kg for blockade of tonic extension seizures, clonic seizures and wild running, respectively. Corresponding ED50 values for phenytoin were 5.0, 10.8 and 20.7 mg/kg. These results support the concept that the anticonvulsant activity of these drugs is due primarily to an ability to block the spread of seizures.

Topics: Acoustic Stimulation; Animals; Anticonvulsants; Brain Ischemia; Epilepsy; Fructose; Male; Phenytoin; Rats; Topiramate

The spontaneously epileptic rat (SER), a double mutant, manifests both tonic and absence-like seizures. The effect of topiramate, a novel antiepileptic drug, on the extracellular levels of excitatory amino acids (EAA) in the hippocampus of SER was investigated using in vivo microdialysis. The basal levels of glutamate and aspartate in dialysates of hippocampus in SER were 2- to 3-fold higher than those in normal Wistar rats. Both the dose-response relationship and the time course of the suppression of tonic seizures by topiramate were similar to the attenuation of glutamate level in SER. Topiramate (40 mg/kg i.p.) significantly (P < 0.05) reduced both glutamate and aspartate levels in SER while showing no effect on normal Wistar rats. These findings suggest that topiramate reduces abnormally high extracellular levels of glutamate and aspartate in the hippocampus of SER. This effect may, at least in part, be related to the anticonvulsant activity of topiramate.

Topics: Animals; Anticonvulsants; Aspartic Acid; Epilepsy; Excitatory Amino Acids; Female; Fructose; Glutamic Acid; Hippocampus; Male; Microdialysis; Rats; Rats, Mutant Strains; Rats, Wistar; Topiramate

Topics: Anticonvulsants; Epilepsy; Epilepsy, Absence; Epilepsy, Tonic-Clonic; Fructose; Humans; Topiramate

Topics: Anticonvulsants; Dose-Response Relationship, Drug; Epilepsy; Epilepsy, Absence; Epilepsy, Tonic-Clonic; Fructose; Humans; Topiramate

Topics: Anticonvulsants; Epilepsy; Fructose; Humans; 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