topiramate and Epilepsy--Absence

To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs [AEDs; gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), tiagabine (TGB), oxcarbazepine (OXC), levetiracetam (LEV), and zonisamide (ZNS), reviewed in the order in which these agents received approval by the U.S. 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 to 2003.. Evidence exists, either from comparative or dose-controlled trials, that GBP, LTG, TPM, and OXC have efficacy as monotherapy in newly diagnosed adolescents and adults with either partial or mixed seizure disorders. Evidence also shows that LTG 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 for which more evidence is necessary.

Topics: Acetates; Adolescent; Adult; Age Factors; Amines; Antipsychotic Agents; Carbamazepine; Child; Clinical Trials as Topic; Cyclohexanecarboxylic Acids; Drug Approval; Epilepsies, Partial; Epilepsy, Absence; Epilepsy, Generalized; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Isoxazoles; Lamotrigine; Levetiracetam; Nipecotic Acids; Oxcarbazepine; Piracetam; Tiagabine; Topiramate; Triazines; United States; United States Food and Drug Administration; Zonisamide

Evaluate the antiepileptic effect of topiramate monotherapy in childhood absence epilepsy (CAE).. Childhood absence epilepsy patients aged 4-9 years were initiated with topiramate 15 or 25 mg/day, which was titrated upwards until patients were free of absence seizures. The primary efficacy outcome was seizure-free rates after a 12-week maintenance period.. The study was terminated early due to lack of efficacy after enrollment of 12 patients. Four patients completed the study; two became clinically seizure-free, but without a significant reduction in the number of electrographic seizures. Six patients discontinued for lack of efficacy, none due to adverse events (AEs). Mean reduction in seizure count was seen on Days 22 (P = 0.0391) and 36 (P = 0.0156) and percentage of days with seizures decreased from baseline. Most AEs were mild.. Although well-tolerated, this pilot study did not demonstrate an antiepileptic effect of topiramate monotherapy for treatment of CAE.

Topics: Anticonvulsants; Child; Child, Preschool; Drug Evaluation; Epilepsy, Absence; Female; Fructose; Humans; Male; Pilot Projects; Time Factors; Topiramate

The aim of this study was to evaluate the efficacy and tolerability of topiramate (TPM) in juvenile myoclonic epilepsy (JME).. We assessed seizure control and adverse effects of TPM in 22 patients (18 females) aged 13 to 53 years. Target TPM dosage was up to 200 mg/day. The patients were subdivided into 3 groups: those treated with seizure control plus side effects (n=4); treated with non-controlled seizures (n=15) and with JME newly diagnosed (n=3).. Sixteen patients completed the first year of the follow-up. Generalized tonic-clonic seizures were completely controlled in 10 (62.5%); more than 50% of reduction in 4 (25.0%) and less than 50% in 2 (12.5%). Myoclonia were controlled in 11 (68.8%) and persisted in 5 (31.2%) patients. Absence seizures were present in 5 (22.7%) of whom 2 (9.0%) showed more than 50% of seizure reduction while 3 (13.6%) presented worsening. Discontinuations were due to inadequate seizure control and adverse events (N=4), low compliance and loss of follow-up (N=2) and subject choice (N=1).. TPM showed to be an effective and well-tolerated drug in the treatment of JME. Although frequently observed, TPM side effects were tolerable and the drug could be maintained in the majority of patients.

Topics: Adolescent; Adult; Anticonvulsants; Diagnostic and Statistical Manual of Mental Disorders; Epilepsy, Absence; Epilepsy, Tonic-Clonic; Female; Follow-Up Studies; Fructose; Humans; Male; Middle Aged; Myoclonic Epilepsy, Juvenile; Prospective Studies; Topiramate; Treatment Outcome

Preliminary data concerning the effectiveness of topiramate (TPM) in the management of resistant primary generalized seizures were obtained from the open-label extension of a double-blind, placebo-controlled trial of TPM. The controlled trial enrolled patients experiencing three or more primary generalized tonic-clonic seizures (PGTCS) during an 8-week baseline period. Twelve of 13 patients who completed double-blind treatment elected to receive extended open therapy with TPM and were followed for periods ranging from 2 to 11 months. Of the 12 patients, 11 (92%) experienced a 50% or greater reduction in tonic-clonic seizures during their last 2 months of open-label TPM therapy compared to their pre-double-blind baseline period, and 7 (58%) were seizure-free during the open extension. Of five patients reporting absence seizures at baseline, four (80%) demonstrated a 50% or greater reduction in seizures. In seven of the 12 patients, a concomitant antiepileptic drug (AED) was discontinued or its dosage was reduced during open TPM treatment. The most common adverse events observed in the open study extension were weight reduction (five patients), weight increase (two patients), and drowsiness (two patients). The results of controlled trials are needed to determine the efficacy of TPM in primary generalized seizures. However, these preliminary findings are encouraging.

Topics: Adult; Anticonvulsants; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Epilepsies, Myoclonic; Epilepsy, Absence; Epilepsy, Generalized; Epilepsy, Tonic-Clonic; Female; Fructose; Humans; Male; Middle Aged; Placebos; Topiramate; Treatment Outcome

Lennox-Gastaut syndrome (LGS) is a catastrophic childhood form of epilepsy. The syndrome is characterized by mental impairment, frequent seizures of multiple types that are particularly resistant to treatment, and high rates of seizure-related injury. With the introduction of newer, but more costly, antiepileptic drugs (AEDs), it is important that decision makers are able to assess their value in the management of this rare and difficult-to-treat condition. To evaluate the cost effectiveness, from the UK NHS perspective, of rufinamide in patients with LGS. An individual patient-simulation model was developed to estimate the total treatment-related costs and clinical benefits of rufinamide compared with topiramate and lamotrigine over a 3-year time horizon. The model examines the treatment scenarios of adding rufinamide, lamotrigine or topiramate to older AEDs (standard therapy), or standard therapy alone within a primary-care or community setting. Three placebo-controlled clinical trials of adjunctive AED treatment for children with LGS were analysed. There are no head-to-head comparator studies. Between 98 and 139 patients were randomized in each study and the mean age in each study was 10, 11 and 14 years. A mixed-treatment comparison using a random-effects model was carried out on the number of patients in each response category, using the placebo arms of the respective trials. The primary outcome measure was the percentage of successfully treated patients, defined as >50% reduction in the frequency of total seizures and drop attacks. The hypothesis being tested was formulated after data collection. Costs ( pound, year 2006/07 values) of patient monitoring, switching treatments, hospitalization due to seizure, treatment of adverse effects, and personal and social services were included in the analysis. Results of 10,000 Monte Carlo simulations were bootstrapped to conduct probabilistic sensitivity analysis. Over 3 years, adjunctive rufinamide resulted in higher total costs than topiramate and lamotrigine; however, with more patients being treated successfully, this leads to acceptable incremental cost-effectiveness ratios. If society is prepared to pay at least 250 pounds for a 1% increase in the number of successfully treated LGS patients, in terms of a 50% reduction in the frequency of drop attacks, the probability of the treatment with rufinamide being cost effective is >80%. This cost-effectiveness analysis suggests that rufinamide results in more

Topics: Adolescent; Adult; Anticonvulsants; Child; Child, Preschool; Computer Simulation; Cost-Benefit Analysis; Epilepsy, Absence; Fructose; Health Care Costs; Humans; Infant; Intellectual Disability; Lamotrigine; Models, Economic; Randomized Controlled Trials as Topic; Syndrome; Time Factors; Topiramate; Treatment Outcome; Triazines; Triazoles; United Kingdom

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

The antiepileptic effects of carisbamate were assessed in two models of genetic epilepsy, a model of absence seizures, the Genetic Absence Epilepsy Rat from Strasbourg (GAERS) and a model of convulsive seizures, the Wistar Audiogenic Sensitive (AS) rat.. GAERS were equipped with four cortical electrodes over the frontoparietal cortex and the duration of spike-and-wave discharges (SWD) was recorded for 20-120 min. In Wistar AS, the occurrence of, latency to, and duration of wild running and tonic seizures were recorded.. In GAERS, carisbamate (10, 30, and 60 mg/kg) dose dependently reduced the expression of SWD that totally disappeared at the two highest doses by 40 min after injection. SWD duration returned to control levels by 100 min after the injection of 30 mg/kg carisbamate while SWDs were totally suppressed for 120 min after the injection of 60 mg/kg carisbamate. In Wistar AS, 10 mg/kg carisbamate increased the latency to the first running episode and induced the occurrence of a second running episode in three of eight rats. This episode was not present in untreated rats and was indicative of decreased sensitivity to the stimulus. This dose of carisbamate increased by 327% the latency to the tonic seizure that still occurred in the six of eight rats studied. At 20 and 30 mg/kg, no rats exhibited any wild running or tonic seizure.. The present results support the broad spectrum of antiepileptic activity of carisbamate confirming its efficacy in animal models of primary generalized seizures of both tonic-clonic and of the absence type.

Topics: Animals; Anticonvulsants; Behavior, Animal; Carbamates; Cerebral Cortex; Disease Models, Animal; Dose-Response Relationship, Drug; Electroencephalography; Epilepsy, Absence; Epilepsy, Generalized; Epilepsy, Reflex; Frontal Lobe; Fructose; Male; Motor Activity; Parietal Lobe; Rats; Rats, Wistar; Reaction Time; Species Specificity; Topiramate

The antiepileptic effects of topiramate (TPM) were assessed in two models of genetically determined generalized epilepsy. The model of nonconvulsive epilepsy used was a model of absence seizures, the GAERS (Genetic Absence Epilepsy Rat from Strasbourg); and the model of convulsive seizures was an audiogenic rat model, the Wistar Audiogenic Sensitive (AS) rat.. GAERS were equipped with four cortical electrodes over the frontoparietal cortex, and the duration of spike-and-wave discharges (SWDs) on the EEG was recorded for periods of 20 to 120 or 300 min. In Wistar AS, the occurrence of, latency to, and duration of one or two wild running episodes and tonic seizures were recorded.. In the 16 GAERS studied, TPM (10, 30, and 60 mg/kg) dose-dependently reduced the expression of SWD that almost totally disappeared at the two highest doses between 40 and 120 min. SWD duration returned to control levels by 180 and 280 min after the injection of 30 and 60 mg/kg TPM, respectively. In Wistar AS, 10 mg/kg TPM induced the occurrence of a second running episode not present in control rats, indicative of a decrease in sensitivity of the rats to the stimulus and increased by 330% the latency to the tonic seizure that still occurred in the eight rats studied. At 30 and 60 mg/kg, the latency to wild running increased by 140%; the second running episode was suppressed in six and seven rats, respectively, whereas the tonic seizure occurred only in one of the eight rats studied at these two doses.. These results support the broad spectrum of antiepileptic activity of TPM, confirming its efficacy in primary generalized seizures of both tonic-clonic and of the absence type.

Topics: Animals; Anticonvulsants; Cerebral Cortex; Disease Models, Animal; Dose-Response Relationship, Drug; Electroencephalography; Epilepsy, Absence; Epilepsy, Generalized; Epilepsy, Reflex; Epilepsy, Tonic-Clonic; Evoked Potentials; Fructose; Rats; Rats, Wistar; Topiramate

This open-label, single-site, pilot study evaluated the therapeutic usefulness of topiramate in five children with typical absence seizures defined as loss of awareness associated with 3 Hz spike-wave activity on 24 hour ambulatory electroencephalogram (EEG). The children were previously untreated or treated unsuccessfully using other antiepileptic medication. Topiramate was initiated at a dose of 1 mg x kg (-1)day (-1), titrated twice weekly in 1 mg x kg (-1)day (-1)increments to 12 mg x kg (-1)day (-1)or individual maximally tolerated dose. Response was assessed after 6 weeks with ambulatory EEG monitoring and patient/parent record of seizure counts. All children completed the study. One previously untreated child became seizure-free on 5 mg x kg (-1)day(-1) topiramate, with no residual spike-wave activity at the final visit. In two patients, the frequency of seizures decreased in the early phases of titration, but rose to baseline levels as the topiramate dose was increased. With a reduction in dose to 6 mg x kg (-1)day (-1), seizure control improved, with substantial reductions in spike-wave activity. Seizure counts were not improved in the two remaining patients. Transient mood changes were noted in two patients. No child was withdrawn secondary to adverse effects. The results suggest that topiramate may be effective in childhood absence epilepsy. Controlled studies are now required to identify the clinically optimal dose.

Topics: Anticonvulsants; Child; Electroencephalography; Epilepsy, Absence; Female; Fructose; Humans; Male; Pilot Projects; Topiramate

Absence status epilepsy (ASE) is an uncommon seizure disorder in children. The primary presentation of new-onset ASE in a pediatric patient is an unusual cause of altered mental status in the emergency department. We describe a previously healthy 8-year-old child who presented with an acutely altered mental state. The patient was awake but confused, with a fluctuating level of alertness and an inability to perform simple routine tasks. The results of general physical and neurologic examination, with the exception of mental status, were normal. Head computed tomography and laboratory test results were normal. Electroencephalographic testing revealed seizure activity consistent with ASE. Administration of intravenous diazepam caused cessation of seizure activity and a return to the patient's baseline mental function. Although rare, ASE should be considered in the differential diagnosis of altered mental status in children.

Topics: Anticonvulsants; Child; Diagnosis, Differential; Diazepam; Drug Therapy, Combination; Electroencephalography; Epilepsy, Absence; Female; Fructose; Humans; Mental Status Schedule; Topiramate; Valproic Acid

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: Animals; Anticonvulsants; Clinical Trials as Topic; Disease Models, Animal; Drug Approval; Epilepsy, Absence; Fructose; Humans; Mice; Mice, Mutant Strains; Topiramate

Traditional methods of preclinical screening have predicted the effects of a putative antiepileptic drug (AED) against human absence seizures by testing its efficacy against clonic seizures in the high-dose pentylenetetrazole (PTZ) model. This high-dose PTZ model correctly predicted the efficacy of ethosuximide (ESM), benzodiazepines, and valproate (VPA) and the lack of efficacy of phenytoin (PHT) and carbamazepine (CBZ). However, the high-dose PTZ model erred in predictions for (a) phenobarbital (PB) (PTZ: efficacy; human: nonefficacy); (b) lamotrigine (LTG) (PTZ: nonefficacy; human: efficacy); (c) vigabatrin (VGB) (PTZ: nonefficacy; human: proabsence effect); and (d) tiagabine (TGB) (PTZ: efficacy; human: possible proabsence). It also appears to have erred in predictions for gabapentin (GBP) (PTZ: efficacy) and topiramate (TPM) (PTZ: efficacy). Because the lh/lh genetic model of absence seizures correctly predicted effects of ESM, clonazepam, VPA, PHT, CBZ, and PB against human absence seizures, we performed this study to test the predictive utility of the lh/lh model for LTG, VGB, TGB, GBP, and TPM.. Bipolar recording electrodes were implanted bilaterally into frontal neocortex of 8-week-old male lh/lh mice. With the exception of VGB, vehicle or drugs were administered intraperitoneally (i.p.) on alternating days, and an EEG was used to record effects on seizure frequency. With VGB, vehicle was administered i.p. on day 1, and gradually increasing doses of VGB were administered on successive days. Drug and vehicle effects were compared in corresponding 15-min epochs of the 150-min period after administration.. LTG (4.8-144 micromol/kg) significantly (p < 0.04) reduced seizure frequency (by 65%) compared with vehicle. In contrast, VGB (0.35-11 mmol/kg) and TGB (0.27-27 micromol/kg) significantly increased seizure frequency (300-700%) and seizure duration (1,700-1,800%; p < 0.001). GBP (18 micromol/kg to 1.8 mmol/kg) and TPM (8.9-295 micromol/kg) had no significant effect on seizure frequency.. In contrast to the high-dose PTZ model, the lh/lh model correctly predicted the antiabsence effect of LTG, the possible proabsence effects of VGB and TGB, and the lack of effect of GBP and TPM. The lh/lh model appears to be superior to the high-dose PTZ model in predicting efficacy of putative AEDs against human absence seizures.

Topics: Acetates; Amines; Animals; Anticonvulsants; Cyclohexanecarboxylic Acids; Disease Models, Animal; Drug Evaluation, Preclinical; Electroencephalography; Epilepsy, Absence; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Lamotrigine; Male; Mice; Nipecotic Acids; Tiagabine; Topiramate; Triazines; Vigabatrin

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

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