Topiramate Monotherapy Research Articles

Efficacy, tolerability, and safety of rapid initiation of topiramate versus phenytoin in patients with new‐onset epilepsy: A randomized double‐blind clinical trial

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.

Anthropometric indexes, insulin resistance, and serum leptin and lipid levels in women with cryptogenic epilepsy receiving topiramate treatment

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 ± 7.1 years) with cryptogenic epilepsy. Body mass index (BMI), waist circumference and serum leptin, insulin and lipid levels were measured at baseline and at 6 months 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.

Seizure and Cognitive Outcomes in Children and Adolescents with Epilepsy Treated with Topiramate

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.

Antiepileptics in brain metastases: safety, efficacy and impact on life expectancy

The aim of the study was to evaluate efficacy, safety and impact on life expectancy of levetiracetam (LEV), oxcarbazepine (OXC) and topiramate (TPM) monotherapy in patients with seizures related to brain metastases. We conducted a prospective observational study on 70 patients with brain metastases. Thirteen patients were excluded because they were in prophylactic therapy with antiepileptics, nine patients did not return to our Center. A total of 48 patients with epilepsy related to brain metastases were enrolled. Patients were treated with LEV, OXC and TPM in monotherapy and followed until their death. Eighteen patients dropped out. Therefore, we followed 30 patients. Mean duration of follow-up was 6.1 months. Upon visiting the patients prior to their death (i.e. last visit preceding the death of the patients), we observed a significant reduction (P < 0.001) in the mean monthly seizure frequency; with 19 patients (63.3%) obtaining complete seizure control in the whole population. A significant improvement of seizure frequency was also observed considering each antiepileptic treatment group separately. Median survival time was similar among the three groups of patients and was similar to Class I of prognostic factors of Radiation Therapy Oncology Group. Logistic regression showed that systemic treatments did not influence the antiepileptics' efficacy on seizure control (P = 0.614). In conclusion, regarding the use of newer antiepileptics in patients with seizures related to brain metastases, our data indicate that LEV, OXC and TPM significantly reduce seizure frequency (independently of systemic treatment), produce few side effects and appear not to affect life expectancy.

Topiramate concentrations in neonates treated with prolonged whole body hypothermia for hypoxic ischemic encephalopathy

Therapeutic hypothermia reduces mortality and neurologic impairment in neonates with hypoxic-ischemic encephalopathy. Topiramate exerts a neuroprotective effect in asphyxiated neonatal animal models. However, no studies have investigated the association of hypothermia and topiramate, because topiramate pharmacokinetics during hypothermia and the optimal administration schedule are unknown. The influence of hypothermia on topiramate pharmacokinetics was evaluated in asphyxiated neonates treated with prolonged whole-body hypothermia and topiramate. Thirteen term newborns were treated with mild or deep whole body hypothermia for 72 h; all received oral topiramate, 5 mg/kg once a day for the first 3 days of life, and seven had concomitant phenobarbital treatment. Topiramate concentrations were measured on serial dried blood spots. Topiramate concentrations were within the reference range in 11 of 13 newborns, whereas concentrations exceeded the upper limit in 2 of 13, both newborns on deep hypothermia. Topiramate concentrations reached a virtual steady state in nine newborns, for whom pharmacokinetic parameters were calculated. Values of topiramate maximal and minimal concentration, half-life, average concentration, and area under the time-concentration curve resulted in considerably higher values than those reported in normothermic infants. With respect to normothermic infants, time of maximal concentration was mildly delayed and apparent total body clearance was lower, suggesting slower absorption and elimination. Pharmacokinetic parameters did not differ significantly between infants on deep versus mild hypothermia and in those on topiramate monotherapy versus add-on phenobarbital. Most neonates on prolonged hypothermia treated with topiramate 5 mg/kg once a day exhibited drug concentrations within the reference range for the entire treatment duration.

Comparison of Open-Label, 8-Week Trials of Olanzapine Monotherapy and Topiramate Augmentation of Olanzapine for the Treatment of Pediatric Bipolar Disorder

The aim of this study was to test the efficacy and safety of olanzapine + topiramate versus olanzapine monotherapy in the treatment of bipolar disorder (BPD) and treatment-attendant weight gain in children and adolescents. Subjects (N = 40) were outpatients of both sexes, 6-17 years of age, with a Diagnostic and Statistical Manual of Mental Disorders, 4(th) edition (DSM-IV) diagnosis of BPD (manic, hypomanic, or mixed) and Young Mania Rating Scale (YMRS) total score of >15 treated over 8-week periods in two partially concurrent open-label trials with olanzapine (n = 17) or olanzapine + topiramate (n = 23). Subjects in both groups experienced a statistically significant reduction in YMRS scores after 8-week, open-label treatment with olanzapine (baseline YMRS = 26.7 +/- 9.5; end-point YMRS = 18.2 +/- 12.5, p = 0.04) and olanzapine +topiramate (baseline YMRS = 31.3 +/- 7.9; end-point YMRS = 20.4 +/- 11.4, p = 0.04). There was no difference in response between the two groups based on YMRS or Clinical Global Impressions-Improvement (CGI-I) scores. Adverse events were few and mild and similar between the two groups, with the exception of weight gain. The weight gain in the olanzapine group was 5.3 +/- 2.1 kg and the weight gain in the olanzapine + topiramate group was statistically significantly lower, 2.6 +/- 3.6 kg. Augmentation of olanzapine with topiramate resulted in a reduced weight gain over the course of an 8-week, open-label trial when compared with olanzapine treatment alone, but did not lead to greater reduction in symptoms of mania.

Topiramate Monotherapy in Epilepsy

The dosing, effectiveness, patient characteristics predictive of effectiveness, and safety of topiramate monotherapy in treatment of epilepsy were evaluated in a 6-month, multicenter, open-label study at UCLA School of Medicine, Mattel Children's Hospital, Los Angeles; and University of Miami School of Medicine, FL.

A multicenter, outpatient, open-label study to evaluate the dosing, effectiveness, and safety of topiramate as monotherapy in the treatment of epilepsy in clinical practice

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.

Urolithiasis With Topiramate in Nonambulatory Children and Young Adults

Urolithiasis occurs infrequently in the pediatric population, where metabolic factors play a primary role in the pathogenesis of stone formation. Topiramate, an antiepileptic drug, is associated with a kidney stone in 1.5% of patients in published clinical trials. However, this risk may be much higher in certain populations with multiple preexisting risk factors. We performed a retrospective review of all nonambulatory and neurologically impaired individuals in a long-term care facility. Three groups were involved: those with no exposure to antiepileptic drugs, those on antiepileptic drugs other than topiramate, and those who had been treated with topiramate. Thirteen of 24 (54%) individuals on topiramate monotherapy or polytherapy developed clinical evidence of urolithiasis after a mean duration of 36.4 months. Our results suggest that nonambulatory and neurologically impaired individuals in a long-term care facility appear to be at higher risk of developing kidney stones with topiramate than previously reported.

Serum concentration/dose ratio of topiramate during pregnancy

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.

Topiramate and Adrenocorticotropic Hormone (ACTH) as Initial Treatment for Infantile Spasms

Historically, adrenocorticotropic hormone was used as a first-line treatment for infantile spasms; however, there has been increasing use of topiramate as initial therapy. Here, we report a retrospective study of adrenocorticotropic hormone (ACTH) and topiramate as initial treatment for infantile spasms. The neurology patient database at the Children's Hospital of Philadelphia was searched using the International Classification of Diseases, Ninth Revision code for infantile spasms, and 50 patients were randomly chosen for chart review. We identified 31 patients receiving either adrenocorticotropic hormone or topiramate monotherapy (adrenocorticotropic hormone n = 12, topiramate n = 19) as a first-line treatment for infantile spasms. A total of 26 patients were symptomatic and 5 cryptogenic. Six patients treated with adrenocorticotropic hormone had resolution of clinical spasms and hypsarrhythmia within a month, but 3 relapsed. Of the 19 patients treated with topiramate, 4 patients eventually, though over a period of 0, 1, 8, or 69 months, had resolution of spasms and hypsarrhythmia.

Teratogenicity and hyperprolactinemia

Byline: Chittaranjan. Andrade CME Questions A) Drugs should be prescribed with caution to women of childbearing age because of the risk of teratogenicity, should conception occur during treatment; this concern is particularly important when prescribing drugs that will be required for long periods, such as in the maintenance therapy of epilepsy, bipolar disorders, neuropathic pain, and migraine. Topiramate and valproate are sometimes prescribed as maintenance medications for certain or all of these indications. With this background, mark True or False against each of the following statements: *Topiramate monotherapy is safe during pregnancy. *The use of topiramate along with other antiepileptic drugs is associated with an unacceptably high teratogenic risk. *Valproate is one of the most teratogenic medications used in psychiatry. *The teratogenicity of valproate is substantially higher when the drug is used in combination with other antiepileptic medications. *The teratogenic risk of valproate is dose-dependent. *Valproate is teratogenic only during weeks 6-12 of gestation. *Exposure to valproate during pregnancy can be associated with low IQ in the offspring. B) Hyperprolactinemia is a common problem with different antipsychotic drugs. Hyperprolactinemia may lead to many adverse consequences, and may thereby jeopardize drug compliance. With this background, mark True or False against each of the following statements: *The normal prolactin level is 25 ng/ml and above. *Hyperprolactinemia may result in increased libido. *Hyperprolactinemia may result in osteoporosis. *Hyperprolactinemia is uncommon with paliperidone. *Aripiprazole augmentation reverses antipsychotic-induced hyperprolactinemia. View Answer CME Answers A) Teratogenicity Answers: 1. False; 2. True; 3. True; 4. True; 5. True; 6. False; 7. True. 1. Topiramate monotherapy during pregnancy Topiramate is a well-established teratogen in animals such as mice, rats, and rabbits. One study[sup] [1] examined the effects of first-trimester topiramate exposure in 52 pregnancies with 41 liveborn infants. Topiramate was observed to reduce birth weight without decreasing gestational age at delivery; there was no increase in the risk of structural birth defects. However, another larger and methodologically superior study[sup] [2] documented substantial teratogenicity with the drug. This study used data from the UK Epilepsy and Pregnancy Register. The subjects were 203 women with epilepsy who had been exposed to topiramate as monotherapy ( n =70) or as part of polytherapy ( n =133) during the first trimester of pregnancy, and who had been referred before the outcome of pregnancy was known. There were 178 live births; the risk of major congenital malformations with topiramate was 9% (95% CI, 5.6%-14.1%) in the entire sample, and 4.8% with topiramate monotherapy. In this context, studies suggest that the risk of major malformations is 2.7-3.5% in epileptic women who do not use antiepileptic drugs during pregnancy, and those who use antiepileptic drugs in monotherapy.[sup] [3],[4] 2. Teratogenicity of topiramate combined with other antiepileptic drugs In the UK Epilepsy and Pregnancy Register study[sup] [2] referred to above, major congenital malformations were more common in women exposed to topiramate combined with other antiepileptic agents (11.2%) than in those exposed to topiramate monotherapy (4.8%) during the first trimester of pregnancy. The highest risk of major malformations was when topiramate was used along with valproate (36%), or along with two or more other antiepileptic drugs (24%). Also, in women receiving topiramate in polytherapy, smallness for gestational age was associated with a higher dose of the drug. 3. Teratogenicity of valproate in monotherapy Data from the North American Antiepileptic Drug Pregnancy Registry,[sup] [4] the UK Epilepsy and Pregnancy Register,[sup] [3] and the Israeli Teratology Information Service database[sup] [5] suggest that the risk of major congenital malformations is 6-11% after first trimester exposure to valproate monotherapy. …

Efficacy of Topiramate in Adult Patients with Symptomatic Epilepsy

Topiramate is a newer generation antiepileptic drug with a wide range of antiepileptic efficacy as monotherapy or as adjunctive therapy, and which has shown positive activity in intractable epilepsy and newly diagnosed epilepsy. Topiramate has also been shown to exert good seizure control with a low incidence of adverse effects in brain tumour-associated epilepsy. However, there have been few reports on the efficacy of topiramate in the treatment of symptomatic epilepsy of varying aetiologies. The aim of the present study was to evaluate the efficacy of topiramate in the treatment of adult patients with symptomatic epilepsy of various aetiologies. This was an open-label, long-term, retrospective observation. 227 patients with symptomatic epilepsy (110 male, 117 female) were enrolled into this study. The underlying aetiologies included low-grade brain tumour, head trauma, cerebrovascular diseases, infection, diabetes mellitus, hydrocephalus and parasitosis. Topiramate was titrated up to a target dosage of 200 mg/day and maintained for at least 1 year. Response to topiramate was defined as > or = 50% reduction in seizure frequency compared with baseline. Seizure free was defined as no seizure occurring during 1 year of topiramate therapy. 157 (69.2%) patients were responders and 124 (54.6%) patients were seizure free with topiramate administration. Responders by subgroup included 40 patients (74.0%) with low-grade brain tumour, 32 (55.2%) with trauma, 30 (90.9%) with cerebrovascular disease, 21 (55.3%) with infection, 18 (81.8%) with diabetes, 12 (85.7%) with parasitosis and 4 (50.0%) with hydrocephalus. The percentage of seizure-free patients by subgroup was 61.0% with brain tumours, 31.0% with trauma, 78.8% with cerebrovascular disease, 44.7% with infection, 59.0% with diabetes, 85.7% with parasitosis and 50.0% with hydrocephalus. The incidence of adverse effects was 36.1%. The most commonly reported adverse effects were weight loss, memory impairments, paraesthesia, headache and dizziness; most were mild to moderate in severity and transient. Sixty-eight (30.0%) patients withdrew from topiramate treatment in this study: topiramate was discontinued in 56 patients because of lack of efficacy and in 12 patients because of adverse effects. At the end of the study, 109 patients received topiramate monotherapy, including 52 newly diagnosed patients and 57 subjects who transferred to topiramate monotherapy successfully; another 118 patients received add-on topiramate therapy. The percentage of patients responding to topiramate was 85.3% in the monotherapy group and 54.2% in the topiramate add-on therapy group; the percentage of seizure-free patients was 68.8% in the topiramate monotherapy group and 41.5% in the topiramate add-on therapy group. When administered either as a single drug or as an add-on drug, topiramate is effective and well tolerated in adult patients with symptomatic epilepsy of various aetiologies.

Conversion from valproic acid onto topiramate in adolescents and adults with epilepsy

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.

Are Migraineurs at Increased Risk of Adverse Drug Responses?: A Meta-Analytic Comparison of Topiramate-Related Adverse Drug Reactions in Epilepsy and Migraine

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.

Long-term treatment with topiramate monotherapy in epilepsy

Methods: Subjects with a diagnosis of epilepsy (ILAE, 1989) who had completed one of two recent trials with topiramate (TOP-GER-5 and TOP-GER-12) were eligible for this 12-month prospective, non-interventional trial. Patients were evaluated during their previous trial and after 3, 6, 9, and 12 months during this trial (seizure frequency, adverse events [AE]). A post-hoc gender-based analysis was added.

Topiramate monotherapy as broad-spectrum antiepileptic drug

Objective: To explore seizure outcomes and tolerability of topiramate (TPM) in mono- or conversion to monotherapy in patients with recently diagnosed epilepsy (epilepsy duration ≤3 years).

Acute encephalopathy with biphasic seizures and late restricted diffusion on MRI in a Japanese child living in the USA

We report an 18-month-old Japanese female living in the USA whose clinical course and radiographic findings were consistent with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD). She was initially diagnosed with complex febrile seizures. However, on day 3 of admission, she had a cluster of complex partial seizures and the onset of a global developmental regression. In contrast to the normal magnetic resonance image of the brain obtained on admission, subsequent imaging demonstrated transient subcortical diffusion-weighted abnormalities in the white matter of the bilateral posterosuperior frontal, parietal, temporal, and occipital regions, with sparing of the perirolandic area. One year later, her developmental delay, although improved, persisted and she continued to experience sporadic seizures while being treated with topiramate monotherapy. Repeat imaging showed diffuse, poorly defined, increased T2 signals in the white matter of the posterosuperior frontal, parietal, temporal and occipital regions and diffuse cerebral volume loss. Previous reports of AESD have been limited to children aged under 4 years living in Japan. With the identification of this case, it is important that all physicians, not only those in Japan, who care for children with febrile seizures be aware of AESD and its associated neurological morbidity.

Topiramate monotherapy in the treatment of newly or recently diagnosed epilepsy

Background: 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. Objective: This article reviews available evidence for the use of TPM as monotherapy in patients with newly or recently diagnosed epilepsy. Methods: 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 ≥20 patients. Results: 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%). Conclusion: In the 3 studies reviewed, TPM monotherapy was effective and generally well tolerated in patients with newly diagnosed epilepsy.

Is Topiramate Tops?

Topiramate Monotherapy in Newly Diagnosed Epilepsy in Children and Adolescents. Glauser TA, Dlugos DJ, Dodson WE, Grinspan A, Wang S, Wu SC; EPMN-106/INT-28 Investigators. J Child Neurol 2007;22(6):693–699. A double-blind, dose-controlled study evaluated topiramate as monotherapy in 470 patients with newly diagnosed (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.