A randomized, placebo-controlled study of topiramate in primary generalized tonic-clonic seizures

Biton, Victor; Montouris, Georgia; Ritter, Frank J.; Riviello, James J.; Reife, R.; Lim, Pilar; Pledger, Gordon

doi:10.1212/wnl.52.7.1330

Cited by 285 publications

(238 citation statements)

References 16 publications

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“…This response rate, perhaps not surprisingly, was substantially higher than that reported in artificial placebo-controlled, fixed-dose regulatory trials using a patient population with more severe epilepsy (7,(9)(10)(11)20). The slower TPM titration schedule may have contributed to the better outcome.…”

Section: Discussionmentioning

confidence: 65%

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Topiramate in Refractory Epilepsy: A Prospective Observational Study

2000

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Summary:Purpose: This prospective observational study explored the efficacy and tolerability of topiramate (TPM) in patients with refractory epilepsy attending a single outpatient clinic.Methods: 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, 250% 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.Results: 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.Conclusions: 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 doseresponse and dose-toxicity relationships may reflect different neurobiologies causing refractory epilepsy and differential efficacy of AED combinations.

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Section: Discussionmentioning

confidence: 65%

“…Accepted March 15, 2000. TPM has proven efficacy as an add-on therapy for partial-onset, myoclonic, and generalized tonic-clonic seizures in adults and children (7)(8)(9)(10)(11)(12). It may also be useful for Lennox-Gastaut syndrome (13) and infantile spasms (14).…”

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confidence: 99%

Topiramate in Refractory Epilepsy: A Prospective Observational Study

2000

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“…Topiramate (TPM) is a new antiepileptic drug used as adjunctive therapy in refractory partial-onset seizures in adults (Yen et al, 2000), partial-onset seizures in children (Elterman et al, 1999), and generalized tonic-clonic seizures of nonfocal origin (Biton et al, 1999). TPM exhibits neuroprotective properties in several models of injury such as global ischemia (Edmonds et al, 2001), focal ischemia (Yang et al, 2000), or SE (Niebauer and Gruenthal, 1999).…”

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confidence: 99%

Neuroprotective Properties of Topiramate in the Lithium-Pilocarpine Model of Epilepsy

Rigoulot¹,

Koning²,

Ferrandon³

et al. 2003

J Pharmacol Exp Ther

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The lithium-pilocarpine model reproduces the main characteristics of human temporal lobe epilepsy. After status epilepticus (SE), rats exhibit a latent seizure-free phase characterized by development of extensive damage in limbic areas and occurrence of spontaneous recurrent seizures. Neuroprotective and antiepileptogenic effects of topiramate were investigated in this model. SE was induced in adult male rats by LiCl (3 mEq/kg) followed 20 h later by pilocarpine (25 mg/kg). Topiramate (10, 30, or 60 mg/kg) was injected at 1 and 10 h of SE. Injections were repeated twice a day for six additional days. Another group received two injections of diazepam on the day of SE and of vehicle for 6 days. Neuronal damage was assessed at 14 days after SE by cell counting on thionin-stained sections. Occurrence of spontaneous recurrent seizures (SRS) was videorecorded for 10 h per day in other groups of rats. In diazepam-treated rats, the number of neurons was dramatically reduced after SE in all subregions of hippocampus and layers II-IV of ventral cortices. At all doses, topiramate induced a 24 to 30% neuroprotection in layer CA1 of hippocampus (p Ͻ 0.05). In CA3b, the 30-mg/kg dose prevented neuronal death. All rats subjected to SE became epileptic. The latency (14 -17 days) to and frequency of SRS were similar in topiramate-and diazepam-treated rats. The high mortality in the 30 mg/kg topiramate group (84%) was possibly the result of interaction between lithium and topiramate. In conclusion, topiramate displayed neuroprotective properties only in CA1 and CA3 that were not sufficient to prevent epileptogenesis.

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“…It is one of the most powerful of the new AEDs, effective in a wide variety of seizure types (5)(6)(7)(8)(9). TPM may become useful in the management of headache, mood disorders, and pain (10)(11)(12).…”

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confidence: 99%

Topiramate Rapidly Raises Brain GABA in Epilepsy Patients

Petroff¹,

Hyder

Rothman

et al. 2001

Epilepsia

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Summary: Purpose:The short-and long-term pharmacodynamic effects of topiramate (TPM) on brain ␥-aminobutyric acid (GABA) metabolism were studied in patients with complex partial seizures.Methods: In vivo measurements of GABA, homocarnosine, and pyrrolidinone were made of a 14-cc volume in the occipital cortex using 1 H spectroscopy with a 2.1-Tesla magnetic resonance spectrometer and an 8-cm surface coil. Fifteen patients (four men) were studied serially after the first, oral dose (100 mg) of TPM.Results: The first dose of TPM increased brain GABA within 1 h. Within 4 h, GABA was increased by 0.9 mM (95% CI, 0.7-1.1). Brain GABA remained elevated for Ն24 h. Pyrrolidinone and homocarnosine increased slowly during the first day. Daily TPM therapy (median, 300 mg; range, 200-500) increased GABA (0.3 mM; 95% CI, 0.1-0.5), homocarnosine (0.4 mM; 95% CI, 0.3-0.5), and pyrrolidinone (0.15 mM; 95% CI, 0.10-0.19), compared with levels before TPM. There was no dose response evident with daily TPM doses of 200-500 mg.Conclusions: TPM promptly elevates brain GABA and presumably offers partial protection against further seizures within hours of the first oral dose. Patients may expect to experience the effects of increased homocarnosine and pyrrolidinone within 24 h.

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A randomized, placebo-controlled study of topiramate in primary generalized tonic-clonic seizures

Abstract: Topiramate is well-tolerated and effective for the adjunctive treatment of PGTC seizures.

Cited by 285 publications

References 16 publications

Topiramate in Refractory Epilepsy: A Prospective Observational Study

Topiramate in Refractory Epilepsy: A Prospective Observational Study

Neuroprotective Properties of Topiramate in the Lithium-Pilocarpine Model of Epilepsy

Topiramate Rapidly Raises Brain GABA in Epilepsy Patients

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