Oxcarbazepine: double-blind, randomized, placebo-control, monotherapy trial for partial seizures

OBJECTIVE: To evaluate the efficacy and safety of oxcarbazepine in a placebo-control trial. METHODS: A multicenter, double-blind, randomized, placebo-control, two-arm parallel group, monotherapy design was used to compare oxcarbazepine administered 1,200 mg twice daily to placebo in hospitalized patients with refractory partial seizures, including simple and complex partial seizures and partial seizures evolving to secondarily generalized seizures. Patients exited the trial after completing the 10-day double-blind treatment phase or after experiencing four partial seizures, two new-onset secondarily generalized seizures, serial seizures, or status epilepticus, whichever came first. RESULTS: Analysis of the primary efficacy variable--time to meeting one of the exit criteria--showed a statistically significant effect in favor of oxcarbazepine (p = 0.0001). The secondary efficacy variables--percentage of patients who met one of the exit criteria (p = 0.0001) and total partial seizure frequency per 9 days during the double-blind treatment (p = 0.0001)--were also statistically significant in favor of oxcarbazepine. CONCLUSION: These results demonstrate that oxcarbazepine given as monotherapy is effective and safe for the treatment of partial seizures in this paradigm.     

Lamotrigine in typical absence epilepsy.

Lamotrigine (LTG) is an anti-epileptic drug effective in partial seizures and generalized epilepsy. There is growing evidence of the usefulness of LTG in childhood (CAE) orjuvenile (JAE) absences resistant to previous treatment. In this study all patients were identified using strict diagnostic criteria and subdivided into two groups. (1) Eight patients affected by absence seizures resistant to valproic acid or ethosuximide, received LTG as an-add-on therapy, (2) seven patients affected by typical absence seizures not previously treated, received LTG monotherapy after the diagnosis. In the patients with resistant absence seizures, a full control of seizures was obtained. In five of them, after a mean period of 12.5 months, the previous anti-epileptic drugs were withdrawn leaving the patients on LTG monotherapy. In one patient, absences relapsed and valproic acid was therefore added again to LTG to regain control of the seizures. In six of the seven patients on LTG monotherapy after the diagnosis, a full control of seizures was obtained. In the seventh patient the drug was stopped due to a skin rash. In conclusion LTG appears to be effective in resistant absence seizures in combination with valproic acid. Moreover, our preliminary data suggest that lamotrigine might be used as monotherapy in typical absence seizures. The advantages and disadvantages of LTG monotherapy in this type of epilepsy are discussed.     

Efficacy of zonisamide: our experience

The current overview of zonisamide use and effectiveness is based on both a long-term prospective postmarketing survey and current zonisamide use at the Saitama Medical College, Department of Neuropsychiatry. Survey data, which were collected from individual physicians and 23 survey groups throughout Japan, assessed the effectiveness of zonisamide in 1631 patients. Zonisamide was highly effective for treating partial seizures, with 70% of patients reporting improvement. More than half of patients with generalized seizures (58%) and half of patients with myoclonic and atypical absence seizures showed improvement with zonisamide treatment. Among the different epileptic syndromes, zonisamide was highly effective in treating generalized idiopathic epilepsy (≥78% improvement) and partial epilepsy (≥58% improvement). However, only 28% of patients with West syndrome or Lennox-Gastaut syndrome showed improvement. Among 60 outpatients treated with zonisamide at our facility as of October 1998, most had partial seizures or generalized seizures subsequent to partial seizures. The majority of patients received zonisamide in combination with other antiepilepsy drugs. Patients receiving zonisamide monotherapy showed greater improvement than did patients receiving polytherapy. We conclude that zonisamide is highly effective for partial seizures and generalized seizures, and that there appears to be no decrease in efficacy with long-term use.     

Vigabatrin as add-on therapy for adult complex partial seizures: a double-blind, placebo-controlled multicentre study. The Canadian Vigabatrin Study Group.

Vigabatrin (VGB) is a novel antiepileptic drug effective as adjunctive therapy in patients with partial seizures. In this study, the efficacy and tolerability of VGB as adjunctive therapy were evaluated in patients with refractory epilepsy. Adult patients with a definite diagnosis of complex partial seizures and/or partial seizures secondarily generalized were recruited from 10 Canadian centres. Patients were randomized to receive either active medication or placebo in a double- blind fashion and entered a 36-week titration and maintenance phase with regularly scheduled visits. Both efficacy parameters and safety assessments were monitored. Clinical laboratory, evoked potential studies, MRI, and neuropsychological tests were also performed. Forty-eight percent of VGB-treated patients vs. 26 percent of placebo-treated patients had a 50 percent or greater reduction in the frequency of complex partial seizures and partial seizures secondarily generalized. Vigabatrin was well tolerated by the majority of patients. Minor neurological side effects were observed in a number of patients in both treatment groups. No serious systemic toxicity was observed. No changes in evoked potential studies or MRI findings were noted. Vigabatrin was found to be an effective and well-tolerated antiepileptic drug when used as adjunctive therapy in patients with difficult to control complex partial seizures and for partial seizures secondarily generalized. Vigabatrin is a selective irreversible inhibitor of the GABA- degradating enzyme GABA transaminase and has shown efficacy in a number of clinical trials in patients with difficult to control partial seizures. Vigabatrin has been found most effective against complex partial and secondarily generalized tonic-clonic seizures in both adults and children. Vigabatrin has also been shown to reduce infantile spasms secondary to various aetiologies and is most effective in spasms associated with tuberous sclerosis. The aim of this study was to further extend the clinical experience with VGB as adjunctive therapy in the treatment of adult patients with difficult to control complex partial seizures and/or partial seizures secondarily generalized. In addition to the assessments of efficacy and tolerability to VGB, neuropsychological evaluations were also carried out.     

A Comment on the Efficacy of Valproate in the Treatment of Partial Seizures

Summary: Discrepancies in the findings of studies sponsored by the Department of Veterans Affairs (VA) in the United States and the Medical Research Council (MRC) in the United Kingdom concerning the efficacy of valproate (VPA) in controlling simple or complex partial seizures, particularly those without secondarily generalized seizures, were reviewed. It was noted that the two studies differed with respect to their subjects' pretreatment seizure frequency. The frequency of complex partial seizures before treatment was obviously greater in the VA study, where carbamazepine (CBZ) provided better seizure control than VPA. Based on other comparative and non-comparative studies as well as the author's over 20 years of experience in the use of VPA in a tertiary epilepsy clinic, it is suggested that although VPA may be effective in controlling both the secondarily generalized seizures of symptomatic localization-related epilepsies and the generalized tonic-clonic seizures of idiopathic and. if not always, symptomatic generalized epilepsies, the efficacy of VPA in controlling simple or complex partial seizures is likely limited to patients with infrequent seizures.     

Zonisamide – a review of experience and use in partial seizures

Zonisamide is a modern antiepileptic drug (AED) that is distinguished from other AEDs by its unique structure and broad mechanistic profile. Preclinical studies have reported a range of potential mechanisms of action for zonisamide, such as blocking voltage-gated sodium channels, reduction of T-type calcium channel currents, and enhancement of gamma-aminobutyric acid (GABA)-mediated inhibition, which are indicative of its broad antiseizure effects. Zonisamide has a favorable linear pharmacokinetic profile, a long half-life, and a low incidence of protein-binding interactions with other AEDs. Hepatically metabolized through the cytochrome P450 pathway, zonisamide does not induce its own metabolism or liver enzymes. For more than 2 decades, zonisamide has been extensively used as monotherapy and adjunctive therapy for the treatment of partial and generalized seizures in pediatric and adult patients in Japan. Zonisamide was approved in the USA in 2000 as adjunctive therapy for partial seizures in adults. With over 2 million patient-years of exposure internationally, zonisamide has demonstrated safety and efficacy against a multitude of epilepsy and seizure types, including both partial and generalized seizures. This review focuses on the experience and use of zonisamide in partial seizures, as well as possible new uses for zonisamide.     

左乙拉西坦单药治疗80例成人癫癎的疗效及安全性

目的：评价左乙拉西坦单药治疗各种类型成人癫癎的疗效和安全性.方法：80例各类型新诊断的成人癫癎患者,口服左乙拉西坦治疗,随访1年,观察治疗后患者癫癎发作次数变化及不良反应发生率.结果：左乙拉西坦单药治疗成人癫癎的总有效率为75.0%;对部分性发作可能更为有效,有效率为77.08 %;不良反应发生率为16.3%.因疗效不佳退出为18.75%.结论：在单药治疗成人癫癎中,左乙拉西坦是一种安全有效的抗癫药物,且对部分性和全面性癫癎发作均有效.     

Reflex occipital lobe epilepsy.

Photosensitivity is a typical feature of photosensitive epilepsy which is usually considered a form of idiopathic generalized epilepsy. Partial seizures featuring visual symptoms are rarely reported in photosensitive epilepsy. In this study, we describe 13 neurologically normal patients in whom daytime seizures were always induced by television and began with elementary visual hallucinations, followed frequently by vomiting, headache and then secondary generalization. Three patients additionally reported nocturnal seizures, which have not been described in previous studies. Two of these latter patients had generalized tonic-clonic seizures, the other always awoke from sleep and could describe typical visual hallucinations at the beginning of the seizure. EEG features included normal background activity and occipital spikes or spike-waves in all but two patients. Eight patients also showed generalized epileptiform activity during intermittent photic stimulation. Seizure frequency was low in all. Apart from two patients, who refused treatment, all patients received antiepileptic drugs. Only one patient continued to have rare seizures after treatment; in the others seizure control was achieved with monotherapy. We conclude that reflex occipital lobe epilepsy is an idiopathic form of the benign partial epilepsies, which may overlap with one another.     

Conversion to valproate monotheraphy in nonretarded adults with primary Generalized tonic-clonic seizures

Studies have demonstrated improved seizure control with fewer side effects when multidrug regimens are converted to valproate monotherapy. We studied 71 nonretarded adults, a group often unwilling to risk changes, with primary generalized tonic-clonic seizures. Their antiepileptic treatment was changed from treatment with one or more antiepileptic medicines to valproate monotherapy because of uncontrolled seizures or unacceptable side effects of the original regimen; 77% were successfully converted. Of those, 71% became seizure-free or had a >50% reduction in seizure frequency. The most frequent side effects of valproate were tremor, weight gain, and initial gastrointestinal irritation. Side effects were usually mild and interfered with the patient's quality of life less than those that prompted treatment conversion (sedation, gingival hypertrophy, cognitive dysfunction). One case of Reyes-like syndrome developed, but the patient recovered fully after valproate was discontinued. We concluded that conversion to valproate monotherapy is safe and effective for most treatment-resistant adults with primary generalized tonic-clonic seizures.     

Monotherapy for partial epilepsy: focus on levetiracetam

Levetiracetam (LEV), the S-enantiomer of alpha-ethyl-2-oxo-1-pyrollidine acetamide, is a recently licensed antiepileptic drug (AED) for adjunctive therapy of partial seizures. Its mechanism of action is uncertain but it exhibits a unique profile of anticonvulsant activity in models of chronic epilepsy. Five randomized, double-blind, placebo-controlled trials enrolling adult or pediatric patients with refractory partial epilepsy have demonstrated the efficacy of LEV as adjunctive therapy, with a responder rate (>/=50% reduction in seizure frequency) of 28%-45%. Long-term efficacy studies suggest retention rates of 60% after one year, with 13% of patients seizure-free for 6 months of the study and 8% seizure-free for 1 year. More recent studies illustrated successful conversion to monotherapy in patients with refractory epilepsy, and its effectiveness as a single agent in partial epilepsy. LEV has also efficacy in generalized epilepsies. Adverse effects of LEV, including somnolence, lethargy, and dizziness, are generally mild and their occurrence rate seems to be not significantly different from that observed in placebo groups. LEV also has no clinically significant pharmacokinetic interactions with other AEDs, or with commonly prescribed medications. The combination of effective antiepileptic properties with a relatively mild adverse effect profile makes LEV an attractive therapy for partial seizures.     

Mono- or polytherapy and the severity of epilepsies

1. Out of 295 outpatients who were followed up by our staff for longer than 4 years, a total of 196 patients was subjected to this retrospective study. The inclusion criterion was that they had inevitably been placed on polytherapy of two or more anti-epileptic drugs (AEDs). In other words, they had failed to reach monotherapy for some reasons. 2. One of the determinant factors for the success or failure of monotherapy was the type of epilepsies. Namely, primary generalized epilepsy (PGE) was relatively easy to attain by monotherapy regardless of the seizure type, whereas secondary generalized epilepsy (SGE) with combined seizures and secondary partial epilepsy (SPE) with mixed seizures were not infrequently difficult to be placed on a monotherapy regimen. In the latter case, however, an abrupt withdrawal of AEDs was apt to cause an exacerbation of seizures. 3. There were some patients who could reach a complete freedom from seizures as a result of bi- or polytherapy and became socially adaptable and acceptable. They themselves are, if not all, afraid of a possible relapse of seizures produced by a reduction in the number of AEDs hitherto prescribed. In some cases, a family member may refuse monotherapy, or even physicians are reluctant to switch to monotherapy because the patients have experienced status epilepticus in the past.(ABSTRACT TRUNCATED AT 250 WORDS)     

Selective mutism and obsessive compulsive disorders associated with zonisamide.

We treated 27 children with idiopathic epilepsy with zonisamide monotherapy over a period of 2 years and observed behaviour disturbances in a prospective study. In all cases, seizure control was excellent; however, two cases (7.4%) had behaviour disturbances. The first (Case 1) was a 14-year-old girl with partial epilepsy which began at age 4 years. Zonisamide was administered at age 6 years, which was effective against her seizures, but selective mutism, violent behaviour, and lack of concentration developed at age 10 years. The second (Case 2) was a 15-year-old girl with generalized tonic-clonic seizures which began at age 10 years. Zonisamide was also effective against her seizures, but obsessive compulsive disorders (OCD) developed at age 13 years. The patients have had no other physical or mental problems and decreasing the dosage of zonisamide reduced the problems. There are few reports of behaviour disturbances provoked by zonisamide monotherapy in epileptic children who are neither physically nor mentally disturbed. While problems can develop several years later, in the present study, decreasing the zonisamide dosage maintained adequate prevention of seizures and eliminated the behaviour disturbances. Zonisamide is still a useful anticonvulsant for epileptic seizures, but physicians should be wary of its adverse behavioural side effects, which may arise several years later.     

New statistical method for analyzing time to first seizure: example using data comparing carbamazepine and valproate monotherapy

INTRODUCTION: Time to first seizure is a common outcome in antiepileptic drug (AED) studies. Previous studies have typically failed to find statistically significant differences between carbamazepine (CBZ) and valproate (VPS). We re-analyzed a meta-analysis comparing CBZ and VPS monotherapy with new powerful statistical methods that incorporate baseline seizure rate information. Methods: Individual patient data were available on 1,265 patients from a meta-analysis of five trials. The outcome measure was time to first seizure after randomization, adjusted for background variables and baseline seizure rate. RESULTS: We found strong evidence of an interaction between treatment and epilepsy type, and between treatment and age. For generalized onset seizures, VPS was statistically significantly better than CBZ: VPS delayed the first seizure after treatment 58%, 52%, 44%, and 36% longer than CBZ for individuals aged 10, 20, 30, or 40, respectively. For partial onset seizures in individuals older than 30, CBZ was significantly better then VPS; CBZ delayed the time to first seizure by 9%, 25%, 44%, and 66% longer than VPS for individuals aged 20, 30, 40, or 50, respectively. CONCLUSION: The results show clear age-varying differences between the effectiveness of CBZ and VPS for generalized onset and partial onset seizures, which have not been identified in previous studies using standard statistical methods. In future trials of AED monotherapy or add-on where time to first or Nth seizure is an outcome, methodology that can incorporate baseline seizure rate information would allow more powerful comparisons between treatments or between treatment and placebo.     

Topiramate: uses in people with an intellectual disability who have epilepsy

The novel anticonvulsant topiramate has been shown to have efficacy across a range of seizure types including both generalized and partial seizures in several well-designed randomized controlled trials. It has also been shown to be effective in atonic seizures associated with Lennox-Gastaut syndrome. Tolerability data show a tendency to neuropsychiatric side-effects, such as confusion and word finding difficulties, when topiramate is used in polytherapy; these side-effects are reduced in monotherapy usage. The efficacy and spectrum of seizures treated by topiramate suggests that it has an important role in managing epilepsy in people with intellectual disability. The predictable side-effects can be monitored in clinical practice and possibly reduced by slow dose increments. The data set of patients with intellectual disability is still too small to rule out idiosyncratic drug reaction.     

Generalized spike-and-wave patterns in children: clinical correlates

All electroencephalograms performed in our institution between 1980 and 1990 were reviewed. The clinical characteristics of children with epilepsy and generalized spike-and-wave (SW) patterns were analyzed. The SW patterns were classified according to their frequency. Electroencephalograms of 154 children with epilepsy revealed SW patterns. Absence seizures were the most common first seizure, but partial seizures were frequent. More than 40% had several types of seizures. Sixty percent of the epileptic syndromes were generalized, but almost 25% were partial. The typical SW pattern was associated with absence seizures, a normal examination and computed tomographic scan, idiopathic generalized epilepsies, monotherapy, freedom from seizures, and lack of recurrence. The slow SW pattern was associated with West syndrome; a younger age at seizure onset; atonic, myoclonic, tonic, and partial simple seizures; an abnormal examination and computed tomographic scan; cryptogenic or symptomatic generalized epilepsy or symptomatic partial epilepsy; polytherapy; and poor seizure control. The fast SW pattern was associated with secondary generalized, partial, tonic-clonic, and complex partial seizures; a normal computed tomographic scan; cryptogenic partial epilepsy; isolated seizures; and seizure recurrence. Epilepsy with a typical SW pattern should be considered benign, epilepsy with a slow SW pattern malignant, and epilepsy with a fast SW pattern treacherous.     

Monotherapy Trials of New Antiepileptic Drugs

Summary: A number of clinical trials that test the efficacy and safety of the newer antiepileptic drugs (AEDs) have recently been concluded. Two dose-response trials in inpatients with refractory partial seizures and outpatients with newly diagnosed partial epilepsy established the efficacy of gabapentin as monotherapy. Lamotrigine was found to have efficacy similar to that of phenytoin and carbamazepine (CBZ) and to be better tolerated than CBZ in patients with newly diagnosed epilepsy. It was also shown to have efficacy as monotherapy in partial seizures, based on the results of an active controlled trial, and in the treatment of absence seizures, based on the results of a responder-enriched study. Topiramate as monotherapy was found to be efficacious for treatment of partial-onset seizures, based on the results of a single-center dose-response trial. A dose-response trial that tested the efficacy of tiagabine monotherapy in patients with refractory partial epilepsy was uninformative. Oxcarbazepine was found to be safe and efficacious in four comparative trials in patients with newly diagnosed epilepsy as well as in one placebo-controlled inpatient trial in patients with refractory partial seizures.     

Mono- or Polytherapy and the Severity of Epilepsies

Abstract: 1. Out of 295 outpatients who were followed up by our staff for longer than 4 years, a total of 196 patients was subjected to this retrospective study. The inclusion criterion was that they had inevitably been placed on polytherapy of two or more anti-epileptic drugs (AEDs). In other words, they had failed to reach monotherapy for some reasons.
2. One of the determinant factors for the success or failure of monotherapy was the type of epilepsies. Namely, primary generalized epilepsy (PGE) was relatively easy to attain by monotherapy regardless of the seizure type, whereas secondary generalized epilepsy (SGE) with combined seizures and secondary partial epilepsy (SPE) with mixed seizures were not infrequently difficult to be placed on a monotherapy regimen. In the latter case, however, an abrupt withdrawal of AEDs was apt to cause an exacerbation of seizures.
3. There were some patients who could reach a complete freedom from seizures as a result of bi- or polytherapy and became socially adaptable and acceptable. They themselves are, if not all, afraid of a possible relapse of seizures produced by a reduc tion in the number of AEDs hitherto prescribed. In some cases, a family member may refuse monotherapy, or even physicians are reluctant to switch to monotherapy because the patients have experienced status epilepticus in the past.
In other words, there are two reasons why polytherapy should not, by all means, be avoided; one is the type or severity of epilepsies from which a given patient has been suffering, and the other is the patient's social factor or "quality of life" in which he or she hesitates to accept a monotherapy regimen. In conclusion, monotherapy WBS not necessarily regarded as the only rational way of having antiepileptic drug (AED) treat ment.     

Zonisamide monotherapy for epilepsy in children and young adults

Several of the newer antiepilepsy drugs have not been tested as monotherapy in controlled trials. Zonisamide is a broad-spectrum antiepilepsy drug indicated for the adjunctive treatment of partial seizures in adults. However, several small, open-label studies have indicated that it may be safe and effective as monotherapy. The present chart review study was conducted to evaluate the safety and effectiveness of zonisamide monotherapy in a pediatric and young adult patient group. Patient records at the Blue Bird Circle Clinic for Pediatric Neurology were reviewed to identify patients receiving zonisamide monotherapy. Efficacy was assessed from seizure diaries and patients' subjective evaluations. Safety and tolerability were evaluated by analysis of adverse events and change in body weight. The study included 131 patients aged 1 to 21.8 years with a broad spectrum of seizure types and epilepsy syndromes. A total of 101 patients (77.1%) achieved a 50% or greater decrease in seizure frequency, including 39 patients who achieved seizure freedom. Zonisamide monotherapy was well tolerated, with three patients (2.3%) discontinuing for adverse events. These results support open-label studies from Japan reporting that zonisamide monotherapy is safe and effective in pediatric and young adult patients.     

Levetiracetam: preliminary efficacy in generalized seizures

Levetiracetam is a novel antiepileptic drug (AED) with proven efficacy against partial seizures, but there is limited information about its effectiveness against generalized seizures. In animal models, levetiracetam protects against seizures in audiogenic susceptible rodents, and it is effective in the Genetic Absence Epilepsy Rat from Strasbourg, a model of absence seizures. In these models, levetiracetam has a therapeutic index that is higher than those of other AEDs. A number of small open-label studies suggest that levetiracetam reduces seizure frequency in patients with generalized seizures, including primarily generalized seizures and myoclonic seizures. Case reports provide additional information regarding the potential efficacy of levetiracetam in postanoxic, post-encephalitic and progressive myoclonus. Although random-ized controlled studies of patients with generalized seizures have not yet been conducted, on the basis of available information, levetiracetam may be prom-ising in the treatment of generalized seizures.