Lamotrigine in add-on therapy: assessment of efficacy in drug resistant epilepsy

The authors presented the results of treatment with lamotrigine (LTG, Lamictal) in 13 patients with drug resistant epilepsy (add-on therapy). There were 8f, 5m. aged 16-60 years, mean age 28.8 years. Generalized seizures occurred in 8 patients (62%). In this group there was 1 patient (aged 16 years) with the Lennox-Gastaut syndrome and 1 patient (aged 20 years) with valproate resistant juvenile myoclonic epilepsy. Complex partial seizures and complex partial with secondary generalization occurred in 5 patients (38%). Before LTG addition mean seizure frequency was from 3/month to several times/day. The mean duration of epilepsy was 16.6 years. The 8 patients were treated with CBZ and VPA, one with PHT and VPA, one CBZ and VGB. Monotherapy with VPA was introduced in 3 patients. After 6 months of treatment with LTG the efficacy was evaluated. 12 patients took LTG with VPA, 1 LTG with CBZ. Complete reduction of seizures was achieved in 3 cases (23%), at least 50% reduction in 3 patients (23%), reduction below 50% in 4 patients (31%). In 3 cases (23%) the results of treatment were negative (increase or no change in seizure frequency). Beneficial psychotropic effect was observed in 9 patients (69%). Adverse effects occurred in 2 patients (15%). Headache, vertigo, sleepness were observed in one case. Rash occurred in 1 patient (treated with LTG and VPA). After 6 months 3 patients were excluded from the study because of negative effects of treatment. LTG is helpful and well tolerated in drug-resistant epilepsy.     

Lamotrigine versus vigabatrin as an add-on therapy in refractory epilepsy: prospective study

Lamotrigine (LTG) and Vigabatrin (VGB) has been licensed widely as adjunctive therapy for partial and secondary generalized seizures. We compared the efficiency of Lamotrigine and Vigabatrin as adjuvant therapy for 33 patients (16 male and 17 female) with drug-resistant partial epileptic seizures (simple and complex) with secondary generalization receiving combination therapy (carbamazepine--CBZ and valproic acid--VPA). Patients were enrolled if they had experienced two partial seizures (simple or complex) and one secondary generalization/month, despite combination therapy. Neurologic evaluation including CT, MRI and EEG was performed every 3 months during observation. Blood specimens for CBZ and VPA plasma concentration were obtained prior to the first LTG or VGB dose and twice a year during the treatment. The assessment of LTG and VGB effectiveness was performed in 2-month intervals during 2-3 years for vigabatrin (mean daily dose 2.0 g) and 1-2 years for Lamotrigine (mean daily dose 0.3 g). The treatment (CBZ, VPA or both) with Vigabatrin or Lamotrigine as adjunctive therapy was effective in about a half of patients with refractory epilepsy. Findings suggest that the reduction in partial seizures (simple or complex) frequency with Vigabatrin is greater than that with Lamotrigine. On the other hand, Lamotrigine seems to be more effective in patients with partial epileptic seizures with secondary generalization.     

加巴喷丁添加治疗难治性部分性癫痫疗效及安全性的Meta分析

目的 初步评价加巴喷丁添加治疗难治性部分性癫痫的疗效及安全性.方法 采用RevMan5.0软件对纳入文献的相关数据进行Meta分析.结果 加巴喷丁组发作频率减少及增加的比例与安慰剂组相比,差异均具有统计学意义.发作频率减少≥50％的OR为2.17,95％ CI为1.53 ～ 3.07;50％≤发作频率减少＜75％的OR为1.87,95％ CI为1.02～3.44;发作频率减少≥75％的OR为2.16,95％CI为1.16 ～4.03.发作频率增加的OR为0.57,95％CI为0.40～0.81.加巴喷丁组因不良反应退出的比例及部分不良反应发生率与安慰剂组相比,差异具有统计学意义.结论 加巴喷丁添加治疗难治性部分性癫痫的疗效高于安慰剂,部分不良反应发生率高于安慰剂.     

Long-term efficacy and tolerability of topiramate as add-on therapy in refractory partial epilepsy: An observational study

Purpose:   To evaluate the long-term efficacy and tolerability of topiramate (TPM) as add-on therapy in patients with refractory partial epilepsy.
Methods:   This is a retrospective, single-center, long-term observational study. Patients fulfilling the criteria of medical intractability proposed by Berg et al. were entered into the study if they were newly prescribed TPM as add-on therapy between January 2000 and June 2002. The usual starting dosage of TPM was 50 mg/day and optimal-dose adjustments were made according to individual clinical responses. Efficacy and tolerability were analyzed every year during 5-year follow-up in the "intention-to-treat (ITT) population." Retention rate was estimated by Kaplan-Meyer analysis.
Results:   A total of 125 patients were included in the study and 107 patients (85.6%) were followed for 5 years. Retention rate was 87.2% at 1 year and 64% at 5 years. At the end of 5 years, the median seizure frequency reduction rate was 69.0% and responder rate was 43.2% in the ITT population. Cumulative seizure-free rate (SFR) was 30.4% and the terminal 1-year SFR was 12.8% in the ITT population (20.0% in completers) at 5-year follow-up. Adverse events (AEs) occurred in 39.2% of patients, including significant AEs leading to antiepileptic drug (AED) withdrawal in 14.4%. The most common AEs were anorexia (16.0%), weight loss (10.4%), and gastrointestinal symptoms (8.8%). Concomitant AEDs were reduced in 25.0% of the completers.
Discussion:   Low-dose and slow-dose escalation of TPM in add-on therapy for patients with refractory partial epilepsy is effective and well tolerated in long-term, individualized clinical practice.     

Evidence for sustained efficacy of levetiracetam as add-on epilepsy therapy

PURPOSE: To evaluate the long-term clinical usefulness of levetiracetam (LEV, Keppra((R))(1)) as add-on therapy in patients with refractory epilepsy. METHODS: Data for all 1422 patients with refractory epilepsy treated with LEV during the development program were analyzed for changes in seizure frequency per week, seizure freedom, and adverse events. RESULTS: Median percent reduction from baseline in seizure frequency per week over the whole treatment period was 39.6%, and no decrease over time was observed within each cohort exposed to LEV for durations ranging from 6 to 54 months. The median treatment period was 399 days (range 1-8 years). The proportion of responders during the first 3 months of LEV treatment was 39.2%. This proportion remained stable at 6 months (36.1%). Overall, 38.6 and 20.1% of patients had reductions in seizure frequency of at least 50 and 75%. Sixty-five (4.6%) patients were seizure-free over their entire treatment period, compared with 167 (11.7%) and 126 (8.9%) during their last 6 and 12 months of follow-up. Ninety-seven (19.8%) of 491 patients who received only one other antiepileptic drug (AED) in addition to LEV were seizure-free during their last 6 months. The proportion of patients who reduced their number of concomitant AEDs was 14.4% (205 patients), while 5.5% (79 patients) were treated with LEV only at the end of follow-up. Accidental injury (28.0%), infection (26.6%), headache (25.8%), somnolence (23%), asthenia (22.6%), and dizziness (18.9%) were among the most common adverse events. CONCLUSION: LEV offers sustained efficacy in patients with refractory partial seizures, and its long-term tolerability is similar to that seen in the short-term placebo-controlled trials.     

Progabide for refractory partial epilepsy: a controlled add-on trial

Progabide, an experimental GABA-ergic antiepileptic drug, was given in a placebo-controlled double-blind cross-over trial to 19 adult patients with chronic partial epilepsy refractory to previous high-dose antiepileptic drug therapy. A mean daily dose of 32 mg/kg (range, 16 to 63) of progabide did not significantly change the seizure frequency. In patients with a therapeutic response, progabide led to an increase in the plasma concentration of phenytoin and phenobarbital. Comedication with carbamazepine was associated with a poor response to progabide. Side effects were mild except for a several-fold increase of SGOT and SGPT, which required withdrawal of progabide in one patient. Progabide does not seem to be the drug urgently needed for failures of previous high-dose drug therapy.     

Lamotrigine as adjunctive therapy in patients with refractory epilepsy and mental retardation

This study evaluated the effects of lamotrigine as adjunctive therapy for refractory epilepsy in patients with mental retardation. Patients with epilepsy and mental retardation having uncontrolled seizures despite treatment with other antiepileptic drugs were eligible (n=67). The open-label study comprised a Baseline Phase, an Escalation Phase during which lamotrigine was titrated to a target dose, an 8-week Maintenance Phase during which doses of lamotrigine and concomitant antiepileptic drugs were maintained, and a 12-week Optimization Phase during which doses of lamotrigine and other antiepileptic drugs could be adjusted. Almost half (44%) of patients experienced a 50% reduction in seizure frequency during the Maintenance Phase after addition of lamotrigine; 15% of patients became seizure-free. A similar pattern of results was reported for the Optimization Phase. Investigator-rated clinical status was improved relative to baseline in 66 and 74% of patients at the end of the Maintenance and Optimization Phases, respectively. Most patients experienced improvements in seizure frequency, duration, and intensity during the Maintenance Phase (62 to 72%) and the Optimization Phase (65 to 74%). Many patients were rated as having improved social functioning during the Maintenance Phase (42%) and the Optimization Phase (46%). The Aberrant Behavior Checklist score for lethargy and the mean Habilitative Improvement Scale score were improved at the ends of the Maintenance and Optimization Phases relative to baseline (P< or =0.04). One limitation of this study is its open-label design, which limits the ability definitively to attribute the clinical improvements to lamotrigine. Adjunctive lamotrigine in patients with refractory epilepsy and mental retardation appears to decrease seizure frequency and improve behavior while permitting a reduction in dose of concomitant antiepileptic drugs.     

托吡酯添加治疗难治性癫癎的临床观察

目的　观察添加托吡酯对难治性癫的临床效果与副作用。方法　对 18例难治性癫患者 ,加用TPM后观察其发作频率并与加用前进行比较 ,计算总有效率。同时进行临床疗效和副作用观察。结果　病人加用托吡酯后总有效率为 5 0 % ,其中显效率达 2 2 2 % (3例未再发作 )。副反应以胃肠道反应及神经系统症状为主 ,发生率为 5 2 6%。结论　加用TPM治疗难治性癫安全有效。     

Double-blind placebo-controlled trial of flunarizine as add-on therapy in refractory childhood epilepsy

Flunarizine (FLN) has been suggested as an add-on treatment in drug-resistant epilepsy patients. In view of the discordant experiences and of the paucity of controlled trials in children, we studied its effectiveness in 20 patients aged 6 to 18 years (10 males and 10 females), affected by drug-resistant epilepsy. 14 had symptomatic generalized epilepsy (the Lennox-Gastaut syndrome in 10; other forms in 4); 3 had cryptogenic generalized epilepsy (the Lennox-Gastaut syndrome in 2; myoclonic absences epilepsy in 1); 3 had symptomatic partial epilepsy (temporal lobe epilepsy). 7 of them were withdrawn: only 1 because of side effects. An initial four-month baseline pretrial period was followed by two four-month periods of administration of FLN or a placebo, under double blind conditions, in a randomized sequence. Preexisting antiepileptic (AEDs) medication was maintained at a constant dose throughout the study. FLN was administered as drops in a single evening dose of 5 mg (patients less than 10 years) or 10 mg. (patients greater than 10 years). During the pretrial phase, after phase 1 and phase 2, a waking EEG was recorded and blood samples were taken for hematology, hepatic-function tests, and AED serum levels. The evaluation of the activity of FLN was based on the total number of seizures. A 30-60% reduction in seizure frequency was found in 5 out of the 13 patients completing the trial (no changes occurred in the remainders). This result did not appear to be due to changes in the plasma levels of the AEDs. No significant differences were seen in the EEG paroxysmal activity in the three phases of the study. Side effects were rare. The serum FLN levels ranged between 16.4 and 109 ng/ml. It seems that the antiepileptic properties of FLN need further validation, particularly in childhood.     

Cost-effectiveness of add-on therapy with pregabalin in patients with refractory partial epilepsy

PURPOSE: To estimate the cost-effectiveness of pregabalin as add-on therapy in patients with refractory partial epilepsy. METHODS: We developed a model to estimate clinical and economic outcomes over 1 year in a hypothetical cohort of patients with refractory partial epilepsy assumed alternatively to receive add-on therapy with pregabalin (300 mg/day) or no add-on therapy. For each patient in the model, we estimated the occurrence of seizure and side effects, using techniques of stochastic simulation. We assigned health-state utilities to each day of follow-up based on whether or not seizure or side effects were predicted to occur. Patients could discontinue therapy due to lack of efficacy or side effects. Outcomes included expected numbers of days without seizure ("seizure-free [SF] days"), quality-adjusted life-years (QALYs), and costs of therapy. Cost-effectiveness was assessed alternatively in terms of incremental cost per SF day gained and incremental cost per QALY gained. RESULTS: Add-on therapy with pregabalin was estimated to result in an average gain of 23.8 SF days over one year; the estimated additional cost of therapy was $678. Incremental cost (mean, 95% CI) per SF day gained was $28.45 ($27.25, $29.44); corresponding estimates of incremental cost per QALY gained were $52,893 ($49,249, $56,983). CONCLUSIONS: In patients with refractory partial epilepsy, the cost-effectiveness of pregabalin 300 mg/day compares favorably with published estimates of cost-effectiveness for other add-on antiepileptic drugs.     

Lamotrigine in the adult-onset epilepsy: efficacy and long-term safety

Background: LTG is a new antiepileptic drug that is nowadays very often used in epileptic patients. Objectives: To determine efficacy and safety of Lamotrigine (LTG) in the first five years after its marketing in patients at a third level university hospital, as well as its impact on the management of classic antiepileptic drugs (AED). Patients and method: We reviewed retrospectively our Epilepsy Unit Database. One hundred patients were treated with LTG in a 5-year period. Efficacy was evaluated comparing seizure frequency in a 6-month period before and after LTG. The type of epilepsy, side effects, blood levels and concomitant treatments were considered in the analysis. Results: LTG was effective in all groups of epileptic patients studied. Eighteen percent of patients became seizure-free. Seventeen percent of patients improved more than 50%. Fifty-seven percent of patients remained treated with LTG after four years of follow-up. Side effects were mild, but frequent; only four patients discontinued LTG because of adverse effects. Serum levels were usually high, but showed no relation with clinical efficacy. The mean number of AED taken per patient increased. Conclusions: LTG is a safe an effective drug in epilepsy. It has a clear impact in the management of the epileptic patients.     

Vigabatrin as add-on therapy in children and adolescents with refractory epilepsy: an open trial

Seventy-seven children and adolescents with drug-resistant epilepsies received vigabatrin as add-on therapy for a median of 18 months (range 4–36 months) at a dose of 50 mg/kg/day divided in two doses; patients with spasms were given a maximum dose of 100 mg/kg/day. In 23 patients (29.9%), seizure frequency decreased by 50–100% and in 12 patients (15.6%) by 25–50%. The number of seizures remained unchanged in 34 patients (44.1%) and increased in seven (9.1%). Vigabatrin was most effective in cryptogenic and symptomatic partial seizures (39% and 43%, respectively), and in infantile spasms (25%). Adverse events occurred in 20 patients (26%), though they were generally mild and transient, suggesting that vigabatrin is well tolerated.     

Fast and sustained efficacy of levetiracetam during titration and the first 3 months of treatment in refractory epilepsy

PURPOSE: To investigate whether the efficacy of levetiracetam (LEV) is sustained in adult patients with refractory partial seizures over a 3-month period. METHODS: Treatment effect was assessed in a post hoc analysis by determining the proportion of seizure-free days during each week of a 3-month period after the initiation of treatment. Pooled data from three randomized, double-blind, placebo-controlled trials (n = 883) were analyzed. RESULTS: The mean proportion of seizure-free days was greater in the LEV group than in the placebo group. The difference, which was statistically significant, was observed as early as the first week after the initiation of treatment. It was higher in the first week of treatment and subsequently was maintained for each week over the 3-month period (p < 0.001 or p = 0.002 at each time point). Patients in the LEV group had on average 74% to 81% days each week without any seizure, compared with 69% to 72% in the placebo group. CONCLUSIONS: LEV is efficient in controlling seizures from the first week of drug initiation, during uptitration, and throughout the first 3 months of treatment. An interesting amplification of efficacy occurs in the first week of therapy, which is intriguing and warrants further investigation.     

Diet therapy in refractory pediatric epilepsy: increased efficacy and tolerability.

Since the resurgence of the ketogenic diet (KD) in the mid 1990s, this diet has been used worldwide for the treatment of refractory pediatric epilepsy, including in Asian countries. However, the KD is not a convenient therapy, especially because the customary diets of Asian countries contain substantially less fat than traditional Western diets. In addition, there are various complications associated with the diet that should be considered. Unfortunately, no international protocols have been developed with the exceptions of the Johns Hopkins Hospital protocol adopted by a substantial number of hospitals. While the Hopkins protocol has been the basic model, several revisions of the initial protocol have been suggested. Changes to the applicable ages, seizure types, etiologies, the initiation of the diet, the ratio of constituents to reduce the fat content, the duration of the diet, and revised formulae, such as ketogenic milk or the all-liquid KD, have attempted to extend the indications of the KD and increase its tolerability and palatability. Recently, less restrictive KDs, including a modified Atkins diet and low-glycemic-index treatment, have been clinically tested. Here, we review these approaches toward a safer and more convenient therapeutic diet for refractory pediatric epilepsy.     

Efficacy and safety of add-on levetiracetam in refractory childhood epilepsy

Purpose: The purpose of the present study was to evaluate the efficacy and safety of levetiracetam (LEV) in refractory epileptic children. Methods: The study group included 61 outpatients (7 generalized, 48 localization-related, 3 undetermined, 3 unclassified) aged between 16 months and 18 years. LEV was given twice daily at a total dose of 10 mg/kg/day. The final mean dose was 50.7 mg/kg/day. The mean number of prior anti-epileptic drugs was 5.2. The entire treatment period was more than 6 months after LEV administration. Results: Fifteen children (24.6%) became seizure-free for 6 months after starting LEV, and 18 (29.5%) had a seizure reduction of more than 50% for the entire 6 months. The response rate was 33/61 (54.1%). Responders included 2/3 of patients (66.7%) with epilepsy with continuous spikes and waves during slow sleep and 13/19 (68.4%) with frontal lobe epilepsy. The effective dosage of LEV in the responders demonstrated a wide range (mean, 46.1 mg/kg/day; range, 19.4–59.1 mg/kg/day), and showed bimodal distribution. Adverse events occurred in only two patients who did not require LEV discontinuation. Conclusion: LEV represents an important addition to the treatments available for refractory epileptic children.     

Lamotrigine: single-dose pharmacokinetics and initial 1 week experience in refractory epilepsy

Twenty-three residential patients on chronic antiepileptic drugs (AEDs) were entered into an open study of 4 weeks duration. Baseline variables and seizure frequency were determined in the first week. All patients received a single dose of lamotrigine in the second week to determine single-dose pharmacokinetic parameters. Twenty patients then received daily or twice daily lamotrigine for a week. Post-treatment seizure frequency was observed for a further week. Patients taking liver enzyme inducing antiepileptic drugs showed a mean lamotrigine plasma elimination half-life (T1/2) of 14 h (+/- 7) (T1/2 of normal volunteers = 24 h) and those taking sodium valproate and an inducing AED showed a mean lamotrigine T1/2 of 30 h (+/- 10). The plasma concentrations of co-administered sodium valproate, phenytoin, carbamazepine, phenobarbitone and primidone were not altered by 1 week lamotrigine dosing. There was a significant reduction in complex partial seizures in the treatment week compared with baseline. Some patients showed a marked increase in seizure frequency on stopping lamotrigine. There was an increase in reports of drowsiness during lamotrigine administration, but there were no clinically significant changes in any safety measure.     

奥卡西平添加治疗成人难治性癫痫部分性发作的临床观察

目的观察奥卡西平添加治疗成人难治性癫痫部分性发作的长期疗效与安全性。方法 96例难治性癫痫部分性发作患者,保持原使用的抗癫痫药不变,加用奥卡西平治疗,观察期为12个月,进行自身对照开放性研究,观察其疗效、不良反应、保留率及安全性。结果 81例患者完成12个月随访观察,经治疗12个月后总有效率44.4%。同治疗前比较,总发作频率减少41.0%(P0.05),其中单纯部分性发作频率减少41.4%(P0.05),复杂部分性发作频率减少38.9%(P0.05),部分性发作继发全面性发作频率减少42.9%(P0.05)。81例患者中39例患者于加量过程中出现轻至中度不良反应,都能得到缓解。奥卡西平添加治疗12个月的保留率为84.4%。结论奥卡西平添加治疗成人难治性癫痫部分性发作疗效好,安全性高,患者耐受好。     

Nifedipine as an add-on drug in the management of refractory epilepsy

We report the effects of the addition of nifedipine, a calcium channel antagonist, to the antiepileptic therapy of 20 patients with severe medically refractory epilepsy. Six patients developed side effects and in two the drug had to be discontinued because of these. The commonest side effects were headaches, dizziness and lethargy. Two patients experienced deterioration in seizure control and only 2 patients showed improved seizure control. One of these patients subsequently developed tolerance at 5 months. In 16 patients there was no change.     

Clobazam as add-on therapy for temporal lobe epilepsy and hippocampal sclerosis

BACKGROUND: Clobazam is a benzodiazepine with known antiepileptic action; however, it is not considered first line therapy in the treatment of epilepsy. The objective of this study was to evaluate the efficacy of clobazam as add-on therapy in adults with temporal lobe epilepsy associated with MRI evidence of hippocampal sclerosis (HS). METHOD: This is a retrospective study, conducted at our epilepsy clinic which evaluated clobazam as add-on therapy in patients with temporal lobe epilepsy and MRI signs of HS. Clobazam was prescribed based on the minimum effective dose up to the maximum tolerated dose. RESULTS: Seventy-eight patients met the inclusion criteria (51 women), ages ranging from 16 to 76 years old (mean=42.2). Dosage of clobazam ranged from 5 to 60 mg/day (mean=22.6 mg/day). Clobazam was used from one month to eight years (mean=29 months). Sixteen (20.5%) patients were seizure-free, 20 (25.5%) had more than 75% improvement in seizure control, eight (10%) had more than 50% and 20 (26%) were non responders to clobazam. In 14 (18%) we could not determine seizure frequency during follow-up. The improvement in seizure control lasted for more than one year in 30 (68%) patients. CONCLUSION: Our data suggest that clobazam should be considered as add-on therapy in the treatment of patients with temporal lobe epilepsy associated with MRI signs of HS.