Double-blind crossover trial of lamotrigine (Lamictal) as add-on therapy in intractable epilepsy

A double-blind, placebo-controlled trial is reported of lamotrigine as add-on treatment in therapy-resistant epilepsy. A within-patients serial design was used, with two 3-month treatment periods and an intervening 6-week washout/crossover period. An unblinded investigator adjusted lamotrigine dosage to achieve a plasma concentration within a previously predicted therapeutic range. All patients had therapy-resistant partial seizures, some in combination with other seizure types and were without serious neurological or intellectual deficit. Of 34 patients recruited only one was withdrawn because of an adverse experience (maculo-papular rash) probably related to the experimental drug and 30 completed the trial. The other 3 withdrawals were due to default during baseline, dispensing error and cholecystectomy. There was a modest statistically significant reduction in total and partial seizures on lamotrigine compared to placebo treatment. There was no difference in adverse experiences or abnormal biochemical or haematological findings between the lamotrigine and placebo periods. The plasma concentrations of concomitantly administered antiepileptic drugs were not affected by lamotrigine treatment. It is concluded that lamotrigine shows promise as an antiepileptic drug with low toxicity.     

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.     

添加拉莫三嗪治疗儿童部分性癫的疗效观察

目的 探讨添加拉莫三嗪治疗儿童部分性癫的临床疗效及耐受性.方法 观察42例部分性癫患儿添加拉莫三嗪治疗后疗效、不同发作类型的有效率及发作频率的改变.结果 添加拉莫三嗪治疗后,患儿月发作频率减少38.1%,简单部分性发作有效率68.4%,部分性发作转为全面性发作有效率66.7%,复杂部分性发作有效率72.7%,总有效率69.0%.治疗前后比较差异有统计学意义(P＜0.05).不良反应轻微.结论 拉莫三嗪添加治疗儿童部分性癫具有良好的临床疗效及耐受性.     

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.     

Open study of pranlukast add-on therapy in intractable partial epilepsy

Innovative treatments of epileptic seizures are needed to improve the outcome of epilepsy. We studied the effect of pranlukast on seizure outcome in patients with intractable partial epilepsy. An open study was conducted to evaluate the clinical efficacy of 24-week pranlukast add-on therapy in 50 patients with intractable partial seizures. Serum concentrations of matrix metalloproteinase (MMP)-9 were determined using Biotrak Activity Assay System. Cytokines in cerebrospinal fluid (CSF) were measured by the BioPlex (BioRad) system and soluble TNF receptor1 (sTNFR1) in CSF was measured by the ELISA. Surface markers of lymphocytes in CSF were examined by cell-sorter. Seizure-free rate (SFR) was 13.6%, responder rate (RR) was 47.7%, and aggravation rate (AR) was 18.2% at the 13–24 week period after starting pranlukast. In patients with increased serum MMP-9 before pranlukast therapy (baseline), comparison of paired serum levels showed a significant decrease after pranlukast therapy. Baseline CSF levels of IL-1β and IL-6 were elevated in patients compared with disease controls. Of four patients with paired data, three (including a responder to pranlukast) showed decreased pro-inflammatory cytokines (IL-1β, IL-6, and TNFα), and four showed decreased sTNFR1, after pranlukast treatment, and only a responder had markedly decreased frequency of CD8+ T cells in CSF. Pranlukast reduces seizure frequencies probably by pleiotropic effects including normalization of MMP-9 in sera, reduced leakage of pro-inflammatory cytokines into CNS, and inhibition of extravasation of leucocytes from brain capillaries. Further investigations by double-blind control study and animal models are warranted.     

Evaluation of vigabatrin as an add-on drug in the management of severe epilepsy.

The effects of the addition of Vigabatrin, a new anti-epileptic drug, to the therapy of 128 patients with severe medically refractory epilepsy is reported. Forty two (33%) of patients experienced side effects, which were predominantly neurotropic. In 28 (22%), the drug was withdrawn because of these side effects. The commonest side effects were drowsiness and behavioural change. The remaining 100 patients were followed for a mean of 30 weeks (range 12-75). Forty one of these patients showed a marked improvement in seizure frequency (a 50% or more reduction when compared with the pre-trial period), and nine (7%) were rendered seizure free. Apparent tolerance to the effects of the drug were noted in five patients. An exacerbation of seizures may occur if the drug is withdrawn too quickly. Vigabatrin appears to be a promising new anti-epileptic drug.     

维生素E添加治疗儿童难治性癫痫的实验研究

目的:为研究抗氧化剂维生素E在儿童难治性癫痫中的治疗作用,将维生素E作为添加剂治疗了35例儿童难治性癫痫患者。方法:实验分两步进行,先行3个月抗癫痫药(AED)基础治疗,然后加用维生素E治疗3个月,观察痫性发作频率的变化,同时检测血清中超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-PX)、谷胱甘肽(GSH)、脂质过氧化物(LPO)的变化。结果:基础治疗期间痫性发作频率为16.29±7.16与维生素E添加治疗期间10.06±3.86相比差异有显著意义(P<0.001),添加维生素E后SOD、GSH-PX均有回升,LPO有所下降,与添加前比较差异有显著性,但GSH变化不大,在研究过程中未见明显不良反应发生。结论:维生素E添加治疗儿童难治性癫痫有效且安全,其机理可能与自由基参与癫痫的发病过程有关,也可能与维生素E的细胞保护作用有关。     

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.     

Allopurinol as an add-on drug in the management of intractable epilepsy

The efficacy of allopurinol as an antiepileptic drug has been assessed in a 12 week add-on open uncontrolled study in a small series of 12 patients with intractable epilepsy. Weekly seizure frequencies were observed to be reduced in 4 patients and increased in 5 patients but these changes were not significant and could be attributed to the random variation of seizures.     

托吡酯添加治疗难治性癫痫初步临床观察

目的　观察添加托吡酯 (TPM)对难治性癫痫 (IE)的临床效果与安全性。方法　IE 2 4例 ,以加用TPM前 3个月的月均发作频率为基准 ,并与加TPM后稳定期 3个月的月均发作频率进行比较。按常规计算有效率。并进行临床观察和实验室检查。原用抗癫痫药 (AED)基本保持不变 ,以测原用AED治疗前后的血浓度 ,协助观察病人用药的依从性。结果　病人用药依从性好 ,有效率为 67 9%～ 70 8% ,其中显效率达 5 0 % (4例未再发作 )。高级神经系统活动一时性副反应达16%。结论　加用TPM治疗IE是安全有效的方法之一。     

Efficacy of lamotrigine and vigabatrin in drug-resistant epilepsies of childhood

It was the purpose of this study to compare the efficacy and side effects of lamotrigine (LTG) and vigabatrin (VGB) as add-on therapy in epilepsies of childhood resistant to conventional drugs. Retrospective analysis of the medical charts and electroencephalograms of 134 children (LTG 57, VGB 77) was performed considering the various epileptic seizures and syndromes. In general, LTG and VGB had similar efficacy, with 30-40% of patients demonstrating significant improvement. Few differences according to seizure type and epileptic syndrome were observed. Primary generalized tonic-clonic seizures more frequently improved and less frequently worsened with LTG than with VGB. In tonic seizures the treatment results were significantly more favorable with VGB. Only insignificantly better results occurred with LTG in the generalized group and with VGB in the localization-related group. VGB was significantly more effective in symptomatic than in idiopathic and cryptogenic syndromes. The frequency of adverse reactions with both drugs was close to 60%. However, treatment had to be discontinued because of severe rashes in only a few patients taking LTG or because of behavior disturbances in patients taking VGB.     

别嘌醇添加治疗难治性癫痫58例疗效观察

目的 :研究别嘌醇作为添加剂治疗难治性癫痫 (IE)的临床疗效与安全性。方法 :选自 1992～ 2 0 0 0年IE 5 8例 ,加用别嘌醇进行开放性自身对照研究 ,原服用的抗癫痫药 (AEDs)种类和剂量不变 ,以加用别嘌醇前 6个月的月发作频率为基线与治疗后 6个月的发作频率进行比较 ,常规计算发作改变百分率、有效率和脑电图好转率。结果 :发作改变百分数较加用前减少 6 7% (P <0 0 1) ,总有效率 5 8 6 2 % ,反应率为 5 0 % ,脑电图总有效率 6 8% (38/ 5 6 )。其临床疗效为全身强直———阵挛发作 (GTCs) >强直性发作 (Ts) >复杂部分性发作 (CPs) >单纯部分性发作 (SPs)。结论 :加用别嘌醇是治疗难治性癫痫的有效方法之一     

Long-term retention rates of lamotrigine, gabapentin, and topiramate in chronic epilepsy

PURPOSE: We sought to determine the long-term retention rates of lamotrigine (LTG), gabapentin (GBP), and topiramate (TPM) therapy for patients at a tertiary referral clinic for chronic, refractory epilepsy. METHODS: We analyzed 424 consecutive patients with chronic, refractory partial and/or generalized epilepsy who were started on LTG, 158 patients who were started on GBP, and 393 patients who were started on TPM. The percentages of patients who continued therapy with LTG, GBP, and TPM were estimated with the use of Kaplan-Meier survival analysis. Factors that influence retention were analyzed with the use of Cox regression analysis. RESULTS: Kaplan-Meier survival analysis showed that at 3 years, 30% continued therapy on TPM compared with 29% on LTG and fewer than 10% on GBP. Adverse events resulted in therapy withdrawal in 40% of patients on TPM compared with GBP (37%) and LTG (22%). Perceived lack of efficacy led to treatment withdrawal in 39% of patients on GBP compared with 34% on LTG and 19% on TPM. Cox regression estimated that a fourth or fewer of patients with chronic partial epilepsy are likely to continue therapy with a new antiepileptic drug beyond 5 years. CONCLUSIONS: The impact of these new antiepileptic drugs on the long-term course of chronic partial epilepsy is likely to be small, as approximately three of four patients will discontinue therapy. More patients appear to continue on TPM compared with LTG or GBP, with a possible reason being better perceived efficacy of TPM, despite having the highest incidence of adverse events.     

加用加巴喷丁治疗难治性癫痫的临床观察

目的观察加用加巴喷丁（ＧＢＰ）对难治性癫痫（ＩＥ）的临床效果与安全性。方法观察ＩＥ２０例，以加用ＧＢＰ前３个月的月均发作频率为基线，与治疗后１６周以上的月均发作频率进行比较，计算反应率，发作改变百分率（ＰＣＨ）和有效率，参照病人或家属病情日记。加用前和治疗中与结束前均定期进行临床和规定实验室检查。结果ＰＣＨ较加用前减少４７８％（Ｐ＜００１），有效率为１２／２０，其临床疗效单纯部分性发作（ＳＰＳ）＞全身强直阵挛性发作（ＧＴＣＳ）＞复杂部分性发作（ＣＰＳ），而对强直性发作（ＴＳ）无效。与其它传统抗痫药无明显交互作用。结论加用ＧＢＰ是治疗ＩＥ有效而安全的选择方法之一。     

Topiramate for intractable childhood epilepsy.

To better define the efficacy and tolerability of the new anticonvulsant topiramate in pediatric patients, the clinical courses of 49 children with intractable seizures were monitored during topiramate therapy. The 80% of children who had complex partial seizures experienced better seizure control with topiramate than the 20% who had generalized seizures. Efficacy was greatest with doses between 2.5 and 7.5 mg/kg/day. More than half the children on topiramate experienced adverse effects which could interfere with learning at school, but 20% demonstrated increased alertness or improved behavior. Topiramate is effective and may be considered as part of the treatment pathway for complex partial seizures in children, although careful monitoring of cognitive function is required.     

The use of stereotactic radiosurgery to treat intractable childhood partial epilepsy

PURPOSE: Although conventional surgery is presently used to treat seizures of temporolimbic and neocortical origin, deep-seated lesions are often associated with morbidity. Stereotactic radiosurgery is a noninvasive procedure that effectively treats patients with vascular malformations and brain tumors, but its efficacy for epileptogenic foci is limited, especially in children. METHODS: Between 1995 and 1999, four candidates who had medically uncontrolled seizures and localized seizure foci were selected for stereotactic radiosurgery, with a mean age of 9.75 years at the time of surgery (range, 4-17 years). Seizure foci were identified on the basis of ictal and interictal video-EEG. Magnetic resonance (MR) images were obtained before and after surgery. Ictal single-photon emission computed tomography (SPECT) was performed by using stabilized hexamethyl-propyleneamine oxime (HMPAO; 300 microcuries/kg) with early injection after electrographic ictal onset. The clinical features of the patients are given. All radiosurgical procedures were performed with the gamma knife unit with the Leksell stereotactic frame, stereotactic MRI imaging, and the Gamma Plan workstation. Seizure outcome was scored according to Engel's classification. RESULTS: Two patients had hypothalamic hamartoma (HH), and two had neocortical epilepsy. At mean follow-up of 39.2 months (range, 26-69 months), two patients were seizure free, one with a HH and one with a suggestive developmental tumor in the insular cortex by MRI findings. The other patient with HH had 90% reduction of seizures. One patient with a widespread seizure focus that involved the motor strip was unimproved. The two patients with HH also exhibited markedly improved neurobehavioral status after surgery. There were no significant complications of radiosurgical therapy. CONCLUSIONS: Our findings suggest that gamma knife surgery is a potentially valuable treatment modality for children with medically intractable epilepsy due to a well-localized seizure focus that is difficult to excise by conventional techniques or for whom they are deemed unsuitable. More widespread application in childhood epilepsy should be investigated in larger series.     

Cost-effectiveness of add-on lamotrigine therapy in clinical practice

OBJECTIVE: This retrospective study addresses the cost-effectiveness of add-on therapy with lamotrigine in clinical practice. METHODS: Two years' observational data of 165 patients were used. Seizure frequency, adverse effects and direct medical costs were recorded for the year before and the year after the start of lamotrigine add-on therapy. Therapy effectiveness was measured by: (1) reduction in seizure frequency and (2) retention time. The incremental cost-effectiveness ratio expressed the direct medical cost per patient treated effectively with lamotrigine. RESULTS: The cost of medication was 492 (95% CI: 399-583) higher after the start of lamotrigine therapy. The extra cost of lamotrigine therapy (622) was partly offset by a reduction of the cost of co-medication (-130; 95% CI: -210 to -50). Overall, the total medical cost was 453 higher in the first year of lamotrigine therapy than in the year before the start of lamotrigine. Lamotrigine was effective in 47% of all the patients, making the resultant incremental cost-effectiveness ratio 954 per year. DISCUSSION: Add-on therapy of lamotrigine for patients with uncontrolled epilepsy offers improved health outcomes. Lamotrigine therapy is associated with increased cost (453) and an annual incremental cost-effectiveness ratio of 954. These data, together with utility data published in the literature, support the notion that lamotrigine should be considered as an add-on therapy in for patients with refractory epilepsy.