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.     

Lamotrigine add-on therapy for childhood-onset refractory epilepsy: comparison of the efficacy between 3 months and 6 months after initiation

We investigated the effect of lamotrigine (LTG) add-on therapy in 50 patients with childhood-onset refractory epilepsy (25 males and 25 females): 15 with localization-related epilepsy, 33 with generalized epilepsy, and 2 with undetermined epilepsy. Twenty-four patients had experienced a period of West syndrome during their clinical course. Age at the start of LTG therapy ranged from 2 years 6 months to 41 years 2 months: <16 years in 43 and > or = 16 years in 7. Seizure frequency was > or = 1 per day in 36 patients (72%) and > or = 1 per week in 14 (28%). We increased the LTG dosage every two weeks in accordance with usage recommendations. We evaluated efficacy at two points: 3 and 6 months after the start of LTG. At the 6-month point, seizure freedom was achieved in 2 patients (4%), > or = 50% seizure reduction in 14 (28%), 25 to 50% seizure reduction in 20 (40%), no effect in 6 (12%), and aggravation in 4 (8%). Only 4 patients (8%) stopped LTG therapy within 6 months due to LTG-related mild skin rash in 2 and suspicion of seizure aggravation in the other 2. In terms of seizure types, seizure freedom or > or = 50% seizure reduction was achieved in 29% for epileptic spasms, 32% for tonic seizures, and 29% for partial seizures. A comparison between the 3- and 6-month points revealed that the efficacy level was increased or maintained in 77% of the patients and decreased in 23%. In most cases, the highest level of efficacy appeared within 3 months with doses that were smaller than maintenance doses. Observed CNS-related adverse effects included somnolence in 16 patients, irritability in 14, and sleep disturbance in 11. Positive psychotropic effects in daily activities were seen in 28 patients (56%). These effects appeared regardless of the change in seizure frequency with doses that were smaller than maintenance doses.     

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.     

Lamotrigine as an add-on drug in typical absence seizures

Introduction - Lamotrigine is licenced in many countries for use in patients with partial seizures. Evidence suggests that it may also be effective in generalised epilepsies. Material & methods - We analysed retrospectively our patients with idiopathic generalised epilepsy with refractory absences. Results - Fifteen patients with idiopathic generalised epilepsies were identified who had been treated with lamotrigine for 3 months or more. All patients were also treated with sodium valproate. Fourteen patients had active absences. Nine (64%) had a total or virtual cessation of absences and in a further patient they became milder and less frequent. One patient reported an increase in seizures. The effective dose of lamotrigine was 1.6-3.0 mg/kg/day in children and 25-50 mg/day in adults. Patients who responded did so after the first or second dose. Lamotrigine was well tolerated. Conclusion - Low-dose lamotrigine added to sodium valproate appears to be effective in typical absence seizures. A therapeutic interaction of the two drugs seems likely.     

Lamotrigine therapy of epilepsy in tuberous sclerosis

PURPOSE: Lamotrigine (LTG), a newer antiepileptic drug (AED), has activity against both partial-onset and generalized seizures. Its reported benefits for behavior, and its effectiveness in Lennox-Gastaut syndrome and other forms of refractory epilepsy, make it a logical choice for treatment of epilepsy in tuberous sclerosis complex (TSC). We present our experience with LTG therapy of epilepsy in 57 patients with TSC. METHODS: Patients fulfilled the diagnostic criteria for clinically definite TSC. LTG was initiated and increased until improvement in seizure frequency was noted, intolerable side effects occurred, or maximal doses were reached. Seizure frequency and behavioral changes were recorded during LTG therapy and compared with those prior to the introduction of LTG. RESULTS: Twenty-four (42%) were seizure free, and 21 (37%) had a >50% reduction in seizure frequency. Eighteen (32%) had subjectively improved behavior and/or alertness with daily activities. Thirty-eight (67%) had no change in this regard, whereas one (2%) became worse. Responders were more likely to not have a history of infantile spasms, and to have experienced only partial seizures (p < 0.05). Otherwise no phenotypic correlations with response were apparent. CONCLUSIONS: Among patients with TSC and epilepsy, LTG was effective and well tolerated, including as initial monotherapy. Improved alertness and behavior were apparent in many patients. The incidence of side effects is similar to that reported for other pediatric populations with symptomatic partial epilepsy. The usefulness of LTG in TSC may relate to an underlying defect of glutamatergic neurotransmission in partial epilepsy.     

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.     

Lamotrigine therapy of epilepsy with Angelman's syndrome

PURPOSE: Angelman syndrome (AS) is a neurogenetic disorder characterized by developmental delay and a frequently refractory epileptic condition. Valproate, clonazepam and/or phenytoin are said to be the most effective antiepileptic drugs (AEDs) against the seizures in AS. Experience with the newer AEDs is very limited despite their better safety profile and tolerability. Considering its favorable side effect profile and its effectiveness against both partial and generalized seizures, we hypothesized that lamotrigine (LTG) might be more efficacious and better tolerated. METHODS: Potential patients for this retrospective study were identified from the epilepsy clinics at Notre-Dame, Sainte-Justine, and Yale New Haven hospitals. Patients were included in the study if they had AS along with refractory seizures. The medical record of each patient was reviewed with interest on seizure types, previous AEDs and response to LTG. RESULTS: Five patients (2M, 3F) were included in this study. Age at LTG ranged from 10 to 33 years old. All had >or=2 seizure types, mainly generalized tonic-clonic, myoclonic seizures, and atypical absences. Previously tried AEDs included valproic acid (5), benzodiazepines (5), phenytoin (4), carbamazepine (3), and topiramate (1). One patient had pancreatitis on phenytoin, one had worsened seizures on carbamazepine, and one developed hepatic encephalopathy on valproic acid. Three patients became seizure-free with LTG (9, 20, and 36 months FU), one was seizure-free for 1 year with subsequent loss of efficacy, and one showed >50% reduction in myoclonic seizures (20 months FU). No side effects were reported. CONCLUSION: LTG can be efficacious and well tolerated in patients with AS.     

Lamotrigine as an add-on drug in the management of Lennox-Gastaut syndrome.

We report our experience with lamotrigine add-on therapy in the treatment of 11 patients with Lennox-Gastaut syndrome. Lamotrigine is a novel antiepileptic drug, chemically unrelated to the major anticonvulsants in current use. Ten patients experienced a > 50% reduction in seizure frequency, 1 patient experienced no change in seizure frequency. All patients tolerated lamotrigine satisfactorily and no side-effects were reported.     

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.     

Losigamone add-on therapy in partial epilepsy: a placebo-controlled study

OBJECTIVES: To evaluate the efficacy and tolerability of losigamone (LSG). PATIENTS AND METHODS: Double-blind, placebo-controlled add-on study with 3x500 mg LSG/die for the treatment of chronic partial seizures in 203 patients (99 treated with LSG, 104 on placebo). RESULTS: The median percent change of seizures was 14.9% (LSG) versus 6.7% (placebo) (P=0.004). Seizure frequency was decreased by more than 50% in 22.3% (LSG) and 14.6% (placebo) of patients (P=0.13). Mean percent change of seizures was best in patients with only one additional anticonvulsant drug (LSG versus placebo, P=0.004). Adverse events (usually CNS-related side effects of mild to moderate intensity) were reported in 59.6% (LSG) and 37.5% (placebo) of patients. CONCLUSIONS: LSG proved to be an effective and well tolerated anticonvulsant drug for the treatment of chronic partial seizures.     

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 dose-ranging trial of flunarizine as add-on therapy in epilepsy

A double-blind placebo-controlled crossover trial of flunarizine as add-on treatment in therapy-resistant epilepsy offered significant evidence of efficacy, but the plasma levels of flunarizine were lower than anticipated, probably due to induction of liver enzymes by comedication. An open dose-ranging trial was therefore undertaken to investigate the relationships among dose, efficacy, side effects, and blood level. With basal medication held constant, flunarizine was added at 3-month intervals in increasing doses of 0, 10, 15, 20, and 25 mg daily, or until side effects occurred or marked seizure reduction was obtained. Forty-seven patients completed the trial; all were adults with therapy-resistant epilepsy who had at least 3 seizures per month. All had complex partial seizures, with additional types in 20. Sixteen patients showed a 50% and 24 a 25% reduction of seizure incidence on flunarizine; 6 and 7, respectively, showed a corresponding increase. The greatest seizure reduction, when observed, occurred generally at a daily dose of 15-20 mg. Side effects, chiefly drowsiness and weight gain, increased markedly between 15 and 20 mg daily. Flunarizine administration produced no change in serum levels of comedication, but flunarizine levels were lower in patients taking more than one other drug. Seizure reduction was obtained most consistently in patients with secondary generalized epilepsy or neurologic deficits. The findings confirm the antiepileptic action of flunarizine in humans and justify further trials.     

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.     

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

In a therapy-resistant epileptic population with partial complex seizures with or without secondary generalization, addition of flunarizine to existing therapy was accompanied by a significant reduction in complex partial and tonic-clonic seizures. This result did not appear to be due to serial effects or changes in the plasma levels of the co-medication. Side effects were rare. The serum flunarizine levels (13.8 ng/ml; range, 3-32.5 ng/ml) were lower than previously reported on a daily dose of 10 mg. This may reflect increased metabolism due to induction of liver enzymes by the co-medication. Given this finding, together with the low incidence of side effects, a further study is required to determine whether higher blood levels would give an improved degree and incidence of seizure reduction.     

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.     

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.     

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.     

Lacosamide as add-on in brain tumor-related epilepsy: preliminary report on efficacy and tolerability

Lacosamide (LCM) is an antiepileptic drug (AED) that has demonstrated a good efficacy in controlling seizures as an add-on in adult epilepsy. To date, there have been no studies on LCM in patients with brain tumor-related epilepsy (BTRE). To evaluate efficacy and tolerability of LCM as an add-on in BTRE, we followed 14 patients suffering from BTRE who had already been treated with other AEDs and who had not experienced adequate seizure control. Eleven patients underwent chemotherapy while being treated with LCM. Mean duration of follow up was 5.4 months (min < 1 max 10 months). Mean seizure number in the last month prior to the introduction of LCM had been 15.4. At last follow-up, the mean seizure number was reduced to 1.9/month. Lacosamide mean dosage was of 332.1 mg/day (min 100 max 400 mg/day). Responder rate was 78.6%. One patient discontinued LCM because of side-effects. There were no other reported side-effects. Preliminary data on the use of LCM in add-on in patients with BTRE indicate that this drug may represent a valid alternative as an add-on in this particular patient population. However, larger samples are necessary in order to draw definitive conclusions.