Topiramate in refractory epilepsy: a prospective observational study

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, > or =50% 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 dose-response and dose-toxicity relationships may reflect different neurobiologies causing refractory epilepsy and differential efficacy of AED combinations.     

妥泰加用治疗成人难治性部分性癫痫的疗效观察

目的：观察妥泰（TPM）加用治疗成人难治性部分性伴或不伴随继发身性发作（GTCS）的疗效,安全性及耐受性。方法：56例在不动原用抗癫痫药（AEDs)的基础上加用TPM治疗20周、前8周为加量期,后12周为维持治疗的稳定期,治疗前（基础期）记录好作频率,用药情况。体重等作为自身对照。TPM自25mg/d开始,逐渐加量,目标剂量为200mg/d,治疗及治疗结束各查基础AEDs血药浓度进行比较,治疗结束行全面疗效分析。结果：TPM加用治疗20周后,与基础期发作频率比较,64．29％患者发作频率降低≥50％;25．00％,患者发生频率降低≥75％＜100％;16．07％完全不发。不良反应轻至中度,但与合AEDs的多少有关。50％患者体重可有不同程度的下降。TPM对止痛民西平及丙戊酸钠血药浓度影响不大。结论：TMP是治疗难治性部分性伴或不伴继发GTCS的表效的药物。     

Levetiracetam in refractory epilepsy: a prospective observational study.

This prospective open-label study used flexible dosing schedules of levetiracetam (LEV) in patients with refractory epilepsy attending a single centre to explore its effectiveness in everyday clinical practice. One hundred and fifty-six patients with uncontrolled localisation-related or idiopathic-generalised epilepsy were prescribed adjunctive LEV following a 3-month baseline. The primary end points were seizure freedom for at least 6 months, > or = 50% reduction (responder) or <50% reduction for 6 months, or discontinuation of LEV due to lack of efficacy, adverse effects or both. Overall, 40 (26%) patients became seizure free on adjunctive LEV, including 8 (40%) with idiopathic-generalised epilepsy. Twenty-five (63%) of the seizure-free patients took 1000 mg LEV per day or less. A further 33 (21%) patients were classified as responders. LEV was withdrawn in 46 (29%) patients (27 adverse effects, 8 lack of efficacy, 11 both). Intolerable sedation, reported by 20 (13%) patients, was the commonest complaint leading to treatment failure. Behavioural side effects led to LEV withdrawal in 7 (5%) patients. LEV is an effective adjunctive treatment for refractory idiopathic and localisation-related epilepsies. Many patients who responded optimally to LEV did so at 1000 mg per day or less.     

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.     

Retrospective study of topiramate in a paediatric population with intractable epilepsy showing promising effects in the West syndrome patients

Topiramate (TPM) is a new anti-epileptic drug with proven efficacy against partial seizures in adults. Its use in children is less well documented. In a retrospective study, 41 patients with intractable childhood epilepsy were treated with TPM as add-on therapy for an average period of 15 months. They were classified according to seizure type and etiology. The dose was titrated for effect and ranged between 2 and 24 mg/kg/d. Of the 41 patients being treated, six became seizure free, ten had a seizure reduction of more than 75% and eight a seizure reduction of between 50 and 75%. The most remarkable effect was seen in seven patients with West syndrome. Of these, four patients became seizure free and one had more than 75% seizure reduction. Adverse effects including sedation, fatigue, difficulties with verbal expression and anorexia were noted in 15 patients. None of these effects were important enough to interrupt treatment. We conclude that TPM as adjunctive therapy is a promising drug in children with intractable epilepsy, especially in the patients with West syndrome.     

Double-Blind, Placebo-Controlled Trial of Topiramate (600 mg Daily) for the Treatment of Refractory Partial Epilepsy

Summary: Purpose : We wished to evaluate adjunctive therapy for partial-onset seizures with topiramate (TPM) for efficacy and safety in a double-blind, placebo-controlled, randomized, parallel-group study.
Methods : Sixty outpatients with epilepsy (47 men and 13 women, mean age 32.9 years) were studied. All had a documented history of partial-onset seizures with or without secondarily generalized seizures. After an 8-week baseline during which patients had at least one seizure per week, 30 patients each were randomized to TPM 300 mg twice daily (b.i.d.) or placebo for 12 weeks.
Results : TPM was significantly superior to placebo, as indicated by all efficacy assessments: greater median percent reduction from baseline in the average monthly seizure rate (46 vs. -12%, p = 0.004); greater number of treatment responders (patients with 50% reduction in seizure rate) (47 vs. 10%, p = 0.001), and better investigator (p = 0.002) and patient (p = 0.010) global assessments of treatment. Among TPM-treated patients, the most commonly reported adverse events (AE) were headache, somnolence, fatigue, dizziness, and abnormal thinking. Most AE were mild or moderate in severity.
Conclusions : The results of the present trial indicate that TPM 600 mgiday is effective in the treatment of refractory partial-onset seizures with or without secondarily generalized seizures.     

Levetiracetam in clinical use—a prospective observational study

This prospective observational study explored the efficacy and tolerability of levetiracetam (LEV) in a prospective series of 200 patients with refractory epilepsy attending a single epilepsy service. Patients were started on adjunctive LEV using one of two titration schedules (slow and fast) and patients were studied for at least 6 months after commencing LEV. Fifty-three patients had severe learning disabilities. 14.3% became seizure free, 57.7% showed >50% reduction, 15.4% showed seizure increase. Patients with learning disability showed less positive but still very worthwhile results. A highly significant improvement in clinical outcomes overall is shown (P<0.0001). 56.6% showed no adverse effects, 27.4% showed minor adverse effects, 16% were withdrawn. The most common adverse effect causing drug withdrawal was seizure exacerbation (12%) which was much commoner in primary generalised epilepsies (P=0.00035). LEV appears to be an effective and well-tolerated anti-epileptic drug in drug resistant partial epilepsies.     

Levetiracetam for people with mental retardation and refractory epilepsy

Levetiracetam (LEV) is a novel antiepileptic drug (AED) with efficacy against a wide range of seizures types. The aim of this observational study was to assess its effectiveness in patients with mental retardation and refractory epilepsy. Sixty-four patients were started on adjunctive LEV after a 3-month baseline. LEV was initially dosed at 250 mg daily and increased by 250 mg every 2 weeks thereafter according to clinical response. Caregivers rated the patient's sleep, appetite, alertness, and behavior as poor (1), reasonable (2), or good (3) at each clinic visit. Patients were reviewed until one of four endpoints was reached: seizure freedom for at least 6 months, > or = 50% reduction in seizure frequency (responder) over a 6-month period, <50% reduction in seizure frequency (marginal effect) over a 6-month period, or LEV withdrawal due to lack of efficacy, adverse effects, or both. Twenty-four (38%) patients became seizure-free, 10 of whom were controlled on LEV 250 mg twice daily. An additional 18 (28%) patients were classified as responders, and 8 (12%) reported only marginal benefit from adjunctive LEV. Fourteen (22%) patients discontinued LEV (6 worsening seizures, 1 lack of efficacy, 7 adverse effects). Caregivers rated combined sleep, appetite, alertness, and behavior scores as "improved" at the end of follow-up (P<0.001). LEV improved seizure control in the majority of patients with mental retardation and may also have enhanced their quality of life.     

Adjunctive Therapy in Resistant Epilepsy

Summary: : It is now established that the overall prognosis for epilepsy is good and that remission will occur in at least 75% of patients following adequate treatment with monotherapy. Patients who fail to respond to monotherapy, who are not suitable for surgery, and who continue to have frequent seizures may have to be considered for an alternative drug regimen. A review of the literature indicates that complete seizure control with adjunctive treatment is rare, but improved seizure control can be obtained in up to 40% of patients. In a study of clobazam as adjunctive treatment, 60% (N = 20) of our patients responded to treatment initially and 33% maintained an improvement over an 18-month period. In 31 patients who failed to respond to carbamazepine as monotherapy, primidone (N = 16) or valproate (N = 15) were prescribed as adjunctive treatment. One patient obtained complete freedom from seizures and 14 (45%) had a > 50% reduction in seizure frequency. Suggested indications for the use of additive treatment in epilepsy are discussed.     

Topiramate as add-on drug in children,adolescents and young adults with Lennox-Gastaut syndrome: an Italian multicentric study

The purpose of the study was to evaluate the efficacy and safety of topiramate (TPM) as adjunctive therapy in children, adolescents and young adults with Lennox-Gastaut syndrome (LGS). We performed a prospective open label add-on study in 45 patients (age 4-34 years, mean 15.9 years) with LGS and refractory seizures. TPM was added to one or two other baseline drugs and the efficacy was rated according to seizure type and frequency. TPM was initiated at the daily dose of 0.5-1 mg/kg, followed by a 2-week titration at increments of 1-3 mg/kg/24 h, up to a maximum daily dose of 12 mg/kg. After a mean period of 15.8 months of treatment (range 3-98 months), at a mean dose of 4.1 mg/kg/24 h (range 1.4-12 mg/kg), 18 patients (40%) had a seizure reduction more than 50%. TPM appeared to be effective mainly in major seizures (drop attacks, tonic and tonic-clonic seizures). Mild to moderate adverse events were present in 24 patients (53.3%), mostly represented by drowsiness, nervousness, hyporexia with or without weight loss and cognitive dulling. In conclusion, TPM adjunctive therapy reduced the number of drop attacks and major motor seizures in 40% of patients with LGS and produced only mild or moderate adverse events.     

Early clinical experience with lacosamide as adjunctive therapy in patients with refractory focal epilepsy and nocturnal seizures

This retrospective study reports the early experience with lacosamide (LCM) as adjunctive therapy in Spanish patients with refractory focal epilepsy. Sixty patients (mean age 38.3 years, 54% women, mean epilepsy duration 27.2 years, mean seizure rate 9.7/month, and 28% with mainly nocturnal seizures) taking ≥2 antiepileptic drugs (mean 2.2) were included. LCM maintenance doses were 200, 300, 400, and 500mg/day in 31, 16, 10, and 3 patients, respectively. Patients were followed up for 13-24 months. Twenty-eight patients (47%) reported a ≥50% reduction in seizure frequency. A ≥50% reduction in seizure frequency was reported by 65% and 40% of patients in the nocturnal seizure and diurnal seizure subgroups, respectively (p>0.05). Of the 28 responders, 2 achieved stable periods of seizure freedom of 6 and 11 months after starting LCM. Twenty patients (33%) reported drug-related adverse events (AEs); the most common was dizziness (16 patients). LCM was withdrawn in 8 patients (13%). There were no serious AEs. These results support the efficacy and safety of adjunctive LCM in patients with partial-onset seizures.     

Efficacy and safety of levetiracetam as adjunctive treatment of refractory partial seizures in a multicentre open-label single-arm trial in Korean patients.

This prospective, open-label study evaluated the efficacy and safety of adjunctive levetiracetam (LEV) in Korean adults with uncontrolled partial epilepsy. Study patients had to have an average of at least 1 and not more than 14 partial seizures per month (averaged over a 3-month historical baseline) despite the use of one or two AEDs. Patients initially received LEV 1000 mg/day (administered bid) and could increase to 2000 mg/day after 2 weeks, and to 3000 mg/day after another 2 weeks, to obtain adequate seizure control. During the 12-week maintenance period, the dose of LEV could be increased or decreased once if seizure control was insufficient or tolerability warranted, respectively. Seizure count and adverse events (AEs) were recorded by patients. Global evaluation scale (GES) and quality of life (QOLIE-31) were also evaluated. A total of 100 patients were enrolled and 92 patients completed the study. The median percent reduction in weekly seizure frequency over the treatment period was 43.2%. The >or=50% and >or=75% responder rates were 45.4% and 36.1%, respectively. Seizure freedom throughout the 16-week treatment period was observed in 17 patients. On investigator's GES, 81 patients were considered improved, with 41 patients showing marked improvement. Most QOLIE-31 scales improved significantly. Treatment-emergent AEs were reported in 59 patients. Three most common AEs were somnolence (36%), dizziness (12%), and headache (8%). Adjunctive LEV therapy was effective and well-tolerated in Korean adults with refractory partial epilepsy.     

妥泰添加治疗Lennox—Gastaut综合征的临床观察

目的：研究妥泰辅助治疗Lennox-Gastaut综合征的安全性。方法：C地13例Lennox-Gastaut综合征患者进行妥泰进行的添加、开放性自身对照研究，以治疗前3个月的发作频度为基础，治疗后平均观察12个月（6－20月）。结果应用妥泰后，3例患者（23．1％）癫痫发作停止，6例（46．2％），癫痫发作频度减少≥50％，总有效率69．3％，妥泰对Lennox-Gastaut综合征的各型癫痫发作均有较好效果。脑电图有改善的倾,妥泰受性较好，治疗前后各项实验室检查未见有临床意义的异常改变。结论：妥泰是辅助Lennox-Gastaut综合征的一种实安全，有效的新型抗癫痫药。     

Postmarketing experience with topiramate and cognition

Ideal antiepileptic drugs (AEDs) are designed to stop seizures with limited central nervous system (CNS) side effects. However, CNS-related treatment-emergent adverse events (TEAEs) often occur in patients receiving AEDs. Topiramate (TPM) is an AED proven to be safe and effective as adjunctive treatment for epilepsy patients with partial seizures. Double-blind, placebo-controlled, multicenter trials demonstrated potential effects on cognition. The P.A.D.S. (post-marketing antiepileptic drug survey) group, a cooperative group of 14 epilepsy centers that collaborate on obtaining data about new AEDs and devices, prospectively collected standardized data forms before and during treatment with TPM for epilepsy, and analyzed the postmarketing experience of CNS TEAEs with TPM. Our results from 701 treated patients show that cognitive complaints were the most common reason to discontinue TPM. The presence of complaints did have predictive value if the patient would discontinue TPM, although was not specific as to when discontinuation would occur. The spectrum of complaints in our open-label prospective multicenter postmarketing study was similar to those observed in controlled clinical trials. We were unable to demonstrate a specific population, dose titration, or concomitant AED that was at risk to discontinue treatment. We conclude that most patients treated with TPM will continue therapy beyond 6 months. Cognitive complaints and not efficacy reflect the primary reason for discontinuing therapy. Psychomotor slowing was the most common complaint, yet most patients elect to continue treatment, with "better" or "much better" ratings of both seizure and global improvement during treatment.     

Topiramate in long-term treatment of epilepsy in the intellectually disabled

Background To study the effectiveness of topiramate (TPM) in refractory epilepsy in patients who have intellectual disability (ID). Methods A representative population sample of 57 patients with ID (age range 2–61, mean 32.8) was administered add-on TPM for drug-refractory epilepsy. Results Seizure freedom for at least for 6 months was attained by 10 (17%), and seizure reduction of ≥ 50% by further 26 (46%). Less than 50% decrease in seizure frequency was found in 16 (29%). TPM was more efficacious in localisation-related than in generalised epilepsies (81% vs. 50%, P = 0.019). An at least 50% decrease in seizure frequency was achieved by patients with temporal lobe epilepsy in 100%, continuous spike–waves during sleep syndrome in 75%, Lennox–Gastaut syndrome in 52%, and those with infantile spasms in 25% of cases. As great decrease in seizure frequency was found in most patients with cortical dysplasia (83%), acquired encephalopathy with mesial temporal sclerosis (MTS) (75%), and genetic disease associated with MTS (66%). Adverse effects occurred in 10% including two (3%) with seizure aggravation and three (5%) necessitating discontinuation. Conclusion TPM is an effective antiepileptic drug which is of value in treating people with seizures that are resistant to other antiepileptic medication. As a broad-spectrum drug it may substitute for polypharmacy and, at the same time decrease adverse effects and costs of therapy.     

Lacosamide in refractory mixed pediatric epilepsy: a prospective add-on study

Lacosamide is a new antiepileptic drug that is currently approved by the US Food and Drug Administration (FDA) for adults 17 years or older for partial-onset seizures. The authors reviewed 21 pediatric patients (<17 years) with various seizure types who were started on oral lacosamide as part of a prospective add-on study as adjunctive therapy for refractory epilepsy. Five patients were excluded due to less than 3 months of meaningful follow-up. Maintenance dosages used ranged from 2.4 to 19.4 mg/kg/d. Eight of 16 (50%) patients had greater than 50% reduction in seizure frequency with adjunctive lacosamide therapy. Eight (50%) patients had generalized epilepsy including 4 with Lennox-Gastaut syndrome. Lacosamide was effective therapy for most seizure types but was particularly effective for partial-onset seizures. Lacosamide was effective in treating 5 of 8 (62.5%) localization-related epilepsies but only 2 of 8 (25%) generalized epilepsies, both Lennox-Gastaut syndrome patients with greater than 90% seizure reduction. None of these very refractory patients remained seizure free.     

The efficacy of topiramate in adult refractory status epilepticus: experience of a tertiary care center

Refractory status epilepticus (RSE) occurs in patients with SE when they fail to respond to traditional medical therapy. Because there are very few case reports of topiramate (TPM) treatment of RSE in adult patients, we examined our experience with TPM with regard to its safety and efficacy in seizure termination in RSE in an adult patient population. We report a retrospective review of 35 adult patients with RSE who were treated with TPM in addition to other antiepileptic drugs (AEDs) between 2003 and 2010. After failure of initial treatments of benzodiazepines and weight-based intravenous loading doses of standard AEDs, TPM tablets were crushed and administered via nasogastric tube. Data were collected on age, gender, history of epilepsy, etiology of RSE, daily dose of TPM, co-therapeutic agents, treatment response, and disposition. Following initiation of TPM use and discontinuation of continuous intravenous anesthetics with no additional AEDs administered, cumulative cessation of RSE in patients was 4/35 (11%) at one day, 10/35 (29%) at two days, and 14/35 (40%) at three days. However, when including all patients and comparing the two patient groups in which RSE was or was not terminated within three days of initiating TPM as the last or not last AED given, there was no significant difference. Time to TPM response was not associated with the type of seizures, etiology of SE, or whether there was a history of epilepsy. There were no documented side effects or complications of therapy with TPM. This study provides support for the use of TPM as an adjunctive agent in the treatment of RSE.     

Topiramate: effect on EEG interictal abnormalities and background activity in patients affected by focal epilepsy

PURPOSE: To evaluate the effects of topiramate (TPM) on interictal epileptiform abnormalities (IEA) and background activity by means of a computerized EEG analysis, in adult patients affected by focal epilepsy, with or without secondarily generalization, treated with TPM as adjunctive therapy or monotherapy. METHODS: Twenty-four patients affected by symptomatic or cryptogenic focal epilepsy underwent long-term video-EEG recording before and after TPM addition (mean dose 175+/-25 mg per day). RESULTS: TPM addition induced a significant reduction of both partial and secondarily generalized tonic-clonic (SGTC) seizures; treatment responder patients (seizure reduction > or = 50%) were 19 out of 24 patients (79.1%), of whom 5 were seizure-free. Quantitative analysis of IEA showed a significant decrease in the mean number of spikes/10 min during TPM therapy ( 4.2+/-4.2 versus 2.2+/-4.4; P<0.003 ). The analysis of spatial distribution of interictal spikes showed that such reduction was more evident at the level of the epileptogenic area rather than on the spreading component. Statistical analysis revealed only a significant decrease of mean relative power of alpha band in the EEG spectral content, recorded at rest in a group of 18 out of 24 epileptic patients during TPM therapy. In addition, during TPM treatment we observed a significant reduction in alpha reactivity without any important changes of alpha indexes (peak frequency and median frequency). CONCLUSION: These findings suggest that TPM has a strong inhibitory effect on IEA, probably acting on the generating processes, and, if used at low dosage and gradually titrated, seems to have only mild interferences with EEG background activity.     

A pooled analysis of adjunctive topiramate in refractory partial epilepsy

OBJECTIVES: To evaluate the impact of different dosages of topiramate (TPM) add-on to stable antiepileptic therapy for refractory partial epilepsy in adults. MATERIAL AND METHODS: Pooled intention-to-treat analysis of six similarly designed double-blind, placebo-controlled trials, including 481 patients treated with doses of TPM 200, 400, 600 and 800 mg/day, and 265 patients receiving placebo. RESULTS: Seizures were reduced by >/=50% from baseline in 41% of TPM-treated patients and 15% of placebo-treated patients (P < 0.001); 5 and 0.8%, respectively, were seizure-free (P < 0.003). TPM was significantly better than placebo regardless of gender, age, baseline seizure rate as well as number and type of concomitant antiepileptic drugs. Efficacy was statistically significant in favour of TPM at all dose levels: at least 50% seizure reduction was achieved in 40% of patients with 200 mg, 41% with 400 mg, 44% with 600 mg and 41% with 800 mg TPM when compared with 15% with placebo (P 相似文献   

Effect of topiramate for patients with intractable epilepsy

The effects of topiramate (TPM) were evaluated in 51 patients with intractable epilepsy. Callosotomy and hemispherotomy were performed in 16 patients and one patient before the administration of TPM, respectively. The 50% responder rate (50%RR) was recorded in 39% of the total patient population and in 58% of patients with symptomatic location-related epilepsy (SLE). TPM was most effective for frontal lobe epilepsy (FLE), and the 50%RR was recorded in 88% of those patients. TPM (50%RR) was more effective in secondary generalized seizures (in 75%) and complex partial seizures (in 67%) in comparison to that of tonic-clonic seizures (in 44%) and drop attacks (in 29%). Seventy-one percent of the patients with atypical absence seizures increased seizure frequency. The 50%RR was recorded in 22% of the patients who underwent epilepsy surgery, and 29% of those patients also showed seizure aggravation due to TPM. These results suggest the efficacy of TPM for intractable epilepsy.