Add-on Therapy In Refractory Epilepsy Research Articles

Immunoglobulin use in childhood epilepsy

Background: Epilepsy's aetiology is well-known to include an immune component. Several clinical and laboratory research have discovered abnormalities in epileptic patients' immune system branches when compared to the general population. Such anomalies include immunoglobulin deficiencies (mainly immunoglobulin A and immunoglobulin G2), an increased prevalence of specific human leukocyte antigen types, and alterations in cytokine and interleukin profiles. In people with epilepsy, autoantibodies were discovered against glutamic acid decarboxylase, components of the voltage-gated potassium channel complex, and the N-methyl-D-aspartate, gamma-aminobutyric acid, a-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid, and glutamate receptor three receptors. Immune modulating drugs like corticosteroids and corticotrophin have also been demonstrated to help with seizures. In view of these findings, immunosuppressive medicine has potential as an add-on therapy for refractory epilepsy. Aim: We aimed to evaluate the efficacy of immunoglobulin in childhood epilepsy. Conclusion: Despite the fact that new medications are constantly being developed to treat intractable infantile epilepsy, the refractory rate remains high. Despite several investigations on the subject, predictive variables for a good intravenous immunoglobulin response have yet to be identified. In some epileptic disorders, such as idiopathic West syndrome and electrical status epilepticus during sleep, intravenous immunoglobulin appears to be beneficial.

Clonazepam add-on therapy for refractory epilepsy in adults and children.

Epilepsy affects about 50 million people worldwide, nearly a quarter of whom have drug-refractory epilepsy. People with drug-refractory epilepsy have increased risks of premature death, injuries, psychosocial dysfunction, and a reduced quality of life. To assess the efficacy and tolerability of clonazepam when used as an add-on therapy for adults and children with refractory focal onset or generalised onset epileptic seizures, when compared with placebo or another antiepileptic agent. We searched the following databases on 14 September 2017: Cochrane Epilepsy Group Specialized Register, Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO), MEDLINE (Ovid 1946 to 14 September 2017), ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP). Double-blind randomised controlled studies of add-on clonazepam in people with refractory focal or generalised onset seizures, with a minimum treatment period of eight weeks. The studies could be of parallel or cross-over design. Two review authors independently selected studies for inclusion, extracted relevant data, and assessed trial quality. We contacted study authors for additional information. No double-blind randomised controlled trials met the inclusion criteria. There is no evidence from double-blind randomised controlled trials for or against the use of clonazepam as an add-on therapy for adults and children with refractory focal or generalised onset epileptic seizures.

Felbamate as an add-on therapy for refractory partial epilepsy

This review is an update of a previously published review in the Cochrane Database of Systematic Reviews (Issue 7, 2014) on 'Felbamate as an add-on therapy for refractory epilepsy'. Epilepsy is a chronic and disabling neurologic disorder, affecting approximately 1% of the population. Up to 30% of people with epilepsy have seizures that are resistant to currently available drugs. Felbamate is one of the second-generation antiepileptic drugs and we have assessed its effects as an add-on therapy to standard drugs in this review. To evaluate the efficacy and tolerability of felbamate versus placebo when used as an add-on treatment for people with refractory partial-onset epilepsy. For the latest update we searched the Cochrane Epilepsy Specialized Register, CENTRAL, MEDLINE, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform, up to 20 October 2016. There were no language and time restrictions. We reviewed the reference lists of retrieved studies to search for additional reports of relevant studies. We also contacted the manufacturers of felbamate and experts in the field for information about any unpublished or ongoing studies. Randomised placebo-controlled add-on studies of people of any age with refractory partial-onset seizures. The studies could be double-blind, single-blind or unblinded and could be of parallel or cross-over design. Two review authors independently selected studies for inclusion and extracted information. We resolved disagreements by discussion. If disagreements persisted, the third review author arbitrated. We assessed the following outcomes: 50% or greater reduction in seizure frequency; absolute or percentage reduction in seizure frequency; treatment withdrawal; adverse effects; quality of life. We included four randomised controlled trials with a total of 236 participants. Two trials were parallel design, the third had a two-period cross-over design, and the fourth had a three-period cross-over design. Two studies were at an unclear risk of bias for random sequence generation and allocation concealment. These two studies did not include any description of their methods for outcome assessment and performance blinding (i.e. participants or doctors). Two studies were at high risk of bias for incomplete outcome data. Due to significant methodological heterogeneity, clinical heterogeneity and differences in outcome measures, it was not possible to perform a meta-analysis of the results. Only one study reported 50% or greater reduction in seizure frequency. One study reported absolute and percentage reduction in seizure frequency compared to placebo, P values were 0.046 and 0.018, respectively. One study reported percentage reduction in seizure frequency compared to placebo, but there were no P values. Adverse effects rates were higher during the felbamate period than the placebo period, particularly headache, nausea and dizziness. In view of the methodological deficiencies, limited number of individual studies and differences in outcome measures, we have found no reliable evidence to support the use of felbamate as an add-on therapy in people with refractory partial-onset epilepsy. A large-scale, randomised controlled trial conducted over a longer period of time is required to inform clinical practice.

Clobazam higher-evening differential dosing as an add-on therapy in refractory epilepsy

PurposeClobazam treatment tailored to the timing of patient's seizures may improve seizure control. We aim to describe the safety and efficacy of higher-evening differential dose of clobazam as add-on therapy in patients with night-time/early morning seizures. MethodDifferential dosing with higher evening dosing was started based on a high proportion of seizures (>80%) at nighttime (6p.m. to 6a.m.). Differential dosing was defined as providing more than 50% of the total daily dose of clobazam after 6p.m. ResultsTwenty-seven patients were treated with clobazam differential dosing as an add-on therapy. The median age was 9.1 years, with 11 (40.7%) females and median of the first follow-up was 2.7 months. Patients with differential dosing tolerated a higher median total clobazam dose of 0.8mg/kg/d at first follow-up, as compared to 0.6mg/kg/d in controls. In differential dose, the median percentage of the total clobazam dose administered in the evening was 66.7%. Differential dose patients exhibited a median seizure reduction of 75% as compared to 50% in controls (p<0.005). Patients with generalized seizures benefited the most from differential dosing with a 77.5% median seizure reduction, as compared to 50% in controls (p=0.017). ConclusionHigher-evening differential dose of clobazam improved seizure control in patients with predominantly nighttime and early-morning seizures. Chronotherapy tailored to the patients’ seizure susceptibility patterns may improve care in epilepsy patients as differential dosing may allow for higher overall treatment doses at times of greatest seizure susceptibility without increased side effects at other times.

Vigabatrin versus carbamazepine monotherapy for epilepsy.

This is an update of a Cochrane review first published in 2012 (Cochrane Database of Systematic Reviews 2012, Issue 1).The efficacy and safety of vigabatrin (VGB) as an add-on therapy for refractory epilepsy have been well established. However, this information needs to be weighed against the risk of development of visual field defects. Whether VGB monotherapy is an effective and safe treatment compared with the standard antiepileptic drug carbamazepine (CBZ) as monotherapy for epilepsy has not been systematically reviewed. To investigate the efficacy and safety of VGB versus CBZ monotherapy for epilepsy in children and adults. For the latest update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 3 of 4), MEDLINE (1948 to July 2015), EMBASE (1974 to July 2015) and the Chinese Biomedical Database (CBM) (1979 to July 2015). We searched trial registers and contacted themanufacturer of VGB and authors of included studies for additional information. We applied no language restrictions. Randomised controlled trials (RCTs) comparing VGB versus CBZ monotherapy for epilepsy. Two review authors independently assessed trial quality and extracted data. The primary outcome was time to treatment withdrawal. Secondary outcomes were time to achieve six-month and 12-month remission after randomisation, time to first seizure after randomisation and adverse events. We presented results as hazard ratios (HRs) with 95% confidence intervals (CIs) (time to event data) or as risk ratios (RRs) with 95% CIs (adverse events). Five studies involving a total of 734 participants were eligible for inclusion. We assessed only one study as good quality and the other four as poor quality. However, it was difficult to perform a meta-analysis by extracting aggregate data to synthesise the results as originally planned, mainly because not all studies reported the same outcomes as those chosen for this review. No significant differences favoured VGB or CBZ in terms of time to treatment withdrawal and time to achieve six-month remission after dose stabilisation from randomisation, but results did show a disadvantage for VGB on time to first seizure after randomisation. Compared with CBZ, VGB was associated with more occurrences of weight gain and fewer occurrences of skin rash and drowsiness. No differences in visual field defects and visual disturbances were noted. Data are currently insufficient to address the risk-benefit balance of VGB versus CBZ monotherapy for epilepsy. Given the high prevalence of visual field defects reported in an existing systematic review of observational studies (Maguire 2010), VGB monotherapy should be prescribed with caution for epilepsy and should not be considered a first-line choice. If necessary, the visual field should be frequently assessed. Future research should focus on investigating the reasons for visual field defects and exploring potential prevention strategies. Moreover, future monotherapy studies of epilepsy should report results according to the recommendations of the International League Against Epilepsy (ILAE) Commission, and methodological quality should be improved.

Felbamate as an add-on therapy for refractory epilepsy.

This review is an update of a previously published review in The Cochrane Database of Systematic Reviews (Issue 1, 2011) on 'Felbamate as an add-on therapy for refractory epilepsy'. Epilepsy is a chronic and disabling neurologic disorder, affecting approximately 1% of the population. Up to 30% of people with epilepsy have seizures that are resistant to currently available drugs. Felbamate is one of the second-generation antiepileptic drugs and its effects as an add-on therapy to standard drugs are assessed in this review. To evaluate the efficacy and tolerability of felbamate versus placebo when used as an add-on treatment for people with refractory partial-onset epilepsy. We searched the Cochrane Epilepsy Group Specialized Register (24 July 2013), the Cochrane Central Register of Controlled Trials (CENTRAL 2013, Issue 6), and PubMed (24 July 2013). This search was run for the original review on 20 May 2010. There were no language and time restrictions. We reviewed the reference lists of retrieved studies to search for additional reports of relevant studies. We also contacted the manufacturers of felbamate and experts in the field for information about any unpublished or ongoing studies. Randomized placebo-controlled add-on studies of people of any age with refractory partial-onset seizures. The studies could be double-blind, single-blind or unblinded and could be of parallel or crossover design. Two review authors independently selected studies for inclusion and extracted information. We resolved disagreements by discussion. If disagreements persisted, the third review author arbitrated. We assessed the following outcomes: 50% or greater reduction in seizure frequency; absolute or percentage reduction in seizure frequency; treatment withdrawal; adverse effects; quality of life. Three randomised controlled trials with a total of 153 participants were included. The first was a parallel design, the second had a two-period crossover design, and the third had a three-period crossover design. One study was at unclear risk of bias for random sequence generation and allocation concealment. And in the same study, there was no description of how to blind outcome assessment, performance blinding was for participants, might not be for doctors. Two studies were at high risk of bias for incomplete outcome data. Due to significant methodological heterogeneity, clinical heterogeneity and differences in outcome measures, it was not possible to perform a meta-analysis of the results. None of the three studies reported 50% or greater reduction in seizure frequency. Only one study reported absolute and percentage reduction in seizure frequency compared to placebo, P values were 0.046 and 0.018, respectively. Adverse effects rates were higher during the felbamate period than the placebo period, particularly headache, nausea and dizziness. In view of the methodological deficiencies, limited number of individual studies and differences in outcome measure, we have found no reliable evidence to support the use of felbamate as an add-on therapy in patients with refractory partial-onset epilepsy. A large-scale, randomised controlled trial conducted over a longer period of time is required to inform clinical practice.Since the last version of this review no new studies have been found.

Experimental re-evaluation of flunarizine as add-on antiepileptic therapy

Background:Experimental studies have found several calcium channel blockers with anticonvulsant property. Flunarizine is one of the most potent calcium channel blockers, which has shown anticonvulsant effect against pentylenetetrazole (PTZ) and maximal electroshock (MES)-induced seizures. However, further experimental and clinical trials have shown varied results. We conducted a PTZ model experimental study to re-evaluate the potential of flunarizine for add-on therapy in the management of refractory epilepsy.Materials and Methods:Experiments were conducted in PTZ model involving Swiss strain mice. Doses producing seizures in 50% and 99% mice, i.e. CD50 and CD99 values of PTZ were obtained from the dose-response study. Animals received graded, single dose of sodium valproate (100–300 mg/kg), lamotrigine (3–12 mg/kg) and flunarizine (5–20 mg/kg), and then each group of mice was injected with CD99 dose of PTZ (65mg/kg i.p.). Another group of mice received single ED50 dose (dose producing seizure protection in 50% mice) of sodium valproate and flunarizine separately in left and right side of abdomen. Results were analysed by Kruskal–Wallis ANOVA on Ranks test.Results:As compared to control, sodium valproate at 250 mg/kg and 300 mg/kg produced statistical significant seizure protection. At none of the pre-treatment dose levels of lamotrigine, the seizure score with PTZ differed significantly from that observed in the vehicle-treated group. Pre-treatment with flunarizine demonstrated dose-dependent decrease in the seizure score to PTZ administration. As compared to control group, flunarizine at 20 mg/kg produced statistical significant seizure protection.Conclusion:As combined use of sodium valproate and flunarizine has shown significant seizure protection in PTZ model, flunarizine has a potential for add-on therapy in refractory cases of partial seizures. It is therefore, we conclude that further experimental studies and multicenter clinical trials involving large sample size are needed to establish flunarizine as add-on therapy in refractory epilepsy.

Prevalence of visual field loss following exposure to vigabatrin therapy: A systematic review

Vigabatrin is an efficacious antiepileptic drug licensed as add-on therapy in refractory epilepsy and used in infantile spasms. Eight years after licensing, there emerged a strong and possibly causative association with bilateral visual field loss. We report a systematic review ascertaining the magnitude of risk of vigabatrin associated visual field loss (VAVFL) and any clinical predictors of risk. Electronic searches, including MEDLINE (1966-2009), EMBASE (1974-2009), and CINAHL (1982-2009), were conducted. Reports, published in full, of observational studies investigating the prevalence of visual field loss in patients with partial epilepsy treated with vigabatrin were included. Outcomes were the proportion with visual field loss, and the relative risk of VAVFL compared to similar nonexposed patients with epilepsy. Thirty-two studies were identified, which included 1,678 patients exposed to vigabatrin and 406 controls. Of the 1,678 exposed patients, 738 (44%) had visual field loss compared to just 30 (7%) among the 406 controls. The random-effects estimate for the proportion of adults with visual field loss was 52% [95% confidence interval (CI) 46-59]. The estimate for children was lower at 34% (95% CI 25-42). The relative risk for field loss in vigabatrin-exposed patients was 4.0 (95% CI 2.9-5.5). Larger mean cumulative dose of vigabatrin and increasing age were associated with a higher proportion of patients with visual field loss. Vigabatrin should be reserved for patients with epilepsy for whom there is no other alternative or for patients who have determined the benefit of ongoing treatment to outweigh the risk of VAVFL.

Efficacy of Clobazam as Add-on Therapy for Refractory Epilepsy

Clobazam (CLB) has proven efficacy against multiple seizure types. Although available in many countries, it is not approved by the US Food and Drug Administration. The objective of this study was to evaluate the usage patterns, efficacy, tolerability, and 1-year retention of CLB in patients with refractory epilepsy seen at a tertiary US epilepsy center. We retrospectively reviewed the use of CLB, 1 measure of efficacy (6-month seizure freedom), 1-year retention, and tolerability in patients with epilepsy who were prescribed CLB as part of their antiepileptic drug regimen at the Columbia Comprehensive Epilepsy Center over a 5-year period. Two hundred fifty-one patients were prescribed CLB, of which 62 were newly started on CLB at our center during this period (29 male and 33 female subjects; mean age, 43.9 years; range, 8-88 years). Clobazam dose ranged from 5 to 60 mg/d (mean, 23.9 mg/d). The mean number of previous antiepileptic drug trials per patient was 7.7. Of the 62 patients newly started on CLB, 7 patients (11.3%) became seizure-free for at least 6 months after introduction of CLB. Binary logistic regression was unable to identify any significant predictors of seizure freedom or CLB retention. Four patients remained seizure-free on CLB for more than 18 months. The Kaplan-Meier 12-month retention curve (n = 54 eligible patients) showed a 1-year retention rate of 61%. In this population of patients with highly refractory epilepsy at a US center, 11% of patients became seizure-free for at least 6 months after addition of CLB, and the 1-year retention rate was 61%.

Aggressive behavior of epilepsy patients in the course of levetiracetam add-on therapy: report of 33 mild to severe cases

Levetiracetam (LEV) was shown to be very efficacious and well tolerated as add-on therapy for refractory epilepsy. Here we report 33 patients with longstanding histories of epilepsy who experienced aggressive episodes during LEV therapy. This corresponds to 3.5% of LEV-treated patients as compared with less than 1% of patients not on LEV. Among these cases, 24 showed only moderate, partly transient irritability, with 10 patients requiring reduction or discontinuation of LEV. More strikingly, 9 patients displayed severe symptoms of aggression with physical violence and, in 2 cases, the need for psychiatric emergency treatment. One patient developed additional psychotic symptoms. We suggest that, specifically in patients with a previous history of aggression, behavioral tolerability of LEV should be carefully monitored.

Monotherapy trials: prerequisite data

Is it possible for an antiepileptic drug (AED) to be effective as add-on therapy in refractory epilepsy but ineffective as monotherapy for the same seizure type(s)? If the answer is ‘no’, why not award a new AED a monotherapy licence once it has been shown to be effective as adjunctive treatment in placebo controlled, dose-ranging studies in patients with difficult-to-control epilepsy? The recent comparative study between carbamazepine and remacemide, however, suggests that subtle pharmacokinetic/pharmacodynamic interactions between established and new AEDs can indicate efficacy in add-on studies that does not necessarily transfer to monotherapy. There is some evidence that an AED whose primary mechanism of action does not involve blockade of voltage-dependent sodium channels may do less well than carbamazepine in terms of efficacy end-points in a double-blind, head-to-head comparison. These observations lead to the conclusion that monotherapy trials are, indeed, required. They should be undertaken after proof of efficacy has been obtained using a single short presurgical AED withdrawal study backed up by a substantive dose-ranging phase III efficacy trial. There is no reason to recommend earlier assessment since the clinical need for new AEDs is in refractory epilepsy. The subsequent monotherapy trial programme should contain elements utilising comparative and withdrawal designs. Sponsors should be able to seek a licence for their drug either as a first choice treatment in newly diagnosed epilepsy or as substitution monotherapy once treatment with at least one other AED has failed.

Flunarizine as add-on therapy in refractory epilepsy: An open trial

We evaluated flunarizine as add-on therapy for control of refractory epilepsy in an open trial in 17 patients. Children received 10 mg/day and adults received 20 mg/day of flunarizine for 6 months. In eight patients, antiepileptic drug (AED) serum levels at baseline and at 3 months of flunarizine therapy were available. Six of the 17 patients had seizure reduction ⩾50%. Three of six had generalized tonic-clonic seizures (GTCS). Most of remaining patients were unchanged or had increased complex partial seizures (CPS). Three of the six patients with ⩾50% seizure reduction were treated with phenobarbital (PB) and phenytoin (PHT) combination. Addition of flunarizine caused no significant alteration in baseline serum AED levels. With the addition of flunarizine, seizure control in patients with GTCS was better than that of patients with CPS. Patients receiving combination PB and PHT treatment responded better with the addition of flunarizine than did those receiving other AED combinations. We conclude that flunarizine had some antiepileptic property as add-on therapy in 35% of our cases with refractory epilepsy.

Gabapentin is safe and effective add-on therapy in refractory epilepsy

Gabapentin is safe and effective add-on therapy in refractory epilepsy