Treatment Of Refractory Partial Epilepsy Research Articles

Talampanel as add-on therapy for the treatment of refractory partial epilepsy

Talampanel as add-on therapy for the treatment of refractory partial epilepsy

PERAMPANEL EFFECTIVENESS IN THE TREATMENT OF REFRACTERY PARTIAL ONSET EPILEPSY WITH OR WITHOUT SECONDARY GENERALIZATION: PHARMACOECONOMIC ANALYSIS FOR THE RUSSIAN FEDERATION HEALTH CARE SYSTEM

Perampanel (PER) is a novel drug for treatment of refractory partial epilepsy in patients≥12 y.o. with proven efficacy and safety. PER is registered and may also be used successfully as adjunctive treatment in therapy of primary generalized tonic-clonic seizures (PGTCS). Objective . To determine the effectiveness of perampanel and it`s clinical stability in patients at different dosing regimens, and evaluate the cost of treatment with perampanel in the Russian Health Care system. Materials and Methods . Results of open multicenter controlled randomized (phase III) international clinical trials in patients over 12 years of age were used. Modeling of the direct costs was based on (i) the probable treatment outcomes: i.e., no clinical effect, treatment cessation due to adverse events, seizures reduction of 50% and more, complete seizure termination, (ii) the expected number of the above outcomes all overRussia, and (iii) the inflation risks in the period until 2020. Results . The comparison of different clinical studies on adjunctive perampanel therapy in refractery partial epilepsy with or without secondary generalization as well as in primary generalized tonic-clonic seizures, reveales that the optimal daily dose of perampanel is 8 mg. Conclusion . Direct costs modeling was performed to estimate annual expenses (per patient) of the adjunctive perampanel therapy. When recalculated for all patients with refractory partial epilepsy and for all patients with PGTCS inRussia, the results indicate that the introduction of perampanel may reduce the costs by more than 40% (up to 4-7 bln. rubles) annually until 2020.

The RNS System: responsive cortical stimulation for the treatment of refractory partial epilepsy

The RNS® System is the first commercially available device to provide closed-loop responsive brain stimulation. The system includes a cranially implanted neurostimulator that continually monitors the electrocorticogram through one or two depth and/or subdural cortical strip leads that are placed at the seizure focus. When abnormal electrographic activity is detected, the neurostimulator delivers brief pulses of electrical stimulation to the seizure focus through the implanted leads. In November 2013, the US FDA approved the RNS System as an adjunctive therapy for patients with drug resistant, partial onset seizures who have undergone diagnostic testing that localized no more than 2 epileptogenic foci. Safety and effectiveness of the RNS System for the indicated patient population was demonstrated in a multicenter, randomized, sham-stimulation controlled 2-year pivotal study. An ongoing, prospective, long-term treatment study is currently gathering an additional 7 years of prospective safety and effectiveness data of the RNS System.

Pharmacoeconomic Outcomes for Pregabalin: A Systematic Review in Neuropathic Pain, Generalized Anxiety Disorder, and Epilepsy from a Spanish Perspective

Pregabalin is an anticonvulsant approved in Europe for the treatment of neuropathic pain, as an adjunct therapy for epileptic seizures, and recently for generalized anxiety disorder. The aim of this study was to conduct a systematic review to evaluate the cost-effectiveness of pregabalin associated with the treatment of its labeled indications from a societal perspective in Spain. Data from the MEDLINE database were searched using algorithms to identify relevant economic evaluations published in English or Spanish on pregabalin for the management of neuropathic pain, generalized anxiety disorder (GAD), and epilepsy in Spanish patients over the last 10years. In total, 52 potentially relevant abstracts were identified from the MEDLINE database. Twenty manuscripts met the inclusion criteria. The majority of the selected papers (14/20) evaluated pregabalin for neuropathic pain from a societal perspective in Spain (5 economic models of pregabalin vs. gabapentin, 4 economic analyses of pregabalin in comparison with usual care, 4 economic evaluations comparing pregabalin monotherapy with add-on strategies, and one that evaluated different times of initiating pregabalin therapy). Five studies analyzed the use of pregabalin in Spain for the management of GAD (one cost-effectiveness model that compared pregabalin with venlafaxine, 2 secondary analyses in benzodiazepine-refractory patients, and 2 studies evaluating pregabalin vs. usual care in patients refractory to standard regimens). The last manuscript described a cost-effectiveness model that compared pregabalin versus levetiracetam use for the treatment of refractory partial epilepsy. The majority of published evidence supports the possibility that pregabalin could be a cost-effective and/or cost-saving alternative for the treatment of refractory epilepsy, GAD, and neuropathic pain, in both treatment-naïve patients and in those who have demonstrated inadequate response or intolerance to previous therapy.

Talampanel as add-on therapy for the treatment of refractory partial epilepsy

Talampanel as add-on therapy for the treatment of refractory partial epilepsy

A new therapy for refractory partial epilepsy: Current shunt

A large number of epileptic patients suffer from refractory epilepsy, despite optimal treatment; thus these patients require new therapeutic approaches. Focal seizure activity is typically initiated in a fixed and localized region, which subsequently spreads to neighboring regions or more distant areas. At the initial onset of a seizure, the epileptic discharge will generate a relatively high voltage in seizure focus, and the discharge subsequently spreads to other relatively low-voltage regions. However, it is unknown whether seizure can be controlled through current shunt using a conduction microelectrode to conduct the epileptic discharge with a relatively high voltage in the seizure focus outside the brain. The current therapies for epilepsy, including drugs, resective surgery and neuromodulation, focus on inhibiting abnormal excessive or synchronous neuronal activity to control seizures; thus, the basic mechanism underlying these therapies is “inhibition”. In contrast, we proposed a “conduction” mechanism, whereby a current shunt with conduction electrode is used to control seizures. To our knowledge, this therapeutic strategy has not been previously reported, and we propose that this approach might be an alternative choice for the treatment of refractory partial epilepsy in the future.

Low‐frequency repetitive transcranial magnetic stimulation for the treatment of refractory partial epilepsy: A controlled clinical study

This study was designed to evaluate the therapeutic effect of low-frequency repetitive transcranial magnetic stimulation (rTMS) on patients with refractory partial epilepsy. Sixty-four patients with refractory focal epilepsy were screened and 60 patients were randomly divided into two groups by stimulation intensity: 90% (group 1) or 20% (group 2) of resting motor threshold (rMT). Seizure frequency and interictal EEG epileptic discharges were compared between the baseline and follow-up periods. Seizures significantly decreased following 2-weeks high intensity (90% rMT) rTMS treatment compared with baseline level (p < 0.05). rTMS also decreased interictal epilepsy discharges and improved the scales of Symptom Checklist-90 significantly (p < 0.05). Seizures and spikes in the follow-up period in the patients who received low intensity (20% rMT) rTMS did not show any difference compared with baseline data (p > 0.05, respectively). Low-frequency high intensity rTMS (90% rMT) delivered into the epileptogenic zone had a significant antiepileptic effect on patients with refractory partial seizures. rTMS treatment can also reduce the interictal epileptic discharge frequency and improve the psychological condition of these patients.

Short-term efficacy and safety of zonisamide as adjunctive treatment for refractory partial seizures: A multicenter open-label single-arm trial in Korean patients

ObjectiveTo evaluate the efficacy and safety of adjunctive zonisamide (ZNS) therapy in Korean adults with uncontrolled partial epilepsy. MethodsStudy patients had an average of at least one seizure per 4-week (averaged over a 12-week historical baseline) despite the use of one to three antiepileptic drugs. The starting dose of ZNS was 100mg/day, and was increased to 200mg/day after 2weeks. During the 12-week maintenance period, the dose of ZNS was adjusted to 200–400mg/day based on the physicians’ discretion. The global evaluation scale (GES) and quality of life (QOLIE-31) were also evaluated. ResultsA total of 121 patients were enrolled, of which 88 patients completed the study. The median percent reduction in weekly seizure frequency over the treatment period was 59.0%. The ≥50% and ≥75% responder rates were 57.3% and 38.5%, respectively. Seizure freedom over the treatment period was observed in 25 patients, but seizure freedom throughout the 16-week treatment period was attained in only 16 patients. On investigator's GES, 84 patients were considered improved, with 33 patients showing marked improvement. In QOLIE-31 scale, seizure worry improved significantly but emotional well-being deteriorated. Treatment-emergent adverse events (AEs) were reported in 80 patients. The most common AEs were dizziness (28.1%), somnolence (24.0%), anorexia (18.2%), headache (14.0%), nausea (13.2%), and weight loss (10.7%). Twenty-two patients discontinued the trial due to drug-related AEs. ConclusionsOur results suggest that adjunctive ZNS therapy for the treatment of refractory partial epilepsy, though efficacious, is associated with significant tolerability problems.

Low-Frequency Repetitive Transcranial Magnetic Stimulation for the Treatment of Refractory Partial Epilepsy

Seventeen refractory partial epilepsy patients were enrolled in an open-label study to evaluate the antiepileptic effect of low-frequency repetitive transcranial magnetic stimulation (rTMS). Seven of the patients had not obtained seizure-free status after epileptogenic focus resection surgery before they were enrolled in the study. All patients were treated with low-frequency rTMS which included 3 sessions per day (0.5 Hz, 90% RMT and 500 pulses each session) and lasted for 2 weeks. Seizure frequency, seizure days and epileptic discharges in the EEG obtained before, during and after stimulation were compared. The psychological conditions of all individual patients were evaluated with Symptom Checklist-90 (SCL-90) before and after rTMS treatment. Mean seizure frequencies per week significantly decreased in the following 4-week rTMS treatment period compared with the pretreatment period (14.09 vs. 5.63, p < 0.05, mean reduction of 60.02% in seizure frequency). Mean seizure days per week during the treatment period and the post-treatment period were lower than that of the pretreatment period (5.18 vs. 2.99 p < 0.05, mean reduction of 42.5% in seizure days). Mean epileptic discharges in the EEG decreased significantly during the treatment period compared to that of the pre-treatment period (78.60 vs. 66.09, p < 0.05, mean reduction of 15.9% in epileptic spikes discharges) in all 17 patients. Fourteen patients completed the test of Symptom Checklist-90 effectively. The scales of Global Severity Index, Depression, Anxiety, Phobic anxiety, Paranoid ideation, Psychoticism, Somatization, Obsession-compulsion, Interpersonal sensitivity, Hostility in patients decreased respectively at the post-treatment periods compared with those of the pre-treatment periods (P < 0.05). Low-frequency rTMS may have a significant antiepileptic effect in patients with refractory partial epilepsy. Additionally, our results indicate rTMS treatment can improve the psychological condition of these patients.

Treatment algorithms in refractory partial epilepsy

An algorithm is a "step-by-step procedure for solving a problem or accomplishing some end....in a finite number of steps." (Merriam-Webster, 2009). Medical algorithms are decision trees to help with diagnostic and therapeutic decisions. For the treatment of epilepsy there is no generally accepted treatment algorithm, as individual epilepsy centers follow different diagnostic and therapeutic guidelines. This article presents two algorithms to guide decisions in the treatment of refractory partial epilepsy. The treatment algorithm describes a stepwise diagnostic and therapeutic approach to intractable medial temporal and neocortical epilepsy. The surgical algorithm guides decisions in the surgical treatment of neocortical epilepsy.

Economic Evaluation of Add-on Levetiracetam for the Treatment of Refractory Partial Epilepsy in Korea

ObjectiveThis study estimated the expected cost-effectiveness ratio expressed as the incremental cost per seizure-free day (SFD) gained and the incremental cost per quality adjusted life year (QALY) gained when using levetiracetam (LEV) as add-on therapy from a third-party payer perspective.MethodsA 1-year dose-escalation decision-tree model comparing LEV plus standard therapy (ST) with ST alone was designed to combine transition probabilities, costs and outcomes. The short-term outcomes and probabilities were derived from a prospective, open-label clinical trial with 100 Korean adults with refractory partial epilepsy. All data for the direct medical costs were derived from Korean cost data extracted from reports published by the National Health Insurance Corporation.ResultsThe average gain in SFDs attributed to LEV add-on was 18.3 days per patient per year and the incremental cost-effectiveness ratios (ICERs) for LEV add-on were US$ 44 per SFD per patient and US$ 11,084 per QALY gained. All sensitivity analyses showed that the model was robust to the assumptions made.ConclusionThe economic evaluation indicates that, given a wide range of assumptions, the increased cost of treating patients having refractory partial epilepsy with LEV may be partially offset by a reduction in other direct medical costs. This reduction is a consequence of an increase in the number of SFDs and improved quality of life.

Long-term safety and efficacy of zonisamide in patients with refractory partial-onset epilepsy

To investigate whether zonisamide remains effective and well tolerated in the treatment of refractory partial epilepsy during long-term treatment and with flexible dosing in clinical practice. Patients with refractory partial epilepsy who completed a fixed-dose, randomized, double-blind clinical trial were recruited in an open-label extension study with adjustment of zonisamide and other antiepileptic drug dosage according to the treating physician's usual clinical practice. An intention-to-treat analysis of 317 patients showed that zonisamide was well tolerated with a predictable safety profile. Patient retention rates at 1, 2 and 3 years were 65.3%, 44.5% and 28.8%, respectively. Zonisamide treatment was associated with a maintained reduction in seizure frequency, with some patients achieving prolonged periods of seizure freedom. Flexible dosing with zonisamide demonstrated a good safety profile and sustained efficacy in the long-term adjunctive treatment of refractory partial epilepsy.

Potential of Levetiracetam in Mood Disorders

Levetiracetam is a newer antiepileptic agent that was first approved by the US FDA in 1999 as an adjunctive therapy for the treatment of refractory partial epilepsy in adults. Since then, it has been approved for a wider patient population, i.e. as adjunctive therapy for partial seizures in patients >4 years of age (worldwide) and as first-line monotherapy for partial seizures in patients >16 years of age (in Europe); and as adjunctive therapy for juvenile myoclonic seizures (in Europe and the US). It has a favourable pharmacokinetic profile and appears to act at a specific site in the CNS. Pharmacodynamic evidence indicates that levetiracetam indirectly facilitates GABAergic function, and an increasing body of evidence suggests an important role for GABA in the pathophysiology of mood disorders. Preclinical studies using animal models of depression, anxiety and mania provide evidence for levetiracetam as a mood stabiliser. Preliminary clinical evidence from case reports and open-label pilot studies indicates that the drug, both as add-on therapy and as monotherapy, has efficacy in a wide range of bipolar spectrum disorders. Most recently, a 31% remission rate was reported in patients with bipolar disorder who were in the depressed phase at baseline and who received levetiracetam as add-on therapy for 8 weeks in an open-label trial. While these results are encouraging, placebo-controlled data are needed to further clarify the role of levetiracetam in the treatment of mood disorders.

Efficacy of gabapentin therapy in children with refractory partial seizures

Thirty-two children with refractory partial epilepsy received open-label gabapentin as an additional medication to their antiepileptic drug regimen. Gabapentin was given in a dose ranging from 10 to 50 mg/kg per day (mean dose, 26.7 mg/kg daily). All patients had partial seizures with or without secondary generalization. Compared with baseline, 11 patients (34.4%) had a greater than 50% decrease in seizure frequency, and 4 (12.5%) had a 25% to 50% decrease in seizure frequency. Of the seven children who received the medication for 6 months or longer, two were seizure free and four were almost seizure free (having one seizure every few months). Mean gabapentin concentration was 4.8 μg/ml, and mean apparent clearance was 372 ml/kg per hour. The major reported side effects were behavioral. These consisted of hyperactivity, irritability, and agitation that occurred in patients with baseline mental retardation with attention deficit. We conclude that gabapentin can be a useful adjunctive medication in the treatment of refractory partial epilepsy in children. (J P EDIATR 1996;128:829-33)

Efficacy and tolerability study of ucb L059 in patients with refractory epilepsy

We compared the experimental drug ucb L059 with placebo as an add-on therapy in a single-blind, ascending-dose pilot study in 17 patients with refractory epilepsy. The dose of ucb L059 was increased every 4 weeks by 500 mg in a stepwise fashion from 500 to 2,000 mg/day, and patients were assessed at weekly intervals for efficacy and safety evaluation. Fourteen patients successfully completed 20 weeks of treatment with placebo and increasing doses of ucb L059. Three patients withdrew because of adverse events (AE) or lack of efficacy. Treatment with ucb L059 was associated with a significant reduction in partial seizures as compared with baseline or placebo. Six patients experienced >50% reduction in seizure frequency, and 3 others experienced a 25–50% reduction. ucb L059 was well tolerated, only mild or moderate AE were reported, including drowsiness, memory impairment, depression, and mood changes. No clinically significant changes in laboratory or safety evaluation was detected during treatment with ucb L059. A variable change in phenytoin (PHT) and ucb L059 was noted, with PHT serum concentrations increasing significantly in some patients. The results suggest that oral ucb L059 may be useful in the treatment of refractory partial epilepsy.

Effect of Gabapentin on the EEG of patients with refractory partial seizures

Gabapentin (GBP) is an effective drug in the treatment of refractory partial epilepsy, but the effect of GBP on the electroencephalogram (EEG) has not been studied. Serial EEGs were performed in 25 patients with refractory partial epilepsy, who took part in an open clinical trial of GBP as add-on therapy. About an equal number of patients had no change, better EEGs, and worse EEGs. Correlation was poor between EEG changes and change in seizure frequency. Thus, inclusion of EEGs in the protocol of a drug trial for epilepsy is probably not beneficial.

The New Anticonvulsant Drugs

Several new antiepileptic drugs offer a worthwhile alternative when standard antiepileptic drugs have failed. Suggestions have been made to improve the risk-benefit ratio of the new antiepileptic agents. More specifically, vigabatrin, which is a very useful and well tolerated new antiepileptic drug for refractory partial epilepsy, should be started at a low dosage of 0.5 g/day with increments of 0.5 g/day every week. Daily dosages exceeding 3 g/day should be restricted to patients with improvement. If necessary, the daily dosage of vigabatrin should be withdrawn slowly, i.e. by not more than 1 g/week. Lamotrigine is also a beneficial new drug for refractory partial and generalized seizures. However, the drug is associated with rash. In patients also receiving valproic acid (sodium valproate) [which inhibits the metabolism of lamotrigine], the incidence of rash can be reduced by slow titration of 25mg every other day for the first week and 25mg per day for the second week. Rare hypersensitivity reactions, e.g. Stevens-Johnson syndrome, remain a problem. The risk-benefit ratio of felbamate has recently been compromised by fatal aplastic anaemia and fatal liver disease in a number of patients. In general, patients should be withdrawn from felbamate, if possible, until further clarification of its definitive risk-benefit ratio. Finally, gabapentin is a very safe add-on medication. Its remarkably low potential to cause adverse effects makes it a welcome addition for the treatment of refractory partial epilepsy.

Efficacy of felbamate in therapy for partial epilepsy in children

Thirty children (2 to 17 years of age) with refractory partial seizures received open-label felbamate as an add-on medication to their background antiepileptic drugs. The dose was increased up to a maximum of 45 mg/kg. Compared with baseline seizure activity, there was a 53% decrease in seizure frequency during felbamate therapy; 50% of the patients had more than a 50% decrease in seizure frequency. Patients older than 10 years of age were more likely to have a favorable response. Age correlated positively with felbamate concentrations and negatively with apparent felbamate clearance. Transient weight loss occurred in 57% of the patients; the weight loss was maximal after 12 weeks of initiation of felbamate, and subsided after the twentieth week of treatment. Anorexia and insomnia were reported in 20% and 16% of the patients, respectively. Adverse effects were generally tolerable; felbamate therapy was discontinued because of side effects in only one patient, because of a rash. We conclude that felbamate can be a useful and well-tolerated medication in the treatment of refractory partial epilepsy in children. However, increased apparent clearance of this drug in younger children should be considered in treatment of this age group.

Zonisamide for add-on treatment of refractory partial epilepsy: a European double-blind trial

The new antiepileptic drug zonisamide was evaluated in a European multicenter parallel-group double-blind trial as add-on treatment for 139 patients with refractory partial epilepsy. During treatment with zonisamide complex partial seizures decreased by 27.7% compared to placebo ( P < 0.05) and the median rate dropped from 12/month with no changes in the placebo group ( P < 0.007). During the 12-week double-blind phase a 50% reduction of all seizures was recorded in 29.9% of the patients treated with zonisamide vs. 9.4% during placebo. Complete remission was observed during treatment with zonisamide in 6.2%. The plasma concentrations of the concomitant antiepileptic drugs did not change markedly when zonisamide was added. Adverse events, mostly fatigue, somnolence, dizziness and ataxia, occurred in 59.2% of the patients compared to 27.9% during placebo. Zonisamide was withdrawn in two patients due to adverse events. Kidney stones were not observed nor any relevant clinical chemistry or hematological changes. Zonisamide is an effective antiepileptic drug for add-on treatment of refractory partial epilepsy.