Treatment Of Refractory Partial Seizures Research Articles

Computational study on gabapentin as a potential therapy for partial seizures

US Food and Drug Administration (USFDA) approved gabapentin as an adjuvant treatment for refractory partial seizures and several diverse disorders. The drug has a relatively safe profile and is well tolerated; however, awareness is required to monitor the patient's medication, its misuse, and how to approach better patient fate. Despite the enormous scientific hypothesis encircling the drug, there is a requisite to research further about the novelty of the drug. The review delineates the drug profile, synthesis, pharmacology, ADME properties, and computational study of gabapentin.

Rare Combination of Adverse Effects Associated With Lamotrigine Treatment

Lamotrigine (LTG) is an antiepileptic drug which is widely used in treatment of epilepsy. It is effective as an adjunctive treatment of refractory partial seizures and idiopathic generalized epilepsy in adults and children. However, patients are subject to some adverse effects with ongoing medication of LTG. Rare events associated with LTG medication such as hematological abnormalities and skin lesions have utmost clinical importance and often cause drug withdrawal. We present a case of a 23-year-old male who had leukopenia, thrombocytopenia and rash associated with LTG treatment. Clinician must be aware of serious side effects of LTG especially at the beginning of the treatment. Serious adverse effects such as leukopenia, thrombocytopenia and rash should be considered along with the other insignificant complaints such as nausea, dizziness and malaise. J Neurol Res. 2018;8(1-2):10-12 doi: https://doi.org/10.14740/jnr442w

Long-Term Effects of Anterior Thalamic Nucleus Deep Brain Stimulation on Spatial Learning in the Pilocarpine Model of Temporal Lobe Epilepsy

Cognitive impairment is a significant comorbidity of temporal lobe epilepsy that is associated with extensive hippocampal cell loss. Deep brain stimulation (DBS) of the anterior thalamic nucleus (ANT) has been used for the treatment of refractory partial seizures. In the pilocarpine model of epilepsy, ANT DBS applied during status epilepticus (SE) reduces hippocampal inflammation and apoptosis. When given to chronic epileptic animals it reduces hippocampal excitability and seizure frequency. Here, we tested whether ANT DBS delivered during SE and the silent phase of the pilocarpine model would reduce cognitive impairment when animals became chronically epileptic. SE was induced by a systemic pilocarpine injection (320 mg/kg). Immediately after SE onset, rats were assigned to receive DBS during the first six hours of SE (n = 8; DBSa group) or during SE + the silent period (i.e., 6 h/day until the animals developed the first spontaneous recurrent seizure; n = 10; DBSs group). Four months following SE, animals underwent water maze testing and histological evaluation. Nonstimulated chronic epileptic animals (n = 13; PCTL group) and age-matched naïve rats (n = 11, CTL group) were used as controls. Results were analyzed by repeated-measures analyses of variance (RM_ANOVA) and one-way ANOVAs, followed by Newman-Keuls post hoc tests. Although all groups learned the spatial task, epileptic animals with or without DBS spent significantly less time in the platform quadrant, denoting a spatial memory deficit (p < 0.02). Despite these negative behavioral results, we found that animals given DBS had a significantly higher number of cells in the CA1 region and dentate gyrus. Mossy fiber sprouting was similar among all epileptic groups. Despite lesser hippocampal neuronal loss, ANT DBS delivered either during SE or during SE and the silent phase of the pilocarpine model did not mitigate memory deficits in chronic epileptic rats.

Rare Combination of Adverse Effects Associated With Lamotrigine Treatment

Lamotrigine (LTG) is an antiepileptic drug which is widely used in treatment of epilepsy. It is effective as an adjunctive treatment of refractory partial seizures and idiopathic generalized epilepsy in adults and children. However, patients are subject to some adverse effects with ongoing medication of LTG. Rare events associated with LTG medication such as hematological abnormalities and skin lesions have utmost clinical importance and often cause drug withdrawal. We present a case of a 23-year-old male who had leukopenia, thrombocytopenia and rash associated with LTG treatment. Clinician must be aware of serious side effects of LTG especially at the beginning of the treatment. Serious adverse effects such as leukopenia, thrombocytopenia and rash should be considered along with the other insignificant complaints such as nausea, dizziness and malaise. J Neurol Res. 2018;8(1-2):10-12 doi: https://doi.org/10.14740/jnr442w

Adjunctive brivaracetam for patients with refractory partial seizures: A meta-analysis of randomized placebo-controlled trials

To evaluate the clinical efficacy and safety of the newer antiepileptic drug (AED), brivaracetam (BRV), as adjunctive therapy for adults with refractory partial seizures. Randomized-controlled trials (RCTs) of BRV in the treatment of refractory partial seizure were systematically reviewed and quantified using fixed- or random-effects meta-analysis. 50% responder rate, seizure free rate and adverse events in the treatment period were analyzed as outcomes for measuring efficacy and safety. Pooled effects of risk ratio (RR) and 95% confidence interval (CI) were derived from meta-analysis implemented in RevMan 5.2. Five RCTs were identified for inclusion, and included a total of 1639 patients. The pooled RR of BRV vs. placebo as adjunctive therapy for adults with refractory partial seizure was 1.80 (95% CI 1.43-2.26, P < 0.00001) for 50% responder rates, 4.11 (95% CI 1.39-12.21, P = 0.01) for seizure free rates, 1.08 (95% CI 0.73-1.59; P = 0.70) for withdrawal rates. There was no evidence of a statistically significant association between the use of BRV and most adverse events, except somnolence (RR 1.63, 95% CI 1.08-2.45, P = 0.02) and fatigue (RR 2.05, 95% CI 1.19-3.53, P = 0.009). This study confirmed significant effects of BRV as adjunctive treatment of refractory partial seizures. This study also demonstrated the good tolerability profile of adjunctive BRV for patients with epilepsy. Further large clinical and pharmacovigilance studies are needed to investigate the long-term efficacy and safety of BRV and, furthermore, to suggest an optimal BRV dosage for clinical use.

Evaluation of the efficacy and safety of topiramate as adjunctive drug in the treatment of refractory partial seizures with Meta-analysis

Background Epilepsy is a chronic neurological condition characterized by paroxysm of seizures due to abnormal electrical discharge from central nervous system neurons. Several new antiepileptic drugs (AEDs) were listed over the past two decades, and they were believed to be equally effective and have better tolerability and side effect profiles. This paper aims to evaluate the efficacy and safety of adjunctive topiramate in refractory partial seizures. Methods Relevant research articles about randomized controlled trials of adjunctive topiramate in refractory partial seizures, with topiramate, Topamax, add-on treatment, adjunctive treatment, add-on therapy, adjunctive therapy, refractory partial seizure, refractory partial epilepsy both in Chinese and English as retrieval words, were retrieved from PubMed (1995-2014), Cochrane Central Register of Controlled Trials (CENTRAL, 1995-2014), The Cochrane Database of Systematic Reviews (CDSR, 1995-2014), China National Knowledge Infrastructure (CNKI, 1995-2014) and Wanfang Data (1999-2014). Two reviewers independently evaluated the quality of the included articles and abstracted the data. A Meta-analysis was conducted using RevMan 5.0 software. Results According to the enrollment criteria, 13 prospective, randomized controlled clinical trials with a total of 1622 patients were finally selected. The proportions of patients with reduction in seizure frequency ≥ 50% ( OR = 3.710, 95% CI: 2.870-4.810; P = 0.000), ≥ 75% ( OR = 7.220, 95% CI: 3.310-15.750; P = 0.000) and seizure free ( OR = 3.380, 95%CI: 1.720-6.640; P = 0.000) in topiramate group were significantly higher than that in control group. The treatment withdrawal ratio was significantly higher compared to placebo in 600 mg/d and 800 mg/d subgroups, but not in 200 mg/d subgroup (200 mg/d: OR = 2.170, 95%CI: 0.470-9.950, P = 0.320; 600 mg/d: OR = 2.090, 95%CI: 1.020-4.270, P = 0.040; 800 mg/d: OR = 8.000, 95%CI: 1.390-46.140, P = 0.020). The common side effects included somnolence, anorexia, ataxia, aprosexia, dizziness, fatigue, nausea, thinking abnormality, paraesthesia and weight loss. The occurrence rate of side effects in topiramate group was higher than that in control group. Conclusions Topiramate is effective when added to existing therapy in patients with refractory partial seizures. The withdrawal rate of 200 mg/d topiramate is similar to control group. Compared with the control group, adverse effects are more common but mild or moderate, mainly related with the central nervous system. However, trials included in this study are of relatively short duration, and provide no evidence for the long-term efficacy of topiramate. doi: 10.3969/j.issn.1672-6731.2014.11.007

Perampanel: A new agent for adjunctive treatment of partial seizures

The pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of perampanel are reviewed. Perampanel, a first-in-class antiepileptic agent, was recently approved for use as adjunctive therapy for the treatment of resistant partial seizures in patients 12 years of age and older. It acts as a selective, noncompetitive antagonist at postsynaptic α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors. Perampanel exhibits linear pharmacokinetics and has a half-life of approximately 105 hours. The drug is rapidly and nearly completely absorbed after oral administration, achieving its maximum serum concentration in approximately 1 hour. Its bioavailability is nearly complete. Several efficacy studies have consistently demonstrated the utility of perampanel as adjunctive therapy for the treatment of refractory partial seizures with or without secondary generalization. Drug interactions have been noted with agents that induce cytochrome P-450 hepatic enzymes, including other antiepileptics, and alterations in perampanel dosing may be necessary when these medications are used concurrently. Adverse effects associated with perampanel use are primarily related to the central nervous system, and slow dosage adjustment and bedtime administration are recommended to maximize patient tolerance. The drug's labeling includes a boxed warning about the possible induction of serious adverse psychiatric and behavioral reactions that necessitate close monitoring. Perampanel is not recommended for individuals with severe liver disease or severely compromised kidney function, including those undergoing hemodialysis. Perampanel is a novel antiepileptic agent specifically designed to exhibit selective noncompetitive antagonist activity at AMPA receptors. Perampanel has consistently demonstrated the ability to control treatment-refractory partial seizures in many patients.

Vigabatrin Retinal Toxicity First Detected with Electroretinographic Changes: A Case Report.

Vigabatrin is an effective antiepileptic drug (AED) typically used in the treatment of refractory partial seizures and infantile spasms. Its use, however, is limited due to the concern of retinal toxicity and subsequent visual field defects. Herewith in we describe a case of vigabatrin toxicity that illustrates electroretinographic (ERG) changes occur before imaging and visual field deterioration. Decrease in maximal ERG b: a ratio was observed before thinning of the retinal nerve fiber layer (RNFL) on optical coherence tomography (OCT).

Trigeminal Nerve Stimulation May Not be Effective for the Treatment of Refractory Partial Seizures

Trigeminal Nerve Stimulation May Not be Effective for the Treatment of Refractory Partial Seizures

Efficacy and safety of adjunctive perampanel for the treatment of refractory partial seizures: A pooled analysis of three phase III studies

Three phase III studies (304 [ClinicalTrials.gov identifier: NCT00699972], 305 [NCT00699582], 306 [NCT00700310]) evaluated perampanel, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, as adjunctive therapy for refractory partial seizures. We report post hoc analyses of pooled study data by randomized dose. Patients with partial seizures despite receiving 1-3 antiepileptic drugs were randomized to once-daily placebo, perampanel 8 or 12 mg (studies 304, 305), or placebo, perampanel 2, 4, or 8 mg (study 306). Studies included a 6-week baseline period and double-blind treatment phase (6-week titration; 13-week maintenance). Primary end points were median change in partial seizure frequency (baseline vs. double-blind phase) and percentage of patients achieving ≥ 50% reduction in seizure frequency (baseline vs. maintenance). Here, these end points, together with secondary, exploratory, and safety end points, were assessed using pooled study data. The pooled intent-to-treat analysis set (randomized, treated patients with any seizure data) included 1,478 patients. Median changes in partial seizure frequency were greater with perampanel than placebo (perampanel 4 mg, -23.3%; 8 mg, -28.8%; 12 mg, -27.2%; placebo, -12.8%; p < 0.01, each dose vs. placebo), as were 50% responder rates (perampanel 4 mg, 28.5%; 8 mg, 35.3%; 12 mg, 35.0%; placebo, 19.3%; p < 0.05, each dose vs. placebo). In addition, median changes in complex partial plus secondary generalized seizure frequency were also greater with perampanel than placebo (perampanel 4 mg, -31.2%; 8 mg, -35.6%; 12 mg, -28.6%; placebo, -13.9%). Perampanel was generally well tolerated. The most frequent treatment-emergent adverse events (TEAEs) were dizziness, somnolence, and headache. Most TEAEs were mild/moderate; relatively few patients experienced severe TEAEs (placebo, 5.4%; perampanel, 8.9%) or serious TEAEs (placebo, 5.0%; perampanel, 5.5%). There were no deaths and no clinically important mean changes in laboratory values, electrocardiography (ECG) findings, or vital signs. Perampanel reduced partial seizure frequency and improved responder rates compared with placebo, with an acceptable tolerability profile.

Efficacy and Tolerability of SPN-804, a Novel, Once-Daily, Extended-Release Formulation of Oxcarbazepine: Adjunctive Treatment of Refractory Partial Seizures in a North American Subpopulation (P02.213)

Efficacy and Tolerability of SPN-804, a Novel, Once-Daily, Extended-Release Formulation of Oxcarbazepine: Adjunctive Treatment of Refractory Partial Seizures in a North American Subpopulation (P02.213)

Vigabatrin-associated retinal damage - potential biochemical mechanisms

Vigabatrin (VGB), an irreversible inhibitor of gamma-aminobutyric acid (GABA) transaminase, is approved as adjunct treatment of refractory partial seizures as well as infantile spasms. Although VGB has been proven to be effective, its use is limited by the risk of retinopathy and associated peripheral visual field defects. This review describes and analyzes current literature related to potential pathophysiologic mechanisms underlying VGB-mediated cellular toxicity. Animal data suggest that GABA mediates neural excitotoxicity. The amino acid taurine is concentrated in retinal cells, and deficiency of this amino acid may be involved in VGB-mediated retinal degeneration and possible phototoxicity.

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.

Neurosteroids as endogenous regulators of seizure susceptibility and use in the treatment of epilepsy.

Neurosteroids such as allopregnanolone are positive allosteric modulators of GABAA receptors with powerful antiseizure activity in diverse animal models. Neurosteroids may be endogenous regulators of seizure susceptibility, for example, in catamenial epilepsy. Clinical trials with the synthetic neurosteroid analog ganaxolone in the treatment of refractory partial seizures and infantile spasms have been encouraging. Neurosteroids and analogs such as ganaxolone show promise in the treatment of diverse forms of epilepsy. For an expanded treatment of this topic see Jasper's basic mechanisms of the epilepsies, 4th ed. (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, eds) published by Oxford University Press (available on the National Library of Medicine Bookshelf [NCBI] at www.ncbi.nlm.nih.gov/books).

A comparison of pregabalin, lamotrigine, and placebo as adjunctive therapy in patients with refractory partial-onset seizures

This study assessed the comparative efficacy of pregabalin for refractory partial seizures. Four-hundred and thirty-four patients with partial seizures were randomized to pregabalin, lamotrigine, or placebo as adjunctive therapy for 17 weeks of double-blind treatment. In phase I (11 weeks), pregabalin was titrated over 1 week and lamotrigine over 5 weeks to fixed dosages of 300mg/day for both. In phase II (6 weeks), patients not yet seizure-free were increased to pregabalin 600mg/day or lamotrigine 400mg/day. During phase I, there was a nonsignificant trend toward a greater reduction in seizures with pregabalin versus placebo and lamotrigine. Across the 17 weeks of treatment, pregabalin showed a median percentage reduction from baseline in seizure frequency of -20.0% (p=.001) versus placebo, and -9.7% (p=.080) versus lamotrigine. The responder rate (> or =50% reduction in seizure frequency) for pregabalin exceeded that of placebo (36% vs 21%; p=.007) and lamotrigine (36% vs 24%; p=.04). Adverse events were consistent with the known safety profiles of pregabalin and lamotrigine. Pregabalin was demonstrated to be noninferior to lamotrigine in the treatment of refractory partial seizures. Overall conclusions were complicated by an unusually large and heterogeneous placebo response.

Evaluation of sleep quality in patients with refractory seizures who undergo epilepsy surgery

The aim of the study was to evaluate excessive daytime sleepiness and subjective sleep quality in patients who undergo epilepsy surgery for treatment of refractory partial seizures. Forty-eight patients were enrolled in this research study. All of them were evaluated 2 days before and 3 months after the surgery. Two questionnaires were used to assess daytime sleepiness (Epworth Sleepiness Scale [ESS]) and sleep quality (Pittsburgh Sleep Quality Index [PSQI]). Global PSQI was high (mean = 5.65 SD = 3.71) before the surgical procedure ( P < 0.001). PSQI evaluation revealed higher and statistically significant scores in three components as well as in the global score, when analyzed by predominance of daytime or nocturnal seizures. ESS and PSQI scores were also analyzed by gender, antiepileptic drug class, age, and seizure frequency, with no significant differences. We concluded that patients with partial recurrent seizures of temporal origin have poor subjective sleep quality that improves significantly after epilepsy surgery.

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.

Zonisamide in the management of epilepsy—Japanese experience

Zonisamide (Zonegran ®), a novel antiepileptic drug (AED) approved in Europe for the adjunctive treatment of refractory partial seizures in adults, has undergone extensive evaluation in pre- and post-marketing double-blind and open-label studies in Japan (where zonisamide is used widely to treat partial and generalised seizures in adults and children). These data indicate that the clinical benefit of zonisamide extends across a range of seizure types and patient ages. In an analysis based on a mixture of controlled and open studies in adults and children with partial seizures, 51–57% responded to zonisamide treatment (achieving ≥50% reduction in baseline seizure frequency). Efficacy extends across a range of generalised seizures and 22–66% of adults and children experiencing tonic–clonic, tonic, clonic, myoclonic or absence seizures responded to treatment. Even greater responder rates have been reported when zonisamide was used as monotherapy for partial seizures and generalised seizures in patients refractory to other AEDs or with newly diagnosed epilepsy. Zonisamide is also efficacious in paediatric epilepsy syndromes, including Lennox-Gastaut Syndrome, West Syndrome and Ohtahara Syndrome. Across the spectrum of epilepsy syndromes studied, zonisamide is well-tolerated with a low incidence of adverse events, which are generally mild and CNS-related. These data indicate that zonisamide represents a valuable broad-spectrum option for the treatment of epilepsy.

Long-term efficacy of levetiracetam for partial seizures

To obtain descriptive safety and efficacy data for long-term levetiracetam therapy and to allow patients benefiting from add-on levetiracetam to continue treatment until the drug was available commercially. This long-term, noncomparative, open-label, follow-up study was conducted at 36 US sites. Patients with refractory partial epileptic seizures were eligible if they had benefited from add-on levetiracetam therapy in a previous study and wished to continue treatment. The levetiracetam dose was individualized over the range of 1,000-4,000 mg/day. Withdrawal of concomitant AEDs to allow levetiracetam monotherapy was permitted. Patients were evaluated every 12 weeks and followed for up to 4 years. Median total seizure frequency per week was the primary efficacy variable. A total of 280 subjects, most of whom had refractory partial seizures with or without secondary generalization, were evaluated. Most were receiving either one (34.6%) or two (53.2%) concomitant antiepileptic drugs (AEDs) at entry. Overall, 199 (71.1%) subjects completed the study and 81 (28.9%) withdrew prematurely, most commonly due to loss or lack of efficacy or adverse events. The median total seizure frequency per week (0.7 at the selection visit) remained stable. The probability of being seizure-free during the first 12 weeks was 13.4% and 3.7% by week 216. Twenty-five (8.9%) subjects received levetiracetam monotherapy for at least 100 days. Levetiracetam was safe and well tolerated; the most common levetiracetam-related adverse events were dizziness (6.8%), convulsion (5.7%), and somnolence (5.0%). Efficacy and safety were maintained during long-term levetiracetam treatment of refractory partial seizures.

Epilepsy in children: the evidence for new antiepileptic drugs

Childhood epilepsy remains a challenge to treat. Despite the availability of antiepileptic drugs (AEDs), >25% of children with childhood epilepsy continue to have seizures. Conventional AEDs have been the mainstay of therapy for many years but are often poorly tolerated and have a tendency to interact with other drugs. Current American Academy of Neurology guidelines support the use of four of the newer AEDs (gabapentin, lamotrigine, topiramate, and oxcarbazepine) as adjunctive treatment of refractory partial seizures in children, based on class I evidence. This paper includes a summary of the results from a recent randomized, double-blind, placebo-controlled study, which shows that levetiracetam is also effective and well tolerated in this pediatric population, and provides evidence supporting its use in refractory partial seizures in children.