The treatment of neonatal seizures: focus on Levetiracetam.

Neonatal crises are a common problem in the first month, where phenobarbital and phenytoin are still the most frequently used medication in treatment. Whereas, Levetiracetam (LEV) is an antiepileptic drug (AED) with an innovative action. Our present review is updated on the current literature regarding the use of LEV in neonatal seizures treatment. The available data is analyzed to assess LEV pharmacokinetics, efficacy and tolerability in neonatal crises treatment. Several clinical trials, prospective and retrospective, comparative and pharmacokinetic studies were evaluated in LEV pharmacokinetics, efficacy, dosage, route of administration and side effects. Many cases were reported on neonatal seizures control in using LEV in certain clinical conditions. In spite of the limitations in current studies available, which have evaluated LEV efficacy and safety in neonatal crises treatment, the authors still believe that LEV seems to be a promising and useful AED in the treatment for neonatal seizures, but likewise further studies are required to better define LEV efficacy and tolerability in term and preterm neonates.

Weight regain after discontinuation of topiramate treatment in patients with migraine: a prospective observational study.

PURPOSE: To monitor weight regain after therapy discontinuation in patients with migraine experiencing weight loss during topiramate (TPM) treatment. METHODS: Patients with migraine without aura were enrolled in this observational prospective study. Weight, body mass index (BMI), waist circumference, systolic and diastolic blood pressure, plasma levels of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, leptin, and ghrelin, and homeostatic model assessment of insulin resistance (HOMA-IR) were evaluated before starting TPM (T1), at 3 (T2) and 6 (T3) months of treatment and 6 months after withdrawal of TPM (T4). Weight loss/regain was considered as a change of 5% of pre-TPM body weight. RESULTS: A total of 241 patients were analyzed. Of these, 87 (36%) patients experienced weight loss on TPM medication. During TPM therapy significant reductions in mean values of weight (p<0.001), BMI (p<0.001), waist circumference (p<0.01), HOMA-IR (p<0.01), and leptin (p<0.01) were observed. After TPM discontinuation, all of these parameters showed a clear trend to increase at T4, achieving pre-TPM values in 27 patients. Among potential predictors, only HOMA-IR before starting TPM (parameter estimate=1.36, effect size=0.75; p=0.006) was significantly associated with weight regain after therapy discontinuation. CONCLUSIONS: Loss of body weight is a reversible effect, which at 6 months after TPM discontinuation shows a clear trend to return to baseline values. HOMA-IR is the only predictive factor of weight regain.

Characterization of the adverse events profile of placebo-treated patients in randomized controlled trials on drug-resistant focal epilepsies.

In epilepsy trials a substantial proportion of patients receiving placebo has some improvement or experience adverse events (AEs) which match those related to active drug. The characterization of factors influencing these responses is crucial for a better comprehension of study results and to improve design of new trials. Seventy-one placebo-controlled, double-blind trials in drug-resistant focal epilepsies has been selected. The effect of multiple factors on some outcome measures were explored using a meta-regression model. For subjective and objective AEs, risk difference (RD) was calculated and entered in an inverse variance-weighted linear meta-regression model as independent variable to evaluate the relationship with data reported in placebo-treated patients. The number of study arms influence the percentage of patients withdrawing because of AEs and the highest dose of the experimental drug used in each RCT correlates with withdrawal because of AEs and with subjective AEs. Higher titration speed is associated with lower percentages of responders and higher reporting of both objective and subjective AEs. The correlation between proportions of placebo-treated patients with subjective and objective neurological AEs and relative RD, was significant (P = 0.002 r = 0.364 and P < 0.001 r = 0.650, respectively). Efficacy and tolerability outcomes of the placebo groups are intrinsically tied to the trial methodology and to the outcomes observed in patients treated with the active drug. The correlation for objective and subjective AEs between RD and the placebo-treated patients suggest that investigators are influenced by factors which operate within each specific trial.

Successful Treatment of Refractory Seizures With Rufinamide in Children With Schizencephaly: Report of 3 Cases.

Schizencephaly is an uncommon malformation of cortical development. Patients with schizencephaly present with a broad range of severe neurologic symptoms including pharmacoresistant epilepsy. Rufinamide is a new antiepileptic drug approved for use as adjunctive therapy of seizures associated with Lennox-Gastaut syndrome and it is also effective for refractory partial seizures. We report 3 cases of pediatric patients aged 7.2, 8.1, and 10.1 years, respectively, with intractable epilepsy associated with bilateral open-lip schizencephaly and septo-optic dysplasia. The follow-up ranged from 3.8 to 4.1 years. In our patients, the introduction of rufinamide as adjunctive drug led to a dramatic decline in the number of seizures and an improvement in EEG epileptic activity without side effects. Rufinamide seems to be efficacious and safe in patients with epileptic encephalopathies associated with pharmacoresistant epilepsy; further and larger clinical reports and controlled studies could confirm the usefulness of this anticonvulsant drug.

Adverse events of placebo-treated, drug-resistant, focal epileptic patients in randomized controlled trials: a systematic review.

Health-related quality of life of patients with epilepsy is heavily influenced by antiepileptic drug (AED) tolerability. However, an accepted method for precise assessment of AED-induced adverse events (AEs) has not yet been established. Assessment of tolerability and of the frequency of predefined AEs among drug-resistant epilepsy patients through an analysis of placebo-treated patients from randomized controlled studies (RCTs) performed in patients with partial onset epilepsies (POS) and evaluation of factors which may influence the occurrence of AEs in these patients are the objectives of this study. We searched all double-blind, placebo-controlled trials investigating any AED on adult patients with POS and extracted both for patients treated with placebo and for those treated with the active drug, number of patients, number of responders, number of patients withdrawing because of AEs, number of patients with AEs, and number of patients with 11 predefined AEs. We also explored the effect of multiple factors on AEs reporting. Seventy-nine RCTs were included in our study with 12,594 patients, 6,793 of whom randomized to placebo. In placebo-treated patients, overall responder rate was 15.2 %, proportion of placebo-treated patients withdrawing because of AEs was 3.9 %, and proportion of patients with AE was 60.3 %. The four most frequently reported AEs were headache (12.4 %) somnolence (8.6 %), dizziness (8.2 %), and fatigue (7.9 %). Several factors were found to influence these outcomes. Several factors influence AEs' appearance in RCTs. Among the most important, we found the expectations of patients and doctors and their attitudes on the positive or negative effect of a drug.

Can ACTH therapy improve the long-term outcome of drug-resistant frontal lobe epilepsy?

Frontal lobe epilepsy is a common focal epilepsy in children and is often difficult to treat. Adrenocorticotropic hormone (ACTH) or steroids have been used for patients with several forms of medically intractable epilepsy. We evaluated the short, medium, and long-term evolution of patients with frontal lobe epilepsy and secondary bilateral synchrony on the EEG, who received ACTH treatment. Patients were recruited for an add-on trial during clinical practice, and data was retrospectively analysed. The study group comprised 6 patients treated with ACTH. The effects of ACTH were assessed in the short term (at the end of a 6-week period of ACTH treatment), medium term (at 6 months after the end of treatment), and long term (at 12 months after the end of treatment). At short-term follow-up, ACTH treatment was effective for all types of seizures in 5 of 6 patients and ineffective in 1 patient. All patients who were seizure-free at the end of ACTH treatment maintained an excellent outcome, remaining seizure-free at the end of follow-up. Our study demonstrates that ACTH may represent an effective treatment for frontal lobe epilepsy with secondary bilateral synchrony. Further double-blind prospective studies are required to confirm our initial findings.

Eslicarbazepine acetate: an update on efficacy and safety in epilepsy.

Epilepsy is a common neurological disorder. Despite a broad range of commonly used antiepileptic drugs, approximately 30% of patients with epilepsy have drug resistance or encounter significant adverse effects. Eslicarbazepine acetate is a new central nervous system-active compound with anticonvulsant activity whose mechanism of action is by blocking the voltage-gated sodium channel. Eslicarbazepine acetate was approved by the European Medicines Agency and launched onto the European market in 2009 for adjunctive treatment in adult subjects of partial-onset seizures, with or without secondary generalization. This article provides an overview on the recent studies on eslicarbazepine acetate in the treatment of drug-resistant partial epilepsy. Efficacy and safety of this drug for partial-onset seizures were assessed in four randomized clinical trials with responder rates ranged between 17% and 43%. Adverse events were usually mild to moderate in intensity and the most common were dizziness, somnolence, nausea, diplopia, headache, vomiting, abnormal coordination, blurred vision, vertigo and fatigue. Eslicarbazepine acetate is not recommended below 18 years, but a published phase II trial had the main goal to evaluate the pharmacokinetics, efficacy and safety of this drug in pediatric population. Eslicarbazepine acetate appears to be a safe and effective drug with a linear pharmacokinetics, very low potential for drug-drug interactions and therefore it can offer a valid alternative to current antiepileptic drugs. Additionally, it is undergoing investigation for monotherapy in subjects with partial epilepsy, and other neurological and psychiatric disorders.

Lacosamide in pediatric and adult patients: comparison of efficacy and safety.

PURPOSE: This multicenter, prospective study investigates the efficacy and safety of lacosamide adjunctive therapy in pediatric and adult patients with uncontrolled epilepsy. METHOD: This study was carried out between September 2010 and December 2011 at 16 Italian and 1 German neurologic centers. Lacosamide was added to the baseline therapy at a starting dose of 1 mg/kg/day in patients aged <16 years (group A) and 100 mg daily in subjects aged 16 and older (group B), and titrated to the target dose, ranging from 3 to 12 mg/kg/day or from 100 to 600 mg daily, respectively. After completing the titration period, patients entered a 12-month maintenance period and they were followed up at 3, 6 and 12 months. The primary assessment of efficacy was based on the change from baseline in seizure frequency per 28 days and was evaluated at 3, 6 and 12 months as follows: number and proportion of 100% responders, 50% responders, non-responders and worsening patients. Safety evaluation was also performed at 3, 6 and 12 months. RESULTS: A total of 118 patients (59 group A, 59 group B) with uncontrolled generalized and focal epilepsy were enrolled. Patient mean±SD age was 15.9±6.80 years and the age range was 4-38 years. At 3-month evaluation, of 118 treated patients 56 subjects (47.4% group A; 47.4% group B; p=0.8537) experienced at least a 50% reduction in seizure frequency. At 6 and 12-month follow-up, the 50% responders were 57 (52.5% group A; 44.1% group B; p=0.4612) and 51 (47.4% group A; 39% group B; p=0.4573), respectively. Thirty-five subjects (30.5% group A; 28.8% group B; p=1) experienced side effects during the treatment period. The most common adverse events were dyspepsia for group A and dizziness for group B. CONCLUSION: Lacosamide may be a useful and safe pharmacological treatment option for both pediatric and adult patients with uncontrolled seizures.

The adverse event profile of lacosamide: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: Defining the tolerability and safety profile of recently marketed antiepileptic drugs, such as lacosamide (LCM), is a prerequisite for their optimal utilization in clinical practice. We aimed to identify any adverse event (AE) associated with LCM treatment by conducting a systematic review and meta-analysis of all available randomized controlled trials (RCTs). We also evaluated the association of serious AEs with LCM, the proportion of study withdrawals due to intolerable AEs at different LCM doses, and whether the tolerability profile of LCM differs according to the disorder in which it was investigated. METHODS: We searched MEDLINE and Cochrane CENTRAL to May 2011 for LCM RCTs. Additional studies were identified from reference lists of retrieved papers and from online clinical databases. We selected placebo-controlled, double-blind RCTs and investigated the therapeutic effects of oral LCM in adults with any condition. AEs were assessed for their association with LCM after identification/exclusion of synonyms, rare AEs, and non-assessable AEs. We used risk differences to evaluate the association of any (99% confidence intervals [CIs]) or serious AEs (95% CIs) with LCM and to investigate dose-response relationships of identified AEs. KEY FINDINGS: Ten RCTs (three in pharmacoresistant epilepsy, four in neuropathic pain, one in migraine, one in fibromyalgia, and one in knee osteoarthritis) were included in our study. Their duration varied from 12-18 weeks. The total number of patients included was 3,148. No serious AE was significantly associated with LCM treatment. Of 21 identified AEs, 11 (52%) were found to be significantly associated with LCM. The number of AEs significantly associated with LCM increased with increasing dose: one at 200 mg/day (dizziness); six at 400 mg/day (dizziness, vertigo, abnormal coordination, abnormal vision, nausea, and vomiting); nine at 600 mg/day (dizziness, vertigo, ataxia, balance disorder, diplopia, fatigue, nausea, vomiting, and tremor). The proportion of AE-related study withdrawals also significantly increased with increasing dose. LCM AEs tended to occur more frequently in patients with drug-resistant epilepsy compared with patients with other disorders. SIGNIFICANCE: A range of AEs suggestive of vestibulocerebellar dysfunction is significantly associated with LCM treatment and their incidence increases with increasing doses.

Lacosamide in patients with pharmacoresistant epilepsy.

INTRODUCTION: Lacosamide is a novel antiepileptic drug licensed in the US and Europe as adjunctive therapy for partial-onset seizures in adults. The efficacy, safety, tolerability and favorable pharmacokinetic profile in the adult population suggest that lacosamide could be of benefit for patients with partial-onset seizures. AREAS COVERED: This paper reviews the available evidence and most recent data concerning the efficacy, safety, tolerability and pharmacokinetics of lacosamide in adults, as well as in the pediatric population. EXPERT OPINION: Lacosamide is one of the newest drugs of the antiepileptic armamentarium, and it is expected to compete directly with compounds that are currently used for adjunctive therapy in adults with refractory partial epilepsy. The intravenous formulation may be used for replacement therapy in patients temporarily unable to take oral medication. An apparent lack of sedative or cognitive effects might render this drug preferable in patients with mental insufficiency and/or epileptic encephalopathy.

Efficacy of rufinamide in drug-resistant epilepsy: a meta-analysis.

Rufinamide is a new orally active antiepileptic drug that has been found to be effective in the treatment of partial seizures and drop attacks associated with Lennox-Gastaut syndrome. We performed a quantitative analysis of the efficacy of this new antiepileptic drug from all double-blind, add-on, randomized, placebo-controlled clinical trials published to date. Data from 918 patients were studied. The number of patients per study varied from 25 to 262. Rufinamide was efficacious in doses up to 45 mg/kg daily when provided as adjunctive therapy in patients with Lennox-Gastaut syndrome and other drug-resistant epilepsies. Further studies are needed to confirm and expand these findings.

Hormonal and reproductive disturbances in epileptic male patients: emerging issues.

OBJECTIVE: To review the relationship between epilepsy, antiepileptic drugs and reproductive function. METHODS: Pertinent articles were identified through a computer PubMed search. References of selected articles were hand searched for additional citations. CONCLUSIONS: Disturbances of reproductive endocrine hormones occur more frequently in men with epilepsy than in the general population; they manifest as loss of libido, impotence and infertility. These disturbances can be caused by epilepsy itself, by chronic use of antiepileptic drugs (AEDs) or both. AEDs can induce various hormonal abnormalities; in particular, the use of the liver enzyme inducing AEDs, such as phenobarbital, phenytoin and carbamazepine, which increases serum sex hormone binding globulin (SHBG) concentrations. This increase leads to diminished bioactivity of testosterone, which may result in diminished potency and thus reduced fertility. Men taking valproic acid have significantly higher dehydroepiandrosterone levels and lower gonadotropin concentration. Better understanding of molecular properties of AEDs and their effect on reproduction function will be the basis for on management of men suffering from epilepsy.

Pharmacotherapy for children and adolescents with epilepsy.

INTRODUCTION: Childhood epilepsies are the most frequent neurological problems that occur in children. Despite the introduction of new antiepileptic drugs (AEDs) 25-30% of children with epilepsy remain refractory to medical therapy. AREAS COVERED: This review aims to highlight the main published data on the treatment of childhood epilepsy. The electronic database, PubMed, and abstract proceedings were used to identify studies. The aim of antiepileptic therapy should be to provide complete seizure control, if possible without the burden of any side effect. Since 1993, new agents have been approved for use as an antiepileptic. Although there are few published data (especially in pediatric populations) to establish that the second-generation AEDs are more efficacious than the older AEDs, they appear to have better tolerability. EXPERT OPINION: Old AEDs are efficacious agents that continue to play a major role in the current treatment of epilepsy. These agents actually remain the first-line treatment for many specific seizure types or epileptic syndromes. The new AEDs were initially approved as adjunct agents and--subsequently--as monotherapy for various seizure types in the adult and children. Despite these improvements, few AEDs are now considered to be a first-choice for the treatment of epilepsy in children.

Focal epilepsy associated with glioneuronal tumors.

Glioneuronal tumors are an increasingly recognized cause of partial seizures that occur primarily in children and young adults. Focal epilepsy associated with glioneuronal tumors is often resistant to pharmacological treatment. The cellular mechanisms underlying the epileptogenicity of glioneuronal tumors remain largely unknown. The involved mechanisms are certain to be multifactorial and depend on specific tumor histology, integrity of the blood-brain barrier, characteristics of the peritumoral environment, circuit abnormalities, or cellular and molecular defects. Glioneuronal tumors presenting with epilepsy were observed to have relatively benign biological behavior. The completeness of the tumor resection is of paramount importance in avoiding tumor progression and malignant transformation, which are rare in cases of epileptogenic glioneuronal tumors. An evolving understanding of the various mechanisms of tumor-related epileptogenicity may also lead to a more defined surgical objective and effective therapeutic strategies, including antiepileptogenic treatments, to prevent epilepsy in at-risk patients.