Angela La Neve

Determinants of health-related quality of life in pharmacoresistant epilepsy: Results from a large multicenter study of consecutively enrolled patients using validated quantitative assessments

Purpose:  To evaluate the relative contribution of demographic and epilepsy‐related variables, depressive symptoms, and adverse effects (AEs) of antiepileptic drugs (AEDs) to health‐related quality of life (HRQOL) in adults with pharmacoresistant epilepsy.

Relationship between adverse effects of antiepileptic drugs, number of coprescribed drugs, and drug load in a large cohort of consecutive patients with drug‐refractory epilepsy

Purpose:  To evaluate the adverse effects (AEs) of antiepileptic drugs (AEDs) in adults with refractory epilepsy and their relationship with number of coprescribed AEDs and AED load.

Citalopram as treatment of depression in patients with epilepsy.

Objectives:To assess the safety of citalopram as a treatment of depression in patients with epilepsy. Methods:This is an open, multicentered, uncontrolled study. Depressed epileptic patients on antiepileptic drugs (AEDs) took part in the study. Patients who had a mild frequency of seizures in the 4 previous months underwent treatment with citalopram (20 mg/d) for 4 consecutive months. A change in seizure frequency from the baseline was chosen as the primary measure for the safety of citalopram and efficacy against depressive symptoms was taken as secondary measure. Depression was rated using the Montgomery–Åsberg and Zung depression rating scales. Clinical assessments were performed at baseline, and at 2 and 4 months of citalopram therapy. Results:Forty-five patients were enrolled. Six patients dropped out of the study early: none of them because of a deterioration of seizure frequency. An overall improvement in seizure frequency was observed in the 39 patients who completed the study. Plasma AED concentrations were unchanged during therapy, and depressive symptoms improved markedly. Twenty-two patients complained of adverse effects, mainly headache, nausea, dizziness, somnolence, and fatigue. Conclusions:In this open, multicentered, uncontrolled study, 4 months’ of treatment with citalopram (20 mg/d) were associated with an improvement in depressive symptoms and reduction in seizure frequency.

Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, P(meta) = 2.5 × 10(-9), OR[T] = 0.81) and 17q21.32 (rs72823592, P(meta) = 9.3 × 10(-9), OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, P(meta) = 9.1 × 10(-9), OR[T] = 0.68) and at 1q43 for JME (rs12059546, P(meta) = 4.1 × 10(-8), OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, P(meta) = 4.0 × 10(-6)) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes.

Changes in the Disposition of Oxcarbazepine and Its Metabolites during Pregnancy and the Puerperium

Summary:  Purpose: To determine potential changes in the plasma concentrations of oxcarbazepine (OXC) and its metabolites during pregnancy and puerperium.

Open label, long-term, pragmatic study on levetiracetam in the treatment of juvenile myoclonic epilepsy

PURPOSE Patients with juvenile myoclonic epilepsy (JME) may be resistant or show adverse effects to valproate. We present a multicenter, prospective, long-term, open-label study evaluating the efficacy and safety of levetiracetam in JME. METHODS Patients with newly diagnosed (10) or resistant/intolerant to previous AEDs JME (38) were enrolled. After a 8 week baseline period, levetiracetam was titrated in 2 weeks to 500 mg b.i.d. and then increased up to 3000 mg/day according to the patients response. Efficacy parameters were: number of seizure-free patients, number of days with myoclonus (DWM), and monthly frequency of generalised tonic-clonic (GTC) seizures. Adverse events were recorded. RESULTS The overall mean dose of levetiracetam was 2208 mg/day. The mean study period was 19 (range 0.3-38) months. Five patients dropped out. 11/38 (28.9%) patients with add-on treatment and 5/10 (50%) newly diagnosed patients were seizure-free for a mean period of 17.2 (+/-8.8) months. Eighteen patients (37.5%) were without myoclonia, and 35 (72.9%) had no GTC seizures over the study period. The mean monthly frequency of DWM and of GTC seizures in the entire group was significantly reduced after levetiracetam. Five patients complained of side effects. CONCLUSIONS This open-label study suggests levetiracetam may be effective and well tolerated in resistant cases of JME or may become a reasonable alternative to valproate in newly diagnosed patients.

Effects of levetiracetam on EEG abnormalities in juvenile myoclonic epilepsy

Purpose: A multicenter, prospective, long‐term, open‐label study to evaluate the effects of levetiracetam on electroencephalogram (EEG) abnormalities and photoparoxysmal response (PPR) of patients affected by juvenile myoclonic epilepsy (JME).

Patterns of prescription of antiepileptic drugs in patients with refractory epilepsy at tertiary referral centres in Italy

PURPOSE To evaluate the pattern of prescription of antiepileptic drugs (AEDs) and other medications in a representative population of patients with refractory epilepsy attending tertiary referral centres in Italy. METHODS Descriptive analysis of data obtained at baseline from 933 adults and 191 children with refractory epilepsy enrolled consecutively in an observational study at 11 tertiary referral centres in Italy. Multivariate logistic regression analysis was used to assess predictors of utilization of the most commonly prescribed AEDs. RESULTS Polytherapy was used in 79% of adults and 75% of children, with over one-third of adults and children being prescribed ≥3 AEDs. In adults, the most commonly used AEDs were levetiracetam (35%), carbamazepine (34%) and lamotrigine (30%). In children, valproic acid was by far the most commonly used AED (46%), followed by carbamazepine (27%), topiramate (21%), and phenobarbital (20%). The most common AED in partial epilepsy was carbamazepine (331 out of 893 patients, 37%), followed by levetiracetam (33%) and lamotrigine (26%). In generalized or undetermined epilepsies, the AEDs most commonly used were valproic acid (139 out of 223 patients, 62%), lamotrigine (33%) and levetiracetam (28%). Second generation AEDs were prescribed in 81% of adults and 54% of children. Comedications used for indications other than epilepsy were used by 32% of adults and 17% of children. CONCLUSIONS Prescription patterns were consistent with current evidence about the spectrum of efficacy of individual AEDs in different epilepsy syndromes. The high prevalence of polytherapy, including combinations of three or more AEDs, is a cause for concern.

Progressive myoclonic epilepsies Definitive and still undetermined causes

Objective: To define the clinical spectrum and etiology of progressive myoclonic epilepsies (PMEs) in Italy using a database developed by the Genetics Commission of the Italian League against Epilepsy. Methods: We collected clinical and laboratory data from patients referred to 25 Italian epilepsy centers regardless of whether a positive causative factor was identified. PMEs of undetermined origins were grouped using 2-step cluster analysis. Results: We collected clinical data from 204 patients, including 77 with a diagnosis of Unverricht-Lundborg disease and 37 with a diagnosis of Lafora body disease; 31 patients had PMEs due to rarer genetic causes, mainly neuronal ceroid lipofuscinoses. Two more patients had celiac disease. Despite extensive investigation, we found no definitive etiology for 57 patients. Cluster analysis indicated that these patients could be grouped into 2 clusters defined by age at disease onset, age at myoclonus onset, previous psychomotor delay, seizure characteristics, photosensitivity, associated signs other than those included in the cardinal definition of PME, and pathologic MRI findings. Conclusions: Information concerning the distribution of different genetic causes of PMEs may provide a framework for an updated diagnostic workup. Phenotypes of the patients with PME of undetermined cause varied widely. The presence of separate clusters suggests that novel forms of PME are yet to be clinically and genetically characterized.

Withdrawal of antiepileptic drugs: guidelines of the Italian League Against Epilepsy.

The Italian League Against Epilepsy has issued evidence‐based guidelines to help practicing physicians in their decision to stop or withhold antiepileptic drugs (AEDs) in patients achieving a prolonged period of seizure freedom. Six adult and two child neurologists, divided into four pairs, critically appraised 128 published reports and provided graded recommendations answering 15 key questions: length of the seizure‐free period after treatment initiation, difference in seizure‐free periods in children and adults, electroencephalography (EEG) pattern at the time of discontinuation, etiology of epilepsy, seizure type(s), patients age and sex, family history of epilepsy, history of febrile seizures, epilepsy syndrome, seizure frequency before entering remission, duration of active epilepsy, tapering period, number and type of AEDs taken at time of discontinuation, combination of risk factors for recurrence, and length of patient monitoring after treatment discontinuation. Based on the available data, the following recommendations can be outlined: (1) antiepileptic treatment might be discontinued after a minimum period of 2 years of seizure freedom; shorter seizure‐free periods are associated to a higher risk of relapse; (2) in children, AED discontinuation could be considered after less than two seizure‐free years because of a marginally higher risk of relapse for early withdrawal; (3) factors, such as abnormal EEG (including epileptiform abnormalities) at the time of treatment discontinuation, a documented etiology of seizures (including mental retardation, perinatal insults, and abnormal neurologic examination), partial seizures, or an older age at disease onset, enhance the risk of relapse; however, patients should not be encouraged to withhold treatment unless a combination of two or more of these factors is present; (4) female sex, family history of epilepsy, history of febrile seizures, disease length/severity, and number and type of drugs taken should not influence the decision to stop treatment; (5) epilepsy syndrome should be always included in the decision process; (6) slow (at least 6 months) AED discontinuation should be encouraged; in any case the duration of the tapering period should be tailored to the patients needs and preference; and (7) patient discontinuing treatment should be followed for no <2 years. As a general habit, the decision to stop treatment should be discussed and shared with each patient, taking into account social and personal complications of a seizure relapse and the medical complications of chronic AED treatment.