The metaplastic effects of NMDA receptors blockade on reactivation of instrumental memories in rats

Metaplasticity, defined as the plasticity of synaptic plasticity, could affect learning and memory at different neural levels. It was hypothesized that metaplasticity changes on glutamate receptors may affect memory destabilization, promoting or preventing reconsolidation. We investigated the metaplastic effect of NMDA channel blocker MK-801 on sucrose instrumental memory reconsolidation in a behavioural rat model associated to the assessment of molecular markers of metaplasticity, memory retrieval, destabilization and reconsolidation. Following instrumental conditioning and forced abstinence, rats were intraperitoneally treated with MK-801 or vehicle 24\u202fh before the exposure to memory retrieval or not-retrieval. Separate groups were tested for in-vivo extinction of responding (24\u202fh and 7\u202fd after reactivation) or ex-vivo assessment of transcription factor Zif268 and ribosomal protein rpS6 phosphorylation in nucleus accumbens (NAc) and amygdala (Amy). MK-801 significantly inhibited instrumental responding at extinction test, suggesting reconsolidation blockade of instrumental memory. The decrease of Zif268 and phosphorylated-rpS6 levels in NAc and Amy in MK-801/Retrieval vs. Vehicle/Retrieval group supported the behavioural findings. An increase of GluN2B, GluA1 and mGluR5 in NAc, and GluN2B in Amy, 24\u202fh after MK-801 indicated the trigger of associated metaplastic changes. Our findings show that metaplastic changes induced by NMDA receptors blockade affected sucrose instrumental memory retrieval as shown by both behavioural and molecular changes. We hypothesize that these findings however suggested a switch to extinction rather than a reconsolidation

Mioclonic-astatic epilepsy (MAE): Longitudinal electroclinical study of 25 subjects,Epilessia Mioclono-Astatica (EMA): Studio elettroclinico longitudinale di 25 soggetti

Following the longitudinal electroclinical study of 25 personal cases, the AA outline how MAE is a well defined myoclonic epilepsy characterized by the association of peculiar generalized convulsive seizures, generalized tonic vibratory seizures, massive myoclonias, myoclonic-atinic and atonic seizures, "absences" realizing in many cases a peculiar epileptic statud of variable duration. In spite of its storming onset realizing an epileptic encephalopathy, if correctly recognized and treated MAE is an idiopathic myoclonic epilepsy with a relatively good prognosis

Epilessia mioclono-astatica (EMA): studio elettroclinico longitudinale di 25 soggetti

Following the longitudinal electroclinical study of 25 personal cases, the AA outline how MAE is a well defined myoclonic epilepsy characterized by the association of peculiar generalized convulsive seizures, generalized tonic vibratory seizures, massive myoclonias, myoclono-atonic and atonic seizures, "absences" realizing in many cases a peculiar epileptic status of variable duration. In spite of its storming onset realizing an epileptic encephalopathy, if correctly recognized and treated MAE is an idiopathic myoclonic epilepsy with a relatively good prognosis

Adjunctive Perampanel in Older Patients With Epilepsy: A Multicenter Study of Clinical Practice

Background: Clinical data regarding use of newer antiseizure medications (ASMs) in an older population are limited. In randomized-controlled, placebo-controlled trials, older patients are under-represented, and protocols deviate markedly from routine clinical practice, limiting the external validity of results. Studies performed in a naturalistic setting are a useful complement to characterize the drug profile. Perampanel is a third-generation ASM and the first and only non-competitive alfa-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor antagonist. Objective: The aim of this study was to assess the effectiveness and tolerability of adjunctive perampanel over a 1‐year period in a population of older patients with epilepsy treated in a real-world setting. Methods: Older (≥ 65 years of age) patients prescribed add-on perampanel at 12 Italian epilepsy centers were retrospectively identified. Seizure occurrence, adverse events (AEs), and drug withdrawal were analyzed. Effectiveness outcomes included the rates of seizure response (≥ 50% reduction in baseline monthly seizure frequency), seizure freedom, and treatment discontinuation. Safety and tolerability outcomes were the rate of treatment discontinuation due to AEs and the incidence of AEs. Results: A total of 92 patients with a median age of 69 (range 65–88) years were included. The median daily dose of perampanel at 12 months was 6 mg (interquartile range 4–6 mg). At 12 months, 53 (57.6%) patients were seizure responders, and 22 (23.9%) patients were seizure free. Twenty (21.7%) patients discontinued perampanel; the reasons for treatment withdrawal were insufficient efficacy (n = 6/20; 30.0%), AEs (n = 12/20; 60.0%), and a combination of both (n = 2/20; 10%). The most common AEs included irritability (8.7%), somnolence (4.3%), and dizziness/vertigo (4.3%). The rate of behavioral and psychiatric AEs was higher in patients with history of psychiatric comorbidities (p = 0.044). There were no differences in the occurrence of behavioral and psychiatric AEs according to the concomitant use of levetiracetam (p = 0.776) and history of cognitive decline (p = 0.332). Conclusions: Adjunctive perampanel was associated with improvement in seizure control and good tolerability in a real-life setting and can represent a viable therapeutic option in older patients with epilepsy

Brivaracetam as add-on treatment in focal epilepsy: A real-world time-based analysis

The study assessed the clinical response to add-on brivaracetam (BRV) in real-world practice by means of time-to-baseline seizure count methodology. Patients with focal epilepsy who were prescribed add-on BRV were identified. Primary endpoint was the time-to-baseline seizure count defined as the number of days until each patient experienced the number of focal seizures that occurred in the 90 days before BRV initiation. Subgroup analysis was performed according to levetiracetam (LEV) status (naive vs prior use). Three-hundred eighty-seven patients were included. The overall median time-to-baseline seizure count was 150 (95% confidence interval [CI] = 130-175) days. The median time-to-baseline seizure count was 198 (lower limit of 95% CI = 168) days for LEV-naive patients, 126 (95% CI = 105-150) days for patients with prior LEV use and withdrawal due to insufficient efficacy, and 170 (95% CI = 128-291) days for patients who discontinued LEV due to adverse events (P =.002). The number of prior antiseizure medications (adjusted hazard ratio [adjHR] = 1.07, 95% CI = 1.02-1.13, P =.009) and baseline monthly seizure frequency (adjHR = 1.004, 95% CI = 1.001-1.008, P =.028) were independently associated with the primary endpoint. Add-on BRV improved seizure control in LEV-naive and LEV-prior patients. The time-to-baseline seizure count represents an informative endpoint alongside traditional study outcomes and designs

Effectiveness and tolerability of perampanel in children and adolescents with refractory epilepsies-An Italian observational multicenter study.Effectiveness and tolerability of perampanel in children and adolescents with refractory epilepsies-An Italian observational multicenter study

31nononePurpose To evaluate the efficacy and tolerability of Perampanel (PER) in children and adolescents with refractory epilepsies in daily clinical practice conditions. Patients and methods This Italian multicenter retrospective observational study was performed in 16 paediatric epilepsy centres. Inclusion criteria were: (i) ≤18 years of age, (ii) history of refractory epilepsy, (iii) a follow-up ≥5 months of PER add-on therapy. Exclusion criteria were: (i) a diagnosis of primary idiopathic generalized epilepsy, (ii) variation of concomitant AEDs during the previous 4 weeks. Response was defined as a ≥50% reduction in monthly seizure frequency compared with the baseline. Results 62 patients suffering from various refractory epilepsies were included in this study: 53% were males, the mean age was 14.2 years (range 6–18 years), 8 patients aged <12 years. Mean age at epilepsy onset was 3.4 years and the mean duration of epilepsy was 10.8 years (range 1–16), which ranged from 2 seizures per-month up to several seizures per-day (mean number = 96.5). Symptomatic focal epilepsy was reported in 62.9% of cases. Mean number of AEDs used in the past was 7.1; mean number of concomitant AEDs was 2.48, with carbamazepine used in 43.5% of patients. Mean PER daily dose was 7.1 mg (2–12 mg). After an average of 6.6 months of follow-up (5–13 months), the retention rate was 77.4% (48/62). The response rate was 50%; 16% of patients achieved ≥75% seizure frequency reduction and 5% became completely seizure free. Seizure aggravation was observed in 9.7% of patients. Adverse events were reported in 19 patients (30.6%) and led to PER discontinuation in 4 patients (6.5%). The most common adverse events were behaviour disturbance (irritability and aggressiveness), dizziness, sedation and fatigue. Conclusion PER was found to be a safe and effective treatment when used as adjunctive therapy in paediatric patients with uncontrolled epilepsy. © 2016 Elsevier B.V.mixedDe Liso, P; Vigevano, F; Specchio, N; De Palma, L; Bonanni, P; Osanni, E; Coppola, G; Parisi, P; Grosso, S; Verrotti, A; Spalice, A; Nicita, F; Zamponi, N; Siliquini, S; Giordano, L; Martelli, P; Guerrini, R; Rosati, A; Ilvento, L; Belcastro, V; Striano, P; Vari, Ms; Capovilla, G; Beccaria, F; Bruni, O; Luchetti, A; Gobbi, G; Russo, A; Pruna, D; Tozzi, Ae; Cusmai, RDe Liso, P; Vigevano, F; Specchio, N; De Palma, L; Bonanni, P; Osanni, E; Coppola, G; Parisi, P; Grosso, Salvatore; Verrotti, A; Spalice, A; Nicita, F; Zamponi, N; Siliquini, S; Giordano, L; Martelli, P; Guerrini, R; Rosati, A; Ilvento, L; Belcastro, V; Striano, P; Vari, Ms; Capovilla, G; Beccaria, F; Bruni, O; Luchetti, A; Gobbi, G; Russo, A; Pruna, D; Tozzi, Ae; Cusmai, R