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Angelman syndrome (AS) is a neurogenetic disorder due to deficient expression of the maternal copy of the UBE3A gene, which encodes ubiquitin ligase E3A protein. Severe developmental delay, seizures and other neurological disorders characterize AS.In this review, we focus on a comprehensive therapeutic approach to the most disabling neurological manifestations of AS: epilepsy, sleep disturbances, behavioral and movement disorders. Articles were identified through PubMed and Google Scholar up to October 2021.Evidence for the treatment of neurological manifestations in AS mainly derives from poor quality studies (case reports, small case series, expert opinions). Seizures can be polymorphic and includes atypical absences, myoclonic, generalized tonic-clonic, unilateral clonic, or atonic attacks. Sodium valproate, levetiracetam, and benzodiazepines are the most commonly used anti-seizure medications. Melatonin or mirtazapine seem to improve sleep quality. Antipsychotics, antidepressants, and anxiolytics have been proposed for the treatment of behavioral manifestations, but no evidence-based studies are available. Non-pharmacological approach may also be useful. Mild dystonia is common but usually does not significantly impact patients' motor performances. Well-conducted clinical trials aimed to evaluate treatment of neurological complications of AS are warranted. Gene and molecular precision therapies represent a fascinating area of research in the future.

Although epilepsy as a comorbidity in neurodegenerative disorders is increasingly recognized, its incidence is still underestimated and the features of epilepsy in the different neurodegenerative conditions are still poorly defined. Improved health care, resulting in increased longevity, will unavoidably lead to an increment of epilepsy cases in the elderly. Thus, it is conceivable to expect that neurologists will have to deal with these comorbid conditions to a growing extent in the future. In this seminar, we provide an updated overview of the clinical features, pathophysiological mechanisms and diagnostic and treatment approaches of epilepsy in the most common neurodegenerative disorders (such as Alzheimer disease and other types of dementia, Parkinson disease, Down syndrome, prion diseases, and progressive myoclonus epilepsies), aiming to provide a tool that can help epileptologists and neurologists in the diagnosis and management of this increasingly reported comorbidity.

Status epilepticus (SE) is associated with high morbidity and mortality. This multicenter retrospective cohort study aims to identify the factors associated with the occurrence of SE and the predictors of its recurrence in patients with adult-onset seizures.We retrospectively analyzed data of 1115 patients with seizure onset18 years, observed from 1983 to 2020 in 7 Italian Centers (median follow-up 2.1 years). Data were collected from the databases of the Centers. Patients with SE were consecutively recruited, and patients without SE history were randomly selected in a 2:1 ratio. To assess determinants of SE, different clinical-demographic variables were evaluated and included in univariate and multivariate logistic regression model.Three hundred forty-seven patients had a SE history, whereas the remaining 768 patients had either isolated seizures or epilepsy without SE history. The occurrence of SE was independently associated with increasing age at onset of disease (OR 1.02, 95% CI 1.01--1.03, p0.001), female sex (OR 1.39, 95% CI 1.05--1.83, p=0.02) and known etiology (OR 3.58, 95% CI 2.61--4.93, p0.001). SE recurred in 21% of patients with adult-onset SE and recurrence was associated with increasing number of anti-seizure medications taken at last follow-up (OR 1.88, 95% CI 1.31--2.71, p0.001).In patients with adult-onset seizures, SE occurrence is associated with known etiologies, advanced age and female sex. Patients with recurrent SE are likely to have a refractory epilepsy, deserving careful treatment to prevent potentially fatal events.

Status epilepticus (SE) is a neurological and medical emergency, defined as a condition resulting either from the failure of the mechanisms responsible of seizure self-limitation or from the initiation of mechanisms which lead to atypically prolonged seizures. Further than death, SE can have long-term consequences, including neuronal injury, depending on the type, cause and duration of seizures with severe associated disabilities. In Europe, SE shows an incidence rate ranging about 9 to 40/100,000/y. In adults, mortality of patients with SE is ~30%, and even higher (up to 40%) in refractory status epilepticus. To date, etiology, duration, presence of comorbidity, level of consciousness, semiology and age are the main clinical predictors of SE outcome.

Introduction Angelman syndrome (AS) is a neurodevelopmental disorder characterized by cognitive disability, speech impairment, hyperactivity and seizures. Movement disorders have been reported in almost all AS subjects and they are described as "tremulous movements of limbs, unsteadiness, clumsiness or quick, jerky motions". The presence of dystonia has barely been mentioned in subjects with AS and has never been studied in detail. The purpose of this study is to evaluate the prevalence, clinical features and severity of dystonia in a series of adolescents and adults with AS. Methods Whole body video recordings of patients with genetically confirmed AS were evaluated. Dystonia was evaluated by mean of the movement subscale of Burke-Fahn-Marsden Dystonia Rating Scale (BFM). Results Forty-four subjects with AS were evaluated. Fourteen recordings were excluded due to poor cooperation. We finally analyzed data of 30 subjects (15 F) with a median age of 28 years (range 15-51). Dystonia was present in 28/30 (93.3%) subjects. Among these, dystonia involved the upper limbs in 28/28 (100%), lower limbs in 8/28 (28.5%), mouth in 7/28 (25%), neck in 3/28 (10.7%), trunk in 1/28 (3.6%). Severity of dystonia ranged from slight to moderate. There was a linear correlation between severity of dystonia and increasing age. There was no difference in terms of severity of dystonia among genetic subgroups. Conclusions Dystonia is a common and previously underrecognized clinical feature of adults and adolescents with AS.

Introduction Juvenile myoclonic epilepsy (JME), also known as Janz syndrome, is a common form of generalized epilepsy of presumed genetic origin representing up to 10% of all epilepsy cases. Despite adequate anti-seizure medication (ASM) treatment, seizures persist in one-third of JME patients. Areas covered A literature search was conducted using Pubmed search on the topics of drug-resistant JME. Expert opinion About 30% of JME patients are drug-resistant. Valproate (VPA) is considered the first-choice drug. In women of childbearing potential, levetiracetam (LEV) should represent the first-choice treatment. Alternative monotherapy or add-on therapy should be considered in subjects with resistant seizures after the exclusion of pseudo-drug resistance. The choice of the add-on ASM depends on the predominant seizure type. In subjects with persistent bilateral tonic-clonic seizures, LEV or lamotrigine should be firstly considered. In patients with difficult-to-treat myoclonic seizures, clonazepam or LEV are recommended. In case of persistent absences, ethosuximide should be considered. With appropriate selection and safeguards in place, VPA should remain available as an option in women of childbearing potential whose seizures are resistant to other treatments.

Introduction typical absences (TAs), are brief, generalized epileptic seizures of abrupt onset and termination clinically manifesting with impairment of awareness and associated with 3 Hz spike-wave discharges on EEG. TAs may occur in different idiopathic generalized epilepsies (IGE). Despite treatment with adequate anti-seizure medications (ASMs), TAs may persist in ~25% of subjects. This narrative review focuses on the therapeutic approach to difficult-to-treat TAs occurring in the setting of IGE. Areas covered a literature search was conducted on the topic of treatment of TAs. Expert opinion ethosuximide (ESX), valproic acid (VPA) and lamotrigine (LTG), alone or in combination, are considered the first-choice drugs. In women of childbearing potential, VPA should be avoided. Alternative therapies (benzodiazepines, levetiracetam, topiramate, or zonisamide) should be considered in subjects unresponsive to monotherapy after the exclusion of pseudo-drug resistance. Newer ASMs such as brivaracetam and perampanel seem to be promising options. Well-conducted clinical trials aimed to evaluate the efficacy of alternative monotherapy (beyond ESX, VPA or LTG) or combination of ASMs on difficult-to-treat TAs, are warranted.

Introduction: Status epilepticus (SE) is a neurologic and medical emergency with significant related morbidity and mortality. Hepatic or renal dysfunction can considerably affect the pharmacokinetics of drugs used for SE through a variety of direct or indirect mechanisms. Areas covered: This review aims to focus on the therapeutic management of SE in patients with hepatic or renal impairment, highlighting drugs' selection and dose changes that may be necessary due to altered drug metabolism and excretion. The references for this review were identified by searches of PubMed and Google Scholar until May 2020. Expert opinion: According to literature evidence and clinical experience, in patients with renal disease, the authors suggest considering lorazepam as the drug of choice in pre-hospital and intra-hospital early-stage SE, phenytoin in definite SE, propofol in refractory or super-refractory SE. In patients with liver disease, the authors suggest the use of lorazepam as drug of choice in pre-hospital and intra-hospital early-stage SE, lacosamide in definite SE, propofol in refractory or super-refractory SE. A list of preferred drugs for all SE stages is provided.

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by cognitive disability, speech impairment, hyperactivity and seizures. Movement disorders have been reported in almost all AS subjects and they are described as "tremulous movements of limbs, unsteadiness, clumsiness or quick, jerky motions". The presence of dystonia has barely been mentioned in subjects with AS and has never been studied in detail. The purpose of this study is to evaluate the prevalence, clinical features and severity of dystonia in a series of adolescents and adults with AS.Whole body video recordings of patients with genetically confirmed AS were evaluated. Dystonia was evaluated by mean of the movement subscale of Burke-Fahn-Marsden Dystonia Rating Scale (BFM).Forty-four subjects with AS were evaluated. Fourteen recordings were excluded due to poor cooperation. We finally analyzed data of 30 subjects (15 F) with a median age of 28 years (range 15-51). Dystonia was present in 28/30 (93.3%) subjects. Among these, dystonia involved the upper limbs in 28/28 (100%), lower limbs in 8/28 (28.5%), mouth in 7/28 (25%), neck in 3/28 (10.7%), trunk in 1/28 (3.6%). Severity of dystonia ranged from slight to moderate. There was a linear correlation between severity of dystonia and increasing age. There was no difference in terms of severity of dystonia among genetic subgroups.Dystonia is a common and previously underrecognized clinical feature of adults and adolescents with AS.

Metabolomics is the analysis of endogenous and exogenous low molecular mass metabolites within cells, tissues, or biofluids of an organism in response to an external stressor. In this chapter, we highlight the importance of the subdiscipline of environmental metabolomics, which investigates the interactions of organisms with environmental stressors such as biotic and abiotic factors, xenobiotics, temperature shifts, and chemical contaminants. Over the past decade, there has been increasing scientific interest in environmental metabolomics, most likely attributable to the comprehensive nature of nontargeted metabolomics. Hypotheses have therefore been developed on complex environmental stressor effects, especially those with unknown modes of action. The availability of a wide variety of model organisms such as freshwater organisms of the food chain has promoted the potential of metabolomics to detect stress from an extensive range of external factors. Furthermore, these dynamics may shift from individuals to populations, contemplating the traditional fields of the ecophysiology and ecology from instantaneous effects to those over evolutionary timescales. In this chapter, we provide an overview of analytical instrumentation, extraction methods, general experimental design, and the statistical methods generally used in environmental metabolomics. Despite the difficulty in understanding the consequences of environmental exposure due to inter- and intra-individual variability, we believe that environmental metabolomics may enrich our understanding of the responses of organisms to the numerous types of environmental stressors.

Introduction The aim of this study was to prospectively investigate the occurrence of early poststroke seizures (within 7 days of stroke) in patients undergoing reperfusion therapies (intravenous rtPA [recombinant tissue plasminogen activator] and/or endovascular thrombectomy) in comparison to those not undergoing these procedures. Methods Patients aged ≥ 18 years with acute ischemic stroke admitted in five Italian centers were prospectively recruited. Clinical data, details on stroke type and etiology, stroke treatment, and radiological data were collected. The frequency of early poststroke seizures was assessed, and predictive factors for their occurrence were evaluated. Results Five hundred and sixteen patients (262 in the reperfusion therapies group) were included. Stroke severity on admission and at discharge was higher among patients undergoing reperfusion therapies. Ten patients (3.8%) undergoing reperfusion therapies and 6 (2.3%) of those not receiving these treatments experienced early poststroke seizures (p = 0.45). There were no differences in any of the baseline characteristics between patients experiencing and those not experiencing early seizures. Conclusion The incidence of early poststroke seizures was overall rare, and no significant differences emerged between patients receiving and those not receiving reperfusion therapies. This article is part of the Special Issue “Seizures and Stroke”.

Background and purpose The purpose of this study was to determine whether switching from branded levetiracetam (Keppra® ) to a levetiracetam generic equivalent product (Matever® ) in an epilepsy cohort could provide adequate results in terms of seizure control and tolerability. Methods To be eligible for the study, patients had to have been taking Keppra® as monotherapy or polytherapy for at least 6 months. Between March 2013 and April 2017, patients were invited to switch to Matever® as part of their follow-up. We evaluated the number of seizures per month, drug-related adverse events and electroencephalography before the switch (T0, baseline) and 6 months after switching (T1). Furthermore, we reported the long-term follow-up of patients who continued to use Matever® after the end of the study, considering the most recent visit for each patient (T2). Results A total of 55 patients refused the switch. Among the remaining 125 patients, 59 (47%) were treated using Keppra® as monotherapy and 66 (53%) were on Keppra® as polytherapy. All 125 patients were subjected to switching from Keppra® to Matever® . Comparing patients before (T0) and after (T1) switching, we found no statistically significant differences in terms of seizure frequency and occurrence of adverse effects. There were no significant differences (number of seizures/month and drug-related adverse events) between patients treated with Matever® as monotherapy and patients who refused the switch and continued to use Keppra® as monotherapy for a long-term follow-up of 48 months. Electroencephalography findings were also unchanged. Conclusion In our sample, brand-to-generic levetiracetam switching was effective and safe in both monotherapy and polytherapy regardless of the epilepsy syndrome.