Search

Gianluca Dini,1 Giuseppe Di Cara,1 Pietro Ferrara,2 Pasquale Striano,3 Alberto Verrotti1 1Department of Pediatrics, University of Perugia, Perugia, Italy; 2Department of Pediatrics, Campus Bio-Medico University, Rome, Italy; 3Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto “G. Gaslini”, Genoa, ItalyCorrespondence: Gianluca Dini, Department of Pediatrics, University of Perugia, Piazzale Giorgio Menghini 1, Perugia, 06129, Italy, Tel +39 3337797213, Email gianlucadini90@gmail.comAbstract: Despite the introduction of new anti-seizure medications in recent years, approximately one-third of the epileptic population continues to experience seizures. Recently, the anti-obesity medication fenfluramine (FFA) has been successfully repurposed, and it has received approval from various regulatory agencies for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome. The potential antiseizure effects of FFA were initially observed in patients with photosensitive epilepsy in the 1980s but it was not rigorously explored as a treatment option until 30 years later. This narrative review aims to provide an overview of the historical progression of FFA’s use, starting from initial clinical observations to preclinical studies and, ultimately, successful clinical trials in the field of epilepsy.Keywords: fenfluramine, seizures, Dravet syndrome, drug-resistant epilepsy, serotonin

Ganna Balagura,1,2 Antonella Riva,2 Francesca Marchese,2 Alberto Verrotti,3 Pasquale Striano1,2 1Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health, University of Genoa, Genoa, Italy; 2Pediatric Neurology and Muscular Diseases Unit, IRCCS ‘G. Gaslini’ Institute, Genoa, Italy; 3Department of Pediatrics, University of L’Aquila, L’Aquila, ItalyCorrespondence: Pasquale Striano Email strianop@gmail.comAbstract: Lennox-Gastaut syndrome (LGS) is a severe, childhood-onset, developmental epileptic encephalopathy, with different etiologies and co-morbidities. Seizure treatment in LGS represents a major challenge; new antiepileptic drugs (AEDs) are developed to especially address seizures resulting in high morbidity and mortality, such as drop seizures. Rufinamide (RFN) is one of the latest AEDs licensed for patients with LGS. Its mechanism of action involves sodium channels in a way that is unrelated to other AEDs. Here we discuss the use of adjunctive RFN in children and adolescents with LGS and its efficacy and safety profile, based on a systematic literature review. RFN shows a very favorable profile in terms of adverse events and drug-interactions in children. It is particularly effective on tonic-atonic seizures and spasms, impacting on the quality of life of the patients. Further studies are needed to clarify the interaction profile with the newest AEDs for LGS and to assess correlations between the etiology of LGS and drug response to individualize treatment and maximize efficacy.Keywords: rufinamide, Lennox-Gastaut, epilepsy, children

Giangennaro Coppola,1 Francesca Felicia Operto,1 Sara Matricardi,2 Alberto Verrotti3 1Child and Adolescent Neuropsychiatry, Department of Medicine, Surgery, and Odontoiatry, University of Salerno, Salerno, Italy; 2Department of Pediatric Neurology, Ospedali Riuniti, Ancona, Italy; 3Department of Pediatrics, University of L’Aquila, L’Aquila, ItalyCorrespondence: Giangennaro CoppolaChild and Adolescent Neuropsychiatry, Department of Medicine, Surgery and Odontoiatry, University of Salerno, Largo d’Ippocrate, 1, Salerno 84100, ItalyTel/Fax +39 089672578Email gcoppola@unisa.itAbstract: Epilepsy is associated with a significantly increased risk of developing depressive disorder during adolescence. On the other hand, depression is highly detected in adolescents with epilepsy. These findings highlight the importance of early identification and proper management of comorbid depression in adolescent age. The prevalence of depressive disorders in adolescents with epilepsy ranges between 8 and 35% and is higher than the general population of the same age. The relationship between epilepsy and depression is complex and potentially bidirectional, thereby suggesting a common underlying pathophysiology. Furthermore, failure to detect and treat depressive disorder mostly in adolescence could lead to several negative implications such as an increased risk of suicidal ideation or behavior and poor quality of life. A number of methods are available to detect depressive disorder, such as psychiatric or psychological assessments, structured or semi-structured interviews, and self-report screening tools. Thus, physicians should be able to regularly screen depressive symptoms in youths with epilepsy. Recently, the NDDI-E-.Y inventory has been developed from the adult NDDI-E, and has been validated in many countries. NDDI-E-Y has showed reliable validity, being a brief screening tool (12 items) that can be easily included in routine epilepsy care. The first step to be considered for the management of depressive disorder in adolescents with epilepsy is to consider potential reversible causes of anxiety and depression (i.e., a new AEDs; seizure control). Secondly, great attention has to be given to the education of the child/adolescent and his/her family, trying to improve knowledge about epilepsy as well as to decrease parental stress and improving the child’s sense of competence. Pharmacological treatment should also be considered in adolescents diagnosed with depression.Keywords: depression, adolescents, monitoring, management, epilepsy

Giangennaro Coppola,1 Giulia Iapadre,2 Francesca Felicia Operto,1 Alberto Verrotti2 1Unit of Child and Adolescent Neuropsychiatry, Department of Medicine and Surgery, University of Salerno, Salerno, 2Department of Pediatrics, University of L’Aquila, L’Aquila, Italy Abstract: Currently, a number of novel anticonvulsant drugs, the so-called third generation, are in various stages of development. Several of them are already available or in ongoing clinical trials. These new compounds should take advantage of new insights into the basic pathophysiology of epileptogenesis, drug metabolism and drug interactions. Many of them still need to be further evaluated mainly in real-world observational trials and registries. Among newer anticonvulsant drugs for partial-onset seizures (POSs), rufinamide, lacosamide, eslicarbazepine and perampanel are those new treatment options for which more substantial clinical evidence is currently available, both in adults and, to some extent, in children. Among the newest anticonvulsant drugs, brivaracetam, a high-affinity synaptic vesicle protein 2A ligand, reported to be 10- to 30-fold more potent than levetiracetam, is highly effective in a broad range of experimental models of focal and generalized seizures. Unlike levetiracetam, brivaracetam does not inhibit high-voltage Ca2+ channels and AMPA receptors and appears to inhibit neuronal voltage-gated sodium channels playing a role as a partial antagonist. Brivaracetam has a linear pharmacokinetic profile, is extensively metabolized and is excreted by urine (only 8%–11% unchanged). It does not seem to influence the pharmacokinetics of other antiepileptic drugs. It was approved in the European Union in January 2016 and in the US in February 2016 as an adjunctive therapy for the treatment of POS in patients older than 16 years of age. To date, its clinical efficacy as adjunctive antiepileptic treatment in adults with refractory POS at doses between 50 and 200 mg daily has been extensively assessed in two Phase IIb and four Phase III randomized controlled studies. Long-term extension studies show sustained efficacy of brivaracetam. Overall, the drug is generally well tolerated with only mild-to-moderate side effects. This is true also by intravenous route. Brivaracetam has not yet been evaluated as monotherapy or in comparison with other new anticonvulsant drugs. Keywords: brivaracetam, partial-onset seizures, epilepsy, antiepileptic drugs, adjunctive therapy

Gaetano Zaccara,1 Fabio Giovannelli,1,2 Massimo Cincotta,1 Alessia Carelli,3 Alberto Verrotti31Department of Medicine, Unit of Neurology, Florence Health Authority, Florence, Italy; 2Department of Neuroscience, Psychology, Pharmacology and Child Health (NEUROFARBA), University of Florence, Florence, Italy; 3Department of Pediatrics, University of Perugia, Perugia, ItalyAbstract: Eslicarbazepine acetate (ESL) is a new antiepileptic drug whose mechanism of action is blockade of the voltage-gated sodium channel (VGSC). However, in respect to carbamazepine and oxcarbazepine, the active ESL metabolite (eslicarbazepine) affects slow inactivation of VGSC and has a similar affinity for the inactivated state and a lower affinity for the resting state of the channel. This new antiepileptic drug has been recently approved in Europe (trade name Zebinix) and in the United States (trade name Stedesa) for adjunctive treatment in adult subjects with partial-onset seizures, with or without secondary generalization. Following oral administration, ESL is rapidly and extensively metabolized by hepatic esterases to eslicarbazepine. This active metabolite has a linear pharmacokinetic profile, a low binding to plasma proteins (

Alberto Verrotti,1 Claudia D’Egidio,1 Sergio Agostinelli,1 Carla Verrotti,2 Piero Pavone31Department of Paediatrics, University of Chieti, 2Department of Obstetrics and Gynecology, University of Parma, 3Unit of Paediatrics, University Hospital “Vittorio Emanuele”, Catania, ItalyAbstract: Catamenial epilepsy is defined as a pattern of seizures that changes in severity during particular phases of the menstrual cycle, wherein estrogens are proconvulsant, increasing the neuronal excitability; and progesterone is anticonvulsant, enhancing GABA-mediated inhibition. Thus, changes in serum estradiol/progesterone ratio throughout a normal reproductive cycle bring about an increased or decreased risk of seizure occurrence. To date, there are no specific drug treatments for catamenial epilepsy however, non-hormonal and hormonal therapies have been proposed. The aim of this review is to report preclinical and clinical evidences about the relationship between female reproductive steroids and epileptic seizures, and to describe treatment approaches for catamenial epilepsy.Keywords: catamenial epilepsy, estrogens, progesterone, neurosteroids

Emilio Franzoni,1 Stefano Gualandi,1 Vincenzo Caretti,2 Adriano Schimmenti,3 Elena Di Pietro,1 Gaetano Pellegrini,1 Giuseppe Craparo,3 Arianna Franchi,1 Alberto Verrotti,4 Alessandro Pellicciari11Child Neuropsychiatry Unit, University of Bologna, Italy; 2Department of Psychology, University of Palermo, Italy; 3Faculty of Human and Social Sciences, Kore University of Enna, Enna, Italy; 4Department of Pediatrics, University of Chieti, ItalyBackground: The connections between eating disorders (EDs) and alexithymia have not been fully clarified. This study aims to define alexithymia's connections with shame, trauma, dissociation, and body image disorders.Methods: We administered the Dissociative Experience Scale-II, Trauma Symptom Inventory, Experience of Shame Scale, Toronto Alexithymia Scale-20, and Body Uneasiness Test questionnaires to 143 ED subjects. Extensive statistical analyses were performed.Results: The subjects showed higher scores on alexithymia, shame, dissociation, and traumatic feelings scales than the nonclinical population. These aspects are linked with each other in a statistically significant way. Partial correlations highlighted that feelings of shame are correlated to body dissatisfaction, irrespective of trauma or depressed mood. Multiple regression analysis demonstrates that shame (anorexic patients) and perceived traumatic conditions (bulimic and ED not otherwise specified) are associated with adverse image disorders.Conclusion: Shame seems to hold a central role in the perception of an adverse self-image. Alexithymia may be interpreted as being a consequence of previous unelaborated traumatic experiences and feelings of shame, and it could therefore be conceptualized as a maladaptive–reactive construct.Keywords: eating disorders, trauma, alexithymia, shame, body image

Abstract The genetic causes underlying epilepsy remain largely unknown, and the impact of available genetic data on the nosology of epilepsy is still limited. Thus, at present, classification of epileptic disorders should be mainly based on electroclinical features. Electro-clinical syndrome is a term used to identify a group of clinical entities showing a cluster of electro-clinical characteristics, with signs and symptoms that together define a distinctive, recognizable, clinical disorder. These often become the focus of treatment trials as well as of genetic, neuropsychological, and neuroimaging investigations. They are distinctive disorders identifiable on the basis of a typical age onset, specific EEG characteristics, seizure types, and often other features which, when taken together, permit a specific diagnosis which, in turn, often has implications for treatment, management, and prognosis. Each electro-clinical syndrome can be classified according to age at onset, cognitive and developmental antecedents and consequences, motor and sensory examinations, EEG features, provoking or triggering factors, and patterns of seizure occurrence with respect to sleep. Therefore, according to the age at onset, here we review the more frequently observed paediatric electro-clinical syndrome from their clinical-EEG, genetic and therapeutic point of views.

Objective: Rare and complex epilepsies encompass a diverse range of disorders characterized by seizures. We aimed to establish a consensus on key issues related to these conditions through collaboration among experienced neurologists, neuropediatricians, and patient advocacy representatives. Methods: Employing a modified Delphi method, a scientific board comprising 20 physicians and 4 patient advocacy representatives synthesized existing literature with their expertise to formulate statements on contentious topics. A final 32‐member expert panel, representing diverse regions of Italy, validated these statements through a two‐round voting process, with consensus defined as an average score ≥7. Results: Sixteen statements reached a consensus, emphasizing the necessity for epidemiological studies to ascertain the true prevalence of rare epilepsies. Etiology emerged as a crucial factor influencing therapeutic strategies and outcome prediction, with particular concern regarding prolonged and tonic–clonic seizures. The importance of early implementation of specific drugs and non‐pharmacological interventions in the treatment algorithm for developmental and epileptic encephalopathies (DEEs) was underscored. Multidisciplinary care involving experts with diverse skills was deemed essential, emphasizing non‐seizure outcomes in adolescence and adulthood. Significance: This national consensus underscores the imperative for personalized, comprehensive, and multidisciplinary management of rare epilepsies/DEEs. It advocates for increased research, particularly in epidemiology and therapeutic approaches, to inform clinical decision‐making and healthcare policies, ultimately enhancing patients' outcomes. Plain Language Summary: The modified Delphi method is broadly used to evaluate debated topics. In this work, we sought the consensus on integrated and social care in epilepsy management. Both representatives of high‐level epilepsy centers and patients' caregivers were directly involved. [ABSTRACT FROM AUTHOR]

Background: Fluorescein angiography (FA) has been a pivotal tool for studying the pathophysiology of retinopathy of prematurity (ROP) in vivo. We examined the course of ROP using FA to assess the predictive value of angiographic features. Methods: This is an observational retrospective cohort study of eyes screened for ROP with a binocular indirect ophthalmoscope and FA. RetCam fundus imaging and video digital fluorescein angiography were performed in the neonatal intensive care unit of Santa Maria Hospital of Perugia. The masked grading of the FA images was retrospectively conducted by two ROP expert ophthalmologists. Results: A total of 80 eyes of 40 patients were included for this study. Among the angiographic features evaluated, leakage, shunts, and tangles were predictive of the development of treatment-requiring ROP (p < 0.05). Conclusions: FA can add to our understanding of the evolution of vascular abnormalities in the course of ROP and can help predict which eyes will go on to treatment. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is characterised by difficulties with social communication, interaction, and repetitive and stereotypical patterns of behaviour. Recent studies suggest that abnormalities in the corpus callosum (CC) can produce autistic symptoms, so this cerebral structure is a target for autism research. It is the largest area of white matter fibre that connects the cerebral hemispheres and has been considered an index of interhemispheric connectivity. The poor connectivity that is a characteristic of autism could be due to CC abnormalities. In this review, we describe empirical studies that have used functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) to investigate the role of the CC in functional and structural brain connectivity in individuals with ASD. Establishing the anatomical correlates of abnormal connectivity in ASD is a major objective of structural and functional connectivity studies. Reduced CC volume is one of the most consistent findings in studies of autistic brains. Structural connectivity studies have shown that the CC is generally altered in ASD. In addition, functional connectivity studies show atypical activity in individuals with ASD during social cognition tasks, working memory tasks, and tests of executive function. Research on functional and structural connectivity has contributed to understanding the role of the CC in the clinical symptoms and social and cognitive deficits associated with ASD.

Myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is characterized by multiple phenotypic conditions such as acute disseminated encephalomyelitis, optic neuritis, and myelitis. MOGAD's spectrum is expanding, with potential symptoms of increased intracranial pressure that are similar to idiopathic intracranial hypertension (IIH). We report a boy with new-onset continuous headache and a brain MRI at onset suggesting idiopathic intracranial hypertension (IIH). The patient showed resistance to treatment with acetazolamide and, after one month, developed optic neuritis in the left eye. Laboratory tests documented positive MOG antibodies (anti-MOG) in the serum. The final diagnosis was MOGAD, with the initial symptoms resembling IIH. [ABSTRACT FROM AUTHOR]

Developmental epileptic encephalopathies (DEEs) pose significant challenges due to their refractory nature and limited treatment options. Despite advancements in genetic understanding, effective therapies targeting underlying pathophysiology are lacking. Serotoninergic dysfunction has been implicated in epilepsy, sparking interest in serotonin as a therapeutic target. This article explores the potential of bexicaserin, a selective 5-HT2C receptor agonist, as an adjunctive antiseizure medication in DEEs. Bexicaserin is thought to modulate GABAergic neurotransmission, suppressing central hyperexcitability. Preclinical studies demonstrate its efficacy across various seizure models. Clinical trials, including the Pacific Study, reveal promising results in reducing motor seizures. However, challenges such as adverse effects and treatment discontinuation underscore the need for further investigation. The efficacy of 5-HT2C serotoninergic agonists, validated in preclinical and clinical studies, highlights serotonin's role in DEEs. Bexicaserin offers new therapeutic possibilities, potentially synergizing with existing antiseizure medications. Polypharmacotherapy, targeting distinct pathways, may enhance therapeutic outcomes. Monitoring pharmacological interactions and addressing central nervous system comorbidities are crucial for optimizing treatment strategies. Further research is needed to elucidate bexicaserin's mechanisms and potential antiepileptogenic effects. [ABSTRACT FROM AUTHOR]

CDKL5 deficiency disorder (CDD) is a clinical condition caused by non-functional or absent CDKL5 protein, resulting in early epileptic encephalopathy and severe developmental delay. Other symptoms include hypotonia, sleep disturbances, movement disorders, visual impairment, dysphagia, and gastrointestinal problems. CDD is more common in females due to its X-linked inheritance. Treatment options for CDD are limited, but recent studies have shown promising results with drugs like ganaxolone and fenfluramine, as well as the use of cannabidiol and palliative surgeries like vagus nerve stimulation and corpus callosotomy. However, further research is needed to fully assess the efficacy of these treatments. [Extracted from the article]