Publications by authors named "Giangennaro Coppola"

151 Publications

Psychiatric Symptoms and Parental Stress in Children and Adolescents With Epilepsy.

Front Neurol 2021 8;12:778410. Epub 2021 Dec 8.

Child Neuropsychiatry Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, Salerno, Italy.

The aim of this study was to identify the presence of emotional and behavioral symptoms in children and adolescents with epilepsy, to measure the stress levels in their parents, and to determine if and how parental stress was linked to emotional and behavioral symptoms of their children. We conducted a cross-sectional observational study including 103 children and adolescents with different form of epilepsy and 93 sex-/age-matched controls. Parental stress and emotional and behavioral symptoms were assessed through two standardized questionnaires: the Parenting Stress Index (PSI) and the Child Behavior Checklist (CBCL), respectively. We also considered the following variables: age, sex, maternal education level, family history of psychiatric disorders, duration of epilepsy, seizure frequency, seizure type, and number of antiseizure medications. The statistical comparison showed that the epilepsy group obtained significantly higher scores than controls in almost all the CBCL and the PSI scales ( < 0.05). The correlation analysis revealed a significant relationship between the PSI Total Stress scale and the following CBCL scales: total problems, internalizing problems, and externalizing problems ( < 0.05). An earlier age of seizure onset was related to a greater presence of externalizing problems, total problems, and total stress ( < 0.05). In the epilepsy group, we found higher levels of parental stress and higher presence of emotional and behavioral symptoms compared to controls, mainly represented by internalizing problems (anxiety and depression symptoms). Therefore, it is important to precociously detect these symptoms and monitor them over time, in order to prevent psychiatric problems. In addition, parents of children with epilepsy should be offered psychological support to cope with parental stress and to improve the relationship with their children.
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http://dx.doi.org/10.3389/fneur.2021.778410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8694379PMC
December 2021

Adaptive Behavior, Emotional/Behavioral Problems and Parental Stress in Children With Autism Spectrum Disorder.

Front Neurosci 2021 25;15:751465. Epub 2021 Nov 25.

Child and Adolescent Neuropsychiatry Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, Salerno, Italy.

The aim of our study was to compare adaptive skills, emotional/behavioral problems, and parental stress among children with different severity levels of Autism Spectrum Disorder (ASD) symptoms. This study included a sample of 88 subjects with ASD (mean age = 6.00 ± 2.70). All subjects underwent standardized neuropsychological tests for the assessment of symptoms of the autism spectrum (Autism Diagnostic Observation Schedule-Second Edition), adaptive level (The Vineland Adaptive Behavior Scales, Survey Interview, 2nd edition), behavioral and emotional problems (Child Behavior CheckList CBCL), and parental stress (Parental Stress Index Short Form-PSI-SF). Non-parametric statistical methods (Kruskal-Wallis test and Mann-Whitney -test for analysis) and linear regression analysis were used in this study. hildren who had higher severity levels of ASD symptoms had less adaptive functioning; younger children showed more severe symptoms of ASD; older children had better communication skills. The presence of greater adaptive difficulties was related to a greater presence of internalizing problems. An increase in parental stress levels was related to an higher severity of ASD symptoms, fewer adaptive skills, and a greater presence of internalizing and externalizing problems. This study suggests that the adaptive behavior should be considered in order to planning a habilitation intervention in children with autism. It is also important to monitor emotional/behavioral problems and parental stress levels in order to provide parenting support and improve the family quality of life.
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http://dx.doi.org/10.3389/fnins.2021.751465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8660640PMC
November 2021

Perampanel as first add-on antiseizure medication: Italian consensus clinical practice statements.

BMC Neurol 2021 Oct 26;21(1):410. Epub 2021 Oct 26.

Department of Medicine, Surgery, Odontoiatry, Medical School of Salerno, University of Salerno, Salerno, Italy.

Background: When use of a single antiseizure medication (ASM) fails to induce seizure remission, add-on therapy is justified. Perampanel (PER) is approved in Europe as adjunctive therapy for focal, focal to bilateral tonic-clonic seizures and generalized tonic-clonic seizures. Aim of the study was to establish whether PER is suitable for first add-on use.

Methods: A Delphi methodology was adopted to assess consensus on a list of 39 statements produced by an Expert Board of 5 epileptologists. Using an iterative process, statements were finalized by a Delphi Panel of 84 Italian pediatric and adult neurologists. Each statement was rated anonymously to determine level of agreement on a 9-point Likert scale. Consensus was established as agreement by at least 80% of the panelists. The relevance of each statement was also assessed on a 3-point scale.

Results: Consensus was achieved for 37 statements. Characteristics of PER considered to justify its use as first add-on include evidence of a positive impact on quality of life based on long term retention data, efficacy, tolerability, and ease of use; no worsening of cognitive functions and sleep quality; a low potential for drug interactions; a unique mechanism of action. Potential unfavorable factors are the need for a relatively slow dose titration; the potential occurrence of behavioral adverse effects; lack of information on safety when used in pregnancy; limited access to plasma PER levels.

Conclusion: Perampanel has many features which justify its use as a first add-on. Choice of an ASM as first add-on should be tailored to individual characteristics.
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http://dx.doi.org/10.1186/s12883-021-02450-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8549193PMC
October 2021

The Effect of Plasma Protein Binding on the Therapeutic Monitoring of Antiseizure Medications.

Pharmaceutics 2021 Aug 5;13(8). Epub 2021 Aug 5.

Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081 Baronissi, Italy.

Epilepsy is a widely diffused neurological disorder including a heterogeneous range of syndromes with different aetiology, severity and prognosis. Pharmacological treatments are based on the use, either in mono- or in polytherapy, of antiseizure medications (ASMs), which act at different synaptic levels, generally modifying the excitatory and/or inhibitory response through different action mechanisms. To reduce the risk of adverse effects and drug interactions, ASMs levels should be closely evaluated in biological fluids performing an appropriate Therapeutic Drug Monitoring (TDM). However, many decisions in TDM are based on the determination of the total drug concentration although measurement of the free fraction, which is not bound to plasma proteins, is becoming of ever-increasing importance since it correlates better with pharmacological and toxicological effects. Aim of this work has been to review methodological aspects concerning the evaluation of the free plasmatic fraction of some ASMs, focusing on the effect and the clinical significance that drug-protein binding has in the case of widely used drugs such as valproic acid, phenytoin, perampanel and carbamazepine. Although several validated methodologies are currently available which are effective in separating and quantifying the different forms of a drug, prospective validation studies are undoubtedly needed to better correlate, in real-world clinical contexts, pharmacokinetic monitoring to clinical outcomes.
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http://dx.doi.org/10.3390/pharmaceutics13081208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8401952PMC
August 2021

Perampanel dosage in plasma samples: development and validation of a novel HPLC method with combined UV-Fluorescence detection.

J Pharm Biomed Anal 2021 Sep 8;204:114252. Epub 2021 Jul 8.

Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Via Salvador Allende 84081, Baronissi, Salerno, Italy; University Hospital "San Giovanni di Dio e Ruggi D'Aragona", Via San Leonardo 84131, Salerno, Italy. Electronic address:

Therapeutic drug monitoring (TDM) is a recognized method to improve the quality of use of antiepileptic drugs, such as perampanel (PRP). It is the first compound in the class of selective non-competitive antagonists of AMPA receptors approved in 2012 in Europe and United States for adjunctive therapy of partial seizures. Although several studies have recently underlined that a general reference range for PRP plasmatic concentration might be difficult to propose, TDM of this drug is important in specific clinical situations, as hepatic or renal impairment or co-administration with enzyme-inducing antiepileptics. Several methods have been described in literature for the determination of PRP in different biological matrices, which include the use of liquid chromatography methods coupled with ultraviolet, fluorescence, mass or tandem-mass spectrometry detection. Here we describe the development and validation of a novel method for the measurement of PRP in plasma samples, based on a HPLC-UV/FL double detection approach and using ketoprofen as internal standard. PRP concentration in a small subset of plasma samples of treated patients was evaluated using both our approach and a commercially available CE-IVD LC-MS/MS method. The results obtained were compared, and confirmed the possibility to use our method as an alternative to LC-MS/MS in clinical routine.
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http://dx.doi.org/10.1016/j.jpba.2021.114252DOI Listing
September 2021

Selection of antiseizure medications for first add-on use: A consensus paper.

Epilepsy Behav 2021 09 24;122:108087. Epub 2021 Jun 24.

Division of Clinical and Experimental Pharmacology, Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy.

Introduction: When monotherapy used alone or sequentially fails to achieve seizure control, a trial of combination therapy may be considered.

Objective: To define optimal criteria to guide choice of an antiseizure medication (ASM) for use as first add-on.

Methods: A standardized Delphi procedure was applied to produce a list of consensus statements. First, an Expert Board consisting of 5 epileptologists agreed on a set of 46 statements relevant to the objective. The statements were then finalized through an iterative process by a Delphi Panel of 84 Italian pediatric and adult neurologists with expertise in the management of epilepsy. Panel members provided anonymous ratings of their level of agreement with each statement on a 9-point Likert scale.

Results: Consensus, defined as agreement by at least 80% of Panel members, was reached for 36 statements. Medication-related factors considered to be important for drug selection included efficacy, tolerability and safety, interaction potential, mechanism of action, and ease of use. The need to optimize adherence and to tailor drug selection to individual characteristics was emphasized.

Conclusions: Choice of an ASM for first add-on requires consideration of many factors, many of which also apply to choose initial treatment. Factors more specifically relevant to add-on use include drug interaction potential and the preference for an ASM with a different mechanism of action.
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http://dx.doi.org/10.1016/j.yebeh.2021.108087DOI Listing
September 2021

Social Cognition in Neurodevelopmental Disorders and Epilepsy.

Front Neurol 2021 14;12:658823. Epub 2021 Apr 14.

Child and Adolescent Neuropsychiatry Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, Salerno, Italy.

The purpose of our study was to perform a comparative analysis of social cognition in children and adolescents with epilepsy, autism spectrum disorder (ASD), specific learning disorder (SLD) and in typical development (TD) controls. The secondary aim was to relate social cognition to some clinical and demographic characteristics. Our work is a transversal observational study. The recruits were 179 children and adolescents aged between 6 and 18 years diagnosed with epilepsy, ASD, or SLD and 32 subjects with TD. All the participants underwent neuropsychological assessment of Emotion Recognition (ER) and Theory of Mind (ToM) skills. All three clinical groups performed significantly worse than controls in ER and ToM. The ASD group achieved significantly lower performance than the other groups; however, the scores of SLD and epilepsy groups were comparable. The ER performances are related to non-verbal intelligence only in the group with epilepsy. Children and adolescents with focal epilepsy, SLD, or ASD may present a deficit of varying extent in emotion recognition and ToM, compared with TD peers. These difficulties are more pronounced in individuals with ASD, but impairment worthy of clinical attention also emerges in individuals with SLD and epilepsy.
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http://dx.doi.org/10.3389/fneur.2021.658823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079621PMC
April 2021

Effects of antiseizure monotherapy on visuospatial memory in pediatric age.

Eur J Paediatr Neurol 2021 May 17;32:106-114. Epub 2021 Apr 17.

Child and Adolescent Neuropsychiatry Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, Salerno, Italy.

Introduction: Visuospatial abilities are fundamental for good school achievements and good daily functioning. Previous studies showed an impairment of visuospatial skills in pediatric patients with epilepsy; pharmacological treatment, although indispensable for the seizure control, could further affect cognitive functions. The aim of our study was to evaluate the visuospatial skills in children and adolescents with different forms of epilepsy well-controlled by antiseizure monotherapy, both at baseline and after one year follow-up, through a standardized neuropsychological assessment.

Methods: We recruited 207 children and adolescents (mean age = 10.35 ± 2.39 years) with epilepsy, well controlled by monotherapy with levetiracetam, valproic acid, ethosuximide, oxcarbazepine or carbamazepine and 45 age/sex-matched controls. All the participants performed the Rey-Osterrieth Complex Figure, a standardized test for visuospatial perception and visuospatial memory assessment, at baseline and after 12 month of drug therapy. Age, sex, executive functions, non-verbal intelligence, age at onset of epilepsy, epilepsy duration, epilepsy type, lobe and side of seizure onset were considered in our analysis. EEG, seizure frequency, and drug dose were also recorded.

Results: At baseline, the epilepsy group performed significantly worse than controls in the Immediate Recall test but not the Direct Copy test, without differences between epilepsy subgroups. Immediate Recall scores were related to age of seizure onset and epilepsy duration and executive functions. The re-assessment after 1 year showed that the Immediate Recall mean scores were not significantly changed in the levetiracetam and oxcarbazepine group, while they significantly worsened in the valproic acid, ethosuximide and carbamazepine groups. The Immediate Recall scores were correlated to age, age at onset of epilepsy, epilepsy duration, and executive functions.

Conclusions: Children with epilepsy may exhibit visuospatial memory impairment compared to their peer, that may be correlated to some features of the epilepsy itself and to the impairment of executive functions. Different antiseizure medications can affect visuospatial memory differently, so it is important monitoring this aspect in pediatric patients.
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http://dx.doi.org/10.1016/j.ejpn.2021.04.004DOI Listing
May 2021

The Ketogenic Diet for the Treatment of Mood Disorders in Comorbidity With Epilepsy in Children and Adolescents.

Front Pharmacol 2020 24;11:578396. Epub 2020 Nov 24.

Department of Medicine, Surgery, and Odontoiatry, Child and Adolescent Neuropsychiatry, University of Salerno, Salerno, Italy.

The ketogenic diet, used for over a century as an alternative therapy for the control of drug-resistant seizures in both children and adults, has recently drawn increasing interest in various neurological or psychiatric disorders other than epilepsy. In particular, there are a few preliminary studies in mood and neurodevelopmental disorders such as anxiety, depression and autism spectrum disorders. Mood disorders in comorbidity with epilepsy are commonly seen in adolescents and young adults both at the onset and during the course of the epileptic disorder. The rationale for the use of the ketogenic diet is based on the potential mood stabilizing effects through level modifications of metabolites such as dopamine and serotonin and the regulation of GABA/glutamatergic neurotransmission, mitochondrial function and oxidative stress. In this review, epilepsies with a higher risk of mood disorders in adolescents will be considered. A brief overview of the various types of ketogenic diet that can currently be offered to young patients in order to improve palatability and compliance with the diet, is also included. The efficacy and tolerability of the ketogenic diet options for the treatment of mood disorders, with or without drug therapy including mood stabilizers and antidepressant drugs, are as well discussed.
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http://dx.doi.org/10.3389/fphar.2020.578396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768824PMC
November 2020

Psychogenic Non-Epileptic Status as Refractory, Generalized Hypertonic Posturing: Report of Two Adolescents.

Medicina (Kaunas) 2020 Sep 28;56(10). Epub 2020 Sep 28.

Department of Medicine, Clinic of Child and Adolescent Neuropsychiatry, Surgery and Dentistry, Medical School University of Salerno, 84081 Baronissi, SA, Italy.

Psychogenic non-epileptic seizures (PNES) or dissociative seizures are found under the umbrella headings of functional/dissociative neurological disorders (FND) in psychiatric classifications (DSM-5; ICD-11). PNES are not characterized by any specific ictal or postictal EEG abnormalities. Patients with PNES can present with motor or non-motor symptoms, frequently associated with a change in the level of consciousness. PNES duration is variable, often longer than that of epileptic seizures. Prolonged PNES, sometimes termed PNES status, involve continuous or repetitive events that exceed 30 min. Prolonged PNES are often misdiagnosed as an epileptic event and are often inappropriately treated with high doses of antiseizure drugs. In this report, we describe two adolescent patients who presented with prolonged PNES characterized by generalized hypertonic posturing and low levels of consciousness. Despite multiple presentation to the Emergency department, and multiple normal video-EEG, the patients were misdiagnosed with epilepsy and were inappropriately treated with antiseizure medications. Both patients presented psychiatric comorbidity, consisting of a major depressive disorder, obsessive-compulsive symptoms, social withdrawal, difficulty of social interaction, and anxious-perfectionist personality traits. The episodes of prolonged PNES gradually declined within 18 months in both patients.
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http://dx.doi.org/10.3390/medicina56100508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600080PMC
September 2020

Digital Devices Use and Language Skills in Children between 8 and 36 Month.

Brain Sci 2020 Sep 21;10(9). Epub 2020 Sep 21.

Child Neuropsychiatry Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, Via Salvator Allende, 84081 Baronissi (Salerno), Italy.

: Over the past decade, the use of digital tools has grown and research evidence suggests that traditional media and new media offer both benefits and health risks for young children. The abilities to understand and use language represent two of the most important competencies developed during the first 3 years of life through the interaction of the child with people, objects, events, and other environmental factors. The main goal of our study is to evaluate the relationship between digital devices use and language abilities in children between 8 and 36 month, also considering the influence of several factors. : We conducted a cross-sectional observational study on digital devices use and language abilities in260 children (140 males = 54%) aged between 8 and 36 months (mean = 23.5 ± 7.18 months). All the parents completed a self-report questionnaire investigating the use of digital devices by their children, and a standardized questionnaire for the assessment of language skills (MacArthur-Bates). Linear regression analysis was used to evaluate the relation between different variables. Subsequent moderation analysis were performed to verify the influence of other factors. : We found a statistically significant negative relation between the total daily time of exposure to digital devices and the Actions and Gestures Quotient (ß = -0.397) in children between 8 and 17 months, and between the total daily time of exposure to digital devices and Lexical Quotient (ß = -0.224) in children between 18 and 36 months. Gender, level of education/job of parents, modality of use/content of digital device did not significantly affect the result of the regression analysis. : In our study we found that a longer time of exposure to digital devices was related to lower mimic-gestural skills in children from 8-17 months and to lower language skills in children between 18 and 36 months, regardless of age, gender, socio-economic status, content, and modality of use. Further studies are needed to confirm and better understand this relation, but parents and pediatricians are advised to limit the use of digital devices by children and encourage the social interaction to support the learning of language and communication skills in this age group.
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http://dx.doi.org/10.3390/brainsci10090656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563257PMC
September 2020

Cognitive, adaptive, and behavioral effects of adjunctive rufinamide in Lennox-Gastaut syndrome: A prospective observational clinical study.

Epilepsy Behav 2020 11 10;112:107445. Epub 2020 Sep 10.

Oasi Research Institute (IRCCS), Unit of Neurology and Clinical Neurophysiopathology, Troina, Italy.

Introduction: Lennox-Gastaut syndrome (LGS) is a severe pediatric epilepsy syndrome characterized by multiple drug-resistant seizure types. Children with LGS usually experience cognitive regression, and LGS is almost always associated with moderate to severe cognitive impairment. Rufinamide (RFM) was approved by the European Medicines Agency in 2007 for the adjunctive treatment of seizures associated with LGS in patients ≥4 years of age. The primary objective of our study was to assess cognitive, adaptive, and behavior functioning of patients with LGS after 12 months of RFM therapy.

Methods: This was an observational, multicenter, prospective study involving 16 patients diagnosed with LGS aged between 7 and 58 years (mean = 22 ± 16.3). Fourteen of 16 patients were already on therapy with 3 antiseizure drugs and 2/16 with 4 antiseizure drugs; RFM has been added with 100 mg/week increments up to a dose of 300-2400 mg/day. The participants and their parents underwent a neuropsychological evaluation for the assessment of intellectual, adaptive, and emotional/behavioral functioning (Leiter International Performance Scale-Revised (LEITER-R), Vineland, and Child Behavior CheckList (CBCL), respectively) before the RFM introduction (baseline) and 12 months after the RFM therapy (T2). Physical and neurological examination, electroencephalography (EEG) recording, seizure type and frequency, and adverse reactions were also considered.

Results: After 12 months, the total intelligence quotient (IQ) assessed by LEITER-R did not show statistical significant changes, such as there were no statistically significant changes in adaptive functions, assessed by Vineland. Furthermore, there were no statistically significant changes in internalizing and externalizing problems assessed by CBCL.

Conclusion: Adjunctive treatment with RFM did not negatively affect cognitive, adaptive function, and emotional profile in patients with LGS after 1 year of follow-up.
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http://dx.doi.org/10.1016/j.yebeh.2020.107445DOI Listing
November 2020

Facial Emotion Recognition in Children and Adolescents with Specific Learning Disorder.

Brain Sci 2020 Jul 23;10(8). Epub 2020 Jul 23.

Child Neuropsychiatry Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, 84125 Salerno, Italy.

Background: Some recent studies suggest that children and adolescents with different neurodevelopmental disorders perform worse in emotions recognition through facial expressions (ER) compared with typically developing peers. This impairment is also described in children with Specific Learning Disorders (SLD), compromising their scholastic achievement, social functioning, and quality of life. The purpose of our study is to evaluate ER skills in children and adolescents with SLD compared to a control group without learning disorders, and correlate them with intelligence and executive functions.

Materials And Methods: Our work is a cross-sectional observational study. Sixty-three children and adolescents aged between 8 and 16 years, diagnosed with SLD, and 32 sex/age-matched controls without learning disorders were recruited. All participants were administered standardized neuropsychological tests, evaluating facial emotion recognition (NEPSY-II), executive functions (EpiTrack Junior), and intelligence profile (WISC-IV).

Results: Emotion recognition mean score was significantly lower in the SLD group than in the controls group on the Mann-Whitney U test for unpaired samples ( < 0.001). The SLD group performed significantly lower than the control group in their abilities to identify neutral expressions, happiness, sadness, anger, and fear compared to controls ( < 0.001). ER scores were positively correlated to the executive functions scores. There was no correlation with the Total Intelligence Quotient scores but there is a significant positive correlation with Working Memory Index and Processing Speed Index measured by WISC.IV.

Conclusion: Our study showed that children and adolescents with Specific Learning Disorders have facial emotion recognition impairment when compared with a group of peers without learning disorders. ER abilities were independent of their global intelligence but potentially related to executive functions.
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http://dx.doi.org/10.3390/brainsci10080473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466138PMC
July 2020

Familial Hemiplegic Migraine with an ATP1A4 Mutation: Clinical Spectrum and Carbamazepine Efficacy.

Brain Sci 2020 Jun 15;10(6). Epub 2020 Jun 15.

Clinic of Child and Adolescent Neuropsychiatry, Department of Medicine, Surgery and Dentistry, Medical School University of Salerno, 84100 Salerno, Italy.

An Italian family with familial hemiplegic migraine (FHM) with the absence of mutations in the known genes associated with this disorder, namely , , , and , has recently been reported. Soon afterward, whole exome sequencing allowed the identification of the carrier status of a heterozygous mutation c.1798 C >T, in four affected members of this family. Here we compare the clinical symptoms of the affected family members with those from the other FHM families linked to mutations in the known genes associated with this disorder. A further two-year follow-up, including clinical response to carbamazepine administered to the proband and the maternal grandmother due to a worsening of the migraine symptoms, is reported. The clinical condition of the proband's brother, carrying the same mutation and suffering from congenital ventricular and supraventricular extrasystoles, isdiscussed as well.
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http://dx.doi.org/10.3390/brainsci10060372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349335PMC
June 2020

Withdrawal seizures: possible risk factors.

Expert Rev Neurother 2020 07 23;20(7):667-672. Epub 2020 Jun 23.

Department of Pediatrics, University of L'Aquila , L'Aquila, Italy.

Introduction: Most of the patients usually achieve seizure freedom under treatment with antiseizure medications (ASMs). Drug withdrawal in seizure-free patients is still one of the most challenging issues in the management of epilepsy. The decision-making process of whether the treatment should be discontinued must be based on the evaluation of possible long-term side effects of chronic treatment and, on the other hand, the risk of seizure relapse.

Areas Covered: This review aims to describe and discuss possible predictors and risk factors for seizure relapse during and after discontinuation, according to the available literature evidence. The most important risk factors for withdrawal failure are the etiology of the epilepsy syndrome and epilepsy-related factors, worsening or persistence of epileptiform abnormalities on EEG recordings at the time of discontinuation or during drug tapering, and brain MRI abnormalities. Each single risk factor should be considered together with possible other concurrent predictors.

Expert Opinion: The decision to withdrawal antiseizure medication in seizure-free patients should be carefully planned and based on the evaluation of predictors. A discontinuation program should include tailored discussion with patients and family members and individualized decision, the taper schedule, and plans for monitoring during and after drug tapering.
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http://dx.doi.org/10.1080/14737175.2020.1780917DOI Listing
July 2020

Reading and writing difficultiesin third and sixth-grade students: a cross-sectional survey.

Minerva Pediatr 2020 Jun 5. Epub 2020 Jun 5.

Department of Medicine, Surgery and Odontostomatology, Medical School of Salerno, University of Salerno, Salerno, Italy.

Background: In southern Italy and, specifically, in the region of Campania, many surveys show that the average of students with reading difficulties is much higher than in northern Italy and abroad. On the other hand, specific learning disorders (SLDs) in Campania are much less certified. Since there are no etiological reasons that can explain this apparent inconsistency, an objective of this cross-sectional study was to evaluate the extent of reading/writing difficulties in students from a province of Campania and then to assess the ability of teachers to identify such difficulties in their students.

Methods: Of a total of 241 enrolled students, 155 (64.31%), including 73 from primary school and 82 from secondary school, belonging to 5 schools in the province of Salerno (Italy), took part in the survey. Students' reading and writing skills were assessed through standardized tests. The tests results were then compared with teacher judgments and context-related variables.

Results: At the reading test, 28.7% of primary school and 13.4% of lower secondary school students fell below the 5th percentile for age. Results of the writing test were even more significant: almost half of the students of both levels of education performed below the 5th percentile. Teacher judgments showed higher agreement with standardized assessments in primary (88%, K of Cohen = 0.68) than in secondary school (78%, K = 0.23).

Conclusions: Reading and writing difficulties were common in our sample. While reading skills tended to improve with age, writing difficulties apparently persisted to some extent in third and sixth-grade classes. The accuracy of teacher judgments on reading skills is relatively high, but teachers seem to hardly report reading difficulties "requiring attention". Although less "severe" than others, such difficulties should be taken into account, mainly because of their potential developmental trajectories.
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http://dx.doi.org/10.23736/S0026-4946.20.05619-4DOI Listing
June 2020

Epilepsy and Electroencephalographic Abnormalities in SATB2-Associated Syndrome.

Pediatr Neurol 2020 11 13;112:94-100. Epub 2020 Apr 13.

Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Background: Seizures are an under-reported feature of the SATB2-associated syndrome phenotype. We describe the electroencephalographic findings and seizure semiology and treatment in a population of individuals with SATB2-associated syndrome.

Methods: We performed a retrospective review of 101 individuals with SATB2-associated syndrome who were reported to have had a previous electroencephalographic study to identify those who had at least one reported abnormal result. For completeness, a supplemental survey was distributed to the caregivers and input from the treating neurologist was obtained whenever possible.

Results: Forty-one subjects were identified as having at least one prior abnormal electroencephalography. Thirty-eight individuals (93%) had epileptiform discharges, 28 (74%) with central localization. Sleep stages were included as part of the electroencephalographies performed in 31 individuals (76%), and epileptiform activity was recorded during sleep in all instances (100%). Definite clinical seizures were diagnosed in 17 individuals (42%) with a mean age of onset of 3.2 years (four months to six years), and focal seizures were the most common type of seizure observed (42%). Six subjects with definite clinical seizures needed polytherapy (35%). Delayed myelination and/or abnormal white matter hyperintensities were seen on neuroimaging in 19 individuals (61%).

Conclusions: Epileptiform abnormalities are commonly seen in individuals with SATB2-associated syndrome. A baseline electroencephalography that preferably includes sleep stages is recommended during the initial evaluation of all individuals with SATB2-associated syndrome, regardless of clinical suspicion of epilepsy.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.04.006DOI Listing
November 2020

Perampanel tolerability in children and adolescents with focal epilepsy: Effects on behavior and executive functions.

Epilepsy Behav 2020 02 11;103(Pt A):106879. Epub 2020 Jan 11.

Oasi Research Institute-IRCCS, Troina, Italy.

Objectives: Perampanel (PER) is a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist recently approved for focal and generalized epilepsies as an add-on therapy. It is well tolerated and effective as treatment of various pediatric epilepsy syndromes; PER does not seem to negatively affect the cognitive profile of children and adolescents, but its influence on executive functions is still to be assessed.

Methods: Our sample included 37 children aged 12-18 years, with focal pharmacoresistant epilepsy already in therapy with 2 or 3 antiepileptic drug (AED); PER was added with 1 mg/week increments up to a dose of 2-4 mg/day. Changes in executive functions were assessed by the EpiTrack Junior test. Emotional and behavioral aspects were evaluated through the interview for parents Child Behavior Checklist (CBCL). Both tests were performed before taking PER and after 6 and 12 months of treatment.

Results: After 12 months of PER in 22/30 patients, global score of the EpiTrack Junior test remained almost unchanged; in 7/30 patients, this score improved. The CBCL did not show significant changes in emotional or behavioral problems.

Conclusions: Adjunctive treatment with PER did not negatively affect executive functions that could also be improved. No emotional/behavioral negative effects have been reported, and this suggests a good tolerability in the middle/long term.
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http://dx.doi.org/10.1016/j.yebeh.2019.106879DOI Listing
February 2020

Infantile spasms followed by childhood absence epilepsy: A case series.

Seizure 2020 Jan 9;74:77-80. Epub 2019 Dec 9.

Department of Pediatrics, University of L'Aquila, L'Aquila, Italy. Electronic address:

Purpose: Infantile spasms (IS) represent a severe seizure disorder of infancy and early childhood characterized by epileptic spasms along with hypsarrhythmia often accompanied by intellectual disability. According to the current classification and terminology (3) IS can be categorized as known etiology, formerly known as "symptomatic", when an underlying cause has been observed prior to the onset of spasms, or of "unknown cause" with "unfavorable" and "favorable" outcome (previously referred as "cryptogenic" or "idiopathic", respectively). Single reports described children with "unknown cause and favorable outcome" (UC/FO) IS who later developed childhood absence epilepsy (CAE). This study aims to determine the prevalence of CAE following IS.

Methods: a multicenter retrospective chart review was performed; children with UC/FO IS who subsequently developed CAE during follow-up were identified. Eight Italian pediatric epilepsy centers participated in this study.

Results: seven out of 24 (29 %) children (3 males) showing a favorable outcome (UC/FO) IS received a second diagnosis of CAE during follow-up. Mean age at IS presentation was 5.8 months (SD ± 0.9). All achieved seizure control of IS at a mean age of 8.5 months (SD ± 1.3) (3 monotherapy, 4 polytherapy). CAE was diagnosed at a mean age of 8.0 years (SD ± 3.0). Six children achieved sustained remission of CAE with valproic acid, whereas 1 child required dual therapy by adding ethosuximide.

Conclusion: although it is not possible to determine whether the association between UC/FO IS and CAE implies a causality relationship, the later occurrence of CAE in patients with UC/FO IS might support a possible role of thalamo-cortical dysfunction.
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http://dx.doi.org/10.1016/j.seizure.2019.12.007DOI Listing
January 2020

A Calorie-Restricted Ketogenic Diet Reduces Cerebral Cortex Vascularization in Prepubertal Rats.

Nutrients 2019 Nov 5;11(11). Epub 2019 Nov 5.

Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081 Baronissi, Italy.

The antiepileptic effect of ketogenic diets is acknowledged but its mechanism of action is poorly understood. The present work aimed to evaluate possible effects of a calorie-restricted ketogenic diet (CRKD) on brain growth and angiogenesis in normal prepubertal rats. Two groups of prepubertal rats were fed with a standard diet (group 1) or a CRKD (group 2) for ten weeks. Then, rats were sacrificed and the thickness for the following structures was evaluated by histology: (1) cerebral cortex, (2) deep cerebral white matter, and (3) substantia nigra. The capillary density was also evaluated within: (1) cerebral cortex, (2) dentate gyrus of the hippocampus, (3) periaqueductal grey matter, and (4) substantia nigra. The results showed a smaller thickness of all the areas examined and a reduced capillary density within the cerebral cortex in the CRKD-treated group compared to the control group. These findings suggest an association between reduced angiogenesis within the cerebral cortex and the antiepileptic effects of CRKD.
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http://dx.doi.org/10.3390/nu11112681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893715PMC
November 2019

Gelastic seizures not associated with hypothalamic hamartoma: A long-term follow-up study.

Epilepsy Behav 2020 02 1;103(Pt A):106578. Epub 2019 Nov 1.

Department of Pediatrics, University of L'Aquila, Via Vetoio, 1. Coppito, L'Aquila, Italy. Electronic address:

Objective: The objective of the study was to describe the electroclinical features, seizure semiology, and the long-term evolution of gelastic seizures (GS) not associated with hypothalamic hamartoma (HH).

Methods: We reviewed video-electroencephalogram (video-EEG) recordings from pediatric patients with GS without HH admitted to 14 Italian epilepsy centers from 1994 to 2013. We collected information about age at onset, seizures semiology, EEG and magnetic resonance imaging (MRI) findings, treatment, and clinical outcome in terms of seizure control after a long-term follow-up.

Results: A total of 30 pediatric patients were stratified into two groups according to neuroimaging findings: group 1 including 19 children (63.3%) with unremarkable neuroimaging and group 2 including 11 children with structural brain abnormalities (36.7%). At the follow-up, patients of group 1 showed better clinical outcome both in terms of seizure control and use of AED polytherapy. Our patients showed remarkable clinical heterogeneity, including seizure semiology and epilepsy severity. Electroencephalogram recordings showed abnormalities mainly in the frontal, temporal, and frontotemporal regions without relevant differences between the two groups. Overall, carbamazepine showed good efficacy to control GS.

Conclusions: Patients with nonlesional GS have a more favorable outcome with better drug response, less need of polytherapy, and good long-term prognosis, both in terms of seizure control and EEG findings.
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http://dx.doi.org/10.1016/j.yebeh.2019.106578DOI Listing
February 2020

Monitoring And Managing Depression In Adolescents With Epilepsy: Current Perspectives.

Neuropsychiatr Dis Treat 2019 24;15:2773-2780. Epub 2019 Sep 24.

Department of Pediatrics, University of L'Aquila, L'Aquila, Italy.

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.
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http://dx.doi.org/10.2147/NDT.S192714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6765392PMC
September 2019

Psychogenic nonepileptic seizures in pediatric population: A review.

Brain Behav 2019 12 30;9(12):e01406. Epub 2019 Sep 30.

Department of Mental and Physical Health and Preventive Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.

Introduction: Psychogenic nonepileptic seizures (PNES) are observable abrupt paroxysmal changes in behavior or consciousness that resemble epileptic seizures, but without concurrent electroencephalographic abnormalities.

Methods: In this manuscript, we reviewed literature concerning pediatric PNES and focused on those articles published in the last 10 years, in order to try to understand what the state of the art is at the moment, particularly as regards relationship and differential diagnosis with epilepsy.

Results: Psychogenic nonepileptic seizures have been extensively described in literature mainly in adults and less frequently in children. Despite the potential negative impact of a misdiagnosis (unnecessary investigations and antiepileptic drugs, structured pathological behavioral patterns), in literature there is little information regarding the real prevalence, clinical features, treatment, and outcome of PNES in children and adolescents.

Conclusion: Psychogenic nonepileptic seizures are common but frequently missed entity in pediatric population. Diagnosis could be difficult, especially in those children who have both epileptic and nonepileptic seizures; video EEG and home video can help clinicians in diagnosis. More studies are needed to better classify PNES in children and facilitate diagnosis and treatment.
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http://dx.doi.org/10.1002/brb3.1406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6908892PMC
December 2019

Cognitive Profile, Emotional-Behavioral Features, and Parental Stress in Boys With 47,XYY Syndrome.

Cogn Behav Neurol 2019 06;32(2):87-94

Child Neuropsychiatry Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, Fisciano, Italy.

Objective: To describe (a) the observed cognitive, emotional, and behavioral phenotype in a cohort of male children with 47,XYY syndrome and (b) stress levels in their parents.

Methods: We conducted a cross-sectional observational study of 11 boys diagnosed with 47,XYY syndrome and compared them with 11 age-matched boys with normal karyotype (46,XY). The participants performed standardized assessments of cognitive function, emotional state, and behavioral features; the parents completed a questionnaire evaluating parental stress. All data were analyzed using parametric and nonparametric statistical methods.

Results: All of the boys exhibited a normal cognitive profile. However, emotional-behavioral profiling revealed that internalizing and externalizing problems were more prevalent in the 47,XYY group. In addition, the stress levels of the parents of the 47,XYY group were reportedly higher than those of the parents of the 46,XY group. We also found that the time of the diagnosis had an effect on the mothers' stress levels; that is, postnatal fetal 47,XYY diagnosis was associated with higher maternal stress, whereas prenatal fetal 47,XYY diagnosis was not.

Conclusions: Generally, 47,XYY syndrome is associated with certain cognitive, emotional, and behavioral features. High stress levels have been reported by the mothers of 47,XYY boys who had been diagnosed postnatally because of unexpected developmental delay and/or learning difficulties. The present study highlights the need to better define the neuropsychiatric phenotype of 47,XYY children; namely, the effect of the chromosomal abnormality on their cognitive function and emotional-behavioral (internalizing and externalizing) features. This study could improve prenatal counseling and pediatric surveillance.
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http://dx.doi.org/10.1097/WNN.0000000000000193DOI Listing
June 2019

Parental stress in a sample of children with epilepsy.

Acta Neurol Scand 2019 Aug 5;140(2):87-92. Epub 2019 May 5.

Child and Adolescent Neuropsychiatry, Medical School, University of Salerno, Salerno, Italy.

Objective: To assess maternal and paternal stress in two groups of children with different types of epilepsy, at the time of diagnosis and after one year of follow-up.

Methods: We investigated parental stress in a sample of 85 children aged between 2 and 14 years, divided into two groups based on the diagnosis: Group 1 (50 patients) with childhood absence epilepsy or idiopathic focal epilepsy with rolandic discharges and Group 2 (35 patients) with different forms of drug-resistant epilepsy. Parents independently completed the Parental Stress Index-Short Form at Time 0, when they received the diagnosis and patients started therapy, and at Time 1, after 1 year of follow-up.

Results: We found high levels of stress in both mothers and fathers at Time 0, without statistically significant differences between the two groups. At Time 1, stress values were unchanged in Group 1 mothers; conversely, the levels of stress in Group 1 fathers reduced, with average values that all fell within the "normal range." In Group 2, stress levels were reduced both in mothers and in fathers at Time 1, compared to Time 0, but equally fell into the "pathological range," for both parents.

Conclusion: In our study, the diagnosis of the epilepsy itself tended to increase parental stress, apparently regardless of the severity of the epilepsy; even after a period of follow-up, when the epilepsy was better controlled, overall parental stress remained high. It might have been related to feelings of parental inadequacy or concerns about issues such as safety or the outcome for the child.
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http://dx.doi.org/10.1111/ane.13106DOI Listing
August 2019

Parental stress in pediatric epilepsy after therapy withdrawal.

Epilepsy Behav 2019 05 9;94:239-242. Epub 2019 Apr 9.

Child and Adolescent Neuropsychiatry, Medical School, University of Salerno, Via Giovanni Paolo II, 132, Fisciano, SA, Italy.

Objective: The objective of the study was to explore stress levels in the parents of children with idiopathic epilepsy at different time points of the disease, specifically, at the time of diagnosis, during follow-up, and 1 and 2 years after discontinuation of antiepileptic drugs.

Methods: Our study included 50 patients between 5 and 14 years of age, who were diagnosed with childhood absence epilepsy or idiopathic focal epilepsy with Rolandic paroxysms. Parents of the participants independently completed the Parenting Stress Index-Short Form at the time of initial diagnosis, and when the children started antiepileptic drugs (Time 0), and at 1 year (Time 1) and 2 years (Time 2) after discontinuation of therapy.

Results: At Time 0, parental stress levels were increased, both in mothers and fathers, with average scores in the "clinical range" of the parental distress (PD), dysfunctional parent-child interaction (P-CDI), and total stress (TS) scales. At Time 1, the scores on these scales remained high. At Time 2, a mild reduction in the stress scores was observed in both parents, despite values remaining in the "clinical range" for all the scales.

Conclusions: Results suggested that parents of children with epilepsy were not reassured about the child's condition, even after clinical improvement. Parental stress levels remained higher than expected, even 2 years after the discontinuation of therapy and freedom from seizures. This was probably due to concerns with the reappearance of new seizures or a more severe type of epilepsy with the discontinuation of drug(s), and feelings of inadequacy with their parental role(s).
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http://dx.doi.org/10.1016/j.yebeh.2019.03.029DOI Listing
May 2019

Epilepsy and genetic in Rett syndrome: A review.

Brain Behav 2019 05 30;9(5):e01250. Epub 2019 Mar 30.

Child and Adolescent Neuropsychiatry, Medical School, University of Salerno, Fisciano, Italy.

Introduction: Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder that primarily affects girls, with an incidence of 1:10,000-20,000. The diagnosis is based on clinical features: an initial period of apparently normal development (ages 6-12 months) followed by a rapid decline with regression of acquired motor skills, loss of spoken language and purposeful hand use, onset of hand stereotypes, abnormal gait, and growth failure. The course of the disease, in its classical form, is characterized by four stages. Three different atypical variants of the disease have been defined. Epilepsy has been reported in 60%-80% of patients with RTT; it differs among the various phenotypes and genotypes and its severity is an important contributor to the clinical severity of the disease.

Methods: In this manuscript we reviewed literature on RTT, focusing on the different genetic entities, the correlation genotype-phenotype, and the peculiar epileptic phenotype associated to each of them.

Results: Mutations in MECP2 gene, located on Xq28, account for 95% of typical RTT cases and 73.2% of atypical RTT. CDKL5 and FOXG1 are other genes identified as causative genes in atypical forms of RTT. In the last few years, a lot of new genes have been identified as causative genes for RTT phenotype.

Conclusions: Recognizing clinical and EEG patterns in different RTT variants may be useful in diagnosis and management of these patients.
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http://dx.doi.org/10.1002/brb3.1250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520293PMC
May 2019

Investigational small molecules in phase II clinical trials for the treatment of epilepsy.

Expert Opin Investig Drugs 2018 12 13;27(12):971-979. Epub 2018 Nov 13.

a Department of Pediatrics , University of L'Aquila , L'Aquila , Italy.

Introduction: Epilepsy is a neurological disorder that significantly impacts the quality of life of affected persons. Despite advances in research, nearly a third of patients have refractory or pharmacoresistant epilepsy. Even though numerous antiepileptic drugs (AEDs) have been approved over the past decade, there are no agents that halt the development of epilepsy. Thus, new and improved AEDs to prevent these conditions are necessary.

Areas Covered: We highlight recent advances in new and innovative drugs for epilepsy disorders. We review three small molecule drugs in phase II clinical trials: Cannabidivarin, BGG492 (Selurampanel) and Ganaloxone.

Expert Opinion: The full potential of Cannabidivarin will be realized by testing in other types of treatment-resistant seizures; if they are beneficial, larger phase III clinical trials would probably be undertaken in the same patient population. About BGG492, the challenge will be to find 'superselective' AMPAR antagonists targeting only calcium-permeable receptors, with specific mechanisms, that may be attractive partners for drugs in polytherapy. Moreover, there is anew interest surrounding Ganaloxone because of a new submicron formulation that improves its absorption and pharmacokinetic profile, but new studies are necessary before progressing. Further clinical innovations will define the future for these small molecule-type drugs in epilepsy therapeutics.
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http://dx.doi.org/10.1080/13543784.2018.1543398DOI Listing
December 2018

The pharmacological management of Lennox-Gastaut syndrome and critical literature review.

Seizure 2018 Dec 26;63:17-25. Epub 2018 Oct 26.

Department of child Neuropsychiatry, Tor Vergata University of Rome, Rome, Italy. Electronic address:

Lennox-Gastaut syndrome (LGS) is a severe epileptic encephalopathy with a prevalence of 1-2% of all patients with epilepsy. It is characterized by multiple pharmaco-resistant seizure types, including tonic, atypical absences and tonic or atonic drop attacks, and the presence of electroencephalographic abnormalities, such as slow-spike waves and paroxysmal fast rhythms. Intellectual disability, behavioural and psychiatric disorders are common comorbidities; these disturbances have a multi-factorial pathogenesis. The selection of the most appropriate drug must be tailored to each patient and guided by the prevalent seizure type. In this paper available pharmacological options are discussed and for each pharmacological agent, current evidence of efficacy and tolerability is provided. Valproic acid represents one of the first-line options in the treatment of LGS. Anyway, other antiepileptic drugs (AEDs) may be considered and added: lamotrigine, rufinamide, topiramate, clobazam can be efficacious. The use of felbamate must be carefully evaluated because of its adverse events. Perampanel, zonisamide, levetiracetam and fenfluramine have shown to be useful in the treatment of selected patients; nevertheless, the lack of RCTs does not allow to recommend their use in a systematic way. Recently, cannabidiol has provided high evidence of efficacy against LGS seizures; however, these data must be confirmed by long-term extensive studies and by trials comparing different AEDs, one to each other.
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http://dx.doi.org/10.1016/j.seizure.2018.10.016DOI Listing
December 2018
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