To the Editor, Increasing evidence has shown that a holistic approach considering the well‐being ... more To the Editor, Increasing evidence has shown that a holistic approach considering the well‐being and overall life satisfaction of people with mental health issues is the most effective and worthwhile approach. Intellectual disability is a mental impairment resulting in significant cognitive deficits most often associated with psychiatric disorders and behavioral abnormalities. The importance of daytime routines in maintaining the stability of people with mental health problems is well‐known. In a recent study, Lyall et al. found that the disruption of a regular daytime routine and circadian rhythmicity is associated with various adverse mental health and well‐being outcomes. However, despite being emphasized as a critical outcome variable in people with intellectual disabilities and psychiatric disorders, quality of life is not always sufficiently considered in cases of acute comorbidities, after emergency needs have been addressed. The Oasi Research Institute is an independent nonp...
Prader-Willi syndrome (PWS) is a rare disease determined by the loss of the paternal copy of the ... more Prader-Willi syndrome (PWS) is a rare disease determined by the loss of the paternal copy of the 15q11-q13 region, characterized by hypotonia, hyperphagia and obesity, short stature, hypogonadism, craniofacial dysmorphisms, cognitive and behavioral disturbances. The aims of this retrospective study were to analyze interictal EEG findings in a group of PWS patients and to correlate them with genetic, clinical and neuroimaging data. Demographic, clinical, genetic, EEG, and neuroimaging data about seventy-four patients were collected. Associations between the presence of EEG paroxysmal abnormalities, genotype, clinical and neuroimaging features were investigated. Four patients (5.4%) presented a drug-sensitive epilepsy. Interictal EEG paroxysmal abnormalities, focal or multifocal, were present in 25.7% of the cases, and normalization of EEG occurred in about 25% of the cases. In 63.2% of the cases paroxysmal abnormalities were localized over the middle-posterior regions bilaterally. Br...
The aim of this study is to better understand the relationship between sensory and feeding proble... more The aim of this study is to better understand the relationship between sensory and feeding problems in Autism Spectrum Disorder (ASD) by comparing sensory responsiveness of ASD children with (ASD-W) and without (ASD-WO) feeding problems. The feeding and sensory characteristics of 111 children with ASD (37 ASD-W and 74 ASD-WO) were assessed by using two questionnaires tapping on feeding problems and two on sensory problems. A comparative study was carried out with between-group as well as intra-group comparisons design; a correlation analysis was also added. A statistically significant correlation was found between sensory and feeding problems. ASD-W children showed more severe and extensively impaired sensory responses than ASD-WO, with lower sensory adaptation and more generalized and severe deficits in all subdomains. Taste/Smell sensitivity was strongly impaired only in ASD-W, whereas in ASD-WO it was found to be a point of strength. Both groups showed a Hyporesponsive profile, t...
We report here a 6-year-old male child, admitted to Oasi Institute for Research on Mental Retarda... more We report here a 6-year-old male child, admitted to Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS) (Troina, Italy), where a diagnosis was made of speech disorder, myoclonic epilepsy, and psychomotor delay. Seizures started at the third month of life and were characterized by myoclonic jerks involving the lower lip and the left hand, lasting approximately 1 h. In the following two months, he presented a few other seizures with loss of consciousness, deviation of the head and eyes towards right, and cyanosis. Subsequently, the child continued to present frequent seizures (about 10 per month), mostly characterized by segmental myoclonic or clonic jerks, often involving the perioral regions and all four limbs, lasting up to 10; focal seizures with loss of consciousness and more rare, generalized tonic–clonic seizures were also reported. Epilepsy resulted resistant to levetiracetam (500 mg/day) and clobazam (7.5 mg/day). At 14 months of age phenobarbital was started, and levetiracetam and clobazam were gradually withdrawn. At the last visit, at 6 years and 3 months of age, with phenobarbital in monotherapy (75 mg/day), focal and generalized seizures were controlled, and only two per month myoclonic or clonic seizures were observed. The urinary concentration of 2-ketoglutaric acid (alternative name: alpha-ketoglutaric acid, 2-oxoglutaric acid) in case index was 45 (mmol/mol creatinine). At 5 years of age, hearing test and electromyography resulted normal. MRI revealed hypotrophy of the posteroinferior regions of the cerebellum with mild cortical signal hyperintensities, and delayed myelination over the periventricular and temporal regions. From 3 months of age, several EEG recordings showed a slow background activity, and sometimes, during sleep, rare sharp waves over the central regions of the left hemisphere. At 5 years of age, EEG showed also numerous spikes over the vertex and the central regions of both hemispheres prevalent on the left side. Genetic counseling was provided, leading to genetic tests related to the epileptic phenotype by next generation sequence (NGS). The sequencing results showed two variants on TBC1D24 gene: ac.G457A (p.E153K) heterozygous variant in exon 2 inherited from the mother and a c.1142 ? 1 G[A heterozygous variant in intron 4 inherited from the father. To confirm mutations identified in patient, Sanger sequencing was performed using the BigDye Terminator v1.1 Cycle Sequencing Kit (Life Technologies) with an ABI 3130 instrument (Life Technologies). The c.1142 ? 1 G[A mutation has never been reported in affected patients [database dbSNP; Human Gene Mutation Database HGMD (http://www.hgmd.cf.ac.uk/ac/ index.php)], or in controls (1000 Genomes Browser). However, Poulat et al. found a homozygous missense mutation, c.457G[A/p.Glu153Lys, in two affected brothers with infantile onset myoclonic epilepsy with the c.G457A variant on the TBC1D24 gene [1]. In the general population, c.G457A (p.E153K) mutation was identified in 1/12,876 alleles (NHLBI Exome Sequencing Project, http://evs.gs.washington.edu/EVS/). In silico analyses performed in c.G457A (p.E153K) mutation with SIFT and Polyphen softwares gave the following & Michele Salemi micezia@tiscali.it
Autism spectrum disorders (ASD) are neurodevelopmental disorders typically diagnosed in childhood... more Autism spectrum disorders (ASD) are neurodevelopmental disorders typically diagnosed in childhood, characterized by core social dysfunction, rigid and repetitive behaviors, restricted interests, and abnormal sensorial sensitivity. ASD belong to multifactorial diseases: both genetic and environmental factors have been considered as potential risk factors for their onset. ASD are often associated with neurological conditions: the co-occurrence of epilepsy is well documented and there is also evidence of a higher prevalence of EEG abnormalities with 4-86% of individuals with ASD presenting epileptiform or not epileptiform EEG abnormalities. The presence of epilepsy in people with ASD may be determined by several structural alterations, genetic conditions, or metabolic dysfunctions, known to play a role in the emergence of both epilepsy and autism. The purpose of this article is to discuss precisely such latter cause of the autism-epilepsy association, focusing specifically on those "synaptic genes," whose mutation predisposes to both the diseases.
Actual knowledge on evolution of Angelman syndrome (AS) relies on questionnaire-based cohort stud... more Actual knowledge on evolution of Angelman syndrome (AS) relies on questionnaire-based cohort studies, phone interviews, or small retrospective cohort studies focused on specific clinical-genetic features. These reports provide conflicting results. The aim of this study was to assess the long-term outcome of epilepsy, sleep disorders, and EEG in a vast series of AS subjects. We collected patients with genetically confirmed AS, aged ≥14years, followed in three tertiary epilepsy Centers or attending the meetings of the Italian Organization for AS (OrSA). Retrospective clinical and EEG data were retrieved from hospital archives or family documents. At index evaluation (IE) (last visit at tertiary Centers or single visit during OrSA meetings), caregivers were interviewed about anamnestic data and filled questionnaires on sleep disorders and daily-living skills. Patients underwent general and neurologic evaluation, and video-EEG recordings. All available EEGs were analyzed to compare evolution of spike-wave index (SWI) over the years. Forty-six subjects aged 14-45years were included: 24 from tertiary Centers, 22 from OrSA meetings. During childhood, 42/46 (91.3%) had seizures, which improved over the years in all subjects. Among patients with epilepsy, 27(64%) became seizure-free at a median age of 10years and 4 remained seizure-free even after antiepileptic withdrawal. During childhood, 39/46 (84.8%) had sleep disorders, which improved in 27/39 (69%) over the years. At IE, daily-living skills corresponded to age≤1.6years in 29/46 (63%). Electroencephalogram showed typical AS patterns in 35/46 (76.1%). In EEGs recorded from 10 patients, SWI was not significantly different between infancy/childhood and adolescence/adulthood. Improvement of epilepsy or sleep disorders should not disregard the clinical suspicion of AS in adolescent or adult patients with suggestive features. Drug withdrawal might be considered in the management of epilepsy despite the persistence of epileptiform abnormalities.
Maternally Derived 15q11.2-q13.1 Duplication in a Child with Lennox–Gastaut-Type Epilepsy and Dys... more Maternally Derived 15q11.2-q13.1 Duplication in a Child with Lennox–Gastaut-Type Epilepsy and Dysmorphic Features: Clinical-Genetic Characterization of the Family and Review of the Literature Alice Bonuccelli, Angelo Valetto,* Alessandro Orsini, Angela Michelucci, Anna Rita Ferrari, Maurizio Elia, and Veronica Bertini Section of Pediatric Neurology, Department of Pediatrics, University of Pisa, Italy Section of Clinical Genetics, AOUP, Pisa, Italy Department of Pediatric Neurology, Oxford Children’s Hospital, Oxford, United Kingdom Epilepsy Unit, Institute of Child Neurology and Psychiatry, IRCCS Stella Maris Foundation, Calambrone, Pisa, Italy Unit of Neurology and Clinical Neurophysiopathology, IRCCS “Associazione Oasi Maria SS”, Troina (EN), Italy
The role of different factors in influencing the risk of seizures during multiple sclerosis (MS) ... more The role of different factors in influencing the risk of seizures during multiple sclerosis (MS) is not known. To perform a systematic review and meta-analysis of risk factors for epilepsy during MS. Pubmed, Google scholar, and Scopus databases were searched. Articles published in English (1986-2016) were included. Nine studies were included (3 retrospective cohort and 6 case-control) enrolling 2845 MS patients (217 with epilepsy; 7.6%). MS patients with epilepsy had a younger age at onset compared to MS patients without seizures (difference in means = -5.42 years, 95% CI -7.19 to -3.66, p < 0.001). Mean EDSS value at inclusion tended to be higher in patients with epilepsy, without reaching statistical significance (difference in means = 0.45, 95% CI -0.01 to 0.91, p = 0.054). No differences were observed in sex distribution (OR = 0.94, 95% CI 0.51-1.72, p = 0.83) and clinical form (OR = 1.03, 95% CI 0.33-3.21, p = 0.96). Two studies evaluated presence and number of cortical lesions as a risk factor for epilepsy in MS using different MRI techniques: in one study, cortical lesions were more frequently observed in patients with epilepsy (OR = 7.06, 95% CI 2.39-20.8; p < 0.001). In the other, cortico-juxtacortical lesions were more frequently observed in patients with epilepsy (OR = 2.6, 95% CI 1.0-6.5; p = 0.047). Studies about risk factors for epilepsy during MS are heterogeneous. Compared to MS patients without seizures, patients with epilepsy have an earlier MS onset and a higher EDSS score after similar disease duration. Clinical form of MS and sex do not predict the appearance of seizures.
Neurofibromatosis type 1 (NF1) is caused by mutations of the NF1 gene and is one of the most comm... more Neurofibromatosis type 1 (NF1) is caused by mutations of the NF1 gene and is one of the most common human autosomal dominant disorders. The patient shows different signs on the skin and other organs from early childhood. The best known are six or more café au lait spots, axillary or inguinal freckling, increased risk of developing benign nerve sheath tumours and plexiform neurofibromas. Mutation detection is complex, due to the large gene size, the large variety of mutations and the presence of pseudogenes. Using Ion Torrent PGM™ Platform, 73 mutations were identified in 79 NF1 Italian patients, 51% of which turned out to be novel mutations. Pathogenic status of each variant was classified using "American College of Medical Genetics and Genomics" guidelines criteria, thus enabling the classification of 96% of the variants identified as being pathogenic. The use of Next Generation Sequencing has proven to be effective as for costs, and time for analysis, and it allowed us to identify a patient with NF1 mosaicism. Furthermore, we designed a new approach aimed to quantify the mosaicism percentage using electropherogram of capillary electrophoresis performed on Sanger method.
RIASSUNTO. Scopo. I deficit delle funzioni esecutive (FE) sono frequentemente osservati nei distu... more RIASSUNTO. Scopo. I deficit delle funzioni esecutive (FE) sono frequentemente osservati nei disturbi dello spettro dell'autismo (ASD) e nel disturbo da deficit di attenzione con iperattività (ADHD). Lo scopo di questo studio è quello di valutare e confrontare le funzioni esecutive metacognitive ed emozionali/motivazionali di bambini con ASD e ADHD, sia fra di loro che con un gruppo di controllo. Metodi. Il campione è costituito da un totale di 58 soggetti, di cui 17 con ASD senza disabilità intellettiva, 18 con ADHD-manifestazione combinata e 23 con sviluppo tipico, abbinati per genere, età cronologica e livello intellettivo. Le valutazioni hanno riguardato alcune aree del funzionamento esecutivo, nello specifico pianificazione, flessibilità mentale, generatività e inibizione della risposta, che rappresentano sia le funzioni esecutive metacognitive sia quelle emozionali/motivazionali. Risultati. I risultati hanno rilevato un'ampia sovrapposizione delle disfunzioni esecutive ...
Epilepsy occurs in *80 % of patients with Angelman syndrome (AS) [1] and in *10 % of trisomy 21 s... more Epilepsy occurs in *80 % of patients with Angelman syndrome (AS) [1] and in *10 % of trisomy 21 subjects. The most frequent seizure types in AS are atypical absences, myoclonic and generalized tonic–clonic seizures. Common seizure types in trisomy 21 include spasms, focal, tonic or generalized tonic–clonic seizures [2, 3]. We describe a unique patient with both AS and trisomy 21, presenting with spontaneous and reflex drugresistant seizures. This 12-year-old boy came for drugresistant seizures. His family history was negative for epilepsy or other genetic diseases. He was born at 38 weeks after assisted conception with the ‘‘intracytoplasmic sperm injection’’ technique. No perinatal complication was reported. Early after birth, due to the presence of typical facial dysmorphisms, he underwent a karyotype study and trisomy 21 was diagnosed. No congenital heart disease was found. He started walking with support at 4 years. Speech was impaired with no use of words. At 8 years old, due to gait ataxia and severe speech impairment, AS was suspected and an imprinting center defect in 15q11–q13 was found. When he was 9 years, he started presenting daily bilateral myoclonic seizures. From age 12 years, his seizures became more prolonged and could evolve into myoclonic status. From the same age, brief (\20 s duration) myoclonic seizures mainly triggered by wearing on or off a shirt, drinking water or eating hot or cold food, were reported. Seizures were refractory to different AED combinations (valproic acid, levetiracetam, topiramate, clonazepam). Brain MRI was unremarkable. At our observation, patient was wheelchair bound due to severe ataxia. Vineland Adaptive Behavior Scales revealed an adaptive functioning of 1 year-level. Interictal EEG showed a pattern typical for AS characterized by slow background activity and delta waves mixed with low voltage spikes, prevalent over posterior regions. A seizure triggered by drinking water was recorded. Clinically, patient presented clonic jerks of upper limbs, head version towards the left side, tongue protrusion, lasting about 20 s. Ictal EEG is shown in the Fig. 1. The coexistence of AS and trisomy 21 gave rise to a quite peculiar and severe phenotype in our patient. In particular, myoclonic seizures presented by this young boy, are a common seizure type of AS [1] while they may rarely occur in older trisomy 21 subjects when dementia develops [3]. Moreover, this patient had recurrent myoclonic status, a typical feature of nonprogressive encephalopathy including AS [1]. Finally, interictal EEG showed a pattern suggestive of AS [1]. Misregulation of the GABA inhibitory system leads to hypersynchronous and excessively rhythmic activity in AS. Reflex seizures are found in *20 % of trisomy 21 patients [2] but have not been reported in AS. Epileptogenesis in trisomy 21 is thought to be related to a combination of structural brain abnormalities including reduction of neuronal density, decreased density and size of synapses, reduction of dendritic spines of pyramidal neurons, atrophy, and lack of growth of dendritic trees, leading to a reduction of inhibitory mechanisms. Seizures triggered by eating and & Umberto Aguglia u.aguglia@tin.it
Evidence-based guidelines, or recommendations, for the management of infants with seizures are la... more Evidence-based guidelines, or recommendations, for the management of infants with seizures are lacking. A Task Force of the Commission of Pediatrics developed a consensus document addressing diagnostic markers, management interventions, and outcome measures for infants with seizures. Levels of evidence to support recommendations and statements were assessed using the American Academy of Neurology Guidelines and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The report contains recommendations for different levels of care, noting which would be regarded as standard care, compared to optimal care, or "state of the art" interventions. The incidence of epilepsy in the infantile period is the highest of all age groups (strong evidence), with epileptic spasms the largest single subgroup and, in the first 2 years of life, febrile seizures are the most commonly occurring seizures. Acute intervention at the time of a febrile seizure does not a...
... Chronic Administration of MPTP to Marmosets *A. Albanese, *M. С Altavista, **S. Gozzo, *P. Ro... more ... Chronic Administration of MPTP to Marmosets *A. Albanese, *M. С Altavista, **S. Gozzo, *P. Rossi, *C. Colosimo, *AR Bentivoglio, **G. Perretta ... After 3 months of dosing, group С and D animals were definitely parkinsonian, showing bradykinesia, tremor, and dys-tonia; group В ...
To the Editor, Increasing evidence has shown that a holistic approach considering the well‐being ... more To the Editor, Increasing evidence has shown that a holistic approach considering the well‐being and overall life satisfaction of people with mental health issues is the most effective and worthwhile approach. Intellectual disability is a mental impairment resulting in significant cognitive deficits most often associated with psychiatric disorders and behavioral abnormalities. The importance of daytime routines in maintaining the stability of people with mental health problems is well‐known. In a recent study, Lyall et al. found that the disruption of a regular daytime routine and circadian rhythmicity is associated with various adverse mental health and well‐being outcomes. However, despite being emphasized as a critical outcome variable in people with intellectual disabilities and psychiatric disorders, quality of life is not always sufficiently considered in cases of acute comorbidities, after emergency needs have been addressed. The Oasi Research Institute is an independent nonp...
Prader-Willi syndrome (PWS) is a rare disease determined by the loss of the paternal copy of the ... more Prader-Willi syndrome (PWS) is a rare disease determined by the loss of the paternal copy of the 15q11-q13 region, characterized by hypotonia, hyperphagia and obesity, short stature, hypogonadism, craniofacial dysmorphisms, cognitive and behavioral disturbances. The aims of this retrospective study were to analyze interictal EEG findings in a group of PWS patients and to correlate them with genetic, clinical and neuroimaging data. Demographic, clinical, genetic, EEG, and neuroimaging data about seventy-four patients were collected. Associations between the presence of EEG paroxysmal abnormalities, genotype, clinical and neuroimaging features were investigated. Four patients (5.4%) presented a drug-sensitive epilepsy. Interictal EEG paroxysmal abnormalities, focal or multifocal, were present in 25.7% of the cases, and normalization of EEG occurred in about 25% of the cases. In 63.2% of the cases paroxysmal abnormalities were localized over the middle-posterior regions bilaterally. Br...
The aim of this study is to better understand the relationship between sensory and feeding proble... more The aim of this study is to better understand the relationship between sensory and feeding problems in Autism Spectrum Disorder (ASD) by comparing sensory responsiveness of ASD children with (ASD-W) and without (ASD-WO) feeding problems. The feeding and sensory characteristics of 111 children with ASD (37 ASD-W and 74 ASD-WO) were assessed by using two questionnaires tapping on feeding problems and two on sensory problems. A comparative study was carried out with between-group as well as intra-group comparisons design; a correlation analysis was also added. A statistically significant correlation was found between sensory and feeding problems. ASD-W children showed more severe and extensively impaired sensory responses than ASD-WO, with lower sensory adaptation and more generalized and severe deficits in all subdomains. Taste/Smell sensitivity was strongly impaired only in ASD-W, whereas in ASD-WO it was found to be a point of strength. Both groups showed a Hyporesponsive profile, t...
We report here a 6-year-old male child, admitted to Oasi Institute for Research on Mental Retarda... more We report here a 6-year-old male child, admitted to Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS) (Troina, Italy), where a diagnosis was made of speech disorder, myoclonic epilepsy, and psychomotor delay. Seizures started at the third month of life and were characterized by myoclonic jerks involving the lower lip and the left hand, lasting approximately 1 h. In the following two months, he presented a few other seizures with loss of consciousness, deviation of the head and eyes towards right, and cyanosis. Subsequently, the child continued to present frequent seizures (about 10 per month), mostly characterized by segmental myoclonic or clonic jerks, often involving the perioral regions and all four limbs, lasting up to 10; focal seizures with loss of consciousness and more rare, generalized tonic–clonic seizures were also reported. Epilepsy resulted resistant to levetiracetam (500 mg/day) and clobazam (7.5 mg/day). At 14 months of age phenobarbital was started, and levetiracetam and clobazam were gradually withdrawn. At the last visit, at 6 years and 3 months of age, with phenobarbital in monotherapy (75 mg/day), focal and generalized seizures were controlled, and only two per month myoclonic or clonic seizures were observed. The urinary concentration of 2-ketoglutaric acid (alternative name: alpha-ketoglutaric acid, 2-oxoglutaric acid) in case index was 45 (mmol/mol creatinine). At 5 years of age, hearing test and electromyography resulted normal. MRI revealed hypotrophy of the posteroinferior regions of the cerebellum with mild cortical signal hyperintensities, and delayed myelination over the periventricular and temporal regions. From 3 months of age, several EEG recordings showed a slow background activity, and sometimes, during sleep, rare sharp waves over the central regions of the left hemisphere. At 5 years of age, EEG showed also numerous spikes over the vertex and the central regions of both hemispheres prevalent on the left side. Genetic counseling was provided, leading to genetic tests related to the epileptic phenotype by next generation sequence (NGS). The sequencing results showed two variants on TBC1D24 gene: ac.G457A (p.E153K) heterozygous variant in exon 2 inherited from the mother and a c.1142 ? 1 G[A heterozygous variant in intron 4 inherited from the father. To confirm mutations identified in patient, Sanger sequencing was performed using the BigDye Terminator v1.1 Cycle Sequencing Kit (Life Technologies) with an ABI 3130 instrument (Life Technologies). The c.1142 ? 1 G[A mutation has never been reported in affected patients [database dbSNP; Human Gene Mutation Database HGMD (http://www.hgmd.cf.ac.uk/ac/ index.php)], or in controls (1000 Genomes Browser). However, Poulat et al. found a homozygous missense mutation, c.457G[A/p.Glu153Lys, in two affected brothers with infantile onset myoclonic epilepsy with the c.G457A variant on the TBC1D24 gene [1]. In the general population, c.G457A (p.E153K) mutation was identified in 1/12,876 alleles (NHLBI Exome Sequencing Project, http://evs.gs.washington.edu/EVS/). In silico analyses performed in c.G457A (p.E153K) mutation with SIFT and Polyphen softwares gave the following & Michele Salemi micezia@tiscali.it
Autism spectrum disorders (ASD) are neurodevelopmental disorders typically diagnosed in childhood... more Autism spectrum disorders (ASD) are neurodevelopmental disorders typically diagnosed in childhood, characterized by core social dysfunction, rigid and repetitive behaviors, restricted interests, and abnormal sensorial sensitivity. ASD belong to multifactorial diseases: both genetic and environmental factors have been considered as potential risk factors for their onset. ASD are often associated with neurological conditions: the co-occurrence of epilepsy is well documented and there is also evidence of a higher prevalence of EEG abnormalities with 4-86% of individuals with ASD presenting epileptiform or not epileptiform EEG abnormalities. The presence of epilepsy in people with ASD may be determined by several structural alterations, genetic conditions, or metabolic dysfunctions, known to play a role in the emergence of both epilepsy and autism. The purpose of this article is to discuss precisely such latter cause of the autism-epilepsy association, focusing specifically on those "synaptic genes," whose mutation predisposes to both the diseases.
Actual knowledge on evolution of Angelman syndrome (AS) relies on questionnaire-based cohort stud... more Actual knowledge on evolution of Angelman syndrome (AS) relies on questionnaire-based cohort studies, phone interviews, or small retrospective cohort studies focused on specific clinical-genetic features. These reports provide conflicting results. The aim of this study was to assess the long-term outcome of epilepsy, sleep disorders, and EEG in a vast series of AS subjects. We collected patients with genetically confirmed AS, aged ≥14years, followed in three tertiary epilepsy Centers or attending the meetings of the Italian Organization for AS (OrSA). Retrospective clinical and EEG data were retrieved from hospital archives or family documents. At index evaluation (IE) (last visit at tertiary Centers or single visit during OrSA meetings), caregivers were interviewed about anamnestic data and filled questionnaires on sleep disorders and daily-living skills. Patients underwent general and neurologic evaluation, and video-EEG recordings. All available EEGs were analyzed to compare evolution of spike-wave index (SWI) over the years. Forty-six subjects aged 14-45years were included: 24 from tertiary Centers, 22 from OrSA meetings. During childhood, 42/46 (91.3%) had seizures, which improved over the years in all subjects. Among patients with epilepsy, 27(64%) became seizure-free at a median age of 10years and 4 remained seizure-free even after antiepileptic withdrawal. During childhood, 39/46 (84.8%) had sleep disorders, which improved in 27/39 (69%) over the years. At IE, daily-living skills corresponded to age≤1.6years in 29/46 (63%). Electroencephalogram showed typical AS patterns in 35/46 (76.1%). In EEGs recorded from 10 patients, SWI was not significantly different between infancy/childhood and adolescence/adulthood. Improvement of epilepsy or sleep disorders should not disregard the clinical suspicion of AS in adolescent or adult patients with suggestive features. Drug withdrawal might be considered in the management of epilepsy despite the persistence of epileptiform abnormalities.
Maternally Derived 15q11.2-q13.1 Duplication in a Child with Lennox–Gastaut-Type Epilepsy and Dys... more Maternally Derived 15q11.2-q13.1 Duplication in a Child with Lennox–Gastaut-Type Epilepsy and Dysmorphic Features: Clinical-Genetic Characterization of the Family and Review of the Literature Alice Bonuccelli, Angelo Valetto,* Alessandro Orsini, Angela Michelucci, Anna Rita Ferrari, Maurizio Elia, and Veronica Bertini Section of Pediatric Neurology, Department of Pediatrics, University of Pisa, Italy Section of Clinical Genetics, AOUP, Pisa, Italy Department of Pediatric Neurology, Oxford Children’s Hospital, Oxford, United Kingdom Epilepsy Unit, Institute of Child Neurology and Psychiatry, IRCCS Stella Maris Foundation, Calambrone, Pisa, Italy Unit of Neurology and Clinical Neurophysiopathology, IRCCS “Associazione Oasi Maria SS”, Troina (EN), Italy
The role of different factors in influencing the risk of seizures during multiple sclerosis (MS) ... more The role of different factors in influencing the risk of seizures during multiple sclerosis (MS) is not known. To perform a systematic review and meta-analysis of risk factors for epilepsy during MS. Pubmed, Google scholar, and Scopus databases were searched. Articles published in English (1986-2016) were included. Nine studies were included (3 retrospective cohort and 6 case-control) enrolling 2845 MS patients (217 with epilepsy; 7.6%). MS patients with epilepsy had a younger age at onset compared to MS patients without seizures (difference in means = -5.42 years, 95% CI -7.19 to -3.66, p < 0.001). Mean EDSS value at inclusion tended to be higher in patients with epilepsy, without reaching statistical significance (difference in means = 0.45, 95% CI -0.01 to 0.91, p = 0.054). No differences were observed in sex distribution (OR = 0.94, 95% CI 0.51-1.72, p = 0.83) and clinical form (OR = 1.03, 95% CI 0.33-3.21, p = 0.96). Two studies evaluated presence and number of cortical lesions as a risk factor for epilepsy in MS using different MRI techniques: in one study, cortical lesions were more frequently observed in patients with epilepsy (OR = 7.06, 95% CI 2.39-20.8; p < 0.001). In the other, cortico-juxtacortical lesions were more frequently observed in patients with epilepsy (OR = 2.6, 95% CI 1.0-6.5; p = 0.047). Studies about risk factors for epilepsy during MS are heterogeneous. Compared to MS patients without seizures, patients with epilepsy have an earlier MS onset and a higher EDSS score after similar disease duration. Clinical form of MS and sex do not predict the appearance of seizures.
Neurofibromatosis type 1 (NF1) is caused by mutations of the NF1 gene and is one of the most comm... more Neurofibromatosis type 1 (NF1) is caused by mutations of the NF1 gene and is one of the most common human autosomal dominant disorders. The patient shows different signs on the skin and other organs from early childhood. The best known are six or more café au lait spots, axillary or inguinal freckling, increased risk of developing benign nerve sheath tumours and plexiform neurofibromas. Mutation detection is complex, due to the large gene size, the large variety of mutations and the presence of pseudogenes. Using Ion Torrent PGM™ Platform, 73 mutations were identified in 79 NF1 Italian patients, 51% of which turned out to be novel mutations. Pathogenic status of each variant was classified using "American College of Medical Genetics and Genomics" guidelines criteria, thus enabling the classification of 96% of the variants identified as being pathogenic. The use of Next Generation Sequencing has proven to be effective as for costs, and time for analysis, and it allowed us to identify a patient with NF1 mosaicism. Furthermore, we designed a new approach aimed to quantify the mosaicism percentage using electropherogram of capillary electrophoresis performed on Sanger method.
RIASSUNTO. Scopo. I deficit delle funzioni esecutive (FE) sono frequentemente osservati nei distu... more RIASSUNTO. Scopo. I deficit delle funzioni esecutive (FE) sono frequentemente osservati nei disturbi dello spettro dell'autismo (ASD) e nel disturbo da deficit di attenzione con iperattività (ADHD). Lo scopo di questo studio è quello di valutare e confrontare le funzioni esecutive metacognitive ed emozionali/motivazionali di bambini con ASD e ADHD, sia fra di loro che con un gruppo di controllo. Metodi. Il campione è costituito da un totale di 58 soggetti, di cui 17 con ASD senza disabilità intellettiva, 18 con ADHD-manifestazione combinata e 23 con sviluppo tipico, abbinati per genere, età cronologica e livello intellettivo. Le valutazioni hanno riguardato alcune aree del funzionamento esecutivo, nello specifico pianificazione, flessibilità mentale, generatività e inibizione della risposta, che rappresentano sia le funzioni esecutive metacognitive sia quelle emozionali/motivazionali. Risultati. I risultati hanno rilevato un'ampia sovrapposizione delle disfunzioni esecutive ...
Epilepsy occurs in *80 % of patients with Angelman syndrome (AS) [1] and in *10 % of trisomy 21 s... more Epilepsy occurs in *80 % of patients with Angelman syndrome (AS) [1] and in *10 % of trisomy 21 subjects. The most frequent seizure types in AS are atypical absences, myoclonic and generalized tonic–clonic seizures. Common seizure types in trisomy 21 include spasms, focal, tonic or generalized tonic–clonic seizures [2, 3]. We describe a unique patient with both AS and trisomy 21, presenting with spontaneous and reflex drugresistant seizures. This 12-year-old boy came for drugresistant seizures. His family history was negative for epilepsy or other genetic diseases. He was born at 38 weeks after assisted conception with the ‘‘intracytoplasmic sperm injection’’ technique. No perinatal complication was reported. Early after birth, due to the presence of typical facial dysmorphisms, he underwent a karyotype study and trisomy 21 was diagnosed. No congenital heart disease was found. He started walking with support at 4 years. Speech was impaired with no use of words. At 8 years old, due to gait ataxia and severe speech impairment, AS was suspected and an imprinting center defect in 15q11–q13 was found. When he was 9 years, he started presenting daily bilateral myoclonic seizures. From age 12 years, his seizures became more prolonged and could evolve into myoclonic status. From the same age, brief (\20 s duration) myoclonic seizures mainly triggered by wearing on or off a shirt, drinking water or eating hot or cold food, were reported. Seizures were refractory to different AED combinations (valproic acid, levetiracetam, topiramate, clonazepam). Brain MRI was unremarkable. At our observation, patient was wheelchair bound due to severe ataxia. Vineland Adaptive Behavior Scales revealed an adaptive functioning of 1 year-level. Interictal EEG showed a pattern typical for AS characterized by slow background activity and delta waves mixed with low voltage spikes, prevalent over posterior regions. A seizure triggered by drinking water was recorded. Clinically, patient presented clonic jerks of upper limbs, head version towards the left side, tongue protrusion, lasting about 20 s. Ictal EEG is shown in the Fig. 1. The coexistence of AS and trisomy 21 gave rise to a quite peculiar and severe phenotype in our patient. In particular, myoclonic seizures presented by this young boy, are a common seizure type of AS [1] while they may rarely occur in older trisomy 21 subjects when dementia develops [3]. Moreover, this patient had recurrent myoclonic status, a typical feature of nonprogressive encephalopathy including AS [1]. Finally, interictal EEG showed a pattern suggestive of AS [1]. Misregulation of the GABA inhibitory system leads to hypersynchronous and excessively rhythmic activity in AS. Reflex seizures are found in *20 % of trisomy 21 patients [2] but have not been reported in AS. Epileptogenesis in trisomy 21 is thought to be related to a combination of structural brain abnormalities including reduction of neuronal density, decreased density and size of synapses, reduction of dendritic spines of pyramidal neurons, atrophy, and lack of growth of dendritic trees, leading to a reduction of inhibitory mechanisms. Seizures triggered by eating and & Umberto Aguglia u.aguglia@tin.it
Evidence-based guidelines, or recommendations, for the management of infants with seizures are la... more Evidence-based guidelines, or recommendations, for the management of infants with seizures are lacking. A Task Force of the Commission of Pediatrics developed a consensus document addressing diagnostic markers, management interventions, and outcome measures for infants with seizures. Levels of evidence to support recommendations and statements were assessed using the American Academy of Neurology Guidelines and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The report contains recommendations for different levels of care, noting which would be regarded as standard care, compared to optimal care, or "state of the art" interventions. The incidence of epilepsy in the infantile period is the highest of all age groups (strong evidence), with epileptic spasms the largest single subgroup and, in the first 2 years of life, febrile seizures are the most commonly occurring seizures. Acute intervention at the time of a febrile seizure does not a...
... Chronic Administration of MPTP to Marmosets *A. Albanese, *M. С Altavista, **S. Gozzo, *P. Ro... more ... Chronic Administration of MPTP to Marmosets *A. Albanese, *M. С Altavista, **S. Gozzo, *P. Rossi, *C. Colosimo, *AR Bentivoglio, **G. Perretta ... After 3 months of dosing, group С and D animals were definitely parkinsonian, showing bradykinesia, tremor, and dys-tonia; group В ...
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