Publications by authors named "Lino Nobili"

163 Publications

Sleep disturbances in craniopharyngioma: a challenging diagnosis.

J Neurol 2021 Sep 14. Epub 2021 Sep 14.

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy.

Craniopharyngiomas are rare solid or mixed solid and cystic tumors that arise from Rathke's pouch remnants along the pituitary-hypothalamic axis, from the sella turcica to the brain third ventricle. Both the tumor and its treatment can lead to significant neurological and endocrinological complications. Due to the essential role of the hypothalamus in the complex neurophysiologic process of sleep, tumors involving the hypothalamic area may be responsible for disturbances in sleep-wake regulation with alterations in the circadian rhythm, sleep fragmentation, and increased daytime sleepiness. We report two cases of patients with craniopharyngioma, who came to our attention due to the occurrence of episodes characterized by psychomotor slowing and afinalistic limb movements, temporal and spatial disorientation, psychomotor agitation, and oneiric stupor like episodes. A comprehensive clinical data collection and a targeted diagnostic work-up led to a diagnosis of severe sleep disorder characterized by hypersomnia, altered sleep-wake rhythm, and sleep-related breathing disorder. In addition, the polysomnography revealed peculiar alterations in the sleep structure. The diagnostic work-up lead to an accurate differential diagnosis between epileptic seizures and episodes expressions of sleep disturbances. These clinical features can be challenging to diagnose and can lead to misdiagnosis and inappropriate treatment. Diagnosis of sleep disorders is crucial, considering the impact of sleep on general health, cognition, and neuropsychological functioning. These findings support the need to incorporate a comprehensive sleep evaluation in childhood brain tumor involving the suprasellar/hypothalamic region.
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http://dx.doi.org/10.1007/s00415-021-10794-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439529PMC
September 2021

Multimodal approach in the pre-surgical evaluation of focal epilepsy surgery candidates: how far are we from a non-invasive ESI-based "sourcectomy"?

Epileptic Disord 2021 Aug;23(4):661-666

Unit of Child Neuropsychiatry, Department of Medical and Surgical Neuroscience and Rehabilitation, IRCCS Istituto Giannina Gaslini, Genoa, Italy, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy.

The management of drug-resistant patients with focal epilepsy is often challenging. Surgery is recognised as a useful and effective treatment option. The identification of the epileptogenic zone relies on the integration of clinical, neurophysiological, and neuroimaging findings. The role of non-invasive functional neuroimaging techniques has been reported to add diagnostic accuracy to first-line evaluations, avoiding invasive presurgical examinations in selected cases. In this view, we report the case of a 16-year-old male suffering from drug-resistant focal epilepsy with episodes rarely evolving to a bilateral tonic-clonic seizure. Conventional 1.5T and 3T MRI were considered uninformative. Based on electro-clinical data, focal cortical dysplasia was suspected. The epileptogenic zone was identified with the integration of further non-invasive functional neuroimaging techniques ([18F]-fluorodeoxyglucose positron emission tomography and arterial spin labelling), where electrical source imaging played the main role. All techniques pointed towards a cortical region, where a 7T brain MRI identified a signal alteration consistent with focal cortical dysplasia. A tailored resection of the lesion located in the inferior frontal sulcus was performed, guided by intraoperative electrocorticography (strip and depth electrodes). Postoperative seizure freedom was achieved. The histopathology confirmed the suspicion of focal cortical dysplasia type IIa. With this case report, we highlight the importance of a multimodal approach in the presurgical evaluation of candidates for epilepsy surgery, which, in selected cases, may allow invasive procedures, such as stereo-EEG, to be avoided in the investigation of the epileptogenic zone. Moreover, we underline the pivotal role of EEG source imaging, especially when focal cortical dysplasia is suspected.
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http://dx.doi.org/10.1684/epd.2021.1309DOI Listing
August 2021

Hemispheric surgery for severe epilepsy in early childhood: a case series.

Epileptic Disord 2021 Aug;23(4):611-622

Unit of Neurosurgery, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

Hemispheric surgery is an effective and cost-effective option for hemispheric epilepsy. Data specifically focusing on very early infancy are scant. In our study, we report the results of hemispheric surgery in children under three years of age, along with clinical, neuroradiological and EEG features, from two Italian epilepsy surgery centres. After reviewing our epilepsy surgery databases (2008-2018), we identified 14 patients (seven males) submitted to hemispheric surgery, under three years (range: 2-29 months), with a follow-up of at least 12 months. No deaths occurred, and surgical complications were observed in 3/17 procedures. At final follow-up visit (mean: 30.8 months; range: 12-90), 10/14 patients (71.4%) achieved Engel Class I (eight Class 1A, one Class 1B, and one Class 1C). Antiepileptic drugs were completely discontinued in three and reduced in eight, thus a significant decrease in drug regimen after surgery was achieved in 11/14 patients (78.6%). Before surgery, severe developmental delay was present in 10 patients, moderate in two and mild in two. At the last follow-up visit, the degree of developmental delay changed from severe to moderate in five patients, remained unchanged in six cases (four severe and two moderate), and changed from mild to moderate in two following surgery. In many cases, hemispheric surgery in children under three years is effective in achieving seizure freedom or reducing seizure frequency, with the possibility of simplifying complex drug regimens. Moreover, it appears to be a safe and well tolerated procedure, leading to improvement in cognition and posture.
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http://dx.doi.org/10.1684/epd.2021.1303DOI Listing
August 2021

International Expert Opinions and Recommendations on the Use of Melatonin in the Treatment of Insomnia and Circadian Sleep Disturbances in Adult Neuropsychiatric Disorders.

Front Psychiatry 2021 10;12:688890. Epub 2021 Jun 10.

Département de psychiatrie et d'addictologie, AP-HP, GHU Paris Nord, DMU Neurosciences, Hopital Bichat - Claude Bernard, Paris, France.

Insomnia and circadian rhythm disorders, such as the delayed sleep phase syndrome, are frequent in psychiatric disorders and their evaluation and management in early stages should be a priority. The aim of this paper was to express recommendations on the use of exogenous melatonin, which exhibits both chronobiotic and sleep-promoting actions, for the treatment of these sleep disturbances in psychiatric disorders. To this aim, we conducted a systematic review according to PRISMA on the use of melatonin for the treatment of insomnia and circadian sleep disorders in neuropsychiatry. We expressed recommendations for the use of melatonin in psychiatric clinical practice for each disorder using the RAND/UCLA appropriateness method. We selected 41 studies, which included mood disorders, schizophrenia, substance use disorders, attention deficit hyperactivity disorders, autism spectrum disorders, neurocognitive disorders, and delirium; no studies were found for both anxiety and eating disorders. The administration of prolonged release melatonin at 2-10 mg, 1-2 h before bedtime, might be used in the treatment of insomnia symptoms or comorbid insomnia in mood disorders, schizophrenia, in adults with autism spectrum disorders, neurocognitive disorders and during sedative-hypnotics discontinuation. Immediate release melatonin at <1 mg might be useful in the treatment of circadian sleep disturbances of neuropsychiatric disorders.
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http://dx.doi.org/10.3389/fpsyt.2021.688890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222620PMC
June 2021

Assessment of self-reported and objective daytime sleepiness in adult-onset myotonic dystrophy type 1.

J Clin Sleep Med 2021 Jun 22. Epub 2021 Jun 22.

Department of Neurology, Tor Vergata University of Rome, Rome, Italy.

Study Objectives: Excessive daytime sleepiness (EDS) in myotonic dystrophy type 1 (DM1) is mostly of central origin but it may coexist with sleep-related breathing disorders. However, there is no consensus on the sleep protocols to be used, assessments vary and only a minority of patients are regularly tested or are on treatment for EDS. Our study presents data on self-reported and objective EDS in adult-onset DM1.

Methods: 63 adult-onset DM1 patients were subjected to EDS-sleep assessments (polysomnography, PSG; Multiple Sleep Latency Test, MSLT; Epworth Sleepiness Scale, ESS. Correlation coefficients were computed to assess the relationship between sleep and sleepiness test results, fatigue, quality of life.

Results: 33% and 48% of patients had EDS based respectively on the ESS and the MSLT with a low concordance between these tests (k = 0.19). Thirteen patients (20%) displayed 2 or more sleep-onset REM periods on MSLT. Patients having EDS by MSLT had a shorter disease duration (p<0.05), higher total sleep time, sleep efficiency and lower WASO (Wake After Sleep Onset) on PSG. Patients with self-reported EDS reported significantly higher fatigue score compared to patients without EDS (p<0.05). No other difference was found in demographic, clinical and respiratory features.

Conclusions: EDS test results are contradictory making treatment options difficult. Combining quantitative tests and self-reported scales may facilitate physicians in planning EDS care with patients and families.
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http://dx.doi.org/10.5664/jcsm.9438DOI Listing
June 2021

Sleep medicine catalogue of knowledge and skills - Revision.

J Sleep Res 2021 06;30(3):e13394

University of Parma, Parma, Italy.

The 'catalogue of knowledge and skills' for sleep medicine presents the blueprint for a curriculum, a textbook, and an examination on sleep medicine. The first catalogue of knowledge and skills was presented by the European Sleep Research Society in 2014. It was developed following a formal Delphi procedure. A revised version was needed in order to incorporate changes that have occurred in the meantime in the International Classification of Sleep Disorders, updates in the manual for scoring sleep and associated events, and, most important, new knowledge in sleep physiology and pathophysiology. In addition, another major change can be observed in sleep medicine: a paradigm shift in sleep medicine has taken place. Sleep medicine is no longer a small interdisciplinary field in medicine. Sleep medicine has increased in terms of recognition and importance in medical care. Consequently, major medical fields (e.g. pneumology, cardiology, neurology, psychiatry, otorhinolaryngology, paediatrics) recognise that sleep disorders become a necessity for education and for diagnostic assessment in their discipline. This paradigm change is considered in the catalogue of knowledge and skills revision by the addition of new chapters.
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http://dx.doi.org/10.1111/jsr.13394DOI Listing
June 2021

Alternating Hemiplegia of Childhood: Genotype-Phenotype Correlations in a Cohort of 39 Italian Patients.

Front Neurol 2021 8;12:658451. Epub 2021 Apr 8.

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.

Alternating hemiplegia of childhood is a rare neurological disease characterized by paroxysmal movement disorders and chronic neurological disturbances, with onset before 18 months of age. Mutations in the gene have been identified in up to 80% of patients. Thirty-nine patients [20 females, 19 males, mean age 25.32 years (7.52-49.34)] have been recruited through the Italian Biobank and Clinical Registry for Alternating Hemiplegia of Childhood. Demographic data, genotype, paroxysmal movement disorders, chronic neurological features, and response to flunarizine have been analyzed. gene mutations have been detected in 92.3% of patients. Patients have been divided into three groups-p.Asp801Asn mutation patients (26%), p.Glu815Lys cases (23%), and patients with other mutations-and statistically compared. The Italian cohort has a higher percentage of gene mutation than reported in literature (92.3%). Our data confirm a more severe phenotype in patients with p.Glu815Lys mutation, with an earlier age of onset of plegic ( = 0.02 in the correlation with other mutations) and tonic attacks. P.Glu815Lys patients most frequently present altered muscle tone, inability to walk ( = 0.01 comparing p.Glu815Lys and p.Asp801Asn mutations), epilepsy, and a more severe grade of dystonia ( < 0.05 comparing p.Glu815Lys and p.Asp801Asn mutations). They have moderate/severe intellectual disability and severe language impairment ( < 0.05). Interestingly, flunarizine seems to be more efficacious in patients with p.Glu815Lys mutation than p.Asp801Asn. In conclusion, our research suggests a genotype-phenotype correlation and provides information on this disorder's features, clinical course, and treatment.
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http://dx.doi.org/10.3389/fneur.2021.658451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060701PMC
April 2021

Case Report: Whole Exome Sequencing Revealed Disease-Causing Variants in Two Genes in a Patient With Autism Spectrum Disorder, Intellectual Disability, Hyperactivity, Sleep and Gastrointestinal Disturbances.

Front Genet 2021 18;12:625564. Epub 2021 Feb 18.

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy.

Autism Spectrum Disorder (ASD) refers to a broad range of conditions characterized by difficulties in communication, social interaction and behavior, and may be accompanied by other medical or psychiatric conditions. Patients with ASD and comorbidities are often difficult to diagnose because of the tendency to consider the multiple symptoms as the presentation of a complicated syndromic form. This view influences variant filtering which might ignore causative variants for specific clinical features shown by the patient. Here we report on a male child diagnosed with ASD, showing cognitive and motor impairments, stereotypies, hyperactivity, sleep, and gastrointestinal disturbances. The analysis of whole exome sequencing (WES) data with bioinformatic tools for oligogenic diseases helped us to identify two major previously unreported pathogenetic variants: a maternally inherited missense variant (p.R4122H) in , an ubiquitin protein ligase associated to X-linked intellectual disability and ASD; and a stop variant (p.Q259X) in , encoding the tryptophan hydroxylase 2 enzyme involved in serotonin synthesis and associated with susceptibility to attention deficit-hyperactivity disorder (ADHD). , expressed in central and peripheral nervous tissues, modulates various physiological functions, including gut motility and sleep. To the best of our knowledge, this is the first case presenting with ASD, cognitive impairment, sleep, and gastrointestinal disturbances linked to both and genes. Our findings could contribute to the existing knowledge on clinical and genetic diagnosis of patients with ASD presentation with comorbidities.
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http://dx.doi.org/10.3389/fgene.2021.625564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930735PMC
February 2021

Mesial Temporal Sclerosis as Late Consequence of Posterior Reversible Encephalopathy Syndrome in Pediatric Haemato-oncological Patients.

J Pediatr Hematol Oncol 2021 Mar 3. Epub 2021 Mar 3.

Hematopoietic Stem Cell Transplantation Unit, Department of Haemato-Oncology Child Neuropsychiatry Unit Neuroradiology Unit, IRCSS Istituto Giannina Gaslini, Genoa, Italy Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa Department of Pediatrics, Pediatric Oncology and Haematology Unit "Lalla Seràgnoli" Child Neurology and Psychiatry Unit, St. Orsola-Malpighi Hospital, University of Bologna Neuroradiology Unit, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna Department of Neuroscience, University of Turin, Turin, Italy.

Objectives: Drug resistant epilepsy has rarely been reported following posterior reversible encephalopathy syndrome (PRES), with few cases of mesial temporal sclerosis (MTS). The aim of this study was to report clinical and neuroimaging features of MTS subsequent to PRES in haemato-oncological/stem cell transplanted children.

Materials And Methods: Among 70 children treated in 2 pediatric haemato-oncological Italian centers between 1994 and 2018 and presenting an episode of PRES, we retrospectively identified and analyzed a subgroup of patients who developed epilepsy and MTS.

Results: Nine of 70 patients (12.8%) developed post-PRES persistent seizures with magnetic resonance imaging evidence of MTS. One patient died few months after MTS diagnosis, because of hematological complications; the remaining 8 patients showed unprovoked seizures over time leading to the diagnosis of epilepsy, focal in all and drug resistant in 4. At PRES diagnosis, all patients with further evidence of epilepsy and MTS suffered of convulsive seizures, evolving into status epilepticus in 3. In 3 patients a borderline cognitive level or intellectual disability were diagnosed after the onset of epilepsy, and 2 had behavioral problems impacting their quality of life.

Conclusions: MTS and long-term focal epilepsy, along with potential cognitive and behavioral disorders, are not uncommon in older pediatric patients following PRES.
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http://dx.doi.org/10.1097/MPH.0000000000002139DOI Listing
March 2021

Genotype-phenotype correlations in patients with de novo pathogenic variants.

Neurol Genet 2020 Dec 30;6(6):e528. Epub 2020 Nov 30.

Department of Neurosciences (F. Malerba, G.B., E.A., A. Riva, V.S., L.N., C. Minetti, F.Z., P.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università degli Studi di Genova; Pediatric Neurology and Muscular Diseases Unit (F. Malerba, G.B., F. Marchese, E.A., A. Riva, M.S.V., V.S., C. Minetti, P.S.), IRCCS Istituto G. Gaslini; Center for Synaptic Neuroscience and Technology ([email protected]) (G.A., L.M., F.B.), Istituto Italiano di Tecnologia; Department of Experimental Medicine (G.A.), Università degli Studi di Genova; Laboratory of Human Genetics (E.G.); Unit of Medical Genetics (F. Madia, F.Z.), IRCCS Istituto G. Gaslini, Genova, Italy; Child Neurology and Neurorehabilitation Unit (M.A.), Department of Pediatrics, Central Hospital of Bolzano, Bolzano; Child Neurology and Psychiatry Unit (L.G., P.A., P.M.), ASST Spedali Civili, Brescia; Neurology Unit (M. Trivisano, N.S.), Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS, Roma; Child Neurology Unit (A. Russo, G.G.), IRCCS, Institute of Neurological Sciences of Bologna; Child Neuropsychiatry Unit (F.R.), U.O.N.P.I.A. ASST-Rhodense, Rho, Milano; Neurology Unit and Laboratories (T.P.), A. Meyer Children's Hospital, Firenze; Child Neurology and Psychiatric Unit (C. Marini), Pediatric Hospital G. Salesi, United Hospital of Ancona; Child Neuropsychiatry Unit (M.M.M., L.N.), IRCCS Istituto G. Gaslini, Genova; Department of Pediatric Neuroscience (E.F.), Fondazione IRCCS Istituto Neurologico Carlo Besta; Unit of Genetics of Neurodegenerative and Metabolic Diseases (B. Castellotti), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano; Department of Child Neuropsychiatry (G.C.), Epilepsy Center, C. Poma Hospital, Mantova; Fondazione Poliambulanza Brescia (G.C.); Epilepsy Center (A.C.), Department of Neuroscience, Reproductive and Odontostomatological Sciences, Università degli Studi di Napoli Federico II, Napoli; Department of Pediatrics (A.V.), University of Perugia; Section of Pharmacology (F. Miceli, M. Taglialatela), Department of Neuroscience, Reproductive and Odontostomatological Sciences, Università degli Studi di Napoli Federico II, Napoli; IRCCS Ospedale Policlinico San Martino (L.M., F.B.), Genova, Italy; Division of Pediatric Neurology (M.R.C.), Saint-Luc University Hospital, and Institute of Experimental and Clinical Research (IREC), Université Catholique de Louvain, Brussels, Belgium; Department of Epilepsy Genetics and Personalized Treatment (K.M.J., R.S.M.), The Danish Epilepsy Center Filadelfia, Dianalund, Denmark; Institute for Regional Health Services (K.M.J., R.S.M.), University of Southern Denmark, Odense, Denmark; Department of Neurology (B. Ceulemans, S.W.), University Hospital Antwerp; Applied & Translational Neurogenomics Group (S.W.), VIB-Center for Molecular Neurology; Laboratory of Neurogenetics (S.W.), Institute Born-Bunge, University of Antwerp, Belgium; and Department of Life and Environmental Sciences (L.M.), Polytechnic University of Marche, Ancona, Italy.

Objective: Early identification of de novo variants in patients with epilepsy raises prognostic issues toward optimal management. We analyzed the clinical and genetic information from a cohort of patients with de novo pathogenic variants to dissect genotype-phenotype correlations.

Methods: Patients with de novo pathogenic variants were identified from Italy, Denmark, and Belgium. Atomic resolution Kv7.2 structures were also generated using homology modeling to map the variants.

Results: We included 34 patients with a mean age of 4.7 years. Median seizure onset was 2 days, mainly with focal seizures with autonomic signs. Twenty-two patients (65%) were seizure free at the mean age of 1.2 years. More than half of the patients (17/32) displayed severe/profound intellectual disability; however, 4 (13%) of them had a normal cognitive outcome.A total of 28 de novo pathogenic variants were identified, most missense (25/28), and clustered in conserved regions of the protein; 6 variants recurred, and 7 were novel. We did not identify a relationship between variant position and seizure offset or cognitive outcome in patients harboring missense variants. Besides, recurrent variants were associated with overlapping epilepsy features but also variable evolution regarding the intellectual outcome.

Conclusions: We highlight the complexity of variant interpretation to assess the impact of a class of de novo mutations. Genetic modifiers could be implicated, but the study paradigms to successfully address the impact of each single mutation need to be developed.
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http://dx.doi.org/10.1212/NXG.0000000000000528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803337PMC
December 2020

CASK related disorder: Epilepsy and developmental outcome.

Eur J Paediatr Neurol 2021 Mar 19;31:61-69. Epub 2021 Feb 19.

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health, University of Genoa, Genova, Italy; Unit of Child Neuropsychiatry, ASST Fatebenefratelli Sacco, Milano, Italy.

Objective: CASK pathogenic variants are associated with variable features, as intellectual disability, optic atrophy, brainstem/cerebellar hypoplasia, and epileptic encephalopathy. Few studies describe the electroclinical features of epilepsy in patients with CASK pathogenic variants and their relationship with developmental delay.

Methods: this national multicentre cohort included genetically confirmed patients with different CASK pathogenic variants. Our findings were compared with cohorts reported in the literature.

Results: we collected 34 patients (29 females) showing from moderate (4 patients) to severe (22) and profound (8) developmental delay; all showed pontine and cerebellar hypoplasia, all except three with microcephaly. Seventeen out of 34 patients (50%) suffered from epileptic seizures, including spasms (11 patients, 32.3%), generalized (5) or focal seizures (1). In 8/17 individuals (47.1%), epilepsy started at or beyond the age of 24 months. Seven (3 males) out of the 11 children with spasms showed EEG features and a course supporting the diagnosis of a developmental and epileptic encephalopathy (DEE). Drug resistance was frequent in our cohort (52.9% of patients with epilepsy). EEG abnormalities included poorly organized background activity with diffuse or multifocal epileptiform abnormalities and sleep-activation, with possible appearance over the follow-up period. Developmental delay degree was not statistically different among patients with or without seizures but feeding difficulties were more frequent in patients with epilepsy.

Conclusions: epilepsy is a frequent comorbidity with a high incidence of spasms and drug resistance. Overall developmental disability does not seem to be more severe in the group of patients with epilepsy nor to be linked to specific epilepsy/EEG characteristics. A childhood onset of epilepsy is frequent, with possible worsening over time, so that serial and systematic monitoring is mandatory.
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http://dx.doi.org/10.1016/j.ejpn.2021.02.006DOI Listing
March 2021

Photoparoxysmal response in ADCK3 autosomal recessive ataxia: a case report and literature review.

Epileptic Disord 2021 Feb;23(1):153-160

Unit of Child Neuropsychiatry, Epilepsy Centre, Department of Medical and Surgical Neuroscience and Rehabilitation, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

Mutations in AarF domain-containing kinase 3 (ADCK3) are responsible for the most frequent form of hereditary coenzyme Q10 (CoQ10) deficiency (Q10 deficiency-4), which is mainly associated with autosomal recessive cerebellar ataxia type 2 (ARCA2). Clinical presentation is characterized by a variable degree of cerebellar atrophy and a broad spectrum of associated symptoms, including muscular involvement, movement disorders, neurosensory loss, cognitive impairment, psychiatric symptoms and epilepsy. In this report, we describe, for the first time, a case of photoparoxysmal response in a female patient with a mutation in ADCK3. Disease onset occurred in early childhood with gait ataxia, and mild-to-moderate degeneration. Seizures appeared at eight years and six months, occurring only during sleep. Photoparoxysmal response was observed at 14 years, almost concomitant with the genetic diagnosis (c.901C>T;c.589-3C>G) and the start of CoQ10 oral supplementation. A year later, disease progression slowed down, and photosensitivity was attenuated. A review of the literature is provided focusing on epileptic features of ADCK3-related disease as well as the physiopathology of photoparoxysmal response and supposed cerebellar involvement in photosensitivity. Moreover, the potential role of CoQ10 oral supplementation is discussed. Prospective studies on larger populations are needed to further understand these data.
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http://dx.doi.org/10.1684/epd.2021.1243DOI Listing
February 2021

Impact of the COVID-19 Outbreak on the Behavior of Families in Italy: A Focus on Children and Adolescents.

Front Public Health 2021;9:608358. Epub 2021 Feb 5.

Child Neuropsychiatry Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

The COVID-19 pandemic has changed individuals' lifestyles to a great extent, particularly in Italy. Although many concerns about it have been highlighted, its impact on children and adolescents has scarcely been examined. The purpose of this study was to explore behavioral consequences and coping strategies related to the pandemic among families in Italy, by focusing on developmental ages from the caregivers' perspective, 3 weeks into quarantine. An exploratory cross-sectional online survey was conducted over 14 days. Google Forms was employed to conduct the survey. Demographic variables and pre-existing Psychological Weaknesses (PsW) were asked. Adults' sleep difficulties (SleepScore) and coping strategies during quarantine were assessed. Behavioral changes related to quarantine of both subjects completing the form (COVIDStress) and their children (when present) were questioned. Of the 6,871 respondents, we selected 6,800 valid questionnaires; 3,245 declared children aged under 18 years of age (caregivers). PsWs were recognizable in 64.9% among non-caregivers and in 61.5% of caregivers, with a mean PsW score of 1.42 ± 1.26 and 1.30 ± 1.25 over 3 points, respectively. The 95.5% of the non-caregivers and the 96.5% of caregivers presented behavioral changes with a mean COVIDStress of 3.85 ± 1.82 and 4.09 ± 1.79 over 8, respectively (<0.001). Sleep difficulties were present in the 61.6% of the non-caregivers and in the 64.4% of the caregivers ( < 0.001), who showed higher SleepScores (2.41 ± 1.26 against 2.57 ± 1.38 points over 6, < 0.001). COVIDStress (and SleepScore) strongly correlated with PsW ( < 0.001). Caregivers observed behavioral changes in their children in the 64.3% of the <6 years old and in 72.5% of 6-18 years old. Caregivers' discomfort related to quarantine (COVIDStress, SleepScore) was strongly associated to behavioral changes in both age groups of <6 and 6-18 ( < 0.001). Presence of caregivers' coping strategies was less associated to behavioral changes in the <6 sample ( = 0.001) but not in the 6-18 ( = 0.06). The COVID-19 pandemic has adversely impacted families in Italy with regard to behavioral changes, especially in high-risk categories with PsWs and caregivers, especially the ones with children aged <6 years. While coping strategies functioned as protective factors, a wide array of stress symptoms had implications for children's and adolescents' behaviors. It is recommended that public children welfare strategies be implemented, especially for higher-psychosocial-risk categories.
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http://dx.doi.org/10.3389/fpubh.2021.608358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893111PMC
March 2021

Sleep disorders in Prader-Willi syndrome, evidence from animal models and humans.

Sleep Med Rev 2021 Jun 20;57:101432. Epub 2021 Jan 20.

Unit of Child Neuropsychiatry, Department of Medical and Surgical Neuroscience and Rehabilitation, IRCCS Istituto Giannina Gaslini, Genoa, Italy; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy. Electronic address:

Prader-Willi Syndrome (PWS) is a complex genetic disorder with multiple cognitive, behavioral and endocrine dysfunctions. Sleep alterations and sleep disorders such as Sleep-disordered breathing and Central disorders of hypersomnolence are frequently recognized (either isolated or in comorbidity). The aim of the review is to highlight the pathophysiology and the clinical features of sleep disorders in PWS, providing the basis for early diagnosis and management. We reviewed the genetic features of the syndrome and the possible relationship with sleep alterations in animal models, and we described sleep phenotypes, diagnostic tools and therapeutic approaches in humans. Moreover, we performed a meta-analysis of cerebrospinal fluid orexin levels in patients with PWS; significantly lower levels of orexin were detected in PWS with respect to control subjects (although significantly higher than the ones of narcoleptic patients). Sleep disorders in humans with PWS are multifaceted and are often the result of different mechanisms. Since hypothalamic dysfunction seems to partially influence metabolic, respiratory and sleep/wake characteristics of this syndrome, additional studies are required in this framework.
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http://dx.doi.org/10.1016/j.smrv.2021.101432DOI Listing
June 2021

The distinctive sleep pattern of the human calcarine cortex: a stereo-electroencephalographic study.

Sleep 2021 07;44(7)

Department of Psychology, "Sapienza" University of Rome, Rome, Italy.

Study Objectives: The aim of this study was to describe the spontaneous electroencephalographic (EEG) features of sleep in the human calcarine cortex, comparing them with the well-established pattern of the parietal cortex.

Methods: We analyzed presurgical intracerebral EEG activity in calcarine and parietal cortices during non-rapid eye movement (NREM) and rapid eye movement (REM) sleep in seven patients with drug-resistant focal epilepsy. The time course of the EEG spectral power and NREM vs REM differences was assessed. Sleep spindles were automatically detected. To assess homeostatic dynamics, we considered the first vs second half of the night ratio in the delta frequency range (0.5-4 Hz) and the rise rate of delta activity during the first sleep cycle.

Results: While the parietal area showed the classically described NREM and REM sleep hallmarks, the calcarine cortex exhibited a distinctive pattern characterized by: (1) the absence of sleep spindles; (2) a large similarity between EEG power spectra of NREM and REM; and (3) reduced signs of homeostatic dynamics, with a decreased delta ratio between the first and the second half of the night, a reduced rise rate of delta activity during the first NREM sleep cycle, and lack of correlation between these measures.

Conclusions: Besides describing for the first time the peculiar sleep EEG pattern in the human calcarine cortex, our findings provide evidence that different cortical areas may exhibit specific sleep EEG pattern, supporting the view of sleep as a local process and promoting the idea that the functional role of sleep EEG features should be considered at a regional level.
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http://dx.doi.org/10.1093/sleep/zsab026DOI Listing
July 2021

Identifying the signature of prospective motor control in children with autism.

Sci Rep 2021 Feb 4;11(1):3165. Epub 2021 Feb 4.

Cognition, Motion and Neuroscience Laboratory, Center for Human Technologies, Istituto Italiano di Tecnologia, Genoa, Italy.

Failure to develop prospective motor control has been proposed to be a core phenotypic marker of autism spectrum disorders (ASD). However, whether genuine differences in prospective motor control permit discriminating between ASD and non-ASD profiles over and above individual differences in motor output remains unclear. Here, we combined high precision measures of hand movement kinematics and rigorous machine learning analyses to determine the true power of prospective movement data to differentiate children with autism and typically developing children. Our results show that while movement is unique to each individual, variations in the kinematic patterning of sequential grasping movements genuinely differentiate children with autism from typically developing children. These findings provide quantitative evidence for a prospective motor control impairment in autism and indicate the potential to draw inferences about autism on the basis of movement kinematics.
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http://dx.doi.org/10.1038/s41598-021-82374-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862688PMC
February 2021

Focal status and acute encephalopathy in a 13-year-old boy with de novo DNM1L mutation: Video-polygraphic pattern and clues for differential diagnosis.

Brain Dev 2021 May 21;43(5):644-651. Epub 2021 Jan 21.

Neonatal and Pediatric Intensive Care Unit, Department of Critical Care, IRCCS Giannina Gaslini, Genova, Italy.

Background: Pathogenic variants in the dynamin 1 like gene are related to abnormal mitochondrial dynamics and distributions and are associated to variable clinical phenotypes. A few patients harboring the p.Arg403Cys missense variant appears to be different from the classical, more severe phenotypes, showing sudden onset of drug resistant seizures after a previously normal or slightly delayed development.

Case Report: We report on a boy with abrupt onset of focal status and coma at the age of 13, initially treated as autoimmune encephalitis, with final diagnosis of de novo missense p.Arg403Cys variant in the DNM1L gene.

Discussion: We compare his clinical, electrophysiological, biochemical, neuroradiological and histopathological picture to the rare cases reported to date and provide diagnostic clues that can help clinicians in differentiate p.Arg403Cys-related phenotype from that of immune-mediated encephalopathies.

Conclusion: The clinical picture related to p.Arg403Cys mutations should be considered alongside acquired pathologies in the differential diagnosis of young patients with focal refractory epilepsy and encephalopathy, also occurring during late childhood or adolescence. Prompt genetic testing allows to avoid unnecessary treatments and procedures and to better define the prognosis and management strategies.
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http://dx.doi.org/10.1016/j.braindev.2020.12.017DOI Listing
May 2021

Fast oscillations >40 Hz localize the epileptogenic zone: An electrical source imaging study using high-density electroencephalography.

Clin Neurophysiol 2021 02 22;132(2):568-580. Epub 2020 Dec 22.

Analytical Neurophysiology Lab, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada; Department of Medicine, Queen's University, Kingston, ON, Canada. Electronic address:

Objective: Fast Oscillations (FO) >40 Hz are a promising biomarker of the epileptogenic zone (EZ). Evidence using scalp electroencephalography (EEG) remains scarce. We assessed if electrical source imaging of FO using 256-channel high-density EEG (HD-EEG) is useful for EZ identification.

Methods: We analyzed HD-EEG recordings of 10 focal drug-resistant epilepsy patients with seizure-free postsurgical outcome. We marked FO candidate events at the time of epileptic spikes and verified them by screening for an isolated peak in the time-frequency plot. We performed electrical source imaging of spikes and FO within the Maximum Entropy of the Mean framework. Source localization maps were validated against the surgical cavity.

Results: We identified FO in five out of 10 patients who had a superficial or intermediate deep generator. The maximum of the FO maps was localized inside the cavity in all patients (100%). Analysis with a reduced electrode coverage using the 10-10 and 10-20 system showed a decreased localization accuracy of 60% and 40% respectively.

Conclusions: FO recorded with HD-EEG localize the EZ. HD-EEG is better suited to detect and localize FO than conventional EEG approaches.

Significance: This study acts as proof-of-concept that FO localization using 256-channel HD-EEG is a viable marker of the EZ.
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http://dx.doi.org/10.1016/j.clinph.2020.11.031DOI Listing
February 2021

How to distinguish seizures from non-epileptic manifestations.

Epileptic Disord 2020 Dec;22(6):716-738

Medical Faculty, Johannes Kepler University, Linz, Austria, Department of Neurology 1, Neuromed Campus, Kepler University Hospital, Linz, Austria.

The first and most important step in establishing diagnosis of epilepsy consists of careful history taking from patients and witnesses. The clinical evaluation of the event will lead the indication for further diagnostic tests including e.g. EEG and MRI. Hence, identifying the paroxysmal event as epileptic or non-epileptic is the very first step in the diagnostic process. Paroxysmal events pose a clinical challenge, as these are unpredictable and do not usually occur in the doctor's office. History taking, hunting for witness reports and home-video recordings are the main tools to conclude whether a paroxysmal event is a seizure or not. In this review, we describe the most common differential diagnoses of epileptic seizures, including syncope, psychogenic non-epileptic seizures, as well as a variety of paroxysmal conditions and behaviours of all age groups. Misdiagnosis of non-epileptic events as epilepsy may not only defer the correct diagnosis and treatment but also poses additional risk by prescribing antiepileptic drugs unnecessarily. Moreover, missing the diagnosis of epilepsy implies risk of additional seizures and therefore possibly injuries, sudden death in people with epilepsy, or status epilepticus. Studies have shown that patient and witness accounts are unreliable in a high percentage of cases. Therefore, the core competency of doctors and medical professionals assessing paroxysmal events is knowledge of the clinical features that help define the different aetiologies, thus empowering them to establish the most accurate appraisal of an event. [Published with video sequences].
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http://dx.doi.org/10.1684/epd.2020.1234DOI Listing
December 2020

[Evaluation and management of insomnia in clinical practice and in the time of CoViD-19 in Italy: expert consensus and task-force recommendations from five scientific societies].

Riv Psichiatr 2020 Nov-Dec;55(6):337-341

Dipartimento di Scienze della Vita e dell'Ambiente, Università di Cagliari; Società Italiana di Neuropsicofarmacologia (SINF).

Insomnia symptoms might affect about 60% of the Italian population. Insomnia is a "24 hours syndrome" and a risk factor for medical and mental disorders. It should always be assessed and treated in the clinical practice. Cognitive Behavioral Therapy for Insomnia is the first line treatment but its availability in Italy is scarce. Pharmacological options in Italy are: melatonin 2 mg prolonged release that should be the first choice in subjects ≥55 years old and used until 13 weeks; and for a short term use (≤4 weeks) Z-drugs or short-acting benzodiazepines (in subjects <65 years old) or a sedating antidepressant.
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http://dx.doi.org/10.1708/3503.34891DOI Listing
December 2020

Standard procedures for the diagnostic pathway of sleep-related epilepsies and comorbid sleep disorders: A European Academy of Neurology, European Sleep Research Society and International League against Epilepsy-Europe consensus review.

J Sleep Res 2020 12 21;29(6):e13184. Epub 2020 Sep 21.

IRCCS Istituto delle Scienze Neurologiche di Bologna, Ospedale Bellaria, Bologna, Italy.

Background: Some epilepsy syndromes (sleep-related epilepsies [SRE]) have a strong link with sleep. Comorbid sleep disorders are common in patients with SRE and can exert a negative impact on seizure control and quality of life.

Purposes: To define the standard procedures for the diagnostic pathway of patients with possible SRE (scenario 1) and the general management of patients with SRE and comorbidity with sleep disorders (scenario 2).

Methods: The project was conducted under the auspices of the European Academy of Neurology (EAN), the European Sleep Research Society (ESRS) and the International League against Epilepsy (ILAE) Europe. The framework of the document entailed the following phases: conception of the clinical scenarios; literature review; statements regarding the standard procedures. For literature search a step-wise approach starting from systematic reviews to primary studies was applied. Published studies were identified from the National Library of Medicine's MEDLINE database and Cochrane Library.

Results: Scenario 1: despite a low quality of evidence, recommendations on anamnestic evaluation, tools for capturing the event at home or in the laboratory are provided for specific SRE. Scenario 2: Early diagnosis and treatment of sleep disorders (especially respiratory disorders) in patients with SRE are likely to be beneficial for seizures control.

Conclusions: Definitive procedures for evaluating patients with SRE are lacking. We provide advice that could be of help for standardising and improving the diagnostic approach of specific SRE. The importance of identifying and treating specific sleep disorders for the management and outcome of patients with SRE is underlined.
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http://dx.doi.org/10.1111/jsr.13184DOI Listing
December 2020

Behavioural and emotional profiles of children and adolescents with disorders of arousal.

J Sleep Res 2021 02 10;30(1):e13188. Epub 2020 Sep 10.

Department of Health Sciences, University of Milan, Milan, Italy.

Disorders of arousals are common sleep disorders characterized by complex motor behaviours that arise episodically out of slow-wave sleep. Psychological distress has long been associated with disorders of arousal, but this link remains controversial, especially in children and adolescents. The aim of this multi-centre study was to characterize behavioural and emotional problems in a sample of children/adolescents with disorders of arousal, and to explore their relationship with the severity of nocturnal episodes. The parents of 41 children/adolescents with a diagnosis of disorders of arousal (11.5 ± 3.3 years old, 61% males) and of a group of 41 age- and gender-matched control participants filled in the Child Behavior Checklist, along with the Sleep Disturbance Scale for Children and the Paris Arousal Disorders Severity Scale. Multilevel t-tests revealed significantly higher total scores and sub-scores of the Child Behavior Checklist for the patient group compared with the control group. Thirty-four percent of the patients obtained pathological total scores, and 12% of them borderline scores. The severity of emotional/behavioural problems in the patient group was positively correlated with the severity of the nocturnal episodes. Interestingly, children/adolescents with disorders of arousal also obtained higher excessive daytime sleepiness and insomnia symptoms sub-scores at the Sleep Disturbance Scale for Children. These results confirmed the hypothesis that behavioural/emotional problems are surprisingly common in children/adolescents with disorders of arousal. Further studies are warranted to investigate the causal relationship between pathological manifestations, subtler sleep abnormalities, and diurnal emotional/behavioural problems in children/adolescents with disorders of arousal.
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http://dx.doi.org/10.1111/jsr.13188DOI Listing
February 2021

Thalamic and neocortical differences in the relationship between the time course of delta and sigma power during NREM sleep in humans.

J Sleep Res 2021 06 24;30(3):e13166. Epub 2020 Aug 24.

Department of Neuroscience (DINOGMI), University of Genoa, Genoa, Italy.

Sleep spindles and slow waves are the hallmarks of non-rapid eye movement (NREM) sleep and are produced by the dynamic interplay between thalamic and cortical regions. Several studies in both human and animal models have focused their attention on the relationship between electroencephalographic (EEG) spindles and slow waves during NREM, using the power in the sigma and delta bands as a surrogate for the production of spindles and slow waves. A typical report is an overall inverse relationship between the time course of sigma and delta power as measured by a single correlation coefficient both within and across NREM episodes. Here we analysed stereotactically implanted intracerebral electrode (Stereo-EEG [SEEG]) recordings during NREM simultaneously acquired from thalamic and from several neocortical sites in six neurosurgical patients. We investigated the relationship between the time course of delta and sigma power and found that, although at the cortical level it shows the expected inverse relationship, these two frequency bands follow a parallel time course at the thalamic level. Both these observations were consistent across patients and across different cortical as well as thalamic regions. These different temporal dynamics at the neocortical and thalamic level are discussed, considering classical as well as more recent interpretations of the neurophysiological determinants of sleep spindles and slow waves. These findings may also help understanding the regulatory mechanisms of these fundamental sleep EEG graphoelements across different brain compartments.
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http://dx.doi.org/10.1111/jsr.13166DOI Listing
June 2021

Expert Opinions and Consensus Recommendations for the Evaluation and Management of Insomnia in Clinical Practice: Joint Statements of Five Italian Scientific Societies.

Front Psychiatry 2020 26;11:558. Epub 2020 Jun 26.

Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy.

Background: Insomnia is the most commonly reported sleep problem in industrialized countries worldwide being present in about 36.8% of the general population. In Italy, such a percentage seems to be even higher. Although insomnia can be an independent disorder, it is most frequently observed as a comorbid condition and may precipitate, exacerbate, or prolong a broad range of comorbid conditions including physical and mental illnesses. Evaluating and targeting insomnia in the Italian clinical practice should be a priority.

Methods: The present expert options and recommendations development process was based on the RAND/UCLA Appropriateness Method for conceptualizing, designing, and carrying out the appropriateness of procedures for the diagnosis and treatment. Only available options in Italy were taken into considerations.

Results: We evaluated 12 international guidelines and 12 most recent systematic reviews for insomnia evaluation and treatment produced in the last 10 years.

Conclusions: Our findings suggested that symptoms of insomnia must always be assessed in the Italian clinical practice by evaluating nocturnal and daytime symptoms, comorbid conditions and lifestyle. In a patient with chronic insomnia with and without comorbidity, insomnia treatment should be always initiated. CBT-Insomnia therapy should be the first option accordingly to availability. The choice of the drug should be based on different factors such as type of insomnia, age, comorbidities, and potential side effects. Melatonin 2 mg prolonged release should be the first choice in subjects >55 years. If the choice would be a Z-drug or a short-acting benzodiazepine (in subjects <65 years old) or a sedating antidepressant, the use should be in the short term (≤4 weeks) and then proceeds to tapering under clinical monitoring.
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http://dx.doi.org/10.3389/fpsyt.2020.00558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332855PMC
June 2020

SAS Care 1: sleep-disordered breathing in acute stroke an transient ischaemic attack - prevalence, evolution and association with functional outcome at 3 months, a prospective observational polysomnography study.

ERJ Open Res 2020 Apr 15;6(2). Epub 2020 Jun 15.

Sleep-Wake-Epilepsy Center, Dept of Neurology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.

Sleep-disordered breathing (SDB) is frequent in patients with acute stroke. Little is known, however about the evolution of SDB after stroke. Most of our knowledge stems from smaller cohort studies applying limited cardiopulmonary sleep recordings or from cross-sectional data collected in different populations. This study aims to determine prevalence, type and intra-individual evolution of SDB based on full-night polysomnography (PSG) in acute stroke and 3 months thereafter. Furthermore, we aimed to identify predictors of SDB in the acute and chronic phase and to evaluate associations between SDB and functional outcome at 3 months (M3). A total of 166 patients with acute cerebrovascular events were evaluated by full PSG at baseline and 105 again at M3. The baseline prevalence of SDB (apnoea-hypopnoea index (AHI)>5·h) was 80.5% and 25.4% of the patients had severe SDB (AHI>30·h). Obstructive sleep apnoea was more prevalent than central sleep apnoea (83.8% 13%). Mean±SD AHI was 21.4±17.6·hand decreased significantly at M3 (18±16.4·h; p=0.018). At M3, 91% of all patients with baseline SDB still had an AHI>5·h and in 68.1% the predominant type of SDB remained unchanged (78.9% in obstructive sleep apnoea and 44.4% in central sleep apnoea). The only predictors of SDB at baseline were higher age and body mass index and in the chronic phase additionally baseline AHI. Baseline AHI was associated with functional outcome (modified Rankin score >3) at M3. The high prevalence of SDB in acute stroke, its persistence after 3 months, and the association with functional outcome supports the recommendation for a rapid SDB screening in stroke patients.
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http://dx.doi.org/10.1183/23120541.00334-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293990PMC
April 2020

Targeted re-sequencing in malformations of cortical development: genotype-phenotype correlations.

Seizure 2020 Aug 3;80:145-152. Epub 2020 Jun 3.

Unit of Child Neuropsychiatry, ARNAS Civico G. Di Cristina Benefratelli, Palermo, Italy.

Purpose: Malformations of cortical development (MCD) are a phenotypically and genetically heterogeneous group of disorders, for which the diagnostic rate of genetic testing in a clinical setting remains to be clarified. In this study we aimed to assess the diagnostic rate of germline and pathogenic variants using a custom panel in a heterogeneous group of subjects with MCD and explore genotype-phenotype correlations.

Methods: A total of 84 subjects with different MCD were enrolled. Genomic DNA was isolated from peripheral blood. Fifty-nine tartget genes were assessed using a custom next-generation sequencing (NGS) panel.

Results: Genetic causes were identified in one-fourth of our cohort (21.4 %). Overall, we identified 19 pathogenic or likely pathogenic single-nucleotide variants in 11 genes among 18 subjects, including PAFAH1B1 (LIS1) (n = 3), TUBA1A (n = 3), DYNC1H1 (n = 3), ACTG1 (n = 2), TUBB2B (n = 1), TUBB3 (n = 1), DCX (n = 1), FLNA (n = 1), LAMA2 (n = 1), POMGNT2 (n = 1) and VLDLR (n = 1). The diagnostic yield was higher in patients with lissencephaly/pachygyria (60 %) (p = 0.001), cobblestone malformation (50 %), and subcortical band heterotopia (SBH) (40 %). Furthermore, five out of six subjects with suspect tubulinopathies on imaging harboured pathogenic variants in tubulin genes. Overall, germline pathogenic variants were more likely to be identified if MCD were diffuse (p = 0.002) and associated with other central nervous system malformations (p = 0.029). Moderate to severe intellectual disability was also more commonly associated with pathogenic variants (p = 0.044).

Conclusion: Customized gene panels may support the diagnostic work-up for some specific MCD, especially when these are diffuse, bilateral and associated with other brain malformations.
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http://dx.doi.org/10.1016/j.seizure.2020.05.023DOI Listing
August 2020

Identifying the epileptogenic zone by four non-invasive imaging techniques versus stereo-EEG in MRI-negative pre-surgery epilepsy patients.

Clin Neurophysiol 2020 08 3;131(8):1815-1823. Epub 2020 Jun 3.

Epilepsy Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Objective: We evaluated four imaging techniques, i.e. Electroencephalography (EEG)-functional Magnetic Resonance Imaging (MRI) (EEG-fMRI), High-resolution EEG (HR-EEG), Magnetoencephalography (MEG) and 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (PET), for the identification of the epileptogenic zone (EZ) in 41 patients with negative MRI, candidate to neurosurgery.

Methods: For each technique, results were compared to the Stereo-EEG. Diagnostic measures were calculated with respect to the post-surgical outcome, either for all the patients (39/41, two patients excluded) and for the subgroup of patients with the EZ involving more than one lobe (20/41).

Results: When considered individually, each functional technique showed accuracy values ranging 54,6%-63,2%, having PET, MEG and HR-EEG higher sensitivity, and EEG-fMRI higher specificity. In patients with multilobar epileptogenic zone, functional techniques achieved the best accuracies (up to 80%) when three techniques, including EEG-fMRI, were considered together.

Conclusions: The study highlights the accuracy of a combination of functional imaging techniques in the identification of EZ in MRI negative focal epilepsy. The best diagnostic yield was obtained if the combination of PET, MEG (or HR-EEG as alternative), EEG-fMRI were considered together.

Significance: The functional imaging techniques may improve the presurgical workup of MRI negative focal epilepsy, if epileptogenic zone involves more than one lobe.
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http://dx.doi.org/10.1016/j.clinph.2020.05.015DOI Listing
August 2020

Safety and pharmacokinetics of medical cannabis preparation in a monocentric series of young patients with drug resistant epilepsy.

Complement Ther Med 2020 Jun 28;51:102402. Epub 2020 Apr 28.

DINOGMI Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Children's Sciences, University of Genoa, Genoa, Italy; Child Neuropsychiatry Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy. Electronic address:

Objectives: To evaluate safety and pharmacokinetic parameters (PK) of medical cannabis in add-on for children and young adults with drug-resistant epilepsy.

Design, Setting: Ten patients (4 females, 6 males, age 2.5-23.2 years) were enrolled in a prospective open trial with a galenic preparation (decoction) of Italian cannabis (FM2, ratio THC:CBD = 3:5, range THC 5.2-7.2 %; CBD 8.2-11.1 %). Patients received the first dose in Hospital, progressively augmented by CBD dose titration (from 1 to 4 mg/kg/day).

Outcome Measures: In order to assess safety, blood parameters, heart rates and electrocardiograms (ECGs) were evaluated before the enrollment and during the follow up. The PK study was performed measuring THC and CBD concentrations by UHPLC-MS/MS in plasma samples collected during the first administration and at each follow-up visit.

Results: Two out of ten patients stopped the treatment for adverse events (detected in 6/10: gastroenteric, sleep or behavioral disorders) and difficulties in drug supply. We observed minor ECG alterations in two patients and asymptomatic transient reductions of fibrinogen after 6 months of therapy. The PK study during follow-up revealed statistically significant correlations between THC-CBD blood concentrations and: volumes of decoction, FM2 and THC-CBD daily dosages.

Conclusions: The present study, although with some limitations, shows a good safety profile of medical cannabis in children and young patients with drug-resistant epilepsy and encourages the possibility of further studies with oral cannabis-based drugs. The correlations between THC-CBD plasma concentrations and their administered dosages underline the need of a therapeutic drug monitoring for cannabinoids therapy.
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http://dx.doi.org/10.1016/j.ctim.2020.102402DOI Listing
June 2020

Optic Atrophy and Generalized Chorea in a Patient Harboring an OPA10/RTN4IP1 Pathogenic Variant.

Neuropediatrics 2020 12 11;51(6):425-429. Epub 2020 May 11.

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal, and Child Health, University of Genoa, Genoa, Italy.

pathogenic variants (OPA10 syndrome) have been described in patients with early-onset recessive optic neuropathy and recently associated with a broader clinical spectrum, from isolated optic neuropathy to severe encephalopathies with epilepsy. Here we present a case of a patient with a complex clinical picture characterized by bilateral optic nerve atrophy, horizontal nystagmus, myopia, mild intellectual disability, generalized chorea, isolated small subependymal heterotopia, and asynchronous self-resolving midbrain MRI (magnetic resonance imaging) lesions. By using massive gene sequencing, we identified in this patient the c.308G > A (p.Arg103His) homozygous pathogenic variant in the gene. Complex movement disorders and relapsing-remitting neuroradiological lesions have not been previously reported in this condition. Our case expands the clinical spectrum of OPA10 syndrome and opens new opportunities for the molecular diagnosis.
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http://dx.doi.org/10.1055/s-0040-1708539DOI Listing
December 2020

Drugs Used in Parasomnia.

Sleep Med Clin 2020 Jun;15(2):289-300

Department of Neuroscience, Centre of Sleep Medicine, Centre for Epilepsy Surgery, Niguarda Hospital, Piazza Ospedale Maggiore, Milan 3-20162, Italy; Department of Neuroscience (DINOGMI), University of Genoa, Child neuropsychiatry, Gaslini Institute, Via Gerolamo Gaslini, Genoa 5-16147, Italy. Electronic address:

Patient education and behavioral management represent the first treatment approaches to the patient with parasomnia, especially in case of disorders of arousal (DOA). A pharmacologic treatment of DOA may be useful when episodes are frequent and persist despite resolution of predisposing factors, are associated with a high risk of injury, or cause significant impairment, such as excessive sleepiness. Approved drugs for DOA are still lacking. The most commonly used medications are benzodiazepines and antidepressants. The pharmacologic treatment of rapid eye movement sleep behavior disorder is symptomatic, and the most commonly used drugs are clonazepam and melatonin.
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http://dx.doi.org/10.1016/j.jsmc.2020.02.014DOI Listing
June 2020
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