Publications by authors named "Maria Paola Canevini"

129 Publications

Sleep and behavior in children and adolescents with tuberous sclerosis complex.

Am J Med Genet A 2021 Mar 1. Epub 2021 Mar 1.

Epilepsy Center-Sleep Medicine Center, Childhood and Adolescence Neuropsychiatry Unit, ASST SS. Paolo e Carlo, San Paolo Hospital, Milan, Italy.

Sleep disorders are frequent in tuberous sclerosis complex (TSC) during the developmental age but are not well characterized. Forty-six TSC patients and 46 healthy age- and sex-matched controls were enrolled. Their parents completed the Sleep Disturbances Scale for Children (SDSC) and the Child Behavior Checklist (CBCL). A total of 17.4% of the TSC patients obtained a total pathologic score at the SDSC versus 4.4% in the control group (p = 0.024). 45.7% of individuals with TSC reported a pathologic score in at least one of the factors. We found a statistically significant difference between the TSC cohort and healthy controls for most of the CBCL scales scores. A significant relationship was found between the Total SDSC score and the Total CBCL score (R-square = 0.387, p < 0.0001), between the Total SDSC score and the Internalizing and Externalizing areas scores (R-square = 0.291, p < 0.0001 and R-square = 0.350, p < 0.0001, respectively) of the CBCL. Sleep disorders are more frequent in TSC than in the general population and correlate with behavior. The use of SDSC and CBCL is proposed as part of the surveillance of TSC patients in the developmental age.
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http://dx.doi.org/10.1002/ajmg.a.62123DOI Listing
March 2021

The Many Faces of Covid-19 at a Glance: A University Hospital Multidisciplinary Account From Milan, Italy.

Front Public Health 2020;8:575029. Epub 2021 Jan 8.

Respiratory Medicine, Department of Health Sciences, San Paolo University Hospital, Azienda Socio Sanitaria Territoriale Santi Paolo e Carlo, University of Milan Medical School, Milan, Italy.

In March 2020, northern Italy became the second country worldwide most affected by Covid-19 and the death toll overtook that in China. Hospital staff soon realized that Covid-19 was far more severe than expected from the few data available at that time. The Covid-19 pandemic forced hospitals to adjust to rapidly changing circumstances. We report our experience in a general teaching hospital in Milan, the capital of Lombardy, the most affected area in Italy. First, we briefly describe Lombardy's regional Covid-19-related health organizational changes as well as general hospital reorganization. We also provide a multidisciplinary report of the main clinical, radiological and pathological Covid-19 findings we observed in our patients.
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http://dx.doi.org/10.3389/fpubh.2020.575029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820812PMC
February 2021

What Will Be the Impact of the Covid-19 Quarantine on Psychological Distress? Considerations Based on a Systematic Review of Pandemic Outbreaks.

Healthcare (Basel) 2021 Jan 19;9(1). Epub 2021 Jan 19.

Asst SS.Paolo e Carlo, S.Paolo Hospital, 20142 Milan, Italy.

: The novel coronavirus (SARS-CoV-2) and related syndrome (COVID-19) has led to worldwide measures with severe consequences for millions of people. In the light of the psychopathological consequences of restrictive measures detected during previous outbreaks, a systematic review was carried out to provide an evidence-based assessment of possible effects of the current COVID-19 quarantine on mental health. : This review included studies that assessed mental health indexes (e.g., overall psychological distress, depressive and PTSD symptoms) during and after quarantine periods adopted to management different outbreaks (e.g., COVID-19, SARS, MERS). : Twenty-one independent studies were included for a total of 82,312 subjects. At least 20% of people exposed to restrictive measures for the management of pandemic infections reported clinically significant levels of psychological distress, especially PTSD (21%) and depressive (22.69%) symptoms. Overall, original studies highlighted relevant methodological limitations. : Nowadays, almost one out of every five people is at risk of development of clinically significant psychological distress. Further research on mental health after the current COVID-19 quarantine measures is warranted.
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http://dx.doi.org/10.3390/healthcare9010101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835976PMC
January 2021

Ring Chromosome 20 Syndrome: Genetics, Clinical Characteristics, and Overlapping Phenotypes.

Front Neurol 2020 8;11:613035. Epub 2020 Dec 8.

Child Neuropsychiatry Unit - Epilepsy Center, Department of Health Sciences, ASST Santi Paolo e Carlo, San Paolo Hospital, Università Degli Studi di Milano, Milan, Italy.

Ring chromosome 20 [r(20)] syndrome is a rare condition characterized by a non-supernumerary ring chromosome 20 replacing a normal chromosome 20. It is commonly seen in a mosaic state and is diagnosed by means of karyotyping. r(20) syndrome is characterized by a recognizable epileptic phenotype with typical EEG pattern, intellectual disability manifesting after seizure onset in otherwise normally developing children, and behavioral changes. Despite the distinctive phenotype, many patients still lack a diagnosis-especially in the genomic era-and the pathomechanisms of ring formation are poorly understood. In this review we address the genetic and clinical aspects of r(20) syndrome, and discuss differential diagnoses and overlapping phenotypes, providing the reader with useful tools for clinical and laboratory practice. We also discuss the current issues in understanding the mechanisms through which ring 20 chromosome causes the typical manifestations, and present unpublished data about methylation studies. Ultimately, we explore future perspectives of r(20) research. Our intended audience is clinical and laboratory geneticists, child and adult neurologists, and genetic counselors.
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http://dx.doi.org/10.3389/fneur.2020.613035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753021PMC
December 2020

A Systematic Review and Provisional Metanalysis on Psychopathologic Burden on Health Care Workers of Coronavirus Outbreaks.

Front Psychiatry 2020 16;11:568664. Epub 2020 Oct 16.

Asst SS.Paolo e Carlo, S.Paolo Hospital, Milan, Italy.

Background: The new coronavirus (SARS-CoV-2) shows several similarities with previous outbreaks of Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). Aim of this systematic review and meta-analysis is to provide evidence of the psychopathologic burden on health care workers (HCWs) of the first two deadly coronavirus outbreaks to get lessons for managing the current burden of COVID-19 outbreak.

Method: According to Cochrane Collaboration guidelines and the PRISMA Statement, the study quantified the effects of frontline work on mental health of HCWs. Major databases - Pubmed, Scopus, Embase, Medline, and Web of Science - were searched for observational and case-control studies evaluating mental health indexes reported by front-line work. This study computed the percentage of sample that reported clinically significant levels of psychiatric symptoms. Cohen's was used for comparing mental health outcomes of health care workers directly involved in addressing pandemic emergency with a control group that was not directly exposed to such conditions. Pooled effect sizes ( ) were estimated whenever at least three independent studies yielded data. Heterogeneity of findings and bias of publication were estimated as well.

Findings: Fifteen studies have been selected for a total of 7,393 HCWs. From 9.6% to 51% of HCWs reported symptoms of Post-Traumatic Stress Disorder (PTSD) and from 20% to 75% reported psychiatric symptoms, with a prevalence of anxiety and depression. From one to the three years after outbreak, from 2% to 19% reported PTSD symptoms and from 5% to 90% psychiatric symptoms. Interestingly, HWCs who were directly involved in pandemic emergency showed significantly higher depressive and anxious symptoms ( = .66 (.46-.85); p <.001) than ones who were not directly exposed. Similarly, the direct involvement significantly affected the severity of PTSD symptoms ( = .30 (.21-.39); p <.001).

Conclusion: Health care professionals in general and most of all frontline workers showed an association with a likely risk of developing psychiatric disorders following outbreaks and for at least three years later. Mental health interventions for professionals exposed to COVID-19 need to be immediately implemented. Further studies are warranted to investigate long-term consequences carefully, and to look for mediating and buffering factors as well. The role of clinical psychologists and psychiatrists in delivering adequate interventions is critically important.
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http://dx.doi.org/10.3389/fpsyt.2020.568664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596413PMC
October 2020

Phenotypes in adult patients with Rett syndrome: results of a 13-year experience and insights into healthcare transition.

J Med Genet 2020 Oct 26. Epub 2020 Oct 26.

Department of Health Sciences, Università degli Studi di Milano, Milano, Lombardia, Italy.

Background: Rett syndrome is a complex genetic disorder with age-specific manifestations and over half of the patients surviving into middle age. However, little information about the phenotype of adult individuals with Rett syndrome is available, and mainly relies on questionnaires completed by caregivers. Here, we assess the clinical manifestations and management of adult patients with Rett syndrome and present our experience in transitioning from the paediatric to the adult clinic.

Methods: We analysed the medical records and molecular data of women aged ≥18 years with a diagnosis of classic Rett syndrome and/or pathogenic variants in , and , who were in charge of our clinic.

Results: Of the 50 women with classic Rett syndrome, 94% had epilepsy (26% drug-resistant), 20% showed extrapyramidal signs, 40% sleep problems and 36% behavioural disorders. Eighty-six % patients exhibited gastrointestinal problems; 70% had scoliosis and 90% low bone density. Breathing irregularities were diagnosed in 60%. None of the patients had cardiac issues. CDKL5 patients experienced fewer breathing abnormalities than women with classic Rett syndrome.

Conclusion: The delineation of an adult phenotype in Rett syndrome demonstrates the importance of a transitional programme and the need of a dedicated multidisciplinary team to optimise the clinical management of these patients.
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http://dx.doi.org/10.1136/jmedgenet-2020-107333DOI Listing
October 2020

Early Life Adversities and Borderline Intellectual Functioning Negatively Impact Limbic System Connectivity in Childhood: A Connectomics-Based Study.

Front Psychiatry 2020 11;11:497116. Epub 2020 Sep 11.

CADiTeR - Center of Advanced Diagnostic, Therapy and Rehabilitation, IRCCS Fondazione Don Carlo Gnocchi ONLUS, Milan, Italy.

Early life adversity (ELA) in childhood is a major risk factor for borderline intellectual functioning (BIF). BIF affects both adaptive and intellectual abilities, commonly leading to school failure and to an increased risk to develop mental and social problems in the adulthood. This study aimed to investigate the neurobiological underpinnings of ELA associated with BIF in terms of global topological organization and structural connectivity and their relation with intellectual functioning. BIF (N=32) and age-matched typical development (TD, N=14) children were evaluated for intelligence quotient (IQ), behavioral competencies, and ELA. Children underwent an anatomical and diffusion-weighted MR imaging (DWI) protocol. Global brain topological organization was assessed measuring segregation and integration indexes. Moreover, structural matrices, measuring normalized number of fibers (NFn), were compared between the 2 groups using network-based statistics. Finally, a linear regression model was used to explore the relationship between network parameters and clinical measures. Results showed increased behavioral difficulties and ELA, together with decreased network integration in BIF children. Moreover, significantly lower NFn was observed in the BIF group (p=.039) in a sub-network comprising anterior and posterior cingulate, the pericallosal sulcus, the orbital frontal areas, amygdala, basal ganglia, the accumbens nucleus, and the hippocampus. Linear regression showed that NFn significantly predicted IQ (p<.0001). This study demonstrated that ELA in children with BIF is associated with a decreased information integration at the global level, and with an altered structural connectivity within the limbic system strictly related to the intellectual functioning.
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http://dx.doi.org/10.3389/fpsyt.2020.497116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518022PMC
September 2020

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

J Sleep Res 2021 Feb 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

The TAND checklist: a useful screening tool in children with tuberous sclerosis and neurofibromatosis type 1.

Orphanet J Rare Dis 2020 09 7;15(1):237. Epub 2020 Sep 7.

Epilepsy Center- Child Neuropsychiatry Unit, ASST Santi Paolo Carlo, Department of Health Sciences, University of Milan, Via di Rudinì 8, 20142, Milan, Italy.

Background: Tuberous Sclerosis Complex (TSC) and Neurofibromatosis type 1 (NF1) are neurocutaneous disorders commonly characterized by neuropsychiatric comorbidities. The TAND (Tuberous Sclerosis Associated Neuropsychiatric Disorders) Checklist is currently used to quickly screen for behavioural, psychiatric, intellectual, academic, neuropsychological and psychosocial manifestations in patients with TSC. We administered the authorized Italian version of the TAND Checklist to the parents of 42 TSC patients and 42 age- and sex-matched NF1 patients, for a total of 84 individuals, aged 4-20 years. Aims of this study: - to test the overall usability of the TAND Checklist in NF1, -to compare the results between children and adolescents with TSC and NF1, and -to examine the association between neuropsychiatric manifestations and severity of the phenotype in terms of epilepsy severity in the TSC cohort and disease severity according to the modified version of the Riccardi severity scale in the NF1 cohort.

Results: TSC cohort: 35.6% had Intellectual Disability (ID), 11.9% Specific Learning Disorders (SLD), 50.0% Attention Deficit Hyperactivity Disorder (ADHD) and 16.6% anxious/mood disorder. 33.3% had a formal diagnosis of Autism Spectrum Disorder (ASD). Paying attention and concentrating (61.9%), impulsivity (54.8%), temper tantrums (54.8%), anxiety (45.2%), overactivity/hyperactivity (40.5%), aggressive outburst (40.5%), absent or delayed onset of language (40.5%), repetitive behaviors (35.7%), academic difficulties (> 40%), deficits in attention (61.9%) and executive skills (50.0%) were the most commonly reported problems. NF1 cohort: 9.5% had ID, 21.4% SLD, 46.6% ADHD, and 33.3% anxious/mood disorder. No one had a diagnosis of ASD. Commonly reported issues were paying attention and concentrating (59.5%), impulsivity (52.4%), anxiety (50.0%), overactivity/hyperactivity (38.1%), temper tantrums (38.1%), academic difficulties (> 40%), deficits in attention (59.5%), and executive skills (38.1%). Neuropsychiatric features in TSC vs NF1: Aggressive outburst and ASD features were reported significantly more frequently in TSC than in NF1. Neuropsychiatric manifestations and phenotype severity: Depressed mood, absent or delayed onset of language, repetitive language, difficulties in relationship with peers, repetitive behaviors, spelling, mathematics, dual-tasking, visuo-spatial tasks, executive skills, and getting disoriented were significantly different among TSC patients with different epilepsy severity. No statistically significant differences in the NF1 subgroups were noted for any of the items in the checklist.

Conclusion: The TAND Checklist used for TSC is acceptable and feasible to complete in a clinical setting, and is able to detect the complexity of neuropsychiatric involvement in NF1 as well. NF1 is mainly characterized by an ADHD profile, anxiety problems and SLD, while ASD features are strongly associated with TSC. In conclusion, the TAND Checklist is a useful and feasible screening tool, in both TSC and NF1.
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http://dx.doi.org/10.1186/s13023-020-01488-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487732PMC
September 2020

Vocal Outcomes in Vagus Nerve Stimulation: A Laryngeal Pattern-Based Objective Analysis.

J Voice 2020 Aug 22. Epub 2020 Aug 22.

Otorhinolaryngology Unit, Luigi Sacco Hospital, Milan, Italy; Department of Community and Clinical Sciences, Università degli Studi di Milano, Milan, Italy.

The aim of our study is to evaluate objective and subjective vocal outcomes in patients undergoing vagus nerve stimulation (VNS) therapy for drug-resistant epilepsy and to assess the vocal outcome in the known laryngeal dysmotility patterns induced by VNS. We enrolled 16 adult patients without cognitive impairment who had undergone VNS implant for drug-resistant epilepsy at least 1 year prior. They were evaluated by flexible fibreoptic laryngeal examination and Voice Handicap Index questionnaire administration; acoustic and perceptual voice analysis was performed both at rest and during VNS activation. All recruited patients were admitted to the study. The VNS implant systematically determined laryngeal motility alterations, which were in turn mirrored by perceptual, subjective, and/or acoustic analysis voice alterations in all patients. Patients with intact vocal fold function at rest performed worse during acoustic voice analysis in terms of jitter during VNS activation and shimmer at rest when compared to other laryngeal patterns (P= 0.027 and P = 0.034, respectively, Kruskal-Wallis test). Furthermore, VNS activation determined an overall worsening of the perceptual and acoustically analysed voice quality: the grade of hoarseness, instability and breathiness parameters of the GRBASI (grade, roughness, breathiness, asthenia, strain, instability) scale and the jitter, shimmer and noise-to-harmonic ratio of the acoustic analysis worsened significantly during VNS activation (P = 0.001, P = 0.021, P = 0.012, P < .001, P = 00.002, P = 0.039, respectively, Wilcoxon test). According to our results, the VNS implant determines a significantly impaired vocal outcome that has a surprisingly mild impact on Voice Handicap Index scores. Such impairment is significantly greater in patients with intact vocal fold function at rest.
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http://dx.doi.org/10.1016/j.jvoice.2020.07.033DOI Listing
August 2020

Tuberous sclerosis complex (TSC), lymphangioleiomyomatosis, and COVID-19: The experience of a TSC clinic in Italy.

Am J Med Genet A 2020 11 17;182(11):2479-2485. Epub 2020 Aug 17.

Child Neuropsychiatry Unit - Epilepsy Center, ASST Santi Paolo e Carlo, San Paolo Hospital, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.

Individuals with comorbidities are at higher risk of coronavirus disease 2019 (COVID-19) and worse outcome, but little information has been available about patients with genetic diseases and COVID-19. This study aims at evaluating the presence and outcome of COVID-19 in a cohort of Italian patients with tuberous sclerosis complex (TSC) and/or lymphangioleiomyomatosis (LAM), and at reviewing the possible effects of mTOR inhibitors on SARS-CoV-2 infection. We included 102 unselected individuals with a diagnosis of TSC and/or LAM assessed between January 1, 2020 and April 24, 2020 (29% children, 71% adults). Twenty-six patients were on mTOR inhibitors. Demographic data, TSC manifestations, presence, and outcomes in individuals with confirmed or suspected SARS-CoV-2 infection were evaluated. Health status and outcomes of all patients on mTOR inhibitors were assessed. One patient with severe TSC had polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection, was admitted to ICU, and died. Nine additional patients either met the definition of suspect case or presented with at least two of the most common symptoms of SARS-CoV-2 infection. All recovered fully. None of the patients treated with mTOR inhibitors for their underlying comorbidities was diagnosed with COVID-19, and those who showed suspicious respiratory symptoms recovered fully. This cohort study provides preliminary information on COVID-19 in people with TSC in Italy and suggests feasibility to systematically evaluate the role of mTOR inhibitors in SARS-CoV-2 infection.
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http://dx.doi.org/10.1002/ajmg.a.61810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461282PMC
November 2020

Does screening for adverse effects improve health outcomes in epilepsy? A randomized trial.

Neurology 2020 07 29;95(3):e239-e246. Epub 2020 Jun 29.

From the Clinical Pharmacology Unit (V.F., G.G., E.P.), University of Pavia; IRCCS Mondino Foundation (V.F., C.F., C.A.G., E.P.), Pavia; Epilepsy Center (M.P.C.), San Paolo Hospital, Milan; Magna Graecia University (G.D.S.), Catanzaro; School of Hospital Pharmacy (G.F.), University of Milan; Epilepsy Center (A.L.N.), Neurology Hospital "Amaducci," University of Bari; Unit of Neurology (E.R.), Usl Centro Toscana Health Authority, Prato; University of Foggia (L.M.S.); Epilepsy Center (S.S.), Federico II University, Naples; and IRCCS (P.T.), Institute of Neurological Sciences of Bologna and Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy.

Objective: To determine whether systematic screening for adverse effects of antiepileptic drugs (AEDs) reduces toxicity burden and improves health-related quality of life in patients with epilepsy.

Methods: Consecutive patients with uncontrolled seizures aged ≥16 years and a high Adverse Event Profile (AEP) score were randomized to 2 groups and followed up for 18 months at 11 referral centers. AEP scores were made available to treating physicians at all visits in the intervention group, but not in the control group. Co-primary endpoints were changes in AEP scores and Quality of Life Inventory for Epilepsy-31 (QOLIE-31) scores.

Results: Of 809 enrolled patients able to complete the AEP questionnaire, 222 had AEP scores ≥45 and were randomized to the intervention (n = 111) or control group (n = 111). A total of 206 patients completed the 18-month follow-up. Compared with baseline, AEP scores decreased on average by 7.2% at 6 months, 12.1% at 12 months, and 13.8% at 18 months in the intervention group ( < 0.0001), and by 7.7% at 6 months, 9.2% at 12 months, and 12.0% at 18 months in controls ( < 0.0001). QOLIE-31 scores also improved from baseline to final visit, with a mean 20.7% increase in the intervention group and a mean 24.9% increase in the control group ( < 0.0001). However, there were no statistically significant differences in outcomes between groups for the 2 co-primary variables.

Conclusions: Contrary to findings from a previous study, systematic screening for adverse effects of AEDs using AEP scores did not lead to a reduced burden of toxicity over usual physician treatment.

Italian Medicines Agency Aifa Identifier: FARM52K2WM_003.

Clinicaltrialsgov Identifier: NCT03939507 (registered retrospectively in 2019; the study was conducted during the 2006-2009 period and registration of clinical trials was not a widely established practice when this study was initiated).

Classification Of Evidence: This study provides Class II evidence that the additional collection of formal questionnaires regarding adverse effects of AEDs does not reduce toxicity burden over usual physician treatment.
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http://dx.doi.org/10.1212/WNL.0000000000009880DOI Listing
July 2020

Pharyngolaryngeal spasm-induced dysphagia in an epileptic patient undergoing vagus nerve stimulation therapy.

Clin Case Rep 2020 May 26;8(5):858-861. Epub 2020 Feb 26.

Otolaryngology Unit ASST Santi Paolo e Carlo Department of Health Sciences Università degli Studi di Milano Milan Italy.

Vagus nerve stimulation for refractory epilepsy may induce laryngeal side effects such as dysphonia and dysphagia. Careful tuning of the stimulation parameters and collaboration between epileptologists and otolaryngologists can help significantly reduce side effects.
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http://dx.doi.org/10.1002/ccr3.2761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250986PMC
May 2020

Intervening on the Developmental Course of Children With Borderline Intellectual Functioning With a Multimodal Intervention: Results From a Randomized Controlled Trial.

Front Psychol 2020 21;11:679. Epub 2020 Apr 21.

IRCCS Fondazione Don Carlo Gnocchi, Milan, Italy.

An adverse social environment is a major risk factor for borderline intellectual functioning (BIF), a condition characterized by an intelligence quotient (IQ) within the low range of normality (70-85) with difficulties in the academic achievements and adaptive behavior. Children with BIF show impairments in planning, language, movement, emotion regulation, and social abilities. Moreover, the BIF condition exposes children to an increased risk of school failures and the development of mental health problems, and poverty in adulthood. Thus, an early and effective intervention capable of improving the neurodevelopmental trajectory of children with BIF is of great relevance.

Aim: The present work aims to report the results of a randomized controlled trial (RCT) in which an intensive, integrated and innovative intervention, the movement cognition and narration of the emotions (MCNT) was compared to standard speech therapy (SST) for the treatment of children with BIF.

Methods: This was a multicenter, interventional, single blind RCT with two groups of children with BIF: the experimental treatment (MCNT) and the treatment as usual (SST). A mixed factorial ANOVA was carried out to assess differences in the effectiveness between treatments. Primary outcome measures were: WISC III, Child Behavior Checklist (CBCL), Vineland II, and Movement ABC.

Results: MCNT proved to be more effective than SST in the increment of full-scale IQ ( = 0.0220), performance IQ ( < 0.0150), socialization abilities ( = 0.0220), and behavior ( = 0.0016). No improvement was observed in motor abilities. Both treatments were linked to improvements in verbal memory, selective attention, planning, and language comprehension. Finally, children in the SST group showed a significant worsening in their behavior.

Conclusion: Our data show that an intensive and multimodal treatment is more effective than a single domain treatment for improving intellectual, adaptive and behavioral functioning in children with BIF. These improvements are relevant as they might represent protective factors against the risk of school failure, poverty and psychopathology to which children with BIF are exposed in the adult age. Limitations of the study are represented by the small number of subjects and the lack of a no-treatment group.

Clinical Trial Registration: ISRCTN Registry (isrctn.com), identifier ISRCTN81710297.
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http://dx.doi.org/10.3389/fpsyg.2020.00679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186416PMC
April 2020

Effects of Combined Transcranial Direct Current Stimulation with Cognitive Training in Girls with Rett Syndrome.

Brain Sci 2020 May 2;10(5). Epub 2020 May 2.

Department of Clinical and Experimental Medicine, University of Messina, Via Bivona, 98100 Messina, Italy.

Background: Transcranial Direct Current Stimulation (tDCS) combined with traditional rehabilitative techniques has not been widely applied to Rett Syndrome (RTT). The aim of this study was to examine the effects of combined cognitive traditional training with tDCS applied to attention and language measures in subjects with RTT.

Methods: 31 subjects with RTT were randomly allocated into two groups: non-sham tDCS ( = 18) and sham tDCS ( = 13). The former received the integrated intervention non-sham tDCS plus cognitive empowerment during the treatment phase. The latter received sham stimulation plus cognitive empowerment. All participants underwent neurological and cognitive assessment to evaluate attention and language measures: before integrated treatment (pre-test phase), at the conclusion of the treatment (post-test phase), and at 1 month after the conclusion of the treatment (follow-up phase).

Results: the results indicated longer attention time in the non-sham tDCS group compared to the sham tDCS group with a stable trend also in the follow-up phase; an increase of the number of vowel/phoneme sounds in the non-sham tDCS group; and an improvement in the neurophysiological parameters in the non-sham tDCS group.

Conclusions: This study supports the use of tDCS as a promising and alternative approach in the RTT rehabilitation field.
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http://dx.doi.org/10.3390/brainsci10050276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287589PMC
May 2020

Sleep disturbances in Italian children and adolescents with epilepsy: A questionnaire study.

Epilepsy Behav 2020 05 28;106:107014. Epub 2020 Mar 28.

Epilepsy Center - Sleep Medicine Center, Childhood and Adolescence Neuropsychiatry Unit, ASST SS. Paolo e Carlo, San Paolo Hospital, Milan, Italy; Department of Health Sciences, University of Milan, Italy.

Sleep and epilepsy interact with each other in a complex bidirectional way. The main objective of this study was to characterize and determine the prevalence of sleep and behavioral disorders among Italian children and adolescents with epilepsy. We asked 84 consecutive parents/caregivers of patients with epilepsy aged between 6 and 17 years old to fill out the Sleep Disturbances Scale for Children (SDSC) and Child Behavior Checklist (CBCL). An abnormal total sleep score was found in 20 subjects with epilepsy (23.8%), compared with 4 (4.4%) of control group (P < .001). Forty-eight patients (57.1%) had an abnormal score in at least one SDSC factor: disorders in initiating and maintaining sleep (DIMS; 13.1%), sleep breathing disorders (SBD; 13.1%), disorders of arousal (DA; 5.9%), sleep-wake transition disorders (SWTD; 15.5%), disorders of excessive somnolence (DOES; 20.2%), and sleep hyperhidrosis (SHY; 5.9%). Patients with epilepsy showed higher prevalence of behavioral/emotional disturbances in all CBCL domains but one compared with patients without epilepsy. The SDSC and CBCL total scores showed a significant correlation (R-square = 0.256; P < .001). Sleep and behavioral/emotional disorders are common in epilepsy during childhood and adolescence. The SDSC could be a valid tool to screen sleep disturbances in this group of patients.
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http://dx.doi.org/10.1016/j.yebeh.2020.107014DOI Listing
May 2020

Antiepileptic Drug Teratogenicity and De Novo Genetic Variation Load.

Ann Neurol 2020 06 15;87(6):897-906. Epub 2020 Apr 15.

Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia.

Objective: The mechanisms by which antiepileptic drugs (AEDs) cause birth defects (BDs) are unknown. Data suggest that AED-induced BDs may result from a genome-wide increase of de novo variants in the embryo, a mechanism that we investigated.

Methods: Whole exome sequencing data from child-parent trios were interrogated for de novo single-nucleotide variants/indels (dnSNVs/indels) and de novo copy number variants (dnCNVs). Generalized linear models were applied to assess de novo variant burdens in children exposed prenatally to AEDs (AED-exposed children) versus children without BDs not exposed prenatally to AEDs (AED-unexposed unaffected children), and AED-exposed children with BDs versus those without BDs, adjusting for confounders. Fisher exact test was used to compare categorical data.

Results: Sixty-seven child-parent trios were included: 10 with AED-exposed children with BDs, 46 with AED-exposed unaffected children, and 11 with AED-unexposed unaffected children. The dnSNV/indel burden did not differ between AED-exposed children and AED-unexposed unaffected children (median dnSNV/indel number/child [range] = 3 [0-7] vs 3 [1-5], p = 0.50). Among AED-exposed children, there were no significant differences between those with BDs and those unaffected. Likely deleterious dnSNVs/indels were detected in 9 of 67 (13%) children, none of whom had BDs. The proportion of cases harboring likely deleterious dnSNVs/indels did not differ significantly between AED-unexposed and AED-exposed children. The dnCNV burden was not associated with AED exposure or birth outcome.

Interpretation: Our study indicates that prenatal AED exposure does not increase the burden of de novo variants, and that this mechanism is not a major contributor to AED-induced BDs. These results can be incorporated in routine patient counseling. ANN NEUROL 2020;87:897-906.
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http://dx.doi.org/10.1002/ana.25724DOI Listing
June 2020

Missense variants in the Arg206 residue of HNRNPH2: Further evidence of causality and expansion of the phenotype.

Am J Med Genet A 2020 04 14;182(4):823-828. Epub 2020 Jan 14.

Child Neuropsychiatry Unit - Epilepsy Center, San Paolo Hospital, Milan, Italy.

Missense variants in HNRNPH2 cause Bain type syndromic X-linked intellectual disability (XLID). To date, only six affected females and three affected males have been reported in the literature, and the phenotype has yet to be delineated in detail. Here, we report on a 35-year-old female with a novel de novo variant in HNRNPH2, providing further evidence that missense changes in the nuclear localization sequence cause Bain type XLID and that aminoacid 206 likely represents a mutational hotspot. We expand the phenotype of Bain type XLID to include breathing, sleep and movement disorders, cerebellar vermis hypoplasia, stereotypies, and hypersensitivity to noise. Our data indicate that the phenotype may be broader and more variable than initially reported, and suggest Rett syndrome as a possible differential diagnosis.
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http://dx.doi.org/10.1002/ajmg.a.61486DOI Listing
April 2020

Mapping the Effect of Interictal Epileptic Activity Density During Wakefulness on Brain Functioning in Focal Childhood Epilepsies With Centrotemporal Spikes.

Front Neurol 2019 19;10:1316. Epub 2019 Dec 19.

Neurology Unit, OCB Hospital, AOU Modena, Modena, Italy.

Childhood epilepsy with centrotemporal spikes (CECTS) is the most common type of "self-limited focal epilepsies." In its typical presentation, CECTS is a condition reflecting non-lesional cortical hyperexcitability of rolandic regions. The benign evolution of this disorder is challenged by the frequent observation of associated neuropsychological deficits and behavioral impairment. The abundance (or frequency) of interictal centrotemporal spikes (CTS) in CECTS is considered a risk factor for deficits in cognition. Herein, we captured the hemodynamic changes triggered by the CTS density measure (i.e., the number of CTS for time bin) obtained in a cohort of CECTS, studied by means of video electroencephalophy/functional MRI during quite wakefulness. We aim to demonstrate a direct influence of the diurnal CTS frequency on epileptogenic and cognitive networks of children with CECTS. A total number of 8,950 CTS (range between 27 and 801) were recorded in 23 CECTS (21 male), with a mean number of 255 CTS/patient and a mean density of CTS/30 s equal to 10,866 ± 11.46. Two independent general linear model models were created for each patient based on the effect of interest: "individual CTS" in model 1 and "CTS density" in model 2. Hemodynamic correlates of CTS density revealed the involvement of a widespread cortical-subcortical network encompassing the sensory-motor cortex, the Broca's area, the premotor cortex, the thalamus, the putamen, and red nucleus, while in the CTS event-related model, changes were limited to blood-oxygen-level-dependent (BOLD) signal increases in the sensory-motor cortices. A linear relationship was observed between the CTS density hemodynamic changes and both disease duration (positive correlation) and age (negative correlation) within the language network and the bilateral insular cortices. Our results strongly support the critical role of the CTS frequency, even during wakefulness, to interfere with the normal functioning of language brain networks.
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http://dx.doi.org/10.3389/fneur.2019.01316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930928PMC
December 2019

A case of modern management of Morgagni-Adam-Stokes syndrome.

Clin Case Rep 2019 Dec 30;7(12):2295-2299. Epub 2019 Sep 30.

Division of Cardiology, Heart and Lung Department, San Paolo Hospital, ASST Santi Paolo and Carlo University of Milan Milan Italy.

Transient loss of consciousness initially diagnosed as epileptic seizures and then documented as paroxysmal atrioventricular block. Cardiac resynchronization and defibrillator therapy guided by a multimodality approach.
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http://dx.doi.org/10.1002/ccr3.2384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935613PMC
December 2019

Effects of postpartum depression on the behaviour of children born to mothers with epilepsy.

Seizure 2019 Dec 31;73:31-38. Epub 2019 Oct 31.

Epilepsy Center-Child Neuropsychiatry Unit, ASST Santi Paolo Carlo, San Paolo Hospital, Milan, Italy; Department of Health Sciences, University of Milan, Italy.

Purpose: Postpartum depression (PPD) is a non-psychotic depressive disorder that begins within 4 weeks of childbirth. This study aimed to evaluate the prevalence of PPD by screening mothers with the Edinburgh Postnatal Depression Scale (EPDS), to assess the behavioural outcome of children born to mothers with and without epilepsy and to investigate the relationship between PPD and children's behavioural problems.

Method: We enrolled 80 pregnancies of women with epilepsy, who filled in EPDS after birth, and afterward we asked them to complete the Child Behavior Checklist (CBCL).

Results: 23.8% of patients presented PPD. Children, when the CBCL were completed, had a mean age of 6.05 ± 3.07 years. The CBCL results indicate the occurrence of at least one behavioural issue in 25.0% (20/80) of children. CBCL scores revealed a higher prevalence of behavioural disturbances with regards to the CBCL Total (P = 0.016), internalizing (P = 0.014) and somatic problems (P = 0.048) in patients with PPD vs. patients without PPD. We found an association between mothers' EPDS total score and children's CBCL global score (P = 0.034), internalizing score (P = 0.021), anxiety problems (P = 0.05), affective problems (P = 0.027) and withdrawn/depressed (P = 0.05). We recorded a statistically higher malformation rate in patients with PPD (P = 0.005) compared to the general population.

Conclusions: Children born from mothers with epilepsy have an increased risk for emotional disorders. These findings highlight the importance of screening for emotional distress and providing adequate interventions to children born to women with epilepsy.
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http://dx.doi.org/10.1016/j.seizure.2019.10.018DOI Listing
December 2019

Obstructive sleep apnea: neurocognitive and behavioral functions before and after treatment.

Funct Neurol 2019 Apr/Jun;34(2):71-78

Obstructive sleep apnea syndrome (OSAS) is a sleep disorder characterized by repetitive episodes of upper airway obstruction. The aim of this study was to evaluate whether continuous positive airway pressure (CPAP) treatment is linked to improvements in cognitive abilities and emotional functions of patients with OSAS. Following the exclusion of four subjects for non-adherence to CPAP treatment, the final study sample was composed of 16 patients with moderate-to-severe OSAS, who were assessed both prior to and after 3 months of CPAP treatment, using a neuropsychological battery and questionnaires to assess mood and anxiety disorders, irritability, quality of life, quality of sleep and daytime sleepiness. We observed significant improvements in Digit Span Backward, Short Story and Corsi Span performances after 3 months of CPAP treatment. Questionnaires showed a significant reduction in daytime sleepiness and improvements in the subjective perception of sleep quality and sleep efficiency, and reduced daytime dysfunction. CPAP treatment has significant effects on different cognitive domains in patients with OSAS, especially working memory, long-term verbal memory, and short-term visuospatial memory.
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February 2020

The impact of perampanel treatment on quality of life and psychiatric symptoms in patients with drug-resistant focal epilepsy: An observational study in Italy.

Epilepsy Behav 2019 10 29;99:106391. Epub 2019 Jul 29.

Epilepsy Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, 20133 Milan, Italy.

An observational, prospective study has been conducted to evaluate the effects of adjunctive treatment with perampanel (PER) on psychological functioning and quality of life (QoL) in patients with drug-resistant focal epilepsy. Fifty-six adult patients treated with PER in addition to antiepileptic drugs (AEDs) were recruited in 2 Italian Epilepsy Centers. Irritability in Adult Patients with Epilepsy (I-EPI), Quality of Life in Epilepsy (QOLIE-31), Beck Depression Inventory II (BDI-II), and State-Trait Anxiety Inventory Y-1 and Y-2 (STAI) questionnaires were administered at baseline and 3 and 6 months after the treatment onset. Adverse events (AEs) were collected during the observational 6 months period. Retention rate of treatment with PER was 82.1% at 3 months and 64.3% at 6 months. Thirteen patients reported a significant seizure frequency reduction, and one seizure freedom case was observed after 4 months of PER treatment. Perampanel was stopped because of inefficacy or paradoxical effects in 28.6% of cases and because of AEs in 7.1%. The peak dose was not associated with discontinuation probability. Irritability, QoL, depression, trait, and state anxiety did not change significantly during the PER therapy. A tendency of association between higher level of irritability at baseline and PER discontinuation was found. The results of this observational study have shown that the addition of PER to AEDs may improve seizure control, does not increase levels of irritability, depression, and anxiety, and does not reduce patients' QoL. This study also confirms the importance of a comprehensive clinical assessment, including psychiatric symptoms evaluation before offering a new treatment, to improve therapy compliance.
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http://dx.doi.org/10.1016/j.yebeh.2019.06.034DOI Listing
October 2019

Cerebellar lesions as potential predictors of neurobehavioural phenotype in tuberous sclerosis complex.

Dev Med Child Neurol 2019 10 16;61(10):1221-1228. Epub 2019 Jul 16.

Neuroradiology Unit, University of Salerno, Salerno, Italy.

Aim: To improve the genetic, clinical, and neuroradiological characterization of cerebellar involvement in tuberous sclerosis complex (TSC) and determine whether cerebellar lesions could be a reliable biomarker of neurological impairment.

Method: This retrospective cohort study, held at two tertiary paediatric university centres, was conducted on patients with a confirmed diagnosis of TSC who underwent brain magnetic resonance imaging between October 2009 and May 2016. The study population consisted of 112 patients with TSC (median age 10y; range 5mo-38y; 61 females, 51 males).

Results: The results from multivariable statistical analysis indicated that cerebellar involvement (34 out of 112 patients, none carrying a TSC1 mutation) was the most powerful predictor of supratentorial cortical tuber load; however, cerebellar involvement was not the best predictor of clinical phenotype when supratentorial tuber load and TSC2 mutations were taken into consideration. The association between cerebellar lesions and a more severe clinical and neuroradiological phenotype was statistically significant and may be due to its strong association with TSC2 mutations and higher cortical tuber load.

Interpretation: Cerebellar involvement is not the best predictor of neurobehavioural outcome, including TSC-related autism, after adjusting for TSC2 and the number of cortical tubers. Its role in the TSC clinical phenotype needs to be investigated further.

What This Paper Adds: Cerebellar involvement is a powerful predictor of supratentorial cortical involvement and a potential biomarker of disease severity. Cerebellar lesions significantly correlate with a more severe clinical and neuroradiological phenotype. Cerebellar involvement is not the best predictor of neurobehavioural outcome.
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http://dx.doi.org/10.1111/dmcn.14313DOI Listing
October 2019

Validated outcome of treatment changes according to International League Against Epilepsy criteria in adults with drug-resistant focal epilepsy.

Epilepsia 2019 06 13;60(6):1114-1123. Epub 2019 Mar 13.

Clinical Pharmacology Unit, Department of Internal Medicine and Therapeutics, University of Pavia and Clinical Trial Center, IRCCS Mondino Foundation, Pavia, Italy.

Objective: Although many studies have attempted to describe treatment outcomes in patients with drug-resistant epilepsy, results are often limited by the adoption of nonhomogeneous criteria and different definitions of seizure freedom. We sought to evaluate treatment outcomes with a newly administered antiepileptic drug (AED) in a large population of adults with drug-resistant focal epilepsy according to the International League Against Epilepsy (ILAE) outcome criteria.

Methods: This is a multicenter, observational, prospective study of 1053 patients with focal epilepsy diagnosed as drug-resistant by the investigators. Patients were assessed at baseline and 6, 12, and 18 months, for up to a maximum of 34 months after introducing another AED into their treatment regimen. Drug resistance status and treatment outcomes were rated according to ILAE criteria by the investigators and by at least two independent members of an external expert panel (EP).

Results: A seizure-free outcome after a newly administered AED according to ILAE criteria ranged from 11.8% after two failed drugs to 2.6% for more than six failures. Significantly fewer patients were rated by the EP as having a "treatment failure" as compared to the judgment of the investigator (46.7% vs 62.9%, P < 0.001), because many more patients were rated as "undetermined outcome" (45.6% vs 27.7%, P < 0.001); 19.3% of the recruited patients were not considered drug-resistant by the EP.

Significance: This study validates the use of ILAE treatment outcome criteria in a real-life setting, providing validated estimates of seizure freedom in patients with drug-resistant focal epilepsy in relation to the number of previously failed AEDs. Fewer than one in 10 patients achieved seizure freedom on a newly introduced AED over the study period. Pseudo drug resistance could be identified in one of five cases.
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http://dx.doi.org/10.1111/epi.14685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850288PMC
June 2019

Level of empowerment and decision-making style of women with epilepsy in childbirth age.

Epilepsy Behav 2019 04 1;93:32-37. Epub 2019 Mar 1.

European Institute of Oncology, Department of Psychoncology, University of Milan, Italy.

Objectives: This research investigates level of empowerment, decisional skills, and the perceived relationship with the clinician, of women in childbirth age, also in relationship with clinical variables such as epilepsy type, seizure frequency, therapy, and pregnancy status. In particular, as concerning therapy, we were interested in women who take valproic acid (VPA), for its specific balance of risks and benefits, especially in pregnant women.

Methods: The sample is composed of 60 women with epilepsy (6 were excluded), who underwent a standardized clinical protocol for assessment of level of empowerment, decisional skills, and of their judgment about how they feel to be involved by their clinician in medical decision making.

Results: Overall, the sample does not show signs of low empowerment level nor of abnormal decision-making patterns. The type of epilepsy, the frequency of seizures, and the treatment type (VPA versus no VPA) do not impact on empowerment, on decision styles, nor on medical relationship, with the only exception of a specific decision style, the avoidant style, that is more frequent in women treated with VPA with respect to those taking other therapies. Interestingly, regarding VPA dosage, we found that women taking equal or more than 700 mg/day of VPA have lower scores on empowerment in all dimensions compared with women with a VPA dosage lower than 700 mg/day.

Conclusions: Shared decision making including improved decision quality, more informed choices and better treatment concordance, should be a central part of epilepsy care. In addition, for clinicians it would be useful to have specific tools to know if the patient has really understood the risks and benefits of antiepileptic drugs (AEDs), particularly VPA, and all treatment alternatives.
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http://dx.doi.org/10.1016/j.yebeh.2019.01.037DOI Listing
April 2019

Clinical spectrum of -related epileptic disorders.

Neurology 2019 03 8;92(11):e1238-e1249. Epub 2019 Feb 8.

From the University of Tübingen (S. Wolking, J.M., Y.G.W., H.L., J.S.), Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, Tübingen, Germany; Luxembourg Centre for Systems Biomedicine (P.M.), University of Luxembourg, Esch-sur-Alzette; Pediatric Neurology and Neurogenetics Unit and Laboratories (D.M., R.G., C.M.), Children's Hospital Anna Meyer, University of Florence, Italy; Danish Epilepsy Centre (R.S.M.), Dianalund; Institute for Regional Health Services (R.S.M.), University of Southern Denmark, Odense; Department of Clinical and Experimental Epilepsy (S.B.), UCL Institute of Neurology and Epilepsy Society, UK, London; Division of Neurology (K.L.H., I.H.), Children's Hospital of Philadelphia, PA; Department of Pediatric Neurology (C.D.A.), Centre de Compétences Maladies Rares, CHU Besançon; Service de Génétique (N.C.), Hospices Civils des Lyon, Bron; GENDEV Team (N.C.), Neurosciences Research Center of Lyon, Bron, France; Neuropediatric Clinic and Clinic for Neurorehabilitation (K.S.), Epilepsy Center for Children and Adolescents, Schoen Klinik Vogtareuth, Germany; Beaumont Hospital (P.W.-W.), Dublin, Ireland; Department of Pediatrics, Division of Medical Genetics, Institute of Human Genetics (B.A.M.), Departments of Neurology and Pediatrics (A.N.), and Departments of Neurology and Pediatrics, and Institute of Human Genetics (M.R.C.), University of California, San Francisco; Department of Neurology (W.V.P.), University Hospitals Leuven, Belgium; Department of Pediatrics (L.L.S.), Hvidovre Hospital, Denmark; King's College Hospital (S.O., E.H., S.G., D.K.P.), London; Evelina London Children's Hospital (S.O., E.H., S.G.), London, UK; Section of Genetics (K.B., M.S.S.), Department of Pediatrics, University of Colorado and Children's Hospital Colorado, Aurora; Clinique Bernoise Montana (T.D.), Crans-Montana, Switzerland; Department of Neuropediatrics (H.M.), University Medical Center Schleswig-Holstein, Christian-Albrechts University, Kiel, Germany; National Institute for Health Research Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics (A.T.P., S.J.L.K., J.C.T.) and Department of Oncology (D.V.V.), University of Oxford, UK; Epilepsy Center (M.P.C.), Health Sciences Department, San Paolo Hospital, University of Milan; Child Neuropsychiatry (F.D.), Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Italy; Departments of Neurology and Clinical Genomics (R.H.G.) and Health Sciences Research and Clinical Genomics (E.W.K., C.K.), Mayo Clinic, Rochester, MN; Ambry Genetics (Z.P.), Aliso Viejo, CA; Department of Clinical Neuroscience (S.T.), King's College London; New Medicines (M.A., D.M.), UCB Pharma, Slough, UK; Neuropediatric Clinic and Clinic for Neurorehabilitation (G.J.K.), Epilepsy Center for Children and Adolescents, Schoen Klinik Vogtareuth, Germany; Research Institute for Rehabilitation, Transition and Palliation (G.J.K.), PMU Salzburg, Austria; Department of Neurology (D.H.L.), University of California, San Francisco; Neurogenetics Group (S. Weckhuysen), Center for Molecular Neurology, VIB, Antwerp; Laboratory of Neurogenetics (S. Weckhuysen), Institute Born-Bunge, University of Antwerp; Department of Neurology (S. Weckhuysen), Antwerp University Hospital, Antwerp, Belgium; Department of Basic & Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience (D.K.P.), MRC Centre for Neurodevelopmental Disorders (D.K.P.), King's College London, UK; Evelina London Children's Hospital (D.K.P.), London, UK; Department of Neuropediatrics (I.H.), University Medical Center Schleswig-Holstein, Christian-Albrechts University, Kiel, Germany; Institute of Neuroscience (R.H.T.), Henry Wellcome Building, Newcastle University; Neurology Research Group (M.I.R.), Institute of Life Science, Swansea University Medical School, Swansea, UK; Service de Génétique (G.L.), Hospices Civils des Lyon, Bron; GENDEV Team (G.L.), Neurosciences Research Center of Lyon, Bron, France; NIHR University College London Hospitals Biomedical Research Centre (S.M.S.), UCL Institute of Neurology, London, UK; Cologne Center for Genomics (D.L.), University of Cologne, Germany; Stanley Center for Psychiatric Research (D.L.) and Program in Medical and Population Genetics (D.L.), Broad Institute of MIT and Harvard, Cambridge; Psychiatric and Neurodevelopmental Genetics Unit (D.L.), Massachusetts General Hospital and Harvard Medical School, Boston.

Objective: The aim of this study was to expand the spectrum of epilepsy syndromes related to , encoding the presynaptic protein syntaxin-1B, and establish genotype-phenotype correlations by identifying further disease-related variants.

Methods: We used next-generation sequencing in the framework of research projects and diagnostic testing. Clinical data and EEGs were reviewed, including already published cases. To estimate the pathogenicity of the variants, we used established and newly developed in silico prediction tools.

Results: We describe 17 new variants in , which are distributed across the whole gene. We discerned 4 different phenotypic groups across the newly identified and previously published patients (49 patients in 23 families): (1) 6 sporadic patients or families (31 affected individuals) with febrile and afebrile seizures with a benign course, generally good drug response, normal development, and without permanent neurologic deficits; (2) 2 patients with genetic generalized epilepsy without febrile seizures and cognitive deficits; (3) 13 patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; (4) 2 patients with focal epilepsy. More often, we found loss-of-function mutations in benign syndromes, whereas missense variants in the SNARE motif of syntaxin-1B were associated with more severe phenotypes.

Conclusion: These data expand the genetic and phenotypic spectrum of -related epilepsies to a diverse range of epilepsies that span the International League Against Epilepsy classification. Variants in are protean and contribute to many different epilepsy phenotypes, similar to , the most important gene associated with fever-associated epilepsies.
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http://dx.doi.org/10.1212/WNL.0000000000007089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511102PMC
March 2019

Perinatal outcome and healthcare resource utilization in the first year of life after antiepileptic exposure during pregnancy.

Epilepsy Behav 2019 03 29;92:14-17. Epub 2018 Dec 29.

Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Healthcare administrative databases of Italy's Lombardy Region were analyzed with the aim to assess perinatal outcomes and healthcare resource utilization during the first year of life in infants exposed to antiepileptic drugs (AEDs) during pregnancy. Drug prescriptions dispensed in the 12 months before delivery to women, who delivered between 2005 and 2011, were analyzed. Neonates were classified as cases if exposed to AEDs, and each case was randomly matched to seven controls. No significant differences were observed in the risk of congenital malformations between 526 cases and 3682 controls except for valproic acid (odds ratio (OR): 2.29; 95% confidence interval (CI): 1.24-4.22) where cases were more likely to be small for gestational age (χ = 7.66; p = 0.006). Cases also had a higher probability than controls of needing at least one specialist visit in a child neuropsychiatry outpatient service (OR: 1.74; 95% CI: 1.22-2.49).
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http://dx.doi.org/10.1016/j.yebeh.2018.09.033DOI Listing
March 2019

Hot water epilepsy and SYN1 variants.

Epilepsia 2018 11;59(11):2162-2163

Child Neuropsychiatric Unit, Epilepsy Center, San Paolo Hospital, Department of Health Sciences, University of Milan, Milan, Italy.

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http://dx.doi.org/10.1111/epi.14572DOI Listing
November 2018

Current concepts on epilepsy management in tuberous sclerosis complex.

Am J Med Genet C Semin Med Genet 2018 09 26;178(3):299-308. Epub 2018 Sep 26.

Department of Neurology and Epileptology, The Children's Memorial Health Institute, Warsaw, Poland.

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disease affecting approximately 1 in 6,000 people, and represents one of the most common genetic causes of epilepsy. Epilepsy affects 90% of the patients and appears in the first 2 years of life in the majority of them. Early onset of epilepsy in the first 12 months of life is associated with high risk of cognitive decline and neuropsychiatric problems including autism. Prenatal or early infantile diagnosis of TSC, before the onset of epilepsy, provides a unique opportunity to monitor EEG before the onset of clinical seizures, thus enabling early intervention in the process of epileptogenesis. In this review, we discuss the current status of knowledge on epileptogenesis in TSC, and present recommendations of American and European experts in the field of epilepsy.
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http://dx.doi.org/10.1002/ajmg.c.31652DOI Listing
September 2018