Publications by authors named "Alexis Arzimanoglou"

138 Publications

Hypothalamic Hamartomas: Evolving Understanding and Management.

Neurology 2021 Oct 4. Epub 2021 Oct 4.

Center for Neuroscience Research, Children's National Hospital, The George Washington University School of Medicine, Washington, DC, USA.

Hypothalamic hamartomas (HH) are rare, basilar developmental lesions with widespread comorbidities often associated with refractory epilepsy and encephalopathy. Imaging advances allow for early, even prenatal, detection. Genetic studies suggest mutations in and other patterning genes are involved in HH pathogenesis. About 50-80% of children with HH suffer from severe rage and aggression and a majority of cases exhibit externalizing disorders. Behavioral disruption and intellectual disability may predate epilepsy. Neuropsychological, sleep and endocrine disorders are typical. The purpose of this paper is to provide a summary of the current understanding of HH, and to highlight opportunities for future research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000012773DOI Listing
October 2021

Safety and efficacy of rufinamide in children and adults with Lennox-Gastaut syndrome: A post hoc analysis from Study 022.

Epilepsy Behav 2021 Sep 9;124:108275. Epub 2021 Sep 9.

Eisai Inc., 100 Tice Boulevard, Woodcliff Lake, NJ 07677, United States.

Background: Lennox-Gastaut syndrome (LGS) is a developmental and epileptic encephalopathy with the first symptoms usually appearing during early childhood. Due to the highly variable underlying etiologies, LGS cannot be considered as one disease but as an electro-clinical entity, often challenging to diagnose early and treat accordingly. The anti-seizure medication, rufinamide, is indicated for the adjunctive treatment of patients with LGS aged ≥1 year. This post hoc analysis assessed the safety and efficacy of adjunctive rufinamide for total and tonic-atonic seizures during Study 022 in children (aged <16 years) and adults (aged ≥16 years).

Methods: Randomized, placebo-controlled, phase III Study 022 included patients with a diagnosis of LGS and a history of multiple seizure types (including tonic-atonic or astatic seizures and atypical absence seizures; ≥90 seizures in the month prior to baseline). Assessments included monitoring of treatment-emergent adverse events (TEAEs), percent change in tonic-atonic seizure frequency/28 days during the double-blind phase relative to study baseline (a primary endpoint), and percentage of patients with ≥25%, ≥50%, or ≥75% reduction in seizure frequency relative to baseline.

Results: Of 138 enrolled patients, 74 received rufinamide (<16 years, n = 49 [66%]) and 64 received placebo (<16 years, n = 43 [67%]). Incidence of TEAEs was generally similar between age groups. The frequency (per 28 days) of tonic-atonic seizures was reduced with rufinamide (vs. placebo) in both younger and older patients: age <16 years (-41% vs. -6%), age ≥16 years (-55% vs. +16%) (p < 0.025; both age groups). In patients aged <16 years receiving rufinamide, 38% and 17% achieved ≥50% and ≥75% reductions in tonic-atonic seizure frequency vs. 18% and 3% with placebo, respectively. Corresponding responder rates for patients aged ≥16 years were 52% and 32% (rufinamide) vs. 15% and 5% (placebo), respectively.

Conclusions: In this post hoc analysis, adjunctive rufinamide was well tolerated and improved seizure control in patients with LGS, irrespective of age.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yebeh.2021.108275DOI Listing
September 2021

Alternating hemiplegia of childhood: evolution over time and mouse model corroboration.

Brain Commun 2021 4;3(3):fcab128. Epub 2021 Jun 4.

Division of Pediatric Neurology and Developmental Medicine, Department of Pediatrics, Duke University, Durham, NC 27710, USA.

Alternating hemiplegia of childhood is a rare neurodevelopmental disorder caused by mutations. Some evidence for disease progression exists, but there are few systematic analyses. Here, we evaluate alternating hemiplegia of childhood progression in humans and in the D801N knock-in alternating hemiplegia of childhood mouse, Mashlool, model. This study performed an ambidirectional (prospective and retrospective data) analysis of an alternating hemiplegia of childhood patient cohort ( = 42, age 10.24 ± 1.48 years) seen at one US centre. To investigate potential disease progression, we used linear mixed effects models incorporating early and subsequent visits, and Wilcoxon Signed Rank test comparing first and last visits. Potential early-life clinical predictors were determined via multivariable regression. We also compared EEG background at first encounter and at last follow-up. We then performed a retrospective confirmation study on a multicentre cohort of alternating hemiplegia of childhood patients from France ( = 52). To investigate disease progression in the Mashlool mouse, we performed behavioural testing on a cohort of Mashlool mice at prepubescent and adult ages ( = 11). Results: US patients, over time, demonstrated mild worsening of non-paroxysmal disability index scores, but not of paroxysmal disability index scores. Increasing age was a predictor of worse scores:  < 0.0001 for the non-paroxysmal disability index, intellectual disability scale and gross motor scores. Earliest non-paroxysmal disability index score was a predictor of last visit non-paroxysmal disability index score ( = 0.022), and earliest intellectual disability score was a predictor of last intellectual disability score ( = 0.035). More patients with EEG background slowing were noted at last follow-up as compared to initial ( = 0.015). Similar worsening of disease with age was also noted in the French cohort: age was a significant predictor of non-paroxysmal disability index score ( = 0.001) and first and last non-paroxysmal disability index score scores significantly differed ( = 0.002). In animal studies, adult Mashlool mice had, as compared to younger Mashlool mice, (i) worse balance beam performance; (ii) wider base of support; (iii) higher severity of seizures and resultant mortality; and (iv) no increased predisposition to hemiplegic or dystonic spells. In conclusion, (i) non-paroxysmal alternating hemiplegia of childhood manifestations show, on average over time, progression associated with severity of early-life non-paroxysmal disability and age. (ii) Progression also occurs in Mashlool mice, confirming that disease can lead to age-related worsening. (iii) Clinical findings provide a basis for counselling patients and for designing therapeutic trials. Animal findings confirm a mouse model for investigation of underlying mechanisms of disease progression, and are also consistent with known mechanisms of -related neurodegeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/braincomms/fcab128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361420PMC
June 2021

Revision of the diagnostic criteria of alternating hemiplegia of childhood.

Eur J Paediatr Neurol 2021 May 4;32:A4-A5. Epub 2021 May 4.

Department of Paediatric Clinical Epileptology, Sleep Disorders and Functional Neurology, Member of the ERN EpiCARE, University Hospitals of Lyon (HCL), Lyon, France; Department of Child Neurology and Epilepsy Research Unit, Member of the ERN EpiCARE, Hospital San Juan de Dios, Barcelona, Spain. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpn.2021.05.004DOI Listing
May 2021

Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities.

Genet Med 2021 08 8;23(8):1484-1491. Epub 2021 Apr 8.

Pediatric and Fetal Imaging Department, Hospices Civils de Lyon, Bron, France.

Purpose: Hypomelanosis of Ito (HI) is a skin marker of somatic mosaicism. Mosaic MTOR pathogenic variants have been reported in HI with brain overgrowth. We sought to delineate further the pigmentary skin phenotype and clinical spectrum of neurodevelopmental manifestations of MTOR-related HI.

Methods: From two cohorts totaling 71 patients with pigmentary mosaicism, we identified 14 patients with Blaschko-linear and one with flag-like pigmentation abnormalities, psychomotor impairment or seizures, and a postzygotic MTOR variant in skin. Patient records, including brain magnetic resonance image (MRI) were reviewed. Immunostaining (n = 3) for melanocyte markers and ultrastructural studies (n = 2) were performed on skin biopsies.

Results: MTOR variants were present in skin, but absent from blood in half of cases. In a patient (p.[Glu2419Lys] variant), phosphorylation of p70S6K was constitutively increased. In hypopigmented skin of two patients, we found a decrease in stage 4 melanosomes in melanocytes and keratinocytes. Most patients (80%) had macrocephaly or (hemi)megalencephaly on MRI.

Conclusion: MTOR-related HI is a recognizable neurocutaneous phenotype of patterned dyspigmentation, epilepsy, intellectual deficiency, and brain overgrowth, and a distinct subtype of hypomelanosis related to somatic mosaicism. Hypopigmentation may be due to a defect in melanogenesis, through mTORC1 activation, similar to hypochromic patches in tuberous sclerosis complex.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-021-01161-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354853PMC
August 2021

The aetiologies of epilepsy.

Epileptic Disord 2021 Feb;23(1):1-16

UCL Queen Square Institute of Neurology, Member of the ERN EpiCARE, London, UK.

The identification of the aetiology of a patient's epilepsy is instrumental in the diagnosis, prognostic counselling and management of the epilepsies. Indeed, the aetiology can be important for determining the recurrence risk of single seizures and so for making a diagnosis of epilepsy. Here, we divide the aetiologies into six categories: structural, genetic, infectious, metabolic, immune (all of which are part of the International League Against Epilepsy [ILAE] classification system) and neurodegenerative (which we have considered separately because of its growing importance in epilepsy). These are not mutually exclusive categories and many aetiologies fall into more than one category. Indeed, genetic factors probably play a role, to varying degrees, in the risk of seizures in all people with epilepsy. In each of the categories, we discuss what we regard as the most important aetiologies; importance being determined not only by prevalence but also by clinical significance. The introduction contains information suitable for level 1 competency (entry level), whilst the subsequent sections contain information aimed at level 2 competency (proficiency level) as part of the new ILAE competency-based curriculum. As we move towards precision medicine and targeted therapies, so aetiologies will play an even greater role in the management of epilepsy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1684/epd.2021.1255DOI Listing
February 2021

A survey of the European Reference Network EpiCARE on clinical practice for selected rare epilepsies.

Epilepsia Open 2021 03 13;6(1):160-170. Epub 2021 Jan 13.

IRCCS Mondino Foundation Pavia Italy.

Objective: Clinical care of rare and complex epilepsies is challenging, because evidence-based treatment guidelines are scarce, the experience of many physicians is limited, and interdisciplinary treatment of comorbidities is required. The pathomechanisms of rare epilepsies are, however, increasingly understood, which potentially fosters novel targeted therapies. The objectives of our survey were to obtain an overview of the clinical practice in European tertiary epilepsy centers treating patients with 5 arbitrarily selected rare epilepsies and to get an estimate of potentially available patients for future studies.

Methods: Members of the ( were invited to participate in a web-based survey on clinical practice of patients with Dravet syndrome, tuberous sclerosis complex (TSC), autoimmune encephalitis, and progressive myoclonic epilepsies including Unverricht Lundborg and Unverricht-like diseases. A consensus-based questionnaire was generated for each disease.

Results: Twenty-six of 30 invited epilepsy centers participated. Cohorts were present in most responding centers for TSC (87%), Dravet syndrome (85%), and autoimmune encephalitis (71%). Patients with TSC and Dravet syndrome represented the largest cohorts in these centers. The antiseizure drug treatments were rather consistent across the centers especially with regard to Dravet syndrome, infantile spasms in TSC, and Unverricht Lundborg / Unverricht-like disease. Available, widely used targeted therapies included everolimus in TSC and immunosuppressive therapies in autoimmune encephalitis. Screening for comorbidities was routinely done, but specific treatment protocols were lacking in most centers.

Significance: The survey summarizes the current clinical practice for selected rare epilepsies in tertiary European epilepsy centers and demonstrates consistency as well as heterogeneity in the treatment, underscoring the need for controlled trials and recommendations. The survey also provides estimates for potential participants of clinical trials recruited via EpiCARE, emphasizing the great potential of Reference Networks for future studies to evaluate new targeted therapies and to identify novel biomarkers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/epi4.12459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918306PMC
March 2021

When neurophysiological investigations and clinical observation walk hand in hand!

J Sleep Res 2020 12;29(6):e13247

European Reference Network for Rare and Complex Epilepsies, EpiCARE, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jsr.13247DOI Listing
December 2020

Basal Ganglia Dysmorphism in Patients With Aicardi Syndrome.

Neurology 2021 03 4;96(9):e1319-e1333. Epub 2020 Dec 4.

From the Department of Brain and Behavioural Neurosciences (S.M., A.P., M. Formica, S.O.) and Department of Public Health Experimental and Forensic Medicine, Biostatistic and Clinical Epidemiology Unit (P. Borrelli), University of Pavia; Pediatric Neurology Unit (S.M., M. Mastrangelo, P.V.), V. Buzzi Children's Hospital, Milan; Department of Neuroradiology (A.P.), Child Neurology and Psychiatry Unit (R.B., V.D.G., S.O.), and Department of Internal Medicine and Therapeutics, Member of the ERN EpiCARE, University of Pavia and Clinical Trial Center (E.P.), IRCCS Mondino Foundation Pavia; Neuroimaging Lab (F.A.) and Neuropsychiatry and Neurorehabilitation Unit (R.R.), Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco; Child Neuropsychiatric Unit (P.A., L.G.), Civilian Hospital, Brescia; Scientific Institute (P. Bonanni, A.D., E.O.), IRCCS E. Medea, Epilepsy and Clinical Neurophysiology Unit, Conegliano, Treviso; UOC Child Neuropsychiatry (B.D.B., F.D.), Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Italy; Département de Neurologie Pédiatrique (N.D.), Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Belgium; AdPueriVitam (O.D.), Antony; Service d'Explorations Fonctionnelles (S.G.), Centre de Médecine du Sommeil, l'Hôpital Àntoine Béclère, AP-HP, Clamart; Pediatrics Departement (S.G.), André-Grégoire Hospital, Centre Hospitalier Inter Communal, Montreuil, France; Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department (R.G., M. Montomoli, M.C.) and Radiology (M. Mortilla), A. Meyer Children's Hospital, Member of the ERN EpiCARE, University of Florence; IRCCS Stella Maris Foundation (R.G.), Pisa; Child Neuropsychiatry Unit, Epilepsy Center (F.L.B., A.V.), San Paolo Hospital, Department of Health Sciences, Università degli Studi di Milano, Milan; Child Neurology, NESMOS Department (P.P.), Faculty of Medicine & Psychology, Sant'Andrea Hospital, Sapienza University, Rome; Department of Neuroradiology (L.P.), Pediatric Neuroradiology Section, ASST Spedali Civili, Brescia; Pediatric Neuroradiology Unit (M.S.), IRCCS Istituto Giannina Gaslini, Genova; Neurology Unit, Department of Neuroscience, Member of the ERN EpiCARE (F.V.), Oncological Neuroradiology Unit, Department of Imaging, IRCCS (G.C.), and Department of Neuroscience and Neurorehabilitation (A.F.), Bambino Gesù Children's Hospital, Rome, Italy; Institut Imagine (N.B.-B.), Université Paris Descartes-Sorbonne Paris Cités; Pediatric Neurology (N.B.-B., I.D.), Necker Enfants Malades Hospital, Member of the ERN EpiCARE, Assistance Publique-Hôpitaux de Paris; INSERM UMR-1163 (N.B.-B., A. Arzimanoglou), Embryology and Genetics of Congenital Malformations, France; UOC Neurochirurgia (A. Accogli, V.C.), Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa (F.Z.), and Laboratory of Neurogenetics and Neuroscience, IRCCS (F.Z.), Istituto Giannina Gaslini, Genoa, Italy; Neurochirurgie Pédiatrique (M.B.), Hôpital NEM, Paris, France; Centre Médico-Chirurgical des Eaux-Vives (V.C.-V.), Swiss Medical Network, Genève, Switzerland; Neuroradiology Unit (L.C.) and Developmental Neurology Unit (S.D.), Foundation IRCCS C. Besta Neurological Institute, Milan; Service de Génétique (M.D.-F.), AMH2, CHU Reims, UFR de Médecine, Reims, France; Epilepsy Centre-Clinic of Nervous System Diseases (G.d.), Riuniti Hospital, Foggia, Italy; MediClubGeorgia Co Ltd (N.E.), Tbilisi, Georgia; Epilepsy Center (N.E.), Medical Center, Faculty of Medicine, University of Freiburg, Germany; Child and Adolescence Neurology and Psychiatry Unit (E. Fazzi), ASST Civil Hospital, Department of Clinical and Experimental Sciences, University of Brescia; Child Neurology Department (E. Fiorini), Verona, Italy; Service de Genetique Clinique (M. Fradin, P.L., C.Q.), CLAD-Ouest, Hospital Sud, Rennes, France; Child Neurology Unit, Pediatric Department (C.F., C.S.), Azienda USL-IRCCS di Reggio Emilia; Department of Pediatric Neuroscience (T.G., R.S.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Member of the ERN EpiCARE, Milan, Italy; Department of Epilepsy Genetics and Personalized Treatment (K.M.J., R.S.M.), The Danish Epilepsy Centre, Dianalund; Institute for Regional Health Services (K.M.J., R.S.M.), University of Southern Denmark, Odense; Unit of Pediatric Neurology and Pediatric Neurorehabilitation (S.L.), Woman-Mother-Child Department, Lausanne University Hospital CHUV, Switzerland; Unit of Neuroradiology (D.M.), Fondazione CNR/Regione Toscana G. Monasterio, Pisa; Pediatric Neurology Unit and Epilepsy Center (E.R., A.R.), Fatebenefratelli Hospital, Milan, Italy; KJF Klinik Josefinum GmbH (C.U.), Klinik für Kinder und Jugendliche, Neuropädiatrie, Augsburg, Germany; Department of Paediatric Clinical Epileptology, Sleep Disorders and Functional Neurology (A. Arzimanoglou), University Hospitals of Lyon, Coordinator of the ERN EpiCARE, France; and Pediatric Epilepsy Unit, Child Neurology Department (P.V.), Hospital San Juan de Dios, Member of the ERN EpiCARE and Universitat de Barcelona, Spain.

Objective: Aiming to detect associations between neuroradiologic and EEG evaluations and long-term clinical outcome in order to detect possible prognostic factors, a detailed clinical and neuroimaging characterization of 67 cases of Aicardi syndrome (AIC), collected through a multicenter collaboration, was performed.

Methods: Only patients who satisfied Sutton diagnostic criteria were included. Clinical outcome was assessed using gross motor function, manual ability, and eating and drinking ability classification systems. Brain imaging studies and statistical analysis were reviewed.

Results: Patients presented early-onset epilepsy, which evolved into drug-resistant seizures. AIC has a variable clinical course, leading to permanent disability in most cases; nevertheless, some cases presented residual motor abilities. Chorioretinal lacunae were present in 86.56% of our patients. Statistical analysis revealed correlations between MRI, EEG at onset, and clinical outcome. On brain imaging, 100% of the patients displayed corpus callosum malformations, 98% cortical dysplasia and nodular heterotopias, and 96.36% intracranial cysts (with similar rates of 2b and 2d). As well as demonstrating that posterior fossa abnormalities (found in 63.63% of cases) should also be considered a common feature in AIC, our study highlighted the presence (in 76.36%) of basal ganglia dysmorphisms (never previously reported).

Conclusion: The AIC neuroradiologic phenotype consists of a complex brain malformation whose presence should be considered central to the diagnosis. Basal ganglia dysmorphisms are frequently associated. Our work underlines the importance of MRI and EEG, both for correct diagnosis and as a factor for predicting long-term outcome.

Classification Of Evidence: This study provides Class II evidence that for patients with AIC, specific MRI abnormalities and EEG at onset are associated with clinical outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000011237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055324PMC
March 2021

Corticosteroids versus clobazam in epileptic encephalopathy with ESES: a European multicentre randomised controlled clinical trial (RESCUE ESES*).

Trials 2020 Nov 23;21(1):957. Epub 2020 Nov 23.

Department of Paediatric Neurology, Brain Center, University Medical Center Utrecht, Member of the European Reference Network EpiCARE, Utrecht University, KC 03.063.0, PO Box 85090, 3508 AB, Utrecht, The Netherlands.

Background: Epileptic encephalopathy with electrical status epilepticus in sleep (ESES) is an epilepsy syndrome occurring almost exclusively in children, usually at an age between 4 and 12 years. It is characterised by abundant sleep-induced epileptic activity in the electroencephalogram (EEG) and by acquired cognitive and behavioural deficits. The goal of treatment is to prevent further decline or even improve cognitive functioning. Based on mostly small and retrospective studies, corticosteroids and clobazam are regarded by many clinicians as the most effective pharmacological treatments. This European multicentre randomised controlled trial is designed to compare the effects of corticosteroids and clobazam on cognitive functioning after 6 months. Secondary outcomes include cognitive functioning after 18 months, EEG abnormalities in sleep, safety and tolerability, and seizure frequency. We also aimed at investigating whether treatment response in epileptic encephalopathy with ESES can be predicted by measurement of inflammatory mediators and autoantibodies in serum.

Methods: The pragmatic study will be performed in centres with expertise in the treatment of rare paediatric epilepsy syndromes across Europe. A total of 130 patients, 2 to 12 years of age, with epileptic encephalopathy with ESES will be enrolled and randomised in a 1:1 ratio to receive either corticosteroids (monthly intravenous methylprednisolone pulses or daily oral prednisolone) or oral clobazam for 6 months according to an open-label parallel-group design. Follow-up visits with clinical assessment, EEGs, and neuropsychological testing are scheduled for up to 18 months. Blood samples for cytokine and autoantibody testing are obtained before treatment and 8 months after treatment initiation.

Discussion: The treatment of epileptic encephalopathy with ESES aims at improving cognitive outcome. This randomised controlled study will compare the most frequently used treatments, i.e. corticosteroids and clobazam. If the study proves superiority of one treatment over the other or identifies biomarkers of treatment response, results will guide clinicians in the early treatment of this severe epilepsy syndrome.

Trial Registration: ISRCTN, ISRCTN42686094 . Registered on 24 May 2013.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13063-020-04874-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686710PMC
November 2020

Establishing criteria for pediatric epilepsy surgery center levels of care: Report from the ILAE Pediatric Epilepsy Surgery Task Force.

Epilepsia 2020 12 14;61(12):2629-2642. Epub 2020 Nov 14.

Department of Neurology, Nicklaus Children's Hospital, Miami, FL, USA.

Presurgical evaluation and surgery in the pediatric age group are unique in challenges related to caring for the very young, range of etiologies, choice of appropriate investigations, and surgical procedures. Accepted standards that define the criteria for levels of presurgical evaluation and epilepsy surgery care do not exist. Through a modified Delphi process involving 61 centers with experience in pediatric epilepsy surgery across 20 countries, including low-middle- to high-income countries, we established consensus for two levels of care. Levels were based on age, etiology, complexity of presurgical evaluation, and surgical procedure. Competencies were assigned to the levels of care relating to personnel, technology, and facilities. Criteria were established when consensus was reached (≥75% agreement). Level 1 care consists of children age 9 years and older, with discrete lesions including hippocampal sclerosis, undergoing lobectomy or lesionectomy, preferably on the cerebral convexity and not close to eloquent cortex, by a team including a pediatric epileptologist, pediatric neurosurgeon, and pediatric neuroradiologist with access to video-electroencephalography and 1.5-T magnetic resonance imaging (MRI). Level 2 care, also encompassing Level 1 care, occurs across the age span and range of etiologies (including tuberous sclerosis complex, Sturge-Weber syndrome, hypothalamic hamartoma) associated with MRI lesions that may be ill-defined, multilobar, hemispheric, or multifocal, and includes children with normal MRI or foci in/abutting eloquent cortex. Available Level 2 technologies includes 3-T MRI, other advanced magnetic resonance technology including functional MRI and diffusion tensor imaging (tractography), positron emission tomography and/or single photon emission computed tomography, source localization with electroencephalography or magnetoencephalography, and the ability to perform intra- or extraoperative invasive monitoring and functional mapping, by a large multidisciplinary team with pediatric expertise in epilepsy, neurophysiology, neuroradiology, epilepsy neurosurgery, neuropsychology, anesthesia, neurocritical care, psychiatry, and nursing. Levels of care will improve safety and outcomes for pediatric epilepsy surgery and provide standards for personnel and technology to achieve these levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/epi.16698DOI Listing
December 2020

The COVID-19 outbreak and approaches to performing EEG in Europe.

Epileptic Disord 2020 Oct;22(5):548-554

Department of Paediatric Clinical Epileptology, Sleep Disorders and Functional Neurology, University Hospitals of Lyon (HCL), Member of the ERN EpiCARE Lyon, France, Epilepsy Unit, San Juan de Dios Children's Hospital, Member of the ERN EpiCARE, Universitat de Barcelona, Barcelona, Spain.

The coronavirus SARS-CoV-2 disease (COVID-19) pandemic affects availability and performance of neurophysiological diagnostic methods, including EEG. Our objective was to outline the current situation regarding EEG-based investigations across Europe. A web-based survey was distributed to centres within the European Reference Network on rare and complex epilepsies (ERN EpiCARE). Responses were collected between April 9 and May 15, 2020. Results were analysed with Microsoft Excel, Python Pandas and SciPy. Representants from 47 EpiCARE centres from 22 countries completed the survey. At the time of completing the survey, inpatient video-EEGs had been stopped or restricted in most centres (61.7% vs. 36.2% for adults, and 38.3% vs. 53.2% for children). Invasive investigations and epilepsy surgery were similarly affected. Acute EEGs continued to be performed, while indications for outpatient EEGs were limited and COVID-19 triage put in place. The strictness of measures varied according to extent of the outbreak in a given country. The results indicate a profound impact of COVID-19 on neurophysiological diagnostics, especially inpatient video-EEGs, invasive investigations, and epilepsy surgery. The COVID-19 pandemic may hamper care for patients in need of EEG-based investigations, particularly patients with seizure disorders. ERN EpiCARE will work on recommendations on how to rapidly adapt to such situations in order to alleviate consequences for our patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1684/epd.2020.1208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753285PMC
October 2020

Interrater agreement of classification of photoparoxysmal electroencephalographic response.

Epilepsia 2020 09 19;61(9):e124-e128. Epub 2020 Sep 19.

Department of Pediatric Clinical Epileptology, Sleep Disorders, and Functional Neurology, University Hospitals of Lyon, Lyon, France.

Our goal was to assess the interrater agreement (IRA) of photoparoxysmal response (PPR) using the classification proposed by a task force of the International League Against Epilepsy (ILAE), and a simplified classification system proposed by our group. In addition, we evaluated IRA of epileptiform discharges (EDs) and the diagnostic significance of the electroencephalographic (EEG) abnormalities. We used EEG recordings from the European Reference Network (EpiCARE) and Standardized Computer-based Organized Reporting of EEG (SCORE). Six raters independently scored EEG recordings from 30 patients. We calculated the agreement coefficient (AC) for each feature. IRA of PPR using the classification proposed by the ILAE task force was only fair (AC = 0.38). This improved to a moderate agreement by using the simplified classification (AC = 0.56; P = .004). IRA of EDs was almost perfect (AC = 0.98), and IRA of scoring the diagnostic significance was moderate (AC = 0.51). Our results suggest that the simplified classification of the PPR is suitable for implementation in clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/epi.16655DOI Listing
September 2020

Neural correlates of verbal working memory in children with epilepsy with centro-temporal spikes.

Neuroimage Clin 2020 20;28:102392. Epub 2020 Aug 20.

Department of Clinical Neurosciences, CHUV, Lausanne, Switzerland.

Background: Previous functional magnetic resonance imaging (fMRI) studies have identified brain systems underlying different components of working memory (WM) in healthy subjects. The aim of this study was to compare the functional integrity of these neural networks in children with self-limited childhood epilepsy with centro-temporal spikes (ECTS) as compared to healthy controls, using a verbal working memory task (WMT).

Methods: Functional MRI of WM in seventeen 6-to-13 year-old children, diagnosed with ECTS, and 17 sex- and age-matched healthy controls were conducted at 3 T. To estimate BOLD responses during the maintenance of low, medium, and high WMT loads, we used a Sternberg verbal WMT. Neuropsychological testing prior to scanning and behavioral data during scanning were also acquired.

Results: Behavioral performances during WMT, in particular accuracy and response time, were poorer in children with ECTS than in controls. Increased WM load was associated with increased BOLD signal in all subjects, with significant clusters detected in frontal and parietal regions, predominantly in the left hemisphere. However, under the high load condition, patients showed reduced activation in the frontal, temporal and parietal regions as compared to controls. In brain regions where WM-triggered BOLD activation differed between groups, this activation correlated with neuropsychological performances in healthy controls but not in patients with ECTS, further suggesting WM network dysfunction in the latter.

Conclusion: Children with ECTS differ from healthy controls in how they control WM processes during tasks with increasing difficulty level, notably for high WM load where patients demonstrate both reduced BOLD activation and behavioral performances.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nicl.2020.102392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495114PMC
June 2021

Cardiac phenotype in -related syndromes: A multicenter cohort study.

Neurology 2020 11 10;95(21):e2866-e2879. Epub 2020 Sep 10.

From the Department of Clinical and Experimental Epilepsy (S.B., S.M.S.), UCL Queen Square Institute of Neurology, London; Chalfont Centre for Epilepsy (S.B., S.M.S.), Bucks, UK; Division of Pediatric Neurology (M.A.M., A.S.H., B.K., M.M., L.P.), Department of Neurobiology, and Division of Cardiology (M.C.), Department of Pediatrics, Duke University, School of Medicine, Durham, NC; Centre for Inherited Cardiovascular Diseases (R.A.G.-R., J.P.K.), Great Ormond Street Hospital for Children NHS Foundation Trust; Institute of Cardiovascular Science(R.A.G.-R., J.P.K.), University College London, London, UK; Child Neuropsychiatry Unit (E.D.G., A.G., L.P., M.S., E.V.), IRCCs Istituto Giannina Gaslini, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health, DINOG-MI, University of Genoa; Department of Pediatric Neuroscience (A.G., T.G., N.N., F.R.), Fondazione IRCCS Istituto Neurologico Carlo Besta; Unit of Child Neuropsychiatry (L.P.), ASST Fatebenefratelli Sacco, Milan, Italy; Paediatric Neurology Department (J.C., C.F., L.P.-P., A.A.), Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona University, Member of the International Alternating Hemiplegia in Childhood Research Consortium IAHCRC and of the European Reference Network ERN EpiCARE, Barcelona, Spain; Department of Neurology (A.B., C.M.), Wake Forest School of Medicine, Winston-Salem, NC; Neurology Department (R.S.), Centro Hospitalar e Universitario do Porto-Hospital de Santo António, Porto, Portugal; Clinic for Child Neurology and Psychiatry (V.B., A.P.), Department of Child Neurology, Medical Faculty University of Belgrade, Serbia; Department of Human Genetics (Q.S.P.), Graduate School of Public Health, University of Pittsburgh, PA; Department of Pediatric Neurology (J.P.), Medical University of Silesia, Katowice, Poland; Clinical Neurosciences (K.V., J.H.C.), Developmental Neuroscience Programme, UCL Great Ormond Street Institute of Child Health, and Great Ormond Street Hospital for Children NHS Foundation Trust, Member of the International Alternating Hemiplegia in Childhood Research Consortium IAHCRC and of the European Reference Network ERN EpiCARE, London, UK; Sydney Children's Hospital (A.M.E.B.), Randwick; Department of Cardiology (A.M.D.), The Royal Children's Hospital, Melbourne, University of Melbourne; Department of Neurology (M.M.R.), Royal Children's Hospital, Melbourne; Agnes Ginges Centre for Molecular Cardiology (C.S.), Centenary Institute, University of Sydney; Epilepsy Research Centre (G.H., I.E.S.), Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC; Department of Paediatrics (I.E.S.), University of Melbourne, Royal Children's Hospital, Florey and Murdoch Children's Research Institutes, Melbourne, Australia; Department of Clinical Epileptology, Sleep Disorders and Functional Neurology in Children (A.A., E.P.), University Hospitals of Lyon (HCL), Member of the International Alternating Hemiplegia in Childhood Research Consortium IAHCRC and of the European Reference Network ERN EpiCARE, Lyon, France; Paediatric Neurology Unit (I.C.), CMIN, Centro Hospitalar e Universitario Porto, Porto, Portugal; Clinical Neurophysiology Unit (C.Z.), IRCCS "E. Medea," Bosisio Parini (LC), Italy; Department of Neurology (J.N.), CHUV and Université de Lausanne, Switzerland; Second Department of Neurology (K.D.), Institute Psychiatry and Neurology, Warsaw, Poland; Association AHC18+ e. V. (Germany) and Polish Association for People Affected by AHC, ahc-pl (M.P.); Department of Developmental Neurology (M.M.B.), Medical University of Gdańsk, Poland; Neurology Department (S.W.), University Hospital Antwerp; Neurogenetics Group (S.W.), University Antwerp, Belgium; First Department of Pediatrics (R.P.), "Agia Sofia" Children Hospital, National & Kapodistrian University of Athens, Greece; Department of Neurology (S.G.), University Medical Center of the Johannes Gutenberg University Mainz, Germany; Ion Channel Research Unit (D.S.S.), Department of Medicine/Cardiology and Pharmacology, Duke University Medical Center, Durham, NC; Cardiovascular Research Institute (G.S.P.), Weill Cornell Medical College, New York, NY; The Heart Centre (A.T.), Queen Mary University of London; Department of Pathology (M.A.), Great Ormond Street Hospital for Children NHS Foundation Trust; Department of Neuropathology (Z.M., M.T.), Institute of Neurology, University College London, UK; and ICT and Data Analysis Section (R.V.), Euro-Mediterranean Institute of Science and Technology (I.E.ME.S.T.), Palermo, Italy.

Objective: To define the risks and consequences of cardiac abnormalities in -related syndromes.

Methods: Patients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an knock-in mouse (Mashl) to determine the sequence of events in seizure-related cardiac death.

Results: Ninety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC and RDP with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3 of 98 (≈3%) patients with AHC. In the mouse model, resting ECGs showed intracardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death.

Conclusions: We found increased prevalence of ECG dynamic abnormalities in all -related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine -related disease. -related syndromes are cardiac diseases and neurologic diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000010794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734736PMC
November 2020

An accelerated shift in the use of remote systems in epilepsy due to the COVID-19 pandemic.

Epilepsy Behav 2020 11 31;112:107376. Epub 2020 Aug 31.

APHP, Reference Centre for Rare Epilepsies, Department of Pediatric Neurology, Hôpital Necker-Enfants Malades, Université de Paris, Paris, France; Laboratory of Translational Research for Neurological Disorders, INSERM UMR 1163, Imagine institute, Université de Paris, France. Electronic address:

Purpose: The purpose of the study was to describe epileptologists' opinion on the increased use of remote systems implemented during the COVID-19 pandemic across clinics, education, and scientific meetings activities.

Methods: Between April and May 2020, we conducted a cross-sectional, electronic survey on remote systems use before and during the COVID-19 pandemic through the European reference center for rare and complex epilepsies (EpiCARE) network, the International and the French Leagues Against Epilepsy, and the International and the French Child Neurology Associations. After descriptive statistical analysis, we compared the results of France, China, and Italy.

Results: One hundred and seventy-two respondents from 35 countries completed the survey. Prior to the COVID-19 pandemic, 63.4% had experienced remote systems for clinical care. During the pandemic, the use of remote clinics, either institutional or personal, significantly increased (p < 10). Eighty-three percent used remote systems with video, either institutional (75%) or personal (25%). During the pandemic, 84.6% of respondents involved in academic activities transformed their courses to online teaching. From February to July 2020, few scientific meetings relevant to epileptologists and routinely attended was adapted to virtual meeting (median: 1 [25th-75th percentile: 0-2]). Responders were quite satisfied with remote systems in all three activity domains. Interestingly, before the COVID-19 pandemic, remote systems were significantly more frequently used in China for clinical activity compared with France or Italy. This difference became less marked during the pandemic.

Conclusion: The COVID-19 pandemic has dramatically altered how academic epileptologists carry out their core missions of clinical care, medical education, and scientific discovery and dissemination. Close attention to the impact of these changes is merited.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yebeh.2020.107376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457939PMC
November 2020

Compassionate use of everolimus for refractory epilepsy in a patient with MTOR mosaic mutation.

Eur J Med Genet 2020 Nov 14;63(11):104036. Epub 2020 Aug 14.

Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est, CHU Dijon Bourgogne, 21079, Dijon, France; Génétique des Anomalies du Développement, UMR1231, Université de Bourgogne, 21079, Dijon, France; Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), CHU Dijon Bourgogne, 21079, Dijon, France. Electronic address:

The MTOR gene encodes the mechanistic target of rapamycin (mTOR), which is a core component of the PI3K-AKT-mTOR signaling pathway. Postzygotic MTOR variants result in various mosaic phenotypes, referred to in OMIM as Smith-Kinsgmore syndrome or focal cortical dysplasia. We report here the case of a patient, with an MTOR mosaic gain-of-function variant (p.Glu2419Lys) in the DNA of 41% skin cells, who received compassionate off-label treatment with everolimus for refractory epilepsy. This 12-year-old-girl presented with psychomotor regression, intractable seizures, hypopigmentation along Blaschko's lines (hypomelanosis of Ito), asymmetric regional body overgrowth, and ocular anomalies, as well as left cerebral hemispheric hypertrophy with some focal underlying migration disorders. In response to the patient's increasingly frequent epileptic seizures, everolimus was initiated (after approval from the hospital ethics committee) at 5 mg/day and progressively increased to 12.5 mg/day. After 5 months of close monitoring (including neuropsychological and electroencephalographic assessment), no decrease in seizure frequency was observed. Though the physiopathological rationale was good, no significant clinical response was noticed under everolimus treatment. A clinical trial would be needed to draw conclusions, but, because the phenotype is extremely rare, it would certainly need to be conducted on an international scale.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmg.2020.104036DOI Listing
November 2020

Did the COVID-19 pandemic silence the needs of people with epilepsy?

Epileptic Disord 2020 Aug;22(4):439-442

Epilepsy Monitoring Unit, Department of Neurology, Hospital del Mar, Barcelona, Spain. Member of ERN EpiCARE, Hospital del Mar Medical Research Institute (IMIM) Barcelona, Spain.

The COVID-19 pandemic shook European healthcare systems, with unavoidable gaps in the management of patients with chronic diseases. We describe the impact of the pandemic on epilepsy care in three tertiary epilepsy centres from Spain and Italy, the most affected European countries. The three epilepsy centres, members of the European EpiCARE network, manage more than 5,700 people with epilepsy. In Bologna and Barcelona, the hospitals housing the epilepsy centres were fully converted into COVID-19 units. We describe the reorganization of the clinics and report on the frequency of SARS-CoV-2 in people with epilepsy as well as the frequency of seizures in patients admitted to the COVID units. Finally, we elaborate on critical issues regarding the second phase of the pandemic. The activities related to epilepsy care were reduced to less than 10% and were deprioritized. Discharges were expedited and elective epilepsy surgeries, including vagal nerve stimulator implantations, cancelled. Hospitalizations and EEG examinations were limited to emergencies. The outpatient visits for new patients were postponed, and follow-up visits mostly managed by telehealth. Antiseizure medication weaning plans and changes in vagal nerve stimulator settings were halted. Among the 5,700 people with epilepsy managed in our centres, only 14 tested positive for SARS-CoV-2, without obvious impact on their epilepsy. None of the 2,122 patients admitted to COVID units experienced seizures among the early symptoms. Epilepsy care was negatively impacted by the pandemic, irrespective of COVID-19 epidemiology or conversion of the hospital into a COVID-19 centre. The pandemic did not silence the needs of people with epilepsy, and this must be considered in the planning of the second phase.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1684/epd.2020.1175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537265PMC
August 2020

Exome sequencing in 57 patients with self-limited focal epilepsies of childhood with typical or atypical presentations suggests novel candidate genes.

Eur J Paediatr Neurol 2020 Jul 29;27:104-110. Epub 2020 May 29.

Department of Medical Genetics, Member of the ERN EpiCARE, University Hospital of Lyon, Lyon, France; Institut NeuroMyoGène, CNRS UMR 5310 - INSERM U1217, Lyon, France; Université de Lyon - Université Claude Bernard Lyon 1, Lyon, France. Electronic address:

Objective: Self-limited focal epilepsies of childhood (SFEC) are amongst the best defined and most frequent epilepsy syndromes affecting children with usually normal developmental milestones. They include core syndromes such as Rolandic epilepsy or "Benign" epilepsy with Centro-Temporal Spikes and the benign occipital epilepsies, the early onset Panayiotopoulos syndrome and the late-onset Gastaut type. Atypical forms exist for all of them. Atypical Rolandic epilepsies are conceptualized as belonging to a continuum reaching from the "benign" RE to the severe end of the Landau-Kleffner (LKS) and Continuous Spike-Waves during Sleep syndromes (CSWS). GRIN2A has been shown to cause the epilepsy-aphasia continuum that includes some patients with atypical Rolandic epilepsy with frequent speech disorders, LKS and CSWS. In the present study, we searched novel genes causing SFEC with typical or atypical presentations.

Methods: Exome sequencing was performed in 57 trios. Patients presented with typical or atypical SFEC, negative for GRIN2A pathogenic variant.

Results: We found rare candidate variants in 20 patients. Thirteen had occurred de novo and were mostly associated to atypical Rolandic Epilepsy. Two of them could be considered as disease related: a null variant in GRIN2B and a missense variant in CAMK2A. Others were considered good candidates, including a substitution affecting a splice site in CACNG2 and missense variants in genes encoding enzymes involved in chromatin remodeling.

Significance: Our results further illustrate the fact that atypical SFEC are more likely to have Mendelian inheritance than typical SFEC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpn.2020.05.003DOI Listing
July 2020

Early-onset epileptic encephalopathy with migrating focal seizures associated with a FARS2 homozygous nonsense variant.

Epileptic Disord 2020 Jun;22(3):327-335

Paediatric Clinical Epileptology and Functional Neurology Department, Reference Center of rare epilepsies, Member of the ERN EpiCARE, University Hospitals of Lyon (HCL), Lyon, France.

Epilepsy of infancy with migrating focal seizures (EIMFS) is now a well-recognized early-onset syndrome included in the ILAE classification of the epilepsies. KCNT1 gain-of-function variants are identified in about half of patients. In the remaining cases, the underlying genetic component is far more heterogeneous with sporadic mutations occasionally reported in SCN1A, SCN2A, SLC12A5, TBC1D24, PLCB1, SLC25A22, and KCNQ2. Here, we report, for the first time, a homozygous deleterious variant in the FARS2 gene, identified using a 115-gene panel for monogenic epilepsies, in a patient with EIMFS. This boy was the second child born to healthy consanguineous parents. The first seizures occurred at six weeks of age. The patient rapidly developed severe epilepsy with focal discharges on EEG, migrating from one brain region to another, highly suggestive of EIMFS. At five months of age, he had daily multifocal clonic seizures and erratic myoclonic fits, which were not consistently related to spikes or spike-and-wave discharges. Neurological status was severely abnormal from onset and the patient died at 10 months of age from respiratory distress. Using the gene panel, a homozygous missense variant of FARS2 was identified, at Chr6 (GRCh37):g.5404829C>T, c.667C>T (NM_001318872.1), inherited from both parents, leading to an arginine-to-cysteine substitution, p.(Arg223Cys). FARS2 is a member of the mitochondrial aminoacyl tRNA transferase (ARS) enzymes. ARS variants are increasingly recognized causes of early-onset epileptic and neurodevelopmental encephalopathies, however, the associated epileptic phenotype is not completely described. This case shows that FARS2-related seizures can mimic EIMFS in the early stage of the disease. Furthermore, in the setting of migrating focal seizures of infancy, FARS2 should be considered as a further candidate gene, and increased lactate level and occurrence of refractory myoclonic seizures are possible key features to suspect FARS deficiency.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1684/epd.2020.1168DOI Listing
June 2020

Brain volumetrics in alternating hemiplegia of childhood.

Eur J Paediatr Neurol 2020 05 22;26. Epub 2020 Apr 22.

Department of Paediatric Clinical Epileptology, Sleep Disorders and Functional Neurology, Coordinator of French Node of the International AHC Consortium and of the ERN on Rare and Complex Epilepsies EpiCARE, University Hospitals of Lyon (HCL), Lyon, France. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpn.2020.04.010DOI Listing
May 2020

Epilepsy in LAMA2-related muscular dystrophy: An electro-clinico-radiological characterization.

Epilepsia 2020 05 8;61(5):971-983. Epub 2020 Apr 8.

Unit of Epilepsy, Sleep and Neurophysiology, Neuropaediatrics Department, Hospital Sant Joan de Déu, Barcelona, Spain.

Objective: To delineate the epileptic phenotype of LAMA2-related muscular dystrophy (MD) and correlate it with the neuroradiological and muscle biopsy findings, as well as the functional motor phenotype.

Methods: Clinical, electrophysiological, neuroradiological, and histopathological data of 25 patients with diagnosis of LAMA2-related MD were analyzed.

Results: Epilepsy occurred in 36% of patients with LAMA2-related MD. Mean age at first seizure was 8 years. The most common presenting seizure type was focal-onset seizures with or without impaired awareness. Visual aura and autonomic signs, including vomiting, were frequently reported. Despite a certain degree of variability, bilateral occipital or temporo-occipital epileptiform abnormalities were by far the most commonly observed. Refractory epilepsy was found in 75% of these patients. Epilepsy in LAMA2-related MD was significantly more prevalent in those patients in whom the cortical malformations were more extensive. In contrast, the occurrence of epilepsy was not found to be associated with the patients' motor ability, the size of their white matter abnormalities, or the amount of residual merosin expressed on muscle.

Significance: The epileptic phenotype of LAMA2-related MD is characterized by focal seizures with prominent visual and autonomic features associated with EEG abnormalities that predominate in the posterior quadrants. A consistent correlation between epileptic phenotype and neuroimaging was identified, suggesting that the extension of the polymicrogyria may serve as a predictor of epilepsy occurrence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/epi.16493DOI Listing
May 2020

Meta-analysis of drug efficacy in adult vs pediatric trials of patients with PGTC seizures.

Neurology 2020 04 1;94(17):e1845-e1852. Epub 2020 Apr 1.

From the University of Chicago (D.R.N.), IL; Mount Sinai School of Medicine (E.B.), New York, NY; Department of Pediatric Clinical Epileptology, Sleep Disorders and Functional Neurology (A.A.), University Hospitals of Lyon (HCL), Member of the European Reference Network EpiCARE, Lyon, France; Paediatric Epilepsy Unit (A.A.), Hospital Sant Joan de Déu, Member of the European Reference Network EpiCARE and Universitat de Barcelona, Spain; Eisai Inc. (J.W., D.K., A.L.), Woodcliff Lake, NJ; and NYU Comprehensive Epilepsy Center (J.F.), New York, NY.

Objective: A meta-analysis of published studies was performed to determine whether the efficacy of antiseizure drugs in adults with primary generalized tonic-clonic seizures (PGTCS) is comparable with that in the pediatric population (2-12 years of age).

Methods: Electronic searches were conducted in EMBASE, Medline, and the Cochrane Central Register of Controlled Trials for clinical trials of PGTCS in adults and children 2-12 years of age. Neurologists used standardized search and study evaluations to select eligible trials. Median percent reduction in seizure frequency from baseline and ≥50% responder rates were used to compare drug efficacy in adults and children.

Results: Among 7 adjunctive-therapy PGTCS trials in adults and children (2-12 years of age) that met evaluation criteria, effect sizes were consistent between adults and children for lamotrigine and topiramate. The baseline-subtracted median percent seizure reduction in seizure frequency ranged from 50.0% to 79.7% in children and 57.0% to 64.0% in adults. The ≥50% responder rate was similar between children and adults in a topiramate study (50% in children compared with 58% in adults).

Conclusions: This meta-analysis supports the use of drug response from antiseizure drug clinical trials for PGTCS in adults to predict comparable treatment response in children 2-12 years of age with PGTCS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000009325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274844PMC
April 2020

Movement disorders in patients with alternating hemiplegia: "Soft" and "stiff" at the same time.

Neurology 2020 03 2;94(13):e1378-e1385. Epub 2020 Mar 2.

From Sleep Disorders and Functional Neurology (E.P., A.A.), Department of Paediatric Clinical Epileptology, University Hospitals of Lyon, member of the ERN EpiCARE; Service de Neurologie Pédiatrique (D.D., T.B.), Hôpital Trousseau, APHP, Paris; Centre d'Investigation Clinique (E.N., N.N.), CHU Montpellier; Department of Medical Genetics (G.L.), Centre de Biologie Est, Lyon University Hospital, Hospices Civils de Lyon, member of the ERN EpiCARE; Laboratoire de Génétique (F.R.), Groupe Hospitalier Lariboisière-Fernand Widal AP-HP, Paris; IGF (S.N.), Univ Montpellier, CNRS, INSERM; Département de Neuropédiatrie (C.D., A.R.), CHU Gui de Chauliac, Montpellier; Service de Neuropédiatrie et Handicaps (M.A.B.), Hôpital Gatien de Clocheville, CHU Tours, France; Pediatric Neurology Unit (M.C.N.), Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium; Service de Neuropédiatrie (A.D.), CHU de Bicêtre, Kremlin-Bicêtre; Service de Neuropédiatrie (L.V.), CHU Lille; Service de Neurochirurgie Pédiatrique (M.B.), Hôpital Necker-Enfants Malades, APHP, Paris; Service de Neurologie Pédiatrique (C.I.), Hôpital Raymond Poincarré, AP-HP, Garches; Service de Neurophysiologie (C.G.), Hôpital Necker, AP-HP, Paris; Département de Pédiatrie (C.L.), CHU Limoges; Service de Neurologie Pédiatrique (M.M.), CHU Timone Enfants, Marseille; Centre de Référence "Déficiences Intellectuelles de Causes Rares" (V.D.P.), Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, Université de Lyon; and INSERM U 1051 (A.R.), Institut des Neurosciences de Montpellier, France.

Objective: To assess nonparoxysmal movement disorders in mutation-positive patients with alternating hemiplegia of childhood (AHC).

Methods: Twenty-eight patients underwent neurologic examination with particular focus on movement phenomenology by a specialist in movement disorders. Video recordings were reviewed by another movement disorders specialist and data were correlated with patients' characteristics.

Results: Ten patients were diagnosed with chorea, 16 with dystonia (nonparoxysmal), 4 with myoclonus, and 2 with ataxia. Nine patients had more than one movement disorder and 8 patients had none. The degree of movement disorder was moderate to severe in 12/28 patients. At inclusion, dystonic patients (n = 16) were older ( = 0.007) than nondystonic patients. Moreover, patients (n = 18) with dystonia or chorea, or both, had earlier disease onset ( = 0.042) and more severe neurologic impairment ( = 0.012), but this did not correlate with genotype. All patients presented with hypotonia, which was characterized as moderate or severe in 16/28. Patients with dystonia or chorea (n = 18) had more pronounced hypotonia ( = 0.011). Bradykinesia (n = 16) was associated with an early age at assessment ( < 0.01). Significant dysarthria was diagnosed in 11/25 cases. A history of acute neurologic deterioration and further regression of motor function, typically after a stressful event, was reported in 7 patients.

Conclusions: Despite the relatively limited number of patients and the cross-sectional nature of the study, this detailed categorization of movement disorders in patients with AHC offers valuable insight into their precise characterization. Further longitudinal studies on this topic are needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000009175DOI Listing
March 2020

Epilepsy and cannabidiol: a guide to treatment.

Epileptic Disord 2020 02;22(1):1-14

Paediatric Epilepsy Dpt., University Hospitals of Lyon (HCL), Member of the ERN EpiCARE, and Inserm U1028 / CNRS UMR5292, Lyon, France

The growing interest in cannabidiol (CBD), specifically a pure form of CBD, as a treatment for epilepsy, among other conditions, is reflected in recent changes in legislation in some countries. Although there has been much speculation about the therapeutic value of cannabis-based products as an anti-seizure treatment for some time, it is only within the last two years that Class I evidence has been available for a pure form of CBD, based on placebo-controlled RCTs for patients with Lennox-Gastaut syndrome and Dravet syndrome. However, just as we are beginning to understand the significance of CBD as a treatment for epilepsy, in recent years, a broad spectrum of products advertised to contain CBD has emerged on the market. The effects of these products are fundamentally dependent on the purity, preparation, and concentration of CBD and other components, and consensus and standardisation are severely lacking regarding their preparation, composition, usage and effectiveness. This review aims to provide information to neurologists and epileptologists on the therapeutic value of CBD products, principally a purified form, in routine practice for patients with intractable epilepsy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1684/epd.2020.1141DOI Listing
February 2020

Trends in pediatric epilepsy surgery in Europe between 2008 and 2015: Country-, center-, and age-specific variation.

Epilepsia 2020 02 26;61(2):216-227. Epub 2019 Dec 26.

Claudio Munari Epilepsy Surgery Center, Niguarda Hospital, Milan, Italy.

Objective: To profile European trends in pediatric epilepsy surgery (<16 years of age) between 2008 and 2015.

Methods: We collected information on volumes and types of surgery, pathology, and seizure outcome from 20 recognized epilepsy surgery reference centers in 10 European countries.

Results: We analyzed retrospective aggregate data on 1859 operations. The proportion of surgeries significantly increased over time (P < .0001). Engel class I outcome was achieved in 69.3% of children, with no significant improvement between 2008 and 2015. The proportion of histopathological findings consistent with glial scars significantly increased between the ages of 7 and 16 years (P for trend = .0033), whereas that of the remaining pathologies did not vary across ages. A significant increase in unilobar extratemporal surgeries (P for trend = .0047) and a significant decrease in unilobar temporal surgeries (P for trend = .0030) were observed between 2008 and 2015. Conversely, the proportion of multilobar surgeries and unrevealing magnetic resonance imaging cases remained unchanged. Invasive investigations significantly increased, especially stereo-electroencephalography. We found different trends comparing centers starting their activity in the 1990s to those whose programs were developed in the past decade. Multivariate analysis revealed a significant variability of the proportion of the different pathologies and surgical approaches across countries, centers, and age groups between 2008 and 2015.

Significance: Between 2008 and 2015, we observed a significant increase in the volume of pediatric epilepsy surgeries, stability in the proportion of Engel class I outcomes, and a modest increment in complexity of the procedures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/epi.16414DOI Listing
February 2020

Epileptogenicity in tuberous sclerosis complex: A stereoelectroencephalographic study.

Epilepsia 2020 01 20;61(1):81-95. Epub 2019 Dec 20.

National Institute of Health and Medical Research U1028/National Center for Scientific Research, Mixed Unit of Research 5292, Lyon Neuroscience Research Center, Lyon, France.

Objective: In tuberous sclerosis complex (TSC)-associated drug-resistant epilepsy, the optimal invasive electroencephalographic (EEG) and operative approach remains unclear. We examined the role of stereo-EEG in TSC and used stereo-EEG data to investigate tuber and surrounding cortex epileptogenicity.

Methods: We analyzed 18 patients with TSC who underwent stereo-EEG (seven adults). One hundred ten seizures were analyzed with the epileptogenicity index (EI). In 13 patients with adequate tuber sampling, five anatomical regions of interest (ROIs) were defined: dominant tuber (tuber with highest median EI), perituber cortex, secondary tuber (tuber with second highest median EI), nearby cortex (normal-appearing cortex in the same lobe as dominant tuber), and distant cortex (in other lobes). At the seizure level, epileptogenicity of ROIs was examined by comparing the highest EI recorded within each anatomical region. At the patient level, epileptogenic zone (EZ) organization was separated into focal tuber (EZ confined to dominant tuber) and complex (all other patterns).

Results: The most epileptogenic ROI was the dominant tuber, with higher EI than perituber cortex, secondary tuber, nearby cortex, and distant cortex (P < .001). A focal tuber EZ organization was identified in seven patients. This group had 80% Engel IA postsurgical outcome and distinct dominant tuber characteristics: continuous interictal discharges (IEDs; 100%), fluid-attenuated inversion recovery (FLAIR) hypointense center (86%), center-to-rim EI gradient, and stimulation-induced seizures (71%). In contrast, six patients had a complex EZ organization, characterized by nearby cortex as the most epileptogenic region and 40% Engel IA outcome. At the intratuber level, the combination of FLAIR hypointense center, continuous IEDs, and stimulation-induced seizures offered 98% specificity for a focal tuber EZ organization.

Significance: Tubers with focal EZ organization have a striking similarity to type II focal cortical dysplasia. The presence of distinct EZ organizations has significant implications for EZ hypothesis generation, invasive EEG approach, and resection strategy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/epi.16410DOI Listing
January 2020

Novel study design to assess the efficacy and tolerability of antiseizure medications for focal-onset seizures in infants and young children: A consensus document from the regulatory task force and the pediatric commission of the International League against Epilepsy (ILAE), in collaboration with the Pediatric Epilepsy Research Consortium (PERC).

Epilepsia Open 2019 Dec 4;4(4):537-543. Epub 2019 Sep 4.

Division of Pediatric Neurology Department of Pediatrics Michigan Medicine Ann Arbor MI USA.

High-quality placebo-controlled drug trials for focal-onset seizures in infants and children younger than 4 years have become increasingly difficult to perform because of eligibility constraints and onerous study designs. Traditional designs used in these populations require a high baseline seizure frequency, two hospitalizations for video-electroencephalography (video-EEG) monitoring, and willingness to accept potential exposure to placebo when the drugs to be tested are usually already available for off-label prescription. To address these constraints, the International League Against Epilepsy (ILAE) regulatory taskforce and the ILAE pediatric commission, in collaboration with the Pediatric Epilepsy Research Consortium (PERC), propose a novel trial design which involves seizure counting by caregivers based on previous video-EEG/video validation of specific seizure semiologies. We present a novel randomized placebo-controlled trial design intended to be used for studying new antiseizure medications (ASMs) for focal-onset seizures (FOS) in children aged one month to four years. This design uses "time to Nth seizure" as the primary outcome and incorporates a new element of variable baseline duration. This approach permits enrollment of infants with lower seizure burden, who might not have video-EEG-recorded seizures within 2-3 days of monitoring. Repeated hospitalizations for video-EEG recordings are avoided, and duration of baseline and exposure to placebo or ineffective treatment(s) are minimized. By broadening eligibility criteria, reducing risks from prolonged placebo exposure, and relying on validated recording of seizure counting by caregivers, clinical trials will be likely to be completed more efficiently than in the recent past.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/epi4.12356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885693PMC
December 2019

BLAST paradigm: A new test to assess brief attentional fluctuations in children with epilepsy, ADHD, and normally developing children.

Epilepsy Behav 2019 10 17;99:106470. Epub 2019 Aug 17.

INSERM, U1028, CNRS, UMR5292, Lyon Neuroscience Research Center, Lyon, France; Department of Paediatric Clinical Epileptology, Sleep Disorders and Functional Neurology, Member of the European Reference Network on Rare and Complex Epilepsies EpiCARE, Hospices Civils de Lyon and University Lyon, Lyon, France.

Background: Pure attentional deficits are still underdiagnosed in children with epilepsy. While attention-deficit hyperactivity disorder (ADHD) is historically the most studied cause of attentional disorders, an important number of children with epilepsy and attentional complaints do not fully meet the DSM-V (Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition) criteria for ADHD and may be excluded from specific care. Clinical tools currently available are insufficient to detect more subtle but clinically relevant attentional fluctuations.

Objective/methods: The recently developed Bron-Lyon Attention Stability Test (BLAST) was used to evaluate brief attentional fluctuations with a high temporal precision. Drawing on two new attentional indices, we evaluated spontaneous fluctuations of response accuracy and timing, underlying attentional stability. The main objective was to assess attentional stability in children with i) epilepsy with comorbid ADHD, ii) epilepsy without comorbid ADHD, iii) ADHD not medicated and without epilepsy, and iv) normal development. Further objectives were to assess the main determinants of attentional stability in those groups, including the effect of factors related to the epileptic condition.

Results: In 122 children with epilepsy (67 with comorbid ADHD), 52 children with ADHD, and 53 healthy controls, we demonstrated lower attentional stability in both the groups with epilepsy and ADHD compared with healthy children. In children with epilepsy, BLAST scores were negatively associated with earlier seizure onset and AED (antiepileptic drug) polytherapy, while the seizure frequency, epilepsy duration, or type did not influence BLAST scores.

Conclusions: This study demonstrates that attentional stability is impaired in children with epilepsy and/or ADHD. Bron-Lyon Attention Stability Test seems to be a sensitive test to detect attentional stability deficit in children with epilepsy and with attentional complaints who did not meet all criteria of ADHD. We propose that BLAST could be a useful clinical neuropsychological tool to assess attentional disorders in children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yebeh.2019.106470DOI Listing
October 2019
-->