102 results on '"Maria Roberta Cilio"'
Search Results
2. Proceedings of the 13th International Newborn Brain Conference: Other forms of brain monitoring, such as NIRS, fMRI, biochemical
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Ekaterina Balashova, Olivia Beaulieu, Imen Benhmida, Ala Birca, Geraldine Boylan, Katherine Carkeek, Rasheda Chowdhury, Maria Roberta Cilio, Anna Consoli, Gabriel Cote Corriveau, Deborah Cuddyer, Dmitriy Degtyarev, Mathieu Dehaes, Eugene Dempsey, Anneleen Dereymaeker, Beatrice Desnous, Mohamed El-Dib, Elhaytham Elsayed, Henry A. Feldman, Daragh Finn, Maria Angela Franceschini, Shoshana Freeman, Marie-Michele Gagnon, Melanie Gagnon, Aisling Garvey, Anirban Ghosh, Yulia Golubtsova, P. Ellen Grant, Susanne C. Hay, Tim Hermans, Emily Herzberg, Chuan-Heng Hsiao, Maria Iennaco, Terrie Inder, Oleg Ionov, Kutlu Kaya, Faith Keister, Miriah Kemigisha, Anna Kirtbaya, Sarah Lee, Lara Leijser, Steve Liao, Pei-Yi Lin, Rachel Lippman, Vicki Livingstone, Thuy Mai Luu, Joshua Magombe, Zamzam Mahdi, Bohdana Marandyuk, Alyssa Martin, Sean Mathieson, Edith Mbabazi, Khorshid Mohammad, Michael Moore, Ronald Mulondo, Chelsea Munster, Deirdre Murray, Esther Nalule, Davis Natukwatsa, Gunnar Naulaers, Mona Noroozi, Brian Nsubuga, John O’Toole, Andreea Pavel, Mallory Peterson, Elana Pinchefsky, Katharine Playter, Jennifer Queally, Ajay Rajaram, Andrey Ryndin, Steven Schiff, Marvin Seruwu, Diiana Sharafutdinova, Yvonne Sheldon, Marie-Noelle Simard, Jessica Sims, Tina Steele, Amelie Stritzke, John Sunwoo, Jason Sutin, Julia Tatz, Taylor Vadset, Zachary Vesoulis, Rutvi Vyas, Moses Wabukoma, Brian Walsh, Joshua Wandukwa, Benjamin Warf, Halana Whitehead, Michael Woglom, Fan-Yu Yen, Lucca Zampolli, Alexander I. Zavriyev, Hussein Zein, Bernhard Zimmermann, and Victor Zubkov
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Pediatrics, Perinatology and Child Health - Published
- 2022
3. Characteristics of Neonates with Cardiopulmonary Disease Who Experience Seizures: A Multicenter Study
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Renée A. Shellhaas, Charles E. McCulloch, Maria Roberta Cilio, Rui Xiao, Catherine J. Chu, Nicholas S. Abend, Hannah C. Glass, Sonia L. Bonifacio, Cameron Thomas, Janet S. Soul, Courtney J. Wusthoff, Shavonne L. Massey, Taeun Chang, Monica E. Lemmon, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Département de pédiatrie
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Pediatrics ,Heart disease ,medicine.medical_treatment ,neonatal seizures ,Neurodegenerative ,Cardiovascular ,congenital diaphragmatic hernia ,Cardiopulmonary disease ,Pediatric ,Electroencephalography ,congenital heart disease ,Heart Disease ,Phenobarbital ,Cohort ,Anticonvulsants ,ECMO ,medicine.drug ,EEG monitoring ,medicine.medical_specialty ,Monitoring ,education ,neonatal neurocritical care ,Article ,Paediatrics and Reproductive Medicine ,Refractory ,Clinical Research ,Seizures ,Extracorporeal membrane oxygenation ,medicine ,Humans ,Physiologic ,Neonatal seizure ,Monitoring, Physiologic ,Epilepsy ,business.industry ,Neurosciences ,Infant, Newborn ,Infant ,Congenital diaphragmatic hernia ,Human Movement and Sports Sciences ,Newborn ,brain injury ,medicine.disease ,Brain Disorders ,Good Health and Well Being ,Pediatrics, Perinatology and Child Health ,business - Abstract
ObjectiveTo compare key seizure and outcome characteristics between neonates with and without cardiopulmonary disease.Study designThe Neonatal Seizure Registry is a multicenter, prospectively acquired cohort of neonates with clinical or electroencephalographic (EEG)-confirmed seizures. Cardiopulmonary disease was defined as congenital heart disease, congenital diaphragmatic hernia, and exposure to extracorporeal membrane oxygenation. We assessed continuous EEG monitoring strategy, seizure characteristics, seizure management, and outcomes for neonates with and without cardiopulmonary disease.ResultsWe evaluated 83 neonates with cardiopulmonary disease and 271 neonates without cardiopulmonary disease. Neonates with cardiopulmonary disease were more likely to have EEG-only seizures (40% vs 21%, P 
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- 2022
4. Clinical and Neurophysiological Phenotypes in Neonates With
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Evelina, Carapancea, Marie-Coralie, Cornet, Mathieu, Milh, Lucrezia, De Cosmo, Eric J, Huang, Tiziana, Granata, Pasquale, Striano, Berten, Ceulemans, Anja, Stein, Deborah, Morris-Rosendahl, Greta, Conti, Nipa, Mitra, F Lucy, Raymond, David H, Rowitch, Roberta, Solazzi, Fabiana, Vercellino, Paola, De Liso, Gianluca, D'Onofrio, Clementina, Boniver, Olivier, Danhaive, Katherine, Carkeek, Vincenzo, Salpietro, Sarah, Weckhuysen, Marny, Fedrigo, Annalisa, Angelini, Barbara, Castellotti, Damien, Lederer, Valerie, Benoit, Federico, Raviglione, Renzo, Guerrini, Robertino, Dilena, and Maria Roberta, Cilio
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Research Article - Abstract
BACKGROUND AND OBJECTIVES: BRAT1 encephalopathy is an ultra-rare autosomal recessive neonatal encephalopathy. We delineate the neonatal electroclinical phenotype at presentation and provide insights for early diagnosis. METHODS: Through a multinational collaborative, we studied a cohort of neonates with encephalopathy associated with biallelic pathogenic variants in BRAT1 for whom detailed clinical, neurophysiologic, and neuroimaging information was available from the onset of symptoms. Neuropathologic changes were also analyzed. RESULTS: We included 19 neonates. Most neonates were born at term (16/19) from nonconsanguineous parents. 15/19 (79%) were admitted soon after birth to a neonatal intensive care unit, exhibiting multifocal myoclonus, both spontaneous and exacerbated by stimulation. 7/19 (37%) had arthrogryposis at birth, and all except 1 progressively developed hypertonia in the first week of life. Multifocal myoclonus, which was present in all but 1 infant, was the most prominent manifestation and did not show any EEG correlate in 16/19 (84%). Video-EEG at onset was unremarkable in 14/19 (74%) infants, and 6 (33%) had initially been misdiagnosed with hyperekplexia. Multifocal seizures were observed at a median age of 14 days (range: 1–29). During the first months of life, all infants developed progressive encephalopathy, acquired microcephaly, prolonged bouts of apnea, and bradycardia, leading to cardiac arrest and death at a median age of 3.5 months (range: 20 days to 30 months). Only 7 infants (37%) received a definite diagnosis before death, at a median age of 34 days (range: 25–126), and almost two-thirds (12/19, 63%) were diagnosed 8 days to 12 years postmortem (median: 6.5 years). Neuropathology examination, performed in 3 patients, revealed severely delayed myelination and diffuse astrogliosis, sparing the upper cortical layers. DISCUSSION: BRAT1 encephalopathy is a neonatal-onset, rapidly progressive neurologic disorder. Neonates are often misdiagnosed as having hyperekplexia, and many die undiagnosed. The key phenotypic features are multifocal myoclonus, an organized EEG, progressive, persistent, and diffuse hypertonia, and an evolution into refractory multifocal seizures, prolonged bouts of apnea, bradycardia, and early death. Early recognition of BRAT1 encephalopathy allows for prompt workup, appropriate management, and genetic counseling.
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- 2023
5. Clinical and Neurophysiologic Phenotypes in Neonates with BRAT1 Encephalopathy
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Evelina Carapancea, Marie-Coralie Cornet, Mathieu Milh, Lucrezia De Cosmo, Eric J. Huang, Tiziana Granata, Pasquale Striano, Berten Ceulemans, Anja Stein, Deborah Morris-Rosendahl, Greta Conti, Nipa Mitra, F. Lucy Raymond, David H. Rowitch, Roberta Solazzi, Fabiana Vercellino, Paola De Liso, Gianluca D'Onofrio, Clementina Boniver, Olivier Danhaive, Katherine Carkeek, Vincenzo Salpietro, Sarah Weckhuysen, Marny Fedrigo, Annalisa Angelini, Barbara Castellotti, Damien Lederer, Valerie Benoit, Federico Raviglione, Renzo Guerrini, Robertino Dilena, and Maria Roberta Cilio
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Myoclonus ,Pediatric ,Brain Diseases ,Neurology & Neurosurgery ,Apnea ,Clinical Sciences ,Neurosciences ,Medizin ,Nuclear Proteins ,Neurodegenerative ,Perinatal Period - Conditions Originating in Perinatal Period ,Brain Disorders ,Phenotype ,Hyperekplexia ,Seizures ,Clinical Research ,Muscle Hypertonia ,Infant Mortality ,Neurological ,Bradycardia ,Humans ,Cognitive Sciences ,Human medicine ,Neurology (clinical) - Abstract
Background and ObjectivesBRAT1encephalopathy is an ultra-rare autosomal recessive neonatal encephalopathy. We delineate the neonatal electroclinical phenotype at presentation and provide insights for early diagnosis.MethodsThrough a multinational collaborative, we studied a cohort of neonates with encephalopathy associated with biallelic pathogenic variants inBRAT1for whom detailed clinical, neurophysiologic, and neuroimaging information was available from the onset of symptoms. Neuropathologic changes were also analyzed.ResultsWe included 19 neonates. Most neonates were born at term (16/19) from nonconsanguineous parents. 15/19 (79%) were admitted soon after birth to a neonatal intensive care unit, exhibiting multifocal myoclonus, both spontaneous and exacerbated by stimulation. 7/19 (37%) had arthrogryposis at birth, and all except 1 progressively developed hypertonia in the first week of life. Multifocal myoclonus, which was present in all but 1 infant, was the most prominent manifestation and did not show any EEG correlate in 16/19 (84%). Video-EEG at onset was unremarkable in 14/19 (74%) infants, and 6 (33%) had initially been misdiagnosed with hyperekplexia. Multifocal seizures were observed at a median age of 14 days (range: 1–29). During the first months of life, all infants developed progressive encephalopathy, acquired microcephaly, prolonged bouts of apnea, and bradycardia, leading to cardiac arrest and death at a median age of 3.5 months (range: 20 days to 30 months). Only 7 infants (37%) received a definite diagnosis before death, at a median age of 34 days (range: 25–126), and almost two-thirds (12/19, 63%) were diagnosed 8 days to 12 years postmortem (median: 6.5 years). Neuropathology examination, performed in 3 patients, revealed severely delayed myelination and diffuse astrogliosis, sparing the upper cortical layers.DiscussionBRAT1encephalopathy is a neonatal-onset, rapidly progressive neurologic disorder. Neonates are often misdiagnosed as having hyperekplexia, and many die undiagnosed. The key phenotypic features are multifocal myoclonus, an organized EEG, progressive, persistent, and diffuse hypertonia, and an evolution into refractory multifocal seizures, prolonged bouts of apnea, bradycardia, and early death. Early recognition ofBRAT1encephalopathy allows for prompt workup, appropriate management, and genetic counseling.
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- 2023
6. Seizure Control in Neonates Undergoing Screening vs Confirmatory EEG Monitoring
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Sonia L. Bonifacio, Catherine J. Chu, Taeun Chang, Hannah C. Glass, Elizabeth E. Rogers, Maria Roberta Cilio, Janet S. Soul, Monica E. Lemmon, Vandana Sundaram, Shavonne L. Massey, Courtney J. Wusthoff, Nicholas S. Abend, Charles E. McCulloch, Renée A. Shellhaas, Cameron Thomas, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Centre du cancer, and UCL - (SLuc) Service de chirurgie et transplantation abdominale
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Male ,Pediatrics ,Outcome Assessment ,Diseases ,Neurodegenerative ,Electroencephalography ,Logistic regression ,Infant, Newborn, Diseases ,Cohort Studies ,Outcome Assessment, Health Care ,Paralysis ,Medicine ,Registries ,Pediatric ,medicine.diagnostic_test ,Neonatal Seizure Registry Group ,Cohort ,Cognitive Sciences ,Anticonvulsants ,Female ,medicine.symptom ,Research Article ,medicine.medical_specialty ,Clinical Sciences ,Encephalopathy ,Loading dose ,Clinical Research ,Seizures ,Humans ,Neonatal seizure ,Epilepsy ,Neurology & Neurosurgery ,business.industry ,Neurosciences ,Infant, Newborn ,Infant ,Symptomatic seizures ,Newborn ,medicine.disease ,Neurophysiological Monitoring ,Brain Disorders ,Health Care ,Good Health and Well Being ,Neurology (clinical) ,business - Abstract
ObjectiveTo determine whether screening continuous EEG monitoring (cEEG) is associated with greater odds of treatment success for neonatal seizures.MethodsWe included term neonates with acute symptomatic seizures enrolled in the Neonatal Seizure Registry (NSR), a prospective, multicenter cohort of neonates with seizures. We compared 2 cEEG approaches: (1) screening cEEG, initiated for indications of encephalopathy or paralysis without suspected clinical seizures; and (2) confirmatory cEEG, initiated for the indication of clinical events suspicious for seizures, either alone or in addition to other indications. The primary outcome was successful response to initial seizure treatment, defined as seizures resolved without recurrence within 30 minutes after initial loading dose of antiseizure medicine. Multivariable logistic regression analyses assessed the association between cEEG approach and successful seizure treatment.ResultsAmong 514 neonates included, 161 (31%) had screening cEEG and 353 (69%) had confirmatory cEEG. Neonates with screening cEEG had a higher proportion of successful initial seizure treatment than neonates with confirmatory cEEG (39% vs 18%; p < 0.0001). After adjusting for covariates, there remained a greater odds ratio (OR) for successful initial seizure treatment in the screening vs confirmatory cEEG groups (adjusted OR 2.44, 95% confidence interval 1.45–4.11, p = 0.0008).ConclusionsThese findings provide evidence from a large, contemporary cohort of neonates that a screening cEEG approach may improve odds of successful treatment of acute seizures.Classification of EvidenceThis study provides Class III evidence that for neonates a screening cEEG approach, compared to a confirmatory EEG approach, increases the probability of successful treatment of acute seizures.
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- 2021
7. Vomiting and retching as presenting signs of focal epilepsy in children
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Marie-Cécile Nassogne, Marion Depermentier, Nathalie Mercier, Renaud Lhommel, Roberto Santalucia, and Maria Roberta Cilio
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medicine.medical_specialty ,Vomiting ,Pyramidal Tracts ,Video Recording ,Functional disorder ,Epilepsy ,medicine ,Humans ,Retching ,Ictal ,Brain Neoplasms ,business.industry ,Electroencephalography ,General Medicine ,Semiology ,medicine.disease ,Magnetic Resonance Imaging ,nervous system diseases ,Neurology ,Migraine ,Epilepsy in children ,Child, Preschool ,Positron-Emission Tomography ,Anesthesia ,Female ,Epilepsies, Partial ,Neurology (clinical) ,medicine.symptom ,business - Abstract
Ictal vomiting is a rare condition easily misdiagnosed as a common disease. We report two children presenting with retching and vomiting as the main ictal manifestation. Patient 1 was a four-year-old girl with a history of daily nocturnal vomiting for two months, first interpreted as a functional disorder, then as a viral infection. She presented with vomiting accompanied by focal right-sided hemifacial clonic jerking, occurring multiple times per day. Video-EEG demonstrated ictal discharges associated with the retching and vomiting, over a normal background, and occasional interictal focal spikes. MRI was normal. PET demonstrated left-sided opercular hypometabolism. Patient 2 was a girl with a history of focal epilepsy, secondary to a right central dysembryoplastic tumour, first resected with subsequent seizure freedom at the age of three years. At five years of age, she presented with recurrent episodes of retching and vomiting initially diagnosed as migraine. Video-EEG showed ictal discharges, clinically correlating with retching, vomiting and clonic facial jerking, with normal interictal activity. Brain MRI showed a progression of the tumour. A second resection resulted in seizure freedom. Ictal vomiting often goes undiagnosed, especially in children, causing treatment delays. An ictal origin should be considered, particularly when the episodes are recurrent and stereotyped. [Published with video sequences].
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- 2020
8. Graph theory in paediatric epilepsy: A systematic review
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Raffaele, Falsaperla, Giovanna, Vitaliti, Simona Domenica, Marino, Andrea Domenico, Praticò, Janette, Mailo, Michela, Spatuzza, Maria Roberta, Cilio, Rosario, Foti, and Martino, Ruggieri
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Brain Mapping ,Cognition ,Epilepsy ,Neurodevelopmental Disorders ,Brain ,Humans ,Electroencephalography ,Nerve Net ,Child ,Magnetic Resonance Imaging - Abstract
Graph theoretical studies have been designed to investigate network topologies during life. Network science and graph theory methods may contribute to a better understanding of brain function, both normal and abnormal, throughout developmental stages. The degree to which childhood epilepsies exert a significant effect on brain network organisation and cognition remains unclear. The hypothesis suggests that the formation of abnormal networks associated with epileptogenesis early in life causes a disruption in normal brain network development and cognition, reflecting abnormalities in later life. Neurological diseases with onset during critical stages of brain maturation, including childhood epilepsy, may threaten this orderly neurodevelopmental process. According to the hypothesis that the formation of abnormal networks associated with epileptogenesis in early life causes a disruption in normal brain network development, it is then mandatory to perform a proper examination of children with new-onset epilepsy early in the disease course and a deep study of their brain network organisation over time. In regards, graph theoretical analysis could add more information. In order to facilitate further development of graph theory in childhood, we performed a systematic review to describe its application in functional dynamic connectivity using electroencephalographic (EEG) analysis, focussing on paediatric epilepsy.
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- 2022
9. Neonatal presentation of genetic epilepsies: Early differentiation from acute provoked seizures
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Adam L. Numis, Valeria Morabito, Hannah C. Glass, Tristan T. Sands, Susana Ferrao Santos, Damien Lederer, Marie-Coralie Cornet, Maria Roberta Cilio, Donna M. Ferriero, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de neurologie, UCL - (SLuc) Service de neurologie pédiatrique, UCL - (SLuc) Centre de référence pour l'épilepsie réfractaire, and UCL - (SLuc) Centre des maladies neuro-cutanées congénitales
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0301 basic medicine ,tonic ,Pediatrics ,Potassium Channels ,Electroencephalography ,Potassium Channels, Sodium-Activated ,Neurodegenerative ,Epilepsy ,0302 clinical medicine ,Child ,Stroke ,Pediatric ,medicine.diagnostic_test ,BRAT1 ,Brain ,Neurology ,Hypoxia-Ischemia, Brain ,Neurological ,video-EEG ,Sodium-Activated ,Adult ,medicine.medical_specialty ,semiology ,Clinical Sciences ,Nerve Tissue Proteins ,Neonatal onset ,03 medical and health sciences ,Seizures ,Intensive care ,Hypoxia-Ischemia ,medicine ,Genetics ,Tonic (music) ,Humans ,Retrospective Studies ,Neurology & Neurosurgery ,business.industry ,Infant, Newborn ,Neurosciences ,Infant ,medicine.disease ,Newborn ,neonates ,Brain Disorders ,030104 developmental biology ,Good Health and Well Being ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,PRRT2 - Abstract
Author(s): Cornet, Marie-Coralie; Morabito, Valeria; Lederer, Damien; Glass, Hannah C; Ferrao Santos, Susana; Numis, Adam L; Ferriero, Donna M; Sands, Tristan T; Cilio, Maria Roberta | Abstract: ObjectiveAlthough most seizures in neonates are due to acute brain injury, some represent the first sign of neonatal onset genetic epilepsies. Delay in recognition and lack of expert assessment of neonates with epilepsy may result in worse developmental outcomes. As in older children and adults, seizure semiology in neonates is an essential determinant in diagnosis. We aimed to establish whether seizure type at presentation in neonates can suggest a genetic etiology.MethodsWe retrospectively analyzed the clinical and electroencephalographic (EEG) characteristics of seizures in neonates admitted in two Level IV neonatal intensive care units, diagnosed with genetic epilepsy, for whom a video-EEG recording at presentation was available for review, and compared them on a 1:2 ratio with neonates with seizures due to stroke or hypoxic-ischemic encephalopathy.ResultsTwenty neonates with genetic epilepsy were identified and compared to 40 neonates with acute provoked seizures. Genetic epilepsies were associated with pathogenic variants in KCNQ2 (nn=n12), KCNQ3 (nn=n2), SCN2A (nn=n2), KCNT1 (nn=n1), PRRT2 (nn=n1), and BRAT1 (nn=n2). All neonates with genetic epilepsy had seizures with clinical correlates that were either tonic (18/20) or myoclonic (2/20). In contrast, 17 of 40 (42%) neonates with acute provoked seizures had electrographic only seizures, and the majority of the remainder had clonic seizures. Time to first seizure was longer in neonates with genetic epilepsies (median = 60nh of life) compared to neonates with acute provoked seizures (median = 15nh of life, pnln.001). Sodium channel-blocking antiseizure medications were effective in 13 of 14 (92%) neonates with tonic seizures who were trialed at onset or during the course of the epilepsy.SignificanceSeizure semiology is an easily accessible sign of genetic epilepsies in neonates. Early identification of the seizure type can prompt appropriate workup and treatment. Tonic seizures are associated with channelopathies and are often controlled by sodium channel-blocking antiseizure medications.
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- 2021
10. Disorders of Neuronal Migration/Organization Convey the Highest Risk of Neonatal Onset Epilepsy Compared With Other Congenital Brain Malformations
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James Barkovich, Elizabeth E. Rogers, Orit A. Glenn, Hannah C. Glass, Roxanne Simmons, Ariadna Borras Martinez, Adam L. Numis, Maria Roberta Cilio, Dawn Gano, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Centre de référence pour l'épilepsie réfractaire, and UCL - (SLuc) Département de pédiatrie
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Male ,Pediatrics ,medicine.medical_specialty ,Encephalopathy ,Antiseizure medication (ASM) ,Neonatal onset ,Neonatal encephalopathy ,Electroencephalography ,Nervous System Malformations ,Hypoxic Ischemic Encephalopathy ,Infant, Newborn, Diseases ,Congenital abnormalities ,Epilepsy ,Developmental Neuroscience ,Cell Movement ,Neurocritical care ,medicine ,Prevalence ,Humans ,EEG ,Retrospective Studies ,medicine.diagnostic_test ,business.industry ,Infant, Newborn ,Neurointensive care ,Brain ,Retrospective cohort study ,Neonatal seizures ,medicine.disease ,Seizure ,Electroencephalogram ,Neurology ,Pediatrics, Perinatology and Child Health ,Female ,Neurology (clinical) ,business - Abstract
Although seizures in neonates are common and often due to acute brain injury, 10-15% are unprovoked from congenital brain malformations. A better understanding of the risk of neonatal-onset epilepsy by the type of brain malformation is essential for counseling and monitoring. In this retrospective cohort study, we evaluated 132 neonates with congenital brain malformations and their risk of neonatal-onset epilepsy. Malformations were classified into one of five categories based on imaging patterns on prenatal or postnatal imaging. Infants were monitored with continuous video EEG (cEEG) for encephalopathy and paroxysmal events in addition to abnormal neuroimaging. Seventy-four of 132 (56%) neonates underwent EEG monitoring, and 18 of 132 (14%) were diagnosed with neonatal-onset epilepsy. The highest prevalence of epilepsy was in neonates with disorders of neuronal migration/organization (9/34, 26%; 95% confidence interval [CI] = 13-44%), followed by disorders of early prosencephalic development (6/38, 16%; 95% CI = 6-31%), complex total brain malformations (2/16, 13%; 95% CI = 2-38%), and disorders of midbrain/hindbrain malformations (1/30, 3%; 95% CI = 0-17%). Of neonates with epilepsy, 5 of 18 (28%) had only electrographic seizures, 13 of 18 (72%) required treatment with two or more antiseizure medicines (ASMs), and 7 of 18 (39%) died within the neonatal period. Our results demonstrate that disorders of neuronal migration/organization represent the highest-risk group for early-onset epilepsy. Seizures are frequently electrographic only, require treatment with multiple ASMs, and portend a high mortality rate. These results support American Clinical Neurophysiology Society recommendations for EEG monitoring during the neonatal period for infants with congenital brain malformations.
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- 2021
11. A Novel Kv7.3 Variant in the Voltage-Sensing S
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Francesco, Miceli, Lidia, Carotenuto, Vincenzo, Barrese, Maria Virginia, Soldovieri, Erin L, Heinzen, Arthur M, Mandel, Natalie, Lippa, Louise, Bier, David B, Goldstein, Edward C, Cooper, Maria Roberta, Cilio, Maurizio, Taglialatela, and Tristan T, Sands
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Pathogenic variants in
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- 2020
12. A Novel Kv7.3 Variant in the Voltage-Sensing S4 Segment in a Family With Benign Neonatal Epilepsy: Functional Characterization and in vitro Rescue by β-Hydroxybutyrate
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Francesco Miceli, Lidia Carotenuto, Vincenzo Barrese, Maria Virginia Soldovieri, Erin L. Heinzen, Arthur M. Mandel, Natalie Lippa, Louise Bier, David B. Goldstein, Edward C. Cooper, Maria Roberta Cilio, Maurizio Taglialatela, Tristan T. Sands, Miceli, F., Carotenuto, L., Barrese, V., Soldovieri, M. V., Heinzen, E. L., Mandel, A. M., Lippa, N., Bier, L., Goldstein, D. B., Cooper, E. C., Cilio, M. R., Taglialatela, M., and Sands, T. T.
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0301 basic medicine ,Physiology ,Biology ,lcsh:Physiology ,Loss of heterozygosity ,03 medical and health sciences ,KCNQ ,0302 clinical medicine ,Physiology (medical) ,Missense mutation ,Homomeric ,BFNE ,channelopathies ,encephalopathy ,ketogenic diet ,Exome sequencing ,Genetics ,lcsh:QP1-981 ,Genetic heterogeneity ,Chinese hamster ovary cell ,channelopathie ,Phenotype ,Transmembrane domain ,030104 developmental biology ,030217 neurology & neurosurgery - Abstract
Pathogenic variants in KCNQ2 and KCNQ3, paralogous genes encoding Kv7.2 and Kv7.3 voltage-gated K+ channel subunits, are responsible for early−onset developmental/epileptic disorders characterized by heterogeneous clinical phenotypes ranging from benign familial neonatal epilepsy (BFNE) to early−onset developmental and epileptic encephalopathy (DEE). KCNQ2 variants account for the majority of pedigrees with BFNE and KCNQ3 variants are responsible for a much smaller subgroup, but the reasons for this imbalance remain unclear. Analysis of additional pedigrees is needed to further clarify the nature of this genetic heterogeneity and to improve prediction of pathogenicity for novel variants. We identified a BFNE family with two siblings and a parent affected. Exome sequencing on samples from both parents and siblings revealed a novel KCNQ3 variant (c.719T>G; p.M240R), segregating in the three affected individuals. The M240 residue is conserved among human Kv7.2-5 and lies between the two arginines (R5 and R6) closest to the intracellular side of the voltage-sensing S4 transmembrane segment. Whole cell patch-clamp recordings in Chinese hamster ovary (CHO) cells revealed that homomeric Kv7.3 M240R channels were not functional, whereas heteromeric channels incorporating Kv7.3 M240R mutant subunits with Kv7.2 and Kv7.3 displayed a depolarizing shift of about 10 mV in activation gating. Molecular modeling results suggested that the M240R substitution preferentially stabilized the resting state and possibly destabilized the activated state of the Kv7.3 subunits, a result consistent with functional data. Exposure to β-hydroxybutyrate (BHB), a ketone body generated during the ketogenic diet (KD), reversed channel dysfunction induced by the M240R variant. In conclusion, we describe the first missense loss-of-function (LoF) pathogenic variant within the S4 segment of Kv7.3 identified in patients with BFNE. Studied under conditions mimicking heterozygosity, the M240R variant mainly affects the voltage sensitivity, in contrast to previously analyzed BFNE Kv7.3 variants that reduce current density. Our pharmacological results provide a rationale for the use of KD in patients carrying LoF variants in Kv7.2 or Kv7.3 subunits.
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- 2020
13. The ClinGen Epilepsy Gene Curation Expert Panel—Bridging the divide between clinical domain knowledge and formal gene curation criteria
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Rebecca K. Siegert, Carrie Anne Barry, Kristen Park, Maria Roberta Cilio, Bekim Sadikovic, Ghayda M. Mirzaa, David A. Dyment, Ingo Helbig, Annapurna Poduri, Tristan T. Sands, Karl Martin Klein, Courtney Thaxton, Jacy L. Wagnon, Erin Rooney Riggs, Erika Axeen, Pasquale Striano, Tanya Bardakjian, Katherine L. Helbig, Heather C Mefford, Elizabeth Butler, Khalida Liaquat, Andrew R. Grant, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service de neurologie pédiatrique
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ClinGen/Clinical Genome Resource ,0301 basic medicine ,Disease ,Computational biology ,Biology ,Article ,gene–disease association ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,clinical validity ,Genetics ,medicine ,Humans ,Genetic Testing ,epilepsy ,epileptic encephalopathy ,Gene ,Genetics (clinical) ,Genetic testing ,Disease entity ,medicine.diagnostic_test ,medicine.disease ,Phenotype ,030104 developmental biology ,Gene selection ,Seizure Disorders ,Mutation ,Gene-disease association ,Domain knowledge ,030217 neurology & neurosurgery - Abstract
The field of epilepsy genetics is advancing rapidly and epilepsy is emerging as a frequent indication for diagnostic genetic testing. Within the larger ClinGen framework, the ClinGen Epilepsy Gene Curation Expert Panel is tasked with connecting two increasingly separate fields: the domain of traditional clinical epileptology, with its own established language and classification criteria, and the rapidly evolving area of diagnostic genetic testing that adheres to formal criteria for gene and variant curation. We identify critical components unique to the epilepsy gene curation effort, including: (1) precise phenotype definitions within existing disease and phenotype ontologies; (2) consideration of when epilepsy should be curated as a distinct disease entity; (3) strategies for gene selection; and (4) emerging rules for evaluating functional models for seizure disorders. Given that de novo variants play a prominent role in many of the epilepsies, sufficient genetic evidence is often awarded early in the curation process. Therefore, the emphasis of gene curation is frequently shifted towards an iterative precuration process to better capture phenotypic associations. We demonstrate that within the spectrum of neurodevelopmental disorders, gene curation for epilepsy-associated genes is feasible and suggest epilepsy-specific conventions, laying the groundwork for a curation process of all major epilepsy-associated genes.
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- 2018
14. Neonatal epilepsies: Clinical management
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Tristan T. Sands, Marie-Coralie Cornet, and Maria Roberta Cilio
- Subjects
0301 basic medicine ,Epilepsy ,business.industry ,Infant, Newborn ,Lissencephaly ,Electroencephalography ,Symptomatic seizures ,Cortical dysplasia ,Gene mutation ,medicine.disease ,Bioinformatics ,Magnetic Resonance Imaging ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Pathognomonic ,Pediatrics, Perinatology and Child Health ,Etiology ,Humans ,Medicine ,STXBP1 ,Anticonvulsants ,business ,030217 neurology & neurosurgery - Abstract
Whereas the majority of seizures in neonates are related to acute brain injury, a substantial minority are the first symptom of a neonatal-onset epilepsy, often linked to a pathogenic genetic variant. This defect may disrupt cortical development (e.g., lissencephaly, focal cortical dysplasia), lead to metabolic changes (e.g., pyridoxine-dependent epilepsy, sulfite oxidase deficiency) or lead to cortical dysfunction without metabolic or macroscopic structural changes (e.g., channelopathies, STXBP1). Historically, studies on treatment response and long-term consequences of neonatal seizures have lumped all etiologies together. However, etiology has been consistently shown to be the most important determinant of outcome. Here, we address the elements differentiating neonatal-onset epilepsies from acute symptomatic seizures. We review some common neonatal-onset epilepsies and emphasize how pathognomonic electro-clinical phenotypes such as the ones associated with KCNQ2 or KCNT1 gene mutation, when recognized early, can lead to targeted diagnostic testing and precision medicine treatment, enabling the possibility of improved outcome.
- Published
- 2018
15. Profile of neonatal epilepsies
- Author
-
Shavonne L. Massey, Courtney J. Wusthoff, Hannah C. Glass, Maria Roberta Cilio, Nicholas S. Abend, Renée A. Shellhaas, Janet S. Soul, Catherine J. Chu, Tammy N. Tsuchida, and Natrujee Wiwattanadittakun
- Subjects
Pediatrics ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Benign neonatal seizures ,Symptomatic seizures ,medicine.disease ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,030225 pediatrics ,Cohort ,medicine ,Etiology ,Neurology (clinical) ,business ,Prospective cohort study ,Neonatal seizure ,030217 neurology & neurosurgery ,Genetic testing - Abstract
Objective:Although individual neonatal epilepsy syndromes are rare, as a group they represent a sizable subgroup of neonatal seizure etiologies. We evaluated the profile of neonatal epilepsies in a prospective cohort of newborns with seizures.Methods:Consecutive newborns with seizures were enrolled in the Neonatal Seizure Registry (an association of 7 US children's hospitals). Treatment and diagnostic testing were at the clinicians' discretion. Neonates with seizures related to epileptic encephalopathies (without structural brain abnormalities), brain malformations, or benign familial epilepsies were included in this analysis.Results:Among 611 consecutive newborns with seizures, 79 (13%) had epilepsy (35 epileptic encephalopathy, 32 congenital brain malformations, 11 benign familial neonatal epilepsy [BFNE], 1 benign neonatal seizures). Twenty-nine (83%) with epileptic encephalopathy had genetic testing and 24/29 (83%) had a genetic etiology. Pathogenic or likely pathogenic KCNQ2 variants (n = 10) were the most commonly identified etiology of epileptic encephalopathy. Among 23 neonates with brain malformations who had genetic testing, 7 had putative genetic etiologies. Six infants with BFNE had genetic testing; 3 had pathogenic KCNQ2 variants and 1 had a pathogenic KCNQ3 variant. Comorbid illnesses that predisposed to acute symptomatic seizures occurred in 3/35 neonates with epileptic encephalopathy vs 10/32 with brain malformations (p = 0.03). Death or discharge to hospice were more common among newborns with brain malformations (11/32) than those with epileptic encephalopathy (3/35, p = 0.01).Conclusions:Neonatal epilepsy is often due to identifiable genetic causes. Genetic testing is now warranted for newborns with epilepsy in order to guide management and inform discussions of prognosis.
- Published
- 2017
16. A Distinctive Ictal Amplitude-Integrated Electroencephalography Pattern in Newborns with Neonatal Epilepsy Associated with KCNQ2 Mutations
- Author
-
Pasquale Striano, Linda S. de Vries, Maria Roberta Cilio, Ana Vilan, Lauren C. Weeke, José Mendes Ribeiro, Eva H. Brilstra, and Sarah Weckhuysen
- Subjects
Pediatrics ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Apnea ,Carbamazepine ,Electroencephalography ,medicine.disease ,Amplitude integrated electroencephalography ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,030225 pediatrics ,Pediatrics, Perinatology and Child Health ,medicine ,Etiology ,Ictal ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Developmental Biology ,medicine.drug ,Genetic testing - Abstract
Background: Recurrent and prolonged seizures are harmful for the developing brain, emphasizing the importance of early seizure recognition and effective therapy. Amplitude-integrated electroencephalography (aEEG) has become a valuable tool to diagnose epileptic seizures, and, in parallel, genetic etiologies are increasingly being recognized, changing the paradigm of the workup and management of neonatal seizures. Objective: To report the ictal aEEG pattern in neonates with KCNQ2-related epilepsy. Subjects and Methods: In this multicenter descriptive study, clinical data and aEEG findings of 9 newborns with KCNQ2 mutations are reported. Results: Refractory seizures occurred in the early neonatal period with similar seizure type, including tonic features, apnea, and desaturation. A distinct aEEG seizure pattern, consisting of a sudden rise of the lower and upper margin of the aEEG, followed by a marked depression of the aEEG amplitude, was found in 8 of the 9 patients. Prompt recognition of this pattern led to early treatment with carbamazepine in the 2 most recent cases. Conclusion: Early recognition of the electroclinical phenotype by using aEEG may direct genetic testing and a precision medicine approach with sodium channel blockers in neonates with KCNQ2 mutations.
- Published
- 2017
17. Rapid and safe response to low-dose carbamazepine in neonatal epilepsy
- Author
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Maurizio Taglialatela, Maria Roberta Cilio, Martina Balestri, Giulia Bellini, Olivier Danhaive, Gregory L. Holmes, Michael S. Oldham, Sarah B. Mulkey, Eliza Hayes Bakken, Tristan T. Sands, Federico Vigevano, Sands, Tristan T, Balestri, Martina, Bellini, Giulia, Mulkey, Sarah B, Danhaive, Olivier, Bakken, Eliza Haye, Taglialatela, Maurizio, Oldham, Michael S, Vigevano, Federico, Holmes, Gregory L, and Cilio, Maria Roberta
- Subjects
Male ,0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Potassium Channels ,Oxcarbazepine ,Gestational Age ,Status epilepticus ,Electroencephalography ,03 medical and health sciences ,0302 clinical medicine ,Benign familial neonatal epilepsy ,medicine ,Humans ,Benign familial neonatal seizures ,Family history ,Neonatal seizure ,KCNQ2 ,Family Health ,KCNQ3 ,NAV1.2 Voltage-Gated Sodium Channel ,medicine.diagnostic_test ,business.industry ,Infant ,Apnea ,Gestational age ,Carbamazepine ,medicine.disease ,Magnetic Resonance Imaging ,Epilepsy, Benign Neonatal ,030104 developmental biology ,Neurology ,Child, Preschool ,Anesthesia ,Mutation ,Anticonvulsants ,Female ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Follow-Up Studies ,medicine.drug - Abstract
SummaryObjective To evaluate treatment responses in benign familial neonatal epilepsy (BFNE). Methods We recruited patients with BFNE through a multicenter international collaboration and reviewed electroclinical and genetic details, and treatment response. All patients were tested at minimum for mutations/deletions in the KCNQ2, KCNQ3, and SCN2A genes. Results Nineteen patients were included in this study. A family history of neonatal seizures was positive in 16 patients, and one additional patient had a family history of infantile seizures. Mutations or deletions of KCNQ2 were found in 14, and of KCNQ3 in 2, of the 19 patients. In all patients, seizures began at 2–5 days of life and occurred multiple times per day. Four patients developed status epilepticus. Seizures were focal, alternating between hemispheres, and characterized by asymmetric tonic posturing associated with apnea and desaturation, followed by unilateral or bilateral asynchronous clonic jerking. Twelve of 19 patients were treated with multiple medications prior to seizure cessation. Seventeen of (88%) 19 patients were seizure-free within hours of receiving oral carbamazepine (CBZ) or oxcarbazepine (OXC). Earlier initiation of CBZ was associated with shorter hospitalization (p < 0.01). No side effects of CBZ were reported. All patients had normal development and remain seizure-free at a mean follow-up period of 7.8 years (6 months–16 years). Significance This study provides evidence that CBZ is safe and rapidly effective in neonates with BFNE, even in status epilepticus. We propose that CBZ should be the drug of choice in benign familial neonatal seizures.
- Published
- 2016
18. Genetics of neonatal-onset epilepsies
- Author
-
Marie-Coralie, Cornet and Maria Roberta, Cilio
- Subjects
Adult ,Epilepsy ,Pregnancy ,Mutation ,Infant, Newborn ,Humans ,KCNQ2 Potassium Channel ,Female ,Nerve Tissue Proteins ,Potassium Channels, Sodium-Activated ,Infant, Newborn, Diseases - Abstract
Although the majority of seizures in neonates are related to acute brain injury, a substantial minority are the first symptom of a neonatal-onset epilepsy often linked to a pathogenic genetic variant. Historically, studies on neonatal seizures including treatment response and long-term consequences have lumped all etiologies together. However, etiology has been consistently shown to be the most important determinant of outcome. In the past few years, an increasing number of monogenic disorders have been described and might explain up to a third of neonatal-onset epilepsy syndromes previously included under the umbrella of Ohtahara syndrome and early myoclonic encephalopathy. In this chapter, we define the concept of genetic epilepsy and review the classification. Then, we review the most relevant monogenic neonatal-onset epilepsies, detail their underlying pathophysiologic mechanisms, and present their electroclinical phenotypes. We highlight that, in some cases, such as neonates with KCNQ2 or KCNT1 gene mutations, the early recognition of the electroclinical phenotype can lead to targeted diagnostic testing and precision medicine treatment, enabling the possibility of improved outcome.
- Published
- 2019
19. Neonatal Genetic Epilepsies: Electroclinical Phenotypes and Basic Mechanisms
- Author
-
Charbel El Kosseifi and Maria-Roberta Cilio
- Subjects
Genetics - Published
- 2019
20. Response to cannabidiol in epilepsy of infancy with migrating focal seizures associated with KCNT1 mutations: An open-label, prospective, interventional study
- Author
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Kelsey Poisson, Chon Lee, Maria Roberta Cilio, Matthew Wong, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service de neurologie pédiatrique
- Subjects
Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Nerve Tissue Proteins ,Potassium Channels, Sodium-Activated ,law.invention ,Treatment resistant epilepsy ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,Dravet syndrome ,Randomized controlled trial ,law ,Seizures ,030225 pediatrics ,medicine ,Cannabidiol ,Humans ,Prospective Studies ,Epilepsy of infancy with migrating focal seizures ,Seizure frequency ,business.industry ,Epileptic encephalopathy ,Infant ,General Medicine ,medicine.disease ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Mutation ,Anticonvulsants ,Female ,Neurology (clinical) ,Open label ,business ,Epileptic Syndromes ,Spasms, Infantile ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Epilepsy of Infancy with Migrating Focal Seizures (EIMFS) is a rare, developmental and epileptic encephalopathy most commonly associated with mutations in KCNT1, a potassium channel. Polymorphous migrating focal seizures begin within 6 months of life and are pharmacoresistant to standard anticonvulsants. Additional therapies are needed to decrease seizure frequency and subsequent developmental deterioration associated with EIMFS. Cannabidiol (CBD) has recently arisen in public interest due to its potential in treatment-resistant epilepsies as demonstrated in randomized controlled trials for Dravet Syndrome and Lennox-Gastaut Syndrome. Here we evaluate the response of three patients, all diagnosed with EIMFS secondary to KCNT1 mutations, to pharmaceutical grade CBD. Two patients showed no benefit and have since voluntarily stopped CBD. One patient showed no overall reduction in seizure frequency, however showed a notable reduction in seizure intensity with possible developmental progression. Further studies are needed to assess the potential benefit of CBD in treatment-resistant epilepsies such as EIMFS, with a focus on early identification and intervention.
- Published
- 2019
21. Neonatal Developmental and Epileptic Encephalopathies
- Author
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Charbel El Kosseifi, Marie-Coralie Cornet, Maria Roberta Cilio, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - SSS/IONS/COSY - Systems & cognitive Neuroscience, and UCL - (SLuc) Service de neurologie pédiatrique
- Subjects
Epilepsy ,Neonatal intensive care unit ,medicine.diagnostic_test ,business.industry ,Encephalopathy ,Infant, Newborn ,Brain ,Infant ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Neuroimaging ,030225 pediatrics ,Pediatrics, Perinatology and Child Health ,medicine ,Humans ,STXBP1 ,Neurology (clinical) ,Early myoclonic encephalopathy ,business ,Neuroscience ,Eeg monitoring ,030217 neurology & neurosurgery ,Genetic testing - Abstract
The new concept of developmental and epileptic encephalopathy is based on the understanding that many genetic epilepsies are associated with developmental impairment as a direct consequence of the genetic mutation, in addition to the effect of the frequent epileptic activity on brain development. As an example, in infants with KCNQ2 or STXBP1 encephalopathy, seizures may be controlled early after onset or cease spontaneously after a few years, but the developmental consequences tend to remain profound. The term "developmental and epileptic encephalopathy" expresses the concept that the genetic defect may be responsible for both the epilepsy and adverse development which is crucial to understanding the disease process for both families and clinicians. The increased use of EEG monitoring, neuroimaging, and metabolic and genetic testing in the Neonatal Intensive Care Unit has greatly improved our understanding of neonatal-onset epilepsies as seen with the syndromes Ohtahara and Early Myoclonic Encephalopathy outlined in the 1970s into distinct etiology-specific electroclinical phenotypes.
- Published
- 2019
22. Preface
- Author
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Jeffrey M. Perlman and Maria Roberta Cilio
- Published
- 2019
23. Toward the elimination of bias in Pediatric Research
- Author
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Sonia L. Bonifacio, Ursula Felderhoff-Müser, James L. Wynn, Frank H. Bloomfield, Nicholas D. Embleton, Nadja Haiden, Namasivayam Ambalavanan, Annemarie Stroustrup, Sidney M. Gospe, Elena Fuentes-Afflick, Kwang Sik Kim, Mark A. Klebanoff, William Gardner, Bruce P. Lanphear, Annamaria Staiano, Dee Wilson-Costello, Seza Ozen, Steven J. Czinn, Peter Lachman, Damian Roland, Max J Coppes, Norman D. Rosenblum, Eleanor J. Molloy, Margaret A. Schwarz, Pierre Gressens, Charles Christoph Roehr, Todd A. Florin, Cynthia F. Bearer, Marissa Hauptman, Maria Roberta Cilio, Dino Guissani, Carlo Agostoni, Enza Maria Valente, Vineet Bhandari, Afif El-Khuffash, Kanwaljeet J. S. Anand, Joseph M. Bliss, Alistair J. Gunn, Irina A. Buhimschi, Donna M. Ferriero, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service de neurologie pédiatrique
- Subjects
Male ,medicine.medical_specialty ,Pediatric research ,MEDLINE ,Publication bias ,Pediatrics ,Sex Factors ,Sex factors ,Family medicine ,Pediatrics, Perinatology and Child Health ,medicine ,Humans ,Female ,Psychology ,Publication Bias - Abstract
There is increasing evidence that unconscious bias can affect realworld decision-making processes in publication just as in many other fields.1 In response, the editorial board of Pediatric Research is working to investigate and reduce the bias in the publication acceptance rates in order to preserve the integrity of the peer review process and publication. As news items have suggested that gender bias is a major problem in academia,2 we reviewed papers submitted between 1 November 2017 and 9 August 2018 to Pediatric Research. Encouragingly, we found that the acceptance rates of manuscripts were not significantly different between corresponding authors who were male or female. However, we incidentally uncovered a higher rejection rate in the manuscripts where the corresponding author had a name that could not be identified as either male or female and did not have a picture on their website so that we could identify their gender.3 It is important to point out that we do not know the reason for this, but its identification is the first step to further exploration, including assessing whether unconscious bias may play a role […]
- Published
- 2019
24. Developmental and epileptic encephalopathy in two siblings with a novel, homozygous missense variant in SCN1B
- Author
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Thoa K. Ha, Eva Barroso, Pierre-Marie Martin, Shannon Rego, Maria Roberta Cilio, Natasha Darras, Anne Slavotinek, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service de neurologie pédiatrique
- Subjects
Male ,Proband ,Developmental and epileptic encephalopathy ,Mutation, Missense ,Biology ,Epilepsy ,Dravet syndrome ,SCN1B ,Exome Sequencing ,Genetics ,medicine ,Humans ,Missense mutation ,Genetic Predisposition to Disease ,Alleles ,Genetic Association Studies ,Genetics (clinical) ,Homozygote ,Electroencephalography ,Voltage-Gated Sodium Channel beta-1 Subunit ,medicine.disease ,Magnetic Resonance Imaging ,Phenotype ,Amino Acid Substitution ,Neurodevelopmental Disorders ,Autism spectrum disorder ,Child, Preschool ,Female ,Generalized epilepsy with febrile seizures plus - Abstract
Developmental and epileptic encephalopathies are genetic disorders in which both the developmental disability and the frequent epileptic activity are the effect of a specific gene variant. While heterozygous variants in SCN1B have been described in families with generalized epilepsy with febrile seizures plus, Type 1, only three cases of homozygous, missense variants in SCN1B have been reported in association with autosomal recessive inheritance of a severe developmental and epileptic encephalopathy. We present two siblings who are homozygous for a novel, missense variant in SCN1B, c.265C>T, predicting p.Arg89Cys. The proband is an 11-year-old female with infantile-onset, fever-induced, intractable generalized tonic-clonic seizures, myoclonic seizures, and developmental slowing and autism spectrum disorder occurring later in the course of the disease. Her 4-year-old brother had a similar epilepsy phenotype, but still displays normal development. This variant has not been previously reported in the homozygous state in control databases. The variant was predicted to be damaging and occurred in the vicinity of other epileptic encephalopathy-associated missense variants that are biallelic and located in the extracellular immunoglobulin loop domain of the protein, which mediates interaction of the beta-1 subunit with cellular adhesion molecules. Our report is the first set of siblings with homozygosity for the p.Arg89Cys variant in SCN1B and further implicates biallelic mutations in this gene as a cause of epileptic encephalopathy mimicking Dravet syndrome. Interestingly, the phenotype we observed was milder compared to that previously described in patients with recessive SCN1B mutations.
- Published
- 2019
25. Neonatal-Onset Epilepsies
- Author
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Tristan T. Sands and Maria Roberta Cilio
- Subjects
Pediatrics ,medicine.medical_specialty ,business.industry ,medicine ,Neonatal onset ,business - Published
- 2019
26. Pharmacokinetics and Tolerability of Multiple Doses of Pharmaceutical-Grade Synthetic Cannabidiol in Pediatric Patients with Treatment-Resistant Epilepsy
- Author
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Steven Sparagana, Neha Parikh, Dennis J. Dlugos, Steven Phillips, Isra Saeed, Maria Roberta Cilio, J. Ben Renfroe, Jin Yu, Colin M. Roberts, D. Alexander Oh, James W. Wheless, Ian Miller, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service de neurologie pédiatrique
- Subjects
Drug Resistant Epilepsy ,medicine.medical_specialty ,Clobazam ,Adolescent ,Administration, Oral ,Gastroenterology ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Internal medicine ,medicine ,Cannabidiol ,Humans ,Pharmacology (medical) ,Original Research Article ,Dosing ,Child ,Adverse effect ,Dose-Response Relationship, Drug ,business.industry ,Infant ,030227 psychiatry ,Psychiatry and Mental health ,Regimen ,Treatment Outcome ,Tolerability ,Child, Preschool ,Concomitant ,Anticonvulsants ,Drug Therapy, Combination ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Background Prior studies have evaluated the use of various constituents of cannabis for their anti-seizure effects. Specifically, cannabidiol, a non-psychoactive component of cannabis, has been investigated for treatment-resistant epilepsy, but more information is needed particularly on its use in a pediatric population. Objective The objective of this study was to evaluate the pharmacokinetics and safety of a synthetic pharmaceutical-grade cannabidiol oral solution in pediatric patients with treatment-resistant epilepsy. Methods In this open-label study, pediatric patients (aged 1 to ≤ 17 years) with treatment-resistant epilepsy received cannabidiol oral solution administered as add-on to their current antiepileptic drug regimen. Patients received a single dose (5, 10, or 20 mg/kg) on day 1 and twice-daily dosing on days 4 through 10 (10-mg/kg [cohort 1], 20-mg/kg [cohort 2], or 40-mg/kg [cohort 3] total daily dose). Serial blood samples were collected on day 1 before dosing and up to 72 h post-dose, and on day 10 before dosing and up to 24 h post-dose. Blood samples to assess trough concentrations of cannabidiol were collected on day 6 (for patients aged 12 to ≤ 17 years), day 8 (for patients aged 2 to ≤ 17 years), and day 9 (for patients aged 6 to ≤ 17 years). Results Overall, 61 patients across three cohorts received one of three doses of cannabidiol oral solution (mean age, 7.6 years). The age composition was similar in the three cohorts. There was a trend for increased cannabidiol exposure with increased cannabidiol oral solution dosing, but overall exposure varied. Approximately 2–6 days of twice-daily dosing provided steady-state concentrations of cannabidiol. A bi-directional drug interaction occurred with cannabidiol and clobazam. Concomitant administration of clobazam with 40 mg/kg/day of cannabidiol oral solution resulted in a 2.5-fold increase in mean cannabidiol exposure. Mean plasma clobazam concentrations were 1.7- and 2.2-fold greater in patients receiving clobazam concomitantly with 40 mg/kg/day of cannabidiol oral solution compared with 10 mg/kg/day and 20 mg/kg/day. Mean plasma norclobazam values were 1.3- and 1.9-fold higher for patients taking clobazam plus 40 mg/kg/day of cannabidiol oral solution compared with the 10-mg/kg/day and 20-mg/kg/day groups. All doses were generally well tolerated, and common adverse events that occurred at > 10% were somnolence (21.3%), anemia (18.0%), and diarrhea (16.4%). Conclusions Inter-individual variability in systemic cannabidiol exposure after pediatric patient treatment with cannabidiol oral solution was observed but decreased with multiple doses. Short-term administration was generally safe and well tolerated. Trial Registration ClinicalTrials.gov (NCT02324673). Electronic supplementary material The online version of this article (10.1007/s40263-019-00624-4) contains supplementary material, which is available to authorized users.
- Published
- 2019
27. Augmented Reticular Thalamic Bursting and Seizures in Scn1a-Dravet Syndrome
- Author
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Jeanne T. Paz, Stefanie Ritter-Makinson, Freek E. Hoebeek, Oscar H J Eelkman Rooda, Eric Bennett, Alexandra Clemente-Perez, Kazuhiro Yamakawa, Frances S. Cho, Ana Chkhaidze, Bruno Delord, Bryan Higashikubo, Marie-Coralie Cornet, Maria Roberta Cilio, Stephanie S. Holden, UCL - SSS/IONS/COSY - Systems & cognitive Neuroscience, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de pédiatrie générale, UCL - (SLuc) Service de neurologie pédiatrique, Neurosciences, and Neurosurgery
- Subjects
0301 basic medicine ,Intellectual and Developmental Disabilities (IDD) ,Medical Physiology ,Optogenetics ,Neurodegenerative ,Epilepsies ,Scn1a ,Inhibitory postsynaptic potential ,General Biochemistry, Genetics and Molecular Biology ,Article ,SK channel ,Thalamocortical oscillations ,Epilepsy ,Bursting ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Dravet syndrome ,Thalamus ,SK current ,Seizures ,medicine ,2.1 Biological and endogenous factors ,Animals ,Humans ,Aetiology ,Loss function ,030304 developmental biology ,0303 health sciences ,Chemistry ,Animal ,Nav1.1 ,Neurosciences ,Thalamocortical circuits ,medicine.disease ,Reticular thalamic nucleus ,Brain Disorders ,030104 developmental biology ,Reticular connective tissue ,Neurological ,Disease Models ,Biochemistry and Cell Biology ,Myoclonic ,Neuroscience ,030217 neurology & neurosurgery - Abstract
SUMMARY Loss of function in the Scn1a gene leads to a severe epileptic encephalopathy called Dravet syndrome (DS). Reduced excitability in cortical inhibitory neurons is thought to be the major cause of DS seizures. Here, in contrast, we show enhanced excitability in thalamic inhibitory neurons that promotes the non-convulsive seizures that are a prominent yet poorly understood feature of DS. In a mouse model of DS with a loss of function in Scn1a, reticular thalamic cells exhibited abnormally long bursts of firing caused by the downregulation of calcium-activated potassium SK channels. Our study supports a mechanism in which loss of SK activity causes the reticular thalamic neurons to become hyperexcitable and promote non-convulsive seizures in DS. We propose that reduced excitability of inhibitory neurons is not global in DS and that non-GABAergic mechanisms such as SK channels may be important targets for treatment., Graphical Abstract, In Brief In a mouse model of Dravet syndrome (DS) resulting from voltage-gated sodium channel deficiency, Ritter-Makinson et al. find that inhibitory neurons of the reticular thalamic nucleus are paradoxically hyperexcitable due to compensatory reductions in a potassium SK current. Boosting this SK current treats nonconvulsive seizures in DS mice.
- Published
- 2019
28. Contributors
- Author
-
Enrico Bertini, Adrienne Bingham, Vann Chau, Maria Roberta Cilio, Adele D’Amico, Linda S. de Vries, Donna M. Ferriero, Dawn Gano, Torin J.A. Glass, Nazia Kabani, Ericalyn Kasdorf, David Kaufman, David W. Kimberlin, Abbot R. Laptook, Jean-Baptiste Le Pichon, Neil Marlow, Claire McLean, Shahab Noori, Jeffrey M. Perlman, Francesco Pisani, Sean M. Riordan, Pablo J. Sánchez, Tristan T. Sands, Michael Seed, Istvan Seri, Steven M. Shapiro, Carlotta Spagnoli, Mona C. Toet, Lauren C. Weeke, Tai Wei-Wu, Andrew Whitelaw, Jerome Y. Yager, Vivien Yap, and Santina Zanelli
- Published
- 2019
29. Genetics of neonatal-onset epilepsies
- Author
-
Maria Roberta Cilio and Marie-Coralie Cornet
- Subjects
0301 basic medicine ,Ohtahara syndrome ,BRAT1 ,business.industry ,CDKL5 ,Neonatal onset ,Gene mutation ,medicine.disease ,Bioinformatics ,03 medical and health sciences ,Epilepsy ,030104 developmental biology ,0302 clinical medicine ,Epilepsy syndromes ,medicine ,business ,Early myoclonic encephalopathy ,030217 neurology & neurosurgery - Abstract
Although the majority of seizures in neonates are related to acute brain injury, a substantial minority are the first symptom of a neonatal-onset epilepsy often linked to a pathogenic genetic variant. Historically, studies on neonatal seizures including treatment response and long-term consequences have lumped all etiologies together. However, etiology has been consistently shown to be the most important determinant of outcome. In the past few years, an increasing number of monogenic disorders have been described and might explain up to a third of neonatal-onset epilepsy syndromes previously included under the umbrella of Ohtahara syndrome and early myoclonic encephalopathy. In this chapter, we define the concept of genetic epilepsy and review the classification. Then, we review the most relevant monogenic neonatal-onset epilepsies, detail their underlying pathophysiologic mechanisms, and present their electroclinical phenotypes. We highlight that, in some cases, such as neonates with KCNQ2 or KCNT1 gene mutations, the early recognition of the electroclinical phenotype can lead to targeted diagnostic testing and precision medicine treatment, enabling the possibility of improved outcome.
- Published
- 2019
30. Long-Term Safety, Tolerability, and Efficacy of Cannabidiol in Children with Refractory Epilepsy: Results from an Expanded Access Program in the US
- Author
-
Maria Roberta Cilio, Michael S. Oldham, Shahryar Rahdari, Eduardo Caminha Nunes, Nicole Tilton, Tristan T. Sands, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service de neurologie pédiatrique
- Subjects
Male ,medicine.medical_specialty ,Adolescent ,Status epilepticus ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,Status Epilepticus ,Weight loss ,Seizures ,Internal medicine ,Medicine ,Cannabidiol ,Humans ,Pharmacology (medical) ,Prospective Studies ,Adverse effect ,Child ,business.industry ,Seizure types ,Valproic Acid ,Infant ,medicine.disease ,United States ,030227 psychiatry ,Psychiatry and Mental health ,Treatment Outcome ,Tolerability ,Expanded access ,Child, Preschool ,Anticonvulsants ,Drug Therapy, Combination ,Female ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
BACKGROUND: Purified cannabidiol is a new antiepileptic drug that has recently been approved for use in patients with Lennox-Gastaut and Dravet syndromes, but most published studies have not extended beyond 12-16 weeks. OBJECTIVE: The objective of this study was to evaluate the long-term safety, tolerability, and efficacy of cannabidiol in children with epilepsy. METHODS: Patients aged 1-17 years with refractory epilepsy were enrolled in an open-label prospective study through individual patient and expanded access programs between April 2013 and December 2014. Seizure types were video-electroencephalogram confirmed prior to enrollment. After a 28-day evaluation period, during which baseline seizure frequency was assessed, cannabidiol was given as add-on therapy at 5 mg/kg/day and titrated weekly by 5-mg/kg increments to a dose of 25 mg/kg/day. Blood tests were performed at baseline, after 1, 2, and 3 months, and every 3 months thereafter. Trough concentrations of concomitant antiepileptic drugs were measured at baseline, after 1, 2, and 3 months of therapy, and as clinically indicated afterwards. Concomitant antiepileptic drugs, ketogenic diet ratio, and vagal nerve stimulator settings remained unchanged during the baseline period and the first 3 months of treatment, unless there was a significant increase in plasma concentrations. Seizure frequency was reported daily in seizure diaries by parents or caregivers. Clinical assessments occurred after 15 days of treatment, at 1 month, at 3 months, and every 3 months thereafter. Diaries of seizure frequency and adverse events were reviewed at each visit. The primary efficacy outcome was a reduction in seizure frequency and responders were defined as those patients achieving a > 50% reduction in motor seizures. RESULTS: Twenty-six children were enrolled. Most had genetic epilepsies with daily or weekly seizures and multiple seizure types. All were refractory to prior antiepileptic drugs (range 4-11, mean 7), and were taking two antiepileptic drugs on average. Duration of therapy ranged from 4 to 53 months (mean 21 months). Adverse events were reported in 21 patients (80.8%), including reduced appetite in ten (38.4%), diarrhea in nine (34.6%), and weight loss in eight (30.7%). Four (15.4%) had changes in antiepileptic drug concentrations and three had elevated aspartate aminotransferase and alanine aminotransferase levels when cannabidiol was administered together with valproate. Serious adverse events, reported in six patients (23.1%), included status epilepticus in three, catatonia in two, and hypoalbuminemia in one. Fifteen patients (57.7%) discontinued cannabidiol for lack of efficacy, one because of status epilepticus, and one for severe weight loss. The retention rate declined rapidly in the first 6 months and more gradually thereafter. At 24 months, the number of patients continuing cannabidiol as adjunctive therapy was nine of the original 26 (34.6%). Of these patients, seven (26.9%) had a sustained > 50% reduction in motor seizures, including three (11.5%) who remain seizure free. CONCLUSION: Over a 4-year period, cannabidiol was effective in 26.9% of children with otherwise refractory epilepsy. It was well tolerated in about 20% of patients, but 80.8% had adverse events, including 23.1% with serious adverse events. Decreased appetite and diarrhea were frequent along with weight loss that became evident only later in the treatment.
- Published
- 2018
31. Genotype-phenotype correlations in patients with de novo KCNQ2 pathogenic variants
- Author
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Maurizio Taglialatela, Elena Freri, Marco Angriman, Maria Margherita Mancardi, Marina Trivisano, Giuseppe Capovilla, Patrizia Accorsi, Ganna Balagura, Paola Martelli, Sarah Weckhuysen, Giuseppe Gobbi, Barbara Castellotti, Angelo Russo, Nicola Specchio, Lino Nobili, Giulio Alberini, Rikke S. Møller, Tiziana Pisano, Maria Stella Vari, Vincenzo Salpietro, Antonella Riva, Carla Marini, Antonietta Coppola, Fabio Benfenati, Maria Roberta Cilio, Berten Ceulemans, Lucio Giordano, Carlo Minetti, Francesco Miceli, Alberto Verrotti, Federico Zara, Kathrine M. Johannesen, Elena Gennaro, Pasquale Striano, Francesca Madia, Federico Raviglione, Federica Malerba, Luca Maragliano, Elisabetta Amadori, Francesca Marchese, Malerba, Federica, Alberini, Giulio, Balagura, Ganna, Marchese, Francesca, Amadori, Elisabetta, Riva, Antonella, Vari, Maria Stella, Gennaro, Elena, Madia, Francesca, Salpietro, Vincenzo, Angriman, Marco, Giordano, Lucio, Accorsi, Patrizia, Trivisano, Marina, Specchio, Nicola, Russo, Angelo, Gobbi, Giuseppe, Raviglione, Federico, Pisano, Tiziana, Marini, Carla, Mancardi, Maria M, Nobili, Lino, Freri, Elena, Castellotti, Barbara, Capovilla, Giuseppe, Coppola, Antonietta, Verrotti, Alberto, Martelli, Paola, Miceli, Francesco, Maragliano, Luca, Benfenati, Fabio, Cilio, Maria R, Johannesen, Kathrine M, Møller, Rikke S, Ceulemans, Berten, Minetti, Carlo, Weckhuysen, Sarah, Zara, Federico, Taglialatela, Maurizio, and Striano, Pasquale
- Subjects
business.industry ,medicine.disease ,Bioinformatics ,Article ,Optimal management ,Epilepsy ,Atomic resolution ,Cohort ,Intellectual disability ,medicine ,Missense mutation ,In patient ,Human medicine ,Neurology (clinical) ,business ,Genotype-Phenotype Correlations ,Genetics (clinical) - Abstract
ObjectiveEarly identification of de novo KCNQ2 variants in patients with epilepsy raises prognostic issues toward optimal management. We analyzed the clinical and genetic information from a cohort of patients with de novo KCNQ2 pathogenic variants to dissect genotype-phenotype correlations.MethodsPatients with de novo KCNQ2 pathogenic variants were identified from Italy, Denmark, and Belgium. Atomic resolution Kv7.2 structures were also generated using homology modeling to map the variants.ResultsWe included 34 patients with a mean age of 4.7 years. Median seizure onset was 2 days, mainly with focal seizures with autonomic signs. Twenty-two patients (65%) were seizure free at the mean age of 1.2 years. More than half of the patients (17/32) displayed severe/profound intellectual disability; however, 4 (13%) of them had a normal cognitive outcome.A total of 28 de novo pathogenic variants were identified, most missense (25/28), and clustered in conserved regions of the protein; 6 variants recurred, and 7 were novel. We did not identify a relationship between variant position and seizure offset or cognitive outcome in patients harboring missense variants. Besides, recurrent variants were associated with overlapping epilepsy features but also variable evolution regarding the intellectual outcome.ConclusionsWe highlight the complexity of variant interpretation to assess the impact of a class of de novo KCNQ2 mutations. Genetic modifiers could be implicated, but the study paradigms to successfully address the impact of each single mutation need to be developed.
- Published
- 2020
32. Current understanding and neurobiology of epileptic encephalopathies
- Author
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Stéphane Auvin, Annamaria Vezzani, and Maria Roberta Cilio
- Subjects
0301 basic medicine ,Ohtahara syndrome ,Epileptic encephalopathy with continuous spikes and waves during sleep ,Lennox-Gastaut syndrome ,lcsh:RC321-571 ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,Dravet syndrome ,medicine ,Animals ,Humans ,Early myoclonic encephalopathy ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Inflammation ,Infantile spasms ,business.industry ,Epileptic encephalopathy ,Brain ,West Syndrome ,Infantile Spasm ,medicine.disease ,030104 developmental biology ,Neurology ,Epilepsy syndromes ,business ,Neuroscience ,030217 neurology & neurosurgery ,Lennox–Gastaut syndrome - Abstract
Epileptic encephalopathies are a group of diseases in which epileptic activity itself contributes to severe cognitive and behavioral impairments above and beyond what might be expected from the underlying pathology alone. These impairments can worsen over time. This concept has been continually redefined since its introduction. A few syndromes are considered epileptic encephalopathies: early myoclonic encephalopathy and Ohtahara syndrome in the neonatal period, epilepsy of infancy with migrating focal seizures, West syndrome or infantile spasms, Dravet syndrome during infancy, Lennox-Gastaut syndrome, epileptic encephalopathy with continuous spikes-and-waves during sleep, and Landau-Kleffner syndrome during childhood. The inappropriate use of this term to refer to all severe epilepsy syndromes with intractable seizures and severe cognitive dysfunction has led to confusion regarding the concept of epileptic encephalopathy. Here, we review our current understanding of those epilepsy syndromes considered to be epileptic encephalopathies. Genetic studies have provided a better knowledge of neonatal and infantile epilepsy syndromes, while neuroimaging studies have shed light on the underlying causes of childhood-onset epileptic encephalopathies such as Lennox-Gastaut syndrome. Apart from infantile spasm models, we lack animal models to explain the neurobiological mechanisms at work in these conditions. Experimental studies suggest that neuroinflammation may be a common neurobiological pathway that contributes to seizure refractoriness and cognitive involvement in the developing brain.
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- 2016
33. Dynamic action potential clamp predicts functional separation in mild familial and severe de novo forms of SCN2A epilepsy
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Samuel F. Berkovic, Megan Oliva, Maria Roberta Cilio, David I. Kaplan, Katherine B. Howell, Ingrid E. Scheffer, Steven Petrou, Yadeesha H Deerasooriya, and Géza Berecki
- Subjects
0301 basic medicine ,Multidisciplinary ,Seizure types ,business.industry ,Voltage clamp ,Sodium channel ,Neurophysiology ,medicine.disease ,Axon initial segment ,03 medical and health sciences ,Epilepsy ,030104 developmental biology ,0302 clinical medicine ,Clamp ,Medicine ,business ,Neuroscience ,030217 neurology & neurosurgery ,Ion channel - Abstract
De novo variants in SCN2A developmental and epileptic encephalopathy (DEE) show distinctive genotype-phenotype correlations. The two most recurrent SCN2A variants in DEE, R1882Q and R853Q, are associated with different ages and seizure types at onset. R1882Q presents on day 1 of life with focal seizures, while infantile spasms is the dominant seizure type seen in R853Q cases, presenting at a median age of 8 months. Voltage clamp, which characterizes the functional properties of ion channels, predicted gain-of-function for R1882Q and loss-of-function for R853Q. Dynamic action potential clamp, that we implement here as a method for modeling neurophysiological consequences of a given epilepsy variant, predicted that the R1882Q variant would cause a dramatic increase in firing, whereas the R853Q variant would cause a marked reduction in action potential firing. Dynamic clamp was also able to functionally separate the L1563V variant, seen in benign familial neonatal-infantile seizures from R1882Q, seen in DEE, suggesting a diagnostic potential for this type of analysis. Overall, the study shows a strong correlation between clinical phenotype, SCN2A genotype, and functional modeling. Dynamic clamp is well positioned to impact our understanding of pathomechanisms and for development of disease mechanism-targeted therapies in genetic epilepsy.
- Published
- 2018
34. Lack of response to quinidine in KCNT1-related neonatal epilepsy
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Adam L. Numis, Akash R. Patel, Anita N Datta, Umesh Nair, Elena V. Gazina, Steven Petrou, Melody Li, Tristan T. Sands, Maria Roberta Cilio, Michael S. Oldham, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service de neurologie pédiatrique
- Subjects
0301 basic medicine ,Oncology ,Male ,Patch-Clamp Techniques ,KCNT1 ,Xenopus ,Electroencephalography ,Membrane Potentials ,Epilepsy ,0302 clinical medicine ,Cerebrospinal fluid ,Transduction, Genetic ,medicine.diagnostic_test ,Magnetic Resonance Imaging ,Quinidine ,epileptic encephalopathy ,Treatment Outcome ,Neurology ,Child, Preschool ,Anticonvulsants ,Female ,medicine.drug ,medicine.medical_specialty ,precision medicine ,03 medical and health sciences ,In vivo ,Internal medicine ,medicine ,Animals ,Humans ,business.industry ,Oocysts ,Infant ,epilepsy of infancy with migrating focal seizures ,electrophysiology ,medicine.disease ,Blockade ,Electrophysiology ,030104 developmental biology ,Mutagenesis ,Pharmacogenetics ,Mutation ,Neurology (clinical) ,business ,Kv1.1 Potassium Channel ,030217 neurology & neurosurgery ,Follow-Up Studies - Abstract
Objective To evaluate the clinical efficacy and safety of quinidine in patients with KCNT1-related epilepsy of infancy with migrating focal seizures (EIMFS) in the infantile period and to compare with the effect of quinidine on mutant channels in vitro. Methods We identified 4 patients with EIMFS with onset in the neonatal period, pathogenic variants in the KCNT1 gene, and lack of response to AEDs. Patients were prospectively enrolled, treated with quinidine, and monitored according to a predefined protocol. Electroclinical, neuroimaging, and genetic data were reviewed. Two patients had novel variants in the KCNT1 gene that were modeled in Xenopus oocytes with channel properties characterized using electrophysiology recordings. Results Three of four patients were treated with quinidine early in their disease course, prior to 6 months of age. No significant side effects were noted with quinidine therapy. In addition, there were no significant changes in electroencephalography (EEG)-confirmed seizure burden during therapy, and patients had near hourly seizures before, during, and after treatment. Two patients had previously reported gain-of-function mutations, which demonstrated sensitivity to high levels of quinidine in the oocyte assay. Two patients with novel variants, showed characteristic gain-of-function and were thus predicted to be pathogenic. Of interest, these variants were essentially insensitive to high levels of quinidine. Significance Patients had no reported benefit to quinidine therapy despite age at treatment initiation. Pharmacogenetic results in oocytes were consistent with clinical treatment failure in 2 patients, suggesting that single-dose pharmacologic assessment may be helpful in predicting which patients are exceedingly unlikely to achieve benefit with quinidine. In the 2 patients who had a lack of therapeutic benefit despite sensitivity to high concentrations of quinidine with in vitro oocyte assay, it is likely that the achievable exposure levels in the brain were too low to cause significant in vivo channel blockade.
- Published
- 2018
35. Dynamic action potential clamp predicts functional separation in mild familial and severe de novo forms of epilepsy
- Author
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Géza, Berecki, Katherine B, Howell, Yadeesha H, Deerasooriya, Maria Roberta, Cilio, Megan K, Oliva, David, Kaplan, Ingrid E, Scheffer, Samuel F, Berkovic, Steven, Petrou, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service de neurologie pédiatrique
- Subjects
Adult ,Male ,Adolescent ,Genotype ,Action Potentials ,Young Adult ,Seizures ,Humans ,Voltage clamp ,Child ,Dynamic action potential clamp ,Genetic Association Studies ,Brain Diseases ,Epilepsy ,NAV1.2 Voltage-Gated Sodium Channel ,De novo SCN2A mutation ,Infant, Newborn ,Modeling ,Genetic Variation ,Infant ,Phenotype ,PNAS Plus ,Child, Preschool ,Female ,Spasms, Infantile - Abstract
De novo variants in developmental and epileptic encephalopathy (DEE) show distinctive genotype-phenotype correlations. The two most recurrent variants in DEE, R1882Q and R853Q, are associated with different ages and seizure types at onset. R1882Q presents on day 1 of life with focal seizures, while infantile spasms is the dominant seizure type seen in R853Q cases, presenting at a median age of 8 months. Voltage clamp, which characterizes the functional properties of ion channels, predicted gain-of-function for R1882Q and loss-of-function for R853Q. Dynamic action potential clamp, that we implement here as a method for modeling neurophysiological consequences of a given epilepsy variant, predicted that the R1882Q variant would cause a dramatic increase in firing, whereas the R853Q variant would cause a marked reduction in action potential firing. Dynamic clamp was also able to functionally separate the L1563V variant, seen in benign familial neonatal-infantile seizures from R1882Q, seen in DEE, suggesting a diagnostic potential for this type of analysis. Overall, the study shows a strong correlation between clinical phenotype, genotype, and functional modeling. Dynamic clamp is well positioned to impact our understanding of pathomechanisms and for development of disease mechanism-targeted therapies in genetic epilepsy.
- Published
- 2018
36. EEG and the newborn
- Author
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Maria Roberta Cilio
- Subjects
Ohtahara syndrome ,Pediatrics ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Electroencephalography ,Subclinical seizure ,medicine.disease ,Epilepsy ,Anesthesia ,Pediatrics, Perinatology and Child Health ,Epilepsy syndromes ,medicine ,Ictal ,Benign familial neonatal seizures ,Neurology (clinical) ,medicine.symptom ,business ,Early myoclonic encephalopathy - Abstract
Despite the evolution of new technologies for assessing neonatal brain function, electroencephalography (EEG) remains a powerful tool for neurological diagnosis and prognosis in neonates. It is considered the gold standard for distinguishing epileptic seizures from non-epileptic paroxysmal events and for detecting subclinical seizure activity in high-risk babies. In those babies severely ill, EEG is even more efficient as predictive test than the neurological examination. The prognostic value of neonatal EEG has been long recognized in term as well as in preterm infants. Background patterns, more that patterns of ictal discharges, correlate significantly with the long-term outcome. Although most abnormalities on the neonatal EEG are nonspecific, certain patterns can be highly suggestive for diagnosis. Prognostic value can be increased by obtaining early recordings, possibly within the first 48 hr of life, prolonged recordings to include samples of different activity states, and serial EEGs at short intervals to assess rapid changes that are likely to occur in high-risk infants. It is important to distinguish neonatal seizures from neonatal-onset epilepsies and epilepsy syndromes. Both benign and malignant neonatal epilepsy syndromes exist. While benign familial neonatal seizures represents a neonatal syndrome with benign outcome, early myoclonic encephalopathy and Ohtahara syndrome are the earliest form of age-dependent severe epilepsy syndromes. Early myoclonic encephalopathy and Ohtahara syndrome are both characterized by the presence of a burst-suppression EEG pattern. This pattern is usually associated with a poor prognosis and is considered the electroencephalographic correlate of a complete disconnection within the thalamocortical systems. Migrating partial seizures in infancy is a newly recognized epilepsy syndrome whose onset can be in the neonatal period. It is characterized by multifocal intractable seizures associated with psychomotor impairment. No etiology has been found so far. Different drugs currently used in neonatal intensive care unit, especially if in the toxic range, can alter the EEG background. Those effects need to be taken in account in the interpretation of neonatal EEG.
- Published
- 2015
37. A Distinctive Ictal Amplitude-Integrated Electroencephalography Pattern in Newborns with Neonatal Epilepsy Associated with KCNQ2 Mutations
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Ana, Vilan, José, Mendes Ribeiro, Pasquale, Striano, Sarah, Weckhuysen, Lauren C, Weeke, Eva, Brilstra, Linda S, de Vries, and Maria Roberta, Cilio
- Subjects
Portugal ,DNA Mutational Analysis ,Infant, Newborn ,Brain ,Electroencephalography ,Brain Waves ,Infant, Newborn, Diseases ,Carbamazepine ,Phenotype ,Treatment Outcome ,Predictive Value of Tests ,Seizures ,Mutation ,Humans ,KCNQ2 Potassium Channel ,Anticonvulsants ,Genetic Predisposition to Disease ,Netherlands - Abstract
Recurrent and prolonged seizures are harmful for the developing brain, emphasizing the importance of early seizure recognition and effective therapy. Amplitude-integrated electroencephalography (aEEG) has become a valuable tool to diagnose epileptic seizures, and, in parallel, genetic etiologies are increasingly being recognized, changing the paradigm of the workup and management of neonatal seizures.To report the ictal aEEG pattern in neonates with KCNQ2-related epilepsy.In this multicenter descriptive study, clinical data and aEEG findings of 9 newborns with KCNQ2 mutations are reported.Refractory seizures occurred in the early neonatal period with similar seizure type, including tonic features, apnea, and desaturation. A distinct aEEG seizure pattern, consisting of a sudden rise of the lower and upper margin of the aEEG, followed by a marked depression of the aEEG amplitude, was found in 8 of the 9 patients. Prompt recognition of this pattern led to early treatment with carbamazepine in the 2 most recent cases.Early recognition of the electroclinical phenotype by using aEEG may direct genetic testing and a precision medicine approach with sodium channel blockers in neonates with KCNQ2 mutations.
- Published
- 2017
38. Contributors
- Author
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Gregory S. Aaen, Nicholas Scott Abend, Amal Abou-Hamden, Jeffrey C. Allen, Anthony A. Amato, Catherine Amlie-Lefond, Stephen Ashwal, Russell C. Bailey, James F. Bale, Brenda Banwell, Kristin W. Barañano, A. James Barkovich, Richard J. Barohn, Ute K. Bartels, Brenda Bartnik-Olson, Ori Barzilai, Alexander Bassuk, David R. Bearden, Liat Ben-Sira, Timothy J. Bernard, Elizabeth Berry-Kravis, Lauren A. Beslow, Jaclyn A. Biegel, Lori Billinghurst, Angela K. Birnbaum, Joanna S. Blackburn, Nuala Bobowski, Adrienne Boire, Carsten G. Bönnemann, Sonia L. Bonifacio, Daniel J. Bonthius, Breck Borcherding, Brian R. Branchford, John Brandsema, Kathryn M. Brennan, J. Nicholas Brenton, Amy R. Brooks-Kayal, Lawrence W. Brown, Jeffrey Buchalter, Carol S. Camfield, Peter R. Camfield, Cristina Campoy, Jessica L. Carpenter, Taeun Chang, Vann Chau, Susan N. Chi, Claudia A. Chiriboga, Yoon-Jae Cho, Cindy W. Christian, Nicholas Chrestian, Maria Roberta Cilio, Robin D. Clark, Bruce H. Cohen, Ronald D. Cohn, Anne M. Connolly, Todd Constable, Shlomi Constantini, Jeannine M. Conway, David L. Coulter, Tina M. Cowan, Russell C. Dale, Benjamin Darbro, Basil T. Darras, Jahannaz Dastgir, Linda De Meirleir, Darryl C. De Vivo, Linda S. de Vries, Jeremy K. Deisch, Paul Deltenre, Jay Desai, Maria Descartes, Gabrielle deVeber, Sameer C. Dhamne, Jullianne Diaz, Salvatore DiMauro, William B. Dobyns, Dan Doherty, Elizabeth J. Donner, Nico U.F. Dosenbach, James J. Dowling, James M. Drake, Cecile Ejerskov, Andrew G. Engel, Gregory M. Enns, María Victoria Escolano-Margarit, Iris Etzion, S. Ali Fatemi, Darcy L. Fehlings, Michelle Lauren Feinberg, Donna M. Ferriero, Pauline A. Filipek, Richard S. Finkel, Paul G. Fisher, Kevin Flanigan, Nicholas K. Foreman, Israel Franco, Yitzchak Frank, Douglas R. Fredrick, Hudson H. Freeze, Cristina Fuente-Mora, Joseph M. Furman, Renata C. Gallagher, Catherine Garel, Emily Gertsch, Donald L. Gilbert, Elizabeth E. Gilles, Christopher C. Giza, Carol A. Glaser, Hannah C. Glass, Tracy Glauser, Joseph Glykys, Amy Goldstein, Hernan Dario Gonorazky, Rodolfo Gonzalez, Howard P. Goodkin, John M. Graham, Alexander L. Greninger, Gary Gronseth, Andrea L. Gropman, Richard Grundy, Renzo Guerrini, Nalin Gupta, Jin S. Hahn, Milton H. Hamblin, Abeer J. Hani, Sharyu Hanmantgad, Mary J. Harbert, Chellamani Harini, Andrea M. Harriott, Chad Heatwole, Andrew D. Hershey, Deborah G. Hirtz, Gregory L. Holmes, Barbara A. Holshouser, Kathleen A. Hurwitz, Eugene Hwang, Rebecca N. Ichord, Paymaan Jafar-Nejad, Sejal V. Jain, Lori Jordan, Marielle A. Kabbouche, Joanne Kacperski, Peter B. Kang, Matthias A. Kariannis, Horacio Kaufmann, Harper L. Kaye, Robert Keating, Colin R. Kennedy, Yasmin Khakoo, Adam Kirton, John T. Kissel, Kelly G. Knupp, Bruce R. Korf, Eric H. Kossoff, Sanjeev V. Kothare, Oren Kupfer, W. Curt LaFrance, Beatrice Latal, Steven M. Leber, Jean-Pyo Lee, Ilo E. Leppik, Tally Lerman-Sagie, Jason T. Lerner, Richard J. Leventer, Daniel J. Licht, Uta Lichter-Konecki, Zvi Lidar, Djin Gie Liem, Tobias Loddenkemper, Roger K. Long, Quyen N. Luc, Mark Mackay, Annette Majnemer, Naila Makhani, Gustavo Malinger, David E. Mandelbaum, Stephen M. Maricich, Kiran P. Maski, Mudit Mathur, Dennis J. Matthews, Kelly McMahon, Megan B. DeMara-Hoth, Bryce Mendelsohn, Julie A. Mennella, Laura R. Ment, Eugenio Mercuri, David J. Michelson, Mohamad A. Mikati, Fady M. Mikhail, Steven Paul Miller, Jeff M. Milunsky, Jonathan W. Mink, Ghayda M. Mirzaa, Wendy G. Mitchell, Michael A. Mohan, Payam Mohassel, Mahendranath Moharir, Umrao R. Monani, Michelle Monje Deisseroth, Manikum Moodley, Andrew Mower, Richard T. Moxley, Sabine Mueller, Alysson R. Muotri, Sandesh C.S. Nagamani, Mohan J. Narayanan, Vinodh Narayanan, Ruth D. Nass, Jeffrey L. Neul, Yoram Nevo, Bobby G. Ng, Katherine C. Nickels, Graeme A.M. Nimmo, Michael J. Noetzel, Lucy Norcliffe-Kaufmann, Douglas R. Nordli, Ulrike Nowak-Göttl, Hope L. O'Brien, Joyce Oleszek, Maryam Oskoui, Alex R. Paciorkowski, Roger J. Packer, Seymour Packman, Jose-Alberto Palma, Andrea C. Pardo, Julie A. Parsons, John Colin Partridge, Gregory M. Pastores, Marc C. Patterson, William J. Pearce, Phillip L. Pearl, Melanie Penner, Leila Percival, Marcia Pereira, Stefan M. Pfister, John Phillips, Barbara Plecko, Sigita Plioplys, Annapurna Poduri, Sharon Poisson, Scott L. Pomeroy, Andrea Poretti, Scott W. Powers, Michael R. Pranzatelli, Allison Przekop, Malcolm Rabie, Sampathkumar Rangasamy, Gerald V. Raymond, Alyssa T. Reddy, Rebecca L. Rendleman, Jong M. Rho, Lance H. Rodan, Sarah M. Roddy, Elizabeth E. Rogers, Stephen M. Rosenthal, N. Paul Rosman, M. Elizabeth Ross, Alexander Rotenberg, Robert S. Rust, Cheryl P. Sanchez, Pedro Sanchez, Iván Sánchez Fernández, Tristan T. Sands, Terence D. Sanger, Kumar Sannagowdara, Dustin Scheinost, Mark S. Scher, Nina F. Schor, Isabelle Schrauwen, Michael M. Segal, Syndi Seinfeld, Duygu Selcen, Laurie E. Seltzer, Margaret Semrud-Clikeman, Dennis W. Shaw, Bennett A. Shaywitz, Sally E. Shaywitz, Renée A. Shellhaas, Elliott H. Sherr, Rita D. Sheth, Michael I. Shevell, Shlomo Shinnar, Ben Shofty, Stanford K. Shu, Michael E. Shy, Laura Silveira Moriyama, Nicholas J. Silvestri, Katherine B. Sims, Harvey S. Singer, Nilika Shah Singhal, Craig M. Smith, Edward Smith, Stephen A. Smith, Evan Y. Snyder, Janet Soul, Christy L. Spalink, Karen A. Spencer, Carl E. Stafstrom, Robert Steinfeld, Jonathan B. Strober, Joseph Sullivan, Kenneth F. Swaiman, Kathryn J. Swoboda, Elizabeth D. Tate, William O. Tatum, Ingrid Tein, Kristyn Tekulve, Jeffrey R. Tenney, Elizabeth A. Thiele, Robert Thompson-Stone, Laura Tochen, Laura M. Tormoehlen, Lily Tran, Doris A. Trauner, Sinan O. Turnacioglu, Nicole J. Ullrich, David K. Urion, Guy Van Camp, Michèle Van Hirtum-Das, Clara D.M. van Karnebeek, Lionel Van Maldergem, Adeline Vanderver, Nicholas A. Vitanza, Michael von Rhein, Emily von Scheven, Ann Wagner, Mark S. Wainwright, Melissa A. Walker, John T. Walkup, Laurence Walsh, Lauren C. Walters-Sen, Raymond Y. Wang, Thomas T. Warner, Harry T. Whelan, Geoffrey A. Weinberg, Elizabeth M. Wells, James W. Wheless, Elaine C. Wirrell, Jeffrey H. Wisoff, Nicole I. Wolf, Gil I. Wolfe, F. Virginia Wright, Nathaniel D. Wycliffe, Michele L. Yang, Christopher J. Yuskaitis, Huda Y. Zoghbi, and Mary L. Zupanc
- Published
- 2017
39. Contributors
- Author
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Soraya Abbasi, James Abbey, N. Scott Adzick, Sun-Young Ahn, Kurt H. Albertine, Karel Allegaert, Seth L. Alper, Gabriel Altit, Steven M. Altschuler, Ruben E. Alvaro, Jennifer M.H. Amorosa, Kelsey L. Anbuhl, Claus Yding Andersen, Richard A. Anderson, David J. Askenazi, Richard Lambert Auten, Julie Autmizguine, Timur Azhibekov, Stephen A. Back, Jérôme Badaut, Peter Russell Baker, Philip L. Ballard, Eduardo H. Bancalari, Tatiana Barichello, Frederick Battaglia, Michel Baum, Simon Beggs, Edward F. Bell, Corinne Benchimol, Manon J.N.L. Benders, Laura Bennet, Phillip R. Bennett, Melvin Berger, Wolfgang Bernhard, John F. Bertram, Vikrant K. Bhosle, Vinod K. Bhutani, M. Jane Black, Joseph M. Bliss, David L. Bolender, Joline E. Brandenburg, Delma L. Broussard, Laura Davidson Brown, Douglas G. Burrin, Barbara Cannon, Michael Caplan, Susan E. Carlson, David P. Carlton, Georgina Caruana, William J. Cashore, Piya Chaemsaithong, Noppadol Chaiyasit, Jennifer R. Charlton, Carol L. Cheatham, Sylvain Chemtob, Yi-Yung Chen, Robert L. Chevalier, Sadhana Chheda, Andrew J. Childs, Robert D. Christensen, Alison Chu, David H. Chu, Maria Roberta Cilio, David A. Clark, Jane Cleary-Goldman, Ethel G. Clemente, John A. Clements, Ronald I. Clyman, Susan S. Cohen, John Colombo, Richard M. Cowett, Peter A. Crawford, James E. Crowe, Luise A. Cullen-McEwen, Wayne S. Cutfield, Mary E. D'Alton, Enrico Danzer, Christophe Delacourt, Sherin U. Devaskar, Thomas G. Diacovo, Nikolina Docheva, John P. Dormans, Kevin Dysart, Afif El-Khuffash, Peter James Ellis, Kerry McGarr Empey, Baris Ercal, Melinda Erdős, Robert P. Erickson, Mohamed A. Fahim, Arij Faksh, Hans-Georg Frank, Philippe S. Friedlich, Jed Friedman, Yuansheng Gao, Marianne Garland, Donna Geddes, Michael K. Georgieff, Jason Gien, Dino A. Giussani, Armond S. Goldman, Efrén González, Misty Good, Denis M. Grant, Lucy R. Green, Emmanouil Grigoriou, Adda Grimberg, Ian Gross, Ruth E. Grunau, Jean-Pierre Guignard, Alistair Jan Gunn, Nursen Gurtunca, Alice Hadchouel, Gabriel G. Haddad, Henrik Hagberg, Thomas Hale, K. Michael Hambidge, Cathy Hammerman, Thor Willy Ruud Hansen, Mark A. Hanson, Richard Harding, Mary Catherine Harris, Peter Hartmann, Foteini Hassiotou, Guttorm Haugen, Colin P. Hawkes, William W. Hay, Christina E. Hayward, Vivi M. Heine, Ann Hellström, Michael A. Helmrath, Karen D. Hendricks-Muñoz, Emilio Herrera, Michael J. Hiatt, Steven B. Hoath, Stuart B. Hooper, Stephen A. Huang, Silvia Iacobellli, Terrie E. Inder, M. Luisa Iruela-Arispe, Sudarshan R. Jadcherla, Deepak Jain, Thomas Jansson, John Lynn Jefferies, Jennifer G. Jetton, Alan H. Jobe, Lois H. Johnson, Richard B. Johnston, Rebecca Lee Jones, Pedro A. Jose, Satish C. Kalhan, Suhas G. Kallapur, Michael Kaplan, Stanley Kaplan, Heidi Eigenrauch Karpen, Saul J. Karpen, S. Ananth Karumanchi, Frederick J. Kaskel, Anup C. Katheria, Lorraine E. Levitt Katz, Susan E. Keeney, Steven E. Kern, Shirin Khanjani, Laurie E. Kilpatrick, Chang-Ryul Kim, John P. Kinsella, Torvid Kiserud, Joyce M. Koenig, Tobias R. Kollmann, Jay K. Kolls, Nancy F. Krebs, Thomas J. Kulik, Jessica Katz Kutikov, Satyan Lakshminrusimha, Angelo A. Lamola, Miguel Angel Lasunción, Pascal M. Lavoie, Tucker W. LeBien, Mary M. Lee, Matthew K. Lee, Yvonne K. Lee, Sandra Leibel, Fred Levine, Ofer Levy, Yang Liu, Steven Lobritto, Cynthia A. Loomis, Colleen A. Lopez, David A. MacIntyre, Maxime M. Mahe, Akhil Maheshwari, Anastasiya Mankouski, Carlos B. Mantilla, Arnaud Marchant, Kara Gross Margolis, M. Michele Mariscalco, László Maródi, Karel Maršál, Richard J. Martin, Douglas G. Matsell, Dwight E. Matthews, Harry J. McArdle, James L. McManaman, Patrick J. McNamara, Patrick S. McQuillen, Tim C. McQuinn, Judith S. Mercer, Giacomo Meschia, Steven P. Miller, Parviz Minoo, Paul Monagle, Jacopo P. Mortola, Louis J. Muglia, Upender K. Munshi, Ran Namgung, Sumana Narasimhan, Jan Nedergaard, Josef Neu, Sanjay K. Nigam, Lawrence M. Nogee, Shahab Noori, Barbara M. O'Brien, Robin K. Ohls, Henar Ortega-Senovilla, Justin M. O'Sullivan, Sarah A. Owusu, Abhijeet Pal, Howard B. Panitch, Anna A. Penn, Raymond B. Penn, Cameron Pernia, Anthony F. Philipps, Joseph A. Picoraro, Francesco Pisani, David Pleasure, Jeanette R. Pleasure, Samuel J. Pleasure, Scott L. Pomeroy, Martin Post, Y.S. Prakash, Joshua D. Prozialeck, Theodore J. Pysher, Raymond Quigley, Marlene Rabinovitch, Thomas M. Raffay, J. Usha Raj, Haley Ramsey, Sarosh Rana, Tara Marie Randis, Manon Ranger, Adam J. Ratner, Timothy R.H. Regnault, Henrique Rigatto, Natalie E. Rintoul, Roberto Romero, James C. Rose, Charles R. Rosenfeld, A. Catharine Ross, Henry J. Rozycki, Thomas D. Ryan, Rakesh Sahni, Eniko Sajti, Harvey B. Sarnat, Lisa M. Satlin, Ola Didrik Saugstad, William Schierding, Frank C. Schmalstieg, George J. Schwartz, Jeffrey Schwartz, Jeffrey L. Segar, David T. Selewski, Istvan Seri, Thomas H. Shaffer, Kara N. Shah, Martin J. Shearer, Sharareh Shojaie, Noah F. Shroyer, Colin P. Sibley, Gary C. Sieck, Rebecca A. Simmons, Emidio M. Sivieri, Francine G. Smith, Lois E.H. Smith, Ian M. Smyth, Brian S. Snarr, Evan Y. Snyder, Martha Sola-Visner, Michael J. Solhaug, Mark A. Sperling, Lakshmi Srinivasan, Andreas Stahl, Charles A. Stanley, Robin H. Steinhorn, Barbara S. Stonestreet, Janette F. Strasburger, Dennis M. Styne, Lori Sussel, Emily W.Y. Tam, Libo Tan, Claire Thornton, Daniel J. Tollin, Beáta Tóth, Jeffrey A. Towbin, Ashley Trocle, William E. Truog, Reginald C. Tsang, Kristin M. Uhler, John N. Van Den Anker, Johannes (Hans) B. van Goudoever, Susan J. Vannucci, Mark H. Vickers, Daniela Virgintino, Joseph J. Volpe, Neeta L. Vora, Neha V. Vyas, Annette Wacker-Gussmann, Megan J. Wallace, Brian H. Walsh, Alice M. Wang, David Warburton, Robert M. Ward, Kristi L. Watterberg, Lynne A. Werner, Barry K. Wershil, Susan E. Wert, Andy Wessels, Jeffrey A. Whitsett, Michael Wise, Matthias T. Wolf, Marla R. Wolfson, Hector R. Wong, James L. Wynn, Lami Yeo, Stephen Yip, Bradley A Yoder, Mervin C. Yoder, Momoko Yoshimoto, Christopher J. Yuskaitis, Dan Zhou, and Ann Zovein
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- 2017
40. Epilepsy Genetics
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Tristan T. Sands and Maria Roberta Cilio
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medicine.medical_specialty ,Epilepsy ,business.industry ,Medicine ,business ,Psychiatry ,medicine.disease - Published
- 2017
41. Electroencephalography in the Preterm and Term Infant
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Maria Roberta Cilio and Francesco Pisani
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Pediatrics ,medicine.medical_specialty ,Term Infant ,medicine.diagnostic_test ,business.industry ,medicine ,Electroencephalography ,business - Published
- 2017
42. Neonatal nonepileptic myoclonus is a prominent clinical feature of KCNQ2 gain-of-function variants R201C and R201H
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Edward C. Cooper, Sarah Weckhuysen, Sabine Grønborg, Maurizio Taglialatela, Yong-hui Jiang, Sarah B. Mulkey, John L. Carroll, Phillip L. Pearl, Rebecca C. Spillmann, Maria Roberta Cilio, Silvia Vieker, Kristen Park, Ingrid E. Scheffer, Nishtha Joshi, David A. Koolen, Megan L. Kelly, Bruria Ben-Zeev, Joost Nicolai, Mohamad A. Mikati, Mulkey, Sarah B, Ben Zeev, Bruria, Nicolai, Joost, Carroll, John L, Grønborg, Sabine, Jiang, Yong Hui, Joshi, Nishtha, Kelly, Megan, Koolen, David A, Mikati, Mohamad A, Park, Kristen, Pearl, Phillip L, Scheffer, Ingrid E, Spillmann, Rebecca C, Taglialatela, Maurizio, Vieker, Silvia, Weckhuysen, Sarah, Cooper, Edward C, Cilio, Maria Roberta, Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), and RS: FHML non-thematic output
- Subjects
0301 basic medicine ,Male ,Myoclonus ,Pediatrics ,Electroencephalography ,Epilepsy ,0302 clinical medicine ,Registries ,POTASSIUM CHANNEL SUBUNITS ,ONSET EPILEPTIC ENCEPHALOPATHY ,KCNQ2 ,medicine.diagnostic_test ,Infantile spasms ,Epileptic encephalopathy ,HYPEREXCITABILITY ,Institutional review board ,Magnetic Resonance Imaging ,Epileptic spasms ,Phenotype ,Neurology ,Anesthesia ,Child, Preschool ,Anticonvulsants ,Female ,medicine.symptom ,Spasms, Infantile ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] ,medicine.medical_specialty ,Encephalopathy ,Arginine ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,VOLTAGE SENSOR ,medicine ,Humans ,KCNQ2 Potassium Channel ,Histidine ,Cysteine ,SUPPRESSION ,SPECTRUM ,Neonatal encephalopathy ,business.industry ,MUTATIONS ,CONVULSIONS ,Infant, Newborn ,Infant ,Neonatal seizures ,medicine.disease ,Respiration Disorders ,030104 developmental biology ,Respiratory failure ,Infantile spasm ,SEIZURES ,Neurology (clinical) ,Human medicine ,business ,030217 neurology & neurosurgery ,Myoclonu - Abstract
Objective: To analyze whether KCNQ2 R201C and R201H variants, which show atypical gain-of-function electrophysiologic properties in vitro, have a distinct clinical presentation and outcome.Methods: Ten children with heterozygous, de novo KCNQ2 R201C or R201H variants were identified worldwide, using an institutional review board (IRB)-approved KCNQ2 patient registry and database. We reviewed medical records and, where possible, interviewed parents and treating physicians using a structured, detailed phenotype inventory focusing on the neonatal presentation and subsequent course.Results: Nine patients had encephalopathy from birth and presented with prominent startle-like myoclonus, which could be triggered by sound or touch. In seven patients, electroencephalography (EEG) was performed in the neonatal period and showed a burst-suppression pattern. However, myoclonus did not have an EEG correlate. In many patients the paroxysmal movements were misdiagnosed as seizures. Seven patients developed epileptic spasms in infancy. In all patients, EEG showed a slow background and multifocal epileptiform discharges later in life. Other prominent features included respiratory dysfunction (perinatal respiratory failure and/or chronic hypoventilation), hypomyelination, reduced brain volume, and profound developmental delay. One patient had a later onset, and sequencing indicated that a low abundance (similar to 20%) R201C variant had arisen by postzygotic mosaicism.Significance: Heterozygous KCNQ2 R201C and R201H gain-of-function variants present with profound neonatal encephalopathy in the absence of neonatal seizures. Neonates present with nonepileptic myoclonus that is often misdiagnosed and treated as seizures. Prognosis is poor. This clinical presentation is distinct from the phenotype associated with loss-of-function variants, supporting the value of in vitro functional screening. These findings suggest that gain-of-function and loss-of-function variants need different targeted therapeutic approaches.
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- 2017
43. Symptomatic Neonatal Seizures Followed by Febrile Status Epilepticus
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Francesco Pisani, Elena Pavlidis, Maria Roberta Cilio, and Carlotta Spagnoli
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Male ,Pediatrics ,medicine.medical_specialty ,Models, Neurological ,neonatal seizures ,febrile status epilepticus ,Context (language use) ,Brain damage ,Status epilepticus ,postneonatal epilepsy ,Epileptogenesis ,Infant, Newborn, Diseases ,Epilepsy ,Status Epilepticus ,Seizures ,Second hit ,medicine ,Humans ,two-hit hypothesis ,Child ,business.industry ,preterm birth ,Infant, Newborn ,Brain ,Electroencephalography ,medicine.disease ,Magnetic Resonance Imaging ,Anesthesia ,Pediatrics, Perinatology and Child Health ,Symptomatic epilepsy ,Immature brain ,Female ,Neurology (clinical) ,medicine.symptom ,business ,Infant, Premature - Abstract
Neonatal seizures have been associated with the later development of postneonatal epilepsy, mainly beginning within the first year of life. Mechanisms of epileptogenesis in the immature brain still need to be fully elucidated but a two-hit hypothesis, showing that an early insult heightens later susceptibility to seizure-induced brain damage, has been demonstrated in animal models. We describe 2 cases of preterm babies sustaining recurrent neonatal seizures in the context of a severe perinatal brain damage who presented with symptomatic epilepsy only after the occurrence of an episode of febrile status epilepticus. In the context of preexisting perinatal brain damage, febrile status epilepticus acted as a second hit for developing epilepsy, confirming animal evidence.
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- 2014
44. Adrenocorticotropic Hormone and Corticosteroids
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Maria Roberta Cilio and Federico Vigevano
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medicine.medical_specialty ,Endocrinology ,Pharmacokinetics ,business.industry ,Internal medicine ,medicine ,Adrenocorticotropic hormone ,business - Published
- 2015
45. Video-EEG monitoring in newborns with hypoxic-ischemic encephalopathy treated with hypothermia
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Donna M. Ferriero, A. J. Barkovich, Maria Roberta Cilio, Kendall B. Nash, Sonia L. Bonifacio, Joseph Sullivan, and Hannah C. Glass
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Male ,Encephalopathy ,Status epilepticus ,Electroencephalography ,Hypoxic Ischemic Encephalopathy ,Cohort Studies ,Hypothermia, Induced ,Seizures ,Humans ,Medicine ,Monitoring, Physiologic ,Subclinical infection ,medicine.diagnostic_test ,business.industry ,Infant, Newborn ,Videotape Recording ,Magnetic resonance imaging ,Articles ,Hypothermia ,medicine.disease ,Magnetic Resonance Imaging ,Burst suppression ,Anesthesia ,Hypoxia-Ischemia, Brain ,Female ,Neurology (clinical) ,medicine.symptom ,business - Abstract
Background: Therapeutic hypothermia (TH) is becoming standard of care in newborns with hypoxic-ischemic encephalopathy (HIE). The prognostic value of the EEG and the incidence of seizures during TH are uncertain. Objective: To describe evolution of EEG background and incidence of seizures during TH, and to identify EEG patterns predictive for MRI brain injury. Methods: A total of 41 newborns with HIE underwent TH. Continuous video-EEG was performed during hypothermia and rewarming. EEG background and seizures were reported in a standardized manner. Newborns underwent MRI after rewarming. Sensitivity and specificity of EEG background for moderate to severe MRI brain injury was assessed at 6-hour intervals during TH and rewarming. Results: EEG background improved in 49%, remained the same in 38%, and worsened in 13%. A normal EEG had a specificity of 100% upon initiation of monitoring and 93% at later time points. Burst suppression and extremely low voltage patterns held the greatest prognostic value only after 24 hours of monitoring, with a specificity of 81% at the beginning of cooling and 100% at later time points. A discontinuous pattern was not associated with adverse outcome in most patients (73%). Electrographic seizures occurred in 34% (14/41), and 10% (4/41) developed status epilepticus. Seizures had a clinical correlate in 57% (8/14) and were subclinical in 43% (6/14). Conclusions: Continuous video-EEG monitoring in newborns with HIE undergoing TH provides prognostic information about early MRI outcome and accurately identifies electrographic seizures, nearly half of which are subclinical.
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- 2011
46. Childhood refractory focal epilepsy following acute febrile encephalopathy
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D. Claps, Daniela Longo, Simonetta Gentile, Marina Trivisano, Giuseppe Fariello, Lucia Fusco, Luigi Maria Specchio, Raffaella Cusmai, Nicola Specchio, Simona Cappelletti, Maria Roberta Cilio, Federico Vigevano, and M. Valeriani
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Pediatrics ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Encephalopathy ,Magnetic resonance imaging ,Status epilepticus ,Electroencephalography ,medicine.disease ,Hyperintensity ,Epilepsy ,Neurology ,Anesthesia ,medicine ,Neurology (clinical) ,medicine.symptom ,business ,Acute Febrile Encephalopathy ,Encephalitis - Abstract
Background: We describe a group of previously normal children who developed severe focal epilepsy after an acute/sub-acute illness resembling encephalitis. Methods: This is a retrospective study. An acute phase (encephalitis/encephalopathy period) and a chronic phase (chronic focal resistant epilepsy) were defined. Results: Eight patients were enrolled. The median age at onset was 6.6 years (range 8 months–17.6 years). In the acute phase, fever was the first symptom in all cases and was associated with seizures and status epilepticus. All patients had focal seizures arising in both hemispheres. Seizure onset occurred in the frontal and temporal regions. EEGs showed slowing background activity associated with focal or diffuse slow waves with rare epileptiform abnormalities. Cerebrospinal fluid oligoclonal bands were observed in four out of six patients tested. MRI images showed bilateral peri-insular hyperintensity in four cases. Five patients received corticosteroids, and in four cases, they were given along with intravenous immunoglobulins. The median duration of the acute phase was 19 days (range 15–30 days). During the chronic phase, which followed the acute phase without interval, patients presented with drug-resistant focal seizures and neuropsychological deficits, which ranged from hyperactivity and attention deficits to short-term verbal memory deficit, pervasive developmental disorders, and language delay. Conclusion: Considering the clinical presentations, EEG findings, and the associated occurrence of non-specific immunological activations, a possible immune-mediated pathogenesis can be hypothesized, although firm conclusions cannot be drawn out.
- Published
- 2010
47. Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies
- Author
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S. Kitsiou Tzeli, Hülya Kayserili, L. Giordano, B. Rodriguez, P. Collignon, V. Sabolic Avramovska, Silvana Briuglia, Christopher A. Walsh, Laila Bastaki, Amy Goldstein, Francesca Faravelli, F. Papadia, A. Permunian, Alessandro Simonati, S. Halldorsson, Gian Marco Ghiggeri, David G. Brooks, Clara Barbot, Kathryn J. Swoboda, Chiara Pantaleoni, O. D'Addato, Jason W. Caldwell, Maria Roberta Cilio, Soumaya Mougou-Zerelli, M. Vascotto, Andreas Zankl, Gaetano Tortorella, Julia Tantau, Elliott H. Sherr, Patrizia Accorsi, Maurizio Genuardi, Carmelo Salpietro, G. Marra, Pierangela Castorina, Petter Strømme, J. Johannsdottir, Bruno Dallapiccola, Kenton R. Holden, Donatella Greco, Maria Spanò, Pasquale Parisi, Roberta Battini, Paola Grammatico, P. Ludvigsson, Dorit Lev, Daria Riva, C. Ae Kim, WB Dobyns, L. Martorell Sampol, Robert P. Cruse, H. Raynes, Sabrina Signorini, A. Seward, Raoul C.M. Hennekam, Elena Andreucci, Manuela Priolo, Banu Anlar, Bernard Stuart, Christopher P. Bennett, S. Comu, Christopher Geoffrey Woods, Vlatka Mejaški-Bošnjak, J. Milisa, Eamonn Sheridan, Melissa Lees, C. Moco, Ender Karaca, Miriam Iannicelli, Annalisa Mazzotta, C. Dacou-Voutetakis, Tania Attié-Bitach, Philippe Loget, D. Petkovic, L. Demerleir, Loredana Boccone, Meriem Tazir, Kalpathy S. Krishnamoorthy, Damir Lončarević, Dominika Swistun, Yves Sznajer, Stefano D'Arrigo, Ginevra Zanni, Angela Barnicoat, Marina Michelson, L. I. Al Gazali, Vincenzo Leuzzi, G. Uziel, A. Adami, B. Gener Querol, V. Udani, M. Di Giacomo, Maryse Bonnière, Enrico Bertini, K. Dias, Edward Blair, Johannes M. Penzien, M. Cazzagon, Susana Quijano-Roy, Trine Prescott, Barbara Scelsa, Giuseppina Vitiello, Francesco Brancati, Gilda Stringini, Trudy McKanna, Roser Pons, Renato Borgatti, M. Gentile, Dean Sarco, C. Von Der Lippe, Eugen Boltshauser, Luigina Spaccini, A. Pessagno, Alex Magee, Marilena Briguglio, Margherita Silengo, Lena Starck, M. L. Di Sabato, Roshan Koul, Nicole I. Wolf, A. M. Laverda, Elizabeth Flori, Clotilde Lagier-Tourenne, A. Matuleviciene, Matloob Azam, Kathrin Ludwig, Ghada M H Abdel-Salam, Atıl Yüksel, Johannes R. Lemke, Stefania Bigoni, Elizabeth Said, Anna Rajab, Mary Kay Koenig, Andreas R. Janecke, Asma A. Al-Tawari, Agnese Suppiej, Henry Sanchez, Wendy K. Chung, P. Guanciali, Heike Philippi, Silvia Majore, E. DeMarco, J. Hahn, Gianluca Caridi, Marc D'Hooghe, M. M. De Jong, M. Akcakus, Franco Stanzial, Silvia Battaglia, Gian Luigi Ardissino, Giangennaro Coppola, Jane A. Hurst, Terry D. Sanger, Alessandra Renieri, Nadia Elkhartoufi, Rita Fischetto, Alex E. Clark, S. Strozzi, S. Romano, Alain Verloes, Marzia Pollazzon, Elisa Fazzi, L. Yates, Faustina Lalatta, Sabine Sigaudy, Alessandra D'Amico, Brigitte Leroy, Joel Victor Fluss, David Viskochil, Alice Abdel-Aleem, Darryl C. De Vivo, Padraic Grattan-Smith, Corrado Romano, D. Nicholl, Regine Schubert, A. Moreira, Claudia Izzi, Barbara Gentilin, Gustavo Maegawa, Céline Gomes, László Sztriha, C. Donahue, Luciana Rigoli, Jean Messer, Sophie Thomas, E. Del Giudice, R. Van Coster, André Mégarbané, Ignacio Pascual-Castroviejo, Alessandra Ferlini, Topcu, R. Touraine, Ginevra Guanti, Lorena Travaglini, L. Ali Pacha, R. De Vescovi, Enza Maria Valente, Filippo Bernardi, L. Carr, Shubha R. Phadke, S. Bernes, Maria Teresa Divizia, C. Daugherty, M. Akgul, C. Macaluso, Maha S. Zaki, E. Finsecke, Itxaso Marti, Lorenzo Pinelli, F. McKay, Maria Amorini, Joseph G. Gleeson, F. Benedicenti, Bruria Ben-Zeev, Carla Uggetti, R. Romoli, Richard J. Leventer, Francesco Emma, T. E. Gallager, P. De Lonlay, Marco Seri, Bernard L. Maria, M.A. Donati, Bosanka Jocic-Jakubi, IANNICELLI M, BRANCATI F, MOUGOU-ZERELLI S, MAZZOTTA A, THOMAS S, ELKHARTOUFI N, TRAVAGLINI L, GOMES C, ARDISSINO GL, BERTINI E, BOLTSHAUSER E, CASTORINA P, D'ARRIGO S, FISCHETTO R, LEROY B, LOGET P, BONNIÈRE M, STARCK L, TANTAU J, GENTILIN B, MAJORE S, SWISTUN D, FLORI E, LALATTA F, PANTALEONI C, PENZIEN J, GRAMMATICO P, INTERNATIONAL JSRD STUDY GROUP, DALLAPICCOLA B, GLEESON JG, ATTIE-BITACH T, VALENTE EM. COLLABORATORS: ALI PACHA L, TAZIR M, ZANKL A, LEVENTER R, GRATTAN-SMITH P, JANECKE A, D'HOOGHE M, SZNAJER Y, VAN COSTER R, DEMERLEIR L, DIAS K, MOCO C, MOREIRA A, AE KIM C, MAEGAWA G, LONCAREVIC D, MEJASKI-BOSNJAK V, PETKOVIC D, ABDEL-SALAM GM, ABDEL-ALEEM A, ZAKI MS, MARTI I, QUIJANO-ROY S, SIGAUDY S, DE LONLAY P, ROMANO S, VERLOES A, TOURAINE R, KOENIG M, LAGIER-TOURENNE C, MESSER J, COLLIGNON P, WOLF N, PHILIPPI H, LEMKE J, DACOU-VOUTETAKIS C, KITSIOU TZELI S, PONS R, SZTRIHA L, HALLDORSSON S, JOHANNSDOTTIR J, LUDVIGSSON P, PHADKE SR, UDANI V, STUART B, MAGEE A, LEV D, MICHELSON M, BEN-ZEEV B, DI GIACOMO M, GENTILE M, GUANTI G, D'ADDATO O, PAPADIA F, SPANO M, BERNARDI F, SERI M, BENEDICENTI F, STANZIAL F, BORGATTI R, ACCORSI P, BATTAGLIA S, FAZZI E, GIORDANO L, IZZI C, PINELLI L, BOCCONE L, GUANCIALI P, ROMOLI R, BIGONI S, FERLINI A, ANDREUCCI E, DONATI MA, GENUARDI M, CARIDI G, DIVIZIA MT, FARAVELLI F, GHIGGERI G, PESSAGNO, AMORINI M, BRIGUGLIO M, BRIUGLIA S, RIGOLI L, SALPIETRO C, TORTORELLA G, ADAMI A, MARRA G, RIVA D, SCELSA B, SPACCINI L, UZIEL G, COPPOLA G, DEL GIUDICE E, VITIELLO G, LAVERDA AM, LUDWIG K, PERMUNIAN A, SUPPIEJ A, MACALUSO C, SIGNORINI S, UGGETTI C, BATTINI R, PRIOLO M, CILIO MR, D'AMICO A, DI SABATO ML, EMMA F, LEUZZI V, PARISI P, STRINGINI G, ZANNI G, POLLAZZON M, RENIERI A, VASCOTTO M, SILENGO M, DE VESCOVI R, GRECO D, ROMANO C, CAZZAGON M, SIMONATI A, AL-TAWARI AA, BASTAKI L, MÉGARBANÉ A, MATULEVICIENE A, SABOLIC AVRAMOVSKA V, SAID E, DE JONG MM, PRESCOTT T, STROMME P, VON DER LIPPE C, KOUL R, RAJAB A, AZAM M, BARBOT C, JOCIC-JAKUBI B, GENER QUEROL B, MARTORELL SAMPOL L, RODRIGUEZ B, PASCUAL-CASTROVIEJO I, STROZZI S, FLUSS J, TEBER S, TOPCU M, ANLAR B, COMU S, KARACA E, KAYSERILI H, YÜKSEL A, AKGUL M, AKCAKUS M, AL GAZALI L, NICHOLL D, WOODS CG, BENNETT C, HURST J, SHERIDAN E, BARNICOAT A, CARR L, HENNEKAM R, LEES M, MCKAY F, YATES L, BLAIR E, BERNES S, SANCHEZ H, CLARK AE, DEMARCO E, DONAHUE C, SHERR E, HAHN J, SANGER TD, GALLAGER TE, DOBYNS WB, DAUGHERTY C, KRISHNAMOORTHY KS, SARCO D, WALSH CA, MCKANNA T, MILISA J, CJUNG WK, DE VIVO DC, RAYNES H, SCHUBERT R, SEWARD A, BROOKS DG, GOLDSTEIN A, CALDWELL J, FINSECKE E, MARIA BL, HOLDEN K, CRUSE RP, SWOBODA KJ, VISKOCHIL D., Pediatric surgery, NCA - Childhood White Matter Diseases, Iannicelli, M, Brancati, F, Mougou Zerelli, S, Mazzotta, A, Thomas, S, Elkhartoufi, N, Travaglini, L, Gomes, C, Ardissino, Gl, Bertini, E, Boltshauser, E, Castorina, P, D'Arrigo, S, Fischetto, R, Leroy, B, Loget, P, Bonnière, M, Starck, L, Tantau, J, Gentilin, B, Majore, S, Swistun, D, Flori, E, Lalatta, F, Pantaleoni, C, Penzien, J, Grammatico, P, Dallapiccola, B, Gleeson, Jg, Attie Bitach, T, Valente, Em, International JSRD Study, Group, DEL GIUDICE, Ennio, University of Zurich, and Attie-Bitach, T
- Subjects
Liver Cirrhosis ,2716 Genetics (clinical) ,meckelin ,Ciliopathies ,Joubert syndrome ,Genotype ,congenital hepatic fibrosis ,coach syndrome ,mks3 ,meckel syndrome ,joubert syndrome ,tmem67 ,TMEM67 ,Meckel syndrome ,DNA Mutational Analysis ,610 Medicine & health ,Biology ,medicine.disease_cause ,MKS3 ,COACH syndrome ,Article ,NO ,1311 Genetics ,Nephronophthisis ,Pregnancy ,Prenatal Diagnosis ,Genetics ,medicine ,COACH syndrome, Congenital hepatic fibrosis, Joubert syndrome, Meckel syndrome, MKS3, TMEM67 ,Missense mutation ,Humans ,Abnormalities, Multiple ,Genetics (clinical) ,Mutation ,Cilium ,Membrane Proteins ,Kidney Diseases, Cystic ,medicine.disease ,Phenotype ,10036 Medical Clinic ,Female - Abstract
Human ciliopathies are hereditary conditions caused by defects of proteins expressed at the primary cilium. Among ciliopathies, Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS) and nephronophthisis (NPH) present clinical and genetic overlap, being allelic at several loci. One of the most interesting gene is TMEM67, encoding the transmembrane protein meckelin. We performed mutation analysis of TMEM67 in 341 probands, including 265 JSRD representative of all clinical subgroups and 76 MKS fetuses. We identified 33 distinct mutations, of which 20 were novel, in 8/10 (80%) JS with liver involvement (COACH phenotype) and 12/76 (16%) MKS fetuses. No mutations were found in other JSRD subtypes, confirming the strong association between TMEM67 mutations and liver involvement. Literature review of all published TMEM67 mutated cases was performed to delineate genotype-phenotype correlates. In particular, comparison of the types of mutations and their distribution along the gene in lethal versus non lethal phenotypes showed in MKS patients a significant enrichment of missense mutations falling in TMEM67 exons 8 to 15, especially when in combination with a truncating mutation. These exons encode for a region of unknown function in the extracellular domain of meckelin.
- Published
- 2010
48. Dorsal Brain Stem Syndrome: MR Imaging Location of Brain Stem Tegmental Lesions in Neonates with Oral Motor Dysfunction
- Author
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Daniela Longo, Fiammetta Piersigilli, Matteo Di Capua, G Seganti, Carlo Cosimo Quattrocchi, Giuseppe Fariello, Maria Roberta Cilio, Olivier Danhaive, Luciana Nogueira Delfino, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de néonatologie, and UCL - (SLuc) Service de neurologie pédiatrique
- Subjects
Male ,Dorsum ,Pathology ,medicine.medical_specialty ,Tegmentum Mesencephali ,Encephalopathy ,Central nervous system ,Pediatrics ,Infant, Newborn, Diseases ,Central nervous system disease ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Retrospective Studies ,Motor Neurons ,Mouth ,Oral motor ,medicine.diagnostic_test ,business.industry ,Infant, Newborn ,Retrospective cohort study ,Magnetic resonance imaging ,medicine.disease ,Magnetic Resonance Imaging ,Mr imaging ,medicine.anatomical_structure ,Hypoxia-Ischemia, Brain ,Female ,Neurology (clinical) ,Deglutition Disorders ,business ,Brain Stem - Abstract
The anatomic extent of brain stem damage may provide information about clinical outcome and prognosis in children with hypoxic-ischemic encephalopathy and oral motor dysfunction. The aim of this study was to retrospectively characterize the location and extent of brain stem lesions in children with oral motor dysfunction. From January 2005 to August 2009, 43 infants hospitalized at our institution were included in the study because of a history of hypoxic-ischemic events. Of this group, 14 patients showed oral motor dysfunction and brain stem tegmental lesions detected at MR imaging. MR imaging showed hypoxic-ischemic lesions in supra- and infratentorial areas. Six of 14 patients revealed only infratentorial lesions. Focal symmetric lesions of the tegmental brain stem were always present. The lesions appeared hyperintense on T2-weighted images and hypointense on IR images. We found a strong association (P < .0001) between oral motor dysfunction and infratentorial lesions on MR imaging. Oral motor dysfunction was associated with brain stem tegmental lesions in posthypoxic-ischemic infants. The MR imaging examination should be directed to the brain stem, especially when a condition of prolonged gavage feeding is necessary in infants.
- Published
- 2010
49. Neonatal seizures
- Author
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Maria Roberta Cilio
- Subjects
Pediatrics, Perinatology and Child Health - Published
- 2009
50. Gating currents from neuronal KV7.4 Channels: General features and correlation with the ionic conductance
- Author
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Maria Roberta Cilio, Francisco Bezanilla, Francesco Miceli, Maurizio Taglialatela, Miceli, Francesco, Cilio, Maria R., Taglialatela, Maurizio, and Bezanilla, Francisco
- Subjects
Voltage-gated ion channel ,Chemistry ,Electrical resistivity and conductivity ,Voltage clamp ,Biophysics ,Analytical chemistry ,Ionic bonding ,Homomeric ,Conductance ,Gating ,Biochemistry ,Potassium channel - Abstract
The K(V)7 (KCNQ) subfamily of voltage-gated K(+) channels consists of five members (K(V)7.1-K(V)7.5) giving rise to non-inactivating, and slowly activating/deactivating currents mainly expressed in cardiac (K(V)7.1) and neuronal (K(V)7.2-K(V)7.5) tissue. In the present study, using the cut-open oocyte voltage clamp, we studied the relation of the ionic currents from homomeric neuronal K(V)7 channels (K(V)7.2-K(V)7.5) with the gating currents recorded after K(+) conductance blockade from the same channels. Increasing the recording temperature from 18 degrees C to 28 degrees C accelerated activation/deactivation kinetics of the ionic currents in all homomeric K(V)7 channels (activation Q(10)s at 0 mV were 3.8, 4.1, 8.3 and 2.8 for K(V)7.2, K(V)7.3, K(V)7.4 and K(V)7.5 channels, respectively), without large changes in currents voltage-dependence; moreover, at 28 degrees C, ionic currents carried by K(V)7.4 channels also showed a significant increase in their maximal value. Gating currents were only resolved in K(V)7.4 and K(V)7.5 channels; the size of the ON gating charges at +40 mV was 1.34 +/- 0.34 nC for K(V)7.4, and 0.79 +/- 0.20 nC for K(V)7.5. At 28 degrees C, K(V)7.4 gating currents had the following salient properties: (1) similar time integral of Q(ON) and Q(OFF), indicating no charge immobilization; (2) a left-shift in the V(1/2) of the Q(ON)/V when compared to the G/V (approximately 50 mV in the presence of 2 mM extracellular Ba(2+)); (3) a Q(ON) decay faster than ionic current activation; and (4) a rising phase in the OFF gating charge after depolarizations larger than 0 mV. These observations suggest that, in K(V)7.4 channels, VSD movement is followed by a slow and/or low bearing charge step linking to pore opening, a result which may help to clarify the molecular consequence of disease-causing mutations and drugs affecting channel gating.
- Published
- 2009
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