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1. Polygenic burden in focal and generalized epilepsies

Author

Leu C., Stevelink R., Smith A. W., Goleva S. B., Kanai M., Ferguson L., Campbell C., Kamatani Y., Okada Y., Sisodiya S. M., Cavalleri G. L., Koeleman B. P. C., Lerche H., Jehi L., Davis L. K., Najm I. M., Palotie A., Daly M. J., Busch R. M., Lal D., Feng Y. -C. A., Howrigan D. P., Abbott L. E., Tashman K., Cerrato F., Churchhouse C., Gupta N., Neale B. M., Berkovic S. F., Goldstein D. B., Lowenstein D. H., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Hakonarson H., Heinzen E. L., Helbig I., Kwan P., Marson A. G., Petrovski S., Kamalakaran S., Stewart R., Weckhuysen S., Depondt C., Dlugos D. J., Scheffer I. E., Striano P., Freyer C., Krause R., May P., McKenna K., Regan B. M., Bellows S. T., Bennett C. A., Johns E. M. C., Macdonald A., Shilling H., Burgess R., Weckhuysen D., Bahlo M., O'Brien T. J., Todaro M., Stamberger H., Andrade D. M., Sadoway T. R., Mo K., Krestel H., Gallati S., Papacostas S. S., Kousiappa I., Tanteles G. A., Sterbova K., Vlckova M., Sedlackova L., Lassuthova P., Klein K. M., Rosenow F., Reif P. S., Knake S., Kunz W. S., Zsurka G., Elger C. E., Bauer J., Rademacher M., Pendziwiat M., Muhle H., Rademacher A., Van Baalen A., Von Spiczak S., Stephani U., Afawi Z., Korczyn A. D., Kanaan M., Canavati C., Kurlemann G., Muller-Schluter K., Kluger G., Hausler M., Blatt I., Lemke J. R., Krey I., Weber Y. G., Wolking S., Becker F., Hengsbach C., Rau S., Maisch A. F., Steinhoff B. J., Schulze-Bonhage A., Schubert-Bast S., Schreiber H., Borggrafe I., Schankin C. J., Mayer T., Korinthenberg R., Brockmann K., Dennig D., Madeleyn R., Kalviainen R., Auvinen P., Saarela A., Linnankivi T., Lehesjoki A. -E., Rees M. I., Chung S. -K., Pickrell W. O., Powell R., Schneider N., Balestrini S., Zagaglia S., Braatz V., Johnson M. R., Auce P., Sills G. J., Baum L. W., Sham P. C., Cherny S. S., Lui C. H. T., Barisic N., Delanty N., Doherty C. P., Shukralla A., McCormack M., El-Naggar H., Canafoglia L., Franceschetti S., Castellotti B., Granata T., Zara F., Iacomino M., Madia F., Vari M. S., Mancardi M. M., Salpietro V., Bisulli F., Tinuper P., Licchetta L., Pippucci T., Stipa C., Muccioli L., Minardi R., Gambardella A., Labate A., Annesi G., Manna L., Gagliardi M., Parrini E., Mei D., Vetro A., Bianchini C., Montomoli M., Doccini V., Marini C., Suzuki T., Inoue Y., Yamakawa K., Birute T., Ruta M., Algirdas U., Ruta P., Jurgita G., Ruta S., Sadleir L. G., King C., Mountier E., Caglayan S. H., Arslan M., Yapici Z., Yis U., Topaloglu P., Kara B., Turkdogan D., Gundogdu-Eken A., Bebek N., Ugur-Iseri S., Baykan B., Salman B., Haryanyan G., Yucesan E., Kesim Y., Ozkara C., Sheidley B. R., Shain C., Poduri A., Buono R. J., Ferraro T. N., Sperling M. R., Lo W., Privitera M., French J. A., Schachter S., Kuzniecky R. I., Devinsky O., Hegde M., Khankhanian P., Helbig K. L., Ellis C. A., Spalletta G., Piras F., Gili T., Ciullo V., Leu C., Stevelink R., Smith A.W., Goleva S.B., Kanai M., Ferguson L., Campbell C., Kamatani Y., Okada Y., Sisodiya S.M., Cavalleri G.L., Koeleman B.P.C., Lerche H., Jehi L., Davis L.K., Najm I.M., Palotie A., Daly M.J., Busch R.M., Lal D., Feng Y.-C.A., Howrigan D.P., Abbott L.E., Tashman K., Cerrato F., Churchhouse C., Gupta N., Neale B.M., Berkovic S.F., Goldstein D.B., Lowenstein D.H., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Hakonarson H., Heinzen E.L., Helbig I., Kwan P., Marson A.G., Petrovski S., Kamalakaran S., Stewart R., Weckhuysen S., Depondt C., Dlugos D.J., Scheffer I.E., Striano P., Freyer C., Krause R., May P., McKenna K., Regan B.M., Bellows S.T., Bennett C.A., Johns E.M.C., Macdonald A., Shilling H., Burgess R., Weckhuysen D., Bahlo M., O'Brien T.J., Todaro M., Stamberger H., Andrade D.M., Sadoway T.R., Mo K., Krestel H., Gallati S., Papacostas S.S., Kousiappa I., Tanteles G.A., Sterbova K., Vlckova M., Sedlackova L., Lassuthova P., Klein K.M., Rosenow F., Reif P.S., Knake S., Kunz W.S., Zsurka G., Elger C.E., Bauer J., Rademacher M., Pendziwiat M., Muhle H., Rademacher A., Van Baalen A., Von Spiczak S., Stephani U., Afawi Z., Korczyn A.D., Kanaan M., Canavati C., Kurlemann G., Muller-Schluter K., Kluger G., Hausler M., Blatt I., Lemke J.R., Krey I., Weber Y.G., Wolking S., Becker F., Hengsbach C., Rau S., Maisch A.F., Steinhoff B.J., Schulze-Bonhage A., Schubert-Bast S., Schreiber H., Borggrafe I., Schankin C.J., Mayer T., Korinthenberg R., Brockmann K., Dennig D., Madeleyn R., Kalviainen R., Auvinen P., Saarela A., Linnankivi T., Lehesjoki A.-E., Rees M.I., Chung S.-K., Pickrell W.O., Powell R., Schneider N., Balestrini S., Zagaglia S., Braatz V., Johnson M.R., Auce P., Sills G.J., Baum L.W., Sham P.C., Cherny S.S., Lui C.H.T., Barisic N., Delanty N., Doherty C.P., Shukralla A., McCormack M., El-Naggar H., Canafoglia L., Franceschetti S., Castellotti B., Granata T., Zara F., Iacomino M., Madia F., Vari M.S., Mancardi M.M., Salpietro V., Bisulli F., Tinuper P., Licchetta L., Pippucci T., Stipa C., Muccioli L., Minardi R., Gambardella A., Labate A., Annesi G., Manna L., Gagliardi M., Parrini E., Mei D., Vetro A., Bianchini C., Montomoli M., Doccini V., Marini C., Suzuki T., Inoue Y., Yamakawa K., Birute T., Ruta M., Algirdas U., Ruta P., Jurgita G., Ruta S., Sadleir L.G., King C., Mountier E., Caglayan S.H., Arslan M., Yapici Z., Yis U., Topaloglu P., Kara B., Turkdogan D., Gundogdu-Eken A., Bebek N., Ugur-Iseri S., Baykan B., Salman B., Haryanyan G., Yucesan E., Kesim Y., Ozkara C., Sheidley B.R., Shain C., Poduri A., Buono R.J., Ferraro T.N., Sperling M.R., Lo W., Privitera M., French J.A., Schachter S., Kuzniecky R.I., Devinsky O., Hegde M., Khankhanian P., Helbig K.L., Ellis C.A., Spalletta G., Piras F., Gili T., Ciullo V., Commission of the European Communities, Medical Research Council (MRC), Tumienė, Birutė, Mameniškienė, Rūta, Utkus, Algirdas, Praninskienė, Rūta, Grikinienė, Jurgita, Samaitienė-Aleknienė, Rūta, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, University of Helsinki, Helsinki Institute of Life Science HiLIFE, and Department of Medical and Clinical Genetics

Subjects
0301 basic medicine, Male, Multifactorial Inheritance, Epi25 Consortium, Databases, Factual, FEATURES, Genome-wide association study, Epilepsies, 3124 Neurology and psychiatry, Cohort Studies, Epilepsy, 0302 clinical medicine, Cost of Illness, 1ST SEIZURE, HISTORY, genetics, POPULATION, 11 Medical and Health Sciences, education.field_of_study, medicine.diagnostic_test, SCORES, Single Nucleotide, Biobank, 3. Good health, 17 Psychology and Cognitive Sciences, Genetic generalized epilepsy, Epilepsy, Generalized, Female, Partial, Cohort study, Human, medicine.medical_specialty, Population, European Continental Ancestry Group, Clinical Neurology, BIOBANK, Polymorphism, Single Nucleotide, epilepsy, genetic generalized epilepsy, common variant risk, Databases, 03 medical and health sciences, Genetic, Internal medicine, medicine, Journal Article, Genetics, Humans, Genetic Predisposition to Disease, Polymorphism, GENOME-WIDE ASSOCIATION, Generalized epilepsy, education, SEIZURE RECURRENCE, Factual, METAANALYSIS, Genetic testing, Neurology & Neurosurgery, RISK PREDICTION, Generalized, business.industry, 3112 Neurosciences, Common variant risk, Genetic Variation, Original Articles, medicine.disease, Comorbidity, Cost of Illne, Epilepsies, Partial, Genome-Wide Association Study, 030104 developmental biology, Neurology (clinical), Cohort Studie, business, 030217 neurology & neurosurgery
Abstract

See Hansen and Møller (doi:10.1093/brain/awz318) for a scientific commentary on this article. Using polygenic risk scores from a genome-wide association study in generalized and focal epilepsy, Leu et al. reveal a significantly higher genetic burden for epilepsy in multiple cohorts of people with epilepsy compared to population controls. Quantification of common variant burden may be valuable for epilepsy prognosis and treatment., Rare genetic variants can cause epilepsy, and genetic testing has been widely adopted for severe, paediatric-onset epilepsies. The phenotypic consequences of common genetic risk burden for epilepsies and their potential future clinical applications have not yet been determined. Using polygenic risk scores (PRS) from a European-ancestry genome-wide association study in generalized and focal epilepsy, we quantified common genetic burden in patients with generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) from two independent non-Finnish European cohorts (Epi25 Consortium, n = 5705; Cleveland Clinic Epilepsy Center, n = 620; both compared to 20 435 controls). One Finnish-ancestry population isolate (Finnish-ancestry Epi25, n = 449; compared to 1559 controls), two European-ancestry biobanks (UK Biobank, n = 383 656; Vanderbilt biorepository, n = 49 494), and one Japanese-ancestry biobank (BioBank Japan, n = 168 680) were used for additional replications. Across 8386 patients with epilepsy and 622 212 population controls, we found and replicated significantly higher GE-PRS in patients with generalized epilepsy of European-ancestry compared to patients with focal epilepsy (Epi25: P = 1.64×10−15; Cleveland: P = 2.85×10−4; Finnish-ancestry Epi25: P = 1.80×10−4) or population controls (Epi25: P = 2.35×10−70; Cleveland: P = 1.43×10−7; Finnish-ancestry Epi25: P = 3.11×10−4; UK Biobank and Vanderbilt biorepository meta-analysis: P = 7.99×10−4). FE-PRS were significantly higher in patients with focal epilepsy compared to controls in the non-Finnish, non-biobank cohorts (Epi25: P = 5.74×10−19; Cleveland: P = 1.69×10−6). European ancestry-derived PRS did not predict generalized epilepsy or focal epilepsy in Japanese-ancestry individuals. Finally, we observed a significant 4.6-fold and a 4.5-fold enrichment of patients with generalized epilepsy compared to controls in the top 0.5% highest GE-PRS of the two non-Finnish European cohorts (Epi25: P = 2.60×10−15; Cleveland: P = 1.39×10−2). We conclude that common variant risk associated with epilepsy is significantly enriched in multiple cohorts of patients with epilepsy compared to controls—in particular for generalized epilepsy. As sample sizes and PRS accuracy continue to increase with further common variant discovery, PRS could complement established clinical biomarkers and augment genetic testing for patient classification, comorbidity research, and potentially targeted treatment.

Published
2019

3. Advanced morphological neuroimaging study in lateral temporal lobe epilepsy: A multicentric study

Author

Roberta Vasta a, 1, Alessia Sarica a, Francesca Bisulli c, Giancarlo Di Gennaro d, Alfredo D'Aniello d, Jacopo C. Difrancesco e, f, Laura Canafoglia f, Marina Casazza f, Silvana Franceschetti f, Carlotta Stipa c, Paolo Tinuper c, Laura Mumoli b, Antonio Gambardella a, b Angelo Labate a, b, 1. Equally contributed, Vasta, Roberta, Sarica, Alessia, Bisulli, Francesca, Di Gennaro, Giancarlo, D'Aniello, Alfredo, Difrancesco, Jacopo C., Canafoglia, Laura, Casazza, Marina, Franceschetti, Silvana, Stipa, Carlotta, Tinuper, Paolo, Mumoli, Laura, Gambardella, Antonio, and Labate, Angelo

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Neuroimaging, Lateral temporal lobe epilepsy, computer.software_genre, Functional Laterality, 030218 nuclear medicine & medical imaging, Temporal lobe, Young Adult, 03 medical and health sciences, Epilepsy, Behavioral Neuroscience, 0302 clinical medicine, Voxel, Imaging alterations, Image Processing, Computer-Assisted, medicine, Humans, Gyrification, Cerebral Cortex, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Multimodal approach, Epilepsy, Temporal Lobe, Neurology, Cohort, Standard protocol, Receptive aphasia, Female, Radiology, Neurology (clinical), Psychology, computer, 030217 neurology & neurosurgery, Imaging alteration
Abstract

Lateral temporal lobe epilepsy (lTLE) is a rare condition characterized by auditory auras or receptive aphasia, negative MRI, and relatively benign evolution. With the low number of cases in the world, our objective was to analyze a cohort of sporadic cases with lTLE (slTLE), in order to investigate possible cerebral morphological alterations. Forty patients with lTLE (34.93 ± 12.08 years of age) and 38 healthy controls (CTRL, 34.55 ± 9.08 years of age) were enrolled from four tertiary Italian epilepsy centers, which provided brain MRI T1-weighted images following a standard protocol for patients with epilepsy. We performed group comparison by following different approaches: voxel-based morphometry (VBM, SPM8), cortical thickness (CT), and local gyrification index (lGI) (FreeSurfer 5.3). At a more conservative threshold (pÂ

Published
2017

5. Epilepsy with auditory features: A heterogeneous clinico-molecular disease.

Author

Pippucci, T, Licchetta, L, Baldassari, S, Palombo, F, Menghi, V, D'Aurizio, R, Leta, C, Stipa, C, Boero, G, d'Orsi, G, Magi, A, Scheffer, I, Seri, M, Tinuper, P, Bisulli, F, Pippucci, T, Licchetta, L, Baldassari, S, Palombo, F, Menghi, V, D'Aurizio, R, Leta, C, Stipa, C, Boero, G, d'Orsi, G, Magi, A, Scheffer, I, Seri, M, Tinuper, P, and Bisulli, F

Abstract

OBJECTIVE: To identify novel genes implicated in epilepsy with auditory features (EAF) in phenotypically heterogeneous families with unknown molecular basis. METHODS: We identified 15 probands with EAF in whom an LGI1 mutation had been excluded. We performed electroclinical phenotyping on all probands and available affected relatives. We used whole-exome sequencing (WES) in 20 individuals with EAF (including all the probands and 5 relatives) to identify single nucleotide variants, small insertions/deletions, and copy number variants. RESULTS: WES revealed likely pathogenic variants in genes that had not been previously associated with EAF: a CNTNAP2 intragenic deletion, 2 truncating mutations of DEPDC5, and a missense SCN1A change. CONCLUSIONS: EAF is a clinically and molecularly heterogeneous disease. The association of EAF with CNTNAP2, DEPDC5, and SCN1A mutations widens the phenotypic spectrum related to these genes. CNTNAP2 encodes CASPR2, a member of the voltage-gated potassium channel complex in which LGI1 plays a role. The finding of a CNTNAP2 deletion emphasizes the importance of this complex in EAF and shows biological convergence.

Published
2015

13. Maximum voluntary retrusion or habitual bite position for mandibular advancement assessment in the treatment of obstructive sleep apnoea patients

Author

Irene Pelligra, Chiara Stipa, Matteo Cameli, Giovanni Sorrenti, Giulio Alessandri-Bonetti, Daniela Rita Ippolito, Ippolito D.R., Stipa C., Cameli M., Sorrenti G., Pelligra I., and Alessandri Bonetti G.

Subjects
Systematic error, obstructive sleep apnoea, 03 medical and health sciences, 0302 clinical medicine, mandibular retruded position, stomatognathic system, Humans, Medicine, habitual bite, General Dentistry, Retrospective Studies, Orthodontics, Sleep Apnea, Obstructive, reliability, business.industry, mandibular range of motion, Reproducibility of Results, Occlusal Splints, Retrospective cohort study, 030206 dentistry, mandibular advancement device, Position (obstetrics), Treatment Outcome, Sleep endoscopy, Random error, Range of motion, business, Mandibular Advancement, 030217 neurology & neurosurgery, Student's t-test
Abstract

Background: There is no consensus on whether the range of mandibular advancement for the construction of mandibular advancement devices in obstructive sleep apnoea (OSA) patients should be measured from a starting position of maximum voluntary retrusion or habitual bite position. Objective: The purposes of this study were to investigate the differences in mandibular advancement registrations starting from maximum voluntary retrusion or from habitual bite position and to evaluate the reliability of these assessments. Methods: A retrospective cohort analysis of 126 patients with OSA was performed. All patients had their mandibular range of motion evaluated twice (starting from maximum voluntary retrusion and from habitual bite position) through the George Gauge before undergoing drug-induced sleep endoscopy. The Dahlberg formula and paired t test were used to calculate random and systematic errors of dental positions assessment. Test-retest reliability was quantified using the intra-class correlation coefficient (ICC). Results: The mean mandibular range starting from maximum voluntary retrusion and from habitual bite position were 12.49±2.19mm and 7.68±2.29mm, respectively, with a mean distance between the two starting positions of 4.81±1.75mm. No systematic error was found (P>.05), and random errors ranged from 0.30 to 0.95mm. ICC values were excellent for maximum voluntary protrusion (ICC=0.986) and maximum voluntary retrusion (ICC=0.956), whereas habitual bite position showed a good value (ICC=0.818). Conclusion: The difference between maximum voluntary retrusion and habitual bite position is potentially relevant. Maximum retrusion is advisable as starting point of the mandibular advancement registration since it provides a more reliable measure.

Published
2019

14. The Impact of the COVID-19 Pandemic on People With Epilepsy. An Italian Survey and a Global Perspective

Author

Barbara Mostacci, Laura Licchetta, Carlotta Cacciavillani, Lidia Di Vito, Lorenzo Ferri, Veronica Menghi, Carlotta Stipa, Patrizia Avoni, Federica Provini, Lorenzo Muccioli, Luca Vignatelli, Stefania Mazzoni, Paolo Tinuper, Francesca Bisulli, Mostacci B., Licchetta L., Cacciavillani C., Di Vito L., Ferri L., Menghi V., Stipa C., Avoni P., Provini F., Muccioli L., Vignatelli L., Mazzoni S., Tinuper P., and Bisulli F.

Subjects
Telemedicine, medicine.medical_specialty, business.industry, emergency, COVID-19, Computer-assisted web interviewing, Affect (psychology), Logistic regression, medicine.disease, lcsh:RC346-429, Test (assessment), Exact test, Epilepsy, Neurology, Emergency medicine, Health care, Medicine, epilepsy, survey, Neurology (clinical), telemedicine, business, lcsh:Neurology. Diseases of the nervous system, Original Research
Abstract

Objectives: We explored the impact of the coronavirus disease-19 (COVID-19) emergency on the health of people with epilepsy (PwE). We also investigated their attitude toward telemedicine.Methods: The PubMed database up to September 10, 2020 was searched for questionnaire-based studies conducted in PwE during the COVID-19 emergency, and the literature retrieved was reviewed. In addition, all patients who had a telephone consultation with our center between May 7 and July 31, 2020 were invited to fill in a 57-item online questionnaire focusing on epilepsy and comorbidities, any changes in lifestyle or clinical conditions and any emergency-related problems arising during the COVID-19 emergency, and their views on telemedicine. Associations between variables were detected through X2 test and Fisher's exact test. Univariate and multivariate logistic regression models were used to evaluate the effects of different factors on clinical conditions.Results: Twelve studies met the literature search criteria. They showed that the rate of seizure worsening during the emergency ranged from 4 to 35% and was mainly correlated with epilepsy severity, sleep disturbances and COVID-19-related issues. Our questionnaire was filled in by 222 PwE or caregivers. One hundred (76.6%) reported unchanged clinical conditions, 25 (11.3%) an improvement, and 27 (12%) a deterioration. Reported clinical worsening was associated with a psychiatric condition and/or medication (OR = 12.59, p < 0.001), sleep disorders (OR = 8.41, p = 0.001), limited access to healthcare (OR = 4.71, p = 0.016), and experiencing seizures during the emergency (OR = 4.51, p = 0.007). Telemedicine was considered acceptable by 116 subjects (52.3%).Conclusions: Most PwE did not experience a significant change in their clinical conditions during the COVID-19 emergency. However, severity of epilepsy, concomitant disability, comorbid psychiatric conditions, sleep disorders and limited access to healthcare may affect their health.

Published
2020

15. Relationship between cephalometric parameters and the apnoea-hypopnoea index in OSA patients: a retrospective cohort study

Author

Matteo Cameli, Daniela Rita Ippolito, Giulio Alessandri-Bonetti, Chiara Stipa, Irene Pelligra, Giovanni Sorrenti, Stipa C., Cameli M., Sorrenti G., Ippolito D.R., Pelligra I., and Alessandri Bonetti G.

Subjects
Adult, obstructive sleep apnoea, Cephalometry, Orthodontics, Severity of Illness Index, Body Mass Index, 03 medical and health sciences, 0302 clinical medicine, stomatognathic system, Tongue, medicine, Humans, 030212 general & internal medicine, apnoea-hypopnoea index, Retrospective Studies, Sleep Apnea, Obstructive, Soft palate, business.industry, Hyoid bone, Confounding, Hyoid Bone, Sleep apnea, Retrospective cohort study, 030206 dentistry, Craniometry, medicine.disease, cephalometric parameters, nervous system diseases, respiratory tract diseases, medicine.anatomical_structure, Jaw, Palate, Soft, business, Body mass index
Abstract

OBJECTIVE: The purpose of this study was to assess the relationship between cephalometric parameters and apnoea-hypopnoea index (AHI) controlling for the effect of gender, age, and body mass index (BMI) on a large sample of patients with obstructive sleep apnoea (OSA). METHODS: This retrospective cohort study was conducted on the lateral cephalograms of 253 Caucasian adult OSA patients. Cephalometric analyses were performed using 14 parameters for skeletal and soft tissue morphology, including antero-posterior and vertical jaw relationships, hyoid bone position, soft palate length and thickness, airway space, and tongue length and height. A hierarchical regression was run to examine the amount of variability in AHI that cephalometric variables explained after controlling for patients' general characteristics (gender, age, and BMI). RESULTS: After controlling for gender, age, and BMI, the increase in AHI variance accounted for by cephalometric parameters was equal to 0.103. Among the cephalometric variables, only MP-H and PNS-P were statistically significant (P < 0.05). LIMITATIONS: Given the retrospective nature of the study, it is difficult to assess whether other confounding variables not considered in the present study could have influenced the relationship between cephalometric parameters and AHI. CONCLUSIONS: This study revealed the existence of a relationship between OSA severity and some cephalometric parameters. Indeed soft palate length and vertical position of the hyoid bone were significant predictors of AHI in adult Caucasian OSA patients.

Published
2020

16. Whole-exome sequencing in adult patients with developmental and epileptic encephalopathy: It is never too late

Author

Paolo Tinuper, Barbara Mostacci, Laura Licchetta, Raffaella Minardi, Marco Seri, Carlotta Stipa, Valerio Carelli, Francesca Bisulli, Maria Chiara Baroni, Giulia Severi, Tommaso Pippucci, Luca Bergonzini, Francesco Toni, Minardi R., Licchetta L., Baroni M.C., Pippucci T., Stipa C., Mostacci B., Severi G., Toni F., Bergonzini L., Carelli V., Seri M., Tinuper P., and Bisulli F.

Subjects
Adult, Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Delayed Diagnosis, Adolescent, Genomics, RARS2, 030105 genetics & heredity, Cohort Studies, Young Adult, 03 medical and health sciences, Epilepsy, Exome Sequencing, Intellectual disability, Genetics, medicine, Humans, Exome, Genetic Predisposition to Disease, Genetic Testing, Child, Genetics (clinical), Exome sequencing, Aged, Genetic testing, medicine.diagnostic_test, business.industry, Genetic heterogeneity, Infant, Arginine-tRNA Ligase, Middle Aged, medicine.disease, Cytoskeletal Proteins, 030104 developmental biology, Neurodevelopmental Disorders, intellectual disability, Child, Preschool, Cohort, APC2, Medical genetics, epilepsy, WES, Female, genetic, business
Abstract

Developmental and epileptic encephalopathies (DEE) encompass rare, sporadic neurodevelopmental disorders and usually with pediatric onset. As these conditions are characterized by marked clinical and genetic heterogeneity, whole-exome sequencing (WES) represents the strategy of choice for the molecular diagnosis. While its usefulness is well-established in pediatric DEE cohorts, our study is aimed at assessing the WES feasibility in adult DEE patients who experienced a diagnostic odyssey prior to the advent of this technique. We analyzed exomes from 71 unrelated adult DEE patients, consecutively recruited from an Italian cohort for the EPI25 Project. All patients underwent accurate clinical and electrophysiological characterization. An overwhelming percentage (90.1%) had already undergone negative genetic testing. Variants were classified according to the American College of Medical Genetics and Genomics guidelines. WES disclosed 24 (likely) pathogenic variants among 18 patients in epilepsy-related genes with either autosomal dominant, recessive or X-linked inheritance. Ten of these were novel. We obtained a diagnostic yield of 25.3%, higher among patients with brain malformations, early-onset epilepsy and dysmorphisms. Despite a median diagnostic delay of 38.7 years, WES analysis provided the long-awaited diagnosis for 18 adult patients, which also had an impact on the clinical management of 50% of them. This article is protected by copyright. All rights reserved.

Published
2020

18. Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals

Author

Yen-Chen Anne Feng, Daniel P. Howrigan, Liam E. Abbott, Katherine Tashman, Felecia Cerrato, Tarjinder Singh, Henrike Heyne, Andrea Byrnes, Claire Churchhouse, Nick Watts, Matthew Solomonson, Dennis Lal, Erin L. Heinzen, Ryan S. Dhindsa, Kate E. Stanley, Gianpiero L. Cavalleri, Hakon Hakonarson, Ingo Helbig, Roland Krause, Patrick May, Sarah Weckhuysen, Slavé Petrovski, Sitharthan Kamalakaran, Sanjay M. Sisodiya, Patrick Cossette, Chris Cotsapas, Peter De Jonghe, Tracy Dixon-Salazar, Renzo Guerrini, Patrick Kwan, Anthony G. Marson, Randy Stewart, Chantal Depondt, Dennis J. Dlugos, Ingrid E. Scheffer, Pasquale Striano, Catharine Freyer, Kevin McKenna, Brigid M. Regan, Susannah T. Bellows, Costin Leu, Caitlin A. Bennett, Esther M.C. Johns, Alexandra Macdonald, Hannah Shilling, Rosemary Burgess, Dorien Weckhuysen, Melanie Bahlo, Terence J. O’Brien, Marian Todaro, Hannah Stamberger, Danielle M. Andrade, Tara R. Sadoway, Kelly Mo, Heinz Krestel, Sabina Gallati, Savvas S. Papacostas, Ioanna Kousiappa, George A. Tanteles, Katalin Štěrbová, Markéta Vlčková, Lucie Sedláčková, Petra Laššuthová, Karl Martin Klein, Felix Rosenow, Philipp S. Reif, Susanne Knake, Wolfram S. Kunz, Gábor Zsurka, Christian E. Elger, Jürgen Bauer, Michael Rademacher, Manuela Pendziwiat, Hiltrud Muhle, Annika Rademacher, Andreas van Baalen, Sarah von Spiczak, Ulrich Stephani, Zaid Afawi, Amos D. Korczyn, Moien Kanaan, Christina Canavati, Gerhard Kurlemann, Karen Müller-Schlüter, Gerhard Kluger, Martin Häusler, Ilan Blatt, Johannes R. Lemke, Ilona Krey, Yvonne G. Weber, Stefan Wolking, Felicitas Becker, Christian Hengsbach, Sarah Rau, Ana F. Maisch, Bernhard J. Steinhoff, Andreas Schulze-Bonhage, Susanne Schubert-Bast, Herbert Schreiber, Ingo Borggräfe, Christoph J. Schankin, Thomas Mayer, Rudolf Korinthenberg, Knut Brockmann, Dieter Dennig, Rene Madeleyn, Reetta Kälviäinen, Pia Auvinen, Anni Saarela, Tarja Linnankivi, Anna-Elina Lehesjoki, Mark I. Rees, Seo-Kyung Chung, William O. Pickrell, Robert Powell, Natascha Schneider, Simona Balestrini, Sara Zagaglia, Vera Braatz, Michael R. Johnson, Pauls Auce, Graeme J. Sills, Larry W. Baum, Pak C. Sham, Stacey S. Cherny, Colin H.T. Lui, Nina Barišić, Norman Delanty, Colin P. Doherty, Arif Shukralla, Mark McCormack, Hany El-Naggar, Laura Canafoglia, Silvana Franceschetti, Barbara Castellotti, Tiziana Granata, Federico Zara, Michele Iacomino, Francesca Madia, Maria Stella Vari, Maria Margherita Mancardi, Vincenzo Salpietro, Francesca Bisulli, Paolo Tinuper, Laura Licchetta, Tommaso Pippucci, Carlotta Stipa, Raffaella Minardi, Antonio Gambardella, Angelo Labate, Grazia Annesi, Lorella Manna, Monica Gagliardi, Elena Parrini, Davide Mei, Annalisa Vetro, Claudia Bianchini, Martino Montomoli, Viola Doccini, Carla Marini, Toshimitsu Suzuki, Yushi Inoue, Kazuhiro Yamakawa, Birute Tumiene, Lynette G. Sadleir, Chontelle King, Emily Mountier, S. Hande Caglayan, Mutluay Arslan, Zuhal Yapıcı, Uluc Yis, Pınar Topaloglu, Bulent Kara, Dilsad Turkdogan, Aslı Gundogdu-Eken, Nerses Bebek, Sibel Uğur-İşeri, Betül Baykan, Barış Salman, Garen Haryanyan, Emrah Yücesan, Yeşim Kesim, Çiğdem Özkara, Annapurna Poduri, Beth R. Shiedley, Catherine Shain, Russell J. Buono, Thomas N. Ferraro, Michael R. Sperling, Warren Lo, Michael Privitera, Jacqueline A. French, Steven Schachter, Ruben I. Kuzniecky, Orrin Devinsky, Manu Hegde, Pouya Khankhanian, Katherine L. Helbig, Colin A. Ellis, Gianfranco Spalletta, Fabrizio Piras, Federica Piras, Tommaso Gili, Valentina Ciullo, Andreas Reif, Andrew McQuillin, Nick Bass, Andrew McIntosh, Douglas Blackwood, Mandy Johnstone, Aarno Palotie, Michele T. Pato, Carlos N. Pato, Evelyn J. Bromet, Celia Barreto Carvalho, Eric D. Achtyes, Maria Helena Azevedo, Roman Kotov, Douglas S. Lehrer, Dolores Malaspina, Stephen R. Marder, Helena Medeiros, Christopher P. Morley, Diana O. Perkins, Janet L. Sobell, Peter F. Buckley, Fabio Macciardi, Mark H. Rapaport, James A. Knowles, Ayman H. Fanous, Steven A. McCarroll, Namrata Gupta, Stacey B. Gabriel, Mark J. Daly, Eric S. Lander, Daniel H. Lowenstein, David B. Goldstein, Holger Lerche, Samuel F. Berkovic, Benjamin M. Neale, Wellcome Trust, Department of Health, Institute of Neurology, UCL, Imperial College Healthcare NHS Trust- BRC Funding, Commission of the European Communities, Medical Research Council (MRC), Feng Y.-C.A., Howrigan D.P., Abbott L.E., Tashman K., Cerrato F., Singh T., Heyne H., Byrnes A., Churchhouse C., Watts N., Solomonson M., Lal D., Heinzen E.L., Dhindsa R.S., Stanley K.E., Cavalleri G.L., Hakonarson H., Helbig I., Krause R., May P., Weckhuysen S., Petrovski S., Kamalakaran S., Sisodiya S.M., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Kwan P., Marson A.G., Stewart R., Depondt C., Dlugos D.J., Scheffer I.E., Striano P., Freyer C., McKenna K., Regan B.M., Bellows S.T., Leu C., Bennett C.A., Johns E.M.C., Macdonald A., Shilling H., Burgess R., Weckhuysen D., Bahlo M., O'Brien T.J., Todaro M., Stamberger H., Andrade D.M., Sadoway T.R., Mo K., Krestel H., Gallati S., Papacostas S.S., Kousiappa I., Tanteles G.A., Sterbova K., Vlckova M., Sedlackova L., Lassuthova P., Klein K.M., Rosenow F., Reif P.S., Knake S., Kunz W.S., Zsurka G., Elger C.E., Bauer J., Rademacher M., Pendziwiat M., Muhle H., Rademacher A., van Baalen A., von Spiczak S., Stephani U., Afawi Z., Korczyn A.D., Kanaan M., Canavati C., Kurlemann G., Muller-Schluter K., Kluger G., Hausler M., Blatt I., Lemke J.R., Krey I., Weber Y.G., Wolking S., Becker F., Hengsbach C., Rau S., Maisch A.F., Steinhoff B.J., Schulze-Bonhage A., Schubert-Bast S., Schreiber H., Borggrafe I., Schankin C.J., Mayer T., Korinthenberg R., Brockmann K., Dennig D., Madeleyn R., Kalviainen R., Auvinen P., Saarela A., Linnankivi T., Lehesjoki A.-E., Rees M.I., Chung S.-K., Pickrell W.O., Powell R., Schneider N., Balestrini S., Zagaglia S., Braatz V., Johnson M.R., Auce P., Sills G.J., Baum L.W., Sham P.C., Cherny S.S., Lui C.H.T., Barisic N., Delanty N., Doherty C.P., Shukralla A., McCormack M., El-Naggar H., Canafoglia L., Franceschetti S., Castellotti B., Granata T., Zara F., Iacomino M., Madia F., Vari M.S., Mancardi M.M., Salpietro V., Bisulli F., Tinuper P., Licchetta L., Pippucci T., Stipa C., Minardi R., Gambardella A., Labate A., Annesi G., Manna L., Gagliardi M., Parrini E., Mei D., Vetro A., Bianchini C., Montomoli M., Doccini V., Marini C., Suzuki T., Inoue Y., Yamakawa K., Tumiene B., Sadleir L.G., King C., Mountier E., Caglayan S.H., Arslan M., Yapici Z., Yis U., Topaloglu P., Kara B., Turkdogan D., Gundogdu-Eken A., Bebek N., Ugur-Iseri S., Baykan B., Salman B., Haryanyan G., Yucesan E., Kesim Y., Ozkara C., Poduri A., Shiedley B.R., Shain C., Buono R.J., Ferraro T.N., Sperling M.R., Lo W., Privitera M., French J.A., Schachter S., Kuzniecky R.I., Devinsky O., Hegde M., Khankhanian P., Helbig K.L., Ellis C.A., Spalletta G., Piras F., Gili T., Ciullo V., Reif A., McQuillin A., Bass N., McIntosh A., Blackwood D., Johnstone M., Palotie A., Pato M.T., Pato C.N., Bromet E.J., Carvalho C.B., Achtyes E.D., Azevedo M.H., Kotov R., Lehrer D.S., Malaspina D., Marder S.R., Medeiros H., Morley C.P., Perkins D.O., Sobell J.L., Buckley P.F., Macciardi F., Rapaport M.H., Knowles J.A., Fanous A.H., McCarroll S.A., Gupta N., Gabriel S.B., Daly M.J., Lander E.S., Lowenstein D.H., Goldstein D.B., Lerche H., Berkovic S.F., Neale B.M., Epi25 Collaborative, YÜCESAN, EMRAH, Institute for Molecular Medicine Finland, Children's Hospital, HUS Children and Adolescents, Department of Medical and Clinical Genetics, University Management, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, and Genomics of Neurological and Neuropsychiatric Disorders

Subjects
s.berkovic@unimelb.edu.au [Epi25 Collaborative. Electronic address], 0301 basic medicine, GAMMA-2-SUBUNIT, burden analysi, DNA Mutational Analysis, PROTEIN, Neurodegenerative, VARIANTS, SUSCEPTIBILITY, Medical and Health Sciences, Epilepsy, 0302 clinical medicine, 2.1 Biological and endogenous factors, EPIDEMIOLOGY, Missense mutation, Exome, Aetiology, Genetics (clinical), Exome sequencing, 11 Medical and Health Sciences, seizures, GABRG2, Genetics, Genetics & Heredity, 0303 health sciences, biology, COMMON EPILEPSIES, 1184 Genetics, developmental biology, physiology, sequencing, Biological Sciences, Epi25 Collaborative, Phenotype, GENOME, epileptic encephalopathy, burden analysis, Neurological, Biotechnology, Genetic Markers, seizure, EEF1A2, Burden analysis, epilepsy, exome, Article, 03 medical and health sciences, Clinical Research, Exome Sequencing, Genetic variation, medicine, Humans, Genetic Predisposition to Disease, Gene, EPILEPTIC SEIZURES, METAANALYSIS, 030304 developmental biology, Human Genome, Neurosciences, Genetic Variation, 06 Biological Sciences, medicine.disease, Brain Disorders, 030104 developmental biology, Genetic marker, DE-NOVO MUTATIONS, Case-Control Studies, biology.protein, 3111 Biomedicine, Human medicine, 030217 neurology & neurosurgery
Abstract

Sequencing-based studies have identified novel risk genes for rare, severe epilepsies and revealed a role of rare deleterious variation in common epilepsies. To identify the shared and distinct ultra-rare genetic risk factors for rare and common epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,364 controls of European ancestry. We focused on three phenotypic groups; the rare but severe developmental and epileptic encephalopathies (DEE), and the commoner phenotypes of genetic generalized epilepsy (GGE) and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy, with the strongest enrichment seen in DEE and the least in NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, while no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEE and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the top associations, including CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study confirms a convergence in the genetics of common and rare epilepsies associated with ultra-rare coding variation and highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology in the largest epilepsy WES study to date.

Published
2019

19. Autosomal dominant partial epilepsy with auditory features: A new locus on chromosome 19q13.11-q13.31

Author

Carlotta Stipa, Tommaso Pippucci, Simona Ferrari, Paolo Tinuper, Giovanni Castegnaro, Francesca Bisulli, Pamela Magini, Sara Baldassari, Marco Seri, Margherita Fabbri, Gilson Edmar Gonçalves e Silva, Ilaria Naldi, Laura Licchetta, Bisulli F, Naldi I, Baldassari S, Magini P, Licchetta L, Castegnaro G, Fabbri M, Stipa C, Ferrari S, Seri M, Gonçalves Silva GE, Tinuper P, and Pippucci T

Subjects
Adult, Male, Sleep Wake Disorders, Candidate gene, Adolescent, Genetic Linkage, Epilepsy, Frontal Lobe, autosomal dominant partial epilepsy with auditory feature, 19q13.11-q13.31, Single-nucleotide polymorphism, Locus (genetics), Biology, Bioinformatics, Polymorphism, Single Nucleotide, Young Adult, Epilepsy, Gene mapping, Genetic linkage, Chromosome 19, medicine, Humans, Genetic Predisposition to Disease, Genetics, Haplotype, Chromosome Mapping, Middle Aged, medicine.disease, new locu, Haplotypes, Neurology, Genetic Loci, Female, Neurology (clinical), Lod Score, Chromosomes, Human, Pair 19
Abstract

Summary Objective To clinically and genetically characterize a large Brazilian family with autosomal dominant partial epilepsy with auditory features (ADPEAF) not related to leucine-rich, glioma-inactivated 1 (LGI1) gene. Methods Seventy family members (four married-ins) participating in the study were assessed by a detailed clinical interview and a complete neurologic examination. Genetic mapping was conducted through autosome-wide single nucleotide polymorphism (SNP) genotyping and subsequent linkage analysis on 16 and haplotype analysis on 25 subjects, respectively. Results The pedigree comprised 15 affected members, of whom 11 were included in the study (male/female: 6/5; mean age 39.5 years). All but two (III:22 and IV:92) had focal seizures with auditory aura followed by secondary generalization in 44.4%. The mean age at onset of epilepsy seizures was 13.7 years. Initial autosome-wide SNP linkage analysis conducted on 12 subjects (8 affected) pointed to a single genomic region on chromosome 19 with a maximum multipoint logarithm of the odds (LOD) score of 2.60. Further refinement of this region through SNP and microsatellite genotyping on 16 subjects (11 affected) increased the LOD score to 3.41, thereby establishing 19q13.11–q13.31 as a novel ADPEAF locus. Haplotype analysis indicated that the underlying mutation is most likely located in a 9.74 Mb interval between markers D19S416 and D19S420. Sequence analysis of the most prominent candidate genes within this critical interval (SCN1B, LGI4, KCNK6, and LRFN1) did not reveal any mutation. Significance This study disclosed a novel ADPEAF locus on chromosome 19q13.11–q13.31, contributing to future identification of a second dominant gene for this epileptic syndrome. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Published
2014

21. Videopolygraphic and functional MRI study of musicogenic epilepsy. A case report and literature review

Author

Antonietta Bisulli, Paolo Tinuper, Pietro Cortelli, Agostino Baruzzi, Francesca Pittau, Carlotta Stipa, Ilaria Naldi, Raffaele Agati, Francesca Bisulli, Marco Leonardi, Daniela Cevolani, Pittau F., Tinuper P., Bisulli F., Naldi I., Cortelli P., Bisulli A., Stipa C., Cevolani D., Agati R., Leonardi M., and Baruzzi A.

Subjects
Adult, Male, Electroencephalography, Right temporal lobe, Auditory cortex, behavioral disciplines and activities, Brain mapping, Epilepsy, Reflex, Behavioral Neuroscience, Epilepsy, Reflex Epilepsy, Image Processing, Computer-Assisted, medicine, Humans, Brain Mapping, medicine.diagnostic_test, Brain, Videotape Recording, Musicogenic epilepsy, medicine.disease, Magnetic Resonance Imaging, humanities, Oxygen, Neurology, Reflex epilepsy, Musicogenic epilepsy, Epilepsy and music, Neurology (clinical), Psychology, Neuroscience, Music, psychological phenomena and processes, Period (music)
Abstract

A 36-year-old right-handed man, who had experienced partial seizures since the age of 24 every time he played or listened to music with a strong emotional charge, underwent videopolygraphic recording, including autonomic variables, and brain fMRI study during which he listened to both ‘‘neutral” and ‘‘emotionally charged” music. Three right temporal seizures recorded during videopolygraphic monitoring were elicited by listening to the triggering song. The fMRI study disclosed activation in right acoustic areas during ‘‘neutral music,” whereas an ‘‘emotionally charged melody” provoked widespread activation over the right fronto-temporo-occipital area before seizure onset. The literature review disclosed 110 published cases of musicogenic epilepsy that seemed to suggest a right-sided predominance of the epileptogenic zone. Our results support the role of the right temporal lobe in musicogenic epilepsy and demonstrate that the cerebral areas activated during the period of strong emotion leading to the seizures encompass the auditory cortex activated by neutral music.

Published
2008

22. LGI1 microdeletions are not a frequent cause of partial epilepsy with auditory features (PEAF)

Author

Paolo Tinuper, Sara Baldassari, Ilaria Naldi, Veronica Menghi, Carlotta Stipa, Laura Licchetta, Francesca Bisulli, Pamela Magini, Marco Seri, Tommaso Pippucci, Magini P, Bisulli F, Baldassari S, Stipa C, Naldi I, Licchetta L, Menghi V, Tinuper P, Seri M, and Pippucci T

Subjects
Adult, Male, Adolescent, DNA Mutational Analysis, Biology, Bioinformatics, Young Adult, Epilepsy, Genetic heterogeneity, PEAF, medicine, Humans, Multiplex ligation-dependent probe amplification, Young adult, Diagnostic screening, Single family, Aged, Sequence Deletion, Partial epilepsy, Genetics, Epilepsy, Partial, Sensory, Point mutation, Intracellular Signaling Peptides and Proteins, Proteins, Middle Aged, medicine.disease, MLPA, LTE, Neurology, Microdeletion, Female, LGI1, Neurology (clinical), Multiplex Polymerase Chain Reaction
Abstract

Heterozygous mutations of the leucine-rich, glioma-inactivated 1 gene (LGI1) are the major known cause of partial epilepsy with auditory features (PEAF), accounting for roughly 50% of families. Recently, a partial gene microdeletion has been reported in a single family. To assess the contribution of LGI1 microrearrangements to the pathogenesis of PEAF, we screened 50 patients negative for point mutations through multiplex ligation-dependent probe amplification (MLPA) analysis. No cryptic imbalances were found in LGI1, suggesting that LGI1 microdeletions are not a frequent cause of PEAF. Despite the small number of examined patients and the need for replication studies, these findings support the hypothesis that diagnostic screening for LGI1 microrearrangements lacks clinical utility, especially for sporadic cases, and further highlight genetic heterogeneity of familial and sporadic PEAF.

Published
2014

23. Semiological study of ictal affective behaviour in epilepsy and mental retardation limited to females (EFMR)

Author

Massimo Mastrangelo, Barbara Mostacci, Carlotta Stipa, Paolo Tinuper, Luigina Spaccini, Davide Mei, Francesca Bisulli, Elena Antelmi, Renzo Guerrini, Antelmi E., Mastrangelo M., Bisulli F., Spaccini L., Stipa C., Mostacci B., Mei D., Guerrini R., and Tinuper P.

Subjects
medicine.medical_specialty, Neurology, protocadherin 19, Electroencephalography, Audiology, Epilepsy, Seizures, Intellectual Disability, Medicine, Humans, Ictal, EEG, Psychiatry, Neuroradiology, ictal fear, medicine.diagnostic_test, business.industry, Neuropsychology, Genetic disorder, General Medicine, medicine.disease, Cognitive regression, epilepsy and mental retardation, Stroke, Mutation, Female, Neurology (clinical), business
Abstract

Epilepsy and mental retardation limited to females (EFMR) is a genetic disorder that affects females but spares transmitting males. The condition is caused by protocadherin 19 mutations and is characterised by seizures beginning at around 1 year of age, frequently associated with cognitive regression at seizure onset or later. Seizures can be generalised or focal, exacerbated by febrile illnesses, and grouped in clusters. This report shows the first video-EEG recording of EFMR, in a 7-year-old female presenting peculiar ictal features. [ Published with video sequences]

Published
2012

24. Diagnostic accuracy of a structured interview for nocturnal frontal lobe epilepsy (SINFLE): a proposal for developing diagnostic criteria

Author

Federica Provini, Ilaria Naldi, Luca Vignatelli, Giuseppe Plazzi, Francesca Bisulli, Pasquale Montagna, Francesca Pittau, Paolo Tinuper, Chiara Leta, Carlotta Stipa, Bisulli F., Vignatelli L., Naldi I., Pittau F., Provini F., Plazzi G., Stipa C., Leta C., Montagna P., and Tinuper P.

Subjects
Questionnaires, Adult, Male, Sleep Wake Disorders, medicine.medical_specialty, Pediatrics, Parasomnias, Adolescent, Aura, Somnambulism, Epilepsy, Frontal Lobe, Disease, Sensitivity and Specificity, Interviews as Topic, Epilepsy, Young Adult, medicine, Odds Ratio, Nocturnal frontal lobe epilepsy, Sleep disorders, Sensitivity and specificity, Medical history taking, Humans, Young adult, Psychiatry, Child, Aged, Aged, 80 and over, Sleep disorder, Likelihood Functions, Confounding, Case-control study, General Medicine, Odds ratio, Middle Aged, medicine.disease, Parasomnia, Case-Control Studies, Structured interview, Female, Psychology
Abstract

Objectives To measure the accuracy of anamnestic features collected during clinical history for the diagnosis of nocturnal frontal lobe epilepsy (NFLE). Methods A case-control diagnostic study. Participants included a case group of people with ascertained target disease (NFLE group) and a control group of people with sleep disorders potentially confounding for NFLS (NOT-NFLE group), defined by means of a consensus procedure among experts (panel diagnosis as reference standard). Two major clinical patterns defining the semeiology of the epileptic event (i.e. dystonic, DP, and/or hyperkinetic pattern, HP), and 13 additional minor features were identified, formulated as questions, and telephonically administered to NFLE and NOT-NFLE groups by a trained doctor blinded to the final diagnosis. The diagnostic accuracy of each characteristic was tested against the reference standard. Results Out of 262 selected subjects, 101 were recruited; 42 were NFLE and 59 NOT-NFLE. A positive history of DP or HP had a sensitivity of 59.5% and a specificity of 91.5%, irrespective of the other minor anamnestic features. The anamnestic model improved, with a sensitivity of 59.5% and specificity of 96.6%, if at least one of the following four minor anamnestic features was added: (a) duration less than two minutes, (b) unstructured vocalization during the episode, (c) experience of an aura preceding the motor attack, and (d) a history of tonic-clonic seizures during sleep. Conclusions The present study disclosed two major anamnestic patterns and four minor features that we called SINFLE, with unsatisfactory sensitivity but high specificity. These patterns could be the basis for developing future NFLE diagnostic criteria and to quantify the diagnostic accuracy of elements usually collected in the clinical history.

Published
2011

25. Epilepsy with auditory features

Author

Francesca Bisulli, Paolo Tinuper, Tommaso Pippucci, Marco Seri, G. Boero, Carlotta Stipa, Laura Licchetta, Alberto Magi, Chiara Leta, Ingrid E. Scheffer, Sara Baldassari, Veronica Menghi, Giuseppe d'Orsi, Romina D'Aurizio, Flavia Palombo, Pippucci, T., Licchetta, L., Baldassari, S., Palombo, F., Menghi, V., D'Aurizio, R., Leta, C., Stipa, C., Boero, G., D'Orsi, G., Magi, A., Scheffer, I., Seri, M., Tinuper, P., and Bisulli, F.

Subjects
Proband, CNTNAP2, epilepsy with auditory feature, Biology, medicine.disease_cause, Article, Genetics, medicine, Missense mutation, Copy-number variation, Genetics (clinical), Mutation, EAF, DEPDC5, Phenotype, 3. Good health, CNV, epilepsy with auditory features, Potassium channel complex, LGI1, Neurology (clinical), Neurology disease
Abstract

Objective: To identify novel genes implicated in epilepsy with auditory features (EAF) in phenotypically heterogeneous families with unknown molecular basis. Methods: We identified 15 probands with EAF in whom an LGI1 mutation had been excluded. We performed electroclinical phenotyping on all probands and available affected relatives. We used whole-exome sequencing (WES) in 20 individuals with EAF (including all the probands and 5 relatives) to identify single nucleotide variants, small insertions/deletions, and copy number variants. Results: WES revealed likely pathogenic variants in genes that had not been previously associated with EAF: a CNTNAP2 intragenic deletion, 2 truncating mutations of DEPDC5, and a missense SCN1A change. Conclusions: EAF is a clinically and molecularly heterogeneous disease. The association of EAF with CNTNAP2, DEPDC5 ,a ndSCN1A mutations widens the phenotypic spectrum related to these genes. CNTNAP2 encodes CASPR2, a member of the voltage-gated potassium channel complex in which LGI1 plays a role. The finding of a CNTNAP2 deletion emphasizes the importance of this complex in EAF and shows biological convergence. Neurol Genet 2015;1:e5; doi

Published
2015

26. Neuropsychological impairment in patients with early onset nocturnal frontal lobe epilepsy

Author

Mostacci, Barbara, Bianchi, Francesca, Poda, Roberto, Francesca Bisulli, Federica Provini, Oppi, Federico, Naldi, Ilaria, Licchetta, Laura, Annio Posar, CARLOTTA STIPA, Gallassi, Roberto, paolo tinuper, Mostacci B., Bianchi F., Poda R., Bisulli F., Provini F., Oppi F., Naldi I., Licchetta L., Posar A., Stipa C., Gallassi R., and Tinuper P.

Subjects
Epilessia frontale notturna, Neuropsicologia, Funzioni cognitive

27. Cerebral areas involved in music perception: Studying musicogenic epilepsy

Author

Pittau, F., Bisulli, F., CARLOTTA STIPA, Naldi, I., Licchetta, L., Di Vito, L., Cevolani, D., Agati, R., Tinuper, P., T.E. IVANOVA, Pittau F., Bisulli F., Stipa C., Naldi I., Licchetta L., Di Vito L., Cevolani D., Agati R., and Tinuper P.

Subjects
behavioral disciplines and activities, humanities
Abstract

Functional cerebral areas involved in listening to emotionally charged music are wider than those activated by neutral music. Based on the pathophysiology of musicogenic epilepsy, a rare form of complex reflex epilepsy in which seizures are triggered by music, we can infer the functional organization of the brain's processing of music. We studied a 36-year-old, right-handed male amateur musician, who has had weekly epileptic partial seizures every time he listened to or played music with a strong emotional charge since the age of 24 years. The patient underwent prolonged video-polygraphic recording which documented three right temporal seizures preceded for several seconds by an increase in heart rate and blood pressure, all triggered by listening to music with an emotional content. During functional neuroimaging (fMRI) he listened to both "neutral" and "emotionally charged" music. The “neutral music” activated only a small eloquent area in the right temporal lobe (acoustic area), whereas an “emotionally charged melody" activated diffuse eloquent areas on the fronto-temporo-occipital lobes of the right hemisphere before seizure onset. Numerous studies have demonstrated the predominant involvement of right hemisphere structures in networks involved in processing musical information. Most cases of musicogenic epilepsy showed the dominant role of the right temporal lobe disclosed by functional neuroimaging and neurophysiological techniques. The triggering stimulus in our patient seems to be a strong emotional feeling induced by specific melodies, as his seizures were preceded by an increase in heart rate and blood pressure. Our results emphasize the role of the right temporal lobe in musicogenic epilepsy and show that the cerebral areas activated during the emotional status leading to seizures encompass the auditory cortex activated by neutral music.

28. Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes.

Author

Chen S, Abou-Khalil BW, Afawi Z, Ali QZ, Amadori E, Anderson A, Anderson J, Andrade DM, Annesi G, Arslan M, Auce P, Bahlo M, Baker MD, Balagura G, Balestrini S, Banks E, Barba C, Barboza K, Bartolomei F, Bass N, Baum LW, Baumgartner TH, Baykan B, Bebek N, Becker F, Bennett CA, Beydoun A, Bianchini C, Bisulli F, Blackwood D, Blatt I, Borggräfe I, Bosselmann C, Braatz V, Brand H, Brockmann K, Buono RJ, Busch RM, Caglayan SH, Canafoglia L, Canavati C, Castellotti B, Cavalleri GL, Cerrato F, Chassoux F, Cherian C, Cherny SS, Cheung CL, Chou IJ, Chung SK, Churchhouse C, Ciullo V, Clark PO, Cole AJ, Cosico M, Cossette P, Cotsapas C, Cusick C, Daly MJ, Davis LK, Jonghe P, Delanty N, Dennig D, Depondt C, Derambure P, Devinsky O, Di Vito L, Dickerson F, Dlugos DJ, Doccini V, Doherty CP, El-Naggar H, Ellis CA, Epstein L, Evans M, Faucon A, Feng YA, Ferguson L, Ferraro TN, Da Silva IF, Ferri L, Feucht M, Fields MC, Fitzgerald M, Fonferko-Shadrach B, Fortunato F, Franceschetti S, French JA, Freri E, Fu JM, Gabriel S, Gagliardi M, Gambardella A, Gauthier L, Giangregorio T, Gili T, Glauser TA, Goldberg E, Goldman A, Goldstein DB, Granata T, Grant R, Greenberg DA, Guerrini R, Gundogdu-Eken A, Gupta N, Haas K, Hakonarson H, Haryanyan G, Häusler M, Hegde M, Heinzen EL, Helbig I, Hengsbach C, Heyne H, Hirose S, Hirsch E, Ho CJ, Hoeper O, Howrigan DP, Hucks D, Hung PC, Iacomino M, Inoue Y, Inuzuka LM, Ishii A, Jehi L, Johnson MR, Johnstone M, Kälviäinen R, Kanaan M, Kara B, Kariuki SM, Kegele J, Kesim Y, Khoueiry-Zgheib N, Khoury J, King C, Klein KM, Kluger G, Knake S, Kok F, Korczyn AD, Korinthenberg R, Koupparis A, Kousiappa I, Krause R, Krenn M, Krestel H, Krey I, Kunz WS, Kurlemann G, Kuzniecky RI, Kwan P, La Vega-Talbott M, Labate A, Lacey A, Lal D, Laššuthová P, Lauxmann S, Lawthom C, Leech SL, Lehesjoki AE, Lemke JR, Lerche H, Lesca G, Leu C, Lewin N, Lewis-Smith D, Li GH, Liao C, Licchetta L, Lin CH, Lin KL, Linnankivi T, Lo W, Lowenstein DH, Lowther C, Lubbers L, Lui CHT, Macedo-Souza LI, Madeleyn R, Madia F, Magri S, Maillard L, Marcuse L, Marques P, Marson AG, Matthews AG, May P, Mayer T, McArdle W, McCarroll SM, McGoldrick P, McGraw CM, McIntosh A, McQuillan A, Meador KJ, Mei D, Michel V, Millichap JJ, Minardi R, Montomoli M, Mostacci B, Muccioli L, Muhle H, Müller-Schlüter K, Najm IM, Nasreddine W, Neaves S, Neubauer BA, Newton CRJC, Noebels JL, Northstone K, Novod S, O'Brien TJ, Owusu-Agyei S, Özkara Ç, Palotie A, Papacostas SS, Parrini E, Pato C, Pato M, Pendziwiat M, Pennell PB, Petrovski S, Pickrell WO, Pinsky R, Pinto D, Pippucci T, Piras F, Piras F, Poduri A, Pondrelli F, Posthuma D, Powell RHW, Privitera M, Rademacher A, Ragona F, Ramirez-Hamouz B, Rau S, Raynes HR, Rees MI, Regan BM, Reif A, Reinthaler E, Rheims S, Ring SM, Riva A, Rojas E, Rosenow F, Ryvlin P, Saarela A, Sadleir LG, Salman B, Salmon A, Salpietro V, Sammarra I, Scala M, Schachter S, Schaller A, Schankin CJ, Scheffer IE, Schneider N, Schubert-Bast S, Schulze-Bonhage A, Scudieri P, Sedláčková L, Shain C, Sham PC, Shiedley BR, Siena SA, Sills GJ, Sisodiya SM, Smoller JW, Solomonson M, Spalletta G, Sparks KR, Sperling MR, Stamberger H, Steinhoff BJ, Stephani U, Štěrbová K, Stewart WC, Stipa C, Striano P, Strzelczyk A, Surges R, Suzuki T, Talarico M, Talkowski ME, Taneja RS, Tanteles GA, Timonen O, Timpson NJ, Tinuper P, Todaro M, Topaloglu P, Tsai MH, Tumiene B, Turkdogan D, Uğur-İşeri S, Utkus A, Vaidiswaran P, Valton L, van Baalen A, Vari MS, Vetro A, Vlčková M, von Brauchitsch S, von Spiczak S, Wagner RG, Watts N, Weber YG, Weckhuysen S, Widdess-Walsh P, Wiebe S, Wolf SM, Wolff M, Wolking S, Wong I, von Wrede R, Wu D, Yamakawa K, Yapıcı Z, Yis U, Yolken R, Yücesan E, Zagaglia S, Zahnert F, Zara F, Zimprich F, Zizovic M, Zsurka G, Neale BM, and Berkovic SF

Abstract

Identifying genetic risk factors for highly heterogeneous disorders like epilepsy remains challenging. Here, we present the largest whole-exome sequencing study of epilepsy to date, with >54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets, and four copy number variants at exome-wide significance. Genes encoding ion channels show strong association with multiple epilepsy subtypes, including epileptic encephalopathies, generalized and focal epilepsies, while most other gene discoveries are subtype-specific, highlighting distinct genetic contributions to different epilepsies. Combining results from rare single nucleotide/short indel-, copy number-, and common variants, we offer an expanded view of the genetic architecture of epilepsy, with growing evidence of convergence among different genetic risk loci on the same genes. Top candidate genes are enriched for roles in synaptic transmission and neuronal excitability, particularly postnatally and in the neocortex. We also identify shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our data can be accessed via an interactive browser, hopefully facilitating diagnostic efforts and accelerating the development of follow-up studies., Competing Interests: Competing Interests B.M.N is a member of the scientific advisory board at Deep Genomics and Neumora. No other authors have competing interests to declare

Published
2024
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29. Tuberous sclerosis complex in adulthood: focus on epilepsy prognosis.

Author

Licchetta L, Bruschi G, Stipa C, Belotti LMB, Ferri L, Mostacci B, Vignatelli L, Minardi R, Di Vito L, Muccioli L, Boni A, Tinuper P, and Bisulli F

Subjects
Child, Adult, Adolescent, Humans, Child, Preschool, Anticonvulsants therapeutic use, Retrospective Studies, Seizures drug therapy, Prognosis, Spasm, Tuberous Sclerosis complications, Tuberous Sclerosis genetics, Tuberous Sclerosis drug therapy, Epilepsy etiology, Epilepsy complications
Abstract

Objective: Typically diagnosed in early childhood or adolescence, TSC is a chronic, multisystemic disorder with age-dependent manifestations posing a challenge for transition and for specific surveillance throughout the lifetime. Data on the clinical features and severity of TSC in adults and on the prognosis of epilepsy are scarce. We analyzed the clinical and genetic features of a cohort of adult patients with TSC, to identify the prognostic predictors of seizure remission after a long follow-up., Method: We conducted a retrospective analysis of patients diagnosed with TSC according to the updated international diagnostic criteria. Pearson's chi-square or Fisher's exact test and Mann Whitney U test were used to compare variables among the Remission (R) and Non-Remission (NR) group. Univariate and multivariate logistic regression analyses were performed., Results: We selected 43 patients with TSC and neurological involvement in terms of epilepsy and/or brain lesions, attending the Epilepsy Center of our Institute: of them, 16 (37.2%) were transitioning from the pediatric care and 6 (13.9%) were referred by other specialists. Multiorgan involvement includes cutaneous (86.0%), nephrological (70.7%), hepatic (40.0%), ocular (34.3%), pneumological (28.6%) and cardiac (26.3%) manifestations. Thirty-nine patients (90.7 %) had epilepsy. The mean age at seizure onset was 4 ± 7.3 years: most patients (29, 76.3 %) presented with focal seizures or spasms by age 3 years; only 2 (5.3 %) had seizure onset in adulthood. Twenty-seven patients (69.2 %) experienced multiple seizure types overtime, 23 (59.0 %) had intellectual disability (ID). At last assessment, 14 (35.9 %) were seizure free (R group) and 25 (64.1 %) had drug-resistant seizures (NR group). At logistic regression univariate analysis, ID (OR 7.9, 95 % CI 1.8--34.7), multiple seizure types lifelong (OR 13.2, 95 % CI 2.6- 67.2), spasms/tonic seizures at presentation (OR 6.5, 95 % CI 1.2--35.2), a higher seizure frequency at onset (OR 5.4, 95 % CI 1.2--24.3), abnormal neurological examination (OR 9.8, 95 % CI 1.1--90.6) and pathogenic variants in TSC2 (OR 5.4, 95 % CI 1.2--24.5) were significantly associated with non-remission. In the multivariate analysis, both ID and multiple seizure types lifelong were confirmed as independent predictors of poor seizure outcome., Conclusions: In our cohort of adult patients with TSC, epilepsy remains one of the main neurological challenges with only 5.3% of cases manifesting in adulthood. Approximately 64% of these patients failed to achieve seizure remission. ID and multiple seizure types were the main predictors of poor outcome. Nephrological manifestations require continuous specific follow-up in adults., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Published
2024
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30. Biallelic pathogenic variants of PARS2 cause developmental and epileptic encephalopathy with spike-and-wave activation in sleep.

Author

Licchetta L, Di Giorgi L, Santucci M, Taruffi L, Stipa C, Minardi R, Carelli V, and Bisulli F

Subjects
Humans, Child, Sleep physiology, Electroencephalography, Phenotype, Spasms, Infantile genetics, Microcephaly
Abstract

Background: Biallelic pathogenic variants in the mitochondrial prolyl-tRNA synthetase 2 gene (PARS2, OMIM * 612036) have been associated with Developmental and Epileptic Encephalopathy-75 (DEE-75, MIM #618437). This condition is typically characterized by early-onset refractory infantile spasms with hypsarrhythmia, intellectual disability, microcephaly, cerebral atrophy with hypomyelination, lactic acidemia, and cardiomyopathy. Most affected individuals do not survive beyond the age of 10 years., Methods: We describe a patient with early-onset DEE, consistently showing an EEG pattern of Spike-and-Wave Activation in Sleep (SWAS) since childhood. The patient underwent extensive clinical, metabolic and genetic investigations, including whole exome sequencing (WES)., Results: WES analysis identified compound heterozygous variants in PARS2 that have been already reported as pathogenic. A literature review of PARS2-associated DEE, focusing mainly on the electroclinical phenotype, did not reveal the association of SWAS with pathogenic variants in PARS2. Notably, unlike previously reported cases with the same genotype, this patient had longer survival without cardiac involvement or lactic acidosis, suggesting potential genetic modifiers contributing to disease variability., Conclusion: These findings widen the genetic heterogeneity of DEE-SWAS, including PARS2 as a causative gene in this syndromic entity, and highlight the importance of prolonged sleep EEG recording for the recognition of SWAS as a possible electroclinical evolution of PARS2-related DEE., (© 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Published
2024
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31. Response to letter to the Editor: Look at the elephant! Commentary on 'Prevalence of temporomandibular disorders in adult obstructive sleep apnoea patients: A cross-sectional controlled study'.

Author

Alessandri-Bonetti G, Incerti-Parenti S, Bartolucci ML, Bortolotti F, Stipa C, and Manfredini D

Subjects
Humans, Adult, Animals, Prevalence, Cross-Sectional Studies, Elephants, Mandibular Advancement, Sleep Apnea, Obstructive complications, Sleep Apnea, Obstructive epidemiology, Temporomandibular Joint Disorders epidemiology
Abstract

Obstructive sleep apnoea and temporomandibular disorders are complex pathologies. Considering dento-skeletal occlusion as their main predisposing factor could be detrimental for optimal patient care., (© 2023 John Wiley & Sons Ltd.)

Published
2023
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32. Real-world experience with cannabidiol as add-on treatment in drug-resistant epilepsy.

Author

Vicino W, Muccioli L, Pondrelli F, Licchetta L, Stipa C, Mostacci B, Vito LD, Ferri L, Cancellerini C, Sold M, Tinuper P, and Bisulli F

Abstract

Purpose: To evaluate the efficacy and safety of cannabidiol (CBD) for the treatment of epilepsy in a real-world setting., Methods: In this retrospective observational study, we included PwE with epilepsy who received a prescription for CBD between 01.03.2019 and 30.11.2022 and had a follow-up period ≥ 3 months. Participants were evaluated at baseline and after 3, 6, and 12 months. "Responders" were defined as individuals experiencing a reduction in seizure frequency > 30% but < 80% compared to baseline, while "super responders" were those with a reduction ≥ 80%. Adverse events were recorded to assess safety., Results: Forty-two PwE were included (mean age 36.1 ± 10.9 years; 14 females). In 24 patients CBD was prescribed on-label (Lennox-Gastaut syndrome, n = 18; Dravet syndrome, n = 5; tuberous sclerosis, n = 1), while 18 patients were treated off-label (ring chromosome 20 syndrome, n = 1; ring chromosome 17 syndrome, n = 1; Lafora disease, n = 3; Unverricht-Lundborg disease, n = 1; polymicrogyria, n = 2; febrile infection-related epilepsy syndrome, n = 1; non-lesional focal epilepsy, n = 2; developmental and/or epileptic encephalopathy of unknown etiology n = 6). The mean number of concomitant antiseizure medications was 3.4 (≥2 for all patients). At 3 months, 10 subjects (23%) were "responders" and 12 (29%) were "super-responders". Efficacy was sustained at 6 and 12 months of follow-up. Twenty-two patients (52.3%) developed AEs, with drowsiness (36.5%) and diarrhea (9.8%) being the most common. The retention rate was 85.7%, 78.6%, and 71.4% at 3, 6, and 12 months, respectively., Conclusions: In this monocentric real-world study, CBD was a safe and effective therapeutic option for highly drug-resistant patients, leading to a dramatic reduction in seizure frequency in over one-fourth of them, including off-label indications., Competing Interests: Declaration of Competing Interest Authors have no conflict of interest to declare, (Copyright © 2023. Published by Elsevier Ltd.)

Published
2023
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33. Prevalence of temporomandibular disorders in adult obstructive sleep apnoea patients: A cross-sectional controlled study.

Author

Bartolucci ML, Bortolotti F, Pelligra I, Stipa C, Sorrenti G, Incerti-Parenti S, and Alessandri-Bonetti G

Subjects
Humans, Adult, Middle Aged, Prevalence, Cross-Sectional Studies, Snoring complications, Snoring epidemiology, Sleep Apnea, Obstructive, Sleep Wake Disorders complications
Abstract

Background: Obstructive sleep apnoea (OSA) is characterised by partial or complete obstruction of the upper airways during sleep and it has been associated with temporomandibular disorders (TMDs) on the basis of several pathophysiological hypotheses., Objectives: To assess the prevalence of TMDs in a population of patients affected by OSA compared to a control group of subjects not affected by OSA., Methods: A cross-sectional controlled study was conducted on a group subjects studied by polygraphy (PG) at the snoring section of the ENT department, Sant'Orsola-Malpighi Hospital - University of Bologna. Patients who received a diagnosis of OSA were included in the study group and subjects with a negative PG diagnosis for Sleep Disordered Breathing and PG respiratory pattern that did not suggest the occurrence of sleep disorders were enrolled in the control group. Both the subjects included in the study group and the control group underwent an examination following the Diagnostic Criteria for Temporomandibular Disorders Axis I and II., Results: Forty-three OSA patients (29 M, 16 F, mean age 52.26 ± 11.40) and 43 healthy controls (25 M, 18 F, mean age 49.95 ± 7.59) were included in the study. No significant differences were found between groups in demographic data. TMD prevalence and Axis II results did not differ between groups., Conclusions: This paper does not highlight a higher prevalence of TMDs in adults with OSA compared to healthy controls. Further high-quality studies are needed to confirm the results and to give possible pathophysiological explanations, providing reliable evidence., (© 2023 The Authors. Journal of Oral Rehabilitation published by John Wiley & Sons Ltd.)

Published
2023
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34. Antero-Posterior Mandibular Excursion in Obstructive Sleep Apnea Patients Treated with Mandibular Advancement Device: A Retrospective Cohort Study.

Author

Stipa C, Incerti-Parenti S, Cameli M, Ippolito DR, Gracco A, and Alessandri-Bonetti G

Subjects
Humans, Retrospective Studies, Occlusal Splints, Treatment Outcome, Mandibular Advancement, Sleep Apnea, Obstructive therapy
Abstract

Since obstructive sleep apnea (OSA) management with a mandibular advancement device (MAD) is likely to be life-long, potential changes in mandibular movements during therapy should be investigated. The purpose of this study was to use a method that has already been shown to be reliable in order to determine whether the range of antero-posterior mandibular excursion, the procedure upon which MAD titration is based, varies between baseline (T0) and at least 1 year of treatment (T1). The distance between maximal voluntary protrusion and maximal voluntary retrusion determined using the millimetric scale of the George Gauge was retrospectively collected from the medical records of 59 OSA patients treated with the MAD and compared between T0 and T1. A regression analysis was performed to evaluate the influence of treatment time, MAD therapeutic advancement and the patient's initial characteristics in excursion range variation. A statistically significant increase of 0.80 ± 1.52 mm (mean ± standard deviation, p < 0.001) was found for antero-posterior mandibular excursion. The longer the treatment time ( p = 0.044) and the smaller the patient's mandibular excursion at T0 ( p = 0.002), the greater the increase was. These findings could be explained by a muscle-tendon unit adaptation to the forward mandibular repositioning induced by the MAD. During MAD therapy, patients can develop a wider range of antero-posterior mandibular excursion, especially those with a smaller initial excursion capacity.

Published
2023
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35. A case of clinical worsening after stereo-electroencephalographic-guided radiofrequency thermocoagulation in a patient with polymicrogyria.

Author

Ferri L, Mai R, di Vito L, Menghi V, Martinoni M, D'Orio P, Licchetta L, Muccioli L, Stipa C, Tinuper P, and Bisulli F

Abstract

Radiofrequency thermocoagulation (RF-TC) is a wide-used procedure for drug-resistant epilepsy. The technique is considered safe with an overall risk of 1.1% of permanent complications, mainly focal neurological deficits. We report the case of a patient with drug-resistant epilepsy who complained of immediate seizure worsening and an unexpected event seven months following RF-TC. A 35-year-old male with drug-resistant epilepsy from the age of 18 years underwent stereoelectroencephalography (SEEG) implantation for a right peri-silvian polymicrogyria. He was excluded from surgery due to extent of the epileptogenic zone and the risk of visual field deficits. RF-TC was attempted to ablate the most epileptogenic zone identified by SEEG. After RF-TC, the patient reported an increase in seizure severity/frequency and experienced episodes of postictal psychosis. Off-label cannabidiol treatment led to improved seizure control and resolution of postictal psychosis. Patients with polymicrogyria (PwP) may present with a disruption of normal anatomy and the co-existence between epileptogenic zone and eloquent cortex within the malformation. RF-TC should be considered in PwP when they are excluded from surgery for prognostic and palliative purposes. However, given the complex interplay between pathological and electrophysiological networks in these patients, the remote possibility of clinical exacerbation after RF-TC should also be taken into account., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Published
2022
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36. The Impact of the COVID-19 Pandemic on People With Epilepsy. An Italian Survey and a Global Perspective.

Author

Mostacci B, Licchetta L, Cacciavillani C, Di Vito L, Ferri L, Menghi V, Stipa C, Avoni P, Provini F, Muccioli L, Vignatelli L, Mazzoni S, Tinuper P, and Bisulli F

Abstract

Objectives: We explored the impact of the coronavirus disease-19 (COVID-19) emergency on the health of people with epilepsy (PwE). We also investigated their attitude toward telemedicine. Methods: The PubMed database up to September 10, 2020 was searched for questionnaire-based studies conducted in PwE during the COVID-19 emergency, and the literature retrieved was reviewed. In addition, all patients who had a telephone consultation with our center between May 7 and July 31, 2020 were invited to fill in a 57-item online questionnaire focusing on epilepsy and comorbidities, any changes in lifestyle or clinical conditions and any emergency-related problems arising during the COVID-19 emergency, and their views on telemedicine. Associations between variables were detected through X 2 test and Fisher's exact test. Univariate and multivariate logistic regression models were used to evaluate the effects of different factors on clinical conditions. Results: Twelve studies met the literature search criteria. They showed that the rate of seizure worsening during the emergency ranged from 4 to 35% and was mainly correlated with epilepsy severity, sleep disturbances and COVID-19-related issues. Our questionnaire was filled in by 222 PwE or caregivers. One hundred (76.6%) reported unchanged clinical conditions, 25 (11.3%) an improvement, and 27 (12%) a deterioration. Reported clinical worsening was associated with a psychiatric condition and/or medication (OR = 12.59, p < 0.001), sleep disorders (OR = 8.41, p = 0.001), limited access to healthcare (OR = 4.71, p = 0.016), and experiencing seizures during the emergency (OR = 4.51, p = 0.007). Telemedicine was considered acceptable by 116 subjects (52.3%). Conclusions: Most PwE did not experience a significant change in their clinical conditions during the COVID-19 emergency. However, severity of epilepsy, concomitant disability, comorbid psychiatric conditions, sleep disorders and limited access to healthcare may affect their health., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Mostacci, Licchetta, Cacciavillani, Di Vito, Ferri, Menghi, Stipa, Avoni, Provini, Muccioli, Vignatelli, Mazzoni, Tinuper and Bisulli.)

Published
2020
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37. Whole-exome sequencing in adult patients with developmental and epileptic encephalopathy: It is never too late.

Author

Minardi R, Licchetta L, Baroni MC, Pippucci T, Stipa C, Mostacci B, Severi G, Toni F, Bergonzini L, Carelli V, Seri M, Tinuper P, and Bisulli F

Subjects
Adolescent, Adult, Aged, Child, Child, Preschool, Cohort Studies, Delayed Diagnosis, Epilepsy diagnosis, Epilepsy pathology, Exome genetics, Female, Genetic Testing, Genomics, Humans, Infant, Male, Middle Aged, Neurodevelopmental Disorders diagnosis, Neurodevelopmental Disorders pathology, Exome Sequencing methods, Young Adult, Arginine-tRNA Ligase genetics, Cytoskeletal Proteins genetics, Epilepsy genetics, Genetic Predisposition to Disease, Neurodevelopmental Disorders genetics
Abstract

Developmental and epileptic encephalopathies (DEE) encompass rare, sporadic neurodevelopmental disorders and usually with pediatric onset. As these conditions are characterized by marked clinical and genetic heterogeneity, whole-exome sequencing (WES) represents the strategy of choice for the molecular diagnosis. While its usefulness is well established in pediatric DEE cohorts, our study is aimed at assessing the WES feasibility in adult DEE patients who experienced a diagnostic odyssey prior to the advent of this technique. We analyzed exomes from 71 unrelated adult DEE patients, consecutively recruited from an Italian cohort for the EPI25 Project. All patients underwent accurate clinical and electrophysiological characterization. An overwhelming percentage (90.1%) had already undergone negative genetic testing. Variants were classified according to the American College of Medical Genetics and Genomics guidelines. WES disclosed 24 (likely) pathogenic variants among 18 patients in epilepsy-related genes with either autosomal dominant, recessive or X-linked inheritance. Ten of these were novel. We obtained a diagnostic yield of 25.3%, higher among patients with brain malformations, early-onset epilepsy and dysmorphisms. Despite a median diagnostic delay of 38.7 years, WES analysis provided the long-awaited diagnosis for 18 adult patients, which also had an impact on the clinical management of 50% of them., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Published
2020
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38. Maximum voluntary retrusion or habitual bite position for mandibular advancement assessment in the treatment of obstructive sleep apnoea patients.

Author

Ippolito DR, Stipa C, Cameli M, Sorrenti G, Pelligra I, and Alessandri-Bonetti G

Subjects
Humans, Occlusal Splints, Reproducibility of Results, Retrospective Studies, Treatment Outcome, Mandibular Advancement, Sleep Apnea, Obstructive
Abstract

Background: There is no consensus on whether the range of mandibular advancement for the construction of mandibular advancement devices in obstructive sleep apnoea (OSA) patients should be measured from a starting position of maximum voluntary retrusion or habitual bite position., Objective: The purposes of this study were to investigate the differences in mandibular advancement registrations starting from maximum voluntary retrusion or from habitual bite position and to evaluate the reliability of these assessments., Methods: A retrospective cohort analysis of 126 patients with OSA was performed. All patients had their mandibular range of motion evaluated twice (starting from maximum voluntary retrusion and from habitual bite position) through the George Gauge before undergoing drug-induced sleep endoscopy. The Dahlberg formula and paired t test were used to calculate random and systematic errors of dental positions assessment. Test-retest reliability was quantified using the intra-class correlation coefficient (ICC)., Results: The mean mandibular range starting from maximum voluntary retrusion and from habitual bite position were 12.49 ± 2.19 mm and 7.68 ± 2.29 mm, respectively, with a mean distance between the two starting positions of 4.81 ± 1.75 mm. No systematic error was found (P > .05), and random errors ranged from 0.30 to 0.95 mm. ICC values were excellent for maximum voluntary protrusion (ICC = 0.986) and maximum voluntary retrusion (ICC = 0.956), whereas habitual bite position showed a good value (ICC = 0.818)., Conclusion: The difference between maximum voluntary retrusion and habitual bite position is potentially relevant. Maximum retrusion is advisable as starting point of the mandibular advancement registration since it provides a more reliable measure., (© 2019 John Wiley & Sons Ltd.)

Published
2020
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39. Relationship between cephalometric parameters and the apnoea-hypopnoea index in OSA patients: a retrospective cohort study.

Author

Stipa C, Cameli M, Sorrenti G, Ippolito DR, Pelligra I, and Alessandri-Bonetti G

Subjects
Adult, Body Mass Index, Humans, Hyoid Bone anatomy & histology, Jaw anatomy & histology, Palate, Soft anatomy & histology, Retrospective Studies, Severity of Illness Index, Cephalometry, Sleep Apnea, Obstructive complications
Abstract

Objective: The purpose of this study was to assess the relationship between cephalometric parameters and apnoea-hypopnoea index (AHI) controlling for the effect of gender, age, and body mass index (BMI) on a large sample of patients with obstructive sleep apnoea (OSA)., Methods: This retrospective cohort study was conducted on the lateral cephalograms of 253 Caucasian adult OSA patients. Cephalometric analyses were performed using 14 parameters for skeletal and soft tissue morphology, including antero-posterior and vertical jaw relationships, hyoid bone position, soft palate length and thickness, airway space, and tongue length and height. A hierarchical regression was run to examine the amount of variability in AHI that cephalometric variables explained after controlling for patients' general characteristics (gender, age, and BMI)., Results: After controlling for gender, age, and BMI, the increase in AHI variance accounted for by cephalometric parameters was equal to 0.103. Among the cephalometric variables, only MP-H and PNS-P were statistically significant (P < 0.05)., Limitations: Given the retrospective nature of the study, it is difficult to assess whether other confounding variables not considered in the present study could have influenced the relationship between cephalometric parameters and AHI., Conclusions: This study revealed the existence of a relationship between OSA severity and some cephalometric parameters. Indeed soft palate length and vertical position of the hyoid bone were significant predictors of AHI in adult Caucasian OSA patients., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Published
2020
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40. Juvenile absence epilepsy relapsing as recurrent absence status, mimicking transient global amnesia, in an elderly patient.

Author

Muccioli L, Licchetta L, Stipa C, Tinuper P, and Bisulli F

Subjects
Aged, Amnesia, Transient Global physiopathology, Brain physiopathology, Diagnosis, Differential, Electroencephalography, Epilepsy, Absence physiopathology, Female, Humans, Recurrence, Amnesia, Transient Global diagnosis, Epilepsy, Absence diagnosis
Abstract

We describe a 68-year-old woman who had typical absence seizures since 14 years of age. The absences were refractory to treatment and persisted into adulthood, with no seizure-free periods until seizure control at 59 years of age. After six years of being seizure-free, she presented with an episode characterized by mental confusion, abnormal behaviour, and amnesia, lasting for several hours. An EEG performed the day after, when the patient had already recovered, was unremarkable. The episode was interpreted as transient global amnesia. After two and three years, respectively, she presented with two analogous episodes lasting >24 hours. An EEG disclosed, on both occasions, subcontinuous generalized spike-and-wave discharges, consistent with absence status epilepticus (AS). The last episode occurred at 68 years of age and was successfully treated with intravenous lorazepam. After one month of follow-up, no further episodes occurred. AS is common in juvenile absence epilepsy, however, our patient showed a rather atypical course, characterized by refractory and persistent absences during adolescence and adulthood, and a tendency for AS to recur with no more absences in later life. Despite the known epilepsy history, AS episodes were initially misdiagnosed. Moreover, EEG recording and subsequent treatment were not performed until the second day of status.

Published
2018
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41. Effect of valproic acid on perampanel pharmacokinetics in patients with epilepsy.

Author

Contin M, Bisulli F, Santucci M, Riva R, Tonon F, Mohamed S, Ferri L, Stipa C, and Tinuper P

Subjects
Adolescent, Adult, Aged, Anticonvulsants adverse effects, Anticonvulsants classification, Child, Cytochrome P-450 Enzyme Inducers adverse effects, Cytochrome P-450 Enzyme Inducers therapeutic use, Cytochrome P-450 Enzyme Inhibitors adverse effects, Cytochrome P-450 Enzyme Inhibitors therapeutic use, Drug Interactions, Drug Therapy, Combination, Epilepsy blood, Female, Humans, Male, Middle Aged, Nitriles, Prospective Studies, Valproic Acid adverse effects, Young Adult, Anticonvulsants therapeutic use, Epilepsy drug therapy, Pyridones pharmacokinetics, Pyridones therapeutic use, Valproic Acid therapeutic use
Abstract

We prospectively examined the effect of antiepileptic (AED) cotherapy on steady state plasma concentrations of perampanel (PMP) in epileptic patients. We classified AEDs as strong enzyme inducers (carbamazepine, phenobarbital, phenytoin, oxcarbazepine), not strong enzyme inducers/not inhibitors (levetiracetam, lamotrigine, topiramate, rufinamide, lacosamide, zonisamide, clobazam), and enzyme inhibitors (valproic acid [VPA]). The main outcome was the comparison of PMP plasma concentration to weight-adjusted dose ratio (C/D; [μg/mL]/mg kg -1  d -1 ) among comedication subgroups. From 79 patients (42 females, 37 males) aged (mean ± standard deviation) 33 ± 13 years (range = 12-66 years), 114 plasma samples were collected. Twenty-eight patients (44 samples) were cotreated with enzyme inducers (group A), 21 (27 samples) with not strong enzyme inducers/not inhibitors (group B), 21 (31 samples) with not strong enzyme inducers/not inhibitors + VPA (group C), and 9 (12 samples) with enzyme inducers + VPA (group D). PMP C/D was reduced (-56%, P < .001) in group A (1.79 ± 0.80) versus group B (4.05 ± 2.16) and increased (P < .001) in group C (6.72 ± 4.04) compared with groups A (+275%), B (+66%), and D (2.76 ± 2.00, +143%). Our study documents the unpublished higher PMP C/D in patients cotreated with VPA. These findings have both theoretical relevance, suggesting better characterization of PMP metabolic pathways with ad hoc studies, and clinical usefulness in managing patients on AED polytherapy., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)

Published
2018
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42. Epilepsy with auditory features: Long-term outcome and predictors of terminal remission.

Author

Bisulli F, Menghi V, Vignatelli L, Licchetta L, Zenesini C, Stipa C, Morigi F, Gizzi M, Avoni P, Provini F, Mostacci B, d'Orsi G, Pippucci T, Muccioli L, and Tinuper P

Subjects
Adult, Cohort Studies, Electroencephalography trends, Epilepsy physiopathology, Female, Follow-Up Studies, Hallucinations physiopathology, Humans, Male, Middle Aged, Prognosis, Retrospective Studies, Time Factors, Treatment Outcome, Epilepsy diagnosis, Epilepsy epidemiology, Hallucinations diagnosis, Hallucinations epidemiology
Abstract

Objective: To assess the long-term outcome of epilepsy with auditory features (EAF) and to identify the clinical predictors for prognosis., Methods: The study involved consecutive EAF patients with a follow-up of ≥5 years. Terminal remission (TR) was defined as a period of ≥5 consecutive years of seizure freedom at the last follow-up. We used Kaplan-Meier estimate to calculate the cumulative time-dependent probability of conversion to TR. Log-rank test and multivariate Cox regression analyses were performed to study the association between time to TR and prognostic determinants., Results: We included 123 EAF patients (male/female = 58/65) with a median follow-up of 11 years (1626.9 person-years). Most were sporadic cases (68.3%), whereas 31.7% reported a family history of epilepsy. At last assessment, 42 patients had achieved TR (34.1%). Of the remaining 81 cases with no TR (65.9%), 37% had been in remission for 1-4 years and 62.9% still had seizures within the past year. The cumulative rates of TR were 26.6%, 35.7%, and 51.6% at 10, 20, and 30 years from inclusion. On multivariate analysis, age at onset > 10 years (hazard ratio [HR] = 3.2, P = .028), auditory aura characterized by distortions only versus simple/complex hallucinations (HR = 2.9, P = .041), and unremarkable scalp electroencephalogram (EEG) versus EEG with focal epileptiform activity (HR = 3.5, P = .041) were associated with TR., Significance: Our data show a wide prognostic spectrum of EAF, ranging from mild forms with spontaneous remission, to severely refractory epilepsy addressed to surgery. The outcome, less favorable than expected from previous studies, appears to be primarily a function of 3 prognostic negative risk factors: age at onset < 10 years, auditory aura characterized by complex auditory hallucinations, and focal epileptiform abnormalities on scalp EEG. These predictors, easy to collect even at the first visit, may inform both clinicians and patients about the long-term prognosis and aid patient management., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)

Published
2018
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43. Phenotype variability of GLUT1 deficiency syndrome: Description of a case series with novel SLC2A1 gene mutations.

Author

Di Vito L, Licchetta L, Pippucci T, Baldassari S, Stipa C, Mostacci B, Alvisi L, Tinuper P, and Bisulli F

Subjects
Adult, Female, Humans, Male, Monosaccharide Transport Proteins genetics, Mutation, Phenotype, Carbohydrate Metabolism, Inborn Errors genetics, Epilepsy, Generalized complications, Epilepsy, Generalized genetics, Genetic Variation genetics, Glucose Transporter Type 1 genetics, Monosaccharide Transport Proteins deficiency, Seizures etiology
Published
2018
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45. Dentoskeletal effects of oral appliance wear in obstructive sleep apnoea and snoring patients.

Author

Alessandri-Bonetti G, D'Antò V, Stipa C, Rongo R, Incerti-Parenti S, and Michelotti A

Subjects
Adult, Aged, Cephalometry methods, Dental Casting Technique, Female, Humans, Incisor pathology, Longitudinal Studies, Male, Malocclusion, Angle Class II etiology, Malocclusion, Angle Class II pathology, Mandible diagnostic imaging, Mandible pathology, Mandibular Advancement adverse effects, Maxilla diagnostic imaging, Maxilla pathology, Middle Aged, Overbite etiology, Overbite pathology, Radiography, Retrospective Studies, Mandibular Advancement instrumentation, Sleep Apnea, Obstructive therapy, Snoring therapy
Abstract

Objectives: To evaluate the dentoskeletal changes associated with long-term and continuous mandibular advancement device (MAD) use in sleep-related breathing disorder patients., Methods: Cephalometric measurements and three-dimensional model analysis were performed at baseline and after 3.5 ± 1.1 years in 20 snoring and obstructive sleep apnoea patients treated with the Silensor® appliance. Intra-group differences were compared using paired t-test or Wilcoxon signed-rank test. A regression analysis was performed for variables that showed a statistically significant difference between time points to evaluate the influence of treatment time and patient's initial characteristics on their variations. The statistical significance was set at P < 0.05., Results: At cephalometric assessment, the maxilla revealed a significant decrease in horizontal position (SNA: -0.4 ± 0.72 degree, P = 0.021) and a significant retroclination of the upper incisor (-1.59 ± 1.07 degree, P < 0.001), while the mandible displayed a significant downward rotation (0.88 ± 1.28 degree, P = 0.006) and a proclination of the lower incisor (2.27 ± 1.38 degree, P < 0.001). Model analysis showed a decrease in upper total space discrepancy (-0.66 ± 0.72 mm, P < 0.002), overjet (OJ; -0.34 ± 0.47 mm, P < 0.011), and overbite (-0.4 ± 0.52 mm, P < 0.004). In the regression analysis, treatment time influenced the lower incisor inclination (Beta = -0.713, P = 0.018) and OJ (Beta = -0.218, P = 0.018); patients' initial characteristics had an effect on OJ (Beta = -0.195, P = 0.011)., Limitations: A larger sample size could increase the generalizability of the findings., Conclusion: MAD wear after a mean of 3.5 years determines statistically significant but clinically irrelevant dentoskeletal changes. Their potential occurrence should be thoroughly discussed with patients; regular follow-up visits by a specialist experienced in dental sleep medicine are also mandatory during treatment in addition to polysomnographic examinations., (© The Author 2016. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For permissions, please email: journals.permissions@oup.com)

Published
2017
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46. Advanced morphological neuroimaging study in lateral temporal lobe epilepsy: A multicentric study.

Author

Vasta R, Sarica A, Bisulli F, Di Gennaro G, D'Aniello A, Difrancesco JC, Canafoglia L, Casazza M, Franceschetti S, Stipa C, Tinuper P, Mumoli L, Gambardella A, and Labate A

Subjects
Adult, Female, Functional Laterality physiology, Humans, Image Processing, Computer-Assisted, Male, Middle Aged, Young Adult, Cerebral Cortex diagnostic imaging, Epilepsy, Temporal Lobe diagnostic imaging, Magnetic Resonance Imaging, Neuroimaging methods
Abstract

Lateral temporal lobe epilepsy (lTLE) is a rare condition characterized by auditory auras or receptive aphasia, negative MRI, and relatively benign evolution. With the low number of cases in the world, our objective was to analyze a cohort of sporadic cases with lTLE (slTLE), in order to investigate possible cerebral morphological alterations. Forty patients with lTLE (34.93±12.08years of age) and 38 healthy controls (CTRL, 34.55±9.08years of age) were enrolled from four tertiary Italian epilepsy centers, which provided brain MRI T1-weighted images following a standard protocol for patients with epilepsy. We performed group comparison by following different approaches: voxel-based morphometry (VBM, SPM8), cortical thickness (CT), and local gyrification index (lGI) (FreeSurfer 5.3). At a more conservative threshold (p<0.05, FWE correction), no significant differences between groups survived, neither in VBM nor CT/lGI. Multicenter studies have more power than smaller studies in conducting sophisticated evaluations of rare diseases, and further investigations are required to develop a full picture of this rare phenotype., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Published
2017
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47. Epilepsy with auditory features: A heterogeneous clinico-molecular disease.

Author

Pippucci T, Licchetta L, Baldassari S, Palombo F, Menghi V, D'Aurizio R, Leta C, Stipa C, Boero G, d'Orsi G, Magi A, Scheffer I, Seri M, Tinuper P, and Bisulli F

Abstract

Objective: To identify novel genes implicated in epilepsy with auditory features (EAF) in phenotypically heterogeneous families with unknown molecular basis., Methods: We identified 15 probands with EAF in whom an LGI1 mutation had been excluded. We performed electroclinical phenotyping on all probands and available affected relatives. We used whole-exome sequencing (WES) in 20 individuals with EAF (including all the probands and 5 relatives) to identify single nucleotide variants, small insertions/deletions, and copy number variants., Results: WES revealed likely pathogenic variants in genes that had not been previously associated with EAF: a CNTNAP2 intragenic deletion, 2 truncating mutations of DEPDC5, and a missense SCN1A change., Conclusions: EAF is a clinically and molecularly heterogeneous disease. The association of EAF with CNTNAP2, DEPDC5, and SCN1A mutations widens the phenotypic spectrum related to these genes. CNTNAP2 encodes CASPR2, a member of the voltage-gated potassium channel complex in which LGI1 plays a role. The finding of a CNTNAP2 deletion emphasizes the importance of this complex in EAF and shows biological convergence.

Published
2015
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48. Auditory aura in nocturnal frontal lobe epilepsy: a red flag to suspect an extra-frontal epileptogenic zone.

Author

Ferri L, Bisulli F, Nobili L, Tassi L, Licchetta L, Mostacci B, Stipa C, Mainieri G, Bernabè G, Provini F, and Tinuper P

Subjects
Adult, Aged, Electroencephalography, Epilepsy, Frontal Lobe pathology, Epilepsy, Frontal Lobe physiopathology, Female, Frontal Lobe physiopathology, Hallucinations physiopathology, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Neuroimaging, Polysomnography, Epilepsy, Frontal Lobe complications, Frontal Lobe pathology, Hallucinations etiology
Abstract

Objective: To describe the anatomo-electro-clinical findings of patients with nocturnal hypermotor seizures (NHS) preceded by auditory symptoms, to evaluate the localizing value of auditory aura., Methods: Our database of 165 patients with nocturnal frontal lobe epilepsy (NFLE) diagnosis confirmed by videopolysomnography (VPSG) was reviewed, selecting those who reported an auditory aura as the initial ictal symptom in at least two NHS during their lifetime., Results: Eleven patients were selected (seven males, four females). According to the anatomo-electro-clinical data, three groups were identified. Group 1 [defined epileptogenic zone (EZ)]: three subjects were studied with stereo-EEG. The EZ lay in the left superior temporal gyrus in two cases, whereas in the third case seizures arose from a dysplastic lesion located in the left temporal lobe. One of these three patients underwent left Heschl's gyrus resection, and is currently seizure-free. Group 2 (presumed EZ): three cases in which a presumed EZ was identified; in the left temporal lobe in two cases and in the left temporal lobe extending to the insula in one subject. Group 3 (uncertain EZ): five cases had anatomo-electro-clinical correlations discordant., Conclusions: This work suggests that auditory aura may be a helpful anamnestic feature suggesting an extra-frontal seizure origin. This finding could guide secondary investigations to improve diagnostic definition and selection of candidates for surgical treatment., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2014
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49. Autosomal dominant partial epilepsy with auditory features: a new locus on chromosome 19q13.11-q13.31.

Author

Bisulli F, Naldi I, Baldassari S, Magini P, Licchetta L, Castegnaro G, Fabbri M, Stipa C, Ferrari S, Seri M, Gonçalves Silva GE, Tinuper P, and Pippucci T

Subjects
Adolescent, Adult, Chromosome Mapping, Female, Genetic Linkage genetics, Genetic Loci genetics, Genetic Predisposition to Disease genetics, Haplotypes genetics, Humans, Lod Score, Male, Middle Aged, Polymorphism, Single Nucleotide genetics, Young Adult, Chromosomes, Human, Pair 19 genetics, Epilepsy, Frontal Lobe genetics, Sleep Wake Disorders genetics
Abstract

Objective: To clinically and genetically characterize a large Brazilian family with autosomal dominant partial epilepsy with auditory features (ADPEAF) not related to leucine-rich, glioma-inactivated 1 (LGI1) gene., Methods: Seventy family members (four married-ins) participating in the study were assessed by a detailed clinical interview and a complete neurologic examination. Genetic mapping was conducted through autosome-wide single nucleotide polymorphism (SNP) genotyping and subsequent linkage analysis on 16 and haplotype analysis on 25 subjects, respectively., Results: The pedigree comprised 15 affected members, of whom 11 were included in the study (male/female: 6/5; mean age 39.5 years). All but two (III:22 and IV:92) had focal seizures with auditory aura followed by secondary generalization in 44.4%. The mean age at onset of epilepsy seizures was 13.7 years. Initial autosome-wide SNP linkage analysis conducted on 12 subjects (8 affected) pointed to a single genomic region on chromosome 19 with a maximum multipoint logarithm of the odds (LOD) score of 2.60. Further refinement of this region through SNP and microsatellite genotyping on 16 subjects (11 affected) increased the LOD score to 3.41, thereby establishing 19q13.11-q13.31 as a novel ADPEAF locus. Haplotype analysis indicated that the underlying mutation is most likely located in a 9.74 Mb interval between markers D19S416 and D19S420. Sequence analysis of the most prominent candidate genes within this critical interval (SCN1B, LGI4, KCNK6, and LRFN1) did not reveal any mutation., Significance: This study disclosed a novel ADPEAF locus on chromosome 19q13.11-q13.31, contributing to future identification of a second dominant gene for this epileptic syndrome. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)

Published
2014
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50. Association of the mtDNA m.4171C>A/MT-ND1 mutation with both optic neuropathy and bilateral brainstem lesions.

Author

La Morgia C, Caporali L, Gandini F, Olivieri A, Toni F, Nassetti S, Brunetto D, Stipa C, Scaduto C, Parmeggiani A, Tonon C, Lodi R, Torroni A, and Carelli V

Subjects
Adolescent, Brain Diseases complications, Humans, Male, Optic Atrophy, Hereditary, Leber complications, Pedigree, Vestibular Nuclei pathology, Brain Diseases genetics, Brain Stem, DNA, Mitochondrial genetics, Mutation genetics, Optic Atrophy, Hereditary, Leber genetics
Abstract

Background: An increasing number of mitochondrial DNA (mtDNA) mutations, mainly in complex I genes, have been associated with variably overlapping phenotypes of Leber's hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy with stroke-like episodes (MELAS) and Leigh syndrome (LS). We here describe the first case in which the m.4171C>A/MT-ND1 mutation, previously reported only in association with LHON, leads also to a Leigh-like phenotype., Case Presentation: A 16-year-old male suffered subacute visual loss and recurrent vomiting and vertigo associated with bilateral brainstem lesions affecting the vestibular nuclei. His mother and one sister also presented subacute visual loss compatible with LHON. Sequencing of the entire mtDNA revealed the homoplasmic m.4171C>A/MT-ND1 mutation, previously associated with pure LHON, on a haplogroup H background. Three additional non-synonymous homoplasmic transitions affecting ND2 (m.4705T>C/MT-ND2 and m.5263C>T/MT-ND2) and ND6 (m.14180T>C/MT-ND6) subunits, well recognized as polymorphisms in other mtDNA haplogroups but never found on the haplogroup H background, were also present., Conclusion: This case widens the phenotypic expression of the rare m.4171C>A/MT-ND1 LHON mutation, which may also lead to Leigh-like brainstem lesions, and indicates that the co-occurrence of other ND non-synonymous variants, found outside of their usual mtDNA backgrounds, may have increased the pathogenic potential of the primary LHON mutation.

Published
2014
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