72 results on '"Holzknecht E"'
Search Results
2. Sex affects REM sleep behavior disorder identification: a comparative analysis of clinical data, screening questionnaires and REM sleep without atonia in women and men
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Ibrahim, A., primary, Serradell, M., additional, Cesari, M., additional, Gaig, C., additional, Holzknecht, E., additional, Marrero, P., additional, Brandauer, E., additional, Pérez-Carbonell, L., additional, Bergmann, M., additional, Fernández-Arcos, A., additional, Matos, N., additional, Santamaria, J., additional, Högl, B., additional, Iranzo, A., additional, and Stefani, A., additional
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- 2024
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3. Effects of acute exposure to altitude on restless legs syndrome
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Ibrahim, A., primary, Holzknecht, E., additional, Faulhaber, M., additional, Gatterer, H., additional, Wild, T., additional, Seelose, N., additional, Sorschag, P., additional, Resch, B., additional, Sevborn, S., additional, Hackner, H., additional, Ulfberg, J., additional, Burtscher, M., additional, Högl, B., additional, and Stefani, A., additional
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- 2024
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4. Computerized analysis of muscular activity in the flexor digitorum superficialis muscles as screening tool for REM sleep without atonia
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Cesari, M., primary, Heidbreder, A., additional, Gaig, C., additional, Bergmann, M., additional, Brandauer, E., additional, Iranzo, A., additional, Holzknecht, E., additional, Santamaria, J., additional, Högl, B., additional, and Stefani, A., additional
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- 2022
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5. Identification of Restless Legs Syndrome Genes by Mutational Load Analysis
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Tilch, E., Schormair, B., Zhao, C., Salminen, A.V., Nikolic, A., Holzknecht, E., Hogl, B., Poewe, W., Bachmann, C.G., Paulus, W., Trenkwalder, C., Oertel, W.H., Hornyak, M., Fietze, I., Berger, K., Lichtner, P., Gieger, C., Peters, A., Muller-Myhsok, B., Hoischen, A., Winkelmann, J., Oexle, K., Tilch, E., Schormair, B., Zhao, C., Salminen, A.V., Nikolic, A., Holzknecht, E., Hogl, B., Poewe, W., Bachmann, C.G., Paulus, W., Trenkwalder, C., Oertel, W.H., Hornyak, M., Fietze, I., Berger, K., Lichtner, P., Gieger, C., Peters, A., Muller-Myhsok, B., Hoischen, A., Winkelmann, J., and Oexle, K.
- Abstract
Contains fulltext : 218278.pdf (Publisher’s version ) (Open Access), OBJECTIVE: Restless legs syndrome is a frequent neurological disorder with substantial burden on individual well-being and public health. Genetic risk loci have been identified, but the causatives genes at these loci are largely unknown, so that functional investigation and clinical translation of molecular research data are still inhibited. To identify putatively causative genes, we searched for highly significant mutational burden in candidate genes. METHODS: We analyzed 84 candidate genes in 4,649 patients and 4,982 controls by next generation sequencing using molecular inversion probes that targeted mainly coding regions. The burden of low-frequency and rare variants was assessed, and in addition, an algorithm (binomial performance deviation analysis) was established to estimate independently the sequence variation in the probe binding regions from the variation in sequencing depth. RESULTS: Highly significant results (considering the number of genes in the genome) of the conventional burden test and the binomial performance deviation analysis overlapped significantly. Fourteen genes were highly significant by one method and confirmed with Bonferroni-corrected significance by the other to show a differential burden of low-frequency and rare variants in restless legs syndrome. Nine of them (AAGAB, ATP2C1, CNTN4, COL6A6, CRBN, GLO1, NTNG1, STEAP4, VAV3) resided in the vicinity of known restless legs syndrome loci, whereas 5 (BBS7, CADM1, CREB5, NRG3, SUN1) have not previously been associated with restless legs syndrome. Burden test and binomial performance deviation analysis also converged significantly in fine-mapping potentially causative domains within these genes. INTERPRETATION: Differential burden with intragenic low-frequency variants reveals putatively causative genes in restless legs syndrome. ANN NEUROL 2020;87:184-193.
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- 2020
6. Analysis of dominant and recessive parkinsonism genes in REM sleep behavior disorder
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Mufti, K., primary, Rudakou, U., additional, Yu, E., additional, Ruskey, J.A., additional, Asavesh, F., additional, Laurent, S.B., additional, Arnulf, I., additional, Hu, M.T.M., additional, Dauvilliers, Y., additional, Högl, B., additional, Stefani, A., additional, Holzknecht, E., additional, Monaca, C.C., additional, Abril, B., additional, Plazzi, G., additional, Antelmi, E., additional, Ferini-Strambi, L., additional, Heidbreder, A., additional, Young, P., additional, De Cock, V. Cochen, additional, Mollenhauer, B., additional, Sixel-Döring, F., additional, Trenkwalder, C., additional, Sonka, K., additional, Kemlink, D., additional, Figorilli, M., additional, Puligheddu, M., additional, Dijkstra, F., additional, Viaene, M., additional, Oertel, W., additional, Boeve, B.F., additional, Gigli, G.L., additional, Valente, M., additional, Gagnon, J.-F., additional, Desautels, A., additional, Montplaisir, J.Y., additional, Postuma, R.B., additional, Rouleau, G.A., additional, and Gan-Or, Z., additional
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- 2020
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7. Objective rest–activity cycle analysis by actigraphy identifies isolated rapid eye movement sleep behavior disorder
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Filardi, M., primary, Stefani, A., additional, Holzknecht, E., additional, Pizza, F., additional, Plazzi, G., additional, and Högl, B., additional
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- 2020
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8. Seasonality of restless legs syndrome: symptoms variability in winter and summer times
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Liguori, C., primary, Holzknecht, E., additional, Placidi, F., additional, Izzi, F., additional, Mercuri, N.B., additional, Högl, B., additional, and Stefani, A., additional
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- 2019
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9. Phasic coherence of forearms muscle activity: a specific measure of rem sleep without atonia evaluated by means of envelope analysis of the electromyogram
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Espinoza, D., primary, Ocampo-Garcés, A., additional, Diaz, J., additional, Holzknecht, E., additional, Stefani, A., additional, Bergmann, M., additional, Bassi, A., additional, Córdova, T., additional, Vivaldi, E.A., additional, and Högl, B., additional
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- 2019
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10. Validation of the self-administered version of the international restless legs syndrome study group severity rating scale - the sIRLS
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Sharon, D., primary, Allen, R., additional, Martinez-Martin, P., additional, Walters, A., additional, Strambi, L. Ferini, additional, Hogl, B., additional, Trotti, L.M., additional, Buchfuhrer, M., additional, Swieca, J., additional, Bogan, R., additional, Zak, R., additional, Hensley, J., additional, Schaefer, L., additional, Marelli, S., additional, Zucconi, M., additional, Stefani, A., additional, Holzknecht, E., additional, Olvera, V., additional, Meaklim, H., additional, Laska, I., additional, and Becker, P., additional
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- 2019
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11. Effects of singing bowl exposure on Karolinska sleepiness scale and pupillographic sleepiness test
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Bergmann, M., primary, Riedinger, S., additional, Stefani, A., additional, Mitterling, T., additional, Holzknecht, E., additional, Grassmayr, P., additional, and Högl, B., additional
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- 2019
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12. Gender differences in clinical, laboratory, and polysomnographic features of restless legs syndrome
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Holzknecht, E., primary, Hochleitner, M., additional, Wenning, G., additional, Högl, B., additional, and Stefani, A., additional
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- 2019
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13. A new diagnostic approach to identify isolated REM sleep behavior disorder (IRBD): 3D video analysis
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Waser, M., primary, Stefani, A., additional, Holzknecht, E., additional, Garn, H., additional, Kohn, B., additional, Hackner, H., additional, Brandauer, E., additional, Bergmann, M., additional, Taupe, P., additional, Gall, M., additional, and Högl, B., additional
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- 2019
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14. COMPUTERIZED ANALYSIS OF MUSCULAR ACTIVITY IN THE FLEXOR DIGITORUM SUPERFICIALIS MUSCLES AS SCREENING TOOL FOR REM SLEEP WITHOUT ATONIA
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Cesari, M., Anna Heidbreder, Gaig, C., Bergmann, M., Brandauer, E., Iranzo, A., Holzknecht, E., Santamaria, J., Hogl, B., and Stefani, A.
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General Medicine
15. Fine-mapping of SNCA variants in REM sleep behavior disorder identifies distinct associations
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Krohn, L., Wu, R., Ruskey, J., Laurent, S., Philstrom, L., Arnulf, I., Hu, M., Dauvilliers, Y., Hogl, B., Stefani, A., Holzknecht, E., Monaca, C., Beatriz, A., Plazzi, G., Antelmi, E., Ferini-Strambi, L., Heidbreder, A., Cochen, V., Mollenhauer, B., Sonka, K., MICHELA FIGORILLI, Dijkstra, F., Viaene, M., Oertel, W., Gagnon, J., Nalls, M., Blauwendraat, C., Singleton, A., Desautels, A., Montplaisir, J., Ross, O., Boeve, B., Dupre, N., Fon, E., Postuma, R., Rouleau, G., and Gan-Or, Z.
16. Fine‐Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies
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Edward A. Fon, Armaghan Alam, Richard Y.J. Wu, Cornelis Blauwendraat, Jennifer A. Ruskey, Luigi Ferini-Strambi, Paul Cannon, Mathias Toft, Mariarosaria Valente, Alex Desautels, Andrew B. Singleton, Valérie Cochen De Cock, Yves Dauvilliers, Elena Antelmi, C. Trenkwalder, Kari Anne Bjørnarå, Abril Beatriz, Christelle Charley Monaca, Jacques Montplaisir, Nicolas Dupré, Mineke Viaene, Peter Young, Birgit Högl, Giuseppe Plazzi, Monica Puligheddu, W. H. Oertel, Marco Toffoli, Bradley F. Boeve, Owen A. Ross, Friederike Sixel-Döring, Lasse Pihlstrøm, Michele T.M. Hu, Isabelle Arnulf, Sandra B. Laurent, Karl Heilbron, Michela Figorilli, Anna Heidbreder, Lynne Krohn, Guy A. Rouleau, Karel Sonka, Ziv Gan-Or, Mike A. Nalls, Jean-François Gagnon, David Kemlink, Evi Holzknecht, Femke Dijkstra, Ambra Stefani, Gian Luigi Gigli, Brit Mollenhauer, Ronald B. Postuma, Krohn L., Wu R.Y.J., Heilbron K., Ruskey J.A., Laurent S.B., Blauwendraat C., Alam A., Arnulf I., Hu M.T.M., Dauvilliers Y., Hogl B., Toft M., Bjornara K.A., Stefani A., Holzknecht E., Monaca C.C., Abril B., Plazzi G., Antelmi E., Ferini-Strambi L., Young P., Heidbreder A., Cochen De Cock V., Mollenhauer B., Sixel-Doring F., Trenkwalder C., Sonka K., Kemlink D., Figorilli M., Puligheddu M., Dijkstra F., Viaene M., Oertel W., Toffoli M., Gigli G.L., Valente M., Gagnon J.-F., Nalls M.A., Singleton A.B., Desautels A., Montplaisir J.Y., Cannon P., Ross O.A., Boeve B.F., Dupre N., Fon E.A., Postuma R.B., Pihlstrom L., Rouleau G.A., Gan-Or Z., Krohn, L., R. Y. J., Wu, Heilbron, K., Ruskey, J. A., Laurent, S. B., Blauwendraat, C., Alam, A., Arnulf, I., M. T. M., Hu, Dauvilliers, Y., Hogl, B., Toft, M., Bjornara, K. A., Stefani, A., Holzknecht, E., Monaca, C. C., Abril, B., Plazzi, G., Antelmi, E., Ferini-Strambi, L., Young, P., Heidbreder, A., Cochen De Cock, V., Mollenhauer, B., Sixel-Doring, F., Trenkwalder, C., Sonka, K., Kemlink, D., Figorilli, M., Puligheddu, M., Dijkstra, F., Viaene, M., Oertel, W., Toffoli, M., Gigli, G. L., Valente, M., Gagnon, J. -F., Nalls, M. A., Singleton, A. B., Desautels, A., Montplaisir, J. Y., Cannon, P., Ross, O. A., Boeve, B. F., Dupre, N., Fon, E. A., Postuma, R. B., Pihlstrom, L., Rouleau, G. A., Gan-Or, Z., McGill University Health Center [Montreal] (MUHC), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], Imperial College London, 23andMe Inc., National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Centre d'investigation clinique Neurosciences [CHU Pitié Salpêtrière] (CIC Neurosciences), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Oxford [Oxford], Nuffield Department of Clinical Neurosciences [Oxford], Département de neurologie [Montpellier], Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Innsbruck Medical University [Austria] (IMU), Oslo University Hospital [Oslo], Service de neurophysiologie clinique (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Alma Mater Studiorum University of Bologna (UNIBO), University of Bologna, Department of Biomedical and Neuromotor Sciences [Bologna, Italy], Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), University of Münster, Clinique Beau Soleil [Montpellier], EuroMov - Digital Health in Motion (Euromov DHM), IMT - MINES ALES (IMT - MINES ALES), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Montpellier (UM), Paracelsus-Elena-Klinik, Kassel, Germany., University Medical Center Göttingen (UMG), First Faculty of Medicine Charles University [Prague], Universita degli Studi di Cagliari [Cagliari], Algemeen Ziekenhuis Sint-Dimpna, Philipps University of Marburg, Università degli Studi di Udine - University of Udine [Italie], University College of London [London] (UCL), Department of Mathematics and Computer Science [Udine], Hôpital du Sacré-Coeur de Montréal, Université du Québec à Montréal = University of Québec in Montréal (UQAM), Data Tecnica International, Centre d'études avancées en Médecine du Sommeil (CEAMS), Université de Montréal (UdeM)-Hôpital du Sacré-Coeur de Montréal, Mayo Clinic [Jacksonville], Mayo Clinic [Rochester], Laval University Medical center, and Université Laval [Québec] (ULaval)
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Male ,0301 basic medicine ,Oncology ,Linkage disequilibrium ,Synucleinopathies ,REM sleep behavior disorder ,MESH: Logistic Models ,REM Sleep Behavior Disorder ,0302 clinical medicine ,synucleinopathy ,SNCA ,Odds Ratio ,RBD-specific risk variants ,MESH: Aged ,MESH: Middle Aged ,Rapid eye movement sleep behavior disorder (RBD) ,MESH: Polymorphism, Single Nucleotide ,MESH: Genetic Predisposition to Disease ,Parkinson Disease ,Middle Aged ,MESH: Case-Control Studies ,3. Good health ,Neurology ,MESH: Synucleinopathies ,alpha-Synuclein ,Female ,Adult ,Lewy Body Disease ,medicine.medical_specialty ,Prodromal Symptoms ,Single-nucleotide polymorphism ,Locus (genetics) ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,Internal medicine ,MESH: alpha-Synuclein ,medicine ,Humans ,Genetic Predisposition to Disease ,MESH: Prodromal Symptoms ,Allele frequency ,MESH: Lewy Body Disease ,Aged ,MESH: Humans ,business.industry ,Dementia with Lewy bodies ,[SCCO.NEUR]Cognitive science/Neuroscience ,MESH: Adult ,Odds ratio ,medicine.disease ,MESH: Odds Ratio ,MESH: Male ,synucleinopathies ,Logistic Models ,030104 developmental biology ,MESH: REM Sleep Behavior Disorder ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Case-Control Studies ,Synuclein ,Neurology (clinical) ,business ,MESH: Female ,MESH: Parkinson Disease ,030217 neurology & neurosurgery - Abstract
Objective: Rapid eye movement sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus to identify RBD-specific risk variants. Methods: Full sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n = 1,076), Parkinson disease (PD, n = 1,013), dementia with Lewy bodies (DLB, n = 415), and control subjects (n = 6,155). The iRBD cases were diagnosed with RBD prior to neurodegeneration, although some have since converted. A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (n = 1,782 cases; n = 131,250 controls). Adjusted logistic regression models and meta-analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan–Meier survival analysis. Results: A 5′-region SNCA variant (rs10005233) was associated with iRBD (odds ratio [OR] = 1.43, p = 1.1E-08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5′ risk variants across the different synucleinopathies. An independent iRBD-specific suggestive association (rs11732740) was detected at the 3′ of SNCA (OR = 1.32, p = 4.7E-04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD-specific SNPs were at highly increased risk for iRBD (OR = 5.74, p = 2E-06). The known top PD-associated variant (3′ variant rs356182) had an opposite direction of effect in iRBD compared to PD. Interpretation: There is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3′ of SNCA. Several 5′ SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies. ANN NEUROL 2020;87:584–598.
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- 2020
17. Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study
- Author
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Postuma, Ronald, Iranzo, Alex, Hu, Michele, Högl, Birgit, Boeve, Bradley, Manni, Raffaele, Oertel, Wolfgang, Arnulf, Isabelle, Ferini-Strambi, Luigi, Puligheddu, Monica, Antelmi, Elena, Cochen De Cock, Valérie, Arnaldi, Dario, Mollenhauer, Brit, Videnovic, Aleksandar, Sonka, Karel, Jung, Ki-Young, Kunz, Dieter, Dauvilliers, Yves, Provini, Federica, Lewis, Simon, Buskova, Jitka, Pavlova, Milena, Heidbreder, Anna, Montplaisir, Jacques, Santamaria, Joan, Barber, Thomas, Stefani, Ambra, St Louis, Erik, Terzaghi, Michele, Janzen, Annette, Leu-Semenescu, Smandra, Plazzi, Guiseppe, Nobili, Flavio, Sixel-Doering, Friederike, Dusek, Petr, Bes, Frederik, Cortelli, Pietro, Ehgoetz Martens, Kaylena, Gagnon, Jean-François, Gaig, Carles, Zucconi, Marco, Trenkwalder, Claudia, Gan-Or, Ziv, Lo, Christine, Rolinski, Michal, Mahlknecht, Philip, Holzknecht, Evi, Boeve, Angel, Teigen, Luke, Toscano, Gianpaolo, Mayer, Geert, Morbelli, Silvia, Dawson, Benjamin, Pelletier, Amélie, St.Louis, Erik, Postuma, R. B., Iranzo, A., Hu, M., Hogl, B., Boeve, B. F., Manni, R., Oertel, W. H., Arnulf, I., Ferini-Strambi, L., Puligheddu, M., Antelmi, E., Cochen De Cock, V., Arnaldi, D., Mollenhauer, B., Videnovic, A., Sonka, K., Jung, K. -Y., Kunz, D., Dauvilliers, Y., Provini, F., Lewis, S. J., Buskova, J., Pavlova, M., Heidbreder, A., Montplaisir, J. Y., Santamaria, J., Barber, T. R., Stefani, A., Louis, S. E. K., Terzaghi, M., Janzen, A., Leu-Semenescu, S., Plazzi, G., Nobili, F., Sixel-Doering, F., Dusek, P., Bes, F., Cortelli, P., Ehgoetz Martens, K., Gagnon, J. -F., Gaig, C., Zucconi, M., Trenkwalder, C., Gan-Or, Z., Lo, C., Rolinski, M., Mahlknecht, P., Holzknecht, E., Boeve, A. R., Teigen, L. N., Toscano, G., Mayer, G., Morbelli, S., Dawson, B., Pelletier, A., Postuma R.B., Iranzo A., Hu M., Hogl B., Boeve B.F., Manni R., Oertel W.H., Arnulf I., Ferini-Strambi L., Puligheddu M., Antelmi E., Cochen De Cock V., Arnaldi D., Mollenhauer B., Videnovic A., Sonka K., Jung K.-Y., Kunz D., Dauvilliers Y., Provini F., Lewis S.J., Buskova J., Pavlova M., Heidbreder A., Montplaisir J.Y., Santamaria J., Barber T.R., Stefani A., Louis S.E.K., Terzaghi M., Janzen A., Leu-Semenescu S., Plazzi G., Nobili F., Sixel-Doering F., Dusek P., Bes F., Cortelli P., Ehgoetz Martens K., Gagnon J.-F., Gaig C., Zucconi M., Trenkwalder C., Gan-Or Z., Lo C., Rolinski M., Mahlknecht P., Holzknecht E., Boeve A.R., Teigen L.N., Toscano G., Mayer G., Morbelli S., Dawson B., Pelletier A., McGill University = Université McGill [Montréal, Canada], Innsbruck Medical University [Austria] (IMU), Mayo Clinic [Rochester], Philipps University of Marburg, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), University of Bologna, Euromov (EuroMov), Université de Montpellier (UM), University of Genoa (UNIGE), University Medical Center Göttingen (UMG), First Faculty of Medicine Charles University [Prague], Seoul National University Hospital, Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University of Münster, Hôpital du Sacré-Coeur de Montréal, University of Oxford [Oxford], Ospedale Bellaria [Bologna, Italy], and Université du Québec à Montréal = University of Québec in Montréal (UQAM)
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0301 basic medicine ,Male ,Parkinson's disease ,multiple system atrophy ,dementia with Lewy bodies ,REM sleep behaviour disorder ,Kaplan-Meier Estimate ,REM Sleep Behavior Disorder ,Cohort Studies ,0302 clinical medicine ,Risk Factors ,Restless legs syndrome ,Prospective Studies ,Depression (differential diagnoses) ,Parkinsonism ,Hazard ratio ,Parkinson Disease ,Middle Aged ,Prognosis ,humanities ,3. Good health ,Disease Progression ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Female ,Parkinson’s disease ,Lewy Body Disease ,medicine.medical_specialty ,Polysomnography ,Prodromal Symptoms ,Parkinson’s disease, REM sleep behaviour disorder, dementia with Lewy bodies, multiple system atrophy ,REM sleep behavior disorder ,03 medical and health sciences ,Parkinsonian Disorders ,Internal medicine ,dementia with Lewy bodie ,mental disorders ,medicine ,Dementia ,Humans ,Aged ,Proportional Hazards Models ,business.industry ,Dementia with Lewy bodies ,Scientific Commentaries ,medicine.disease ,030104 developmental biology ,Neurology (clinical) ,business ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,030217 neurology & neurosurgery ,Forecasting - Abstract
International audience; Idiopathic REM sleep behaviour disorder (iRBD) is a powerful early sign of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. This provides an unprecedented opportunity to directly observe prodromal neurodegenerative states, and potentially intervene with neuroprotective therapy. For future neuroprotective trials, it is essential to accurately estimate phenoconversion rate and identify potential predictors of phenoconversion. This study assessed the neurodegenerative disease risk and predictors of neurodegeneration in a large multicentre cohort of iRBD. We combined prospective follow-up data from 24 centres of the International RBD Study Group. At baseline, patients with polysomnographically-confirmed iRBD without parkinsonism or dementia underwent sleep, motor, cognitive, autonomic and special sensory testing. Patients were then prospectively followed, during which risk of dementia and parkinsonsim were assessed. The risk of dementia and parkinsonism was estimated with Kaplan-Meier analysis. Predictors of phenoconversion were assessed with Cox proportional hazards analysis, adjusting for age, sex, and centre. Sample size estimates for disease-modifying trials were calculated using a time-to-event analysis. Overall, 1280 patients were recruited. The average age was 66.3 ± 8.4 and 82.5% were male. Average follow-up was 4.6 years (range = 1-19 years). The overall conversion rate from iRBD to an overt neurodegenerative syndrome was 6.3% per year, with 73.5% converting after 12-year follow-up. The rate of phenoconversion was significantly increased with abnormal quantitative motor testing [hazard ratio (HR) = 3.16], objective motor examination (HR = 3.03), olfactory deficit (HR = 2.62), mild cognitive impairment (HR = 1.91-2.37), erectile dysfunction (HR = 2.13), motor symptoms (HR = 2.11), an abnormal DAT scan (HR = 1.98), colour vision abnormalities (HR = 1.69), constipation (HR = 1.67), REM atonia loss (HR = 1.54), and age (HR = 1.54). There was no significant predictive value of sex, daytime somnolence, insomnia, restless legs syndrome, sleep apnoea, urinary dysfunction, orthostatic symptoms, depression, anxiety, or hyperechogenicity on substantia nigra ultrasound. Among predictive markers, only cognitive variables were different at baseline between those converting to primary dementia versus parkinsonism. Sample size estimates for definitive neuroprotective trials ranged from 142 to 366 patients per arm. This large multicentre study documents the high phenoconversion rate from iRBD to an overt neurodegenerative syndrome. Our findings provide estimates of the relative predictive value of prodromal markers, which can be used to stratify patients for neuroprotective trials.
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- 2019
18. Validation of the self-administered version of the international Restless Legs Syndrome study group severity rating scale – The sIRLS
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Birgit Högl, Irena Laska, Rochelle S. Zak, Lynn Marie Trotti, Hailey Meaklim, Arthur S. Walters, Luigi Ferini Strambi, Marco Zucconi, Laurel A. Schaefer, Evi Holzknecht, Philip M. Becker, Denise Sharon, Richard K. Bogan, Ambra Stefani, Richard P. Allen, John Swieca, Sara Marelli, Mark J. Buchfuhrer, Victoria Olvera, Pablo Martinez-Martin, Jennifer G. Hensley, Sharon, D., Allen, R. P., Martinez-Martin, P., Walters, A. S., Ferini Strambi, L., Hogl, B., Trotti, L. M., Buchfuhrer, M., Swieca, J., Bogan, R. K., Zak, R., Hensley, J. G., Schaefer, L. A., Marelli, S., Zucconi, M., Stefani, A., Holzknecht, E., Olvera, V., Meaklim, H., Laska, I., and Becker, P. M.
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Adult ,Male ,medicine.medical_specialty ,Patient completed ,Psychometrics ,Scale (ratio) ,Intraclass correlation ,International Cooperation ,Validity/reliability ,RLS symptoms ,Severity of Illness Index ,Diagnostic Self Evaluation ,03 medical and health sciences ,0302 clinical medicine ,Cronbach's alpha ,Rating scale ,Restless Legs Syndrome ,Surveys and Questionnaires ,Severity scale ,medicine ,Humans ,Restless legs syndrome ,Reliability (statistics) ,Aged ,business.industry ,Reproducibility of Results ,General Medicine ,Middle Aged ,medicine.disease ,Standard error ,030228 respiratory system ,Physical therapy ,Ceiling effect ,Female ,business ,Self-administered ,030217 neurology & neurosurgery - Abstract
Introduction The International Restless Legs Study Group (IRLSSG) has developed the IRLS (International Restless Legs Syndrome Severity Scale) and validated it as a clinician/researcher administered scale to be used when both patient and examiner are present. The IRLSSG recognized the need for a self-completing scale that can be used economically in clinical practice and in large population-based studies. In this study the validity and the reliability of the IRLS as a self-administered scale (sIRLS) is assessed. Methods Established RLS patients were recruited by eight centers in four countries and consented to participate in this study. The validity of the sIRLS was assessed by patients completing the sIRLS before a clinician administered the IRLS. The reliability of the sIRLS was assessed by patients completing the sIRLS again, two weeks after the first one, provided no change had occurred. Results Overall, 173 patients were recruited and 164 of them were included in the analyses. The sIRLS showed satisfactory scaling assumptions and no relevant floor or ceiling effect. One factor explained 61.3% of the variance. Cronbach's alpha was 0.93 and the item homogeneity index was 0.59. Intraclass correlation coefficient between the sIRLS and the IRLS was 0.94. The sIRLS standard error of measurement was 3.61 (½ SD at baseline = 4.11). The results mostly overlapped those of the IRLS analyzed in parallel. Discussion The sIRLS is a reliable, valid and precise instrument that showed tight association with the IRLS. These findings support the use of the sIRLS for self-evaluation of RLS severity. The responses obtained on the sIRLS and the IRLS scale varied slightly. Therefore, we recommend that either the sIRLS or the IRLS scale be used as the only scale for serial measures over time.
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- 2019
19. Comprehensive Analysis of Familial Parkinsonism Genes in Rapid‐Eye‐Movement Sleep Behavior Disorder
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Christelle Charley Monaca, Alex Desautels, Yves Dauvilliers, Beatriz Abril, Elena Antelmi, Ambra Stefani, Giuseppe Plazzi, Karel Sonka, Monica Puligheddu, Brit Mollenhauer, Birgit Högl, Sandra B. Laurent, Eric Yu, Farnaz Asayesh, Luigi Ferini-Strambi, Mariarosaria Valente, Jennifer A. Ruskey, Michela Figorilli, Uladzislau Rudakou, Annette Janzen, Ziv Gan-Or, Francesco Janes, Mineke Viaene, Ronald B. Postuma, Valérie Cochen De Cock, Bradley F. Boeve, David Kemlink, Evi Holzknecht, Dan Spiegelman, Jacques Montplaisir, Anna Heidbreder, Gian Luigi Gigli, Michele T.M. Hu, Friederike Sixel-Döring, Lynne Krohn, Kheireddin Mufti, Guy A. Rouleau, Isabelle Arnulf, Claudia Trenkwalder, Wolfgang H. Oertel, Femke Dijkstra, Jean-François Gagnon, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Clinique Beau Soleil [Montpellier], EuroMov - Digital Health in Motion (Euromov DHM), IMT - MINES ALES (IMT - MINES ALES), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Montpellier (UM), CHU Lille, Université de Lille, Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Mufti, K., Rudakou, U., Yu, E., Krohn, L., Ruskey, J. A., Asayesh, F., Laurent, S. B., Spiegelman, D., Arnulf, I., M. T. M., Hu, Montplaisir, J. Y., Gagnon, J. -F., Desautels, A., Dauvilliers, Y., Gigli, G. L., Valente, M., Janes, F., Hogl, B., Stefani, A., Holzknecht, E., Sonka, K., Kemlink, D., Oertel, W., Janzen, A., Plazzi, G., Antelmi, E., Figorilli, M., Puligheddu, M., Mollenhauer, B., Trenkwalder, C., Sixel-Doring, F., Cochen De Cock, V., Monaca, C. C., Heidbreder, A., Ferini-Strambi, L., Dijkstra, F., Viaene, M., Abril, B., Boeve, B. F., Postuma, R. B., Rouleau, G. A., and Gan-Or, Z.
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0301 basic medicine ,Heterozygote ,Parkinson's disease ,MESH: Sleep ,[SDV]Life Sciences [q-bio] ,REM sleep behavior disorder ,Rapid eye movement sleep ,Disease ,genetic analysis ,Compound heterozygosity ,Genetic analysis ,03 medical and health sciences ,0302 clinical medicine ,Parkinsonian Disorders ,Medicine ,Humans ,MESH: Heterozygote ,Genetics ,MESH: Humans ,business.industry ,MESH: Parkinsonian Disorders ,PARK7 ,Parkinson Disease ,medicine.disease ,LRRK2 ,3. Good health ,030104 developmental biology ,Neurology ,MESH: REM Sleep Behavior Disorder ,Human medicine ,Neurology (clinical) ,business ,Sleep ,030217 neurology & neurosurgery ,MESH: Parkinson Disease - Abstract
International audience; Background: There is only partial overlap in the genetic background of isolated rapid-eye-movement sleep behavior disorder (iRBD) and Parkinson's disease (PD).Objective: To examine the role of autosomal dominant and recessive PD or atypical parkinsonism genes in the risk of iRBD.Methods: Ten genes, comprising the recessive genes PRKN, DJ-1 (PARK7), PINK1, VPS13C, ATP13A2, FBXO7, and PLA2G6 and the dominant genes LRRK2, GCH1, and VPS35, were fully sequenced in 1039 iRBD patients and 1852 controls of European ancestry, followed by association tests.Results: We found no association between rare heterozygous variants in the tested genes and risk of iRBD. Several homozygous and compound heterozygous carriers were identified, yet there was no overrepresentation in iRBD patients versus controls.Conclusion: Our results do not support a major role for variants in these genes in the risk of iRBD. © 2020 International Parkinson and Movement Disorder Society.
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- 2021
20. Objective rest-activity cycle analysis by actigraphy identifies isolated rapid eye movement sleep behavior disorder
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Marco Filardi, Giuseppe Plazzi, Ambra Stefani, Evi Holzknecht, Birgit Högl, Fabio Pizza, Filardi M., Stefani A., Holzknecht E., Pizza F., Plazzi G., and Hogl B.
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Activity Cycles ,medicine.medical_specialty ,Polysomnography ,Population ,Rapid eye movement sleep ,Sleep, REM ,REM Sleep Behavior Disorder ,Audiology ,REM sleep behavior disorder ,03 medical and health sciences ,0302 clinical medicine ,mental disorders ,Medicine ,Humans ,030212 general & internal medicine ,education ,education.field_of_study ,non-parametric analysi ,business.industry ,screening ,rest–activity rhythm ,Sleep apnea ,Actigraphy ,medicine.disease ,Sleep in non-human animals ,REM sleep behaviour disorder ,actigraphy ,non-parametric analysis ,Nap ,Neurology ,Neurology (clinical) ,Sleep onset ,business ,030217 neurology & neurosurgery - Abstract
Background and purpose: Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is characterized by abnormal behaviours during REM sleep. Several studies showed that iRBD is a prodromal stage of synucleinopathies. Therefore, identifying iRBD in the general population is of utmost importance. In this study, we explore whether the assessment of rest–activity rhythm features can distinguish patients with iRBD from patients with disorders characterized by other pathological motor activity during sleep and healthy controls. Methods: Nineteen patients with video-polysomnographic diagnosis of iRBD, 39 patients with other disorders with motor activity during sleep [19 with restless leg syndrome (RLS) and 20 with untreated sleep apnea syndrome (SAS)] and 16 healthy controls underwent 2-week actigraphy and video-polysomnography, and completed REM sleep behavior disorder screening questionnaires. Non-parametric analyses were applied to assess the rest–activity rhythm features. Results: Patients with iRBD showed lower sleep efficiency, increased estimated wake after sleep onset and increased frequency of prolonged activity bouts compared to those with RLS and controls, while no difference emerged compared with SAS patients. Moreover, patients with iRBD presented increased occurrence of estimated nap in comparison to those with RLS, those with SAS and controls. The I 
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- 2020
21. SMPD1 variants do not have a major role in rapid eye movement sleep behavior disorder
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Marco Toffoli, Uladzislau Rudakou, Anna Heidbreder, Michele T.M. Hu, Isabelle Arnulf, Lynne Krohn, Jean-François Gagnon, Femke Dijkstra, Yves Dauvilliers, Beatriz Abril, Elena Antelmi, Brit Mollenhauer, Annette Janzen, Naomi C. Futhey, Ambra Stefani, Jacques Montplaisir, W. H. Oertel, David Kemlink, Evi Holzknecht, Armaghan Alam, Paul Cannon, Luigi Ferini-Strambi, Guy A. Rouleau, Claudia Trenkwalder, Mineke Viaene, Karel Sonka, Birgit Högl, Christelle Charley Monaca, Ronald B. Postuma, Monica Puligheddu, Alex Desautels, Mariarosaria Valente, Bradley F. Boeve, Karl Heilbron, Valérie Cochen De Cock, Michela Figorilli, Friederike Sixel-Döring, Ziv Gan-Or, Gian Luigi Gigli, Jennifer A. Ruskey, Giuseppe Plazzi, Rudakou, U., Futhey, N. C., Krohn, L., Ruskey, J. A., Heilbron, K., Cannon, P., Alam, A., Arnulf, I., M. T. M., Hu, Montplaisir, J. Y., Gagnon, J. -F., Desautels, A., Dauvilliers, Y., Toffoli, M., Gigli, G. L., Valente, M., Hogl, B., Stefani, A., Holzknecht, E., Sonka, K., Kemlink, D., Oertel, W., Janzen, A., Plazzi, G., Antelmi, E., Figorilli, M., Puligheddu, M., Mollenhauer, B., Trenkwalder, C., Sixel-Doring, F., De Cock, V. C., Monaca, C. C., Heidbreder, A., Ferini-Strambi, L., Dijkstra, F., Viaene, M., Abril, B., Boeve, B. F., Postuma, R. B., Rouleau, G. A., Gan-Or, Z., Salvy-Córdoba, Nathalie, Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], 23andMe Inc., Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Nuffield Department of Clinical Neurosciences [Oxford], University of Oxford, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Centre d'études avancées en Médecine du Sommeil (CEAMS), Université de Montréal (UdeM)-Hôpital du Sacré-Coeur de Montréal, Université du Québec à Montréal = University of Québec in Montréal (UQAM), Hôpital Gui de Chauliac [Montpellier], Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Università degli Studi di Udine - University of Udine [Italie], UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, University of Udine and University Hospital of Udine, Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), First Faculty of Medicine Charles University [Prague], Philipps Universität Marburg = Philipps University of Marburg, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Institute of Neurological Sciences of Bologna IRCCS, University of Cagliari, Paracelsus-Elena-Klinik, Kassel, Germany., department of neurology, clinical dementia center and DZNE, goettingen, Allemagne., Georg-August-University = Georg-August-Universität Göttingen, Department of Psychiatry and Psychotherapy, University Medical Center Goettingen (UMG), Göttingen, Clinique Beau Soleil [Montpellier], Euromov (EuroMov), Université de Montpellier (UM), CHU Lille, University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), Algemeen Ziekenhuis Sint-Dimpna, Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Mayo Clinic [Rochester], Hôpital du Sacré-Coeur de Montréal, and Department of Human Genetics [Montréal]
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Male ,0301 basic medicine ,Aging ,REM sleep behavior disorder ,Disease ,Bioinformatics ,European descent ,Behavior disorder ,0302 clinical medicine ,Medicine ,MESH: Genetic Variation ,MESH: High-Throughput Nucleotide Sequencing ,MESH: Genetic Association Studies ,education.field_of_study ,General Neuroscience ,sphingomyelin phosphodiesterase 1 ,High-Throughput Nucleotide Sequencing ,MESH: Negative Results ,MESH: Sleep Wake Disorders ,Association study ,Sphingomyelin Phosphodiesterase ,Female ,Sphingomyelin phosphodiesterase 1 ,Sleep Wake Disorders ,Rapid eye movement sleep ,Sleep, REM ,[SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics ,association study ,03 medical and health sciences ,Humans ,education ,Genetic Association Studies ,MESH: Humans ,business.industry ,Dementia with Lewy bodies ,[SCCO.NEUR]Cognitive science/Neuroscience ,[SCCO.NEUR] Cognitive science/Neuroscience ,Genetic Variation ,medicine.disease ,MESH: Sleep, REM ,MESH: Male ,030104 developmental biology ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,MESH: Sphingomyelin Phosphodiesterase ,Neurology (clinical) ,Geriatrics and Gerontology ,business ,MESH: Female ,Negative Results ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
International audience; Mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene were reported to be associated with Parkinson's disease and dementia with Lewy bodies. In the current study, we aimed to evaluate the role of SMPD1 variants in isolated rapid eye movement sleep behavior disorder (iRBD). SMPD1 and its untranslated regions were sequenced using targeted next-generation sequencing in 959 iRBD patients and 1287 controls from European descent. Our study reports no statistically significant association of SMPD1 variants and iRBD. It is hence unlikely that SMPD1 plays a major role in iRBD.
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- 2020
22. Spoken Language Alterations can Predict Phenoconversion in Isolated Rapid Eye Movement Sleep Behavior Disorder: A Multicenter Study.
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Šubert M, Novotný M, Tykalová T, Hlavnička J, Dušek P, Růžička E, Škrabal D, Pelletier A, Postuma RB, Montplaisir J, Gagnon JF, Galbiati A, Ferini-Strambi L, Marelli S, St Louis EK, Timm PC, Teigen LN, Janzen A, Oertel W, Heim B, Holzknecht E, Stefani A, Högl B, Dauvilliers Y, Evangelista E, Šonka K, and Rusz J
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- Humans, Neurodegenerative Diseases, REM Sleep Behavior Disorder diagnosis, Parkinsonian Disorders, Cognitive Dysfunction diagnosis, Dementia
- Abstract
Objective: This study assessed the relationship between speech and language impairment and outcome in a multicenter cohort of isolated/idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD)., Methods: Patients with iRBD from 7 centers speaking Czech, English, German, French, and Italian languages underwent a detailed speech assessment at baseline. Story-tale narratives were transcribed and linguistically annotated using fully automated methods based on automatic speech recognition and natural language processing algorithms, leading to the 3 distinctive linguistic and 2 acoustic patterns of language deterioration and associated composite indexes of their overall severity. Patients were then prospectively followed and received assessments for parkinsonism or dementia during follow-up. The Cox proportional hazard was performed to evaluate the predictive value of language patterns for phenoconversion over a follow-up period of 5 years., Results: Of 180 patients free of parkinsonism or dementia, 156 provided follow-up information. After a mean follow-up of 2.7 years, 42 (26.9%) patients developed neurodegenerative disease. Patients with higher severity of linguistic abnormalities (hazard ratio [HR = 2.35]) and acoustic abnormalities (HR = 1.92) were more likely to develop a defined neurodegenerative disease, with converters having lower content richness (HR = 1.74), slower articulation rate (HR = 1.58), and prolonged pauses (HR = 1.46). Dementia-first (n = 16) and parkinsonism-first with mild cognitive impairment (n = 9) converters had higher severity of linguistic abnormalities than parkinsonism-first with normal cognition converters (n = 17)., Interpretation: Automated language analysis might provide a predictor of phenoconversion from iRBD into synucleinopathy subtypes with cognitive impairment, and thus can be used to stratify patients for neuroprotective trials. ANN NEUROL 2024;95:530-543., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)
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- 2024
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23. Effects of periodic breathing on sleep at high altitude: a randomized, placebo-controlled, crossover study using inspiratory CO 2 .
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Ibrahim A, Stefani A, Cesari M, Roche J, Gatterer H, Holzknecht E, Turner R, Vinetti G, Furian M, Heidbreder A, Högl B, and Siebenmann C
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Hypoxia at high altitude facilitates changes in ventilatory control that can lead to nocturnal periodic breathing (nPB). Here, we introduce a placebo-controlled approach to prevent nPB by increasing inspiratory CO
2 and used it to assess whether nPB contributes to the adverse effects of hypoxia on sleep architecture. In a randomized, single-blinded, crossover design, 12 men underwent two sojourns (three days/nights each, separated by 4 weeks) in hypobaric hypoxia corresponding to 4000 m altitude, with polysomnography during the first and third night of each sojourn. During all nights, subjects' heads were encompassed by a canopy retaining exhaled CO2 , and CO2 concentration in the canopy (i.e. inspiratory CO2 concentration) was controlled by adjustment of fresh air inflow. Throughout the placebo sojourn inspiratory CO2 was ≤0.2%, whereas throughout the other sojourn it was increased to 1.76% (IQR, 1.07%-2.44%). During the placebo sojourn, total sleep time (TST) with nPB was 54.3% (37.4%-80.8%) and 45.0% (24.5%-56.5%) during the first and the third night, respectively (P = 0.042). Increased inspiratory CO2 reduced TST with nPB by an absolute 38.1% (28.1%-48.1%), the apnoea-hypopnoea index by 58.1/h (40.1-76.1/h), and oxygen desaturation index ≥3% by 56.0/h (38.9.1-73.2/h) (all P < 0.001), whereas it increased the mean arterial oxygen saturation in TST by 2.0% (0.4%-3.5%, P = 0.035). Increased inspiratory CO2 slightly increased the percentage of N3 sleep during the third night (P = 0.045), without other effects on sleep architecture. Increasing inspiratory CO2 effectively prevented hypoxia-induced nPB without affecting sleep macro-architecture, indicating that nPB does not explain the sleep deterioration commonly observed at high altitudes. KEY POINTS: Periodic breathing is common during sleep at high altitude, and it is unclear how this affects sleep architecture. We developed a placebo-controlled approach to prevent nocturnal periodic breathing (nPB) with inspiratory CO2 administration and used it to assess the effects of nPB on sleep in hypobaric hypoxia. Nocturnal periodic breathing was effectively mitigated by an increased inspiratory CO2 fraction in a blinded manner. Prevention of nPB did not lead to relevant changes in sleep architecture in hypobaric hypoxia. We conclude that nPB does not explain the deterioration in sleep architecture commonly observed at high altitude., (© 2024 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)- Published
- 2024
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24. Is REM Sleep Behavior Disorder Changing? Secular Changes Versus Referral Patterns.
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Joza S, Iranzo A, Stefani A, Pelletier A, Serradell M, Muñoz-Lopetegi A, Ibrahim A, Holzknecht E, Montplaisir JY, Mayà G, Santamaria J, Gaig C, Bergmann M, Brandauer E, Högl B, Gagnon JF, and Postuma RB
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Background: Since 2014, there has been increasing public outreach effort regarding isolated/idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) in Montreal., Objective: To assess if, over time, milder iRBD cases are presenting earlier., Methods: Disease-free survival was compared in two iRBD recruitment epochs: 2004 to 2013 ("earlier") versus 2014to 2022 ("later " ) and by referral type ("self-referral" vs. "conventional-referral") in three large centers., Results: In Montreal, among 209 subjects followed prospectively, shorter time to phenoconversion was observed in the earlier epoch (5-year phenoconversion = 42% earlier vs. 23% later); diagnosis before 2014 had a 1.8-fold phenoconversion hazard. However, no difference was observed in 248 subjects from Barcelona and 166 from Innsbruck. Analysis of Montreal data found that increased survival in the later epoch was driven by an increasing number of self-referrals, who phenoconverted at 1/3 the rate of physician-referred subjects., Conclusions: Increased patient awareness of iRBD results in earlier presentation to clinical attention, with a longer time to phenoconversion., (© 2023 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)
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- 2023
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25. Improved automatic identification of isolated rapid eye movement sleep behavior disorder with a 3D time-of-flight camera.
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Cesari M, Ruzicka L, Högl B, Ibrahim A, Holzknecht E, Heidbreder A, Bergmann M, Brandauer E, Garn H, Kohn B, and Stefani A
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- Humans, Movement, Sleep, REM, Polysomnography, REM Sleep Behavior Disorder diagnosis
- Abstract
Background and Purpose: Automatic 3D video analysis of the lower body during rapid eye movement (REM) sleep has been recently proposed as a novel tool for identifying people with isolated REM sleep behavior disorder (iRBD), but, so far, it has not been validated on unseen subjects. This study aims at validating this technology in a large cohort and at improving its performances by also including an analysis of movements in the head, hands and upper body., Methods: Fifty-three people with iRBD and 128 people without RBD (of whom 89 had sleep disorders considered RBD differential diagnoses) were included in the study. An automatic algorithm identified movements from 3D videos during REM sleep in four regions of interest (ROIs): head, hands, upper body and lower body. The movements were divided into categories according to duration: short (0.1-2 s), medium (2-15 s) and long (15-300 s). For each ROI and duration range, features were obtained from the identified movements. Logistic regression models using as predictors the features from one single ROI or a combination of ROIs were trained and tested in a 10-runs 10-fold cross-validation scheme on the task of differentiating people with iRBD from people without RBD., Results: The best differentiation was achieved using short movements in all four ROIs (test accuracy 0.866 ± 0.007, test F1 score = 0.783 ± 0.010). Single group analyses showed that people with iRBD were distinguished successfully from subjects with RBD differential diagnoses., Conclusions: Automatic 3D video analysis might be implemented in clinical routine as a supportive screening tool for identifying people with RBD., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)
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- 2023
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26. Low Specificity of Rapid Eye Movement Sleep Behavior Disorder Questionnaires: Need for Better Screening Methods.
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Stefani A, Serradell M, Holzknecht E, Gaig C, Ibrahim A, Marrero P, Cesari M, Pérez-Carbonell L, Brandauer E, Fernández-Arcos A, Bergmann M, Matos N, Santamaria J, Högl B, and Iranzo A
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- Male, Humans, Middle Aged, Female, Prospective Studies, Polysomnography methods, Surveys and Questionnaires, REM Sleep Behavior Disorder diagnosis, Parkinson Disease diagnosis
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Background: Correct diagnosis of rapid eye movement sleep behavior disorder (RBD) is critical due to its link to α-synucleinopathies and risk of injuries and requires video-polysomnography (V-PSG). Usefulness of screening questionnaires outside the context of validation studies is limited., Objective: The aim was to assess the performance of three validated RBD screening questionnaires compared with gold-standard V-PSG., Methods: In this bicentric prospective study, 400 consecutive subjects referred to a sleep center for the first time filled three RBD questionnaires (RBD Screening Questionnaire, RBD Single Question, and Innsbruck RBD Inventory) in random order before sleep experts' interview. Subjects positive for at least one questionnaire were invited to undergo V-PSG. Data from patients negative for all questionnaires undergoing V-PSG for other reasons were also evaluated. Questionnaire performances were compared to gold-standard V-PSG RBD diagnosis., Results: Three hundred ninety-nine patients (median age: 51 [interquartile range: 37-64] years, 54.9% men) participated. Two hundred thirty-eight (59.6%) were positive for at least one questionnaire, and RBD was diagnosed using V-PSG in 30 patients (7.5%). Questionnaire specificity was 48.1% to 67.4%, sensitivity 80% to 92%, accuracy 51% to 68.3%, negative predictive value 94.2% to 98%, and positive predictive value 14.1% to 20.7%, with no relevant differences in performances among the evaluated questionnaires., Conclusions: RBD questionnaires have low specificity and low positive predictive value and should not be used as a standalone tool for the diagnosis of RBD. Further development of RBD screening methods is needed, particularly for upcoming neuroprotective trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)
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- 2023
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27. Automatic analysis of muscular activity in the flexor digitorum superficialis muscles: a fast screening method for rapid eye movement sleep without atonia.
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Cesari M, Heidbreder A, Gaig C, Bergmann M, Brandauer E, Iranzo A, Holzknecht E, Santamaria J, Högl B, and Stefani A
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- Humans, Electromyography methods, Muscle, Skeletal physiology, Muscle Hypotonia diagnosis, Facial Muscles, Sleep, REM physiology, REM Sleep Behavior Disorder diagnosis
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Study Objectives: To identify a fast and reliable method for rapid eye movement (REM) sleep without atonia (RWA) quantification., Methods: We analyzed 36 video-polysomnographies (v-PSGs) of isolated REM sleep behavior disorder (iRBD) patients and 35 controls' v-PSGs. Patients diagnosed with RBD had: i) RWA, quantified with a reference method, i.e. automatic and artifact-corrected 3-s Sleep Innsbruck Barcelona (SINBAR) index in REM sleep periods (RSPs, i.e. manually selected portions of REM sleep); and ii) v-PSG-documented RBD behaviors. We quantified RWA with other (semi)-automated methods requiring less human intervention than the reference one: the indices proposed by the SINBAR group (the 3-s and 30-s phasic flexor digitorum superficialis (FDS), phasic/"any"/tonic mentalis), and the REM atonia, short and long muscle activity indices (in mentalis/submentalis/FDS muscles). They were calculated in whole REM sleep (i.e. REM sleep scored following international guidelines), in RSPs, with and without manual artifact correction. Area under curves (AUC) discriminating iRBD from controls were computed. Using published cut-offs, the indices' sensitivity and specificity for iRBD identification were calculated. Apnea-hypopnea index in REM sleep (AHIREM) was considered in the analyses., Results: RWA indices from FDS muscles alone had the highest AUCs and all of them had 100% sensitivity. Without manual RSP selection and artifact correction, the "30-s phasic FDS" and the "FDS long muscle activity" had the highest specificity (85%) with AHIREM < 15/h. RWA indices were less reliable when AHIREM≥15/h., Conclusions: If AHIREM<15/h, FDS muscular activity in whole REM sleep and without artifact correction is fast and reliable to rule out RWA., (© Sleep Research Society 2022. Published by Oxford University Press on behalf of the Sleep Research Society.)
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- 2023
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28. TeaSpam: A Novel Method of TEmporal And SPAtial Movement Encoding during Sleep.
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Kohn B, Ruzicka L, Hogl B, Ibrahim A, Garn H, Heidbreder A, Bergmann M, Brandauer E, Holzknecht E, Stefani A, and Cesari M
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- Humans, Movement, Polysomnography methods, Sleep, Sleep Initiation and Maintenance Disorders, Sleep Wake Disorders
- Abstract
Movements during sleep characterize sleep disorders, which can disturb sleep or its onset, impacting sleep quantity and quality. Video-polysomnography is the current gold standard to assess movements during sleep, but its availability is limited. Using data recorded with a 3D time of flight sensor, we developed a novel method of encoding temporal and spatial information of automatically identified movements during sleep. In a cohort of 20 insomnia patients and 18 controls, we showed that this novel method holds important information able to discriminate the groups. Future studies will explore the methodology in the context of other sleep disorders.
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- 2022
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29. Language analysis of spontaneous descriptions of restless legs syndrome: Gender differences?
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Holzknecht E, Domahs F, Brandauer E, Bergmann M, Zengin T, Delazer M, Hochleitner M, Högl B, and Stefani A
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- Female, Humans, Language, Male, Prospective Studies, Sex Factors, Restless Legs Syndrome
- Abstract
Patients with restless legs syndrome (RLS) use various terms when describing their symptoms. Whether gender might influence this has not been investigated so far. The aim of this study was to evaluate possible gender differences in spontaneous descriptions of RLS symptoms. This prospective study, conducted in 100 consecutive German-speaking RLS patients, used a single standardized question. Answers were digitally recorded and transcribed. A content-related linguistic analysis of the transcripts was performed by two independent blinded raters. The lengths of the answers and content-related linguistic features were compared between women and men. Ninety-eight patients were included in the final analysis, 59 women (60.2%) and 39 men (39.8%), with a median age of 62 (23-94) and 63 (31-82) years, respectively (p = 0.602). Demographic and clinical features, including educational level and RLS treatment class, did not differ between genders (p > 0.05). Total word or sentence count showed no gender differences (p = 0.159 and 0.259, respectively), although men used more words per sentence than women (p = 0.018). More men than women described quiescegenic (i.e., triggered by rest or inactivity) symptoms (p = 0.006) and successful attempts at relief (p = 0.039). There was a non-significant trend toward a more frequent use of the first-person perspective in men (median times used = 5 [0-10.5] vs. 3.8 [0-17.5], p = 0.068). The more frequent mention of quiescegenic symptoms and successful attempts at relief in men could indicate differences in phenotypic presentation of RLS between genders, a more precise description of RLS symptoms or a higher experience of self-efficacy in men compared to women., (© 2021 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)
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- 2022
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30. Automatic 3D Video Analysis of Upper and Lower Body Movements to Identify Isolated REM Sleep Behavior Disorder: A Pilot Study .
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Cesari M, Kohn B, Holzknecht E, Ibrahim A, Heidbreder A, Bergmann M, Brandauer E, Hogl B, Garn H, and Stefani A
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- Humans, Pilot Projects, Polysomnography, Sleep, REM, Parkinson Disease diagnosis, REM Sleep Behavior Disorder diagnosis
- Abstract
Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by dream enactment, abnormal jerks and movements during REM sleep. Isolated RBD (iRBD) is recognized as the early stage of alpha-synucleinopathies, i.e. dementia with Lewy bodies, Parkinson's disease and multiple system atrophy. The certain diagnosis of iRBD requires video-polysomnography, evaluated by experts with time-consuming visual analyses. In this study, we propose automatic analysis of movements detected with 3D contactless video as a promising technology to assist sleep experts in the identification of patients with iRBD. By using automatically detected upper and lower body movements occurring during REM sleep with a duration between 4s and 5s, we could discriminate 20 iRBD patients from 24 patients with sleep-disordered breathing with an accuracy of 0.91 and F1-score of 0.90. This pilot study shows that 3D contactless video can be successfully used as a non-invasive technology to assist clinicians in identifying abnormal movements during REM sleep, and therefore to recognize patients with iRBD. Future investigations in larger cohorts are needed to validate the proposed technology and methodology.
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- 2021
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31. Flexor digitorum superficialis muscular activity is more reliable than mentalis muscular activity for rapid eye movement sleep without atonia quantification: A study of interrater reliability for artifact correction in the context of semiautomated scoring of rapid eye movement sleep without atonia.
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Cesari M, Heidbreder A, Bergmann M, Holzknecht E, Högl B, and Stefani A
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- Artifacts, Electromyography, Humans, Reproducibility of Results, REM Sleep Behavior Disorder, Sleep, REM
- Abstract
Study Objectives: To evaluate interrater reliability for artifact correction in the context of semiautomated quantification of rapid eye movement (REM) sleep without atonia (RWA) in the mentalis and flexor digitorum superficialis (FDS) muscles., Methods: We included video-polysomnographies of 14 subjects with apnea-hypopnea index in REM sleep (AHIREM) < 15/h and 11 subjects with AHIREM ≥ 15/h. Eight subjects had isolated REM sleep behavior disorder. A validated algorithm (www.osg.be) automatically scored phasic and "any" EMG activity in the mentalis muscle, and phasic EMG activity in the FDS muscles. Four independent expert scorers performed artifact correction according to the SINBAR (Sleep Innsbruck Barcelona) recommendations. Interrater reliability for artifact correction was computed with B-statistics. The variability across scorers of four RWA indices (phasic mentalis, "any" mentalis, phasic FDS and SINBAR-i.e. "any" mentalis and/or phasic FDS-EMG activity indices) was computed. With Friedman tests, we compared B-statistics obtained for mentalis and FDS muscles, and the variability of the RWA indices. Influence of AHIREM and REM sleep behavior disorder (RBD) diagnosis on the RWA indices variability was evaluated with linear regressions., Results: Interrater reliability for artifact correction was higher in the FDS than in the mentalis muscle (p < 0.001). Phasic FDS activity was minimally affected by artifacts. Accordingly, the phasic FDS EMG activity index had the lowest variability across scorers (p < 0.001). Variability across scorers of the RWA indices including the mentalis muscle increased with AHIREM and was independent from RBD diagnosis., Conclusions: Due to the consistently found low number of artifacts, phasic FDS activity is a reliable measure of RWA., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2021
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32. Rapid eye movement sleep behavior disorder and rapid eye movement sleep without atonia are more frequent in advanced versus early Parkinson's disease.
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Sringean J, Stefani A, Marini K, Bergmann M, Werkmann M, Holzknecht E, De Marzi R, Brandauer E, Hackner H, Djamshidian A, Stockner H, Gaig C, Iranzo A, Santamaria J, Tolosa E, Seppi K, Poewe W, and Högl B
- Subjects
- Electromyography, Humans, Sleep, Sleep, REM, Parkinson Disease complications, Parkinson Disease diagnosis, REM Sleep Behavior Disorder diagnosis
- Abstract
Study Objectives: To evaluate macro sleep architecture and characterize rapid eye movement (REM) sleep without atonia (RWA) by using the SINBAR excessive electromyographic (EMG) montage including mentalis and upper extremity muscles in early and advanced Parkinson's disease (PD)., Methods: We recruited 30 patients with early- and advanced-stage of PD according to Movement Disorder Society (MDS) Clinical Diagnostic Criteria. Participants were classified as early-stage PD if they were treatment-naïve or had no motor complications and had been diagnosed with PD within the previous 6 years. Advanced PD was defined as a disease duration equal to or >6 years with or without motor complications., Results: There was significantly shorter REM sleep latency in early as compared to the advanced stage of PD. We found that the sleep Innsbruck Barcelona (SINBAR) EMG index and tonic EMG activity of the mentalis muscle in advanced-stage PD were significantly higher than in early-stage PD with a trend in phasic EMG activity of the flexor digitorum superficialis muscles. The SINBAR EMG index, tonic and any EMG activity of the mentalis muscle, and phasic EMG activity of flexor digitorum superficialis muscles significantly correlated with disease duration., Conclusions: This study analyzed RWA using the SINBAR EMG montage in early- and advanced-stage of PD and showed higher RWA in mentalis and flexor digitorum superficialis muscles and SINBAR EMG index in advanced-PD patients compared to patients in the early stage. Also, polysomnography-confirmed REM sleep behavior disorder was more common in advanced versus early-stage patients. Our findings suggest that RWA worsens or is more intense or more frequent with disease progression., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2021
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33. Speech Biomarkers in Rapid Eye Movement Sleep Behavior Disorder and Parkinson Disease.
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Rusz J, Hlavnička J, Novotný M, Tykalová T, Pelletier A, Montplaisir J, Gagnon JF, Dušek P, Galbiati A, Marelli S, Timm PC, Teigen LN, Janzen A, Habibi M, Stefani A, Holzknecht E, Seppi K, Evangelista E, Rassu AL, Dauvilliers Y, Högl B, Oertel W, St Louis EK, Ferini-Strambi L, Růžička E, Postuma RB, and Šonka K
- Subjects
- Aged, Aged, 80 and over, Biomarkers, Disease Progression, Europe, Female, Humans, Male, Middle Aged, Parkinson Disease physiopathology, Prodromal Symptoms, REM Sleep Behavior Disorder physiopathology, Parkinson Disease diagnosis, REM Sleep Behavior Disorder diagnosis, Speech physiology
- Abstract
Objective: This multilanguage study used simple speech recording and high-end pattern analysis to provide sensitive and reliable noninvasive biomarkers of prodromal versus manifest α-synucleinopathy in patients with idiopathic rapid eye movement sleep behavior disorder (iRBD) and early-stage Parkinson disease (PD)., Methods: We performed a multicenter study across the Czech, English, German, French, and Italian languages at 7 centers in Europe and North America. A total of 448 participants (337 males), including 150 with iRBD (mean duration of iRBD across language groups 0.5-3.4 years), 149 with PD (mean duration of disease across language groups 1.7-2.5 years), and 149 healthy controls were recorded; 350 of the participants completed the 12-month follow-up. We developed a fully automated acoustic quantitative assessment approach for the 7 distinctive patterns of hypokinetic dysarthria., Results: No differences in language that impacted clinical parkinsonian phenotypes were found. Compared with the controls, we found significant abnormalities of an overall acoustic speech severity measure via composite dysarthria index for both iRBD (p = 0.002) and PD (p < 0.001). However, only PD (p < 0.001) was perceptually distinct in a blinded subjective analysis. We found significant group differences between PD and controls for monopitch (p < 0.001), prolonged pauses (p < 0.001), and imprecise consonants (p = 0.03); only monopitch was able to differentiate iRBD patients from controls (p = 0.004). At the 12-month follow-up, a slight progression of overall acoustic speech impairment was noted for the iRBD (p = 0.04) and PD (p = 0.03) groups., Interpretation: Automated speech analysis might provide a useful additional biomarker of parkinsonism for the assessment of disease progression and therapeutic interventions. ANN NEUROL 2021;90:62-75., (© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)
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- 2021
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34. Alpha-synuclein seeds in olfactory mucosa of patients with isolated REM sleep behaviour disorder.
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Stefani A, Iranzo A, Holzknecht E, Perra D, Bongianni M, Gaig C, Heim B, Serradell M, Sacchetto L, Garrido A, Capaldi S, Sánchez-Gómez A, Cecchini MP, Mariotto S, Ferrari S, Fiorini M, Schmutzhard J, Cocchiara P, Vilaseca I, Brozzetti L, Monaco S, Jose Marti M, Seppi K, Tolosa E, Santamaria J, Högl B, Poewe W, and Zanusso G
- Subjects
- Aged, Biomarkers analysis, Biomarkers metabolism, Case-Control Studies, Cross-Sectional Studies, Early Diagnosis, Female, Humans, Male, Middle Aged, Parkinson Disease diagnosis, Parkinson Disease metabolism, Prodromal Symptoms, REM Sleep Behavior Disorder metabolism, Sensitivity and Specificity, alpha-Synuclein metabolism, Olfactory Mucosa metabolism, Parkinson Disease pathology, REM Sleep Behavior Disorder pathology, alpha-Synuclein analysis
- Abstract
Isolated REM sleep behaviour disorder (RBD) is an early-stage α-synucleinopathy in most, if not all, affected subjects. Detection of pathological α-synuclein in peripheral tissues of patients with isolated RBD may identify those progressing to Parkinson's disease, dementia with Lewy bodies or multiple system atrophy, with the ultimate goal of testing preventive therapies. Real-time quaking-induced conversion (RT-QuIC) provided evidence of α-synuclein seeding activity in CSF and olfactory mucosa of patients with α-synucleinopathies. The aim of this study was to explore RT-QuIC detection of α-synuclein aggregates in olfactory mucosa of a large cohort of subjects with isolated RBD compared to patients with Parkinson's disease and control subjects. This cross-sectional case-control study was performed at the Medical University of Innsbruck, Austria, the Hospital Clinic de Barcelona, Spain, and the University of Verona, Italy. Olfactory mucosa samples obtained by nasal swab in 63 patients with isolated RBD, 41 matched Parkinson's disease patients and 59 matched control subjects were analysed by α-synuclein RT-QuIC in a blinded fashion at the University of Verona, Italy. Median age of patients with isolated RBD was 70 years, 85.7% were male. All participants were tested for smell, autonomic, cognitive and motor functions. Olfactory mucosa was α-synuclein RT-QuIC positive in 44.4% isolated RBD patients, 46.3% Parkinson's disease patients and 10.2% control subjects. While the sensitivity for isolated RBD plus Parkinson's disease versus controls was 45.2%, specificity was high (89.8%). Among isolated RBD patients with positive α-synuclein RT-QuIC, 78.6% had olfactory dysfunction compared to 21.4% with negative α-synuclein RT-QuIC (P < 0.001). The extent of olfactory dysfunction was more severe in isolated RBD patients positive than negative for olfactory mucosa a-synuclein RT-QuIC (P < 0.001). We provide evidence that the α-synuclein RT-QuIC assay enables the molecular detection of neuronal α-synuclein aggregates in olfactory mucosa of patients with isolated RBD and Parkinson's disease. Although the overall sensitivity was moderate in this study, nasal swabbing is attractive as a simple, non-invasive test and might be useful as part of a screening battery to identify subjects in the prodromal stages of α-synucleinopathies. Further studies are needed to enhance sensitivity, and better understand the temporal dynamics of α-synuclein seeding in the olfactory mucosa and spreading to other brain areas during the progression from isolated RBD to overt α-synucleinopathy, as well the impact of timing, disease subgroups and sampling technique on the overall sensitivity., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2021
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35. Novel Associations of BST1 and LAMP3 With REM Sleep Behavior Disorder.
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Mufti K, Yu E, Rudakou U, Krohn L, Ruskey JA, Asayesh F, Laurent SB, Spiegelman D, Arnulf I, Hu MTM, Montplaisir JY, Gagnon JF, Desautels A, Dauvilliers Y, Gigli GL, Valente M, Janes F, Bernardini A, Högl B, Stefani A, Holzknecht E, Sonka K, Kemlink D, Oertel W, Janzen A, Plazzi G, Antelmi E, Figorilli M, Puligheddu M, Mollenhauer B, Trenkwalder C, Sixel-Döring F, Cochen De Cock V, Monaca CC, Heidbreder A, Ferini-Strambi L, Dijkstra F, Viaene M, Abril B, Boeve BF, Trempe JF, Rouleau GA, Postuma RB, and Gan-Or Z
- Subjects
- Aged, Computer Simulation, Databases, Genetic, Female, GPI-Linked Proteins genetics, Genetic Variation, Genome-Wide Association Study, Heterozygote, Humans, Male, Middle Aged, Polysomnography, Protein Structure, Secondary, REM Sleep Behavior Disorder epidemiology, ADP-ribosyl Cyclase genetics, Antigens, CD genetics, Lysosomal Membrane Proteins genetics, Neoplasm Proteins genetics, REM Sleep Behavior Disorder genetics
- Abstract
Objective: To examine the role of genes identified through genome-wide association studies (GWASs) of Parkinson disease (PD) in the risk of isolated REM sleep behavior disorder (iRBD)., Methods: We fully sequenced 25 genes previously identified in GWASs of PD in a total of 1,039 patients with iRBD and 1,852 controls. The role of rare heterozygous variants in these genes was examined with burden tests. The contribution of biallelic variants was further tested. To examine the potential effect of rare nonsynonymous BST1 variants on the protein structure, we performed in silico structural analysis. Finally, we examined the association of common variants using logistic regression adjusted for age and sex., Results: We found an association between rare heterozygous nonsynonymous variants in BST1 and iRBD ( p = 0.0003 at coverage >50× and 0.0004 at >30×), driven mainly by 3 nonsynonymous variants (p.V85M, p.I101V, and p.V272M) found in 22 (1.2%) controls vs 2 (0.2%) patients. All 3 variants seem to be loss-of-function variants with a potential effect on the protein structure and stability. Rare noncoding heterozygous variants in LAMP3 were also associated with iRBD ( p = 0.0006 at >30×). We found no association between rare heterozygous variants in the rest of genes and iRBD. Several carriers of biallelic variants were identified, yet there was no overrepresentation in iRBD., Conclusion: Our results suggest that rare coding variants in BST1 and rare noncoding variants in LAMP3 are associated with iRBD. Additional studies are required to replicate these results and to examine whether loss of function of BST1 could be a therapeutic target., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
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- 2021
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36. Central Sleep Apnea and Pacing-Induced Cardiomyopathy.
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Barbieri F, Adukauskaite A, Heidbreder A, Brandauer E, Bergmann M, Stefani A, Holzknecht E, Senoner T, Rubatscher A, Schgör W, Stühlinger M, Pfeifer BE, Bauer A, Hintringer F, Högl B, and Dichtl W
- Subjects
- Aged, Cardiomyopathies diagnosis, Cardiomyopathies physiopathology, Echocardiography, Female, Follow-Up Studies, Heart Failure complications, Heart Failure physiopathology, Humans, Male, Middle Aged, Polysomnography, Prospective Studies, Sleep Apnea, Central physiopathology, Cardiac Pacing, Artificial adverse effects, Cardiomyopathies etiology, Heart Failure therapy, Sleep Apnea, Central complications, Stroke Volume physiology, Ventricular Function, Left physiology
- Abstract
The role of central sleep apnea (CSA) in pacing-induced cardiomyopathy (PICM) remains speculative. In a prospective trial entitled UPGRADE, the presence of CSA was assessed by single-night polysomnography (PSG) in 54 PICM patients within 1 month after left ventricular lead implantation (with biventricular stimulation still not activated). CSA was diagnosed in half of patients (n = 27). Patients with moderate or severe CSA were randomized to cardiac resynchronization therapy (CRT) versus right ventricular pacing (RVP) in a double-blinded cross-over design and re-scheduled for a follow-up PSG within 3 to 5 months. After crossing-over of stimulation mode another PSG was conducted 3 to 5 months later. CRT led to a significant increase in left ventricular ejection fraction and significant reduction in left ventricular end systolic volumes and N-terminal pro brain natriuretic peptide plasma levels, whereas no significant effects were observed with ongoing RVP. CSA was significantly improved after 3.9 (3.2 to 4.4) months of CRT: apnea-hypopnea index decreased from 39.1 (32.1 to 54.0) events per hour at baseline to 22.2/h (10.9 to 36.7) by CRT (p <0.001). Central apnea index decreased from 27.1/h (17.7 to 36.1) at baseline to 6.8/h (1.1 to 14.4) after CRT activation (p <0.001). Ongoing RVP yielded only a minor improvement in apnea-hypopnea index and central apnea index. Pre-existent CSA did not affect structural response rate and had no impact on mid-term follow-up (median 2.8 years). In conclusion, CSA is highly prevalent in patients with PICM. CRT upgrading significantly improves CSA leading to a similar outcome in PICM patients without pre-existent CSA., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2021
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37. Comprehensive Analysis of Familial Parkinsonism Genes in Rapid-Eye-Movement Sleep Behavior Disorder.
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Mufti K, Rudakou U, Yu E, Krohn L, Ruskey JA, Asayesh F, Laurent SB, Spiegelman D, Arnulf I, Hu MTM, Montplaisir JY, Gagnon JF, Desautels A, Dauvilliers Y, Gigli GL, Valente M, Janes F, Högl B, Stefani A, Holzknecht E, Šonka K, Kemlink D, Oertel W, Janzen A, Plazzi G, Antelmi E, Figorilli M, Puligheddu M, Mollenhauer B, Trenkwalder C, Sixel-Döring F, Cochen De Cock V, Monaca CC, Heidbreder A, Ferini-Strambi L, Dijkstra F, Viaene M, Abril B, Boeve BF, Postuma RB, Rouleau GA, and Gan-Or Z
- Subjects
- Heterozygote, Humans, Sleep, Parkinson Disease genetics, Parkinsonian Disorders genetics, REM Sleep Behavior Disorder genetics
- Abstract
Background: There is only partial overlap in the genetic background of isolated rapid-eye-movement sleep behavior disorder (iRBD) and Parkinson's disease (PD)., Objective: To examine the role of autosomal dominant and recessive PD or atypical parkinsonism genes in the risk of iRBD., Methods: Ten genes, comprising the recessive genes PRKN, DJ-1 (PARK7), PINK1, VPS13C, ATP13A2, FBXO7, and PLA2G6 and the dominant genes LRRK2, GCH1, and VPS35, were fully sequenced in 1039 iRBD patients and 1852 controls of European ancestry, followed by association tests., Results: We found no association between rare heterozygous variants in the tested genes and risk of iRBD. Several homozygous and compound heterozygous carriers were identified, yet there was no overrepresentation in iRBD patients versus controls., Conclusion: Our results do not support a major role for variants in these genes in the risk of iRBD. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)
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- 2021
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38. Automated 3D video analysis of lower limb movements during REM sleep: a new diagnostic tool for isolated REM sleep behavior disorder.
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Waser M, Stefani A, Holzknecht E, Kohn B, Hackner H, Brandauer E, Bergmann M, Taupe P, Gall M, Garn H, and Högl B
- Subjects
- Humans, Lower Extremity, Polysomnography, Sleep Stages, Sleep, REM, REM Sleep Behavior Disorder diagnosis
- Abstract
Study Objectives: The differentiation of isolated rapid eye movement (REM) sleep behavior disorder (iRBD) or its prodromal phase (prodromal RBD) from other disorders with motor activity during sleep is critical for identifying α-synucleinopathy in an early stage. Currently, definite RBD diagnosis requires video polysomnography (vPSG). The aim of this study was to evaluate automated 3D video analysis of leg movements during REM sleep as objective diagnostic tool for iRBD., Methods: A total of 122 participants (40 iRBD, 18 prodromal RBD, 64 participants with other disorders with motor activity during sleep) were recruited among patients undergoing vPSG at the Sleep Disorders Unit, Department of Neurology, Medical University of Innsbruck. 3D videos synchronous to vPSG were recorded. Lower limb movements rate, duration, extent, and intensity were computed using a newly developed software., Results: The analyzed 3D movement features were significantly increased in subjects with iRBD compared to prodromal RBD and other disorders with motor activity during sleep. Minor leg jerks with a duration < 2 seconds discriminated with the highest accuracy (90.4%) iRBD from other motor activity during sleep. Automatic 3D analysis did not differentiate between prodromal RBD and other disorders with motor activity during sleep., Conclusions: Automated 3D video analysis of leg movements during REM sleep is a promising diagnostic tool for identifying subjects with iRBD in a sleep laboratory population and is able to distinguish iRBD from subjects with other motor activities during sleep. For future application as a screening, further studies should investigate usefulness of this tool when no information about sleep stages from vPSG is available and in the home environment., (© Sleep Research Society 2020. Published by Oxford University Press on behalf of the Sleep Research Society.)
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- 2020
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39. Augmentation in restless legs syndrome: an eye tracking study on emotion processing.
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Ellmerer P, Heim B, Stefani A, Peball M, Werkmann M, Holzknecht E, Bergmann M, Brandauer E, Sojer M, Zamarian L, Delazer M, Seppi K, Högl B, Poewe W, and Djamshidian A
- Subjects
- Aged, Eye-Tracking Technology, Female, Humans, Male, Middle Aged, Restless Legs Syndrome drug therapy, Affective Symptoms physiopathology, Disruptive, Impulse Control, and Conduct Disorders chemically induced, Disruptive, Impulse Control, and Conduct Disorders physiopathology, Dopamine Agonists adverse effects, Facial Recognition physiology, Restless Legs Syndrome chemically induced, Restless Legs Syndrome physiopathology
- Abstract
Objective: To assess emotional processing and alexithymia in patients with restless legs syndrome (RLS) with augmentation versus those who never had augmentation., Methods: We recruited 26 patients who had a history of augmentation (AUG), either current or past, 27 RLS patients treated with dopamine agonists who never had augmentation (RLS controls), and 21 healthy controls (HC). All participants were screened for impulse control disorders (ICDs). Alexithymia was assessed by means of the Toronto Alexithymia Scale - 20 (TAS-20). Facial emotion recognition was tested through an eye-tracking task. Furthermore, all participants performed neuropsychological tests assessing global cognitive status, impulsivity, anxiety, and depression., Results: ICD symptoms occurred more frequently in AUG patients than in RLS controls (P = 0.047). Patients with AUG scored higher on the TAS-20 (P = 0.007) and the attentional subdomain of an impulsivity scale (BIS-11; P = 0.015) compared to HC. Patients with AUG also performed worse on the facial emotion recognition task relative to RLS controls (P = 0.009) and HC (P = 0.003). We found a group difference for the time to first fixation and the fixation count in the mouth region (P = 0.019 and P = 0.021, respectively). There were no other differences in the eye tracking examination., Interpretation: This study showed evidence of poorer emotional processing in patients who had augmentation compared to RLS patients without augmentation and healthy controls. The altered exploration pattern of faces and the higher alexithymia scores suggest abnormalities in emotion processing in patients with augmentation., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)
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- 2020
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40. SMPD1 variants do not have a major role in rapid eye movement sleep behavior disorder.
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Rudakou U, Futhey NC, Krohn L, Ruskey JA, Heilbron K, Cannon P, Alam A, Arnulf I, Hu MTM, Montplaisir JY, Gagnon JF, Desautels A, Dauvilliers Y, Toffoli M, Gigli GL, Valente M, Högl B, Stefani A, Holzknecht E, Sonka K, Kemlink D, Oertel W, Janzen A, Plazzi G, Antelmi E, Figorilli M, Puligheddu M, Mollenhauer B, Trenkwalder C, Sixel-Döring F, De Cock VC, Monaca CC, Heidbreder A, Ferini-Strambi L, Dijkstra F, Viaene M, Abril B, Boeve BF, Postuma RB, Rouleau GA, and Gan-Or Z
- Subjects
- Female, High-Throughput Nucleotide Sequencing, Humans, Male, Sphingomyelin Phosphodiesterase physiology, Genetic Association Studies, Genetic Variation, Negative Results, Sleep Wake Disorders genetics, Sleep Wake Disorders physiopathology, Sleep, REM genetics, Sphingomyelin Phosphodiesterase genetics
- Abstract
Mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene were reported to be associated with Parkinson's disease and dementia with Lewy bodies. In the current study, we aimed to evaluate the role of SMPD1 variants in isolated rapid eye movement sleep behavior disorder (iRBD). SMPD1 and its untranslated regions were sequenced using targeted next-generation sequencing in 959 iRBD patients and 1287 controls from European descent. Our study reports no statistically significant association of SMPD1 variants and iRBD. It is hence unlikely that SMPD1 plays a major role in iRBD., (Copyright © 2020 Elsevier Inc. All rights reserved.)
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- 2020
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41. Effects of singing bowl exposure on Karolinska sleepiness scale and pupillographic sleepiness test: A randomised crossover study.
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Bergmann M, Riedinger S, Stefani A, Mitterling T, Holzknecht E, Grassmayr P, and Högl B
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- Acoustic Stimulation methods, Adult, Cross-Over Studies, Disorders of Excessive Somnolence diagnosis, Disorders of Excessive Somnolence physiopathology, Female, Healthy Volunteers, Humans, Male, Middle Aged, Polysomnography, Prospective Studies, Pupil physiology, Sleep Stages physiology, Young Adult, Acoustic Stimulation instrumentation, Disorders of Excessive Somnolence rehabilitation, Relaxation physiology, Sleepiness, Wakefulness physiology
- Abstract
Background: The aim of this study was to investigate the effects on subjective and objective sleepiness of a stay above a large struck singing bowl compared to a relaxation period in a silent singing bowl., Methods: Fifty-eight healthy subjects were recruited for the study, 48 participated on two days, one week apart, during the same timeslot. The Karolinska sleepiness scale was used to evaluate current subjective sleepiness, and the relative pupillary unrest index to assess objective sleepiness. In this randomized cross-over study, the intervention consisted of a 20-minute stay in a hammock while the singing bowl, positioned beneath, was struck seven times. The controlled comparator was a 20-minute stay in the same hammock above the singing bowl, but without being struck. After these two interventions subjective and objective sleepiness were re-evaluated., Results: The mean relative pupillary unrest index values after relaxation in the struck and silent singing bowl groups were 0.74 and respectively 0.71 (p = 0.460). The median Karolinska sleepiness scale value after relaxation with the struck singing bowl was 3 compared with 4 (p = 0.041) for the silent singing bowl., Discussion: This study evaluated the influence of a struck singing bowl on sleepiness during daytime. Subjective sleepiness was significantly lower after relaxation above a struck singing bowl. After gender stratification, the difference was still significant in women. Objective sleepiness was not different in both groups. Finally, we can only speculate if women may be more susceptible to subjective improvements in case of sleepiness and show another perception of relaxation in a struck singing bowl compared to men., Competing Interests: BH reports speaker honoraria from Otsuka, UCB, Eli Lilly, Janssen Cilag, Lundbeck Abbvie, Nutricia, Inspire; consulting/ advisory boards for Mundipharma, Benevolent Bio, Axovant, AoP Orphan, Roche; travel support from Habel Medizintechnik, Vivisol Austria. AS reports travel support from Habel Medizintechnik, OSG, UCB; support for research and consulting from Axovant. TM reports personal fees from UCB and AoP Orphan, outside the submitted work. PG is the owner of the Bell Foundry Grassmayr. There are no patents, products in development or marketed products to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The remaining authors declare no other competing interests.
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- 2020
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42. Gender differences in clinical, laboratory and polysomnographic features of restless legs syndrome.
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Holzknecht E, Hochleitner M, Wenning GK, Högl B, and Stefani A
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- Female, Humans, Male, Middle Aged, Retrospective Studies, Sex Characteristics, Polysomnography methods, Restless Legs Syndrome diagnosis
- Abstract
Restless legs syndrome is a common neurological disorder with a clear female predominance. This study aims to evaluate gender differences in clinical, laboratory and polysomnographic features in patients with restless legs syndrome. For this retrospective analysis, 42 women and 42 men from the Innsbruck RLS database matched by age and therapy were included. Demographic data as well as different severity scales (IRLS, RLS-6 and CGI) were evaluated. Laboratory parameters included several indicators of serum iron status. In all patients, polysomnography was performed according to the AASM guidelines, and periodic leg movements during sleep were scored according to the AASM criteria. IRLS, RLS-6 and CGI revealed more severe symptoms in women (IRLS median [range]: 17.5 [0-35] versus 13.5 [0-32], p = 0.028; RLS-6 median [range]: 18 [0-39] versus 12 [1-42], p = 0.014). Women had lower serum ferritin levels than men (median [range] in μg L
-1 : 74 [9-346] versus 167 [15-389], p < 0.001). Twenty-two women and eight men (53.7% versus 22.2%, p = 0.003) had ferritin values below 75 μg L-1 . Periodic leg movements during sleep indices were significantly lower in women than in men (median [range] in number per hr: 11.4 [0-62.5] versus 40 [0-154], p = 0.004, and 12.6 [0-58.5] versus 40 [0.5-208], p = 0.002, for night I and night II, respectively). Restless legs syndrome severity as measured by validated scales was worse in women, while periodic leg movements during sleep indices were higher in men. These results suggest a possible gender difference in phenotypical presentation of restless legs syndrome, manifesting with predominantly sensory symptoms in women and predominantly motor symptoms in men., (© 2019 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)- Published
- 2020
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43. Left-hemispheric predominance of nigrostriatal deficit in isolated REM sleep behavior disorder.
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Iranzo A, Stefani A, Niñerola-Baizan A, Stokner H, Serradell M, Vilas D, Holzknecht E, Gaig C, Pavia J, Lomeña F, Reyes D, Seppi K, Santamaria J, Högl B, Tolosa E, and Poewe W
- Subjects
- Adult, Aged, Corpus Striatum metabolism, Corpus Striatum physiopathology, Dopamine Plasma Membrane Transport Proteins metabolism, Female, Humans, Male, Middle Aged, Neuroimaging methods, Parkinson Disease metabolism, Putamen diagnostic imaging, REM Sleep Behavior Disorder diagnosis, REM Sleep Behavior Disorder metabolism, Substantia Nigra diagnostic imaging, Substantia Nigra physiopathology, Ultrasonography, Doppler, Transcranial methods, Dopamine metabolism, Dopamine Plasma Membrane Transport Proteins pharmacology, Parkinson Disease physiopathology, REM Sleep Behavior Disorder physiopathology
- Abstract
Objective: Unilateral onset of parkinsonism due to nigrostriatal damage of the contralateral hemisphere is frequent in Parkinson disease (PD). There is evidence for a left-hemispheric bias of motor asymmetry in right-handed patients with PD indicating a hemispheric dominance. Isolated REM sleep behavior disorder (IRBD) constitutes the prodromal stage of PD and other synucleinopathies. To test the hypothesis that right-handed patients with IRBD exhibit left-hemispheric predominance of subclinical nigrostriatal dysfunction, we evaluated this aspect using neuroimaging instruments., Methods: In 167 right-handed patients with IRBD without parkinsonism, we evaluated in each hemisphere the integrity of the striatal dopaminergic terminals by dopamine transporter (DAT)-SPECT and the substantia nigra echogenicity by transcranial sonography., Results: DAT-SPECT showed lower specific binding ratio (SBR) in the left striatum and left caudate nucleus than in the right striatum and right caudate nucleus. The percentage of patients with lower SBR was greater in the left striatum and left caudate nucleus than in the right striatum and right caudate nucleus. In those who developed a synucleinopathy in <5 years from DAT-SPECT, there was a lower SBR in the left putamen and left caudate nucleus than in the right putamen and right caudate nucleus. Substantia nigra echogenic size was greater in the left than in the right side in patients with hyperechogenicity and among individuals who phenoconverted in <5 years from transcranial sonography., Conclusion: Right-handed patients with IRBD exhibit left-hemispheric predominance of subclinical nigrostriatal dysfunction. In premotor PD, the neurodegenerative process begins asymmetrically, initially impairing the nigrostriatal system of the dominant hemisphere., (© 2020 American Academy of Neurology.)
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- 2020
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44. Fine-Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies.
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Krohn L, Wu RYJ, Heilbron K, Ruskey JA, Laurent SB, Blauwendraat C, Alam A, Arnulf I, Hu MTM, Dauvilliers Y, Högl B, Toft M, Bjørnarå KA, Stefani A, Holzknecht E, Monaca CC, Abril B, Plazzi G, Antelmi E, Ferini-Strambi L, Young P, Heidbreder A, Cochen De Cock V, Mollenhauer B, Sixel-Döring F, Trenkwalder C, Sonka K, Kemlink D, Figorilli M, Puligheddu M, Dijkstra F, Viaene M, Oertel W, Toffoli M, Gigli GL, Valente M, Gagnon JF, Nalls MA, Singleton AB, Desautels A, Montplaisir JY, Cannon P, Ross OA, Boeve BF, Dupré N, Fon EA, Postuma RB, Pihlstrøm L, Rouleau GA, and Gan-Or Z
- Subjects
- Adult, Aged, Case-Control Studies, Female, Genetic Predisposition to Disease, Humans, Logistic Models, Male, Middle Aged, Odds Ratio, Polymorphism, Single Nucleotide, Synucleinopathies genetics, Lewy Body Disease genetics, Parkinson Disease genetics, Prodromal Symptoms, REM Sleep Behavior Disorder genetics, alpha-Synuclein genetics
- Abstract
Objective: Rapid eye movement sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus to identify RBD-specific risk variants., Methods: Full sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n = 1,076), Parkinson disease (PD, n = 1,013), dementia with Lewy bodies (DLB, n = 415), and control subjects (n = 6,155). The iRBD cases were diagnosed with RBD prior to neurodegeneration, although some have since converted. A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (n = 1,782 cases; n = 131,250 controls). Adjusted logistic regression models and meta-analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan-Meier survival analysis., Results: A 5'-region SNCA variant (rs10005233) was associated with iRBD (odds ratio [OR] = 1.43, p = 1.1E-08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5' risk variants across the different synucleinopathies. An independent iRBD-specific suggestive association (rs11732740) was detected at the 3' of SNCA (OR = 1.32, p = 4.7E-04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD-specific SNPs were at highly increased risk for iRBD (OR = 5.74, p = 2E-06). The known top PD-associated variant (3' variant rs356182) had an opposite direction of effect in iRBD compared to PD., Interpretation: There is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3' of SNCA. Several 5' SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies. ANN NEUROL 2020;87:584-598., (© 2020 American Neurological Association.)
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- 2020
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45. Seasonality of restless legs syndrome: symptom variability in winter and summer times.
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Liguori C, Holzknecht E, Placidi F, Izzi F, Mercuri NB, Högl B, and Stefani A
- Subjects
- Disorders of Excessive Somnolence etiology, Female, Humans, Italy, Male, Middle Aged, Retrospective Studies, Sex Factors, Switzerland, Restless Legs Syndrome complications, Restless Legs Syndrome therapy, Seasons, Severity of Illness Index
- Abstract
Introduction: Restless legs syndrome (RLS) is a common sensorimotor neurological disorder, with symptoms that might cause sleep fragmentation leading to excessive daytime sleepiness. A seasonality of RLS symptoms has been suggested; however, to date, no study focused on this aspect. In order to detect a possible seasonality of RLS manifestations, we evaluated RLS symptom severity and excessive daytime sleepiness in winter and summer in RLS patients., Methods: RLS patients who performed two follow-up visits in summer and winter were included in this retrospective bicentric analysis. RLS severity, measured with the International RLS Study Group rating scale (IRLS), and daytime sleepiness, measured with the Epworth Sleepiness Scale (ESS), were recorded in both seasons in Innsbruck and Rome Sleep Medicine Centers., Results: In sum, 64 RLS patients were included. In the overall sample, IRLS in summer was higher than in winter (p = 0.008). After gender stratification, this held true only in men (p = 0.008). When stratifying for centers, the seasonal variation in RLS severity was present exclusively in Rome (p < 0.001). Moreover, 20 RLS patients completed ESS in both seasonal periods, and scores in summer were higher than in winter (p < 0.001)., Conclusion: This retrospective observational study showed an increase of RLS severity during summer compared to winter, supporting the hypothesis that RLS symptoms are more troublesome when temperatures are higher. Changes in microvascular regulation, sweating, and serum iron level changes may support this difference in RLS symptoms across the year. The documented seasonal variation in RLS severity with worsening in the warmer months needs to be investigated further in prospective studies., (Copyright © 2019 Elsevier B.V. All rights reserved.)
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- 2020
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46. Identification of Restless Legs Syndrome Genes by Mutational Load Analysis.
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Tilch E, Schormair B, Zhao C, Salminen AV, Antic Nikolic A, Holzknecht E, Högl B, Poewe W, Bachmann CG, Paulus W, Trenkwalder C, Oertel WH, Hornyak M, Fietze I, Berger K, Lichtner P, Gieger C, Peters A, Müller-Myhsok B, Hoischen A, Winkelmann J, and Oexle K
- Subjects
- Case-Control Studies, Chromosome Mapping statistics & numerical data, Female, Humans, Male, Middle Aged, DNA Mutational Analysis, Genetic Predisposition to Disease genetics, Restless Legs Syndrome genetics
- Abstract
Objective: Restless legs syndrome is a frequent neurological disorder with substantial burden on individual well-being and public health. Genetic risk loci have been identified, but the causatives genes at these loci are largely unknown, so that functional investigation and clinical translation of molecular research data are still inhibited. To identify putatively causative genes, we searched for highly significant mutational burden in candidate genes., Methods: We analyzed 84 candidate genes in 4,649 patients and 4,982 controls by next generation sequencing using molecular inversion probes that targeted mainly coding regions. The burden of low-frequency and rare variants was assessed, and in addition, an algorithm (binomial performance deviation analysis) was established to estimate independently the sequence variation in the probe binding regions from the variation in sequencing depth., Results: Highly significant results (considering the number of genes in the genome) of the conventional burden test and the binomial performance deviation analysis overlapped significantly. Fourteen genes were highly significant by one method and confirmed with Bonferroni-corrected significance by the other to show a differential burden of low-frequency and rare variants in restless legs syndrome. Nine of them (AAGAB, ATP2C1, CNTN4, COL6A6, CRBN, GLO1, NTNG1, STEAP4, VAV3) resided in the vicinity of known restless legs syndrome loci, whereas 5 (BBS7, CADM1, CREB5, NRG3, SUN1) have not previously been associated with restless legs syndrome. Burden test and binomial performance deviation analysis also converged significantly in fine-mapping potentially causative domains within these genes., Interpretation: Differential burden with intragenic low-frequency variants reveals putatively causative genes in restless legs syndrome. ANN NEUROL 2020;87:184-193., (© 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)
- Published
- 2020
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47. Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study.
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Postuma RB, Iranzo A, Hu M, Högl B, Boeve BF, Manni R, Oertel WH, Arnulf I, Ferini-Strambi L, Puligheddu M, Antelmi E, Cochen De Cock V, Arnaldi D, Mollenhauer B, Videnovic A, Sonka K, Jung KY, Kunz D, Dauvilliers Y, Provini F, Lewis SJ, Buskova J, Pavlova M, Heidbreder A, Montplaisir JY, Santamaria J, Barber TR, Stefani A, St Louis EK, Terzaghi M, Janzen A, Leu-Semenescu S, Plazzi G, Nobili F, Sixel-Doering F, Dusek P, Bes F, Cortelli P, Ehgoetz Martens K, Gagnon JF, Gaig C, Zucconi M, Trenkwalder C, Gan-Or Z, Lo C, Rolinski M, Mahlknecht P, Holzknecht E, Boeve AR, Teigen LN, Toscano G, Mayer G, Morbelli S, Dawson B, and Pelletier A
- Subjects
- Aged, Cohort Studies, Disease Progression, Female, Forecasting methods, Humans, Kaplan-Meier Estimate, Lewy Body Disease physiopathology, Male, Middle Aged, Parkinsonian Disorders diagnosis, Polysomnography, Prodromal Symptoms, Prognosis, Proportional Hazards Models, Prospective Studies, Risk Factors, Dementia physiopathology, Parkinson Disease physiopathology, REM Sleep Behavior Disorder physiopathology
- Abstract
Idiopathic REM sleep behaviour disorder (iRBD) is a powerful early sign of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. This provides an unprecedented opportunity to directly observe prodromal neurodegenerative states, and potentially intervene with neuroprotective therapy. For future neuroprotective trials, it is essential to accurately estimate phenoconversion rate and identify potential predictors of phenoconversion. This study assessed the neurodegenerative disease risk and predictors of neurodegeneration in a large multicentre cohort of iRBD. We combined prospective follow-up data from 24 centres of the International RBD Study Group. At baseline, patients with polysomnographically-confirmed iRBD without parkinsonism or dementia underwent sleep, motor, cognitive, autonomic and special sensory testing. Patients were then prospectively followed, during which risk of dementia and parkinsonsim were assessed. The risk of dementia and parkinsonism was estimated with Kaplan-Meier analysis. Predictors of phenoconversion were assessed with Cox proportional hazards analysis, adjusting for age, sex, and centre. Sample size estimates for disease-modifying trials were calculated using a time-to-event analysis. Overall, 1280 patients were recruited. The average age was 66.3 ± 8.4 and 82.5% were male. Average follow-up was 4.6 years (range = 1-19 years). The overall conversion rate from iRBD to an overt neurodegenerative syndrome was 6.3% per year, with 73.5% converting after 12-year follow-up. The rate of phenoconversion was significantly increased with abnormal quantitative motor testing [hazard ratio (HR) = 3.16], objective motor examination (HR = 3.03), olfactory deficit (HR = 2.62), mild cognitive impairment (HR = 1.91-2.37), erectile dysfunction (HR = 2.13), motor symptoms (HR = 2.11), an abnormal DAT scan (HR = 1.98), colour vision abnormalities (HR = 1.69), constipation (HR = 1.67), REM atonia loss (HR = 1.54), and age (HR = 1.54). There was no significant predictive value of sex, daytime somnolence, insomnia, restless legs syndrome, sleep apnoea, urinary dysfunction, orthostatic symptoms, depression, anxiety, or hyperechogenicity on substantia nigra ultrasound. Among predictive markers, only cognitive variables were different at baseline between those converting to primary dementia versus parkinsonism. Sample size estimates for definitive neuroprotective trials ranged from 142 to 366 patients per arm. This large multicentre study documents the high phenoconversion rate from iRBD to an overt neurodegenerative syndrome. Our findings provide estimates of the relative predictive value of prodromal markers, which can be used to stratify patients for neuroprotective trials., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.)
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- 2019
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48. Hypnagogic Foot Tremor, Alternating Leg Muscle Activation or High Frequency Leg Movements: clinical and phenomenological considerations in two cousins.
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Bergmann M, Stefani A, Brandauer E, Holzknecht E, Hackner H, and Högl B
- Subjects
- Adult, Female, Humans, Middle Aged, Polysomnography, Sleep Apnea, Central, Foot physiopathology, Leg physiology, Movement physiology, Nocturnal Myoclonus Syndrome physiopathology, Tremor physiopathology
- Published
- 2019
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49. Association of mitochondrial iron deficiency and dysfunction with idiopathic restless legs syndrome.
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Haschka D, Volani C, Stefani A, Tymoszuk P, Mitterling T, Holzknecht E, Heidbreder A, Coassin S, Sumbalova Z, Seifert M, Dichtl S, Theurl I, Gnaiger E, Kronenberg F, Frauscher B, Högl B, and Weiss G
- Subjects
- Anemia, Iron-Deficiency drug therapy, Female, Humans, Male, Mitochondria metabolism, Quality of Life, Dopamine Agents therapeutic use, Dopamine Agonists therapeutic use, Homeostasis drug effects, Mitochondria drug effects, Restless Legs Syndrome drug therapy
- Abstract
Background: Restless legs syndrome is a sensorimotor neurological disorder of the limbs that impairs quality of life and disturbs sleep. However, there has been progress in understanding the disease involving the dopaminergic system as well as iron metabolism. The exact pathophysiological mechanisms of restless legs syndrome remain elusive. We tried to elucidate the underlying mechanisms in iron metabolism in restless legs syndrome subjects on a systemic, cellular, and mitochondrial level., Methods: We conducted a study prospectively recruiting 168 restless legs syndrome patients and 119 age-matched healthy controls focusing on iron metabolism using human monocytes as surrogates., Results: Evaluation of systemic iron metabolism parameters in the circulation showed no significant difference between patients and controls. We observed a significant reduction in mRNA levels of heme oxygenase 1 and mitochondrial iron genes like mitoferrin 1 and 2 in monocytes isolated from restless legs syndrome patients, indicating mitochondrial iron deficiency. Interestingly, we also observed reduced expression of iron regulatory protein 2 along with impaired activity of mitochondrial aconitase and reduced mitochondrial superoxide formation in restless legs syndrome subjects. Along this line, patients had reduced mitochondrial respiratory capacity that improved in restless legs syndrome subjects under treatment with dopaminergic drugs compared with untreated patients., Conclusions: Our data suggest that restless legs syndrome is linked to mitochondrial iron deficiency and associated impairment of mitochondrial function. This is partly corrected by treatment with dopaminergic drugs compared with untreated patients, which may be linked to an effect of dopamine on cellular iron homeostasis. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)
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- 2019
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50. Clinical neurophysiology of REM parasomnias.
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Stefani A, Holzknecht E, and Högl B
- Subjects
- Animals, Humans, REM Sleep Parasomnias physiopathology
- Abstract
Rapid eye movement (REM) sleep behavior disorder (RBD), sleep paralysis, and nightmare disorder are the three REM sleep parasomnias outlined by the International Classification of Sleep Disorders. In this review we address the clinical neurophysiology of these disorders. The majority of neurophysiologic studies have been conducted in RBD, and fewer studies have evaluated patients with nightmare disorder or isolated sleep paralysis. Neurophysiologic studies of REM sleep parasomnias mostly used polysomnography (PSG), or were performed on animals to shed light on the pathophysiology of these disorders. Fewer studies used electoencephalography or electromyography outside the context of PSG, evoked potentials, or autonomic neurophysiologic studies. In this chapter, the main neurophysiologic findings in REM sleep parasomnias are described and their implications and relevance are discussed., (Copyright © 2019 Elsevier B.V. All rights reserved.)
- Published
- 2019
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