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39 results on '"Katrin Gross-Paju"'

1. 3018 A multi-centre longitudinal study analysing disease modifying therapy prescribing patterns during the COVID-19 pandemic

Author

Nevin John, Steve Vucic, Riadh Gouider, Tomas Kalincik, Guillermo Izquierdo, Alexandre Prat, Marc Girard, Pierre Duquette, Pierre Grammond, Serkan Ozakbas, Jeannette Lechner-Scott, Cavit Boz, Julie Prevost, Recai Turkoglu, Vincent Van Pesch, Cristina Ramo-Tello, Mark Slee, Raed Alroughani, Vahid Shaygannejad, Daniele Spitaleri, José Luis Sánchez-Menoyo, Suzanne Hodgkinson, Rana Karabudak, Tim Spelman, Helmut Butzkueven, Noriko Isobe, Paul G Sanfilippo, Michael Barnett, Orla Gray, Maria José Sá, Allan Kermode, Guy Laureys, Richard Macdonell, Anneke Van Der Walt, Ayse Altintas, Mario Habek, Pamela McCombe, Seyed Mohammad Baghbanian, Yi Chao Foong, Riki Matsumoto, Abdullah Al-Asmi, Bruce Taylor, Samia J Khoury, Todd Hardy, Katherine Buzzard, Marzena Fabis-Pedrini, Louise Rath, Olga Skibina, Jiwon Oh, William M Carroll, Katrin Gross-Paju, Jan Schepel, Sara Eichau, Elisabetta Cartechini, Aysun Soysal, Davide Maimone, Anoushka Lal, Masoud Etemadifar, Oliver Gerlach, Saloua Mrabet, Emanuele D'Amico, Yolanda Blanco, Matteo Foschi, Melissa Cambron, Andrea Surcinelli, David Levitz, Liesbeth Van Hijfte, Mehmet Fatih Yetkin, Simón Cárdenas-Robledo, Emmanuelle Lapointe, Abdorreza Naser Moghadasi, Gregor Brecl Jakob, and Talal Al-Harbi

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Published
2024
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2. The Birth Prevalence of Spinal Muscular Atrophy: A Population Specific Approach in Estonia

Author

Siiri Sarv, Tiina Kahre, Eve Vaidla, Sander Pajusalu, Kai Muru, Haide Põder, Katrin Gross-Paju, Sandra Ütt, Riina Žordania, Inga Talvik, Eve Õiglane-Shlik, Kristina Muhu, and Katrin Õunap

Subjects
spinal muscular atrophy, epidemiology, newborn screening, birth prevalence, neuromuscular disease, Genetics, QH426-470
Abstract

Background: Rare diseases are an important population health issue and many promising therapies have been developed in recent years. In light of novel genetic treatments expected to significantly improve spinal muscular atrophy (SMA) patients’ quality of life and the urgent need for SMA newborn screening (NBS), new epidemiological data were needed to implement SMA NBS in Estonia.Objective: We aimed to describe the birth prevalence of SMA in the years 1996–2020 and to compare the results with previously published data.Methods: We retrospectively analyzed clinical and laboratory data of SMA patients referred to the Department of Clinical Genetics of Tartu University Hospital and its branch in Tallinn.Results: Fifty-seven patients were molecularly diagnosed with SMA. SMA birth prevalence was 1 per 8,286 (95% CI 1 per 6,130–11,494) in Estonia. Patients were classified as SMA type 0 (1.8%), SMA I (43.9%), SMA II (22.8%), SMA III (29.8%), and SMA IV (1.8%). Two patients were compound heterozygotes with an SMN1 deletion in trans with a novel single nucleotide variant NM_000344.3:c.410dup, p.(Asn137Lysfs*11). SMN2 copy number was assessed in 51 patients.Conclusion: In Estonia, the birth prevalence of SMA is similar to the median birth prevalence in Europe. This study gathered valuable information on the current epidemiology of SMA, which can guide the implementation of spinal muscular atrophy to the newborn screening program in Estonia.

Published
2021
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3. Implementation of the Helsinki Model at West Tallinn Central Hospital

Author

Katrin Gross-Paju, Ulvi Thomson, Raul Adlas, Helle Jaakmees, Karin Kannel, Sandra Marii Mallene, Svetlana Mironenko, Agnes Reitsnik, Ain Vares, and Sandra Ütt

Subjects
stroke, pre-hospital care, door-to-needle time, thrombolysis, service provision, outcome, Medicine (General), R5-920
Abstract

Ischemic stroke is defined as neurological deficit caused by brain infarction. The intravenous tissue plasminogen activator, alteplase, is an effective treatment. However, efficacy of this method is time dependent. An important step in improving outcome and increasing the number of patients receiving alteplase is the shortening of waiting times at the hospital, the so-called door-to-needle time (DNT). The comprehensive Helsinki model was proposed in 2012, which enabled the shortening of the DNT to less than 20 min. Background and Objectives: The aim of this study was to analyze the transferability of the suggested model to the West Tallinn Central Hospital (WTCH). Materials and Methods: Since the first thrombolysis in 2005, all patients are registered in the WTCH thrombolysis registry. Several steps following the Helsinki model have been implemented over the years. Results: The results demonstrate that the number and also the percent of thrombolysed stroke patients increased during the years, from a few thrombolysis annually, to 260 in 2021. The mean DNT dropped significantly to 33 min after the implementation of several steps, from the emergency medical services (EMS) prenotification with a phone call to the neurologists, to the setting-up of a thrombolysis team based in the stroke unit. Also, the immediate start of treatment using a computed tomography table was introduced. Conclusions: In conclusion, several implemented steps enabled the shortening of the DNT from 30 to 25.2 min. Short DNTs were achieved and maintained only with EMS prenotification.

Published
2022
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4. Changes in Blood B Cell-Activating Factor (BAFF) Levels in Multiple Sclerosis: A Sign of Treatment Outcome.

Author

Karin Kannel, Kristi Alnek, Liina Vahter, Katrin Gross-Paju, Raivo Uibo, and Kalle V Kisand

Subjects
Medicine, Science
Abstract

Multiple sclerosis (MS) is mediated primarily by autoreactive T cells. However, evidence suggesting the involvement of humoral immunity in brain diseases has increased interest in the role of B cells and their products during MS pathogenesis. The major survival factor for B cells, BAFF has been shown to play a role in several autoimmune conditions. Elevated BAFF levels have been reported in MS animal model and during MS relapse in patients. Moreover, disease-modifying treatments (DMT) reportedly influence blood BAFF levels in MS patients, but the significance of these changes remains unclear. The present study addresses how blood BAFF levels are associated with the clinical course of relapsing-remitting MS and the effectiveness of DMT and short-term steroid treatment. During a prospective longitudinal follow-up of 2.3 years, BAFF was measured in the blood of 170 MS patients in the stable phase and within 186 relapses. BAFF levels were significantly higher in MS patients compared to healthy controls. However, stable MS patients without relapses exhibited significantly higher BAFF levels than relapsing patients. Treatment with interferon-β and immunosuppressants raised BAFF blood levels. Interestingly, a similar effect was not seen in patients treated with glatiramer acetate. Short-term treatment with high doses of intravenous methylprednisolone did not significantly alter plasma BAFF levels in 65% of relapsing-remitting MS patients. BAFF were correlated weakly but significantly with monocyte and basophil counts, but not with other blood cell types (neutrophils, lymphocytes, or eosinophils) or inflammatory biomarkers. To our knowledge, this is the first report demonstrating that higher blood BAFF levels may reflect a more stable and effective MS treatment outcome. These results challenge hypotheses suggesting that elevated blood BAFF levels are associated with more severe disease presentation and could explain the recent failure of pharmaceutical trials targeting BAFF with soluble receptor for MS treatment.

Published
2015
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7. Developments in quality of stroke care in Estonia

Author

Janika Kõrv, Katrin Antsov, Katrin Gross-Paju, Inga Kalju, Andrus Kreis, Aive Liigant, and Riina Vibo

Subjects
ESO EAST Project Supplement, Neurology (clinical), Cardiology and Cardiovascular Medicine
Abstract

Background: Monitoring and measuring different aspects of stroke care pathway is the cornerstone for improvement of quality. We aim to analyze and give an overview of improvements of stroke care quality in Estonia. Patients and methods: National stroke care quality indicators are collected and reported using reimbursement data and include all adult stroke cases. In Estonia, five stroke-ready hospitals are participating in Registry of Stroke Care Quality (RES-Q), providing data on all stroke patients 1 month every year. Data from the national quality indicators and RES-Q from 2015 to 2021 are presented. Results: The proportion of intravenous thrombolysis for all Estonian hospitalized ischemic stroke cases increased from 16% (95% Confidence Interval, CI 15%–18%) in 2015 to 28% (95% CI 27%–30%) in 2021. Mechanical thrombectomy was provided to 9% (95% CI 8%–10%) in 2021. The 30-day mortality rate has decreased from 21% (95% CI 20%–23%) to 19% (95% CI 18%–20%). More than 90% of patients with cardioembolic stroke are prescribed anticoagulants at discharge, but only 50% are on anticoagulant treatment 1 year after stroke. Also, the availability of inpatient rehabilitation needs improvement, being 21% (95% CI 20%–23%) in 2021. A total of 848 patients are included in the RES-Q. The proportion of patients receiving recanalization therapies was comparable to the national stroke care quality indicators. All stroke-ready hospitals show good onset-to-door times. Conclusion: The overall stroke care quality in Estonia is good, especially the availability of recanalization treatments. However, secondary prevention and the availability of rehabilitation services need improvement in the future.

Published
2022

9. Safety and efficacy of teriflunomide in paediatric multiple sclerosis (TERIKIDS): a multicentre, double-blind, phase 3, randomised, placebo-controlled trial

Author

Tanuja Chitnis, Brenda Banwell, Ludwig Kappos, Douglas L Arnold, Kivilcim Gücüyener, Kumaran Deiva, Natalia Skripchenko, Li-Ying Cui, Stephane Saubadu, Wenruo Hu, Myriam Benamor, Annaig Le-Halpere, Philippe Truffinet, Marc Tardieu, Benedicte Dubois, Helene Verhelst, Veneta Bojinova-Tchamova, Jean Mah, Fang Fang, Yunpeng Hao, Li Jiang, Ling Li, Ding'An Mao, Wei Qiu, Guojun Tan, Ye Wu, Meini Zhang, Hongyu Zhou, Shuizhen Zhou, Katrin Gross-Paju, Emmanuel Cheuret, Giles Edan, Sandra Vukusic, George Chrousos, Dimitrios Zafeiriou, Anat Achiron, Adi Vaknin-Dembinsky, Bassem Yamout, Jurate Laurynaitiene, Nerija Vaiciene-Magistris, Vladimir Bojkovski, Vesna Trajkova, Sana Chaouki, Najib Kissani, Rinze Neuteboom, Filipe Palavra, Anna Belova, Alexey Boyko, Evgeny Evdoshenko, Ekaterina Kairbekova, Nadezhda Malkova, Maria Shumilina, Natalya Skripchenko, Dimitrije Nikolic, Jose Meca-Lallana, Chahnez Charfi Triki, Mhiri Chokri, Riadh Gouider, Banu Anlar, Ayse Semra Hiz, Egemen Idiman, Recai Turkoglu, Zuhal Yapici, Unsal Yilmaz, Lyudmyla Tantsura, Nataliia Voloshyna, Ming Lim, Evangeline Wassmer, Mark Cascione, Christopher LaGanke, Kevin Rathke, John Scagnelli, Immunology, and Neurology

Subjects
Adult, medicine.medical_specialty, Multiple Sclerosis, Adolescent, Toluidines, Population, Placebo-controlled study, Hydroxybutyrates, Placebo, chemistry.chemical_compound, Multiple Sclerosis, Relapsing-Remitting, Double-Blind Method, Internal medicine, Nitriles, Teriflunomide, Clinical endpoint, Humans, Medicine, Child, education, education.field_of_study, business.industry, Multiple sclerosis, Hazard ratio, medicine.disease, Treatment Outcome, Pancreatitis, chemistry, Crotonates, Relative risk, Acute Disease, Neurology (clinical), business
Abstract

Background: Therapeutic options for children with multiple sclerosis are scarce. Teriflunomide is approved in more than 80 countries for the treatment of adults with relapsing multiple sclerosis. The TERIKIDS study examined the safety and efficacy of teriflunomide in children with relapsing multiple sclerosis. Methods: The TERIKIDS trial was a multicentre, phase 3, double-blind, parallel-group, randomised, placebo-controlled study conducted at 57 clinical centres in 22 countries in Asia, Europe, the Middle East, North Africa, and North America. The trial enrolled patients aged 10–17 years, diagnosed with relapsing multiple sclerosis and with at least one relapse in the year preceding screening or at least two relapses in the 2 years preceding screening. Patients were randomly assigned (2:1) to oral teriflunomide (dosage equivalent to 14 mg in adults) or matching placebo, using an interactive web and voice response system, for up to 96 weeks. Personnel in all sites and all patients were masked to study treatment in the double-blind period. Early entry into a subsequent 96-week open-label extension phase was possible before the end of the double-blind period for patients with confirmed clinical relapse or high MRI activity (at least five new or enlarged T2 lesions at week 24, followed by at least nine new or enlarged T2 lesions at week 36, or at least five new or enlarged T2 lesions at weeks 36 and 48, or at weeks 48 and 72). The primary endpoint was time to first confirmed clinical relapse by the end of the double-blind period. Key secondary imaging endpoints were number of new or enlarged T2 lesions and number of gadolinium-enhancing lesions per MRI scan. Efficacy endpoints were analysed in the intention-to-treat population, and safety was assessed in all patients randomly assigned to treatment and exposed to the double-blind study medication. This study is registered with ClinicalTrials.gov (trial number NCT02201108) and is closed to recruitment, but an additional optional open-label extension is ongoing. Findings: Between July 24, 2014, and the date of last patient visit on Oct 25, 2019, 185 patients were screened for eligibility, 166 (90%) were enrolled, and 109 were randomly assigned teriflunomide and 57 were randomly assigned placebo. 102 (94%) of 109 and 53 (93%) of 57 completed the double-blind period. Switch to the ongoing open-label extension because of high MRI activity was more frequent than anticipated in the placebo group (14 [13%] of 109 patients in the teriflunomide group vs 15 [26%] of 57 in the placebo group), decreasing the power of the study. After 96 weeks, there was no difference in time to first confirmed clinical relapse with teriflunomide compared with placebo (hazard ratio 0·66, 95% CI 0·39–1·11; p=0·29). Teriflunomide reduced the number of new or enlarged T2 lesions versus placebo by 55% (relative risk 0·45, 95% CI 0·29–0·71; p=0·00061), and the number of gadolinium-enhancing lesions by 75% (relative risk 0·25, 0·13–0·51; p

Published
2021

10. Ofatumumab versus Teriflunomide in Multiple Sclerosis

Author

Hauser S. L., Bar-Or A., Cohen J. A., Comi G., Correale J., Coyle P. K., Cross A. H., de Seze J., Leppert D., Montalban X., Selmaj K., Wiendl H., Kerloeguen C., Willi R., Li B., Kakarieka A., Tomic D., Goodyear A., Pingili R., Haring D. A., Ramanathan K., Merschhemke M., Kappos L., Stephen L Hauser, Ludwig Kappos, Amit Bar-Or, Jeffrey A Cohen, Giancarlo Comi, Jorge Correale, Patricia K Coyle, Anne Cross, Jerome de Seze, Xavier Montalban, Krzysztof Selmaj, Heinz Wiendl, Stephen C Reingold, Garry R Cutter, Thomas Doerner, Hans-Peter Hartung, Per Soelberg Sørensen, Israel Steiner, Jerry S Wolinsky, Carlos Ballario, Christian Calvo Vildoso, Jorge Gustavo Jose, Norma Haydee Deri, Susana Liwacki, Jeannette Lechner-Scott, John Parratt, Suzanne Hodgkinson, Eva-Maria Maida, Fritz Leutmezer, Barbara Willekens, Bart Van Wijmeersch, Guy Laureys, Jo Caekebeke, Karine Geens, Ludo Vanopdenbosch, Olivier Deryck, Valerie Delvaux, Vincent Van Pesch, Ivan Milanov, Ivaylo Tarnev, Lyubomir Haralanov, Maria Manova Slavova, Penko Shotekov, Francois Emond, Francois Grandmaison, Francois Jacques, Liesly Lee, Marie Sarah Gagne Brosseau, Mark Freedman, Martin Cloutier, Robert Carruthers, Sarah Morrow, Yves Lapierre, Anton Vladic, Hana Bokun, Igor Antoncic, Marija Bosnjak Pasic, Mario Habek, Silva Butkovic Soldo, Vladimira Vuletic, Alena Martinkova, Eva Meluzinova, Ivana Stetkarova, Jan Mares, Jolana Markova, Marta Vachova, Martin Valis, Michaela Tyblova, Michal Dufek, Ondrej Skoda, Pavel Hradilek, Ana Voldsgaard Jensen, Helle Hvilsted Nielsen, Kristina Svendsen, Mads Ravnborg, Peter Vestergaard Rasmussen, Katrin Gross-Paju, Sulev Haldre, Juha Pekka Eralinna, Marja-Liisa Sumelahti, Bruno Brochet, Celine Louapre, Christine Lebrun-Frenay, David Axel Laplaud, Gilles Edan, Giovanni Castelnovo, Marc Debouverie, Patrick Vermersch, Pierre Clavelou, Pierre Labauge, Achim Berthele, Aiden Haghikia, Anselm Kornhuber, Arnfin Bergmann, Benedikt Frank, Birte Elias-Hamp, Bjoern Tackenberg, Brigitte Wildemann, Erik Strauss, Eugen Schlegel, Florian Then Bergh, Gereon Nelles, Hayrettin Tumani, Karl-Otto Sigel, Martin Stangel, Matthias Boehringer, Olaf Martin Hoffmann, Patrick Oschmann, Reinhard Hohlfeld, Silke Walter, Sylvia Menck, Till Sprenger, Tjalf Ziemssen, Veit Ulrich Becker, Vera Straeten, Konstantinos Kilidireas, Konstantinos Voumvourakis, Nikolaos Fakas, Nikolaos Grigoriadis, Agnes Koves, Csilla Rozsa, Krisztina Kovacs, Laszlo Vecsei, Satori Maria, Zita Biro, Anshu Rohatgi, Dheeraj Khurana, Jeyaraj Durai Pandian, Joy Dev Mukherji, Lekha Pandit, Meena Angamuthu Kanikannan, Pahari Ghosh, Rahul Chakor, Rahul Kulkarni, Roopkumar Gursahani, Sangeeta Ravat, Srinivasa Rangasetty, Suresh Kumar, Alla Shifrin, Arnon Karni, Radi Shahien, Ron Milo, Antonio Uccelli, Carlo Pozzilli, Francesco Sacca, Giacomo Lus, Girolama Alessandra Marfia, Laura Brambilla, Marco Salvetti, Massimo Filippi, Mauro Zaffaroni, Paolo Gallo, Silvia Rossi, Simona Bonavita, Valeria Studer, Andrejs Millers, Guntis Karelis, Jolanta Kalnina, Dalia Mickeviciene, Rasa Kizlaitiene, Angelica Carbajal Ramirez, Juan Jose Lopez Prieto, Beatrijs Wokke, Bob W Van Oosten, Peter Van Domburg, Raymond Hupperts, Rogier Q Hintzen, Astrid Edland, Cesar Castaneda, Julio Perez, Martin Gavidia, Andrzej Wiak, Bartosz Karaszewski, Elzbieta Jasinska, Halina Bartosik Psujek, Iwona Jastrzebska, Jaroslaw Slawek, Maciej Maciejowski, Miroslaw Dziki, Monika Adamczyk Sowa, Robert Bonek, Waldemar Fryze, Ana Martins Da Silva, Angela Timoteo, Antonio Vasco Salgado, Carlos Capela, Carlos Veira, Filipe Correia, Joao Cerqueira, Joao De Sa, Livia De Sousa, Raquel Gouveia, Alina Sergeevna Agafina, Anna Naumovna Belova, Denis Viktorovich Sazonov, Dmitry Pokhabov, Ekaterina Igorevna Kairbekova, Elena Gennadievna Arefieva, Farit Axatovich Khabirov, Igor Vyacheslavovich Litvinenko, Igor Stolyarov, Irina Aleksandrovna Sokolova, Larisa Ivanovna Volkova, Maria Vafaevna Davydovskaya, Maria Nikolaevna Zaharova, Nadezhda Alekseevna Malkova, Natalia Agafonovna Totolyan, Nikolay Vasilievich Dorogov, Stella Anatolievna Sivertseva, Egon Kurca, Georgi Krastev, Miroslav Brozman, Peter Koleda, Peter Turcani, Peter Valkovic, Viera Hancinova, Vladimir Donath, Chris Retief, Michael Isaacs, Albert Saiz Hinarejos, Alfredo Rodriguez Antigüedad, Bonaventura Casanova Estruch, Celia Oreja-Guevara, Gemma Reig Rosello, Jose Carlos Alvarez Cermeño, Jose Martinez Rodriguez, Jose Meca Lallana, Juan Antonio Garcia Merino, Lucia Forero Diaz, Lucienne Costa Frossard Franca, Luis Querol Gutierrez, Lluis Ramio Torrenta, Pedro Serrano Castro, Rafael Arroyo Gonzalez, Sara Eichau Madueño, Sergio Martinez Yelamos, Tamara Castillo Trivino, Virgina Meca Lallana, Xaviere Montalban Gairin, Fredrik Piehl, Jan Lycke, Chiara Zecca, Tobias Derfuss, Thy-Sheng Lin, Somsak Tiamkao, Ayse Nur Yuceyar, Aysun Soysal, Belgin Petek Balci, Cavit Boz, Husnu Efendi, Murat Terzi, Serhan Sevim, Serkan Ozakbas, Andrew Gale, Ben Turner, David Barnes, David Paling, Eli Silber, James Overell, Matthew Craner, Aaron Carlson, Adam Wolff, Adaeze Onuoha, Adnan Subei, Ahmad Ata, Aimee Borazanci, Akram Dastagir, Alberto Vasquez, Alison Brooke Allen, Andrew P Keegan, Angel Carrasco, Angel R Chinea Martinez, Ann Bass, Annette Okai, April Erwin, Ariel Antezana-Antezana, Barbara Green, Bharathy E Sundaram, Bhupendra Khatri, Bhupesh Dihenia, Bogdan Gheorghiu, Brian Costell, Brian Steingo, Bruce L Hughes, Carrie M Hersh, Christopher Laganke, Christopher Luzzio, Corey Ford, Craig Edward Herrman, Craig Senzon, Cynthia Huffman, Daniel R Wynn, David D O Bear, David Lesch, David H Mattson, David Weisman, Deborah A Burke, Dennis W Dietrich, Deren Huang, Derrick Robertson, Djamchid Lotfi, Don Joseph Alfonso, Dusan Stefoski, Edward J Fox, Emily Pharr, Enrique Alvarez, Evanthia Bernitsas, Faria Amjad, Gabriel Pardo, Geoffrey Eubank, Gerald Mcintosh, Giles F Crowell, Hemanth Rao, J Michael Hemphill, Jack H Florin, Jacqueline Nicholas, James Napier, James Scott, Jason M Silversteen, Javier Vasallo, Jean-Raphael Schneider, Jeanette Wendt, Jeffrey Cohen, Jeffrey Gross, Jeffrey Groves, Jeffrey Kaplan, Jessica Stulc, Joanna A Cooper, John Foley, John Scagnelli, Jonathan C Calkwood, Jose Pizarro Otero, Jose Rafecas, Joshua Katz, Juliette S Saad, Katherine Standley, Keith Edwards, Kenneth Sharlin, Khurram Bashir, Kimberly Wagner, Kore Liow, Larry Lee Blankenship Jr, Laszlo Mate, Liliana Montoya, Lon D Lynn, Mark Agius, Mark Cascione, Mark Allan Goldstein, Mark Janicki, Martin R Bialow, Mary Denise Hughes, Matthew J Baker, Michelle Apperson, Michelle B Kuczma, M Mateo Paz Soldan, Mirela Cerghet, Nathaniel Robb Whaley, Paul K Winner, Pavle Repovic, Praful Kelkar, Romero Rekha Pillai, Ricardo Ayala, Richard Sater, Randall Trudell, Robert Fairborn Armstrong, Robert Thomas Nahouraii, Robert Naismith, Ronald S Murray, Samuel Hunter, Sara Qureshi, Sharon Lynch, Sibyl Wray, Silvia R Delgado, Stacy Donlon, Stanley Cohan, Stanya Smith, Stuart James Shafer, Susan Azalone, Susan Hibbs, Tamara A Miller, Thomas Giancarlo, Troy Desai, Varun K Saxena, Virginia Simnad, William David Honeycutt, William Logan, William E McElveen, William Wagner, University of California [San Francisco] (UCSF), University of California, Perelman School of Medicine, University of Pennsylvania [Philadelphia], Cleveland Clinic, IRCCS Ospedale San Raffaele [Milan, Italy], Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia [Buenos Aires] (FLENI), FLENI, Stony Brook University [SUNY] (SBU), State University of New York (SUNY), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), CIC Strasbourg (Centre d’Investigation Clinique Plurithématique (CIC - P) ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)-Hôpital de Hautepierre [Strasbourg]-Nouvel Hôpital Civil de Strasbourg, University Hospital Basel [Basel], Vall d'Hebron University Hospital [Barcelona], University of Warmia and Mazury [Olsztyn], University of Münster, Novartis Pharma S.A.S., Novartis Pharmaceuticals, University of Basel (Unibas), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Willekens, Barbara, ASCLEPIOS I and ASCLEPIOS II Trial Groups, Hauser, S. L., Bar-Or, A., Cohen, J. A., Comi, G., Correale, J., Coyle, P. K., Cross, A. H., de Seze, J., Leppert, D., Montalban, X., Selmaj, K., Wiendl, H., Kerloeguen, C., Willi, R., Li, B., Kakarieka, A., Tomic, D., Goodyear, A., Pingili, R., Haring, D. A., Ramanathan, K., Merschhemke, M., Kappos, L., Asclepios, I and ASCLEPIOS II Trial Group, Filippi, M, L Hauser, Stephen, Kappos, Ludwig, Bar-Or, Amit, A Cohen, Jeffrey, Comi, Giancarlo, Correale, Jorge, K Coyle, Patricia, Cross, Anne, de Seze, Jerome, Montalban, Xavier, Selmaj, Krzysztof, Wiendl, Heinz, C Reingold, Stephen, R Cutter, Garry, Doerner, Thoma, Hartung, Hans-Peter, Soelberg Sørensen, Per, Steiner, Israel, S Wolinsky, Jerry, Ballario, Carlo, Calvo Vildoso, Christian, Gustavo Jose, Jorge, Haydee Deri, Norma, Liwacki, Susana, Lechner-Scott, Jeannette, Parratt, John, Hodgkinson, Suzanne, Maida, Eva-Maria, Leutmezer, Fritz, Van Wijmeersch, Bart, Laureys, Guy, Caekebeke, Jo, Geens, Karine, Vanopdenbosch, Ludo, Deryck, Olivier, Delvaux, Valerie, Van Pesch, Vincent, Milanov, Ivan, Tarnev, Ivaylo, Haralanov, Lyubomir, Manova Slavova, Maria, Shotekov, Penko, Emond, Francoi, Grandmaison, Francoi, Jacques, Francoi, Lee, Liesly, Sarah Gagne Brosseau, Marie, Freedman, Mark, Cloutier, Martin, Carruthers, Robert, Morrow, Sarah, Lapierre, Yve, Vladic, Anton, Bokun, Hana, Antoncic, Igor, Bosnjak Pasic, Marija, Habek, Mario, Butkovic Soldo, Silva, Vuletic, Vladimira, Martinkova, Alena, Meluzinova, Eva, Stetkarova, Ivana, Mares, Jan, Markova, Jolana, Vachova, Marta, Valis, Martin, Tyblova, Michaela, Dufek, Michal, Skoda, Ondrej, Hradilek, Pavel, Voldsgaard Jensen, Ana, Hvilsted Nielsen, Helle, Svendsen, Kristina, Ravnborg, Mad, Vestergaard Rasmussen, Peter, Gross-Paju, Katrin, Haldre, Sulev, Pekka Eralinna, Juha, Sumelahti, Marja-Liisa, Brochet, Bruno, Louapre, Celine, Lebrun-Frenay, Christine, Axel Laplaud, David, Edan, Gille, Castelnovo, Giovanni, Debouverie, Marc, Vermersch, Patrick, Clavelou, Pierre, Labauge, Pierre, Berthele, Achim, Haghikia, Aiden, Kornhuber, Anselm, Bergmann, Arnfin, Frank, Benedikt, Elias-Hamp, Birte, Tackenberg, Bjoern, Wildemann, Brigitte, Strauss, Erik, Schlegel, Eugen, Then Bergh, Florian, Nelles, Gereon, Tumani, Hayrettin, Sigel, Karl-Otto, Stangel, Martin, Boehringer, Matthia, Martin Hoffmann, Olaf, Oschmann, Patrick, Hohlfeld, Reinhard, Walter, Silke, Menck, Sylvia, Sprenger, Till, Ziemssen, Tjalf, Ulrich Becker, Veit, Straeten, Vera, Kilidireas, Konstantino, Voumvourakis, Konstantino, Fakas, Nikolao, Grigoriadis, Nikolao, Koves, Agne, Rozsa, Csilla, Kovacs, Krisztina, Vecsei, Laszlo, Maria, Satori, Biro, Zita, Rohatgi, Anshu, Khurana, Dheeraj, Durai Pandian, Jeyaraj, Dev Mukherji, Joy, Pandit, Lekha, Angamuthu Kanikannan, Meena, Ghosh, Pahari, Chakor, Rahul, Kulkarni, Rahul, Gursahani, Roopkumar, Ravat, Sangeeta, Rangasetty, Srinivasa, Kumar, Suresh, Shifrin, Alla, Karni, Arnon, Shahien, Radi, Milo, Ron, Uccelli, Antonio, Pozzilli, Carlo, Sacca, Francesco, Lus, Giacomo, Alessandra Marfia, Girolama, Brambilla, Laura, Salvetti, Marco, Filippi, Massimo, Zaffaroni, Mauro, Gallo, Paolo, Rossi, Silvia, Bonavita, Simona, Studer, Valeria, Millers, Andrej, Karelis, Gunti, Kalnina, Jolanta, Mickeviciene, Dalia, Kizlaitiene, Rasa, Carbajal Ramirez, Angelica, Jose Lopez Prieto, Juan, Wokke, Beatrij, W Van Oosten, Bob, Van Domburg, Peter, Hupperts, Raymond, Q Hintzen, Rogier, Edland, Astrid, Castaneda, Cesar, Perez, Julio, Gavidia, Martin, Wiak, Andrzej, Karaszewski, Bartosz, Jasinska, Elzbieta, Bartosik Psujek, Halina, Jastrzebska, Iwona, Slawek, Jaroslaw, Maciejowski, Maciej, Dziki, Miroslaw, Adamczyk Sowa, Monika, Bonek, Robert, Fryze, Waldemar, Martins Da Silva, Ana, Timoteo, Angela, Vasco Salgado, Antonio, Capela, Carlo, Veira, Carlo, Correia, Filipe, Cerqueira, Joao, De Sa, Joao, De Sousa, Livia, Gouveia, Raquel, Sergeevna Agafina, Alina, Naumovna Belova, Anna, Viktorovich Sazonov, Deni, Pokhabov, Dmitry, Igorevna Kairbekova, Ekaterina, Gennadievna Arefieva, Elena, Axatovich Khabirov, Farit, Vyacheslavovich Litvinenko, Igor, Stolyarov, Igor, Aleksandrovna Sokolova, Irina, Ivanovna Volkova, Larisa, Vafaevna Davydovskaya, Maria, Nikolaevna Zaharova, Maria, Alekseevna Malkova, Nadezhda, Agafonovna Totolyan, Natalia, Vasilievich Dorogov, Nikolay, Anatolievna Sivertseva, Stella, Kurca, Egon, Krastev, Georgi, Brozman, Miroslav, Koleda, Peter, Turcani, Peter, Valkovic, Peter, Hancinova, Viera, Donath, Vladimir, Retief, Chri, Isaacs, Michael, Saiz Hinarejos, Albert, Rodriguez Antigüedad, Alfredo, Casanova Estruch, Bonaventura, Oreja-Guevara, Celia, Reig Rosello, Gemma, Carlos Alvarez Cermeño, Jose, Martinez Rodriguez, Jose, Meca Lallana, Jose, Antonio Garcia Merino, Juan, Forero Diaz, Lucia, Costa Frossard Franca, Lucienne, Querol Gutierrez, Lui, Ramio Torrenta, Llui, Serrano Castro, Pedro, Arroyo Gonzalez, Rafael, Eichau Madueño, Sara, Martinez Yelamos, Sergio, Castillo Trivino, Tamara, Meca Lallana, Virgina, Montalban Gairin, Xaviere, Piehl, Fredrik, Lycke, Jan, Zecca, Chiara, Derfuss, Tobia, Lin, Thy-Sheng, Tiamkao, Somsak, Nur Yuceyar, Ayse, Soysal, Aysun, Petek Balci, Belgin, Boz, Cavit, Efendi, Husnu, Terzi, Murat, Sevim, Serhan, Ozakbas, Serkan, Gale, Andrew, Turner, Ben, Barnes, David, Paling, David, Silber, Eli, Overell, Jame, Craner, Matthew, Carlson, Aaron, Wolff, Adam, Onuoha, Adaeze, Subei, Adnan, Ata, Ahmad, Borazanci, Aimee, Dastagir, Akram, Vasquez, Alberto, Brooke Allen, Alison, P Keegan, Andrew, Carrasco, Angel, R Chinea Martinez, Angel, Bass, Ann, Okai, Annette, Erwin, April, Antezana-Antezana, Ariel, Green, Barbara, E Sundaram, Bharathy, Khatri, Bhupendra, Dihenia, Bhupesh, Gheorghiu, Bogdan, Costell, Brian, Steingo, Brian, L Hughes, Bruce, M Hersh, Carrie, Laganke, Christopher, Luzzio, Christopher, Ford, Corey, Edward Herrman, Craig, Senzon, Craig, Huffman, Cynthia, R Wynn, Daniel, O Bear, David D, Lesch, David, H Mattson, David, Weisman, David, A Burke, Deborah, W Dietrich, Denni, Huang, Deren, Robertson, Derrick, Lotfi, Djamchid, Joseph Alfonso, Don, Stefoski, Dusan, J Fox, Edward, Pharr, Emily, Alvarez, Enrique, Bernitsas, Evanthia, Amjad, Faria, Pardo, Gabriel, Eubank, Geoffrey, Mcintosh, Gerald, F Crowell, Gile, Rao, Hemanth, Michael Hemphill, J, H Florin, Jack, Nicholas, Jacqueline, Napier, Jame, Scott, Jame, M Silversteen, Jason, Vasallo, Javier, Schneider, Jean-Raphael, Wendt, Jeanette, Cohen, Jeffrey, Gross, Jeffrey, Groves, Jeffrey, Kaplan, Jeffrey, Stulc, Jessica, A Cooper, Joanna, Foley, John, Scagnelli, John, C Calkwood, Jonathan, Pizarro Otero, Jose, Rafecas, Jose, Katz, Joshua, S Saad, Juliette, Standley, Katherine, Edwards, Keith, Sharlin, Kenneth, Bashir, Khurram, Wagner, Kimberly, Liow, Kore, Lee Blankenship Jr, Larry, Mate, Laszlo, Montoya, Liliana, D Lynn, Lon, Agius, Mark, Cascione, Mark, Allan Goldstein, Mark, Janicki, Mark, R Bialow, Martin, Denise Hughes, Mary, J Baker, Matthew, Apperson, Michelle, B Kuczma, Michelle, Mateo Paz Soldan, M, Cerghet, Mirela, Robb Whaley, Nathaniel, K Winner, Paul, Repovic, Pavle, Kelkar, Praful, Rekha Pillai, Romero, Ayala, Ricardo, Sater, Richard, Trudell, Randall, Fairborn Armstrong, Robert, Thomas Nahouraii, Robert, Naismith, Robert, S Murray, Ronald, Hunter, Samuel, Qureshi, Sara, Lynch, Sharon, Wray, Sibyl, R Delgado, Silvia, Donlon, Stacy, Cohan, Stanley, Smith, Stanya, James Shafer, Stuart, Azalone, Susan, Hibbs, Susan, A Miller, Tamara, Giancarlo, Thoma, Desai, Troy, K Saxena, Varun, Simnad, Virginia, David Honeycutt, William, Logan, William, E McElveen, William, Wagner, William, Stephen, L Hauser, Ludwig, Kappo, Amit, Bar-Or, Jeffrey, A Cohen, Giancarlo, Comi, Jorge, Correale, Patricia, K Coyle, Anne, Cro, Jerome de Seze, Xavier, Montalban, Krzysztof, Selmaj, Heinz, Wiendl, Stephen, C Reingold, Garry, R Cutter, Thomas, Doerner, Hans-Peter, Hartung, Per Soelberg Sørensen, Israel, Steiner, Jerry, S Wolinsky, Carlos, Ballario, Christian Calvo Vildoso, Jorge Gustavo Jose, Norma Haydee Deri, Susana, Liwacki, Jeannette, Lechner-Scott, John, Parratt, Suzanne, Hodgkinson, Eva-Maria, Maida, Fritz, Leutmezer, Barbara, Willeken, Bart Van Wijmeersch, Guy, Laurey, Karine, Geen, Ludo, Vanopdenbosch, Olivier, Deryck, Valerie, Delvaux, Vincent Van Pesch, Ivan, Milanov, Ivaylo, Tarnev, Lyubomir, Haralanov, Maria Manova Slavova, Penko, Shotekov, Francois, Emond, Francois, Grandmaison, Francois, Jacque, Liesly, Lee, Marie Sarah Gagne Brosseau, Mark, Freedman, Martin, Cloutier, Robert, Carruther, Sarah, Morrow, Yves, Lapierre, Anton, Vladic, Hana, Bokun, Igor, Antoncic, Marija Bosnjak Pasic, Mario, Habek, Silva Butkovic Soldo, Vladimira, Vuletic, Alena, Martinkova, Eva, Meluzinova, Ivana, Stetkarova, Jan, Mare, Jolana, Markova, Marta, Vachova, Martin, Vali, Michaela, Tyblova, Michal, Dufek, Ondrej, Skoda, Pavel, Hradilek, Ana Voldsgaard Jensen, Helle Hvilsted Nielsen, Kristina, Svendsen, Mads, Ravnborg, Peter Vestergaard Rasmussen, Katrin, Gross-Paju, Sulev, Haldre, Juha Pekka Eralinna, Marja-Liisa, Sumelahti, Bruno, Brochet, Celine, Louapre, Christine, Lebrun-Frenay, David Axel Laplaud, Gilles, Edan, Giovanni, Castelnovo, Marc, Debouverie, Patrick, Vermersch, Pierre, Clavelou, Pierre, Labauge, Achim, Berthele, Aiden, Haghikia, Anselm, Kornhuber, Arnfin, Bergmann, Benedikt, Frank, Birte, Elias-Hamp, Bjoern, Tackenberg, Brigitte, Wildemann, Erik, Strau, Eugen, Schlegel, Florian Then Bergh, Gereon, Nelle, Hayrettin, Tumani, Karl-Otto, Sigel, Martin, Stangel, Matthias, Boehringer, Olaf Martin Hoffmann, Patrick, Oschmann, Reinhard, Hohlfeld, Silke, Walter, Sylvia, Menck, Till, Sprenger, Tjalf, Ziemssen, Veit Ulrich Becker, Vera, Straeten, Konstantinos, Kilidirea, Konstantinos, Voumvouraki, Nikolaos, Faka, Nikolaos, Grigoriadi, Agnes, Kove, Csilla, Rozsa, Krisztina, Kovac, Laszlo, Vecsei, Satori, Maria, Zita, Biro, Anshu, Rohatgi, Dheeraj, Khurana, Jeyaraj Durai Pandian, Joy Dev Mukherji, Lekha, Pandit, Meena Angamuthu Kanikannan, Pahari, Ghosh, Rahul, Chakor, Rahul, Kulkarni, Roopkumar, Gursahani, Sangeeta, Ravat, Srinivasa, Rangasetty, Suresh, Kumar, Alla, Shifrin, Arnon, Karni, Radi, Shahien, Ron, Milo, Antonio, Uccelli, Carlo, Pozzilli, Sacca', Francesco, Giacomo, Lu, Girolama Alessandra Marfia, Laura, Brambilla, Marco, Salvetti, Massimo, Filippi, Mauro, Zaffaroni, Paolo, Gallo, Silvia, Rossi, Simona, Bonavita, Valeria, Studer, Andrejs, Miller, Guntis, Kareli, Jolanta, Kalnina, Dalia, Mickeviciene, Rasa, Kizlaitiene, Angelica Carbajal Ramirez, Juan Jose Lopez Prieto, Beatrijs, Wokke, Bob, W Van Oosten, Peter Van Domburg, Raymond, Huppert, Rogier, Q Hintzen, Astrid, Edland, Cesar, Castaneda, Julio, Perez, Martin, Gavidia, Andrzej, Wiak, Bartosz, Karaszewski, Elzbieta, Jasinska, Halina Bartosik Psujek, Iwona, Jastrzebska, Jaroslaw, Slawek, Maciej, Maciejowski, Miroslaw, Dziki, Monika Adamczyk Sowa, Robert, Bonek, Waldemar, Fryze, Ana Martins Da Silva, Angela, Timoteo, Antonio Vasco Salgado, Carlos, Capela, Carlos, Veira, Filipe, Correia, Joao, Cerqueira, Joao De Sa, Livia De Sousa, Raquel, Gouveia, Alina Sergeevna Agafina, Anna Naumovna Belova, Denis Viktorovich Sazonov, Dmitry, Pokhabov, Ekaterina Igorevna Kairbekova, Elena Gennadievna Arefieva, Farit Axatovich Khabirov, Igor Vyacheslavovich Litvinenko, Igor, Stolyarov, Irina Aleksandrovna Sokolova, Larisa Ivanovna Volkova, Maria Vafaevna Davydovskaya, Maria Nikolaevna Zaharova, Nadezhda Alekseevna Malkova, Natalia Agafonovna Totolyan, Nikolay Vasilievich Dorogov, Stella Anatolievna Sivertseva, Egon, Kurca, Georgi, Krastev, Miroslav, Brozman, Peter, Koleda, Peter, Turcani, Peter, Valkovic, Viera, Hancinova, Vladimir, Donath, Chris, Retief, Michael, Isaac, Albert Saiz Hinarejos, Alfredo Rodriguez Antigüedad, Bonaventura Casanova Estruch, Celia, Oreja-Guevara, Gemma Reig Rosello, Jose Carlos Alvarez Cermeño, Jose Martinez Rodriguez, Jose Meca Lallana, Juan Antonio Garcia Merino, Lucia Forero Diaz, Lucienne Costa Frossard Franca, Luis Querol Gutierrez, Lluis Ramio Torrenta, Pedro Serrano Castro, Rafael Arroyo Gonzalez, Sara Eichau Madueño, Sergio Martinez Yelamos, Tamara Castillo Trivino, Virgina Meca Lallana, Xaviere Montalban Gairin, Fredrik, Piehl, Jan, Lycke, Chiara, Zecca, Tobias, Derfu, Thy-Sheng, Lin, Somsak, Tiamkao, Ayse Nur Yuceyar, Aysun, Soysal, Belgin Petek Balci, Cavit, Boz, Husnu, Efendi, Murat, Terzi, Serhan, Sevim, Serkan, Ozakba, Andrew, Gale, Ben, Turner, David, Barne, David, Paling, Eli, Silber, James, Overell, Matthew, Craner, Aaron, Carlson, Adam, Wolff, Adaeze, Onuoha, Adnan, Subei, Ahmad, Ata, Aimee, Borazanci, Akram, Dastagir, Alberto, Vasquez, Alison Brooke Allen, Andrew, P Keegan, Angel, Carrasco, Angel, R Chinea Martinez, Ann, Ba, Annette, Okai, April, Erwin, Ariel, Antezana-Antezana, Barbara, Green, Bharathy, E Sundaram, Bhupendra, Khatri, Bhupesh, Dihenia, Bogdan, Gheorghiu, Brian, Costell, Brian, Steingo, Bruce, L Hughe, Carrie, M Hersh, Christopher, Laganke, Christopher, Luzzio, Corey, Ford, Craig Edward Herrman, Craig, Senzon, Cynthia, Huffman, Daniel, R Wynn, David D, O Bear, David, Lesch, David, H Mattson, David, Weisman, Deborah, A Burke, Dennis, W Dietrich, Deren, Huang, Derrick, Robertson, Djamchid, Lotfi, Don Joseph Alfonso, Dusan, Stefoski, Edward, J Fox, Emily, Pharr, Enrique, Alvarez, Evanthia, Bernitsa, Faria, Amjad, Gabriel, Pardo, Geoffrey, Eubank, Gerald, Mcintosh, Giles, F Crowell, Hemanth, Rao, J Michael Hemphill, Jack, H Florin, Jacqueline, Nichola, James, Napier, James, Scott, Jason, M Silversteen, Javier, Vasallo, Jean-Raphael, Schneider, Jeanette, Wendt, Jeffrey, Cohen, Jeffrey, Gro, Jeffrey, Grove, Jeffrey, Kaplan, Jessica, Stulc, Joanna, A Cooper, John, Foley, John, Scagnelli, Jonathan, C Calkwood, Jose Pizarro Otero, Jose, Rafeca, Joshua, Katz, Juliette, S Saad, Katherine, Standley, Keith, Edward, Kenneth, Sharlin, Khurram, Bashir, Kimberly, Wagner, Kore, Liow, Larry Lee Blankenship Jr, Laszlo, Mate, Liliana, Montoya, Lon, D Lynn, Mark, Agiu, Mark, Cascione, Mark Allan Goldstein, Mark, Janicki, Martin, R Bialow, Mary Denise Hughes, Matthew, J Baker, Michelle, Apperson, Michelle, B Kuczma, M Mateo Paz Soldan, Mirela, Cerghet, Nathaniel Robb Whaley, Paul, K Winner, Pavle, Repovic, Praful, Kelkar, Romero Rekha Pillai, Ricardo, Ayala, Richard, Sater, Randall, Trudell, Robert Fairborn Armstrong, Robert Thomas Nahouraii, Robert, Naismith, Ronald, S Murray, Samuel, Hunter, Sara, Qureshi, Sharon, Lynch, Sibyl, Wray, Silvia, R Delgado, Stacy, Donlon, Stanley, Cohan, Stanya, Smith, Stuart James Shafer, Susan, Azalone, Susan, Hibb, Tamara, A Miller, Thomas, Giancarlo, Troy, Desai, Varun, K Saxena, Virginia, Simnad, William David Honeycutt, William, Logan, William, E McElveen, William, Wagner, University of California [San Francisco] (UC San Francisco), University of California (UC), University of Pennsylvania, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nouvel Hôpital Civil de Strasbourg-Hôpital de Hautepierre [Strasbourg], Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Herrada, Anthony, and UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire

Subjects
Male, MESH: Multiple Sclerosis, Relapsing-Remitting, T-Lymphocytes, Hydroxybutyrates, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, Pharmacology, Relapsing-Remitting, MESH: Magnetic Resonance Imaging, chemistry.chemical_compound, 0302 clinical medicine, Teriflunomide, Monoclonal, MESH: Double-Blind Method, 030212 general & internal medicine, Humanized, MESH: Toluidines, B-Lymphocytes, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, Subcutaneous, B-Lymphocyte, Brain, General Medicine, Magnetic Resonance Imaging, MESH: Crotonates, Crotonates, Pyrimidine metabolism, Disease Progression, Female, MESH: Disease Progression, Antibody, Human, Adult, Multiple Sclerosis, Toluidines, medicine.drug_class, Injections, Subcutaneous, Injections, Subcutaneou, Monoclonal antibody, Ofatumumab, Settore MED/26, Antibodies, Monoclonal, Humanized, Crotonate, Antibodies, Injections, 03 medical and health sciences, MESH: Brain, Multiple Sclerosis, Relapsing-Remitting, Double-Blind Method, MESH: B-Lymphocytes, Nitriles, medicine, Humans, MESH: Kaplan-Meier Estimate, MESH: Humans, business.industry, Multiple sclerosis, MESH: Injections, Subcutaneous, MESH: Adult, medicine.disease, MESH: Male, MESH: T-Lymphocytes, T-Lymphocyte, Multicenter study, chemistry, MESH: Antibodies, Monoclonal, Humanized, biology.protein, Human medicine, business, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Background: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known.Methods: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume.Results: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95% confidence interval [CI], -0.16 to -0.06; P

Published
2020
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11. Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b, randomised, double-blind, placebo-controlled trial

Author

Daniel S Reich, Douglas L Arnold, Patrick Vermersch, Amit Bar-Or, Robert J Fox, Andre Matta, Timothy Turner, Erik Wallström, Xinyan Zhang, Miroslav Mareš, Farit A Khabirov, Anthony Traboulsee, Francois Grand'Maison, Francois Jacques, Michaela Tyblova, Eva Meluzinova, Radek Ampapa, Martin Valis, Pavel Hradilke, Pavel Stourac, Katrin Gross-Paju, David Laplaud, Guillaume Mathey, Bernard Uitdehaag, Evgeny Evdoshenkoo, Ekaterina Popova, Maria Zakharova, Natalia Totolyan, Igor Litvinenko, Farit Khabirov, Stella Sivertseva, Viera Hancinova, Ema Kantorova, Maria Luisa Martinez Gines, Xavier Montalban, Sara Eichau Maduano, Jose Meca-Lallana, Lluís Ramió-Torrentà, Tetyanna Nehrych, Valeriy Pashkovskyy, Sergii Moskovko, Oleksandr Kalbus, Marta Khavunka, Volodymyr Pryshchepa, Alla Goloborodko, Daniel Wynn, William Honeycutt, Sibyl Wray, Brian Steingo, Christopher LaGanke, Deren Huang, John Michael Hemphill, Lawrence Goldstick, and Derrick Robertson

Subjects
Adult, Central Nervous System, Male, medicine.medical_specialty, Population, Placebo-controlled study, Placebo, law.invention, Young Adult, Multiple Sclerosis, Relapsing-Remitting, Randomized controlled trial, Double-Blind Method, law, Recurrence, Internal medicine, Outcome Assessment, Health Care, Agammaglobulinaemia Tyrosine Kinase, Medicine, Humans, education, Protein Kinase Inhibitors, Inflammation, education.field_of_study, Cross-Over Studies, Dose-Response Relationship, Drug, business.industry, Multiple sclerosis, Middle Aged, medicine.disease, Crossover study, Magnetic Resonance Imaging, Clinical trial, Cohort, Female, Neurology (clinical), business
Abstract

Summary Background Tolebrutinib is an oral, CNS-penetrant, irreversible inhibitor of Bruton’s tyrosine kinase, an enzyme expressed in B lymphocytes and myeloid cells including microglia, which are major drivers of inflammation in multiple sclerosis. We aimed to determine the dose-response relationship between tolebrutinib and the reduction in new active brain MRI lesions in patients with relapsing multiple sclerosis. Methods We did a 16-week, phase 2b, randomised, double-blind, placebo-controlled, crossover, dose-finding trial at 40 centres (academic sites, specialty clinics, and general neurology centres) in ten countries in Europe and North America. Eligible participants were adults aged 18–55 years with diagnosed relapsing multiple sclerosis (either relapsing-remitting or relapsing secondary progressive multiple sclerosis), and one or more of the following criteria: at least one relapse within the previous year, at least two relapses within the previous 2 years, or at least one active gadolinium-enhancing brain lesion in the 6 months before screening. Exclusion criteria included a diagnosis of primary progressive multiple sclerosis or a diagnosis of secondary progressive multiple sclerosis without relapse. We used a two-step randomisation process to randomly assign eligible participants (1:1) to two cohorts, then further randomly assign participants in each cohort (1:1:1:1) to four tolebrutinib dose groups (5, 15, 30, and 60 mg administered once daily as an oral tablet). Cohort 1 received tolebrutinib for 12 weeks, then matched placebo (ie, identical looking tablets) for 4 weeks; cohort 2 received 4 weeks of placebo followed by 12 weeks of tolebrutinib. Participants and investigators were masked for dose and tolebrutinib-placebo administration sequence; investigators, study team members, and study participants did not have access to unmasked data. MRI scans were done at screening and every 4 weeks over 16 weeks. The primary efficacy endpoint was the number of new gadolinium-enhancing lesions detected on the scan done after 12 weeks of tolebrutinib treatment (assessed at week 12 for cohort 1 and week 16 for cohort 2), relative to the scan done 4 weeks previously, and compared with the lesions accumulated during 4 weeks of placebo run-in period in cohort 2. Efficacy data were analysed in a modified intention-to-treat population, using a two-step multiple comparison procedure with modelling analysis. Safety was assessed for all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03889639), EudraCT (2018-003927-12), and WHO (U1111-1220-0572), and has been completed. Findings Between May 14, 2019, and Jan 2, 2020, we enrolled and randomly assigned 130 participants to tolebrutinib: 33 to 5 mg, 32 to 15 mg, 33 to 30 mg, and 32 to 60 mg. 129 (99%) completed the treatment regimen and 126 were included in the primary analysis. At treatment week 12, there was a dose-dependent reduction in the number of new gadolinium-enhancing lesions (mean [SD] lesions per patient: placebo, 1·03 [2·50]; 5 mg, 1·39 [3·20]; 15 mg, 0·77 [1·48]; 30 mg, 0·76 [3·31]; 60 mg, 0·13 [0·43]; p=0·03). One serious adverse event was reported (one patient in the 60 mg group was admitted to hospital because of a multiple sclerosis relapse). The most common non-serious adverse event during tolebrutinib treatment was headache (in one [3%] of 33 in the 5 mg group; three [9%] of 32 in the 15 mg group; one [3%] of 33 in the 30 mg group; and four [13%] of 32 in the 60 mg group). No safety-related discontinuations or treatment-related deaths occurred. Interpretation 12 weeks of tolebrutinib treatment led to a dose-dependent reduction in new gadolinium-enhancing lesions, the 60 mg dose being the most efficacious, and the drug was well tolerated. Reduction of acute inflammation, combined with the potential to modulate the immune response within the CNS, provides a scientific rationale to pursue phase 3 clinical trials of tolebrutinib in patients with relapsing and progressive forms of multiple sclerosis. Funding Sanofi.

Published
2021

12. Placebo effect in chronic inflammatory demyelinating polyneuropathy: The PATH study and a systematic review

Author

Martin Stangel, K. George, Inna Rubanovits, A. Kutschenko, Michael Schroeter, Juliane Klehmet, Tsugio Akutsu, Robert D. Henderson, S. Mumfrey, Takuya Ohkubo, Helmar C. Lehmann, Mari Auranen, Paul Bassett, Giuseppe Lauria, A. Di Muzio, Kenichi Kaida, David Yarnitsky, S. Larue, R. Gold, Fabian Klostermann, Karissa L. Gable, Ivo N. van Schaik, Gens Sobue, A Schenone, U. Sorro, Jeffrey A. Allen, S. Attarian, A. Algom, U. Chyrchel-Paszkiewicz, J. Haas, Jens Ejbye Schmidt, I. N. van Schaik, Jasper M. Morrow, Ingemar S. J. Merkies, R. Carne, C. Marquez Infante, Michael P. Lunn, Khema Sharma, E. Chi Ho Lai, Billie L. Durn, Satoshi Kuwabara, D. Kramer, David Gosal, P. MacDonald, Janneke G. J. Hoeijmakers, Giovanni Antonini, Senda Ajroud-Driss, S. Muley, Takanori Yokota, Tim Hagenacker, Eroboghene E. Ubogu, M. Kawai, Maria Salvado, Jean Pouget, Mika Saarela, John T. Kissel, Alexander Shtilbans, K. Kanai, B. Murinson, Olaf Hoffmann, Claudia Sommer, Sandro Sorbi, P. Berlit, Norman Latov, Nora A. Visser, C. G. Faber, A. Wielanek, J. Demeestere, Ericka Simpson, Ginna Gonzalez, Konrad Rejdak, C. Casanovas Pons, Alessandro Testori, Orell Mielke, T. Kalous, Alexa Cleasby, Vera Bril, J. Sussova, D. Mueller, Katrin Gross-Paju, Dale J. Lange, Nicolette C. Notermans, Florian Then Bergh, R. Talab, Kazumasa Yokoyama, M. Zibetti, C. Trebst, Marina Grandis, Miriam Freimer, E. Delmon, David R. Cornblath, Masahiro Mori, H. Onoue, Richard J. Barohn, D. Liebetanz, M. Chatzopoulos, J. Oechtering, F. Ciccocioppo, T. Rao, P. Van Damme, A. Sabet, Takashi Kanda, J. Zschuentzsch, Hans-Peter Hartung, S. Benitez, D. Aufauvre, M. Bednar, M. Tomiyama, G. Le Masson, C. D'Amour, Richard A. Lewis, Anne D. Sperfeld, I. Melamed, Lisa D. Hobson-Webb, Stefan Blum, Dario Cocito, K. Nishiyama, Daniele Cazzato, F. Bethke, Toomas Toomsoo, Said R. Beydoun, Leslie Roberts, David Walk, Josep Gamez, Masahiro Iijima, A. Jaspert-Grehl, Israel V. Drory, P. Kunc, John-Philip Lawo, C. Goerlitz, H. Johl, R. Yoon, Daniela M. Menichella, T. Lavin, Stefania Morino, K. Ohyama, Masayuki Baba, M. Antonia, Shafeeq Ladha, Claude Desnuelle, Pierre Clavelou, Andreas Meisel, Martin Vališ, Filip Eftimov, P. Baum, Sabrina Matà, Russell L. Chin, Mazen M. Dimachkie, ANS - Neuroinfection & -inflammation, Neurology, and AII - Inflammatory diseases

Subjects
Research design, CIDP, immunoglobulin, non-relapse, placebo, relapse, Humans, Polyradiculoneuropathy, Chronic Inflammatory Demyelinating, Immunologic Factors, Outcome Assessment, Health Care, Placebo Effect, Randomized Controlled Trials as Topic, Research Design, Research Report, medicine.medical_specialty, Outcome Assessment, SUBCUTANEOUS IMMUNOGLOBULIN, Polyradiculoneuropathy, non‐relapse, Severe disease, PLASMA-EXCHANGE, Chronic inflammatory demyelinating polyneuropathy, Placebo, THERAPY, Immunoglobulin G, 03 medical and health sciences, DOUBLE-BLIND, 0302 clinical medicine, Internal medicine, Clinical endpoint, Medicine, Chronic Inflammatory Demyelinating, biology, business.industry, General Neuroscience, INTRAVENOUS IMMUNOGLOBULIN TREATMENT, Research Reports, medicine.disease, Health Care, INTERFERON BETA-1A, 030220 oncology & carcinogenesis, biology.protein, TRIAL, Neurology (clinical), business, Polyneuropathy, 030217 neurology & neurosurgery
Abstract

The Polyneuropathy And Treatment with Hizentra (PATH) study required subjects with chronic inflammatory demyelinating polyneuropathy (CIDP) to show dependency on immunoglobulin G (IgG) and then be restabilized on IgG before being randomized to placebo or one of two doses of subcutaneous immunoglobulin (SCIG). Nineteen of the 51 subjects (37%) randomized to placebo did not relapse over the next 24 weeks. This article explores the reasons for this effect. A post‐hoc analysis of the PATH placebo group was undertaken. A literature search identified other placebo‐controlled CIDP trials for review and comparison. In PATH, subjects randomized to placebo who did not relapse were significantly older, had more severe disease, and took longer to deteriorate in the IgG dependency period compared with those who relapsed. Published trials in CIDP, whose primary endpoint was stability or deterioration, had a mean non‐deterioration (placebo effect) of 43%, while trials with a primary endpoint of improvement had a placebo response of only 11%. Placebo is an important variable in the design of CIDP trials. Trials designed to show clinical improvement will have a significantly lower effect of this phenomenon than those designed to show stability or deterioration.

Published
2020

13. Approaches and challenges in the diagnosis and management of secondary progressive multiple sclerosis: A Central Eastern European perspective from healthcare professionals

Author

Christina Therapontos, Dana Horakova, Katrin Gross-Paju, Jarmila Szilasiova, Ieva Sereike, Tereza Gabelić, Alexey Boyko, Krzysztof Selmaj, Ron Milo, Jolanta Kalniņa, Julia Kolontareva, and Uroš Rot

Subjects
Adult, medicine.medical_specialty, Multiple Sclerosis, Population, Disease, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Multiple Sclerosis, Relapsing-Remitting, Epidemiology, Clinical endpoint, Medicine, Humans, 030212 general & internal medicine, education, Intensive care medicine, Retrospective Studies, education.field_of_study, Expanded Disability Status Scale, business.industry, biomarkers, Central and Eastern Europe, diagnosis, epidemiology, secondary progressive multiple sclerosis, treatment, General Medicine, Multiple Sclerosis, Chronic Progressive, Review article, Eastern european, Europe, Siponimod, Neurology, chemistry, Disease Progression, Neurology (clinical), business, Delivery of Health Care, 030217 neurology & neurosurgery
Abstract

Secondary progressive multiple sclerosis (SPMS) is a debilitating condition characterized by gradual worsening after an initial relapsing disease course. Despite the recent advances in our understanding of the disease, the diagnosis and treatment of SPMS continue to be challenging in routine clinical practice. The aim of this review article is to present the views of leading MS experts on the challenges in the diagnosis and management of SPMS and clinicians' perspectives in Central and Eastern Europe. This article also provides recommendations of MS experts to improve the situation with diagnosis and management of SPMS. Many countries within Central and Eastern Europe have high prevalence of MS (>100 per 100, 000 population). Consistent with the global trend, in the absence of reliable tests or biomarkers, SPMS at early stage remains undiagnosed. Due to diagnostic uncertainty and lack of a universally accepted disease definition, clinicians rely more on retrospective analysis of the clinical symptoms to confirm the diagnosis. With the lack of awareness and poor understanding of the timing of the onset of SPMS, clinicians may tend to direct attention to relapses than the symptoms of progression, which leads to underestimation of SPMS. Although several predictors of progression to SPMS have been identified, their predictive value is highly variable. Therefore, defining the transitioning period as a separate stage of MS is essential. According to experts' opinion, frequent follow-up of patients and periodic assessment of progression are recommended for the timely identification of patients transitioning from RRMS to SPMS. MSProDiscuss Tool is an example of a quick assessment tool for identifying patients progressing from RRMS to SPMS. MS progression is usually assessed by changes in Expanded Disability Status Scale (EDSS) scores. As EDSS scores tend to fluctuate when measured in the short term (3-6 months), a longer period (≥12 months) may be needed to confirm the progression. Assessment of cognitive function is also important for evaluating secondary progression. Compartmentalization of inflammation within the central nervous system is an important reason behind the limited success of disease-modifying therapies (DMTs) for treating SPMS. Most of the DMTs fail to cross the blood-brain barrier ; only 38% of the tested DMTs achieved their primary endpoint in SPMS. In Europe, siponimod is the first oral treatment for adults with active SPMS. Particularly, in Central and Eastern Europe, patients with SPMS are still being prescribed less efficacious DMTs and interferons. The absence of alternative treatments in SPMS supports the use of new products (siponimod and others) ; however the decision to initiate siponimod therapy in more severe patients (EDSS score of 7 or higher) should be individualized in consultation with the payers. The focus should be on early treatment initiation to delay disease progression.

Published
2020

14. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study

Author

Ludwig Kappos, Amit Bar-Or, Bruce A C Cree, Robert J Fox, Gavin Giovannoni, Ralf Gold, Patrick Vermersch, Douglas L Arnold, Sophie Arnould, Tatiana Scherz, Christian Wolf, Erik Wallström, Frank Dahlke, Anat Achiron, Lutz Achtnichts, Kadriye Agan, Gulsen Akman-Demir, Alison B Allen, Jack P Antel, Alfredo Rodriguez Antiguedad, Michelle Apperson, Angela M Applebee, Guillermo Izquierdo Ayuso, Masayuki Baba, Ovidiu Bajenaru, Rodica Balasa, Belgin Petek Balci, Michael Barnett, Ann Bass, Veit U Becker, Mihaela Bejinariu, Florian Then Bergh, Arnfin Bergmann, Evanthia Bernitsas, Achim Berthele, Virender Bhan, Felix Bischof, Randall John Bjork, Gregg Blevins, Matthias Boehringer, Thomas Boerner, Robert Bonek, James D Bowen, Allen Bowling, Alexey N Boyko, Cavit Boz, Vera Bracknies, Stefan Braune, Vincenzo Brescia Morra, Bruno Brochet, Waldemar Brola, Paul Kenneth Brownstone, Miroslav Brozman, Donald Brunet, Ioan Buraga, Margaret Burnett, Mathias Buttmann, Helmut Butzkueven, Jonathan Cahill, Jonathan C Calkwood, William Camu, Mark Cascione, Giovani Castelnovo, Diego Centonze, Joao Cerqueira, Andrew Chan, Andrea Cimprichova, Stanley Cohan, Giancarlo Comi, Jill Conway, Joanna A Cooper, John Corboy, Jorge Correale, Brian Costell, David A Cottrell, Patricia K Coyle, Matthew Craner, Liying Cui, Luis Cunha, Anna Czlonkowska, Ana Martins da Silva, Joao de Sa, Jérôme de Seze, Marc Debouverie, Jan Debruyne, Danny Decoo, Gilles Defer, Tobias Derfuss, Norma H Deri, Bhupesh Dihenia, Peter Dioszeghy, Vladimir Donath, Benedicte Dubois, Martin Duddy, Pierre Duquette, Gilles Edan, Husnu Efendi, Stanton Elias, Peter J Emrich, Bonaventura Casanova Estruch, Evgeniy P Evdoshenko, Juergen Faiss, Alexander S Fedyanin, Wolfgang Feneberg, Jiske Fermont, Oscar Fernandez Fernandez, Francisco Coret Ferrer, Katharina Fink, Helen Ford, Corey Ford, Ada Francia, Mark Freedman, Benjamin Frishberg, Simonetta Galgani, George P Garmany, Klaus Gehring, Jeffrey Gitt, Claudio Gobbi, Lawrence P Goldstick, Rafael Arroyo Gonzalez, Francois Grandmaison, Nikolaos Grigoriadis, Olga Grigorova, Luigi Maria Edoardo Grimaldi, Jeffrey Gross, Katrin Gross-Paju, Mark Gudesblatt, Daniel Guillaume, Judith Haas, Viera Hancinova, Anca Hancu, Orla Hardiman, Arndt Harmjanz, Fedor R Heidenreich, G J D Hengstman, Joseph Herbert, Mark Herring, Suzanne Hodgkinson, Olaf M Hoffmann, Werner E Hofmann, William D Honeycutt, Le Hanh Hua, Dehui Huang, Yining Huang, DeRen Huang, Raymond Hupperts, Piroska Imre, Alan Keith Jacobs, Gabor Jakab, Elzbieta Jasinska, Kenichi Kaida, Jolanta Kalnina, Ara Kaprelyan, Guntis Karelis, Dimitrios Karussis, Amos Katz, Farit A Khabirov, Bhupendra Khatri, Takashi Kimura, Ilya Kister, Rasa Kizlaitiene, Eleonora Klimova, Juergen Koehler, Aparna Komatineni, Anselm Kornhuber, Krisztina Kovacs, Agnes Koves, Wojciech Kozubski, Georgi Krastev, Lauren B Krupp, Egon Kurca, Christoph Lassek, Guy Laureys, Liesly Lee, Eckart Lensch, Fritz Leutmezer, Hongzeng Li, Ralf A Linker, Michael Linnebank, Petra Liskova, Cristina Llanera, Jiahong Lu, Andreas Lutterotti, Jan Lycke, Richard Macdonell, Maciej Maciejowski, Mathias Maeurer, Rim V Magzhanov, Eva-Maria Maida, Lina Malciene, Yang Mao-Draayer, Girolama Alessandra Marfia, Clyde Markowitz, Vasileios Mastorodimos, Klotild Matyas, Jose Meca-Lallana, Juan Antonio Garcia Merino, Ioan Gheorghe Mihetiu, Ivan Milanov, Aaron E Miller, Andrejs Millers, Massimiliano Mirabella, Masanori Mizuno, Xavier Montalban, Lilina Montoya, Masahiro Mori, Stefanie Mueller, Jin Nakahara, Yuji Nakatsuji, Scott Newsome, Richard Nicholas, A Scott Nielsen, Esmaeil Nikfekr, Ugo Nocentini, Chiyoko Nohara, Kyoichi Nomura, Miroslav M Odinak, Tomas Olsson, B W van Oosten, Celia Oreja-Guevara, Patrick Oschmann, James Overell, Andrew Pachner, Gyula Panczel, Massimo Pandolfo, Caroline Papeix, Liliana Patrucco, Jean Pelletier, Raul Piedrabuena, Misha Pless, Udo Polzer, Krisztian Pozsegovits, Daiva Rastenyte, Sebastian Rauer, Gerd Reifschneider, Roberto Rey, Syed A Rizvi, Derrick Robertson, Jose Martinez Rodriguez, David Rog, Homayoun Roshanisefat, Vernon Rowe, Csilla Rozsa, Susan Rubin, Stanislaw Rusek, Francesco Saccà, Takahiko Saida, Antonio Vasco Salgado, Victoria Eugenia Fernandez Sanchez, Kalina Sanders, Maria Satori, Denis V Sazonov, Elio Angelo Scarpini, Eugen Schlegel, Myriam Schluep, Stephan Schmidt, Erich Scholz, H M Schrijver, Matthias Schwab, Raymond Schwartz, James Scott, Krzysztof Selmaj, Stuart Shafer, Basil Sharrack, Ivan A Shchukin, Yuko Shimizu, Penko Shotekov, Arno Siever, Karl-Otto Sigel, Scott Silliman, Magdolna Simo, Mihaela Simu, Vladimiro Sinay, Antonio Escartin Siquier, Aksel Siva, Ondrej Skoda, Andrew Solomon, Martin Stangel, Dusan Stefoski, Brian Steingo, Igor D Stolyarov, Pavel Stourac, Katrin Strassburger-Krogias, Erik Strauss, Olaf Stuve, Ivaylo Tarnev, Antonios Tavernarakis, Cristina Ramo Tello, Murat Terzi, Veronika Ticha, Marina Ticmeanu, Klaus Tiel-Wilck, Toomas Toomsoo, Niall Tubridy, Mark J Tullman, Hayrettin Tumani, Peter Turcani, Ben Turner, Antonio Uccelli, Francisco Javier Olascoaga Urtaza, Marta Vachova, Attila Valikovics, Silke Walter, Bart Van Wijmeersch, Ludo Vanopdenbosch, Joerg R Weber, Sara Weiss, Robert Weissert, Timothy West, Heinz Wiendl, Sandrine Wiertlewski, Brigitte Wildemann, Barbara Willekens, L H Visser, Galina Vorobeychik, Xianhao Xu, Takashi Yamamura, Yi N Yang, Sergio Martinez Yelamos, Michael Yeung, Alan Zacharias, Marvin Zelkowitz, Uwe Zettl, Meini Zhang, Hongyu Zhou, Ulf Zieman, Tjalf Ziemssen, Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital, University of Basel, Basel, Center for Neuroinflammation and Neurotherapeutics, and Multiple Sclerosis Division, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, Neuroimmunology Unit, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, UCSF Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, Mellen Centre for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, Department of Neurology St. Josef-Hospital, Ruhr University Bochum, Germany, Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Montreal Neurological Institute, McGill University, Montreal, QC, Canada, NeuroRx Research, Montreal, QC, Novartis Pharma AG, Lycalis, Brussels, AP-HM, CHU Timone, Pole de Neurosciences Cliniques, Department of Neurology, Marseille, France., Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Exploration Métabolique par Résonance Magnétique [Hôpital de la Timone - APHM] (CEMEREM), Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Kappos, Ludwig, Bar-Or, Amit, Cree, Bruce A C, Fox, Robert J, Giovannoni, Gavin, Gold, Ralf, Vermersch, Patrick, Arnold, Douglas L, Arnould, Sophie, Scherz, Tatiana, Wolf, Christian, Wallström, Erik, Dahlke, Frank, Achiron, Anat, Achtnichts, Lutz, Agan, Kadriye, Akman-Demir, Gulsen, Allen, Alison B, Antel, Jack P, Antiguedad, Alfredo Rodriguez, Apperson, Michelle, Applebee, Angela M, Ayuso, Guillermo Izquierdo, Baba, Masayuki, Bajenaru, Ovidiu, Balasa, Rodica, Balci, Belgin Petek, Barnett, Michael, Bass, Ann, Becker, Veit U, Bejinariu, Mihaela, Bergh, Florian Then, Bergmann, Arnfin, Bernitsas, Evanthia, Berthele, Achim, Bhan, Virender, Bischof, Felix, Bjork, Randall John, Blevins, Gregg, Boehringer, Matthia, Boerner, Thoma, Bonek, Robert, Bowen, James D, Bowling, Allen, Boyko, Alexey N, Boz, Cavit, Bracknies, Vera, Braune, Stefan, Brescia Morra, Vincenzo, Brochet, Bruno, Brola, Waldemar, Brownstone, Paul Kenneth, Brozman, Miroslav, Brunet, Donald, Buraga, Ioan, Burnett, Margaret, Buttmann, Mathia, Butzkueven, Helmut, Cahill, Jonathan, Calkwood, Jonathan C, Camu, William, Cascione, Mark, Castelnovo, Giovani, Centonze, Diego, Cerqueira, Joao, Chan, Andrew, Cimprichova, Andrea, Cohan, Stanley, Comi, Giancarlo, Conway, Jill, Cooper, Joanna A, Corboy, John, Correale, Jorge, Costell, Brian, Cottrell, David A, Coyle, Patricia K, Craner, Matthew, Cui, Liying, Cunha, Lui, Czlonkowska, Anna, da Silva, Ana Martin, de Sa, Joao, de Seze, Jérôme, Debouverie, Marc, Debruyne, Jan, Decoo, Danny, Defer, Gille, Derfuss, Tobia, Deri, Norma H, Dihenia, Bhupesh, Dioszeghy, Peter, Donath, Vladimir, Dubois, Benedicte, Duddy, Martin, Duquette, Pierre, Edan, Gille, Efendi, Husnu, Elias, Stanton, Emrich, Peter J, Estruch, Bonaventura Casanova, Evdoshenko, Evgeniy P, Faiss, Juergen, Fedyanin, Alexander S, Feneberg, Wolfgang, Fermont, Jiske, Fernandez, Oscar Fernandez, Ferrer, Francisco Coret, Fink, Katharina, Ford, Helen, Ford, Corey, Francia, Ada, Freedman, Mark, Frishberg, Benjamin, Galgani, Simonetta, Garmany, George P, Gehring, Klau, Gitt, Jeffrey, Gobbi, Claudio, Goldstick, Lawrence P, Gonzalez, Rafael Arroyo, Grandmaison, Francoi, Grigoriadis, Nikolao, Grigorova, Olga, Grimaldi, Luigi Maria Edoardo, Gross, Jeffrey, Gross-Paju, Katrin, Gudesblatt, Mark, Guillaume, Daniel, Haas, Judith, Hancinova, Viera, Hancu, Anca, Hardiman, Orla, Harmjanz, Arndt, Heidenreich, Fedor R, Hengstman, G J D, Herbert, Joseph, Herring, Mark, Hodgkinson, Suzanne, Hoffmann, Olaf M, Hofmann, Werner E, Honeycutt, William D, Hua, Le Hanh, Huang, Dehui, Huang, Yining, Huang, Deren, Hupperts, Raymond, Imre, Piroska, Jacobs, Alan Keith, Jakab, Gabor, Jasinska, Elzbieta, Kaida, Kenichi, Kalnina, Jolanta, Kaprelyan, Ara, Karelis, Gunti, Karussis, Dimitrio, Katz, Amo, Khabirov, Farit A, Khatri, Bhupendra, Kimura, Takashi, Kister, Ilya, Kizlaitiene, Rasa, Klimova, Eleonora, Koehler, Juergen, Komatineni, Aparna, Kornhuber, Anselm, Kovacs, Krisztina, Koves, Agne, Kozubski, Wojciech, Krastev, Georgi, Krupp, Lauren B, Kurca, Egon, Lassek, Christoph, Laureys, Guy, Lee, Liesly, Lensch, Eckart, Leutmezer, Fritz, Li, Hongzeng, Linker, Ralf A, Linnebank, Michael, Liskova, Petra, Llanera, Cristina, Lu, Jiahong, Lutterotti, Andrea, Lycke, Jan, Macdonell, Richard, Maciejowski, Maciej, Maeurer, Mathia, Magzhanov, Rim V, Maida, Eva-Maria, Malciene, Lina, Mao-Draayer, Yang, Marfia, Girolama Alessandra, Markowitz, Clyde, Mastorodimos, Vasileio, Matyas, Klotild, Meca-Lallana, Jose, Merino, Juan Antonio Garcia, Mihetiu, Ioan Gheorghe, Milanov, Ivan, Miller, Aaron E, Millers, Andrej, Mirabella, Massimiliano, Mizuno, Masanori, Montalban, Xavier, Montoya, Lilina, Mori, Masahiro, Mueller, Stefanie, Nakahara, Jin, Nakatsuji, Yuji, Newsome, Scott, Nicholas, Richard, Nielsen, A Scott, Nikfekr, Esmaeil, Nocentini, Ugo, Nohara, Chiyoko, Nomura, Kyoichi, Odinak, Miroslav M, Olsson, Toma, van Oosten, B W, Oreja-Guevara, Celia, Oschmann, Patrick, Overell, Jame, Pachner, Andrew, Panczel, Gyula, Pandolfo, Massimo, Papeix, Caroline, Patrucco, Liliana, Pelletier, Jean, Piedrabuena, Raul, Pless, Misha, Polzer, Udo, Pozsegovits, Krisztian, Rastenyte, Daiva, Rauer, Sebastian, Reifschneider, Gerd, Rey, Roberto, Rizvi, Syed A, Robertson, Derrick, Rodriguez, Jose Martinez, Rog, David, Roshanisefat, Homayoun, Rowe, Vernon, Rozsa, Csilla, Rubin, Susan, Rusek, Stanislaw, Saccà, Francesco, Saida, Takahiko, Salgado, Antonio Vasco, Sanchez, Victoria Eugenia Fernandez, Sanders, Kalina, Satori, Maria, Sazonov, Denis V, Scarpini, Elio Angelo, Schlegel, Eugen, Schluep, Myriam, Schmidt, Stephan, Scholz, Erich, Schrijver, H M, Schwab, Matthia, Schwartz, Raymond, Scott, Jame, Selmaj, Krzysztof, Shafer, Stuart, Sharrack, Basil, Shchukin, Ivan A, Shimizu, Yuko, Shotekov, Penko, Siever, Arno, Sigel, Karl-Otto, Silliman, Scott, Simo, Magdolna, Simu, Mihaela, Sinay, Vladimiro, Siquier, Antonio Escartin, Siva, Aksel, Skoda, Ondrej, Solomon, Andrew, Stangel, Martin, Stefoski, Dusan, Steingo, Brian, Stolyarov, Igor D, Stourac, Pavel, Strassburger-Krogias, Katrin, Strauss, Erik, Stuve, Olaf, Tarnev, Ivaylo, Tavernarakis, Antonio, Tello, Cristina Ramo, Terzi, Murat, Ticha, Veronika, Ticmeanu, Marina, Tiel-Wilck, Klau, Toomsoo, Tooma, Tubridy, Niall, Tullman, Mark J, Tumani, Hayrettin, Turcani, Peter, Turner, Ben, Uccelli, Antonio, Urtaza, Francisco Javier Olascoaga, Vachova, Marta, Valikovics, Attila, Walter, Silke, Van Wijmeersch, Bart, Vanopdenbosch, Ludo, Weber, Joerg R, Weiss, Sara, Weissert, Robert, West, Timothy, Wiendl, Heinz, Wiertlewski, Sandrine, Wildemann, Brigitte, Willekens, Barbara, Visser, L H, Vorobeychik, Galina, Xu, Xianhao, Yamamura, Takashi, Yang, Yi N, Yelamos, Sergio Martinez, Yeung, Michael, Zacharias, Alan, Zelkowitz, Marvin, Zettl, Uwe, Zhang, Meini, Zhou, Hongyu, Zieman, Ulf, Ziemssen, Tjalf, and EXPAND Clinical Investigators

Subjects
Adult, Male, 0301 basic medicine, Relative risk reduction, medicine.medical_specialty, Adolescent, Placebo, law.invention, Cohort Studies, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, Multiple Sclerosis, Chronic Progressive / drug therapy, 0302 clinical medicine, Double-Blind Method, Randomized controlled trial, law, Internal medicine, Benzyl Compounds, Clinical endpoint, Humans, Medicine, ComputingMilieux_MISCELLANEOUS, Settore MED/36 - DIAGNOSTICA PER IMMAGINI E RADIOTERAPIA, Expanded Disability Status Scale, Dose-Response Relationship, Drug, business.industry, Hazard ratio, General Medicine, Middle Aged, Multiple Sclerosis, Chronic Progressive, Fingolimod, Treatment Outcome, Settore M-EDF/01 - METODI E DIDATTICHE DELLE ATTIVITÀ MOTORIE, 030104 developmental biology, Siponimod, chemistry, Disease Progression, Azetidines, Female, Settore MED/26 - Neurologia, Human medicine, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery, medicine.drug
Abstract

Summary Background No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor 1,5 modulator, on disability progression in patients with SPMS. Methods This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatment arms, patients (age 18–60 years) with SPMS and an Expanded Disability Status Scale score of 3·0–6·5 were randomly assigned (2:1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with ClinicalTrials.gov, number NCT01665144. Findings 1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16·8 years (SD 8·3), and the mean time since conversion to SPMS was 3·8 years (SD 3·5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0·79, 95% CI 0·65–0·95; relative risk reduction 21%; p=0·013). Adverse events occurred in 975 (89%) of 1099 patients receiving siponimod versus 445 (82%) of 546 patients receiving placebo; serious adverse events were reported for 197 (18%) patients in the siponimod group versus 83 (15%) patients in the placebo group. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo. Initial dose titration mitigated cardiac first-dose effects. Frequencies of infections, malignancies, and fatalities did not differ between groups. Interpretation Siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators and is likely to be a useful treatment for SPMS. Funding Novartis Pharma AG.

Published
2018
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15. Restabilization treatment after intravenous immunoglobulin withdrawal in chronic inflammatory demyelinating polyneuropathy: Results from the pre-randomization phase of the Polyneuropathy And Treatment with Hizentra study

Author

Michael Schroeter, Amgad Shebl, Leslie Roberts, Takuya Ohkubo, M. Chatzopoulos, Nan van Geloven, Robert D. Henderson, Catharina G. Faber, R. Talab, K. George, A. Kutschenko, E. Chi-Ho Lai, M. Bednar, Inna Rubanovits, Claudia Sommer, J. Oechtering, M. Tomiyama, Hans-Peter Hartung, Mari Auranen, G. Le Masson, Konrad Rejdak, Marina Grandis, Eroboghene E. Ubogu, Senda Ajroud-Driss, Tim Hagenacker, Lisa D. Hobson-Webb, Masayuki Baba, Khema Sharma, Miriam Freimer, Kazumasa Yokoyama, U. Chyrchel-Paszkiewicz, Karissa L. Gable, P. Van Damme, J. Zschuentzsch, I. N. van Schaik, S. Benitez, K. Nishiyama, J. Demeestere, Daniele Cazzato, F. Bethke, R. Carne, Gen Sobue, C. Marquez Infante, Norman Latov, David Walk, B. Murinson, Katrin Gross-Paju, Helmar C. Lehmann, M. Antonia, Ginna Gonzalez, M. Zibetti, Anne-Cécile Wielanek-Bachelet, Vera Bril, Stefania Morino, Mika Saarela, S. Mumfrey, Said R. Beydoun, Takanori Yokota, Maria Salvado, John T. Kissel, C. D'Amour, Ericka Simpson, D. Aufauvre, P. MacDonald, Orell Mielke, David R. Cornblath, Masahiro Iijima, Janneke G. J. Hoeijmakers, Nora A. Visser, Takashi Kanda, K. Kanai, Jeffrey A. Allen, Richard A. Lewis, Anne D. Sperfeld, J. Sussova, D. Mueller, A. Algom, Fabian Klostermann, I. Melamed, David Yarnitsky, J. Haas, Josep Gamez, A Schenone, P. Kunc, Ingemar S. J. Merkies, C. Trebst, F. Ciccocioppo, Ralf Gold, Vivian E. Drory, H. Onoue, Stefan Blum, P. Berlit, S. Muley, Tsugio Akutsu, T. Kalous, Michael P. Lunn, Alessandro Testori, Dale J. Lange, Giuseppe Lauria, D. Liebetanz, A. Jaspert-Grehl, Giovanni Antonini, Masahiro Mori, S. Larue, John-Philip Lawo, C. Goerlitz, H. Johl, M. Kawai, Nicolette C. Notermans, U. Sorro, R. Yoon, Daniela M. Menichella, T. Lavin, Billie L. Durn, J. Morrow, Richard J. Barohn, Dario Cocito, T. Rao, Martin Stangel, Satoshi Kuwabara, Jean Pouget, Emilien Delmont, David Gosal, Alexander Shtilbans, Sandro Sorbi, Florian Then Bergh, J. Schmidt, Shahram Attarian, Pierre Clavelou, Andreas Meisel, Sabrina Matà, Russell L. Chin, Mazen M. Dimachkie, Juliane Klehmet, K. Ohyama, Martin Vališ, Filip Eftimov, Shafeeq Ladha, A. Sabet, P. Baum, Claude Desnuelle, Kenichi Kaida, D. Kramer, Olaf Hoffmann, C. Casanovas Pons, A. Di Muzio, Ivo N. van Schaik, Toomas Toomsoo, Amsterdam Neuroscience - Neuroinfection & -inflammation, Neurology, AII - Inflammatory diseases, CSL Behring, Meridian HealthComms, and Demeestere, Jelle

Subjects
Research Report, Male, Outcome Assessment, inflammatory neuropathy cause and treatment (INCAT), chronic inflammatory demyelinating polyneuropathy (CIDP), intravenous immunoglobulin (IVIG), polyneuropathy and treatment with Hizentra (PATH), Privigen, Neuroscience (all), Neurology (clinical), Medizin, Polyneuropathy and treatment with Hizentra (PATH), Chronic inflammatory demyelinating polyneuropathy, law.invention, Chronic inflammatory demyelinating polyneuropathy (CIDP), 0302 clinical medicine, Randomized controlled trial, law, hemic and lymphatic diseases, Outcome Assessment, Health Care, 80 and over, Young adult, Chronic Inflammatory Demyelinating, Aged, 80 and over, biology, Intravenous immunoglobulin (IVIG), General Neuroscience, Immunoglobulins, Intravenous, Middle Aged, 3. Good health, Methylprednisolone, chronic inflammatory demyelinating polyneuropathy (cidp), inflammatory neuropathy cause and treatment (incat), intravenous immunoglobulin (ivig), polyneuropathy and treatment with hizentra (path), privigen, 030220 oncology & carcinogenesis, Anesthesia, Female, Antibody, Intravenous, Polyneuropathy, Adult, Aged, Follow-Up Studies, Humans, Immunoglobulin G, Immunologic Factors, Polyradiculoneuropathy, Chronic Inflammatory Demyelinating, Young Adult, medicine.drug, Randomization, Neuroscience(all), Clinical Neurology, Polyradiculoneuropathy, Immunoglobulins, Inflammatory neuropathy cause and treatment (INCAT), 03 medical and health sciences, medicine, Journal Article, business.industry, Research Reports, medicine.disease, Health Care, biology.protein, business, 030217 neurology & neurosurgery
Abstract

PATH study group., In patients with chronic inflammatory demyelinating polyneuropathy (CIDP), intravenous immunoglobulin (IVIG) is recommended to be periodically reduced to assess the need for ongoing therapy. However, little is known about the effectiveness of restabilization with IVIG in patients who worsen after IVIG withdrawal. In the Polyneuropathy And Treatment with Hizentra (PATH) study, the pre‐randomization period included sudden stopping of IVIG followed by 12 weeks of observation. Those deteriorating were then restabilized with IVIG. Of 245 subjects who stopped IVIG, 28 did not show signs of clinical deterioration within 12 weeks. Two hundred and seven received IVIG restabilization with an induction dose of 2 g/kg bodyweight (bw) IgPro10 (Privigen, CSL Behring, King of Prussia, Pennsylvania) and maintenance doses of 1 g/kg bw every 3 weeks for up to 13 weeks. Signs of clinical improvement were seen in almost all (n = 188; 91%) subjects. During IVIG restabilization, 35 subjects either did not show CIDP stability (n = 21, analyzed as n = 22 as an additional subject was randomized in error) or withdrew for other reasons (n = 14). Of the 22 subjects who did not achieve clinical stability, follow‐up information in 16 subjects after an additional 4 weeks was obtained. Nine subjects were reported to have improved, leaving a maximum of 27 subjects (13%) who either showed no signs of clinical improvement during the restabilization phase and 4 weeks post‐study or withdrew for other reasons. In conclusion, sudden IVIG withdrawal was effective in detecting ongoing immunoglobulin G dependency with a small risk for subjects not returning to their baseline 17 weeks after withdrawal., Editorial support was provided by Meridian HealthComms Ltd, funded by CSL Behring.

Published
2019

16. Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy (PATH) : a randomised, double-blind, placebo-controlled, phase 3 trial

Author

Michael Schroeter, Mazen M. Dimachkie, J. Zschuentssch, Takuya Ohkubo, Kenichi Kaida, M. Bednar, M. Tomiyama, J. Sussova, D. Mueller, E. Chi-Ho Lai, Nicolette C. Notermans, Toomas Toomsoo, C. D'Amour, J. Haas, B. Murinson, Masahiro Mori, Richard A. Lewis, Masayuki Baba, Anne D. Sperfeld, Vivian E. Drory, Hans-Peter Hartung, J. Demeestere, Satoshi Kuwabara, Leslie Roberts, S. Mumfrey, David Gosal, Katrin Gross-Paju, M. Zibetti, Martin Vališ, Filip Eftimov, David Yarnitsky, D. Aufauvre, G. Le Masson, Takashi Kanda, Lisa D. Hobson-Webb, I. Melamed, Alexander Shtilbans, Inna Rubanovits, P. MacDonald, Janneke G. J. Hoeijmakers, Vera Bril, Ericka Simpson, Orell Mielke, Michaela Praus, Martin Stangel, Masahiro Iijima, Richard J. Barohn, Robert D. Henderson, P. Baum, Mari Auranen, David Walk, Said R. Beydoun, A. Jaspert-Grehl, Alessandro Testori, Giovanni Antonini, Ingemar S. J. Merkies, Sabrina Matà, A. Di Muzio, Ivo N. van Schaik, T. Kalous, Josep Gamez, Juliane Klehmet, Dario Cocito, Angelo Schenone, R. Carne, P. Kunc, Dale J. Lange, Miriam Freimer, S. Muley, Norman Latov, T. Rao, Jens Ejbye Schmidt, Jasper M. Morrow, Ari Breiner, C. Marquez Infante, C. G. Faber, U. Chyrchel-Paszkiewicz, Anne-Cécile Wielanek-Bachelet, Russell L. Chin, John-Philip Lawo, I. N. van Schaik, C. Goerlitz, M. Chatzopoulos, Tim Hagenacker, Claudia Sommer, H. Johl, D. Kramer, Stefania Morino, R. Yoon, Daniela M. Menichella, M. Alberti Aguiló, K. Nishiyama, Daniele Cazzato, F. Bethke, Helmar C. Lehmann, Konrad Rejdak, T. Lavin, Kazumasa Yokoyama, Olaf Hoffmann, M. Kawai, C. Casanovas Pons, Sandro Sorbi, Takanori Yokota, Nora A. Visser, R. Talab, Eroboghene E. Ubogu, Florian Then Bergh, Stefan Blum, Ginna Gonzalez, J. Oechtering, David R. Cornblath, F. Ciccocioppo, A. Sabet, Fabian Klostermann, Nan van Geloven, K. George, A. Kutschenko, S. Benitez Rivero, Karissa L. Gable, Michael P. Lunn, Senda Ajroud-Driss, Shahram Attarian, Marina Grandis, P. Van Damme, C. Trebst, Jeffrey A. Allen, A. Algom, H. Onoue, D. Liebetanz, Billie L. Durn, Maria Salvado Figueras, Jean Pouget, Emilien Delmont, Khema Sharma, Gen Sobue, K. Ohyama, John T. Kissel, K. Kanai, Tsugio Akutsu, Pierre Clavelou, Andreas Meisel, Giuseppe Lauria, M. Saarela, S. Larue, R. Gold, U. Sorro, Shafeeq Ladha, Claude Desnuelle, P. Berlit, Neurologian yksikkö, Clinicum, HUS Neurocenter, ANS - Neuroinfection & -inflammation, AII - Inflammatory diseases, Other departments, Neurology, AII - Amsterdam institute for Infection and Immunity, Hagenacker, Tim (Beitragende*r), and RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience

Subjects
0301 basic medicine, Male, SATISFACTION, Clinical Trial, Phase III, Medizin, Chronic inflammatory demyelinating polyneuropathy, THERAPY, 3124 Neurology and psychiatry, law.invention, MUSCLE STRENGTH, 0302 clinical medicine, Randomized controlled trial, Quality of life, law, QUALITY-OF-LIFE, Chronic Inflammatory Demyelinating, Subcutaneous, Absolute risk reduction, IGG SELF-INFUSIONS, Middle Aged, Clinical Trial, 3. Good health, Randomized Controlled Trial, POLYRADICULONEUROPATHY, Female, aged, double-blind method, female, humans, immunoglobulins, immunologic factors, injections, subcutaneous, male, middle aged, polyradiculoneuropathy, chronic inflammatory demyelinating, outcome assessment (health care), neurology (clinical), medicine.medical_specialty, Injections, Subcutaneous, Clinical Neurology, Immunoglobulins, CIDP, Placebo, Injections, 03 medical and health sciences, Outcome Assessment (Health Care), Phase III, Double-Blind Method, Internal medicine, medicine, Journal Article, Humans, Immunologic Factors, HOME, Adverse effect, Aged, business.industry, ICE, 3112 Neurosciences, Polyradiculoneuropathy, medicine.disease, Surgery, Clinical trial, 030104 developmental biology, Polyradiculoneuropathy, Chronic Inflammatory Demyelinating, PRIMARY ANTIBODY DEFICIENCIES, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Mika Saarela työryhmän jäsenenä. Background Approximately two-thirds of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) need long-term intravenous immunoglobulin. Subcutaneous immunoglobulin (SCIg) is an alternative option for immunoglobulin delivery, but has not previously been investigated in a large trial of CIDP. The PATH study compared relapse rates in patients given SCIg versus placebo. Methods Between March 12, 2012, and Sept 20, 2016, we studied patients from 69 neuromuscular centres in North America, Europe, Israel, Australia, and Japan. Adults with definite or probable CIDP who responded to intravenous immunoglobulin treatment were eligible. We randomly allocated participants to 0.2 g/kg or 0.4 g/kg of a 20% SCIg solution (IgPro20) weekly versus placebo (2% human albumin solution) for maintenance treatment for 24 weeks. We did randomisation in a 1: 1:1 ratio with an interactive voice and web response system with a block size of six, stratified by region (Japan or non-Japan). The primary outcome was the proportion of patients with a CIDP relapse or who were withdrawn for any other reason during 24 weeks of treatment. Patients, caregivers, and study personnel, including those assessing outcomes, were masked to treatment assignment. Analyses were done in the intention-to-treat and per-protocol sets. This trial is registered with ClinicalTrials. gov, number NCT01545076. Findings In this randomised, double-blind, placebo-controlled trial, we randomly allocated 172 patients: 57 (33%) to the placebo group, 57 (33%) to the low-dose group, and 58 (34%) to the high-dose group. In the intention-to-treat set, 36 (63% [95% CI 50-74]) patients on placebo, 22 (39% [27-52]) on low-dose SCIg, and 19 (33% [22-46]) on high-dose SCIg had a relapse or were withdrawn from the study for other reasons (p=0.0007). Absolute risk reductions were 25% (95% CI 6-41) for low-dose versus placebo (p=0.007), 30% (12-46) for high-dose versus placebo (p=0.001), and 6% (-11 to 23) for high-dose versus low-dose (p=0.32). Causally related adverse events occurred in 47 (27%) patients (ten [18%] in the placebo group, 17 [30%] in the low-dose group, and 20 [34%] in the high-dose group). Six (3%) patients had 11 serious adverse events: one (2%) patient in the placebo group, three (5%) in the low-dose group, and two (3%) in the high-dose group; only one (an acute allergic skin reaction in the low-dose group) was assessed to be causally related. Interpretation This study, which is to our knowledge, the largest trial of CIDP to date and the first to study two administrations of immunoglobulins and two doses, showed that both doses of SCIg IgPro20 were efficacious and well tolerated, suggesting that SCIg can be used as a maintenance treatment for CIDP.

Published
2018

17. Intravenous versus subcutaneous immunoglobulin – Authors' reply

Author

Ivo N van Schaik, Orell Mielke, Arman Sabet, Koshy George, Leslie Roberts, Ross Carne, Stefan Blum, Robert Henderson, Philip Van Damme, Jelle Demeestere, Sandrine Larue, Catherine-Andree Pinard D'Amour, Vera Bril, Ari Breiner, Pavel Kunc, Martin Valis, Jana Sussova, Tomas Kalous, Radomir Talab, Michal Bednar, Toomas Toomsoo, Inna Rubanovits, Katrin Gross-Paju, Ulvi Sorro, Mika Saarela, Mari Auranen, Jean Pouget, Shahram Attarian, Gwendal Le Masson, Anne-Cécile Wielanek-Bachelet, Claude Desnuelle, Emilien Delmont, Pierre Clavelou, Dominique Aufauvre, Jens Schmidt, Jana Zschuentssch, Claudia Sommer, Daniela Kramer, Olaf Hoffmann, Carsten Goerlitz, Judith Haas, Marko Chatzopoulos, Min-Suk Yoon, Ralf Gold, Peter Berlit, Andrea Jaspert-Grehl, David Liebetanz, Anna Kutschenko, Martin Stangel, Corinna Trebst, Petra Baum, Florian Then Bergh, Juliane Klehmet, Andreas Meisel, Fabian Klostermann, Johanna Oechtering, Helmar Lehmann, Michael Schroeter, Tim Hagenacker, Daniel Mueller, Anne-Dorte Sperfeld, Florian Bethke, Hans-Peter Hartung, Vivian Drory, Avi Algom, David Yarnitsky, Beth Brianna Murinson, Antonio Di Muzio, Fausta Ciccocioppo, Sandro Sorbi, Sabrina Mata, Angelo Schenone, Marina Grandis, Giuseppe Lauria, Daniele Cazzato, Giovanni Antonini, Stefania Morino, Dario Cocito, Maurizio Zibetti, Takanori Yokota, Takuya Ohkubo, Takashi Kanda, Motoharu Kawai, Kenichi Kaida, Hiroyuki Onoue, Satoshi Kuwabara, Masahiro Mori, Masahiro Iijima, Ken Ohyama, Gen Sobue, Masayuki Baba, Masahiko Tomiyama, Kazutoshi Nishiyama, Tsugio Akutsu, Kazumasa Yokoyama, Kazuaki Kanai, Ivo N. van Schaik, Filip Eftimov, Nicolette. C. Notermans, Nora. A. Visser, Catharina Faber, Janneke. G.J. Hoeijmakers, Ingemar S.J. Merkies, Nan van Geloven, Konrad Rejdak, Urszula Chyrchel-Paszkiewicz, Carlos Casanovas Pons, María Antonia Alberti Aguiló, Josep Gamez, María Figueras, Celedonio Marquez Infante, Sonia Benitez Rivero, Michael Lunn, Jasper Morrow, David Gosal, Timothy Myles Lavin, Isaac Melamed, Alessandro Testori, Senda Ajroud-Driss, Daniela Menichella, Ericka Simpson, Eugene Chi-Ho Lai, Mazen Dimachkie, Richard J. Barohn, Said Beydoun, Harpreet Johl, Dale Lange, Alexander Shtilbans, Suraj Muley, Shafeeq Ladha, Miriam Freimer, John Kissel, Norman Latov, Russell Chin, Eroboghene Ubogu, Sandi Mumfrey, T. Hermanth P. Rao, Paul MacDonald, Khema Sharma, Ginna Gonzalez, Jeffrey Allen, David Walk, Lisa Hobson-Webb, Karissa Gable, Richard A. Lewis, David R. Cornblath, John-Phillip Lawo, Michaela Praus, Billie L. Durn, Hagenacker, Tim (Beitragende*r), Amsterdam Neuroscience - Neuroinfection & -inflammation, AII - Inflammatory diseases, and Neurology

Subjects
medicine.medical_specialty, biology, business.industry, Medizin, Immunoglobulins, Intravenous, Chronic inflammatory demyelinating polyneuropathy, Subcutaneous immunoglobulin, medicine.disease, Gastroenterology, Pharmacokinetics, Internal medicine, biology.protein, medicine, Administration, Intravenous, Neurology (clinical), Antibody, business
Abstract

We thank Ravi Uniyal and colleagues for their comments on our results from the PATH trial1 on subcutaneous immunoglobulin (SCIg) for maintenance treatment in chronic inflammatory demyelinating polyneuropathy (CIDP). They express concern about the relapse rates in the treatment groups and hypothesise the cause being the pharmacokinetics of SCIg.

Published
2018

18. The prevalence of cognitive dysfunction in the estonian population of the hereditary spastic paraplegia

Author

Sulev Haldre, Pille Kool, Katrin Gross-Paju, Liina Vahter, Mark Braschinsky, and Tiina Talvik

Subjects
medicine.medical_specialty, education.field_of_study, medicine.diagnostic_test, Recall, Hereditary spastic paraplegia, Population, Neuropsychology, Cognition, Neuropsychological test, medicine.disease, Physical medicine and rehabilitation, Internal medicine, medicine, Dementia, Verbal memory, Psychology, education
Abstract

The hereditary spastic paraplegias (HSPs) are neu-rodegenerative disorders of the motor system. The information about the prevalence of the cognitive dysfunction in HSP is inconsistent. The aim of the study was to describe the prevalence of cognitive dysfunction and the cognitive profiles of persons with HSP (pwHSP) compared to healthy controls. Subjects. Participating in the cognition study were 48 persons with HSP from the epidemiological study and 48 healthy controls. Of those with HSP, 81% (39/48) had pure and 19% (9/48) had complex forms. Among pwHSP, 20.8% (10/48) had pathogenic and 14.6% (7/48) had non-pathogenic mutations in the SPAST gene. There were no mutations detected in 31 persons with the SPAST gene. Methods. Neuropsychological test battery, MMSE Results. The results of the neuropsychological tests were significantly lower in persons with HSP than in the controls (Bonferroni correction, p < 0.00625). There were statistically significant differences in subtests measuring consistent long term retrieval (p < 0.001), later recall (p = 0.004) in verbal memory and symbol digit modalities (p = 0.0015). Five persons with HSP had an MMSE score of 24 or less. Conclusions. Our results demonstrate that cognitive dysfunction is present in 16.7 to 33.3% of persons with HSP, depending on the criteria applied. There was cognitive dysfunction in 30% of persons with a known pathogenic mutation in the SPAST gene. The most frequently damaged functions in HSP are consistent long term retrieval and later recall in verbal memory and symbol digit modalities tests that discriminate between controls and pwHSP with dysfunction (1.5 SD) in three or more domains. Dementia in HSP is rare.

Published
2012
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19. Changes in Quality of Prehospital Care and Time Delays in Acute Stroke in Tallinn, Estonia from 2005 to 2016

Author

Agnes Reitsnik, Katrin Gross-Paju, Valli Kaljula, Raul Adlas, Karin Kannel, Sandra Ütt, Svetlana Mironenko, Ulvi Thomson, Helle Jaakmees, Kateriine Orav, and Ain Vares

Subjects
Time delays, business.industry, media_common.quotation_subject, Emergency Medicine, medicine, Quality (business), Medical emergency, Emergency Nursing, medicine.disease, business, media_common, Acute stroke
Published
2017
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20. Cognitive dysfunction during anti-NMDA-receptor encephalitis is present in early phase of the disease

Author

Katrin Gross-Paju, Liina Vahter, Tiina Talvik, H. Jaakmees, U. Sorro, and Karin Kannel

Subjects
Anti-NMDA receptor encephalitis, medicine.medical_specialty, Movement disorders, business.industry, Dysautonomia, Cognition, Case Reports, Disease, medicine.disease, Microbiology, Infectious Diseases, Dyskinesia, Medicine, Anxiety, Parasitology, sense organs, medicine.symptom, business, Psychiatry, Neuroscience, Encephalitis
Abstract

Anti-NMDA-receptor encephalitis is an autoimmune disorder with a well-defined set of clinical features including psychiatric changes (anxiety, agitation, bizarre behaviour, delusional or paranoid thoughts), epileptic seizures and cognitive disturbance followed by movement disorders including orofacial dyskinesias, alterations in the level of consciousness and dysautonomia. Although the cognitive changes are not always very clear at presentation, they can persist after recovery from the acute and often prolonged illness. However, there are few studies describing neuropsychiatric changes in depth, both in the early course of the disease and in long-term follow-up.

Published
2014
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21. Cases of dopa-responsive dystonia (Segawa disease) in Estonia

Author

Tiina Talvik, Katrin Gross-Paju, Kadi Veri, Masaya Segawa, and Inga Talvik

Subjects
Estonia, Male, Dopa-Responsive Dystonia, Pediatrics, medicine.medical_specialty, Levodopa, Adolescent, Treatment outcome, MEDLINE, Disease, Developmental Neuroscience, otorhinolaryngologic diseases, Humans, Medicine, Child, Dystonia, business.industry, General Medicine, medicine.disease, nervous system diseases, Treatment Outcome, Child, Preschool, Pediatrics, Perinatology and Child Health, Physical therapy, Female, Neurology (clinical), business, Clinical evaluation, medicine.drug
Abstract

The aim of this report is to present the first four cases from three families of dopa-responsive dystonia diagnosed in Estonia. Diagnosis was performed by clinical evaluation and response to levodopa and was confirmed by gene analyses. The prevalence of dopa-responsive dystonia in Estonia was 1.4 per 100,000 (95%CI=0.39-3.65) children less than 18 years of age. In all children with dystonia it is important to think about possible dopa-responsive dystonia as this is treatable condition and improving the quality of life of children.

Published
2010
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22. Subjective complaints compared to the results of neuropsychological assessment in patients with epilepsy: The influence of comorbid depression

Author

Liina Vahter, Katrin Gross-Paju, Maarika Liik, and Sulev Haldre

Subjects
Adult, Estonia, Male, medicine.medical_specialty, Adolescent, Comorbidity, Neuropsychological Tests, Young Adult, Surveys and Questionnaires, medicine, Humans, Longitudinal Studies, Effects of sleep deprivation on cognitive performance, Neuropsychological assessment, Cognitive skill, Psychiatry, Depression (differential diagnoses), Aged, Psychiatric Status Rating Scales, Epilepsy, medicine.diagnostic_test, Depression, Neuropsychology, Beck Depression Inventory, Cognition, Middle Aged, Neurology, Objective test, Female, Neurology (clinical), Cognition Disorders, Psychology
Abstract

The aim of the study was to compare subjective complaints of epilepsy patients with objective results of neuropsychological assessment and to investigate the possible influence of depression on self-reported complaints. 62 patients from the neurology clinic were included in the study. They were asked to fill the subjective complaints questionnaire, Beck Depression Inventory and a series of neuropsychological tests. The results indicated that self-reported cognitive complaints are not strongly associated with objective tests of different cognitive performance measures. We conclude that the discrepancy between subjective and objective cognitive functioning does not only affect the area of memory but a wide range of cognitive domains. Depression is an important factor influencing the level of different subjective complaints.

Published
2009
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23. The Prevalence of Hereditary Spastic Paraplegia and the Occurrence of SPG4 Mutations in Estonia

Author

Katrin Gross-Paju, Mark Braschinsky, Siiri-Merike Lüüs, and Sulev Haldre

Subjects
Adult, Estonia, Male, Pediatrics, medicine.medical_specialty, Spastin, Adolescent, Epidemiology, Hereditary spastic paraplegia, Prevalence, Young Adult, Genotype, medicine, Humans, Child, Aged, Retrospective Studies, Adenosine Triphosphatases, Spastic Paraplegia, Hereditary, Genetic heterogeneity, business.industry, Middle Aged, medicine.disease, nervous system diseases, Surgery, Multicenter study, Mutation, Female, Neurology (clinical), Paraplegia, business
Abstract

Background: Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous disorder, with a variable reported prevalence ranging from 0.5 to 12 per 100,000. The aim of this retrospective study was to evaluate the prevalence of HSP and estimate the percentage of SPG4 mutations in the Estonian population. Methods: A simple model with multiple data sources was selected to enable as many patients as possible to be detected. All relevant case histories from Estonian regional neurological centers for the last 20 years were reviewed; all neurologists and general practitioners were contacted. Results: A total of 737 case records were captured for secondary evaluation. Among these cases, 88 potential HSP-affected subjects were identified. During this study 59 patients with HSP were identified, giving a crude prevalence rate of 4.4 per 100,000. Eleven persons (21.6% of all studied Estonian HSP patients) with HSP were found to have mutations in the spastin gene (SPG4). Conclusions: Our epidemiological data are comparable with the results from epidemiological studies performed elsewhere, indicating that the clinical diagnostic management of HSP patients in Estonia is adequate and the chosen methodological approach for data collection was reliable.

Published
2008
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24. Comparative Study of Four Instrumented Mobility Analysis Tests on Neurological Disease Patients

Author

Enar Reilent, Alar Kuusik, Heigo Maamagi, and Katrin Gross-Paju

Subjects
Mobility analysis, Robustness (computer science), Computer science, Gait analysis, High variability, Assessment methods, Wearable computer, Disease, Patient assessment, Simulation
Abstract

Wearable inertial sensor systems are widely used for mobility analysis of neurological disease patients. Different assessment methodologies, including - Timed Up and Go, Sit and Stand, walking tests and different sensor configurations are used in practice. Sensor signal processing complexities of competing methods have not been thoroughly investigated. Apparently, computational robustness and noise insensitivity are the key parameters for instrumented mobility monitoring, when automated patient assessment is targeted. This paper describes results of comparisons of 4 different mobility assessment methods conducted on 35 multiple sclerosis patients with variable clinical disability scores. The results demonstrate high variability in inertial sensor signal patterns, even for patients with rather weak disability symptoms. Efficiency of widely used instrumented mobility analysis methodologies is discussed, concluding with the authors' proposals.

Published
2014
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25. A questionnaire assessment of unmet needs for rehabilitation services and resources for people with multiple sclerosis: results of a pilot survey in five European countries

Author

R Bencivenga, P Ketelaer, C Beneton, Paula Kersten, Alan J. Thompson, Katrin Gross-Paju, N Grigoriadis, D.L. McLellan, and M Charlier

Subjects
030506 rehabilitation, medicine.medical_specialty, Rehabilitation, European community, business.industry, medicine.medical_treatment, Public health, Multiple sclerosis, Pilot survey, Physical Therapy, Sports Therapy and Rehabilitation, medicine.disease, Unmet needs, 03 medical and health sciences, Identification (information), 0302 clinical medicine, Family medicine, Needs assessment, medicine, 0305 other medical science, business, 030217 neurology & neurosurgery, Demography
Abstract

Objective: To develop an international services and needs assessment instrument (SUN) for people with multiple sclerosis and their carers and to pilot this in different countries of the European Community. Design: Interview study of people with multiple sclerosis, their carers and nominated key professionals examining the unmet needs of patients and carers. Setting: Belgium, Estonia, Greece, Italy and the United Kingdom. Main outcome measures: Needs assessment questionnaire. Results: The study comprised 137 people with multiple sclerosis, 125 carers and 111 professionals. Patients reported on average 2.9 unmet needs for themselves; their carers and professionals reported on average 2.4. Needs were categorized into seven broad categories. Due to difficulties experienced by the local researchers in distinguishing between needs and objectives a large proportion of needs had to be assigned to the ‘other’ category. Conclusions: The SUN is a valuable and practicable tool for the identification of unmet needs for people with multiple sclerosis and their carers. Formal validation and reliability testing of the different language versions is recommended.

Published
2000
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26. The risk of motor neurone disease and multiple sclerosis is different in Estonians and Russians. Data from South Estonia

Author

Siiri-Merike Lüüs, M. Ööpik, I. Kalbe, Katrin Gross-Paju, and Ain-Elmar Kaasik

Subjects
Adult, Estonia, Male, medicine.medical_specialty, Pediatrics, Multiple Sclerosis, Prevalence, Russia, Risk Factors, Epidemiology, medicine, Humans, Motor Neuron Disease, Amyotrophic lateral sclerosis, High prevalence, business.industry, Multiple sclerosis, Incidence (epidemiology), Middle Aged, University hospital, medicine.disease, Neurology, Female, Neurology (clinical), business, Motor neurone disease
Abstract

Epidemiological studies were performed in South Estonia to establish the prevalence rate of multiple sclerosis (MS) and motor neurone disease (MND). The case finding method included information from the hospital records of the central hospital in the region-the University Hospital (for MS from 1942 to 1989), from all neurologists in the region, from the Estonian MS Society and Association of Muscular Disorders, and from nursing homes in the region. The prevalence day was 31 December 1989. MND incidence was established for the period of 1986-1995. The results demonstrated high prevalence rates of MS among native Estonians (55.3 per 100 000), somewhat lower prevalence among native-born representatives of other nationalities (43.6 per 100 000) and the lowest prevalence rate of MS among non-Estonian immigrants (26.6 per 100 000). The differences were not statistically significant. The results for MND demonstrated the opposite pattern. The mean annual incidence rate of MND for 10 years was statistically significantly higher among people of other nationalities (2.5 per 100 000) and Russians (2.6 per 100 000), and lower in native-born Estonians (1.1 per 100 000). No differences in health care or clinical picture were established. The reasons for the demonstrated differences in MND incidence remain unclear.

Published
1999
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27. Motor neurone disease in South Estonia Diagnosis and incidence rate

Author

M. Ööpik, A.-E. Kaasik, T. Lepik, Katrin Gross-Paju, Siiri-Merike Lüüs, I. Kalbe, and L. Puksa

Subjects
Adult, Diagnostic Imaging, Estonia, Male, medicine.medical_specialty, Pediatrics, Quality Assurance, Health Care, Bulbar Palsy, Progressive, Diagnosis, Differential, Muscular Atrophy, Spinal, Central nervous system disease, Degenerative disease, Epidemiology, medicine, Humans, Motor Neuron Disease, Amyotrophic lateral sclerosis, Developing Countries, Aged, Neurologic Examination, business.industry, Incidence, Incidence (epidemiology), Amyotrophic Lateral Sclerosis, Brain, General Medicine, Middle Aged, Progressive muscular atrophy, University hospital, medicine.disease, Surgery, Cross-Sectional Studies, Neurology, Female, Neurology (clinical), business, Motor neurone disease
Abstract

The current study evaluated the diagnostic standards of MND and epidemiological markers of MND in Estonia. A total of 108 patients were referred to the University Hospital from 1986 to 1995 with the first suggested diagnosis or final diagnosis of amyotrophic syndrome, amyotrophic lateral sclerosis (ALS), progressive bulbar paralysis (PBP) or progressive muscular atrophy (PMA). In addition neurologists of the region and the National Society of Neuromuscular disorders were contacted. Some 94 patients satisfied the diagnostic criteria. The annual incidence rate in South Estonia and in the city of Tartu ranged from 0.5 to 2.8 per 100,000. The mean annual incidence rate in Tartu is 1.98 and in South Estonia in general 1.3. The highest incidence rate was 8.3 for men in the age group 60 to 64 years and 7.49 in the age group 70-74; among female patients the highest incidence rate -4.6 was in the age group from 65 to 69.

Published
1998
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28. 123I-ADAM SPET imaging of serotonin transporter in patients with epilepsy and comorbid depression

Author

Maarika Liik, Katrin Gross-Paju, Sulev Haldre, Liina Vahter, and Malle Paris

Subjects
Adult, Male, Serotonin, medicine.medical_specialty, Neurology, Clinical Neurology, Comorbidity, Gastroenterology, Young Adult, Epilepsy, 123I-ADAM, Internal medicine, medicine, Humans, Neurochemistry, Generalized epilepsy, Psychiatry, Serotonin transporter, Depression (differential diagnoses), Psychiatric Status Rating Scales, Serotonin Plasma Membrane Transport Proteins, Tomography, Emission-Computed, Single-Photon, biology, Depression, business.industry, Cinanserin, Beck Depression Inventory, General Medicine, Middle Aged, medicine.disease, SPET, biology.protein, Female, Neurology (clinical), Radiopharmaceuticals, business, Research Article
Abstract

Background Purpose of the study was to investigate alterations in midbrain serotonin transporter (SERT) binding in patients with epilepsy and symptoms of depression compared to patients with epilepsy with no symptoms of depression. Methods We studied 12 patients with epilepsy (7 patients had focal and 5 had generalized epilepsy syndromes). The presence of self-reported symptoms of depression was assessed using Beck Depression Inventory (BDI) and the Emotional State Questionnaire (EST-Q). The binding potential of the SERT was assessed by performing brain single photon emission tomography (SPET) using the SERT radioligand 2-((2-((dimethylamino)methyl)phenyl)thio)-5-(123)iodophenylamine (123I-ADAM). Results Seven patients had BDI and EST-Q subscale scores greater than 11 points, which was interpreted as the presence of symptoms of depression. We found that 123I-ADAM binding was not significantly different between patients with epilepsy with and without symptoms of depression. In addition, 123I-ADAM binding did not show a significant correlation to either BDI or EST-Q depression subscale scores and did not differ between patients with focal vs. generalized epilepsy. Conclusion The results of our study failed to demonstrate alterations of SERT binding properties in patients with epilepsy with or without symptoms of depression.

Published
2013
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29. Cognitive Profile and Depressive Symptoms in Patients With Epilepsy

Author

Liina Vahter, Katrin Gross-Paju, Sulev Haldre, and Maarika Liik

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Neuropsychological Tests, Audiology, Executive Function, Young Adult, Epilepsy, Cognition, Humans, Medicine, Verbal fluency test, Generalized epilepsy, Aged, cognitive functions, depression, epilepsy, neuropsychology, Psychiatric Status Rating Scales, Depression, business.industry, Beck Depression Inventory, Neuropsychology, General Medicine, Middle Aged, medicine.disease, Cognitive test, Epilepsy, Generalized, Female, Epilepsies, Partial, Verbal memory, Cognition Disorders, business
Abstract

Background and Objective. The aim of the present study was to describe the cognitive profile of patients with focal and generalized epilepsy syndrome in comparison with healthy control subjects and to investigate whether depression was related to neuropsychological functioning in these patients. Material and Methods. A total of 36 patients with focal epilepsy and 26 patients with generalized epilepsy were compared with the control group of healthy volunteers (n=53). A battery of neuropsychological tests assessing verbal and visual spatial memory and executive functioning was carried out in addition to the completion of the Beck Depression Inventory (BDI). Results. The results indicated that patients with epilepsy performed significantly worse than controls on all verbal memory subscales and verbal fluency domains. The patients with focal epilepsy scored significantly worse than the patients with generalized epilepsy. The BDI scores were significantly correlated with several scores of the cognitive test in both patients’ groups but not in the control group. Conclusions. Our results suggest that patients with epilepsy, especially with focal-onset epilepsy, show cognitive disturbances predominantly in the verbal memory domain. In addition, depression was found to have a negative effect on cognitive functioning in patients with epilepsy.

Published
2013
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30. Health-related quality of life in patients with hereditary spastic paraplegia in Estonia

Author

U Krikmann, Katrin Gross-Paju, Sulev Haldre, Kristiina Rannikmae, S-M Lüüs, Mark Braschinsky, and Aire Raidvee

Subjects
Adult, Estonia, Male, Adolescent, Hereditary spastic paraplegia, Health Status, Population, Cohort Studies, Young Adult, Quality of life, medicine, Humans, Young adult, education, Aged, Quality of Health Care, Response rate (survey), education.field_of_study, business.industry, Spastic Paraplegia, Hereditary, General Medicine, Middle Aged, medicine.disease, Mental health, Health Surveys, Neurology, Quality of Life, Observational study, Female, Neurology (clinical), business, Cohort study, Demography
Abstract

Observational population-based cohort study. The main aim of this study was to examine the relative effect of hereditary spastic paraplegia (HSP) on the health-related quality of life (HRQoL). HRQoL was evaluated using a RAND 36-Item Health Survey 1.0 questionnaire. Fifty-eight patients received a questionnaire through mail and signed an informed consent. The results for the control group were obtained from the RAND-36 data collected in 2004 in the European Social Survey. R2.9.0 and Statistica 6.1 were used to analyze the RAND-36 data. The study was performed in Estonia, a country with a population of 1.3 million. Completed questionnaires were received from 49 participants (response rate was 84.5%). The control group consisted of 549 individuals from the Estonian population. Patients with HSP had lower mean scores in all categories as compared with the control group. Six of the eight categories showed significant differences, with P

Published
2010

31. Unique spectrum of SPAST variants in Estonian HSP patients: presence of benign missense changes but lack of exonic rearrangements

Author

Sulev Haldre, Elena Sachez-Ferrero, Christian Beetz, Katrin Gross-Paju, Andres Metspalu, Elve Raukas, Riin Tamm, Mark Braschinsky, Federico Canzian, Siiri-Merike Lüüs, and Catherine Boillot

Subjects
Male, Pathology, Spastin, lcsh:RC346-429, Russia, Exon, 0302 clinical medicine, INDEL Mutation, Missense mutation, Medicine, Child, Adenosine Triphosphatases, Aged, 80 and over, Genetics, 0303 health sciences, education.field_of_study, Exons, General Medicine, Middle Aged, Phenotype, 3. Good health, Female, Adult, Estonia, medicine.medical_specialty, Adolescent, Hereditary spastic paraplegia, Population, Mutation, Missense, Clinical Neurology, Polymorphism, Single Nucleotide, Denaturing high performance liquid chromatography, Young Adult, 03 medical and health sciences, Research article, Humans, Family, Multiplex ligation-dependent probe amplification, education, lcsh:Neurology. Diseases of the nervous system, Aged, 030304 developmental biology, Spastic Paraplegia, Hereditary, business.industry, Genetic heterogeneity, medicine.disease, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Background Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous disorder that can be an autosomal-dominant, autosomal-recessive, or X-linked disease. The most common autosomal-dominant form of the disease derives from mutations in the SPAST gene. Methods The aim of this study was to analyze 49 patients diagnosed with HSP from the Estonian population for sequence variants of the SPAST gene and to describe the associated phenotypes. Healthy control individuals (n = 100) with no family history of HSP were also analyzed. All patient samples were screened using denaturing high performance liquid chromatography (DHPLC) and multiplex ligation-dependent probe amplification (MLPA) assay. Samples with abnormal DHPLC and MLPA profiles were sequenced, with the same regions sequenced in control samples. Results Sequence variants of SPAST were identified in 19/49 HSP patients (38.8%), twelve among them had pathogenic mutations. Within the latter group there was one sporadic case. Eight patients had pure, and four - complex HSP. The twelve variants were identified: seven pathogenic (c.1174-1G>C, c.1185delA, c.1276C>T, c.1352_1356delGAGAA, c.1378C>A, c.1518_1519insTC, c.1841_1842insA) and five non-pathogenic (c.131C>T, c.484G>A, c.685A>G, c.1245+202delG, c.1245+215G>C). Only 2 of these mutations had previously been described (c.131C>T, c.1245+202delG). Three mutations, c.1174-1G>C, c.1276 C>T, c.1378C>A, showed intrafamilial segregation. Conclusion This study identified new variants of the SPAST gene which included benign missense variants and short insertions/deletions. No large rearrangements were found. Based on these data, 7 new pathogenic variants of HSP are associated with clinical phenotypes.

Published
2010

32. Bladder dysfunction in hereditary spastic paraplegia: what to expect?

Author

Katrin Gross-Paju, Mart Kals, Sulev Haldre, Inga Zopp, and Mark Braschinsky

Subjects
Adult, Male, medicine.medical_specialty, Neuromuscular disease, Spastin, Adolescent, Hereditary spastic paraplegia, Urinary system, media_common.quotation_subject, DNA Mutational Analysis, Hyperreflexia, Urination, Central nervous system disease, Young Adult, Internal medicine, medicine, Humans, Urinary Bladder, Neurogenic, Child, Neurogenic bladder dysfunction, media_common, Aged, Ultrasonography, Adenosine Triphosphatases, Urinary bladder, business.industry, Spastic Paraplegia, Hereditary, Middle Aged, medicine.disease, Surgery, Psychiatry and Mental health, Urodynamics, medicine.anatomical_structure, Female, Neurology (clinical), medicine.symptom, business
Abstract

Background Hereditary spastic paraplegia (HSP) comprises a group of rare neurodegenerative disorders characterised by progressive spasticity and hyperreflexia of the legs. Neurogenic bladder dysfunction is a well recognised problem in patients with HSP but it has not yet been described systematically in the literature. The aim of this study was to provide an evidential overview of the ways in which urinary dysfunction presents in HSP. Methods 49 patients with HSP were included and underwent evaluation. A history was followed by a semi-structured interview and, in those patients who consented, measurement of residual volume of urine (PVR) and urodynamic evaluation. Results 38 subjects (77.6%) reported some type of urinary symptom. Subjective complaints of bladder problems showed a correlation with verified urinary dysfunction. There were no significant differences in the occurrence of urinary disturbances between the pure and complex forms of HSP. The most frequent symptoms were incontinence (69.4%), hesitancy (59.2%), increased frequency of micturition (55.1%) and urgency (51.0%). Incomplete bladder emptying was the rarest (36.7%). The most common combination of symptoms was to have all of them (14.3%). Incomplete bladder emptying as a complaint was associated with an increased risk of PVR. Women had a higher risk of increased voiding frequency. Conclusions To our knowledge, this work is the first systematic and disease oriented overview of neurogenic bladder disturbances in patients with HSP. Our results may be useful to the clinicians who work with HSP patients, allowing them to make appropriate screening and management decisions.

Published
2009

33. The prevalence of depression in hereditary spastic paraplegia

Author

Mark Braschinsky, Liina Vahter, Katrin Gross-Paju, and Sulev Haldre

Subjects
Adult, Estonia, Male, medicine.medical_specialty, Pediatrics, Beck depression inventory score, Hereditary spastic paraplegia, Depression, Spastic Paraplegia, Hereditary, Rehabilitation, Beck Depression Inventory, Physical Therapy, Sports Therapy and Rehabilitation, Middle Aged, medicine.disease, Sensitivity and Specificity, Epidemiology, medicine, Physical therapy, Prevalence, Brief Psychiatric Rating Scale, Humans, Female, Psychology, Depression (differential diagnoses)
Abstract

Objective: To evaluate the prevalence of depression and sensitivity and specificity of the single-item interview ‘Are you depressed?’ for people with hereditary spastic paraplegia in Estonia. Design: Single-item interview ‘Are you depressed?’ was used as a screening question for depression; all participants then completed the Beck Depression Inventory. Setting: People with hereditary spastic paraplegia identified from the epidemiological database who agreed to participate in the study. Main measures: Beck Depression Inventory, clinical interview. Results: The epidemiological database consisted of 59 patients with clinically confirmed diagnosis of hereditary spastic paraplegia. Forty-eight of these consented to participate in the study. The Beck Depression Inventory score was higher than cut-off point in 58% (28/48) and lower in 42% (20/48). Of the study group, 44% (21/48) had mild, 13% (6/48) moderate and one person revealed severe depression. There was a statistically significant correlation between Beck Depression Inventory score and level of mobility; no other significant correlations with other measures were detected. Of the participants, 54% (26/48) had subjective complaints about depression and answered ‘Yes’ to the single-item interview ‘Are you depressed?’. The sensitivity of the one-item interview in the hereditary spastic paraplegia group was 75% and specificity 75%. Conclusions: Our results show that mild depression is prevalent among people with hereditary spastic paraplegia. Although the single question may be helpful, it cannot be relied upon entirely when assessing a person for depression.

Published
2009

34. Functional assessment of lower extremities in hereditary spastic paraplegia

Author

Katrin Gross-Paju, Mark Braschinsky, Heigo Maamagi, Kadri Parts, and Sulev Haldre

Subjects
musculoskeletal diseases, Adult, Male, medicine.medical_specialty, Adolescent, Hereditary spastic paraplegia, Modified Ashworth scale, Population, Physical Therapy, Sports Therapy and Rehabilitation, Statistics, Nonparametric, Cohort Studies, Disability Evaluation, Physical medicine and rehabilitation, medicine, Humans, Spasticity, Range of Motion, Articular, education, Child, Gait Disorders, Neurologic, Aged, education.field_of_study, business.industry, Spastic Paraplegia, Hereditary, Rehabilitation, Middle Aged, medicine.disease, Gait, nervous system diseases, Preferred walking speed, Lower Extremity, Physical therapy, Female, medicine.symptom, business, Range of motion, human activities, Cohort study
Abstract

Braschinsky M, Parts K, Maamagi H, Gross-Paju K, Haldre S. Functional assessment of lower extremities in hereditary spastic paraplegia. Objectives To characterize the spasticity and range of motion (ROM) in patients with hereditary spastic paraplegia (HSP) and to correlate these parameters with walking speed. Design An observational population-based cohort study. Setting Patient data were acquired from a population-based epidemiologic study performed earlier in Estonia. Participants Persons (N=46) (mean age, 50.1y) with clinically confirmed HSP diagnosis (mean duration, 20.9y) participated in the study. Interventions Active and passive ROMs were measured with a plastic 360° goniometer. Spasticity was evaluated by using the modified Ashworth scale (MAS). The time it took a patient to walk 10m was recorded. Main Outcome Measures Measurements included testing of active and passive ROM as a marker for mobility, the MAS for spasticity, and time to complete a 10-m walk. Results A higher degree of spasticity in hip muscles was associated with lower values of active ROM and slower walking. Walking speed was negatively correlated to disease duration and participant age. Conclusions The present study provides analysis of the contributions of spasticity and ROM to walking speed in HSP, both factors negatively influence gait in persons with HSP.

Published
2009

35. Clean intermittent self-catheterization in persons with multiple sclerosis: the influence of cognitive dysfunction

Author

Pille Kool, I Zopp, Liina Vahter, Tiina Talvik, M. Kreegipuu, and Katrin Gross-Paju

Subjects
Adult, Male, medicine.medical_specialty, Physical disability, medicine.medical_treatment, Disability Evaluation, Multiple Sclerosis, Relapsing-Remitting, Patient Education as Topic, Medicine, Humans, Cognitive decline, Rehabilitation, Expanded Disability Status Scale, business.industry, Cognitive disorder, Neuropsychology, Cognition, Middle Aged, Multiple Sclerosis, Chronic Progressive, Urinary Retention, medicine.disease, Cognitive test, Self Care, Neurology, Physical therapy, Quality of Life, Female, Neurology (clinical), business, Cognition Disorders, Urinary Catheterization
Abstract

Background Bladder problems are very common in persons with multiple sclerosis (PwMS). Objective The aim of this study was to investigate the ability of PwMS to learn clean intermittent self-catheterization (CISC). Methods The physical disability of 23 PwMS was evaluated with the Expanded Disability Status Scale (EDSS), and cognitive status was evaluated with the Brief Repeatable Battery of Neuropsychological Tests (BRB-N). CISC was taught by the same continence advisor who was blinded to the cognitive test results. The ability to learn CISC was evaluated immediately after sessions and 3 months later. Twenty-three consecutive PwMS participated in the study. Results In all, 87% (20/23) of the PwMS successfully finished CISC training. The number of lessons needed to acquire CISC skills differed significantly depending on the EDSS (Spearman r = 0.682, P = 0.0003), but the total cognitive decline subscore did not influence the ability to learn CISC. Only 13% (3/23) of the PwMS failed to learn CISC. The ability to learn CISC depended on the number of lessons needed to acquire CISC ( r = −0.499, P = 0.0313) and the EDSS score ( r = −0.433, P = 0.0390) but not on the course of the disease ( r = 0.125, P = 0.5696) or on cognitive decline ( r = −0.311, P = 0.1480). After 3 months of follow-up, 30% (6/20) of the PwMS had ceased performing CISC. A follow-up indicated no statistically significant correlations among any of the subscores of the cognitive test battery, the EDSS score, the course of the disease, and the time required to learn CISC and effective bladder management. Conclusions Our study thus confirmed that most (87%) PwMS were able to learn CISC in spite of cognitive dysfunction and therefore to improve their quality of life.

Published
2008

36. One question as a screening instrument for depression in people with multiple sclerosis

Author

Tiina Talvik, Liina Vahter, M. Kreegipuu, and Katrin Gross-Paju

Subjects
Adult, Estonia, Male, medicine.medical_specialty, Multiple Sclerosis, Screening test, Physical Therapy, Sports Therapy and Rehabilitation, Interviews as Topic, 03 medical and health sciences, 0302 clinical medicine, International Classification of Diseases, Intervention (counseling), medicine, Humans, Psychiatry, Screening instrument, Depression (differential diagnoses), Depressive Disorder, Inpatients, Multiple sclerosis, Rehabilitation, Beck Depression Inventory, Reproducibility of Results, medicine.disease, 030227 psychiatry, Mood, Clinical diagnosis, Female, Psychology, 030217 neurology & neurosurgery, Clinical psychology
Abstract

Objective : To evaluate how effectively one question `Are you depressed?' works as a screening tool for depression in people with multiple sclerosis. Design : The results from a single question were compared with formal clinical diagnosis and the classification from a standard questionnaire. Setting : Estonian Multiple Sclerosis Centre, from October 2001 to April 2002. Subjects : One hundred and thirty-four consecutive inpatients with multiple sclerosis. Intervention : During two weeks of inpatient stay the mood disorder was analysed. On the basis of clinical interview and Beck Depression Inventory the diagnosis of depression was confirmed. Main measures : Beck Depression Inventory and structured clinical interview. Results : Fifty-seven per cent (77/134) of people with multiple sclerosis answered `Yes' to the question `Are you depressed?'. The diagnosis of depression was confirmed in 94% (72/77) of people with multiple sclerosis and not confirmed in 6% (5/77). Hence, the screening test sensitivity was 91%. Forty-three per cent (57/134) answered `No'; 70% (40/57) did not have depression. In this case the sensitivity was 54%. In this group 30% (17/57) were actually depressed according to tests and clinical impression. The age, sex, duration of disease, cognitive abilities and physical disability did not influence consistency of the answers with test results and clinical opinion. Conclusions : One-question interview is a useful tool for screening for depression in people with multiple sclerosis as it confirms existing depression (sensitivity 91%), but the results should be treated with caution if the person denies mood problems.

Published
2007

37. Conservative bladder management in advanced multiple sclerosis

Author

M Stagnaro, JC Segal, A. Nordenbo, Dieter Ost, Piet Eelen, Dirk De Ridder, C Beneton, F. Van Der Aa, Katrin Gross-Paju, Cj. Fowler, M. Harper, and H Limbourg

Subjects
030506 rehabilitation, medicine.medical_specialty, Multiple Sclerosis, medicine.medical_treatment, Urinary incontinence, Urinary catheterization, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Intensive care medicine, Rehabilitation, Urinary bladder, Evidence-Based Medicine, business.industry, Evidence-based medicine, medicine.disease, Surgery, Catheter, Sexual dysfunction, medicine.anatomical_structure, Urinary Incontinence, Neurology, Overactive bladder, Practice Guidelines as Topic, Neurology (clinical), medicine.symptom, 0305 other medical science, business, Urinary Catheterization, 030217 neurology & neurosurgery
Abstract

Anticholinergics and intermittent catheterization are the cornerstones of bladder management in early multiple sclerosis (MS). In advanced MS however, bladder management is based more on tradition than on evidence. Nurses seem to deal with catheter problems and chronic incontinence. Despite the abundant use of indwelling catheters, there is a lack for guidelines on catheter-induced problems. The psychosexual and social impact of bladder problems in advanced MS is often neglected. The international multidisciplinary special interest group on sexual, urological and bowel dysfunction in MS (SUBDIMS) as a special interest group of the Rehabilitation in Multiple Sclerosis (RIMS) was confronted with a high variability in practice and a lack of guidelines. A literature review was prepared during three multidisciplinary expert meetings. This review will be the basis of further initiatives to improve the urological treatment of patients with advanced MS.

Published
2005

38. (P2-5) Pre- and in-Hospital Time Delays in Acute Stroke Management in Estonia

Author

Katrin Gross-Paju, R. Adlas, and U. Sorro

Subjects
Time delays, medicine.medical_specialty, business.industry, Emergency medicine, Emergency Medicine, medicine, Emergency Nursing, business, Acute stroke
Abstract

BackgroundShort intervals between stroke onset and thrombolysis determine the efficacy of this procedure. Guidelines for stroke management were introduced in 2005 in the West-Tallinn Stroke Centre and in 2008 in the Tallinn Emergency Medical Services. Since 2006, annual joint stroke meetings of pre- and in-hospital staff have been held. These meetings included analysis of time delays of thrombolyzed patients.ObjectiveThe aim of the study was to analyze changes in time delays in acute stroke management and adherence to treatment guidelines.MethodsPre- and in-hospital data of all consecutive ischemic stroke patients who received intravenous thrombolytic therapy were recorded prospectively at the Stroke Centre. Data from the implementation period of thrombolysis (2005–2008 i.e., 1st period) were compared to recent data from 2009 to 01 September 2010 (2nd period). The data from all stroke patients presenting to ambulance services were analyzed separately from 01 September 2009 to 01 September 2010. Recorded procedures were compared to current treatment guidelines.ResultsA total of 115 patients received thrombolysis at the Stroke Centre. The Alarm Centre assigned the correct priority (C, lights and sirens) for 31% of thrombolyzed patients during the 1st period, and for 80% during the 2nd period. The mean time ambulance personnel spent at the home was 20 minutes during both periods. In-hospital door-to-needle time was < 60 minutes in 11% of patients during the 1st period, and in 56% during the 2nd period. Ambulance personnel treated 1,094 stroke patients during the study. All procedures were performed and documented correctly in 10% of visits. The most frequent deviation from guidelines was under-reported values of blood glucose. In 44.7% of patients, an ECG was performed, which is not required by guidelines.ConclusionsAcute stroke management improved significantly. Adherence to recently developed stroke guidelines in the ambulance services must be improved.

Published
2011
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39. Wearable m-assessment system for neurological disease patients

Author

Muhammad Mahtab Alam, Triin Kask, Katrin Gross-Paju, and Alar Kuusik

Subjects
medicine.medical_specialty, Activities of daily living, Computer science, 010401 analytical chemistry, Wearable computer, Environment controlled, 020206 networking & telecommunications, 02 engineering and technology, Disease, 01 natural sciences, 0104 chemical sciences, Gait (human), Physical medicine and rehabilitation, 0202 electrical engineering, electronic engineering, information engineering, medicine
Abstract

Wearable motion sensors are widely used in monitoring of activities of daily living (ADL). Professional wearable motion trackers are also used for clinical gait and motor performance analysis in a medically controlled environment. We developed a motor condition assessment system for home use that targets patients with progressive neurodegenerative disease (namely multiple sclerosis). The system consists of at least one wearable sensor and an appropriate assessment methodology. Paper describes the technological implementation of the solution and patient trial results conducted during a three-year study at home and in a hospital environment.

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