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2. natalizumab plus interferon beta 1a reduces lesion formation in relapsing multiple sclerosis

Author

RADUE EW, STUART WH, CALABRESI PA, CONFAVREUX C, GALETTA SL, RUDICK RA, LUBLIN FD, WEINSTOCK GUTTMAN B, WYNN DR, FISHER E, PAPDOPOULU A, LYNN F, PANZARA MA, SANDROCK AW, COMI , GIANCARLO, Radue, Ew, Stuart, Wh, Calabresi, Pa, Confavreux, C, Galetta, Sl, Rudick, Ra, Lublin, Fd, WEINSTOCK GUTTMAN, B, Wynn, Dr, Fisher, E, Papdopoulu, A, Lynn, F, Panzara, Ma, Sandrock, Aw, and Comi, Giancarlo

Published
2010

3. Double-blind randomized multicenter dose-comparison study of interferon-β-1a (AVONEX): rationale, design and baseline data

Author

Kristoferitsch, W, Seeldrayers, P, Kyriallis, K, Brochet, B, Confavreux, C, Clanet, M, Cesaro, P, Defer, G, Edan, G, Lyon-Caen, O, Pelletier, J, Rumbach, L, Roullet, E, Vermersch, P, Dengler, R, Zschenderlein, R, Storch-Hagenlocher, B, Sailer, M, Hohlfeld, R, Kunze, KP, Heesen, C, Bamborschke, P, Grunwald, F, Hartung, HP, Rieckmann, P, DeKeyser, J, Montalban, [No Value], Fernandez, U, Arbizu, T, Sandberg, M, Kappos, L, Bates, D, Campbell, MJ, Capildeo, R, Compston, A, McLellan, DL, Wroe, S, Young, C, Radue, EW, Polman, C, Kesselring, J, Thompson, A, Wekerle, H, and Whitehead, J

Subjects
Adult, Male, interferon-beta-1a, Multiple Sclerosis, Interferon-beta, MRI follow-up, Middle Aged, Magnetic Resonance Imaging, dose-comparison study design, 03 medical and health sciences, 0302 clinical medicine, Adjuvants, Immunologic, Double-Blind Method, Neurology, MAGNETIC-RESONANCE, Humans, Multicenter Studies as Topic, Female, 030212 general & internal medicine, Neurology (clinical), RELAPSING MULTIPLE-SCLEROSIS, Interferon beta-1a, 030217 neurology & neurosurgery, Follow-Up Studies, Randomized Controlled Trials as Topic
Abstract

We describe the rationale and design of a double-blind, randomized multicenter, dose-comparison study of interferon-beta-Ia (IFN-beta -Ia: AVONEX(R) in the treatment of relapsing multiple sclerosis (MS). The study is expected to provide quantitative insights on the dose range for optimal clinical benefits in MS. The study involves 802 patients in 10 European countries who have EDSS scores 2.0-5.5, and who have experienced at least two relapses within the 3 years prior to enrolment Patients ore randomized to receive once-weekly intramuscular injections of IFN-beta -Ia 30 or 60 mcg for at least 3 years. The primary endpoint of the study is the effect of IFN-beta -Ia therapy on the time to sustained progression of disability. For patients with a baseline EDSS less than or equal to 4.5, sustained progression of disability is defined as a I point increase in EDSS from baseline, maintained for 6 months. For patients with baseline EDSS less than or equal to 5, sustained progression of disability is defined as reaching on EDSS greater than or equal to 6.0 maintained for 6 months. EDSS scores will be determined every 3 months. A series of prospectively defined secondary and tertiary efficacy endpoints will be examined Safety will be monitored throughout the study. Magnetic resonance imaging (MRI) with and without gadolinium-enhancement has been Performed in at least 358 patients at baseline and repeated annually after enrolment In a subset of these patients, a frequent MRI study is also being performed.

Published
2001
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7. Phase II study of oral fingolimod (FTY720) in multiple sclerosis: 3-year results

Author

Comi, G, O'Connor, P, Montalban, X, Antel, J, Radue, Ew, Karlsson, G, Pohlmann, H, Aradhye, S, Kappos, L, Easton, Jd, Kesselring, J, Weinshenker, Bg, Laupacis, A, Zarbin, M, Calandra, T, Temkin, N, Dimarco, J, Hudson, Ld, Durcan, L, Bar Or, A, Duquette, P, Bernier, G, Freedman, M, Maclean, H, Costello, F, Gray, Ta, Hohol, M, Devonshire, V, Oger, J, Hashimoto, S, Sørensen, Ps, Datta, P, Faber Rod JC, Frederiksen, J, Knudsen, S, Petrenaite, V, Färkkila, M, Harno, H, Halavaara, J, Elovaara, I, Kuusisto, H, Palmio, J, Airas, L, Kaasinen, V, Laaksonen, M, Vermersch, P, Pelletier, J, Feuillet, L, Suchet, L, Mauch, E, Gunser, C, Oberbeck, K, Rieckmann, P, Buttmann, M, Klein, M, Ghezzi, A, Zaffaroni, M, Baldini, S, Mancardi, G, Cioli, F, Capello, E, Rodegher, M, Radaelli, M, Pozzilli, C, Onesti, Emanuela, Romano, Silvia, Czlonkowska, A, Litwin, T, Darda Ledzion, L, Kwiecinski, H, Golebiowski, M, Podlecka, A, Cunha, L, Sousa, L, Matias, F, Pedrosa, R, Almeida, M, Pena, Je, de Sá, J, Ferreira, J, Rosa, M, Arbizu, T, Carmona, O, Casado, V, Tintore, M, Pelayo, R, Arroyo, R, Bartolome, M, De las Heras, V, Casanova, B, Bosca, I, Fernandez, O, Leon, A, Romero, F, Izquierdo, G, Gamero, M, Garcia, Jm, Kuhle, J, Mehling, M, Achtnichts, L, Goebels, N, Skulina, C, Waskoenig, J, Bates, D, Nichols, P, Bendfeldt, K, de Vera, A, Gruenbauer, W., Ben Dahan, David, Centre de résonance magnétique biologique et médicale (CRMBM), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), and Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Oral, Adult, Male, medicine.medical_specialty, Multiple Sclerosis, Time Factors, Adolescent, Phases of clinical research, Administration, Oral, Kaplan-Meier Estimate, Relapsing-Remitting, administration /&/ dosage/adverse effects, Placebo, law.invention, Pulmonary function testing, 03 medical and health sciences, Disability Evaluation, Young Adult, 0302 clinical medicine, Multiple Sclerosis, Relapsing-Remitting, Randomized controlled trial, law, Sphingosine, Internal medicine, Fingolimod Hydrochloride, administration /&/ dosage/adverse effects/analogs /&/ derivatives, medicine, Humans, Adverse effect, business.industry, Fingolimod, Magnetic Resonance Imaging, diagnosis/drug therapy/pathology, Administration, Oral, Adolescent, Adult, Disability Evaluation, Female, Humans, Immunosuppressive Agents, administration /&/ dosage/adverse effects, Kaplan-Meier Estimate, Magnetic Resonance Imaging, Male, Multiple Sclerosis, diagnosis/drug therapy/pathology, Propylene Glycols, administration /&/ dosage/adverse effects, Sphingosine, administration /&/ dosage/adverse effects/analogs /&/ derivatives, Time Factors, Treatment Outcome, Young Adult, 3. Good health, Surgery, Clinical trial, Treatment Outcome, Neurology, Propylene Glycols, 030220 oncology & carcinogenesis, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, Immunosuppressive Agents, medicine.drug
Abstract

In a 6-month, placebo-controlled trial, oral fingolimod (FTY720) 1.25 or 5.0 mg, once daily, significantly reduced MRI inflammatory activity and annualized relapse rate compared with placebo in patients with relapsing multiple sclerosis (MS). The objectives were to monitor the 36-month, interim efficacy and safety results of the ongoing extension of this study. In the extension (months 7—36), placebo-treated patients were re-randomized to either dose of fingolimod; fingolimod-treated patients continued at the same dose. During months 15—24, all patients receiving fingolimod 5.0 mg switched to 1.25 mg. Of the 250 patients who entered the extension study, 173 (69%) continued to month 36. Most patients were free from gadolinium-enhanced lesions (88—89%) or new T2 lesions (70—78%) at month 36. Patients receiving continuous fingolimod treatment had sustained low annualized relapse rates of 0.20—0.21, and 68—73% remained relapse-free at month 36. Over 36 months, nasopharyngitis (34%), headache (30%), fatigue (19%) and influenza (18%) were the most commonly reported adverse events. Pulmonary function remained stable and blood pressure was stable after an initial increase (3—5 mmHg) during the first 6 months of fingolimod treatment; serious adverse events included infections and skin cancer. The low MRI and clinical disease activity at 6 months were maintained at 36 months with fingolimod, which was generally well tolerated by most patients. The efficacy and safety of oral fingolimod are being further evaluated in a large phase III MS study programme.

Published
2010

8. Oral fingolimod (FTY720) in multiple sclerosis: two-year results of a phase II extension study

Author

O'Connor, P, Comi, G, Montalban, X, Antel, J, Radue, Ew, de Vera, A, Pohlmann, H, Kappos, L, Easton, Jd, Kesselring, J, Weinshenker, Bg, Laupacis, A, Zarbin, M, Calandra, T, Temkin, N, Dimarco, J, Hudson, Ld, Durcan, L, Bar Or, A, Duquette, P, Bernier, G, Freedman, M, Maclean, H, Costello, F, Gray, Ta, Hohol, M, Devonshire, V, Hashimoto, S, Sørensen, Ps, Datta, P, Faber Rod JC, Frederiksen, J, Knudsen, S, Petrenaite, V, Harno, H, Färkkila, M, Halavaara, J, Elovaara, I, Kuusisto, H, Palmio, J, Airas, L, Kaasinen, V, Laaksonen, M, Vermersch, P, Pelletier, J, Feuillet, L, Suchet, L, Mauch, E, Gunser, C, Oberbeck, K, Rieckmann, P, Buttmann, M, Klein, M, Ghezzi, A, Zaffaroni, M, Baldini, S, Mancardi, G, Cioli, F, Capello, E, Rodegher, M, Radaelli, M, Pozzilli, C, Onesti, Emanuela, Romano, Silvia, Czlonkowska, A, Litwin, T, Darda Ledzion, L, Kwiecinski, H, Golebiowski, M, Podlecka, A, Nojszewska, K, Cunha, L, Sousa, L, Matias, F, Pedrosa, R, Almeida, M, Pena, Je, de Sá, J, Ferreira, J, Rosa, M, Arbizu, T, Carmona, O, Casado, V, Tintore, M, Pelayo, R, Arroyo, R, Bartolome, M, De las Heras, V, Casanova, B, Bosca, I, Fernandez, O, Leon, A, Romero, F, Izquierdo, G, Gamero, M, Garcia, Jm, Kuhle, J, Mehling, M, Achtnichts, L, Goebels, N, Skulina, C, Waskoenig, J, Bates, D, Nichols, P, Bendfeldt, K, Karlsson, G, Burtin, P, Zubal, T., Oconnor, P., Comi, G., Montalban, X., Antel, J., Radue, E. W., De Vera, A., Pohlmann, H., Kappos, L., and Radaelli, M

Subjects
Male, Time Factors, Administration, Oral, Kaplan-Meier Estimate, Gastroenterology, Severity of Illness Index, law.invention, Immunosuppressive Agent, Disability Evaluation, Randomized controlled trial, law, Oral administration, Sphingosine, hemic and lymphatic diseases, Multiple Sclerosi, administration /&/ dosage, Respiratory Function Test, Incidence, Middle Aged, Fingolimod, Propylene Glycol, Magnetic Resonance Imaging, Respiratory Function Tests, Tolerability, Administration, Female, Oral, Adolescent, Adult, Disability Evaluation, Double-Blind Method, Female, Humans, Immunosuppressive Agents, administration /&/ dosage, Incidence, Kaplan-Meier Estimate, Magnetic Resonance Imaging, Male, Middle Aged, Multiple Sclerosis, drug therapy/mortality, Propylene Glycols, administration /&/ dosage, Respiratory Function Tests, methods, Severity of Illness Index, Sphingosine, administration /&/ dosage/analogs /&/ derivatives, Time Factors, Young Adult, medicine.symptom, Immunosuppressive Agents, medicine.drug, Human, Oral, Adult, medicine.medical_specialty, Multiple Sclerosis, Time Factor, Adolescent, Placebo, methods, Lesion, Young Adult, Double-Blind Method, Internal medicine, administration /&/ dosage/analogs /&/ derivatives, Severity of illness, medicine, drug therapy/mortality, Humans, business.industry, Fingolimod Hydrochloride, Surgery, Clinical trial, Propylene Glycols, Neurology (clinical), business
Abstract

Objective:: To report the results of a 24-month extension of a phase II trial assessing the efficacy, safety, and tolerability of the once-daily oral sphingosine-1-phosphate receptor modulator, fingolimod (FTY720), in relapsing multiple sclerosis (MS). METHODS:: In the randomized, double-blind, placebo-controlled core study, 281 patients received placebo or FTY720, 1.25 or 5.0 mg/day, for 6 months. During the subsequent dose-blinded extension, patients assigned to placebo were re-randomized to either dose of FTY720; those originally assigned to FTY720 continued at the same dose. Patients receiving FTY720 5.0 mg were switched to 1.25 mg during the month 15 to month 24 study visits. RESULTS:: Of 281 patients randomized in the core study, 250 (89%) entered the extension phase, and 189 (75.6%) received treatment for 24 months. During the core study, FTY720 significantly reduced gadolinium-enhanced (Gd) lesions and annualized relapse rate (ARR) compared with placebo, with no differences between doses. During the extension phase, patients who switched from placebo to FTY720 showed clear reductions in ARR and lesion counts compared with the placebo phase; ARR and lesion counts remained low in patients who continued FTY720 treatment. After 24 months, 79 to 91% of patients were free from Gd lesions and up to 77% of patients remained relapse free. FTY720 was well tolerated; no new safety concerns emerged during months 7 to 24 compared with the 6-month core study. CONCLUSIONS:: Once-daily oral treatment with FTY720, 1.25 or 5.0 mg, for up to 2 years, was well tolerated and was associated with low relapse rates and lesion activity. © 2009 AAN Enterprises, Inc.

Published
2009

9. The incidence and significance of anti-natalizumab antibodies: results from AFFIRM and SENTINEL

Author

Calabresi, Pa, Giovannoni, G, Confavreux, C, Galetta, Sl, Havrdova, E, Hutchinson, M, Kappos, L, Miller, Dh, O'Connor, Pw, Phillips, Jt, Polman, Ch, Radue, Ew, Rudick, Ra, Stuart, Wh, Lublin, Fd, Wajgt, A, Weinstock Guttman, B, Wynn, Dr, Lynn, F, Panzara, Ma, Affirm, Investigators, Fazekas, SENTINEL Investigators including: F., Enzinger, C., Seifert, T., Storch, M., Strasser Fuchs, S., Berger, T., Dilitz, E., Egg, R., Eisenhammer, F., Decoo J. Lampaert, D. Decoo J. Lampaert, Bartholome J. Bier, E. Bartholome J. Bier, Stenager, E., Rasmussen, M., Binzer, M., Shorsh, K., Christensen, M., Ravnborg, M., Soelberg Sørensen, P., Blinkenberg, M., Petersen, B., Hansen, H. J., Bech, E., Petersen, T., Kirkegaard, M., Eralinna, J., Ruutiainen, J., Soilu Hänninen, M., Säkö, E., Laaksonen, M., Reunanen, M., Remes, A., Keskinarkaus, I., Moreau, T., Noblet, M., Rouaud, O., Couvreur, G., Edan, G., Lepage, E., Drapier, S., De Burghgraeve, V., Yaouanq, J., Merienne, M., Cahagne, V., Gout, O., Deschamps, R., Le Canuet, P., Moulignier, A., Vermersch, P., De Seze, J., Stojkovic, T., Griffié, G., Engles, A., Ferriby, D., Debouverie, M., Pittionvouyouvitch, S., Lacour, J. C., Pelletier, J., Feuillet, L., Suchet, L., Dalecky, A., Tammam, D., Lubetzki, C., Youssov, K., Mrejen, S., Charles, P., Yaici, S., Clavelou, P., Aufauvre, D., Renouil Guy, N., Cesaro, P., Degos, F., Benisty, S., Rumbach P. Decavel, L. Rumbach P. Decavel, Confavreux, C., Blanc, S., Aubertin, P., Riche, G., Brochet, B., Ouallet, J. C., Anne, O., Menck, S., Grupe, A., Guttman, E., Lensch, E., Fucik, E., Heitmann, S., Hartung, H. P., Schröter, M., Kurz, F. M. W., Heidenreich, F., Trebst, C., Pul, R., Hohlfeld, R., Krumbholz, M., Pellkofer, H., Haas, J., Segert, A., Meyer, R., Anagnostou, P., Kabus, C., Poehlau, D., Schneider, K., Hoffmann, V., Zettl, U., Steinhagen, V., Adler, S., Steinbrecher, A., Rothenfusser Körber, E., Zellner, R., Baum, K., Günther, A., Bläsing, H., Stoll, G., Gold, R., Bayas, A., Kleinschnitz, C., Limmroth, V., Katsarava, Z., Kastrup, O., Haller, P., Stoeve, S., Höbel, D., Oschmann, P., Voigt, K., Burger, C. V., Abramsky D. Karusiss, O. Abramsky D. Karusiss, Achiron, A., Kishner, I., Stern, Y., Sarove Pinhas, I., Dolev, M., Magalashvili, D., Pozzili, C., Lenzi, D., Scontrini, A., Millefiorini, E., Buttinelli, C., Gallo, P., Ranzato, F., Tiberio, M., Perini, P., Laroni, Alice, Marrosu, M., Cocco P. Marchi, E. Cocco P. Marchi, Spinicci, G., Massole, S., Mascia, M., Floris, G., Trojano, M., Bellacosa, A., Paolicelli, D., Bosco Zimatore, G., Simone, I. L., Giorelli, M., Di Monte, E., Mancardi, GIOVANNI LUIGI, Pizzorno, M., Murialdo, A., Narciso, E., Capello, A., Comi, G., Martinelli, V., Rodegher, M., Esposito, F., Colombo, B., Rossi, P., Polman, C. H., Jasperse, M. M. S., Zwemmer, J. N. P., Nielsen, J., Kragt, J. J., Jongen, P. J. H., De Smet, E., Tacken, H., Frequin, S. T. F. M., Siegers, H. P., Mauser, H. W., Fern ez Fern ez, O., León, A., Romero, F., Alonso, A., Tamayo, J., Montalban, X., Nos, C., Pelayo, R., Tellez, N., Rio, J., Tintore, M., Arbizu, T., Romero, L., Moral, E., Martinez, S., Kappos, L., Achtnichts, L., Wilmes, S., Karabudak, R., Kurne, A., Erdem, S., Siva, A., Saip, S., Altintas, A., Atamer, A., Eraksoy, M., Bilgili, F., Topcular, B., Giovannoni ET Lim, G. Giovannoni E. T. Lim, Lava, N., Murnane, M., Dentinger, M., Zimmerman, E., Reiss V. Gupta, M. Reiss V. Gupta, Scott, T., Brillman, J., Kunschner, L., Wright, D., Perel A. Babu, A. Perel A. Babu, Rivera, V., Killian, J., Hutton, G., Lai, E., Picone, M., Cadivid, D., Kamin, S., Shanawani, M., Gauthier, S., Morgan, A., Buckle, G., Margolin, D., Weinstock Guttman, B., Kwen, P. L., Garg, N., Munschauer, F., Khatri, B., Rassouli, M., Saxena, V., Ahmed, A., Turner, A., Fox, E., Couch, C., Tyler, R., Horvit, A., Fodor S. Humphries, P. Fodor S. Humphries, Wynn, D., Nagar, C., O’Brien, D., Allen, N., Turel, A., Friedenberg, S., Carlson, J., Hosey, J., Crayton, H., Richert, J., Tornatore, C., Sirdofsky, M., Greenstein, J., Shpigel, Y., S. M, El, Adbelhak, T., Schmerler, M., Zadikoff, C., Rorick, M., Reed, R., Elias, S., Feit, H., Angus, E., Sripathi, N., Herbert, J., Kiprovski, K., Qu, X., Del Bene, M., Mattson, D., Hingtgen, C., Fleck, J., Horak, H., Kaiser, J. Javerbaum, Elmore, R., Garcia, E., Tasch, E., Gruener, G., Celesia, G., Chawla, J., Miller, A., Drexler, E., Keilson, M., Wolintz, R., Drasby, E., Muscat, P., Belden, J., Sullivan, R., Cohen, J., Stone, L., Marrie, R. A., Fox, R., Hughes, B., Babikian, P., Jacoby, M., Doro, J., Puricelli, M., Rossman, H., Boudoris, W., Belkin, M., Pierce, R., Eggenberger, E., Birbeck, G., Martin, J., Kaufman, D., Stuart, W., English, J. B., Stuart, D. S., Gilbert, R. W., Kaufman, M., Putman, S., Diedrich, A., Follmer, R., Pelletier, D., Waubant, E., Cree, B., Genain, C., Goodin, D., Guarnaccia, J., Patwa, H., Rizo, M., Kitaj, M., Blevins, J., Smith, T., Mcgee, F., Honeycutt, W., Brown, M., Isa, A., Nieves Quinones, D., Krupp, L., Smiroldo, J., Zarif, M., Perkins, C., Sumner, A., Fisher, A., Gutierrez, A., Jacoby, R., Svoboda, S., Dorn, D., Groeschel, A., Steingo R. Kishner, B. Steingo R. Kishner, Cohen, B., Melen, O., Simuni, T., Zee, P., Cohan M. Yerby, S. Cohan M. Yerby, Hendin, B., Levine, T., Tamm, H., Travis, L. H., Freedman, S. M., Tim, R., Ferrell, W., Stefoski, D., Stevens, S., Katsamakis, G., Topel, J., KoD Gelber C. Fortin, M. K. o. D. Gelber C. Fortin, Green, B., Logan, W., Carpenter, D., Temple, L., Sadiq, S., Sylvester, A., Sim, G., Mihai, C., Vertino, M., Jubelt, B., Mejico, L., Phillips, J. T., Martin, A., Heitzman, D., Greenfield, C. F., Riskind, P., Cabo, A., Paskavitz, J., Moonis, M., Bashir, K., Brockington, J., Nicholas, A., Slaughter, R., Archer, R., Harik, S., Haddad, N., Pippenger, M. A., Van den Noort, S., Thai, G., Olek, M., Demetriou, M., Shin, R., Calabresi, P., Rus, H., Bever, C., Johnson, K., Sheremata, W., Delgado, S., Sherbert, R., Herndon, R., Uschmann, H., Ch ler, A., Markowitz, C., Jacobs, D., Balcer, L., Mitchell, G., Chakravorty, S., Heyman, R., Stauber, Z., Goodman, A., Segal, B., Schwid, S., Samkoff, L., Levin, M., Jacewicz, M., Menkes, D., Pulsinelli, W., Frohman, E., Racke, M., Hawker, K., Ulrich, R., Panitch, H., Hamill, R., R. T, On, Dulaney, E., Simnad, V., Miller, J., Wooten, G. F., Harrison, M., Bowen, J., Doherty, M., Wundes, A., Garden, G. A., Distad, J., Kachuck, N., Berkovich, R., Burnett, M., Sahai, S., Ari, D. B, Weiner, L., Storey, J. R., Beesley, B., Hart, D., Moses, H., Sriram, S., Fang, J., O’Duffy, A., Kita, M., Taylor, L., Elliott, M., Roberts, J., Jeffery, D., Maxwell, S., Lefkowitz, D., Kumar, S., Sinclair EW Radue, M. S. i. n. c. l. a. i. r. E. W. Radue, de Vera, A., Bacelar, O., Kuster, P., and Kappos, L. .

Subjects
medicine.medical_specialty, Multiple Sclerosis, Enzyme-Linked Immunosorbent Assay, Relapsing-Remitting, Antibodies, Monoclonal, Humanized, Gastroenterology, Antibodies, law.invention, Disability Evaluation, Natalizumab, Multiple Sclerosis, Relapsing-Remitting, Randomized controlled trial, Double-Blind Method, law, Antibody Specificity, Internal medicine, Monoclonal, medicine, Secondary Prevention, Humans, Adverse effect, Antibodies, Blocking, Humanized, Antibodies, Monoclonal, Brain, Flow Cytometry, Interferon-beta, Magnetic Resonance Imaging, Placebo Effect, Treatment Outcome, Neuroscience (all), Expanded Disability Status Scale, business.industry, Multiple sclerosis, Incidence (epidemiology), Interferon beta-1a, medicine.disease, Blocking, Multiple sclerosis functional composite, Immunology, Neurology (clinical), business, medicine.drug
Abstract

Objective: To determine the incidence and clinical effects of antibodies that develop during treatment with natalizumab. Methods: In two randomized, double-blind, placebo-controlled studies (natalizumab safety and efficacy in relapsing remitting multiple sclerosis [MS, AFFIRM] and safety and efficacy of natalizumab in combination with interferon β-1a [INFβ1a] in patients with relapsing remitting MS [SENTINEL]) of patients with relapsing multiple sclerosis, blood samples were obtained at baseline and every 12 weeks to determine the presence of antibodies against natalizumab. Antibodies to natalizumab were measured using an ELISA. Patients were categorized as “transiently positive” if they had detectable antibodies (≥0.5 μg/mL) at a single time point or “persistently positive” if they had antibodies at two or more time points ≥6 weeks apart. Results: In the AFFIRM study, antibodies were detected in 57 of 625 (9%) of natalizumab-treated patients: Twenty (3%) were transiently positive and 37 (6%) were persistently positive. Persistently positive patients showed a loss of clinical efficacy as measured by disability progression ( p ≤ 0.05), relapse rate ( p = 0.009), and MRI ( p ≤ 0.05) compared with antibody-negative patients. In transiently positive patients, full efficacy was achieved after approximately 6 months of treatment, the time when patients were becoming antibody negative. The incidence of infusion-related adverse events was significantly higher in persistently positive patients. Results of SENTINEL were similar to AFFIRM, except with regard to sustained disability progression; differences between persistently positive and antibody-negative patients were not statistically significant. Conclusions: The incidence of persistent antibody positivity associated with natalizumab is 6%. Reduced clinical efficacy is apparent in persistently positive patients. Patients with a suboptimal clinical response or persistent infusion-related adverse events should be considered for antibody testing. GLOSSARY: BLQ = below the limit of quantification; EDSS = Expanded Disability Status Scale; Gd+ = gadolinium enhancing; IFNβ1a = interferon β-1a; MS = multiple sclerosis; MSFC = multiple sclerosis functional composite; OD = optical density.

Published
2007

10. Health-related quality of life in multiple sclerosis: Effects of natalizumab

Author

Rudick, R. A., Miller, D., Hass, S., Hutchinson, M, Calabresi, P. A., Confavreux, C., Galetta, S. L., Giovannoni, G., Havrdova, E., Kappos, L., Lublin, F. D., Miller, D. H., O'Connor, P. W., Phillips, J. T., Polman, C. H., Radue, Ew, Stuart, W. H., Wajgt, A., Weinstock Guttman, B., Wynn, D. R., Lynn, F., Panzara, M. A., Affirm, Macdonell, SENTINEL Investigators including: R., Hughes, A., Taylor, I., Lee, Y. C., Ma, H., King, J., Kilpatrick, T., Butzkueven, H., Marriott, M., Pollard, J., Spring, P., Spies, J., Barnett, M., Dehaene, I., Vanopdenbosch, L., D’Hooghe, M., Van Zandijcke, M., Derijck, O., Seeldrayers, P., Jacquy, J., Piette, T., De Cock, C., Medaer, R., Soors, P., Vanroose, E., Vanderhoven, L., Nagels, G., Dubois, B., Deville, M. C., D’Haene, R., Jacques, F., Hallé, D., Gagnon, S., Likavcan, E., Murray, T. J., Bhan, V., Mackelvey, R., Maxner, C. E., Christie, S., Giaccone, R., Guzman, D. A., Melanson, M., Esfahani, F., Gomori, A. J., Nagaria, M. H., Grand’Maison, F., Berger, L., Nasreddine, Z., Duplessis, M., Brunet, D., Jackson, A., Pari, G., O’Connor, P., Gray, T., Hohol, M., Marchetti, P., Lee, L., Murray, B., Sahlas, J., Perry, J., Devonshire, V., Hooge, J., Hashimoto, S., Oger, J., Smyth, P., Rice, G., Kremenchutzky, M., Stourac, P., Kadanka, Z., Benesova, Y., Niedermayerova, I., Meluzinova, E., Marusic, P., M, Bojar, Zarubova, K., Houzvicková, E., Piková, J., Talab, R., Faculty, Hospital Olomouc, Olomouc, B. Muchova, Urbánek, K, Kettnerova, Z., Mares, J., Otruba, P., Zapletalová, O., Hradilek, P., Ddolezil, D. Dolezil, Woznicova, I., Höfer, R., Ambler J. Fiedler, Z. Ambler J. Fiedler, Sucha, J., Matousek, V., Rektor, I., Dufek, M., Mikulik, R., Mastik, J., Tyrlikova, I., General, Teaching Hospital, Prague, E. Havrdová, Horakova, D., Kalistová, H., Týblová, M., Ehler, E., Novotná, A., Geier, P., Soelberg Sorensen, P., Ravnborg, M., Petersen, B., Blinkenberg, M., Färkkilä, M., Harno, H., Kallela, M., Häppölä, O., Elovaara, I., Kuusisto, H., Ukkonen, M., Peltola, J., Palmio, J., Pelletier, J., Feuillet, L., Suchet, L., Dalecky, A., Tammam, D., Edan, G., Le Page, E., Mérienne, M., Yaouanq, J., Clanet, M., Mekies, C., Azais Vuillemin, C., Senard, A., Lau, G., Steinmetz, G., Warter V. Wolff, J. Warter V. Wolff, Fleury, M., Tranchant, C., Stark, E., Buckpesch Heberer, U., Henn, K. H., Skoberne, T., Schimrigk, S., Hellwig, K., Brune, N., Weiller, C., Gbadamosi, J., Röther, J., Heesen, C., Buhmann, C., Karageorgiou, C., Korakaki, D., Giannoulis, D. r., Tsiara, S., Thomaides, T., Thomopoulos, I., Papageorgiou, H., Armakola, F., Komoly, S., Rózsa, C., Matolcsi, J., Szabó, G. y., Molnár, B., Lovas, G., Dioszeghy, P., Szulics, P., Magyar, Z., Incze, J., Farkas, J., Clemens, B., Kánya, J., Valicskó, Z. s., Bense, E., Nagy, Z. s., Geréby, G., Perényi, J., Simon, Z. s., Szapper, M., Gedeon, L., Csanyi, A., Rum, G., Lipóth, S., Szegedi, A., Jávor, L., Nagy, I., Adám, I., Szirmai, I., Simó, M., Ertsey, C., I, Amrein, Kamondi, A., Harcos, P., Dobos, E., Szabó, B., Balas, V., Guseo, A., Fodor, E., Jófejü, E., Eizler, K., Csiba, L., Csépány, T., Pallagi, E., Bereczki, D., Jakab, G., Juhász, M., Bszabó, B. Szabó I. Mayer, Katona, G., Hutchinson, M., O’Dwyer, J., O’Rourke, K., Sanders, E. A. C. M., Rijk van Andel, J. F., Bomhof, M. A. M., van Erven, P., Hintzen I. Hoppenbrouwers, R. Q. Hintzen I. Hoppenbrouwers, Neuteboom, R. F., Zemel, D., van Doorn, P. A., Jacobs, B. C., Munster, E. T. h. L. Van, ter Bruggen, J. P., Bernsen, R., Jongen, P. J. H., de Smet, E. A. A., Tacken, H. F. H., Polman, C., Zwemmer, J., Nielsen, J., Kalkers, N., Kragt, J., Jasperse, B., Willoughby, E., Anderson, N. E., Barber, A., Anderson, T., Parkin, P. J., Fink, J., Avery, S., Mason, D., Kwiecinski, H., Zakrzewska Pniewska, B., Kaminska, A., Podlecka, A., Nojszewska, M., Czlonkowska, A., Zaborski, J., Wicha, W., Kruszewska Ozimowska, J., Darda Ledzion, L., Selmaj, K., Mochecka Thoelke, A., Pentela Nowicka, J., Walczak, A., Stasiolek, M., Stelmasiak, Z., Bartosik Psujek, H., Mitosek Szewczyk, K., Belniak, E., Chyrchel, U., Maciejowski, M., Strzyzewska Lubos, L., Lubos, L., Matusik, E., Maciejek, Z., Niezgodzinska Maciejek, A., Sobczynska, D., Slotala, T., Wawrzyniak, S., Kochanowicz K. Kuczynski, J. Kochanowicz K. Kuczynski, Zimnoch, R., Pryszmont, M., Drozdowski, W., Baniukiewicz, E., Kulakowska, A., Borowik, H., Lewonowska, M., Szczudlik, A., Róg, T., Gryz Kurek, E., Pankiewicz, J., Furgal, J., Kimkowicz, A., Fryze, W., Wierbicki, T., Michalak, L., Kowalewska, J., Swiatkiewicz, J., Hillert, J., Åkesson, E, Fredrikson, S., Diener, P, Olsson, T., Wallström, E., Fpiehl, F. Piehl L. Hopia, Brundin, L., Marta, M., Andersson, M., Lycke, J., Runmarker, B., Malmeström, C., Vaghfeldt, P., Skoog, B., Schluep, M., Bogousslavskyr, J., Du Pasquier, R., Achtnichts, L., Kuhle, J., Buitrago Telez, C., Schläger, R., Naegelin, Y., Eraksoy, M., Bebek, N., Akman Demir, G., Topcuoglu, B., Kurtuncu, M., Istanbul, University, Istanbul:, A. Siva, Saip, S., Altintas, A., Kiyat, A., Sharief, M., Kasti, M., Lim, E. T., Rashid, W., Silber, E., Saldanha, G., Hawkins, C., Mamutse, G., Woolmore, J., Hawkes, C., Findley, L., Dasilva, R., Gunasekara, H., Palace, J., Cader, Z., Littleton, E., Burke, G., Sharrack O. Suliman, B. Sharrack O. Suliman, Klaffke, S., Swash, M., Dhillon, H., Bates, D., Westwood, M., Nichol, P., Barnes, D., Wren, D., Stoy, N., Robertson, N., Pickersgill, T., Pearson, O., Lawthom, C., Young, C., Mills, R., Lecky, B., Ford, C., Katzman, J., Rosenberg, G., Cooper, J., Wrubel, B., Richardson, B., Lynch, S., Ridings, L., Mcvey, A., Nowack, W., Rae Grant, A., Mackin, G. A., Castaldo, J. E., Spikol, L. J., Carter, J., Wingerchuk, D., Caselli, R., Dodick, D., Scarberry, S., Bailly, R., Garnaas, K., Haake, B., Rossman, H., Belkin, M., Boudouris, W. D., Pierce, R. P., Mass, M., Yadav, V., Bourdette, D., Whitham, R. H., Heitzman, D., Martin, A., Greenfield, C. F., Agius, M., Richman, D. P., Vijayan, N., Wheelock, V. L., Reder, A., Arnason, B., Noronha, A., Balabanov, R., Ray, A., Sheremata, W., Delgado, S., Shebert, B., Maldonado, J., Bowen, J., Garden, G. A., Distad, B. J., Carrithers, M., Rizzo, M., Vollmer, T., Reiningerova, J., Guarnaccia, J., Lo, A., Richardson, G. B., Fazekas, F., Enzinger, C., Seifert, T., Storch, M., Strasser Fuchs, S., Berger, T., Dilitz, E., Egg, R., Deisenhammer, F., Decoo, : D, Lampaert, J., Bartholome, E., Bier, J., Stenager, : E., Rasmussen, M., Binzer, M., Shorsh, K., Christensen, M., Soelberg Sørensen, P., Hansen, H. J., Bech, E., Petersen, T., Kirkegaard, M., Eralinna, : J., Ruutiainen, J., Soilu Hänninen, M., Säkö, E., Laaksonen, M., Reunanen, M., Remes, A., Keskinarkaus, I., Moreau, : T., Noblet, M., Rouaud, O., Couvreur, G., Lepage, E., Drapier, S., De Burghgraeve, V., Merienne, M., Cahagne, V., Gout, O., Deschamps, R., Le Canuet, P., Moulignier, A., Vermersch, P., De Seze, J., Stojkovic, T., Griffié, G., Engles, Ferriby, D., Debouverie, M., Pittion Vouyouvitch, S., Lacour, J. C., Lubetzki, C., Youssov, K., Mrejen, S., Charles, P., Yaici, S., Clavelou, P., Aufauvre, D., Renouil Guy, N., Cesaro, P., Degos, F., Benisty, S., Rumbach, L., Decavel, P., Blanc, S., Aubertin, P., Riche, G., Brochet, B., Ouallet, J. C., Anne, O., Menck, : S., Grupe, A., Gutmann, E., Lensch, E., Fucik, E., Heitmann, S., Hartung, H. P., Schröter, M., Kurz, F. M. W., Heidenreich, F., Trebst, C., Pul, R., Hohlfeld, R., Krumbholz, M., Pellkofer, H., Haas, J., Segert, A., Meyer, R., Anagnostou, P., Kabus, C., Poehlau, D., Schneider, K., Hoffmann, V., Zettl, U., Steinhagen, V., Adler, S., Steinbrecher E. Rothenfusser Körber, A. Steinbrecher E. Rothenfusser Körber, Zellner, R., Baum, K., Günther, A., Bläsing, H., Stoll, G., Gold, R., Bayas, A., Kleinschnitz, C., Limmroth, V., Katsarava, Z., Kastrup, O., Haller, P., Stoeve, S., Höbel, D., Oschmann, P., Voigt, K., Burger, C. V., Abramsky, : O., Karusiss, D., Achiron, A., Kishner, I., Stern, Y., Sarove Pinhas, I., Dolev, M., Magalashvili, D., Pozzili, : C., Lenzi, D., Scontrini, A., Millefiorini, E., Buttinelli, C., Gallo, P., Ranzato, F., Tiberio, M., Perini, P., Laroni, Alice, Marrosu, M., Cocco P. Marchi, E. Cocco P. Marchi, Spinicci, G., Massole, S., Mascia, M., Floris, G., Trojano, M., Bellacosa, A., Paolicelli, D., Bosco Zimatore, G., Simone, I. L., Giorelli, M., Di Monte, E., Mancardi, GIOVANNI LUIGI, Pizzorno, M., Murialdo, A., Narciso, E., Capello, A., Comi, G., Martinelli, V., Rodegher, M., Esposito, F., Colombo, B., Rossi, P., Polman, : C. H., Jasperse, M. M. S., Zwemmer, J. N. P., Kragt, J. J., De Smet, E., Tacken, H., Frequin, S. T. F. M., Siegers, H. P., Mauser, H. W., Fernandez Fernandez, : O., León, A., Romero, F., Alonso, A., Tamayo, J., Montalban, X., Nos, C., Pelayo, R., Tellez, N., Rio, J., Tintore, M., Arbizu, T., Romero, L., Moral, E., Martinez, S., Kappos, : L., Wilmes, S., Karabudak, : R., Kurne, A., Erdem, S., Siva, A., Atamer, A., Bilgili, F., Topcular, B., Giovannoni, : G., Lava, : N., Murnane, M., Dentinger, M., Zimmerman, E., Reiss, M., Gupta, V., Scott, T., Brillman, J., Kunschner, L., Wright, D., Perel, A., Babu, A., Rivera, V., Killian, J., Hutton, G., Lai, E., Picone, M., Cadivid, D., Kamin, S., Shanawani, M., Gauthier, S., Morgan, A., Buckle, G., Margolin, D., Kwen, P. L., Garg, N., Munschauer, F., Khatri, B., Rassouli, M., Saxena, V., Ahmed, A., Turner, A., Fox, E., Couch, C., Tyler, R., Horvit, A., Fodor, P., Humphries, S., Wynn, D., Nagar, C., O’Brien, D., Allen, N., Turel, A., Friedenberg, S., Carlson, J., Hosey, J., Crayton, H., Richert, J., Tornatore, C., Sirdofsky, M., Greenstein, J., Shpigel, Y., Mandel, S., Adbelhak, T., Schmerler, M., Zadikoff, C., Rorick, M., Reed, R., Elias, S., Feit, H., Angus, E., Sripathi, N., Herbert, J., Kiprovski, K., Qu, X., Del Bene, M., Mattson, D., Hingtgen, C., Fleck, J., Horak, H., Javerbaum, J., Elmore, R., Garcia, E., Tasch, E., Gruener, G., Celesia, G., Chawla, J., Miller, A., Drexler, E., Keilson, M., Wolintz, R., Drasby, E., Muscat, P., Belden, J., Sullivan, R., Cohen, J., Stone, L., Marrie, R. A., Fox, R., Hughes, B., Babikian, P., Jacoby, M., Doro, J., Puricelli, M., Boudoris, W., Pierce, R., Eggenberger, E., Birbeck, G., Martin, J., Kaufman, D., Stuart, W., English, J. B., Stuart, D. S., Gilbert, R. W., Kaufman, M., Putman, S., Diedrich, A., Follmer, R., Pelletier, D., Waubant, E., Cree, B., Genain, C., Goodin, D., Patwa, H., Rizo, M., Kitaj, M., Blevins, J., Smith, T., Mcgee, F., Honeycutt, W., Brown, M., Isa, A., Nieves Quinones, D., Krupp, L., Smiroldo, J., Zarif, M., Perkins, C., Sumner, A., Fisher, A., Gutierrez, A., Jacoby, R., Svoboda, S., Dorn, D., Groeschel, A., Steingo, B., Kishner, R., Cohen, B., Melen, O., Simuni, T., Zee, P., Cohan, S., Yerby, M., Hendin, B., Levine, T., Tamm, H., Travis, L. H., Freedman, S. M., Tim, R., Ferrell, W., Stefoski, D., Stevens, S., Katsamakis, G., Topel, J., Ko, M., Gelber, D., Fortin, C., Green, B., Logan, W., Carpenter, D., Temple, L., Sadiq, S., Sylvester, A., Sim, G., Mihai, C., Vertino, M., Jubelt, B., Mejico, L., Riskind, P., Cabo, A., Paskavitz, J., Moonis, M., Bashir J. Brockington, K. Bashir J. Brockington, Nicholas, A., Slaughter, R., Archer S. Harik, R. Archer S. Harik, Haddad, N., Pippenger, M. A., Van den Noort, S., Thai, G., Olek, M., Demetriou, M., Shin, R., Calabresi, P., Rus, H., Bever, C., Johnson, K., Sherbert, R., Herndon, R., Uschmann, H., Chandler, A., Markowitz, C., Jacobs, D., Balcer, L., Mitchell, G., Chakravorty, S., Heyman, R., Stauber, Z., Goodman, A., Segal, B., Schwid, S., Samkoff, L., Levin, M., Jacewicz, M., Menkes, D., Pulsinelli, W., Frohman, E., Racke, M., Hawker, K., Ulrich, R., Panitch, H., Hamill, R., Tandon, R., Dulaney, E., Simnad, V., Miller, J., Wooten, G. F., Harrison, M., Doherty, M., Wundes, A., Distad, J., Kachuck, N., Berkovich, R., Burnett, M., Sahai, S., Bandari, D., Weiner, L., Storey, J. R., Beesley, B., Hart, D., Moses, H., Sriram, S., Fang, J., O’Duffy, A., Kita, M., Taylor, L., Elliott, M., Roberts, J., Jeffery, D., Maxwell, S., Lefkowitz, D., Kumar, S., Sinclair, M., Radue, E. W., de Vera, A., Bacelar, O., and Kuster, P.

Subjects
Adult, Male, medicine.medical_specialty, Multiple Sclerosis, Visual analogue scale, Health Status, Population, Pain, Comorbidity, Placebo, Antibodies, law.invention, Natalizumab, Randomized controlled trial, Quality of life, Double-Blind Method, law, Internal medicine, Surveys and Questionnaires, Monoclonal, medicine, Prevalence, Humans, Longitudinal Studies, education, Humanized, education.field_of_study, Expanded Disability Status Scale, Neuroscience (all), business.industry, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Female, Patient Satisfaction, Treatment Outcome, United States, Quality of Life, Multiple sclerosis, medicine.disease, Neurology, Physical therapy, Neurology (clinical), business, medicine.drug
Abstract

Objective To report the relationship between disease activity and health-related quality of life (HRQoL) in relapsing multiple sclerosis, and the impact of natalizumab. Methods HRQoL data were available from 2,113 multiple sclerosis patients in natalizumab clinical studies. In the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) study, patients received natalizumab 300mg (n = 627) or placebo (n = 315); in the Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis (SENTINEL) study, patients received interferon beta-1a (IFN-β-1a) plus natalizumab 300mg (n = 589), or IFN-β-1a plus placebo (n = 582). The Short Form-36 (SF-36) and a subject global assessment visual analog scale were administered at baseline and weeks 24, 52, and 104. Prespecified analyses included changes from baseline to week 104 in SF-36 and visual analog scale scores. Odds ratios for clinically meaningful improvement or worsening on the SF-36 Physical Component Summary (PCS) and Mental Component Summary were calculated. Results Mean baseline SF-36 scores were significantly less than the general US population and correlated with Expanded Disability Status Scale scores, sustained disability progression, relapse number, and increased volume of brain magnetic resonance imaging lesions. Natalizumab significantly improved SF-36 PCS and Mental Component Summary scores at week 104 in AFFIRM. PCS changes were significantly improved by week 24 and at all subsequent time points. Natalizumab-treated patients in both studies were more likely to experience clinically important improvement and less likely to experience clinically important deterioration on the SF-36 PCS. The visual analog scale also showed significantly improved HRQoL with natalizumab. Interpretation HRQoL was impaired in relapsing multiple sclerosis patients, correlated with severity of disease as measured by neurological ratings or magnetic resonance imaging, and improved significantly with natalizumab. Ann Neurol 2007

Published
2007

11. The incidence and significance of anti-natalizumab antibodies. Results from the AFFIRM and SENTINEL

Author

Calabresi, Pa, Giovannoni, G, Confavreux, C, Galetta, Sl, Havrdova, E, Hutchinson, M, Kappos, L, Miller, Dh, O'Connor, Pw, Phillips, Jt, Polman, Ch, Radue, Ew, Rudick, Ra, Stuart, Wh, Lublin, Fd, Wajgt, A, Weinstock Guttman, B, Wynn, Dr, Lynn, F, Panzara, Ma, Fazekas, The following investigators participated in the SENTINEL study: F., Enzinger, * C., Seifert, T., Storch, M., Strasser Fuchs, S., Berger, T., Dilitz, * E., Egg, R., Deisenhammer, F., Lampaert, D. Decoo* J., Bier, E. Bartholome* J., Stenager, Denmark: E., Rasmussen, * M., Binzer, M., Ravnborg, M., Soelberg Sørensen, * P., Blinkenberg, M., Petersen, B., Hansen, H. J., Bech, * E., Petersen, T., Kirkegaard, M., Eralinna, J., Ruutiainen, * J., Soilu Hänninen, M., Reunanen, M., Remes, * A., Keskinarkaus, I., Moreau, T., Noblet, * M., Rouaud, O., Couvreur, G., Edan, G., Lepage, * E., Drapier, S., De Burghgraeve, V., Yaouanq, J., Gout, O., Deschamps, * R., Le Canuet, P., Moulignier, A., Vermersch, P., De Seze, * J., Stojkovic, T., Griffié, G., Engles, A., Ferriby, D., Debouverie, M., Pittion Vouyouvitch, * S., Lacour, J. C., Pelletier, J., Feuillet, * L., Suchet, L., Dalecky, A., Tammam, D., Lubetzki, C., Youssov, * K., Mrejen, S., Charles, P., Yaici, S., Clavelou, P., Aufauvre, * D., Renouil Guy, N., Cesaro, P., Degos, * F., Benisty, S., Decavel, L. Rumbach* P., Confavreux, C., Blanc, * S., Aubertin, P., Riche, G., Brochet, B., Ouallet, * J. C., Anne, O., Menck, S., Grupe, * A., Guttman, E., Lensch, E., Fucik, * E., Heitmann, S., Hartung, H. P., Schröter, * M., Kurz, F. M. W., Heidenreich, F., Trebst, * C., Pul, R., Hohlfeld, R., Krumbholz, * M., Pellkofer, H., Haas, J., Segert, * A., Meyer, R., Anagnostou, P., Kabus, C., Poehlau, D., Schneider, * K., Hoffmann, V., Zettl, U., Steinhagen, * V., Adler, S., Steinbrecher, A., Rothenfusser Körber, * E., Zellner, R., Baum, K., Günther, * A., Bläsing, H., Stoll, G., Gold, * R., Bayas, * A., Kleinschnitz, C., Limmroth, V., Katsarava, * Z., Kastrup, O., Haller, P., Stoeve, * S., Höbel, D., Oschmann, P., Voigt, * K., Burger, C. V., Karusiss, O. Abramsky* D., Achiron, A., Kishner, * I., Stern, Y., Sarove Pinhas, I., Dolev, M., Magalashvili, D., Pozzili, C., Lenzi, * D., Scontrini, A., Millefiorini, E., Buttinelli, C., Gallo, Paolo, Ranzato, * F., Tiberio, M., Perini, P., Laroni, A., Marrosu, M., Marchi, * E. Cocco P., Spinicci, G., Massole, S., Mascia, M., Floris, G., Trojano, M., Bellacosa, * A., Paolicelli, D., Bosco Zimatore, G., Simone, I. L., Giorelli, M., Di Monte, E., Mancardi, G., Pizzorno, * M., Murialdo, A., Narciso, E., Capello, A., Comi, G., Martinelli, * V., Rodegher, M., Esposito, F., Colombo, B., Rossi, P., Polman, C. H., Jasperse, * M. M. S., Zwemmer, J. N. P., Nielsen, J., Kragt, J. J., Jongen, P. J. H., De Smet, * E., Tacken, H., Frequin, S. T. F. M., Siegers, * H. P., Mauser, H. W., Fernandez Fernandez, O., León, * A., Romero, F., Alonso, A., Tamayo, J., Montalban, X., Nos, * C., Pelayo, R., Tellez, N., Rio, J., Tintore, M., Arbizu, T., Romero, * L., Moral, E., Martinez, S., Kappos, L., Achtnichts, * L., Wilmes, S., Karabudak, R., Kurne, * A., Erdem, S., Siva, A., Saip, * S., Altintas, A., Atamer, A., Eraksoy, M., Bilgili, * F., Topcular, B., Lim, G. Giovannoni* E. T., Lava, N., Murnane, * M., Dentinger, M., Zimmerman, E., Gupta, M. Reiss* V., Scott, T., Brillman, * J., Kunschner, L., Wright, D., Babu, A. Perel* A., Rivera, V., Killian, * J., Hutton, G., Lai, E., Picone, Bernard W. M., Cadivid, * D., Kamin, S., Shanawani, M., Gauthier, S., Morgan, * A., Buckle, G., Margolin, D., Weinstock Guttman, B., Kwen, * P. L., Garg, N., Munschauer, F., Khatri, B., Rassouli, * M., Saxena, V., Ahmed, A., Turner, A., Fox, E., Couch, * C., Tyler, R., Horvit, A., Humphries, P. Fodor* S., Wynn, D., Nagar, * C., O’Brien, D., Allen, N., Turel, A., Friedenberg, * S., Carlson, J., Hosey, J., Crayton, H., Richert, * J., Tornatore, C., Sirdofsky, M., Greenstein, J., Shpigel, * Y., Mandel, S., Adbelhak, T., Schmerler, M., Zadikoff, * C., Rorick, M., Reed, R., Elias, S., Feit, * H., Angus, E., Sripathi, N., Herbert, J., Kiprovski, * K., Qu, X., Del Bene, M., Mattson, D., Hingtgen, * C., Fleck, J., Horak, H., Javerbaum, J., Elmore, * R., Garcia, E., Tasch, E., Gruener, G., Celesia, * G., Chawla, J., Miller, A., Drexler, * E., Keilson, M., Wolintz, R., Drasby, E., Muscat, * P., Belden, J., Sullivan, R., Cohen, J., Stone, * L., Marrie, R. A., Fox, R., Hughes, B., Babikian, * P., Jacoby, M., Doro, J., Puricelli, M., Rossman, H., Boudoris, * W., Belkin, M., Pierce, R., Eggenberger, E., Birbeck, * G., Martin, J., Kaufman, D., Stuart, W., English, * J. B., Stuart, D. S., Gilbert, R. W., Kaufman, MS M., Putman, . *. S., Diedrich, A., Follmer, R., Pelletier, D., Waubant, * E., Cree, B., Genain, C., Goodin, D., Guarnaccia, J., Patwa, * H., Rizo, M., Kitaj, M., Blevins, Neurolo J., Smith, * T., Mcgee, F., Honeycutt, W., Brown, * M., Isa, A., Nieves Quinones, D., Krupp, L., Smiroldo, * J., Zarif, M., Perkins, C., Sumner, A., Fisher, A., Gutierrez, A., Jacoby, R., Svoboda, * S., Dorn, D., Groeschel, A., Kishner, B. Steingo* R., Cohen, B., Melen, * O., Simuni, T., Zee, P., Yerby, S. Cohan* M., Hendin, B., Levine, * T., Tamm, H., Travis, L. H., Freedman, S. M., Tim, * R., Ferrell, W., Stefoski, D., Stevens, * S., Katsamakis, G., Topel, J., Ko, M., Fortin, D. Gelber* C., Green, B., Logan, * W., Carpenter, D., Temple, L., Sadiq, S., Sylvester, * A., Sim, G., Mihai, C., Vertino, * M., Jubelt, B., Mejico, L., Phillips, J. T., Martin, * A., Heitzman, D., Greenfield, C. F., Riskind, P., Cabo, * A., Paskavitz, J., Moonis, M., Bashir, K., Brockington, * J., Nicholas, A., Slaughter, R., Archer, R., Harik, * S., Haddad, N., Pippenger, M. A., Van den Noort, S., Thai, * G., Olek, M., Demetriou, M., Shin, R., Cala bresi, * P., Rus, H., Bever, C., Johnson, K., Sheremata, W., Delgado, * S., Sherbert, R., Herndon, R., Uschmann, * H., Chandler, A., Markowitz, C., Jacobs, * D., Balcer, L., Mitchell, G., Chakra vorty, * S., Heyman, R., Stauber, Z., Goodman, A., Segal, * B., Schwid, S., Samkoff, L., Levin, M., Jacewicz, * M., Menkes, D., Pulsinelli, W., Frohman, E., Racke, * M., Hawker, K., Ulrich, R., Panitch, H., Hamill, * R., Tandon, R., Dulaney, E., Simnad, V., Miller, * J., Wooten, G. F., Harrison, M., Bowen, J., Doherty, * M., Wundes, A., Garden, G. A., Distad, J., Kachuck, N., Berkovich, * R., Burnett, M., Sahai, S., Bandari, D., Weiner, L., Storey, J. R., Beesley, * B., Hart, D., Moses, H., Sriram, * S., Fang, J., O’Duffy, A., Kita, M., Taylor, * L., Elliott, M., Roberts, J., Jeffery, D., Maxwell, * S., Lefkowitz, D., Kumar, S., and Sinclair, M.

Published
2007

16. Spatiotemporal relations between longitudinal gray matter and white matter lesion changes in multiple sclerosis – A combined parametric and non-parametric voxel-based morphometry study

Author

Bendfeldt, K, primary, Blumhagen, JO, additional, Kuster, P, additional, Traud, S, additional, Egger, H, additional, Naegelin, Y, additional, Gass, A, additional, Hirsch, J, additional, Kappos, L, additional, Matthews, PM, additional, Nichols, TE, additional, Radue, EW, additional, and Borgwardt, SJ, additional

Published
2009
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18. Medial medullary syndrome due to vertebral artery dissection

Author

Radue Ew and Leppert D

Subjects
medicine.medical_specialty, Weakness, genetic structures, Vertebral artery dissection, Vertebral artery, Dissection (medical), Central nervous system disease, Vertigo, medicine.artery, medicine, Humans, Medial medullary syndrome, Vertebral Artery Dissection, Brain Diseases, Medulla Oblongata, Neurological Picture, biology, business.industry, Anatomy, Middle Aged, medicine.disease, biology.organism_classification, Magnetic Resonance Imaging, Gaze, Surgery, Radiography, Psychiatry and Mental health, Female, Neurology (clinical), medicine.symptom, business, Magnetic Resonance Angiography
Abstract

A 61 year old woman presented at the emergency ward with a 3 day history of fluctuating vertigo and lateropulsion to the right. Clinical examination showed slurred speech, conjugated right beating horizontal nystagmus in primary gaze that increased on gaze to the right, and a right sided tongue paresis (figure A). In addition, slight motor weakness, decreased joint position, and vibration sense on the left arm were present. During the next 4 hours a …

Published
2001
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19. Five-year results from a phase 2 study of oral fingolimod in relapsing multiple sclerosis.

Author

Izquierdo, G, O’Connor, P, Montalban, X, von Rosenstiel, P, Cremer, M, de Vera, A, Sfikas, N, Francis, G, Radue, EW, and Kappos, L

Subjects
FINGOLIMOD, MULTIPLE sclerosis, PLACEBOS, PROGNOSIS, MAGNETIC resonance imaging
Abstract

We present here results at 60 months (M), from the extension component of a phase 2, randomized, placebo-controlled, double-blind, six-month study evaluating oral fingolimod (1.25 mg or 5 mg daily) in relapsing multiple sclerosis. Placebo patients from the core study were re-randomized to fingolimod 1.25 mg or 5 mg in the extension. All patients received 1.25 mg fingolimod after the M24 visit. A total of 140/281 (49.8%) patients completed M60. Fingolimod treatment was associated with a low annualized relapse rate (0.2 relapses/ year), low MRI activity, and a modest rate of disability progression in those treated for five years. No new safety issues were reported. [ABSTRACT FROM PUBLISHER]

Published
2014
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20. Prediction of long-term disability in multiple sclerosis.

Author

Schlaeger, R, D’Souza, M, Schindler, C, Grize, L, Dellas, S, Radue, EW, Kappos, L, and Fuhr, P

Subjects
MULTIPLE sclerosis research, EVOKED potentials (Electrophysiology), MAGNETIC resonance imaging, REGRESSION analysis, CLINICAL trials, LOGICAL prediction
Abstract

Background: Little is known about the predictive value of neurophysiological measures for the long-term course of multiple sclerosis (MS).Objective: To prospectively investigate whether combined visual (VEP) and motor evoked potentials (MEP) allow prediction of disability over 14 years.Methods: A total of 30 patients with relapsing–remitting and secondary progressive MS were prospectively investigated with VEPs, MEPs and the Expanded Disability Status Scale (EDSS) at entry (T0) and after 6, 12 and 24 months, and with cranial MRI scans at entry (T2-weighted and gadolinium-enhanced T1-weighted images). EDSS was again assessed at year 14 (T4). The association between evoked potential (EP), magnetic resonance (MR) data and EDSS was measured using Spearman’s rank correlation. Multivariable linear regression was performed to predict EDSST4 as a function of z-transformed EP-latenciesT0. The model was validated using a jack-knife procedure and the potential for improving it by inclusion of additional baseline variables was examined.Results: EDSS valuesT4 correlated with the sum of z-transformed EP-latenciesT0 (rho = 0.68, p < 0.0001), but not with MR-parametersT0. EDSST4 as predicted by the formula EDSST4 = 4.194 + 0.088 * z-score P100T0 + 0.071 * z-score CMCTUE, T0 correlated with the observed values (rho = 0.69, p < 0.0001).Conclusion: Combined EPs allow prediction of long-term disability in small groups of patients with MS. This may have implications for the choice of monitoring methods in clinical trials and for daily practice decisions. [ABSTRACT FROM AUTHOR]

Published
2012
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27. A randomized, double-blind, dose-comparison study of weekly interferon beta-1a in relapsing MS.

Author

Clanet M, Radue EW, Kappos L, Hartung HP, Hohlfeld R, Sandberg-Wollheim M, Kooijmans-Coutinho MF, Tsao EC, Sandrock AW, European IFNß-1a (Avonex) Dose-Comparison Study Investigators, Clanet, M, Radue, E W, Kappos, L, Hartung, H P, Hohlfeld, R, Sandberg-Wollheim, M, Kooijmans-Coutinho, M F, Tsao, E C, Sandrock, A W, and European IFNbeta-1a (Avonex) Dose-Comparison Study Investigators

Published
2002
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28. Metabolic changes in the brain of patients with anorexia and bulimia nervosa as detected by proton magnetic resonance spectroscopy.

Author

Roser W, Bubl R, Buergin D, Seelig J, Radue EW, and Rost B

Abstract

OBJECTIVE: To investigate the brain of patients with anorexia and bulimia nervosa by localized proton magnetic resonance spectroscopy (1H-MRS) and to look for metabolic alterations. METHOD: Twenty patients with anorexia and bulimia nervosa were investigated by magnetic resonance imaging (MRI) and 1H-MRS in three regions of the brain. Age and sex-matched healthy subjects were investigated as controls. RESULTS: 1H-MRS revealed metabolic changes, such as a significant decrease of both myo-inositol and lipid compounds within the frontal white matter. The concentration of these compounds was further reduced with decreasing body mass index. Reduced lipid signals were also found in the occipital gray matter. In the cerebellum, the concentration of all metabolites including water, except lipids, was increased. DISCUSSION: The metabolic changes found in this study seem to be a consequence of nutritional deficiency. It has to be further investigated whether these findings have any relevance for brain function. 1H-MRS might serve as a valuable investigative tool to observe eating disorders as anorexia and bulimia nervosa and to follow the success of therapy. [ABSTRACT FROM AUTHOR]

Published
1999
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31. MRI monitoring of immunomodulation in relapse-onset multiple sclerosis trials.

Author

Barkhof F, Simon JH, Fazekas F, Rovaris M, Kappos L, de Stefano N, Polman CH, Petkau J, Radue EW, Sormani MP, Li DK, O'Connor P, Montalban X, Miller DH, Filippi M, Barkhof, Frederik, Simon, Jack H, Fazekas, Franz, Rovaris, Marco, and Kappos, Ludwig

Abstract

Over the past 15 years, MRI lesion activity has become the accepted surrogate primary outcome measure in proof-of-concept placebo-controlled clinical trials of new immunomodulating therapies in relapse-onset multiple sclerosis (MS). In parallel, the number of patients that are available for the placebo arm of trials has declined, and more-aggressive drugs are being developed. A critical review is warranted to ensure efficient MRI--and patient--resource utilization. Recently, an international panel reviewed the methodology for efficient use of MRI-monitored trials in relapse-onset MS. In this article, we provide up-to-date recommendations for scan acquisition, image analysis, outcome-measure definition and standards of reporting. Factors to consider for optimizing trial design, such as outcome measure selection and the unique requirements of phase II and phase III trials, including active-comparator studies, are outlined. Finally, we address safety considerations in the use of MRI in MS trials, and the safety-related responsibilities of the various parties involved in conducting such trials. [ABSTRACT FROM AUTHOR]

Published
2012
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32. Oral fingolimod (FTY720) for relapsing multiple sclerosis.

Author

Kappos L, Antel J, Comi G, Montalban X, O'Connor P, Polman CH, Haas T, Korn AA, Karlsson G, Radue EW, FTY720 D2201 Study Group, Kappos, Ludwig, Antel, Jack, Comi, Giancarlo, Montalban, Xavier, O'Connor, Paul, Polman, Chris H, Haas, Tomas, Korn, Alexander A, and Karlsson, Goeril

Abstract

Background: Fingolimod (FTY720) is a new oral immunomodulating agent under evaluation for the treatment of relapsing multiple sclerosis.Methods: We randomly assigned 281 patients to receive oral fingolimod, at a dose of 1.25 mg or 5.0 mg, or a placebo once daily, and we followed these patients for 6 months with magnetic resonance imaging (MRI) and clinical evaluations (core study, months 0 to 6). The primary end point was the total number of gadolinium-enhanced lesions recorded on T(1)-weighted MRI at monthly intervals for 6 months. In an extension study in which the investigators and patients remained unaware of the dose assignments (months 7 to 12), patients who received placebo underwent randomization again to one of the fingolimod doses.Results: A total of 255 patients completed the core study. The median total number of gadolinium-enhanced lesions on MRI was lower with 1.25 mg of fingolimod (1 lesion, P<0.001) and 5.0 mg of fingolimod (3 lesions, P=0.006) than with placebo (5 lesions). The annualized relapse rate was 0.77 in the placebo group, as compared with 0.35 in the group given 1.25 mg of fingolimod (P=0.009) and 0.36 in the group given 5.0 mg of fingolimod (P=0.01). For the 227 patients who completed the extension study, the number of gadolinium-enhanced lesions and relapse rates remained low in the groups that received continuous fingolimod, and both measures decreased in patients who switched from placebo to fingolimod. Adverse events included nasopharyngitis, dyspnea, headache, diarrhea, and nausea. Clinically asymptomatic elevations of alanine aminotransferase levels were more frequent with fingolimod (10 to 12%, vs. 1% in the placebo group). One case of the posterior reversible encephalopathy syndrome occurred in the 5.0-mg group. Fingolimod was also associated with an initial reduction in the heart rate and a modest decrease in the forced expiratory volume in 1 second.Conclusions: In this proof-of-concept study, fingolimod reduced the number of lesions detected on MRI and clinical disease activity in patients with multiple sclerosis. Evaluation in larger, longer-term studies is warranted. (Clinicaltrials.gov numbers, NCT00333138 [core study] and NCT00235430 [ClinicalTrials.gov] [extension].). [ABSTRACT FROM AUTHOR]

Published
2006

33. MEsenchymal StEm cells for Multiple Sclerosis (MESEMS): a randomized, double blind, cross-over phase I/II clinical trial with autologous mesenchymal stem cells for the therapy of multiple sclerosis

Author

Uccelli, Antonio, Laroni, Alice, Brundin, Lou, Clanet, Michel, Fernandez, Oscar, Nabavi, Seyed Massood, Muraro, Paolo A., Oliveri, Roberto S., Radue, Ernst W., Sellner, Johann, Soelberg Sorensen, Per, Sormani, Maria Pia, Wuerfel, Jens Thomas, Battaglia, Mario A., Freedman, Mark S., Bonetti, Bruno, Rush, Carolina, Herrera, Concepción, Ramo Tello, Cristina, Miller, David, Szwajcer, David, Strunk, Dirk, Wall, Donna, Aguera-Morales, Eduardo, Rohde, Eva, Dazzi, Francesco, Comi, Giancarlo, Martino, Gianvito, Izquierdo Ayuso, Guillermo, Rabinovitch, H., MacLean, Heather, Marriott, James, Racosta, Juan, Arab, Leila, Gimona, Mario, Introna, Martino, Blinkenberg, Morten, Aghdami, Naser, Ali, Rehiana, Vosoughi, Reza, Nicholas, Richard, Marrie, Ruth Ann, Karimi, Shahedeh, The UK Stem Cell Foundation, Multiple Sclerosis Society, MESEMS study group, [Uccelli,A, Laroni,A] Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health and Center of Excellence for Biomedical Research (CEBR), University of Genova, Genoa, Italy. [Uccelli,A, Laroni,A] IRCCS Ospedale Policlinico San Martino, Genoa, Italy. [Brundin,L] Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden [Clanet,M] CHU Toulouse, Université Paul Sabatier, Toulouse, France. [Fernandez,O] Instituto de Investigación Biomédica de Málaga (IBIMA), Regional University Hospital of Malaga, Malaga, Spain. [Nabavi,SM] Department of Brain and Cognitive Sciences, Royan Institute for Stem Cell Biology and Technology, Royan, Iran. [Nabavi,SM] ACCR, Iran and Regenerative Biomedicine Center, MS, Neurology Clinic and Research Unit, Tehran, Iran. [Muraro,PA] Department of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK. [Oliveri,RS] Cell Therapy Unit, Department of Clinical Immunology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. [Radue,EW, Wuerfel,JT] Medical Image Analysis Centre Basel (MIAC AG), Basel, Switzerland. [Sellner,J] Department of Neurology, Christian Doppler Medical Center, Paracelsus Medical University, Salzburg, Austria. [Soelberg Sorensen,P] Danish MS Center Department of Neurology, University of Copenhagen and Rigshospitalet, Copenhagen, Denmark. [Sormani,MP] Department of Health Sciences, University of Genoa, Genoa, Italy. [Wuerfel,JT] Department of Biomedical Engineering, University Basel, Basel, Switzerland. [Battaglia,MA] Italian Multiple Sclerosis Foundation, Genoa, Italy. [Battaglia,MA] Department of Life Sciences, University of Siena, Siena, Italy. [Freedman,MS] Department of Medicine (Neurology), University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada., The MESEMS network received a grant from Fondazione Italiana Sclerosi Multipla (FISM, sponsor of the Italian Clinical Trial, of the CRO activities and of part of centralized MRI activities), European Committee for Multiple Sclerosis (ECTRIMS), Multiple Sclerosis International Foundation (MSIF) for centralized activities. Individual trials participating in the MESEMS network are funded by: FISM (Italy), The Danish Multiple Sclerosis Society, The Toyota Foundation, and Danish Blood Donors’ Research Foundation (Denmark), Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, Salzburg, Austria (Austria), ARSEP Foundation, AFM (France). The UK trial (London) is supported by a Collaborative Grant from the UK MS Society [938/10], by the NIHR Biomedical Research Centre funding scheme to Imperial College and by the NIHR Imperial Clinical Research Facility., Uccelli, A., Laroni, A., Brundin, L., Clanet, M., Fernandez, O., Nabavi, S. M., Muraro, P. A., Oliveri, R. S., Radue, E. W., Sellner, J., Soelberg Sorensen, P., Sormani, M. P., Wuerfel, J. T., Battaglia, M. A., Freedman, M. S., Bonetti, B., Rush, C., Herrera, C., Ramo Tello, C., Miller, D., Szwajcer, D., Strunk, D., Wall, D., Aguera-Morales, E., Rohde, E., Dazzi, F., Comi, G., Martino, G., Izquierdo Ayuso, G., Rabinovitch, H., Maclean, H., Marriott, J., Racosta, J., Arab, L., Gimona, M., Introna, M., Blinkenberg, M., Aghdami, N., Ali, R., Vosoughi, R., Nicholas, R., Marrie, R. A., and Karimi, S.

Subjects
Male, Time Factors, Phenomena and Processes::Physical Phenomena::Time::Time Factors [Medical Subject Headings], Mesenchymal stromal cells, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Diagnostic Imaging::Magnetic Resonance Imaging [Medical Subject Headings], Medicine (miscellaneous), Phases of clinical research, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Surgical Procedures, Operative::Transplantation::Transplantation, Autologous [Medical Subject Headings], NEUROLOGICAL DISEASES, Research & Experimental Medicine, Geographical Locations::Geographic Locations::Europe::Europe, Eastern [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Clinical Trials as Topic::Clinical Trials, Phase I as Topic [Medical Subject Headings], Study Protocol, Disability Evaluation, Clinical trial, Mesenchymal stem cells, Mesenchymal stromal cells, Multiple sclerosis, 0302 clinical medicine, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Clinical Trials as Topic::Multicenter Studies as Topic [Medical Subject Headings], Multicenter Studies as Topic, Pharmacology (medical), 030212 general & internal medicine, 1102 Cardiorespiratory Medicine and Haematology, Randomized Controlled Trials as Topic, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Clinical Trials as Topic::Controlled Clinical Trials as Topic::Randomized Controlled Trials as Topic [Medical Subject Headings], Cross over, lcsh:R5-920, Cross-Over Studies, Clinical Trials, Phase I as Topic, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Clinical Trials as Topic::Clinical Trials, Phase II as Topic [Medical Subject Headings], Middle Aged, Magnetic Resonance Imaging, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Disability Evaluation [Medical Subject Headings], Clinical trial, Europe, Treatment Outcome, Medicine, Research & Experimental, EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS, Female, lcsh:Medicine (General), Autologous, Life Sciences & Biomedicine, Adult, medicine.medical_specialty, Multiple Sclerosis, Adolescent, Células madre mesenquimatosas, Check Tags::Male [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Surgical Procedures, Operative::Transplantation::Cell Transplantation::Stem Cell Transplantation::Mesenchymal Stem Cell Transplantation [Medical Subject Headings], Phase I as Topic, Diseases::Nervous System Diseases::Autoimmune Diseases of the Nervous System::Demyelinating Autoimmune Diseases, CNS::Multiple Sclerosis [Medical Subject Headings], Mesenchymal Stem Cell Transplantation, Placebo, Transplantation, Autologous, Persons::Persons::Age Groups::Adolescent [Medical Subject Headings], Double blind, Young Adult, 03 medical and health sciences, Clinical Trials, Phase II as Topic, Double-Blind Method, General & Internal Medicine, Internal medicine, Ensayo clínico, medicine, Humans, Clinical Trials, Persons::Persons::Age Groups::Adult [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Prognosis::Treatment Outcome [Medical Subject Headings], Science & Technology, TRANSPLANTATION, business.industry, Multiple sclerosis, Phase II as Topic, Mesenchymal stem cell, MESEMS study group, Persons::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings], 1103 Clinical Sciences, Recovery of Function, medicine.disease, Phenomena and Processes::Biological Phenomena::Recovery of Function [Medical Subject Headings], Transplantation, Check Tags::Female [Medical Subject Headings], Cardiovascular System & Hematology, Esclerosis múltiple, Mesenchymal stem cells, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Research Design::Cross-Over Studies [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Research Design::Double-Blind Method [Medical Subject Headings], business, 030217 neurology & neurosurgery
Abstract

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system with a degenerative component, leading to irreversible disability. Mesenchymal stem cells (MSC) have been shown to prevent inflammation and neurodegeneration in animal models of MS, but no large phase II clinical trials have yet assessed the exploratory efficacy of MSC for MS. This is an academic, investigator-initiated, randomized, double-blind, placebo-compared phase I/II clinical trial with autologous, bone-marrow derived MSC in MS. Enrolled subjects will receive autologous MSC at either baseline or at week 24, through a cross-over design. Primary co-objectives are to test safety and efficacy of MSC treatment compared to placebo at 6 months. Secondary objectives will evaluate the efficacy of MSC at clinical and MRI levels. In order to overcome funding constraints, the MEsenchymal StEm cells for Multiple Sclerosis (MESEMS) study has been designed to merge partially independent clinical trials, following harmonized protocols and sharing some key centralized procedures, including data collection and analyses. Results will provide patients and the scientific community with data on the safety and efficacy of MSC for MS. The innovative approach utilized to obtain funds to support the MESEMS trial could represent a new model to circumvent limitation of funds encountered by academic trials. Andalusia: NCT01745783 , registered on Dec 10, 2012. Badalona: NCT02035514 EudraCT, 2010–024081–21. Registered on 2012. Canada: ClinicalTrials.gov, NCT02239393 . Registered on September 12, 2014. Copenhagen: EudraCT, 2012–000518-13 . Registered on June 21, 2012. Italy: EudraCT, 2011–001295-19, and ClinicalTrials.gov, NCT01854957 . Retrospectively registered on May 16, 2013. London: Eudra CT 2012–002357-35, and ClinicalTrials.gov, NCT01606215 . Registered on May 25, 2012. Salzburg: EudraCT, 2015–000137-78 . Registered on September 15, 2015. Stockholm: ClinicalTrials.gov, NCT01730547 . Registered on November 21, 2012. Toulouse: ClinicalTrials.gov, NCT02403947 . Registered on March 31, 2015.

Published
2019
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34. The Swiss Multiple Sclerosis Cohort-Study (SMSC): A Prospective Swiss Wide Investigation of Key Phases in Disease Evolution and New Treatment Options

Author

Ludwig Kappos, Till Sprenger, Jens Kuhle, Johannes Lorscheider, Krassen Nedeltchev, Simon Ramseier, Oliver Findling, Ernst-Wilhelm Radue, Jean-François Louvion, Myriam Schluep, Giulio Disanto, Lutz Achtnichts, Renaud Du Pasquier, Claudio Gobbi, Christoph Stippich, Heinrich Mattle, Jochen Vehoff, Patrice H. Lalive, Pascal Benkert, Chiara Zecca, Christoph Lotter, Özgür Yaldizli, Smsc Scientific Board, Tobias Derfuss, Caroline Pot, Christian P. Kamm, Stefanie Karin Mueller, SMSC Scientific, Board, Ramseier, S., Achtnichts, L., Findling, O., Saxer, J., Nedeltchev, K., Remonda, L., Boxheimer, L., Kuhle, J., Kappos, L., Yaldizli£££Özguer£££ Ö., Derfuss, T., Sprenger, T., Limberg, M., Scheerer, I., Orleth, A., Treppke, F., Beregi, E., Stippich, C., Reinhardt, J., Fellner, I., Würfel, J., Radue, EW., Thoeni, A., Palatini, A., Pauli-Magnus, C., Fabbro, T., Benkert, P., Roesler, A., Mechati, S., Louvion, JF., Kamm, C., Chan, A., Mattle, H., Salmen, A., Kaeser, M., Wagner, F., Verma, R., Lalive, P., Di Marco, M., Haller, S., Lovblad, KO., Du Pasquier, R., Schluep, M., Pot, C., Granziera, C., Hagmann, P., Maeder, P., Gobbi, C., Zecca, C., Disanto, G., Tschuor, S., Cianfoni, A., Müller, S., Vehoff, J., Weber, J., and Lotter, C.

Subjects
Male, 0301 basic medicine, Physiology, Adult, Biomarkers/blood, Biomarkers/cerebrospinal fluid, Brain/radiography, Cohort Studies, Demography, Female, Fingolimod Hydrochloride/therapeutic use, Follow-Up Studies, Humans, Immunosuppressive Agents/therapeutic use, Magnetic Resonance Imaging, Middle Aged, Multiple Sclerosis/diagnosis, Multiple Sclerosis/drug therapy, Natalizumab/therapeutic use, Prognosis, Prospective Studies, Recurrence, Switzerland, lcsh:Medicine, ddc:616.07, Nervous System, Diagnostic Radiology, Geographical Locations, 0302 clinical medicine, Natalizumab, Medicine and Health Sciences, Medicine, 10. No inequality, Prospective cohort study, lcsh:Science, Cerebrospinal Fluid, Multidisciplinary, Clinically isolated syndrome, Radiology and Imaging, Brain, Neurodegenerative Diseases, Fingolimod, Body Fluids, 3. Good health, Europe, Neurology, Research Design, Cohort, Observational Studies, Anatomy, Immunosuppressive Agents, Research Article, medicine.drug, Cohort study, medicine.medical_specialty, Multiple Sclerosis, Imaging Techniques, Immunology, Research and Analysis Methods, Autoimmune Diseases, 03 medical and health sciences, Diagnostic Medicine, Internal medicine, Expanded Disability Status Scale, Fingolimod Hydrochloride, business.industry, Multiple sclerosis, lcsh:R, Biology and Life Sciences, medicine.disease, Demyelinating Disorders, Long-Term Care, Surgery, Health Care, Radiography, 030104 developmental biology, People and Places, Clinical Immunology, lcsh:Q, Clinical Medicine, business, Biomarkers, 030217 neurology & neurosurgery
Abstract

The mechanisms leading to disability and the long-term efficacy and safety of disease modifying drugs (DMDs) in multiple sclerosis (MS) are unclear. We aimed at building a prospective cohort of MS patients with standardized collection of demographic, clinical, MRI data and body fluids that can be used to develop prognostic indicators and biomarkers of disease evolution and therapeutic response. The Swiss MS Cohort (SMSC) is a prospective observational study performed across seven Swiss MS centers including patients with MS, clinically isolated syndrome (CIS), radiologically isolated syndrome or neuromyelitis optica. Neurological and radiological assessments and biological samples are collected every 6-12 months. We recruited 872 patients (clinically isolated syndrome [CIS] 5.5%, relapsing-remitting MS [RRMS] 85.8%, primary progressive MS [PPMS] 3.5%, secondary progressive MS [SPMS] 5.2%) between June 2012 and July 2015. We performed 2,286 visits (median follow-up 398 days) and collected 2,274 serum, plasma and blood samples, 152 cerebrospinal fluid samples and 1,276 brain MRI scans. 158 relapses occurred and expanded disability status scale (EDSS) scores increased in PPMS, SPMS and RRMS patients experiencing relapses. Most RRMS patients were treated with fingolimod (33.4%), natalizumab (24.5%) or injectable DMDs (13.6%). The SMSC will provide relevant information regarding DMDs efficacy and safety and will serve as a comprehensive infrastructure available for nested research projects.

Published
2016

35. Predictive value of gadolinium-enhanced magnetic resonance imaging for relapse rate and changes in disability or impairment in multiple sclerosis: a meta-analysis

Author

Kati Schweikert, Claudio Gasperini, Frederik Barkhof, Andreas Schoetzau, David Moeri, Ludwig Kappos, Ernst Wilhelm Radue, David Miller, Howard L. Weiner, Massimo Filippi, Charles R.G. Guttmann, VU University medical center, Kappos, L, Moeri, D, Radue, Ew, Schoetzau, A, Schweikert, K, Barkhof, F, Miller, D, Guttmann, Crg, Weiner, Hl, Gasperini, C, and Filippi, Massimo

Subjects
medicine.medical_specialty, Expanded Disability Status Scale, medicine.diagnostic_test, business.industry, Multiple sclerosis, Magnetic resonance imaging, General Medicine, Odds ratio, medicine.disease, Central nervous system disease, Lesion, Meta-analysis, Relative risk, medicine, Radiology, medicine.symptom, business, Nuclear medicine
Abstract

Summary Background Reliable prognostic factors are lacking for multiple sclerosis (MS). Gadolinium enhancement in magnetic resonance imaging (MRI) of the brain detects with high sensitivity disturbance of the blood-brain barrier, an early event in the development of inflammatory lesions in MS. To investigate the prognostic value of gadolinium-enhanced MRI, we did a meta-analysis of longitudinal MRI studies. Methods From the members of MAGNIMS (European Magnetic Resonance Network in Multiple Sclerosis) and additional centres in the USA, we collected data from five natural-course studies and four placebo groups of clinical trials completed between 1992 and 1995. We included a total of 307 patients, 237 with relapsing disease course and 70 with secondary progressive disease course. We investigated by regression analysis the relation between initial count of gadolinium-enhancing lesions and subsequent worsening of disability or impairment as measured by the expanded disability status scale (EDSS) and relapse rate. Findings The relapse rate in the first year was predicted with moderate ability by the mean number of gadolinium-enhancing lesions in monthly scans during the first 6 months (relative risk per five lesions 1·13, p=0·023). The predictive value of the number of gadolinium-enhancing lesions in one baseline scan was less strong. The best predictor for relapse rate was the variation (SD) of lesion counts in the first six monthly scans which allowed an estimate of relapse in the first year (relative risk 1·2, p=0·020) and in the second year (risk ratio=1·59, p=0·010). Neither the initial scan nor monthly scans over six months were predictive of change in the EDSS in the subsequent 12 months or 24 months. The mean of gadolinium-enhancing-lesion counts in the first six monthly scans was weakly predictive of EDSS change after 1 year (odds ratio=1·34, p=0·082) and 2 years (odds ratio=1·65, p=0·049). Interpretation Although disturbance of the blood-brain barrier as shown by gadolinium enhancement in MRI is a predictor of the occurrence of relapses, it is not a strong predictor of the development of cumulative impairment or disability. This discrepancy supports the idea that variant pathogenetic mechanisms are operative in the occurrence of relapses and in the development of long-term disability in MS.

Published
1999
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36. Magnetic resonance imaging pattern in natalizumab-associated progressive multifocal leukoencephalopathy

Author

Diego Cadavid, Massimo Filippi, Nancy Richert, Tarek A. Yousry, Daniel Pelletier, Achim Gass, Ernst Wilhelm Radue, Yousry, Ta, Pelletier, D, Cadavid, D, Gass, A, Richert, Nd, Radue, Ew, and Filippi, Massimo

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Multiple Sclerosis, Time Factors, Antibodies, Monoclonal, Humanized, White matter, Leukoencephalopathy, Natalizumab, Immune reconstitution inflammatory syndrome, Image Processing, Computer-Assisted, Product Surveillance, Postmarketing, medicine, Humans, Retrospective Studies, medicine.diagnostic_test, business.industry, Progressive multifocal leukoencephalopathy, Multiple sclerosis, Leukoencephalopathy, Progressive Multifocal, Brain, Magnetic resonance imaging, Retrospective cohort study, Middle Aged, medicine.disease, Magnetic Resonance Imaging, medicine.anatomical_structure, Neurology, Female, Neurology (clinical), Radiology, business, Follow-Up Studies, medicine.drug
Abstract

Objective: Natalizumab is an effective treatment for patients with multiple sclerosis (MS) that is associated with a risk of progressive multifocal leukoencephalopathy (PML). Recommendations were published in 2006 to improve early diagnosis of PML using magnetic resonance imaging (MRI). However, due to the small number of MS patients initially diagnosed with PML, the imaging criteria could only be derived from PML lesions in patients with human immunodeficiency virus. Therefore, there is an urgent need to assess the MRI characteristics of PML in MS patients to update the existing recommendations. Methods: In this retrospective review, the first 40 natalizumab-treated MS patients diagnosed with PML in the postmarketing setting were identified, of whom 22 (10 with clinically diagnosed immune reconstitution inflammatory syndrome) fulfilled the inclusion criteria for this study. Magnetic resonance images were analyzed according to predefined criteria by 5 independent readers. Results: The most frequent lesion pattern in early scans from PML patients was that of large (>3 cm, 15 of 18), subcortical (18 of 18), T2 or fluid-attenuated inversion recovery hyperintense (18 of 18), T1-hypointense (17 of 18), and diffusion-hyperintense (15 of 15) lesions, with a sharp border toward the gray matter and an ill-defined border toward the white matter (18 of 18) on T2-weighted images. We could detect contrast enhancement in 41% (7 of 17) of the cases on the first scan at clinical presentation. Interpretation: Attention to characteristic MRI patterns, especially the presence of contrast enhancement, and the subcortical location may have utility in screening and early diagnosis of PML in natalizumab-treated MS patients. ANN NEUROL 2012;72:779–787

Published
2012

37. Improving interobserver variation in reporting gadolinium-enhanced MRI lesions in multiple sclerosis

Author

J.H.T.M. van Waesberghe, G. J. Lycklama à Nijeholt, H.J. Adèr, Niall Tubridy, P D Molyneux, David Miller, E. W. Radue, Tarek A. Yousry, Marco Rovaris, Frederik Barkhof, Massimo Filippi, Barkhof, F, Filippi, Massimo, van Waesberghe, Jh, Molyneux, P, Rovaris, M, Nijeholt, Gla, Tubridy, N, Miller, Dh, Yousry, Ta, Radue, Ew, and Ader, Hj

Subjects
Observer Variation, Analysis of Variance, medicine.medical_specialty, Multiple Sclerosis, business.industry, Multiple sclerosis, Brain, Consensus formation, Gadolinium, Lesion types, medicine.disease, Magnetic Resonance Imaging, Education, Surgery, Outcome parameter, Disease activity, Central nervous system disease, Interobserver Variation, Practice Guidelines as Topic, medicine, Humans, Neurology (clinical), Radiology, business, Kappa
Abstract

Gadolinium-enhanced MRI is a sensitive and objective means to monitor disease activity in multiple sclerosis (MS). We evaluated the interobserver agreement and the value of observer training in reporting enhancing lesions from serial MRI. Scans of 16 MS patients were evaluated by five inexperienced and five experienced observers before and after consensus formation and training. The number of lesions at baseline, and the number of new and persistent lesions at follow-up were scored. For each condition, weighted kappa values (kappa) and the mean average difference to the median (MADM) scores were calculated. Without training, the experienced readers showed good agreement on number of lesions at baseline and new lesions at follow-up, and moderate agreement for persistent lesions. The inexperienced readers showed poor agreement for baseline and persistent lesions, and moderate agreement for new lesions. After training, both groups reported lower absolute numbers of lesions, especially the inexperienced readers. The experienced readers showed good agreement for all lesion types, the inexperienced readers showed agreement for baseline and new lesions, and agreement was moderate for persistent lesions. In both groups MADM scores were0.72 for baseline and new lesions, but1.2 for persistent lesions. Interobserver agreement is improved by training, especially in inexperienced readers. Interobserver agreement in reporting gadolinium-enhanced lesions is high, which validates the use of serial, enhanced MRI as an outcome parameter in treatment trials in MS.

Published
1997

38. Switching from natalizumab to fingolimod: A randomized, placebo-controlled study in RRMS

Author

Kappos L, Ew, Radue, Comi G, Montalban X, Helmut Butzkueven, Wiendl H, Giovannoni G, Hp, Hartung, Derfuss T, Naegelin Y, Sprenger T, Mueller-Lenke N, Griffiths S, von Rosenstiel P, Gottschalk R, Zhang Y, Dahlke F, Tomic D, Kappos, L, Radue, Ew, Comi, Giancarlo, Montalban, X, Butzkueven, H, Wiendl, H, Giovannoni, G, Hartung, Hp, Derfuss, T, Naegelin, Y, Sprenger, T, Mueller Lenke, N, Griffiths, S, von Rosenstiel, P, Gottschalk, R, Zhang, Y, Dahlke, F, and Tomic, D.

39. Longitudinal analysis of new multiple sclerosis lesions with magnetization transfer and diffusion tensor imaging.

Author

Gloor M, Andelova M, Gaetano L, Papadopoulou A, Burguet Villena F, Sprenger T, Radue EW, Kappos L, Bieri O, and Garcia M

Subjects
Humans, Brain diagnostic imaging, Brain pathology, Magnetic Resonance Imaging methods, Anisotropy, Diffusion Tensor Imaging methods, Multiple Sclerosis diagnostic imaging, Multiple Sclerosis pathology
Abstract

Objective: The potential of magnetization transfer imaging (MTI) and diffusion tensor imaging (DTI) for the detection and evolution of new multiple sclerosis (MS) lesions was analyzed., Methods: Nineteen patients with MS obtained conventional MRI, MTI, and DTI examinations bimonthly for 12 months and again after 24 months at 1.5 T MRI. MTI was acquired with balanced steady-state free precession (bSSFP) in 10 min (1.3 mm 3 isotropic resolution) yielding both magnetization transfer ratio (MTR) and quantitative magnetization transfer (qMT) parameters (pool size ratio (F), exchange rate (kf), and relaxation times (T1/T2)). DTI provided fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD)., Results: At the time of their appearance on MRI, the 21 newly detected MS lesions showed significantly reduced MTR/F/kf and prolonged T1/T2 parameters, as well as significantly reduced FA and increased AD/MD/RD. Significant differences were already observed for MTR 4 months and for qMT parameters 2 months prior to lesions' detection on MRI. DTI did not show any significant pre-lesional differences. Slightly reversed trends were observed for most lesions up to 8 months after their detection for qMT and less pronounced for MTR and three diffusion parameters, while appearing unchanged on MRI., Conclusions: MTI provides more information than DTI in MS lesions and detects tissue changes 2 to 4 months prior to their appearance on MRI. After lesions' detection, qMT parameter changes promise to be more sensitive than MTR for the lesions' evolutional assessment. Overall, bSSFP-based MTI adumbrates to be more sensitive than MRI and DTI for the early detection and follow-up assessment of MS lesions., Clinical Relevance Statement: When additionally acquired in routine MRI, fast bSSFP-based MTI can complement the MRI/DTI longitudinal lesion assessment by detecting MS lesions 2-4 months earlier than with MRI, which could implicate earlier clinical decisions and better follow-up/treatment assessment in MS patients., Key Points: • Magnetization transfer imaging provides more information than DTI in multiple sclerosis lesions and can detect tissue changes 2 to 4 months prior to their appearance on MRI. • After lesions' detection, quantitative magnetization transfer changes are more pronounced than magnetization transfer ratio changes and therefore promise to be more sensitive for the lesions' evolutional assessment. • Balanced steady-state free precession-based magnetization transfer imaging is more sensitive than MRI and DTI for the early detection and follow-up assessment of multiple sclerosis lesions., (© 2023. The Author(s).)

Published
2024
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40. Association of Spinal Cord Atrophy and Brain Paramagnetic Rim Lesions With Progression Independent of Relapse Activity in People With MS.

Author

Cagol A, Benkert P, Melie-Garcia L, Schaedelin SA, Leber S, Tsagkas C, Barakovic M, Galbusera R, Lu PJ, Weigel M, Ruberte E, Radue EW, Yaldizli Ö, Oechtering J, Lorscheider J, D'Souza M, Fischer-Barnicol B, Müller S, Achtnichts L, Vehoff J, Disanto G, Findling O, Chan A, Salmen A, Pot C, Bridel C, Zecca C, Derfuss T, Lieb JM, Remonda L, Wagner F, Vargas MI, Du Pasquier RA, Lalive PH, Pravatà E, Weber J, Cattin PC, Absinta M, Gobbi C, Leppert D, Kappos L, Kuhle J, and Granziera C

Subjects
Humans, Female, Child, Male, Cohort Studies, Cross-Sectional Studies, Brain diagnostic imaging, Chronic Disease, Multiple Sclerosis, Multiple Sclerosis, Chronic Progressive diagnostic imaging
Abstract

Background and Objectives: Progression independent of relapse activity (PIRA) is a crucial determinant of overall disability accumulation in multiple sclerosis (MS). Accelerated brain atrophy has been shown in patients experiencing PIRA. In this study, we assessed the relation between PIRA and neurodegenerative processes reflected by (1) longitudinal spinal cord atrophy and (2) brain paramagnetic rim lesions (PRLs). Besides, the same relationship was investigated in progressive MS (PMS). Last, we explored the value of cross-sectional brain and spinal cord volumetric measurements in predicting PIRA., Methods: From an ongoing multicentric cohort study, we selected patients with MS with (1) availability of a susceptibility-based MRI scan and (2) regular clinical and conventional MRI follow-up in the 4 years before the susceptibility-based MRI. Comparisons in spinal cord atrophy rates (explored with linear mixed-effect models) and PRL count (explored with negative binomial regression models) were performed between: (1) relapsing-remitting (RRMS) and PMS phenotypes and (2) patients experiencing PIRA and patients without confirmed disability accumulation (CDA) during follow-up (both considering the entire cohort and the subgroup of patients with RRMS). Associations between baseline MRI volumetric measurements and time to PIRA were explored with multivariable Cox regression analyses., Results: In total, 445 patients with MS (64.9% female; mean [SD] age at baseline 45.0 [11.4] years; 11.2% with PMS) were enrolled. Compared with patients with RRMS, those with PMS had accelerated cervical cord atrophy (mean difference in annual percentage volume change [MD-APC] -1.41; p = 0.004) and higher PRL load (incidence rate ratio [IRR] 1.93; p = 0.005). Increased spinal cord atrophy (MD-APC -1.39; p = 0.0008) and PRL burden (IRR 1.95; p = 0.0008) were measured in patients with PIRA compared with patients without CDA; such differences were also confirmed when restricting the analysis to patients with RRMS. Baseline volumetric measurements of the cervical cord, whole brain, and cerebral cortex significantly predicted time to PIRA (all p ≤ 0.002)., Discussion: Our results show that PIRA is associated with both increased spinal cord atrophy and PRL burden, and this association is evident also in patients with RRMS. These findings further point to the need to develop targeted treatment strategies for PIRA to prevent irreversible neuroaxonal loss and optimize long-term outcomes of patients with MS.

Published
2024
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41. A Multicenter Longitudinal MRI Study Assessing LeMan-PV Software Accuracy in the Detection of White Matter Lesions in Multiple Sclerosis Patients.

Author

Todea AR, Melie-Garcia L, Barakovic M, Cagol A, Rahmanzadeh R, Galbusera R, Lu PJ, Weigel M, Ruberte E, Radue EW, Schaedelin S, Benkert P, Oezguer Y, Sinnecker T, Müller S, Achtnichts L, Vehoff J, Disanto G, Findling O, Chan A, Salmen A, Pot C, Lalive P, Bridel C, Zecca C, Derfuss T, Remonda L, Wagner F, Vargas M, Du Pasquier R, Pravata E, Weber J, Gobbi C, Leppert D, Wuerfel J, Kober T, Marechal B, Corredor-Jerez R, Psychogios M, Lieb J, Kappos L, Cuadra MB, Kuhle J, and Granziera C

Subjects
Male, Humans, Adult, Middle Aged, Cohort Studies, Retrospective Studies, Magnetic Resonance Imaging methods, Brain diagnostic imaging, Brain pathology, Multiple Sclerosis diagnostic imaging, Multiple Sclerosis pathology, White Matter diagnostic imaging, White Matter pathology
Abstract

Background: Detecting new and enlarged lesions in multiple sclerosis (MS) patients is needed to determine their disease activity. LeMan-PV is a software embedded in the scanner reconstruction system of one vendor, which automatically assesses new and enlarged white matter lesions (NELs) in the follow-up of MS patients; however, multicenter validation studies are lacking., Purpose: To assess the accuracy of LeMan-PV for the longitudinal detection NEL white-matter MS lesions in a multicenter clinical setting., Study Type: Retrospective, longitudinal., Subjects: A total of 206 patients with a definitive MS diagnosis and at least two follow-up MRI studies from five centers participating in the Swiss Multiple Sclerosis Cohort study. Mean age at first follow-up = 45.2 years (range: 36.9-52.8 years); 70 males., Field Strength/sequence: Fluid attenuated inversion recovery (FLAIR) and T1-weighted magnetization prepared rapid gradient echo (T1-MPRAGE) sequences at 1.5 T and 3 T., Assessment: The study included 313 MRI pairs of datasets. Data were analyzed with LeMan-PV and compared with a manual "reference standard" provided by a neuroradiologist. A second rater (neurologist) performed the same analysis in a subset of MRI pairs to evaluate the rating-accuracy. The Sensitivity (Se), Specificity (Sp), Accuracy (Acc), F1-score, lesion-wise False-Positive-Rate (aFPR), and other measures were used to assess LeMan-PV performance for the detection of NEL at 1.5 T and 3 T. The performance was also evaluated in the subgroup of 123 MRI pairs at 3 T., Statistical Tests: Intraclass correlation coefficient (ICC) and Cohen's kappa (CK) were used to evaluate the agreement between readers., Results: The interreader agreement was high for detecting new lesions (ICC = 0.97, Pvalue < 10 -20 , CK = 0.82, P value = 0) and good (ICC = 0.75, P value < 10 -12 , CK = 0.68, P value = 0) for detecting enlarged lesions. Across all centers, scanner field strengths (1.5 T, 3 T), and for NEL, LeMan-PV achieved: Acc = 61%, Se = 65%, Sp = 60%, F1-score = 0.44, aFPR = 1.31. When both follow-ups were acquired at 3 T, LeMan-PV accuracy was higher (Acc = 66%, Se = 66%, Sp = 66%, F1-score = 0.28, aFPR = 3.03)., Data Conclusion: In this multicenter study using clinical data settings acquired at 1.5 T and 3 T, and variations in MRI protocols, LeMan-PV showed similar sensitivity in detecting NEL with respect to other recent 3 T multicentric studies based on neural networks. While LeMan-PV performance is not optimal, its main advantage is that it provides automated clinical decision support integrated into the radiological-routine flow., Evidence Level: 4 TECHNICAL EFFICACY: Stage 2., (© 2023 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Published
2023
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42. A New Advanced MRI Biomarker for Remyelinated Lesions in Multiple Sclerosis.

Author

Rahmanzadeh R, Galbusera R, Lu PJ, Bahn E, Weigel M, Barakovic M, Franz J, Nguyen TD, Spincemaille P, Schiavi S, Daducci A, La Rosa F, Absinta M, Sati P, Bach Cuadra M, Radue EW, Leppert D, Kuhle J, Kappos L, Brück W, Reich DS, Stadelmann C, Wang Y, and Granziera C

Subjects
Biomarkers, Brain pathology, Cross-Sectional Studies, Humans, Longitudinal Studies, Magnetic Resonance Imaging methods, Prospective Studies, Water, Multiple Sclerosis diagnostic imaging, Multiple Sclerosis pathology
Abstract

Objectives: Neuropathological studies have shown that multiple sclerosis (MS) lesions are heterogeneous in terms of myelin/axon damage and repair as well as iron content. However, it remains a challenge to identify specific chronic lesion types, especially remyelinated lesions, in vivo in patients with MS., Methods: We performed 3 studies: (1) a cross-sectional study in a prospective cohort of 115 patients with MS and 76 healthy controls, who underwent 3 T magnetic resonance imaging (MRI) for quantitative susceptibility mapping (QSM), myelin water fraction (MWF), and neurite density index (NDI) maps. White matter (WM) lesions in QSM were classified into 5 QSM lesion types (iso-intense, hypo-intense, hyperintense, lesions with hypo-intense rims, and lesions with paramagnetic rim legions [PRLs]); (2) a longitudinal study of 40 patients with MS to study the evolution of lesions over 2 years; (3) a postmortem histopathology-QSM validation study in 3 brains of patients with MS to assess the accuracy of QSM classification to identify neuropathological lesion types in 63 WM lesions., Results: At baseline, hypo- and isointense lesions showed higher mean MWF and NDI values compared to other QSM lesion types (p < 0.0001). Further, at 2-year follow-up, hypo-/iso-intense lesions showed an increase in MWF. Postmortem analyses revealed that QSM highly accurately identifies (1) fully remyelinated areas as hypo-/iso-intense (sensitivity = 88.89% and specificity = 100%), (2) chronic inactive lesions as hyperintense (sensitivity = 71.43% and specificity = 92.00%), and (3) chronic active/smoldering lesions as PRLs (sensitivity = 92.86% and specificity = 86.36%)., Interpretation: These results provide the first evidence that it is possible to distinguish chronic MS lesions in a clinical setting, hereby supporting with new biomarkers to develop and assess remyelinating treatments. ANN NEUROL 2022;92:486-502., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Published
2022
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43. Association of Brain Atrophy With Disease Progression Independent of Relapse Activity in Patients With Relapsing Multiple Sclerosis.

Author

Cagol A, Schaedelin S, Barakovic M, Benkert P, Todea RA, Rahmanzadeh R, Galbusera R, Lu PJ, Weigel M, Melie-Garcia L, Ruberte E, Siebenborn N, Battaglini M, Radue EW, Yaldizli Ö, Oechtering J, Sinnecker T, Lorscheider J, Fischer-Barnicol B, Müller S, Achtnichts L, Vehoff J, Disanto G, Findling O, Chan A, Salmen A, Pot C, Bridel C, Zecca C, Derfuss T, Lieb JM, Remonda L, Wagner F, Vargas MI, Du Pasquier R, Lalive PH, Pravatà E, Weber J, Cattin PC, Gobbi C, Leppert D, Kappos L, Kuhle J, and Granziera C

Subjects
Adult, Atrophy pathology, Brain diagnostic imaging, Brain pathology, Disability Evaluation, Disease Progression, Female, Gray Matter diagnostic imaging, Gray Matter pathology, Humans, Longitudinal Studies, Magnetic Resonance Imaging methods, Male, Recurrence, Central Nervous System Diseases pathology, Multiple Sclerosis drug therapy, Multiple Sclerosis, Relapsing-Remitting complications, Multiple Sclerosis, Relapsing-Remitting diagnostic imaging, Multiple Sclerosis, Relapsing-Remitting drug therapy, Nervous System Malformations, Neurodegenerative Diseases pathology
Abstract

Importance: The mechanisms driving neurodegeneration and brain atrophy in relapsing multiple sclerosis (RMS) are not completely understood., Objective: To determine whether disability progression independent of relapse activity (PIRA) in patients with RMS is associated with accelerated brain tissue loss., Design, Setting, and Participants: In this observational, longitudinal cohort study with median (IQR) follow-up of 3.2 years (2.0-4.9), data were acquired from January 2012 to September 2019 in a consortium of tertiary university and nonuniversity referral hospitals. Patients were included if they had regular clinical follow-up and at least 2 brain magnetic resonance imaging (MRI) scans suitable for volumetric analysis. Data were analyzed between January 2020 and March 2021., Exposures: According to the clinical evolution during the entire observation, patients were classified as those presenting (1) relapse activity only, (2) PIRA episodes only, (3) mixed activity, or (4) clinical stability., Main Outcomes and Measures: Mean difference in annual percentage change (MD-APC) in brain volume/cortical thickness between groups, calculated after propensity score matching. Brain atrophy rates, and their association with the variables of interest, were explored with linear mixed-effect models., Results: Included were 1904 brain MRI scans from 516 patients with RMS (67.4% female; mean [SD] age, 41.4 [11.1] years; median [IQR] Expanded Disability Status Scale score, 2.0 [1.5-3.0]). Scans with insufficient quality were excluded (n = 19). Radiological inflammatory activity was associated with increased atrophy rates in several brain compartments, while an increased annualized relapse rate was linked to accelerated deep gray matter (GM) volume loss. When compared with clinically stable patients, patients with PIRA had an increased rate of brain volume loss (MD-APC, -0.36; 95% CI, -0.60 to -0.12; P = .02), mainly driven by GM loss in the cerebral cortex. Patients who were relapsing presented increased whole brain atrophy (MD-APC, -0.18; 95% CI, -0.34 to -0.02; P = .04) with respect to clinically stable patients, with accelerated GM loss in both cerebral cortex and deep GM. No differences in brain atrophy rates were measured between patients with PIRA and those presenting relapse activity., Conclusions and Relevance: Our study shows that patients with RMS and PIRA exhibit accelerated brain atrophy, especially in the cerebral cortex. These results point to the need to recognize the insidious manifestations of PIRA in clinical practice and to further evaluate treatment strategies for patients with PIRA in clinical trials.

Published
2022
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44. A comparative assessment of myelin-sensitive measures in multiple sclerosis patients and healthy subjects.

Author

Rahmanzadeh R, Weigel M, Lu PJ, Melie-Garcia L, Nguyen TD, Cagol A, La Rosa F, Barakovic M, Lutti A, Wang Y, Bach Cuadra M, Radue EW, Gaetano L, Kappos L, Kuhle J, Magon S, and Granziera C

Subjects
Humans, Reproducibility of Results, Magnetic Resonance Imaging methods, Water, Brain diagnostic imaging, Brain pathology, Myelin Sheath pathology, Multiple Sclerosis diagnostic imaging, Multiple Sclerosis pathology
Abstract

Introduction: Multiple Sclerosis (MS) is a common neurological disease primarily characterized by myelin damage in lesions and in normal - appearing white and gray matter (NAWM, NAGM). Several quantitative MRI (qMRI) methods are sensitive to myelin characteristics by measuring specific tissue biophysical properties. However, there are currently few studies assessing the relative reproducibility and sensitivity of qMRI measures to MS pathology in vivo in patients., Methods: We performed two studies. The first study assessed of the sensitivity of qMRI measures to MS pathology: in this work, we recruited 150 MS and 100 healthy subjects, who underwent brain MRI at 3 T including quantitative T1 mapping (qT1), quantitative susceptibility mapping (QSM), magnetization transfer saturation imaging (MTsat) and myelin water imaging for myelin water fraction (MWF). The sensitivity of qMRIs to MS focal pathology (MS lesions vs peri-plaque white/gray matter (PPWM/PPGM)) was studied lesion-wise; the sensitivity to diffuse normal appearing (NA) pathology was measured using voxel-wise threshold-free cluster enhancement (TFCE) in NAWM and vertex-wise inflated cortex analysis in NAGM. Furthermore, the sensitivity of qMRI to the identification of lesion tissue was investigated using a voxel-wise logistic regression analysis to distinguish MS lesion and PP voxels. The second study assessed the reproducibility of myelin-sensitive qMRI measures in a single scanner. To evaluate the intra-session and inter-session reproducibility of qMRI measures, we have investigated 10 healthy subjects, who underwent two brain 3 T MRIs within the same day (without repositioning), and one after 1-week interval. Five region of interest (ROIs) in white and deep grey matter areas were segmented, and inter- and intra- session reproducibility was studied using the intra-class correlation coefficient (ICC). Further, we also investigated the voxel-wise reproducibility of qMRI measures in NAWM and NAGM., Results: qT1 and QSM showed the highest sensitivity to distinguish MS focal WM and cortical pathology from peri-plaque WM (P < 0.0001), although QSM also showed the highest variance when applied to lesions. MWF and MTsat exhibited the highest sensitivity to NAWM pathology (P < 0.01). On the other hand, qT1 appeared to be the most sensitive measure to NAGM pathology (P < 0.01). All myelin-sensitive qMRI measures exhibited high inter/intra sessional ICCs in various WM and deep GM ROIs, in NAWM and in NAGM (ICC 0.82 ± 0.12)., Conclusion: This work shows that the applied qT1, MWF, MTsat and QSM are highly reproducible and exhibit differential sensitivity to focal and diffuse WM and GM pathology in MS patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2022
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45. Myelin and axon pathology in multiple sclerosis assessed by myelin water and multi-shell diffusion imaging.

Author

Rahmanzadeh R, Lu PJ, Barakovic M, Weigel M, Maggi P, Nguyen TD, Schiavi S, Daducci A, La Rosa F, Schaedelin S, Absinta M, Reich DS, Sati P, Wang Y, Bach Cuadra M, Radue EW, Kuhle J, Kappos L, and Granziera C

Subjects
Adult, Brain diagnostic imaging, Female, Humans, Image Interpretation, Computer-Assisted methods, Male, Middle Aged, Multiple Sclerosis diagnostic imaging, Neuroimaging methods, Water, Axons pathology, Brain pathology, Diffusion Magnetic Resonance Imaging methods, Multiple Sclerosis pathology, Myelin Sheath pathology
Abstract

Damage to the myelin sheath and the neuroaxonal unit is a cardinal feature of multiple sclerosis; however, a detailed characterization of the interaction between myelin and axon damage in vivo remains challenging. We applied myelin water and multi-shell diffusion imaging to quantify the relative damage to myelin and axons (i) among different lesion types; (ii) in normal-appearing tissue; and (iii) across multiple sclerosis clinical subtypes and healthy controls. We also assessed the relation of focal myelin/axon damage with disability and serum neurofilament light chain as a global biological measure of neuroaxonal damage. Ninety-one multiple sclerosis patients (62 relapsing-remitting, 29 progressive) and 72 healthy controls were enrolled in the study. Differences in myelin water fraction and neurite density index were substantial when lesions were compared to healthy control subjects and normal-appearing multiple sclerosis tissue: both white matter and cortical lesions exhibited a decreased myelin water fraction and neurite density index compared with healthy (P < 0.0001) and peri-plaque white matter (P < 0.0001). Periventricular lesions showed decreased myelin water fraction and neurite density index compared with lesions in the juxtacortical region (P < 0.0001 and P < 0.05). Similarly, lesions with paramagnetic rims showed decreased myelin water fraction and neurite density index relative to lesions without a rim (P < 0.0001). Also, in 75% of white matter lesions, the reduction in neurite density index was higher than the reduction in the myelin water fraction. Besides, normal-appearing white and grey matter revealed diffuse reduction of myelin water fraction and neurite density index in multiple sclerosis compared to healthy controls (P < 0.01). Further, a more extensive reduction in myelin water fraction and neurite density index in normal-appearing cortex was observed in progressive versus relapsing-remitting participants. Neurite density index in white matter lesions correlated with disability in patients with clinical deficits (P < 0.01, beta = -10.00); and neurite density index and myelin water fraction in white matter lesions were associated to serum neurofilament light chain in the entire patient cohort (P < 0.01, beta = -3.60 and P < 0.01, beta = 0.13, respectively). These findings suggest that (i) myelin and axon pathology in multiple sclerosis is extensive in both lesions and normal-appearing tissue; (ii) particular types of lesions exhibit more damage to myelin and axons than others; (iii) progressive patients differ from relapsing-remitting patients because of more extensive axon/myelin damage in the cortex; and (iv) myelin and axon pathology in lesions is related to disability in patients with clinical deficits and global measures of neuroaxonal damage., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Published
2021
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46. Long-term safety and efficacy of daclizumab beta in relapsing-remitting multiple sclerosis: 6-year results from the SELECTED open-label extension study.

Author

Gold R, Radue EW, Giovannoni G, Selmaj K, Havrdova EK, Montalban X, Stefoski D, Sprenger T, Robinson RR, Fam S, Smith J, Chalkias S, Giannattasio G, Lima G, and Castro-Borrero W

Subjects
Adult, Antibodies, Monoclonal, Humanized, Female, Humans, Immunoglobulin G, Male, Daclizumab adverse effects, Daclizumab therapeutic use, Immunosuppressive Agents adverse effects, Immunosuppressive Agents therapeutic use, Multiple Sclerosis, Multiple Sclerosis, Relapsing-Remitting drug therapy
Abstract

Objective: SELECTED, an open-label extension study, evaluated daclizumab beta treatment for up to 6 years in participants with relapsing multiple sclerosis who completed the randomized SELECT/SELECTION studies. We report final results of SELECTED., Methods: Eligible participants who completed 1-2 years of daclizumab beta treatment in SELECT/SELECTION received daclizumab beta 150 mg subcutaneously every 4 weeks for up to 6 years in SELECTED. Safety assessments were evaluated for the SELECTED treatment period; efficacy data were evaluated from first dose of daclizumab beta in SELECT/SELECTION., Results: Ninety percent (410/455) of participants who completed treatment in SELECTION enrolled in SELECTED. Within SELECTED, 69% of participants received daclizumab beta for > 3 years, 39% for > 4 years, and 9% for > 5 years; 87% of participants experienced an adverse event and 26% a serious adverse event (excluding multiple sclerosis relapse). No deaths occurred. Overall, hepatic events were reported in 25% of participants; serious hepatic events in 2%. There were no confirmed cases of immune-mediated encephalitis. Based on weeks from the first daclizumab beta dose in SELECT/SELECTION, adjusted annualized relapse rate (95% confidence interval) for weeks 0-24 was 0.21 (0.16-0.29) and remained low on continued treatment. Overall incidence of 24-week confirmed disability progression was 17.4%. Mean numbers of new/newly enlarging T2 hyperintense lesions remained low; percentage change in whole brain volume decreased over time., Conclusions: The effects of daclizumab beta on clinical and radiologic outcomes were sustained for up to ~ 8 years of treatment. No new safety concerns were identified in SELECTED., Trial Registration: Clinicaltrials.gov NCT01051349; first registered on January 15, 2010.

Published
2020
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47. Association of brain volume loss and long-term disability outcomes in patients with multiple sclerosis treated with teriflunomide.

Author

Sprenger T, Kappos L, Radue EW, Gaetano L, Mueller-Lenke N, Wuerfel J, Poole EM, and Cavalier S

Subjects
Brain diagnostic imaging, Crotonates, Humans, Hydroxybutyrates, Nitriles, Toluidines, Multiple Sclerosis, Multiple Sclerosis, Relapsing-Remitting drug therapy
Abstract

Background: Teriflunomide 14 mg significantly reduced brain volume loss (BVL) and confirmed disability worsening (CDW) compared with placebo in the TEMSO core study., Objective: To investigate the relationship between BVL from Baseline to Year 2 in the TEMSO core study and long-term CDW (Year 7) in the TEMSO long-term extension (NCT00803049)., Methods: Structural Image Evaluation using Normalization of Atrophy determined BVL. Long-term CDW was assessed by Expanded Disability Status Scale confirmed for 12 and 24 weeks. An additional analysis evaluated the relative contribution of BVL (Year 2) and other outcomes as potential mediators of the effect of teriflunomide 14 mg on 12-week CDW., Results: Patients with the least BVL were significantly less likely to have 12- and 24-week CDW at Year 7 compared with patients with the most BVL. A mediation analysis revealed that BVL (Year 2) explained 51.3% of the treatment effect on CDW; new or enlarging T 2w lesions over 2 years explained 30.8%, and relapses in the first 2 years explained 38.5%., Conclusions: These results highlight the potential predictive value of BVL earlier in the disease course on long-term disability outcomes. The mediation analysis suggests that teriflunomide may prevent disability worsening largely through its effects on BVL.

Published
2020
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48. White matter lesion location correlates with disability in relapsing multiple sclerosis.

Author

Gaetano L, Magnusson B, Kindalova P, Tomic D, Silva D, Altermatt A, Magon S, Müller-Lenke N, Radue EW, Leppert D, Kappos L, Wuerfel J, Häring DA, and Sprenger T

Abstract

Background: Lesion location is a prognostic factor of disease progression and disability accrual., Objective: To investigate lesion formation in 11 brain regions, assess correlation between lesion location and physical and cognitive disability measures and investigate treatment effects by region., Methods: In 2355 relapsing-remitting multiple sclerosis patients from the FREEDOMS and FREEDOMS II studies, we extracted T2-weighted lesion number, volume and density for each brain region; we investigated the (Spearman) correlation in lesion formation between brain regions, studied association between location and disability (at baseline and change over 2 years) using linear/logistic regression and assessed the regional effects of fingolimod versus placebo in negative binomial models., Results: At baseline, the majority of lesions were found in the supratentorial brain. New and enlarging lesions over 24 months developed mainly in the frontal and sublobar regions and were substantially correlated to pre-existing lesions at baseline in the supratentorial brain ( p  = 0.37-0.52), less so infratentorially ( p  = -0.04-0.23). High sublobar lesion density was consistently and significantly associated with most disability measures at baseline and worsening of physical disability over 24 months. The treatment effect of fingolimod 0.5 mg was consistent across the investigated areas and tracts., Conclusion: These results highlight the role of sublobar lesions for the accrual of disability in relapsing-remitting multiple sclerosis., (© The Author(s) 2020.)

Published
2020
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49. Accurate, rapid and reliable, fully automated MRI brainstem segmentation for application in multiple sclerosis and neurodegenerative diseases.

Author

Sander L, Pezold S, Andermatt S, Amann M, Meier D, Wendebourg MJ, Sinnecker T, Radue EW, Naegelin Y, Granziera C, Kappos L, Wuerfel J, Cattin P, and Schlaeger R

Subjects
Adult, Aged, Deep Learning, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Brain Stem diagnostic imaging, Image Interpretation, Computer-Assisted methods, Multiple Sclerosis diagnostic imaging, Neurodegenerative Diseases diagnostic imaging, Neuroimaging methods
Abstract

Neurodegenerative disorders, such as Alzheimer's disease (AD) and progressive forms of multiple sclerosis (MS), can affect the brainstem and are associated with atrophy that can be visualized by MRI. Anatomically accurate, large-scale assessments of brainstem atrophy are challenging due to lack of automated, accurate segmentation methods. We present a novel method for brainstem volumetry using a fully-automated segmentation approach based on multi-dimensional gated recurrent units (MD-GRU), a deep learning based semantic segmentation approach employing a convolutional adaptation of gated recurrent units. The neural network was trained on 67 3D-high resolution T1-weighted MRI scans from MS patients and healthy controls (HC) and refined using segmentations of 20 independent MS patients' scans. Reproducibility was assessed in MR test-retest experiments in 33 HC. Accuracy and robustness were examined by Dice scores comparing MD-GRU to FreeSurfer and manual brainstem segmentations in independent MS and AD datasets. The mean %-change/SD between test-retest brainstem volumes were 0.45%/0.005 (MD-GRU), 0.95%/0.009 (FreeSurfer), 0.86%/0.007 (manually edited segmentations). Comparing MD-GRU to manually edited segmentations the mean Dice scores/SD were: 0.97/0.005 (brainstem), 0.95/0.013 (mesencephalon), 0.98/0.006 (pons), 0.95/0.015 (medulla oblongata). Compared to the manual gold standard, MD-GRU brainstem segmentations were more accurate than FreeSurfer segmentations (p < .001). In the multi-centric acquired AD data, the mean Dice score/SD for the MD-GRU-manual segmentation comparison was 0.97/0.006. The fully automated brainstem segmentation method MD-GRU provides accurate, highly reproducible, and robust segmentations in HC and patients with MS and AD in 200 s/scan on an Nvidia GeForce GTX 1080 GPU and shows potential for application in large and longitudinal datasets., (© 2019 Wiley Periodicals, Inc.)

Published
2019
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50. MRI-based prediction of conversion from clinically isolated syndrome to clinically definite multiple sclerosis using SVM and lesion geometry.

Author

Bendfeldt K, Taschler B, Gaetano L, Madoerin P, Kuster P, Mueller-Lenke N, Amann M, Vrenken H, Wottschel V, Barkhof F, Borgwardt S, Klöppel S, Wicklein EM, Kappos L, Edan G, Freedman MS, Montalbán X, Hartung HP, Pohl C, Sandbrink R, Sprenger T, Radue EW, Wuerfel J, and Nichols TE

Subjects
Adult, Female, Humans, Magnetic Resonance Imaging, Male, Randomized Controlled Trials as Topic, Disease Progression, Gray Matter pathology, Multiple Sclerosis diagnostic imaging, Multiple Sclerosis pathology, Support Vector Machine
Abstract

Neuroanatomical pattern classification using support vector machines (SVMs) has shown promising results in classifying Multiple Sclerosis (MS) patients based on individual structural magnetic resonance images (MRI). To determine whether pattern classification using SVMs facilitates predicting conversion to clinically definite multiple sclerosis (CDMS) from clinically isolated syndrome (CIS). We used baseline MRI data from 364 patients with CIS, randomised to interferon beta-1b or placebo. Non-linear SVMs and 10-fold cross-validation were applied to predict converters/non-converters (175/189) at two years follow-up based on clinical and demographic data, lesion-specific quantitative geometric features and grey-matter-to-whole-brain volume ratios. We applied linear SVM analysis and leave-one-out cross-validation to subgroups of converters (n = 25) and non-converters (n = 44) based on cortical grey matter segmentations. Highest prediction accuracies of 70.4% (p = 8e-5) were reached with a combination of lesion-specific geometric (image-based) and demographic/clinical features. Cortical grey matter was informative for the placebo group (acc.: 64.6%, p = 0.002) but not for the interferon group. Classification based on demographic/clinical covariates only resulted in an accuracy of 56% (p = 0.05). Overall, lesion geometry was more informative in the interferon group, EDSS and sex were more important for the placebo cohort. Alongside standard demographic and clinical measures, both lesion geometry and grey matter based information can aid prediction of conversion to CDMS.

Published
2019
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