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1. Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

Author

Mantegazza, R., Wolfe, G. I., Muppidi, S., Wiendl, H., Fujita, K. P., O'Brien, F. L., Booth, H. D. E., Howard, J. F., Claudio Gabriel Mazia, Miguel, Wilken, Fabio, Barroso, Juliet, Saba, Marcelo, Rugiero, Mariela, Bettini, Marcelo, Chaves, Gonzalo, Vidal, Alejandra Dalila Garcia, Jan De Bleecker, Guy Van den Abeele, Kathy de Koning, Katrien De Mey, Rudy, Mercelis, Délphine, Mahieu, Linda, Wagemaekers, Philip Van Damme, Annelies, Depreitere, Caroline, Schotte, Charlotte, Smetcoren, Olivier, Stevens, Sien Van Daele, Nicolas, Vandenbussche, Annelies, Vanhee, Sarah, Verjans, Jan, Vynckier, Ann, D'Hont, Petra, Tilkin, Alzira Alves de Siqueira Carvalho, Igor Dias Brockhausen, David, Feder, Daniel, Ambrosio, Gabor Lovasamela César, Ana Paula Melo, Renata Martins Ribeiro, Rosana, Rocha, Bruno Bezerra Rosa, Thabata, Veiga, Luiz Augusto da Silva, Murilo Santos Engel, Jordana Gonçalves Geraldo, Maria da Penha Ananias Morita, Erica Nogueira Coelho, Gabriel, Paiva, Marina, Pozo, Natalia, Prando, Debora Dada Martineli Torres, Cristiani Fernanda Butinhao, Gustavo, Duran, Tomás Augusto Suriane Fialho, Tamires Cristina Gomes da Silva, Luiz Otavio Maia Gonçalves, Lucas Eduardo Pazetto, Luciana Renata Cubas Volpe, Luciana Souza Duca, Maurício AndréGheller Friedrich, Alexandre, Guerreiro, Henrique, Mohr, Maurer Pereira Martins, Daiane da Cruz Pacheco, Luciana, Ferreira, Ana Paula Macagnan, Graziela, Pinto, Aline de Cassia Santos, Acary Souza Bulle Oliveira, Ana Carolina Amaral de Andrade, Marcelo, Annes, Liene Duarte Silva, Valeria Cavalcante Lino, Wladimir, Pinto, Natália, Assis, Fernanda, Carrara, Carolina, Miranda, Iandra, Souza, Patrícia, Fernandes, Zaeem, Siddiqi, Cecile, Phan, Jeffrey, Narayan, Derrick, Blackmore, Ashley, Mallon, Rikki, Roderus, Elizabeth, Watt, Stanislav, Vohanka, Josef, Bednarik, Magda, Chmelikova, Marek, Cierny, Stanislava, Toncrova, Jana, Junkerova, Barbora, Kurkova, Katarina, Reguliova, Olga, Zapletalova, Jiri, Pitha, Iveta, Novakova, Michaela, Tyblova, Ivana, Jurajdova, Marcela, Wolfova, Henning, Andersen, Thomas, Harbo, Lotte, Vinge, Susanne, Krogh, Anita, Mogensen, John, Vissing, Joan, Højgaard, Nanna, Witting, Anne Mette Ostergaard Autzen, Jane, Pedersen, Juha-Pekka, Erälinna, Mikko, Laaksonen, Olli, Oksaranta, Tuula, Harrison, Jaana, Eriksson, Csilla, Rozsa, Melinda, Horvath, Gabor, Lovas, Judit, Matolcsi, Gedeonne, Jakab, Gyorgyi, Szabo, Brigitta, Szabadosne, Laszlo, Vecsei, Livia, Dezsi, Edina, Varga, Monika, Konyane, Antonini, Giovanni, Antonella Di Pasquale, Garibaldi, Matteo, Morino, Stefania, Troili, Fernanda, Fionda, Laura, Amelia, Evoli, Paolo Emilio Alboini, Valentina, D'Amato, Raffaele, Iorio, Inghilleri, Maurizio, Frasca, Vittorio, Elena, Giacomelli, Gori, MARIA CRISTINA, Diego, Lopergolo, Onesti, Emanuela, Maria, Gabriele, Francesco, Saccà, Alessandro, Filla, Teresa, Costabile, Enrico, Marano, Angiola, Fasanaro, Angela, Marsili, Giorgia, Puorro, Carlo, Antozzi, Silvia, Bonanno, Giorgia, Camera, Alberta, Locatelli, Lorenzo, Maggi, Maria, Pasanisi, Angela, Campanella, Akiyuki, Uzawa, Tetsuya, Kanai, Naoki, Kawaguchi, Masahiro, Mori, Yoko, Kaneko, Akiko, Kanzaki, Eri, Kobayashi, Hiroyuki, Murai, Katsuhisa, Masaki, Dai, Matsuse, Takuya, Matsushita, Taira, Uehara, Misa, Shimpo, Maki, Jingu, Keiko, Kikutake, Yumiko, Nakamura, Yoshiko, Sano, Kimiaki, Utsugisawa, Yuriko, Nagane, Ikuko, Kamegamori, Tomoko, Tsuda, Yuko, Fujii, Kazumi, Futono, Yukiko, Ozawa, Aya, Mizugami, Yuka, Saito, Makoto, Samukawa, Hidekazu, Suzuki, Miyuki, Morikawa, Sachiko, Kamakura, Eriko, Miyawaki, Meinoshin, Okumura, Soichiro, Funaka, Tomohiro, Kawamura, Masayuki, Nakamori, Masanori, Takahashi, Namie, Taichi, Tomoya, Hasuike, Eriko, Higuchi, Hisako, Kobayashi, Kaori, Osakada, Hirokazu, Shiraishi, Teiichiro, Miyazaki, Masakatsu, Motomura, Akihiro, Mukaino, Shunsuke, Yoshimura, Shizuka, Asada, Seiko, Yoshida, Shoko, Amamoto, Tomomi, Kobashikawa, Megumi, Koga, Maeda, Yasuko, Kazumi, Takada, Mihoko, Takada, Masako, Tsurumaru, Yumi, Yamashita, Yasushi, Suzuki, Tetsuya, Akiyama, Koichi, Narikawa, Ohito, Tano, Kenichi, Tsukita, Rikako, Kurihara, Fumie, Meguro, Yusuke, Fukuda, Miwako, Sato, Tomihiro, Imai, Emiko, Tsuda, Shun, Shimohama, Takashi, Hayashi, Shin, Hisahara, Jun, Kawamata, Takashi, Murahara, Masaki, Saitoh, Shuichiro, Suzuki, Daisuke, Yamamoto, Yoko, Ishiyama, Naoko, Ishiyama, Mayuko, Noshiro, Rumi, Takeyama, Kaori, Uwasa, Ikuko, Yasuda, Anneke van der Kooi, Marianne de Visser, Tamar, Gibson, Byung-Jo, Kim, Chang Nyoung Lee, Yong Seo Koo, Hung Youl Seok, Hoo Nam Kang, Hyejin, Ra, Byoung Joon Kim, Eun Bin Cho, Misong, Choi, Hyelim, Lee, Ju-Hong, Min, Jinmyoung, Seok, Jieun, Lee, Da Yoon Koh, Juyoung, Kwon, Sangae, Park, Eun Haw Choi, Yoon-Ho, Hong, So-Hyun, Ahn, Dae Lim Koo, Jae-Sung, Lim, Chae Won Shin, Ji Ye Hwang, Miri, Kim, Seung Min Kim, Ha-Neul, Jeong, Jinwoo, Jung, Yool-Hee, Kim, Hyung Seok Lee, Ha Young Shin, Eun Bi Hwang, Miju, Shin, Carlos, Casasnovas, Maria Antonia Alberti Aguilo, Christian, Homedes-Pedret, Natalia Julia Palacios, Laura Diez Porras, Valentina Velez Santamaria, Ana, Lazaro, Josep Gamez Carbonell, Pilar, Sune, Maria Salvado Figueras, Gisela, Gili, Gonzalo, Mazuela, Isabel, Illa, Elena Cortes Vicente, Jordi, Diaz-Manera, Luis Antonio Querol Gutiérrez, Ricardo Rojas Garcia, Nuria, Vidal, Elisabet, Arribas-Ibar, Exuperio Diez Tejedor, Pilar Gomez Salcedo, Mireya, Fernandez-Fournier, Pedro Lopez Ruiz, Francisco Javier Rodriguez de Rivera, Maria, Sastre, Fredrik, Piehl, Albert, Hietala, Lena, Bjarbo, Ihsan, Sengun, Arzu, Meherremova, Pinar, Ozcelik, Bengu, Balkan, Celal, Tuga, Muzeyyen, Ugur, Sevim, Erdem-Ozdamar, Can Ebru Bekircan-Kurt, Nazire Pinar Acar, Ezgi, Yilmaz, Yagmur, Caliskan, Gulsah, Orsel, Husnu, Efendi, Seda, Aydinlik, Hakan, Cavus, Ayse, Kutlu, Gulsah, Becerikli, Cansu, Semiz, Ozlem, Tun, Murat, Terzi, Baki, Dogan, Musa Kazim Onar, Sedat, Sen, Tugce Kirbas Cavdar, Adife, Veske, Fiona, Norwood, Aikaterini, Dimitriou, Jakit, Gollogly, Mohamed, Mahdi-Rogers, Arshira, Seddigh, Giannis, Sokratous, Gal, Maier, Faisal, Sohail, Saiju, Jacob, Girija, Sadalage, Pravin, Torane, Claire, Brown, Amna, Shah, Sivakumar, Sathasivam, Heike, Arndt, Debbie, Davies, Dave, Watling, Anthony, Amato, Thomas, Cochrane, Mohammed, Salajegheh, Kristen, Roe, Katherine, Amato, Shirli, Toska, Nicholas, Silvestri, Kara, Patrick, Karen, Zakalik, Jonathan, Katz, Robert, Miller, Marguerite, Engel, Dallas, Forshew, Elena, Bravver, Benjamin, Brooks, Mohammed, Sanjak, Sarah, Plevka, Maryanne, Burdette, Scott, Cunningham, Megan, Kramer, Joanne, Nemeth, Clara, Schommer, Tierney, Scott, Vern, Juel, Jeffrey, Guptill, Lisa, Hobson-Webb, Janice, Massey, Kate, Beck, Donna, Carnes, John, Loor, Amanda, Anderson, Robert, Pascuzzi, Cynthia, Bodkin, John, Kincaid, Riley, Snook, Sandra, Guingrich, Angela, Micheels, Vinay, Chaudhry, Andrea, Corse, Betsy, Mosmiller, Andrea, Kelley, Doreen, Ho, Jayashri, Srinivasan, Michal, Vytopil, Jordan, Jara, Nicholas, Ventura, Cynthia, Carter, Craig, Donahue, Carol, Herbert, Stephanie, Scala, Elaine, Weiner, Sharmeen, Alam, Jonathan, Mckinnon, Laura, Haar, Naya, Mckinnon, Karan, Alcon, Kaitlyn, Mckenna, Nadia, Sattar, Kevin, Daniels, Dennis, Jeffery, Miriam, Freimer, Joseph Chad Hoyle, John, Kissel, Julie, Agriesti, Sharon, Chelnick, Louisa, Mezache, Colleen, Pineda, Filiz, Muharrem, Chafic, Karam, Julie, Khoury, Tessa, Marburger, Harpreet, Kaur, Diana, Dimitrova, James, Gilchrist, Brajesh, Agrawal, Mona, Elsayed, Stephanie, Kohlrus, Angela, Ardoin, Taylor, Darnell, Laura, Golden, Barbara, Lokaitis, Jenna, Seelbach, Neelam, Goyal, Sarada, Sakamuri, Yuen, T So, Shirley, Paulose, Sabrina, Pol, Lesly, Welsh, Ratna, Bhavaraju-Sanka, Alejandro Tobon Gonzalez, Lorraine, Dishman, Floyd, Jones, Anna, Gonzalez, Patricia, Padilla, Amy, Saklad, Marcela, Silva, Sharon, Nations, Jaya, Trivedi, Steve, Hopkins, Mohamed, Kazamel, Mohammad, Alsharabati, Liang, Lu, Kenkichi, Nozaki, Sandi, Mumfrey-Thomas, Amy, Woodall, Tahseen, Mozaffar, Tiyonnoh, Cash, Namita, Goyal, Gulmohor, Roy, Veena, Mathew, Fatima, Maqsood, Brian, Minton, H James Jones, Jeffrey, Rosenfeld, Rebekah, Garcia, Laura, Echevarria, Sonia, Garcia, Michael, Pulley, Shachie, Aranke, Alan Ross Berger, Jaimin, Shah, Yasmeen, Shabbir, Lisa, Smith, Mary, Varghese, Laurie, Gutmann, Ludwig, Gutmann, Nivedita, Jerath, Christopher, Nance, Andrea, Swenson, Heena, Olalde, Nicole, Kressin, Jeri, Sieren, Richard, Barohn, Mazen, Dimachkie, Melanie, Glenn, April, Mcvey, Mamatha, Pasnoor, Jeffery, Statland, Yunxia, Wang, Tina, Liu, Kelley, Emmons, Nicole, Jenci, Jerry, Locheke, Alex, Fondaw, Kathryn, Johns, Gabrielle, Rico, Maureen, Walsh, Laura, Herbelin, Charlene, Hafer-Macko, Justin, Kwan, Lindsay, Zilliox, Karen, Callison, Valerie, Young, Beth, Disanzo, Kerry, Naunton, Michael, Benatar, Martin, Bilsker, Khema, Sharma, Anne, Cooley, Eliana, Reyes, Sara-Claude, Michon, Danielle, Sheldon, Julie, Steele, Rebecca, Traub, Manisha, Chopra, Tuan, Vu, Lara, Katzin, Terry, Mcclain, Brittany, Harvey, Adam, Hart, Kristin, Huynh, Said, Beydoun, Amaiak, Chilingaryan, Victor, Doan, Brian, Droker, Hui, Gong, Sanaz, Karimi, Frank, Lin, Krishna, Polaka, Akshay, Shah, Anh, Tran, Salma, Akhter, Ali, Malekniazi, Rup, Tandan, Michael, Hehir, Waqar, Waheed, Shannon, Lucy, Michael, Weiss, Jane, Distad, Susan, Strom, Sharon, Downing, Bryan, Kim, Tulio, Bertorini, Thomas, Arnold, Kendrick, Henderson, Rekha, Pillai, Liu, Ye, Lauren, Wheeler, Jasmine, Hewlett, Mollie, Vanderhook, Richard, Nowak, Daniel, Dicapua, Benison, Keung, Aditya, Kumar, Huned, Patwa, Kimberly, Robeson, Irene, Yang, Joan, Nye, and Hong, Vu

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Clinical Neurology, Antibodies, Monoclonal, Humanized, Placebo, Article, Antibodies, Post-intervention, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Refractory, law, Internal medicine, Monoclonal, Myasthenia Gravis, Medicine and Health Sciences, Humans, Medicine, Humanized, Science & Technology, business.industry, Middle Aged, Eculizumab, Complement Inactivating Agents, Female, Treatment Outcome, EFFICACY, medicine.disease, Myasthenia gravis, Clinical trial, 030104 developmental biology, SAFETY, Neurosciences & Neurology, Neurology (clinical), business, Life Sciences & Biomedicine, COMPLEMENT INHIBITOR ECULIZUMAB, 030217 neurology & neurosurgery, medicine.drug
Abstract

ObjectiveTo evaluate whether eculizumab helps patients with anti–acetylcholine receptor–positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension.MethodsPatients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study.ResultsA total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1–4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected.ConclusionEculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population.ClinicalTrials.gov IdentifierREGAIN, NCT01997229; REGAIN open-label extension, NCT02301624.Classification of EvidenceThis study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo.

Published
2020

2. Safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of the novel enzyme replacement therapy avalglucosidase alfa (neoGAA) in treatment-naive and alglucosidase alfa-treated patients with late-onset Pompe disease: A phase 1, open-label, multicenter, multinational, ascending dose study

Author

Philip Van Damme, Pascal Laforêt, Benedikt Schoser, Barry J. Byrne, Loren D.M. Pena, Richard J. Barohn, Ozlem Goker-Alpan, Kerry Culm-Merdek, Ans T. van der Ploeg, Volker Straub, Karl Eugen Mengel, Beth L. Thurberg, Jean Pouget, Raheel Shafi, Katherine Kacena, Alan Pestronk, Peter Young, John Vissing, Shafeeq Ladha, Claude Desnuelle, Jaya Trivedi, and Pediatrics

Subjects
Avalglucosidase alfa (neoGAA), 0301 basic medicine, Male, GLUCOSE TETRASACCHARIDE, Lysosomal acid alpha-glucosidase (GAA) deficiency, CHILDREN, Pulmonary function testing, MOTOR FUNCTION, 0302 clinical medicine, Medicine, Genetics (clinical), Late-onset Pompe disease (LOPD), Glycogen Storage Disease Type II, Alglucosidase alfa, MOUSE MODEL, Enzyme replacement therapy, Middle Aged, Treatment Outcome, Neurology, Tolerability, SKELETAL-MUSCLE, Female, Life Sciences & Biomedicine, MUSCLE TRAINING RMT, Glycogen, 6-MINUTE WALK, medicine.drug, Adult, medicine.medical_specialty, Clinical Neurology, GLYCOGEN, 03 medical and health sciences, FEV1/FVC ratio, Pharmacokinetics, Internal medicine, Humans, Enzyme Replacement Therapy, Adverse effect, Science & Technology, business.industry, Neurosciences, alpha-Glucosidases, ADULTS, Glycogen storage disease type II, SEVERITY, 030104 developmental biology, Pharmacodynamics, Pediatrics, Perinatology and Child Health, Neurosciences & Neurology, Neurology (clinical), Glucan 1,4-alpha-Glucosidase, business, 030217 neurology & neurosurgery
Abstract

This multicenter/multinational, open-label, ascending-dose study (NCT01898364) evaluated safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of repeat-dose avalglucosidase alfa (neoGAA), a second-generation, recombinant acid α-glucosidase replacement therapy, in late-onset Pompe disease (LOPD). Patients ≥18 years, alglucosidase alfa naïve (Naïve) or previously receiving alglucosidase alfa for ≥9 months (Switch), with baseline FVC ≥50% predicted and independently ambulatory, received every-other-week avalglucosidase alfa 5, 10, or 20 mg/kg over 24 weeks. 9/10 Naïve and 12/14 Switch patients completed the study. Avalglucosidase alfa was well-tolerated; no deaths/life-threatening serious adverse events (SAEs). One Naïve patient withdrew for study drug-related SAEs (respiratory distress/chest discomfort). Infusion-associated reactions (IARs) affected 8 patients. Most treatment-emergent AEs/IARs were non-serious with mild-to-moderate intensity. At screening, 5 Switch patients tested positive for anti-avalglucosidase alfa antibodies; on-treatment, 2 Switch and 9 Naïve patients seroconverted. Post-infusion, avalglucosidase alfa plasma concentrations declined monoexponentially (t1/2z∼1.0 h). AUC was 5-6 × higher in the 20 vs 5 mg/kg group. Pharmacokinetics were similar between Switch and Naïve groups and over time. Baseline quadriceps muscle glycogen was low (∼6%) in most patients, generally remaining unchanged thereafter. Exploratory efficacy parameters (pulmonary function/functional capacity) generally remained stable or improved. Avalglucosidase alfa's well-tolerated safety profile and exploratory efficacy results support further avalglucosidase alfa development. ispartof: NEUROMUSCULAR DISORDERS vol:29 issue:3 pages:167-186 ispartof: location:England status: published

Published
2019

3. Investigating Late-Onset Pompe Prevalence in Neuromuscular Medicine Academic Practices: The IPaNeMA Study

Author

Namita Goyal, Miriam Freimer, Nicholas E. Johnson, Sankar Bandyopadhay, Tahseen Mozaffar, Neelam Goyal, Matthew Wicklund, Jeffrey W. Ralph, Chafic Karam, Melissa Hays, Marie Wencel, Mazen M. Dimachkie, Zinah Rasheed, Angela Genge, Steve Hopkins, Julaine Florence, Laurie Gutmann, Jaya Trivedi, Aziz Shaibani, and Alan Pestronk

Subjects
medicine.medical_specialty, Proximal muscle weakness, Splice site mutation, Neck muscle weakness, business.industry, Liver Disease, Chronic Liver Disease and Cirrhosis, Neurosciences, Prevalence, Disease, Neuromuscular medicine, Clinical trial, Rare Diseases, Clinical Research, Internal medicine, Pseudodeficiency alleles, Genetics, Medicine, Genetic Testing, Neurology (clinical), Digestive Diseases, business, Genetics (clinical)
Abstract

Background and Objectives We investigated the prevalence of late-onset Pompe disease (LOPD) in patients presenting to 13 academic, tertiary neuromuscular practices in the United States and Canada. Methods All successive patients presenting with proximal muscle weakness or isolated hyperCKemia and/or neck muscle weakness to these 13 centers were invited to participate in the study. Whole blood was tested for acid alpha-glucosidase (GAA) assay through the fluorometric method, and all cases with enzyme levels of ≤10 pmoL/punch/h were reflexed to molecular testing for mutations in the GAA gene. Clinical and demographic information was abstracted from their clinical visit and, along with study data, entered into a purpose-built REDCap database, and analyzed at the University of California, Irvine. Results GAA enzyme assay results were available on 906 of the 921 participants who consented for the study. LOPD was confirmed in 9 participants (1% prevalence). Another 9 (1%) were determined to have pseudodeficiency of GAA, whereas 19 (1.9%) were found to be heterozygous for a pathogenic GAA mutation (carriers). Of the definite LOPD participants, 8 (89%) were Caucasian and were heterozygous for the common leaky (IVS1) splice site mutation in the GAA gene (c -32-13T>G), with a second mutation that was previously confirmed to be pathogenic. Discussion The prevalence of LOPD in undiagnosed patients meeting the criteria of proximal muscle weakness, high creatine kinase, and/or neck weakness in academic, tertiary neuromuscular practices in the United States and Canada is estimated to be 1%, with an equal prevalence rate of pseudodeficiency alleles. Trial Registration Information Clinical trial registration number: NCT02838368.

Published
2021

4. Comparing Four Medicines to Treat Pain from Cryptogenic Sensory Polyneuropathy—The PAIN-CONTRoLS Study

Author

James Wymer, Tuan Vu, Yuebing Li, Pariwat Thaisetthawatkul, M Jacoby, Andrea Swenson, Aiesha Ahmed, Jau Shin Lou, Mamatha Pasnoor, Ted M. Burns, C Parks, Michael K. Hehir, David Walk, Stephen N. Scelsa, Shafeeq Ladha, Ghazala Hayat, Gordon Smith, Jaya Trivedi, Byron J. Gajewski, William Mallonee, Richard J. Barohn, P Shlemon, Omar Jawdat, Robert M. Pascuzzi, Matthew Wicklund, Tiyonnoh M. Cash, Noah Kolb, Sindhu Ramchandren, Jeffrey W. Ralph, L Brown, Paul Twydell, Hani Kushlaf, Gil I. Wolfe, Mazen M. Dimachkie, S Austin, Michael Pulley, Y Hussainn, David Saperstein, Stanley Iyadurai, Dianna Quan, T Liu, Chafic Karam, Amro M. Stino, D Heitzman, Anza B. Memon, Thomas H. Brannagan, A Tobon, Khema Sharma, M Ahmed, Kim S. Kimminau, Vera Bril, John T. Kissel, Christen Kutz, N Verma, M Bazant, Richard A. Lewis, Suur Biliciler, Alexandru Barboi, K Salajegheh, and Laura Herbelin

Subjects
medicine.medical_specialty, business.industry, Internal medicine, Sensory polyneuropathy, Medicine, business
Published
2020

5. Guidelines on clinical presentation and management of nondystrophic myotonias

Author

Jeffrey Statland, W. David Arnold, Giovanni Meola, Michael G. Hanna, Samantha LoRusso, Baziel G.M. van Engelen, Stephen C. Cannon, Emma Matthews, Valeria A. Sansone, Jaya Trivedi, Bertrand Fontaine, Bas C. Stunnenberg, Richard J. Barohn, Robert C. Griggs, Savine Vicart, Gestionnaire, HAL Sorbonne Université 5, Radboud University Medical Center [Nijmegen], Ohio State University [Columbus] (OSU), University of Kansas Medical Center [Kansas City, KS, USA], David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), University of Rochester Medical Center (URMC), Institute of Neurology [London], University College of London [London] (UCL), Università degli Studi di Milano = University of Milan (UNIMI), University of Texas Southwestern Medical Center [Dallas], University of Kansas Medical Center [Lawrence], University of California-University of California, Centre de Recherche en Myologie, and University of Milan

Subjects
0301 basic medicine, Physiology, Electromyography, 030105 genetics & heredity, 0302 clinical medicine, Ranolazine, Age of Onset, NAV1.4 Voltage-Gated Sodium Channel, Carbonic Anhydrase Inhibitors, Fatigue, Voltage-Gated Sodium Channel Blockers, Muscle Weakness, biology, medicine.diagnostic_test, Electrodiagnosis, skeletal muscle channelopathies, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], 3. Good health, Muscle relaxation, Paramyotonia congenita, Practice Guidelines as Topic, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, myotonia congenita, management, medicine.drug, Myotonic Disorders, Sodium Channel Blockers, musculoskeletal diseases, Weakness, medicine.medical_specialty, Mexiletine, Lamotrigine, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Chloride Channels, Physiology (medical), Internal medicine, medicine, Humans, Genetic Testing, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Muscle, Skeletal, nondystrophic myotonias, CLCN1, Myotonia congenita, business.industry, Myalgia, medicine.disease, Myotonia, paramyotonia congenita, Acetazolamide, biology.protein, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 229739.pdf (Publisher’s version ) (Closed access) The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1 gene. Clinically, they are characterized by myotonia, defined as delayed muscle relaxation after voluntary contraction, which leads to symptoms of muscle stiffness, pain, fatigue, and weakness. Diagnosis is based on history and examination findings, the presence of electrical myotonia on electromyography, and genetic confirmation. In the absence of genetic confirmation, the diagnosis is supported by detailed electrophysiological testing, exclusion of other related disorders, and analysis of a variant of uncertain significance if present. Symptomatic treatment with a sodium channel blocker, such as mexiletine, is usually the first step in management, as well as educating patients about potential anesthetic complications.

Published
2020

6. Validation of serum neurofilaments as prognostic and potential pharmacodynamic biomarkers for ALS

Author

Michael, Benatar, Lanyu, Zhang, Lily, Wang, Volkan, Granit, Jeffrey, Statland, Richard, Barohn, Andrea, Swenson, John, Ravits, Carlayne, Jackson, Ted M, Burns, Jaya, Trivedi, Erik P, Pioro, James, Caress, Jonathan, Katz, Jacob L, McCauley, Rosa, Rademakers, Andrea, Malaspina, Lyle W, Ostrow, Joanne, Wuu, Marka van, Blitterswijk, and CReATe Consortium

Subjects
0301 basic medicine, Oncology, Adult, Male, medicine.medical_specialty, Neurofilament, Neurofilament light, Intermediate Filaments, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Amyotrophic lateral sclerosis, Biology, Aged, business.industry, Amyotrophic Lateral Sclerosis, Progressive muscular atrophy, Middle Aged, Serum samples, medicine.disease, Prognosis, 030104 developmental biology, Sample size determination, Pharmacodynamics, Biomarker (medicine), Female, Neurology (clinical), Human medicine, business, 030217 neurology & neurosurgery, Biomarkers
Abstract

ObjectiveTo identify preferred neurofilament assays and clinically validate serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) as prognostic and potential pharmacodynamic biomarkers relevant to amyotrophic lateral sclerosis (ALS) therapy development.MethodsIn this prospective, multicenter, longitudinal observational study of patients with ALS (n = 229), primary lateral sclerosis (n = 20), and progressive muscular atrophy (n = 11), biological specimens were collected, processed, and stored according to strict standard operating procedures (SOPs). Neurofilament assays were performed in a blinded manner by independent contract research organizations.ResultsFor serum NfL and pNfH measured using the Simoa assay, there were no missing data (i.e., technical replicates below the lower limit of detection were not encountered). For the Iron Horse and Euroimmun pNfH assays, such missingness was encountered in ∼4% and ∼10% of serum samples, respectively. Mean coefficients of variation for NfL in serum and CSF were both ∼3%. Mean coefficients of variation for pNfH in serum and CSF were ∼4%–5% and ∼2%–3%, respectively, in all assays. Baseline serum NfL concentration, but not pNfH, predicted the future Revised ALS Functional Rating Scale (ALSFRS-R) slope and survival. Incorporation of baseline serum NfL into mixed effects models of ALSFRS-R slopes yields an estimated sample size saving of ∼8%. Depending on the method used to estimate effect size, use of serum NfL (and perhaps pNfH) as pharmacodynamic biomarkers, instead of the ALSFRS-R slope, yields significantly larger sample size savings.ConclusionsSerum NfL may be considered a clinically validated prognostic biomarker for ALS. Serum NfL (and perhaps pNfH), quantified using the Simoa assay, has potential utility as a pharmacodynamic biomarker of treatment effect.

Published
2020

7. Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study

Author

Kazumi Takada, Vladislav Abramov, Seiko Yoshida, Pinar Ozcelik, Carolina Miranda, Jennifer Kane, Kaitlyn McKenna, Natasha Campbell, Sharon P. Nations, Shitiz Kumar Sriwastava, Yuko Fujii, Mayumi Murata, Linda Wagemaekers, Angela Andoin, Mollie Vanderhook, Yoshinori Okubo, Martin Bilsker, Taira Uehara, Vera Bril, Julia Wanschitz, Stanislava Toncrova, Mariela Bettini, Kazumi Futono, Shachie Aranke, Yool-hee Kim, Hiroyuki Murai, Anne Nyrhinen, Vinay Chaudhry, Raffaele Iorio, Takashi Kanda, Brittany Harvey, Francisco Javier Rodriguez de Rivera, Henning Andersen, Marianne de Visser, Miwako Sato, Yasuhiro Maeda, Fabienne Deruelle, Marina Pozo, Adam Hart, Masaki Saitoh, Wladimir Bocca Vieira de Rezende Pinto, Said R. Beydoun, Lindsay Zilliox, Akihiro Mukaino, Cinzia Caserta, Mahi Jasinarachchi, Andrea M. Corse, Nikoletta Papadopoulou, JuYoung Kwon, Fernanda Carrara, Juliet Saba, Masayuki Makamori, Vittorio Frasca, Luciana Souza Duca, Hoo Nam Kang, C. Trebst, Celile Phan, Muzeyyen Ugur, Eduardo Ng, Jonathan McKinnon, Hila Bali Kuperman, David Feder, Judit Matolcsi, Jiri Pitha, Martin Stangel, Kate Beck, Gabriel Paiva, Diego Lopergolo, Katrien De Mey, Hidenori Matsuo, Lucas Eduardo Pazetto, Eugene Lai, Amanda Anderson, Ann D'Hondt, Tetsuya Akiyama, Beverly Fyfe, Bella Gross, Elisabet Arribas-Ibar, Kathy de Koning, Gulmohor Roy, Dmitry Pokhabov, Maria Johanna Keijzers, Nicholas Ventura, Tessa Marburger, John Loor, Ji Eun Lee, Alessandro Filla, Celal Tuga, Stephanie Scala, Rudy Mercelis, Marc H. De Baets, Hisako Kobayashi, Stanislav Vohanka, Ana Paula Macagnan, Ana Carolina Amaral de Andrade, Heike Arndt, Giovanni Antonini, Yumi Yamashita, Gwendal Le Masson, Sonia Garcia, Sarah Verjans, James F. Howard, Zaeem A. Siddiqi, Yuen T. So, Megumi Koga, Exuperio Diez Tejedor, Teresa Costabile, Mihoko Takada Takada, Steve Hopkins, Jonathan S. Katz, Charlene Hafer-Macko, Erica Nogueira Coelho, Hung Youl Seok, Carol Herbert, Yuriko Nagane, Didem Altiparmak, Sachiko Kamakura, Mohammad Sanjak, Caroline Moreau, Jordi Díaz-Manera, Sivakumar Sathasivam, Michael Vytopil, Amelia Evoli, Masakatsu Motomura, Ester Reggio, Guy Van den Abeele, Hélène Zéphir, Asya Yarmoschuk, Jasmine Hewlett, Amy Wilson, Sachie Fukui, Cavit Boz, Iandra Souza, Morgane Gaboreau, Ivana Jurajdova, Sonia Decressac, Yong Seo Koo, Valentina Pegoraro, Seung Min Kim, Benison Keung, Rosana Rocha, Nanna Witting, John Vissing, Elaine Weiner, Ali Malekniazi, Larisa Babenko, Amanda C. Guidon, Gal Maier, Charlotte Smetcoren, Robert M. Pascuzzi, Domenico Marco Bonifati, Yumiko Nakamura, Tamires Cristina Gomes da Silva, Takashi Murahara, Sarah Plevka, Tomoko Tsuda, John C. Kincaid, Arnaud Lacour, Ibrez Bandukwala, Alan R. Berger, Chang Nyoung Lee, Jae-Sung Lim, Vern C. Juel, Tulio E. Bertorini, Valeria Cavalcante Lino, Namie Taichi, Ju-Hong Min, Josep Gamez, Nelly Greenbereg, William S. David, Srikanth Muppidi, Husnu Efendi, Pedro Lopez Ruiz, Baki Dogan, Cansu Semiz, Natalia Julia Palacios, Sharon Downing, Paola Cudia, Daniel Jacobs, Can Ebru Bekircan-Kurt, Takayasu Fukudome, Kristen Roe, Lena Bjarbo, Nicole Kassebaum, Makoto Samukawa, Shizuka Asada, Christina Dheel, Fatima Maqsood, Eun Bi Hwang, Kevin Daniels, Sevim Erdem-Ozdamar, Olivier Stevens, Claudio Mazia, Karan Alcon, Sibel Gazioglu, Keiko Kikutake, Luis Lay, Petra Tilkin, Corrado Angelini, Derrick Blackmore, Kimiaki Utsugisawa, Despoina Charalambous, Tuula Harrison, Kristin Huynh, Huned S. Patwa, Laura Echevarria, Henrique Mohr, Christian Homedes-Pedret, Richard J. Barohn, Byung Jo Kim, Daniel DiCapua, Terry McClain, Debora Dada Martineli Torres, Maria Salvado Figueras, Ana Paula Melo, Riley Snook, Miki Ogawa, Marcelo Annes, Yuka Saito, Isabel Illa, Evanthia Bernitsas, Nicole Smalley, Molly Lindsay, Robert G. Miller, Olga Azrilin, Silvia Bonanno, Evgeniya Kosykh, Marcela Wolfova, Olivier Outteryck, Shirli Toska, Anna Kostera-Pruszczyk, HyeJin Ra, Rup Tandan, Sotirios Papagiannopoulos, Natasha Willlems, Anne Mette Ostergaard Autzen, Meinoshin Okumura, Patrick Vermersch, Sarada Sakamuri, Maria Antonia Alberti Aguilo, Shigemi Shimose, Cynthia Carter, Ira Blount, Lisa Thompson, Maurer Pereira Martins, Richard Nowak, Hyung Seok Lee, Anna Kaminska, Joan Bratton, Nazire Pinar Acar, Junichi Ogasawara, Mohamed Mahdi-Rogers, Teiichiro Mitazaki, Marek Čierny, Craig Donahue, Jaya Trivedi, Neelam Goyal, Gonzalo Vidal, Brandy Quarles, Akiko Kanzaki, Yasuko Ikeda, Tomomi Kobashikawa, Morris Brown, Daisuke Yamamoto, Michel Deneve, Denis Korobko, Beth DiSanzo, Benedikt Schoser, Heidi Boterhoven, Eri Kobayashi, Maoko Shirane, Cristiani Fernanda Butinhao, Eriko Higuchi, Takashi Hayashi, Masanori Takahashi, Anne-Cécile Wielanek-Bachelet, Benjamin Rix Brooks, Emanuela Onesti, Tahseen Mozaffar, Liang Lu, Sevasti Bostantzopoulou, Christophe Vial, Shawn J. Bird, Sandi Mumfrey-Thomas, Julie Khoury, Kara Patrick, Kenichi Tsukita, Yoshiko Sano, Hiroshi Nakazora, David P. Richman, Gavin Brown, Yoon-Ho Hong, Tomohiro Kawamura, Igor Dias Brockhausen, Ye Liu, Acary Souza Bulle Oliveira, Soichiro Funaka, Tomoya Hasuike, Frank Lin, Luis Antonio Querol Gutierrez, Namita Goyal, Elena Pinzan, Michelle Mellion, Silvia Messina, Christopher Lindberg, Csilla Rozsa, J. Chad Hoyle, Yoko Kaneko, Gustavo Duran, Francesco Patti, Arshira Seddigh, Ele Kim Perez, Jayashri Srinivasan, Michael Benatar, Philip Van Damme, Salma Akhter, Daniel Ambrosio, Maria Salvado, Floyd Jones, Mark Sivak, Anneke J. van der Kooi, Karen Callison, Catherine Nigro, Rebekah Garcia, Thomas Arnold, Hideki Arima, Brigid Crabtree, Mary Varghese, Aditya Kumar, Miri Kim, Fanny O'Brien, Naya McKinnon, Lauren Wheeler, Hong Vu, Shunsuke Yoshimura, Masatoshi Omoto, Jeffrey T. Guptill, Maria Gabriele, Francoise Bouhour, Veena Mathew, Ritsu Nakayama, Rosa Hasan, Francesco Saccà, Mohammed Salajegheh, Diana Dimitrova, Alzira Alves de Siqueira Carvalho, Maurizio Inghilleri, George Sachs, Rekha Pillai, Enrico Marano, Monika Konyane, Anh Tran, Seda Aydinlik, Kendrick Henderson, Fumie Meguro, Alexandre Guerreiro, Amaiak Chilingaryan, Tiyonnoh Cash, Jun Kawamata, Julie Steele, Helene Gervais-Bernard, Thomas Harbo, Alejandra Dalila Garcia, Musa Kazim Onar, Sabrina Sacconi, Carlos Casasnovas Pons, Nadezhda Malkova, Denis Sazonov, Mireya Fernandez-Fournier, Karin Fricke, Laurie Gutmann, Amy Saklad, Clara Schommer, Sandra Taber, Fiona Norwood, Tugce Kirbas Cavdar, Monique Miesen, Fernanda Troili, Masanori Watanabe, Ratna Bhavaraju-Sanka, Ted M. Burns, Sari Atula, Faisal Sohail, Barbora Kurkova, Brigitta Szabadosne, Luciana Renata Cubas Volpe, Jane Pedersen, Jing Jing Wang, Masashi Inoue, Antonella Di Pasquale, Megan Kramer, Magda Chmelikova, Mehran Soltani, Tuan Vu, Laura Fionda, Eliz Agopian, Susan Shin, Anthony A. Amato, Lotte Vinge, Hakan Cavus, Gil I. Wolfe, Joan Nye, Delphine Mahieu, Miguel Wilken, Markus Färkkilä, Catherine Faber, Erin Manning, Emiko Tsuda, Rami Massie, Paolo Emilio Alboini, Yasmeen Shabbir, Angela Campanella, Aikaterini Dimitriou, Marcelo Rugiero, Cynthia Bodkin, Gyorgyi Szabo, Sharon Halton, Akshay Shah, Yasuko Maeda, Hans D. Katzberg, Yagmur Caliskan, Jaimin Shah, Katsuhisa Masaki, Valentina Damato, Blanka Andersson, Aline de Cassia Santos, Masahiro Mori, Renato Mantegazza, Misa Shimpo, Joanne Nemeth, Livia Dezsi, Anna De Rosa, Doreen Ho, Julie Moutarde, Efstathia Mitropoulou, Amy Woodall, Angela Micheels, László Vécsei, Byoung Joon Kim, Lisa Smith, Tomihiro Imai, Harpreet Kaur, Lorenzo Maggi, Jane Distad, Anita Mogensen, Ericka Simpson, Anne Cooley, Eliana Reyes, Ha Young Shin, Da Yoon Koh, Stefan Gingele, Susan Strom, Ezgi Yilmaz, Manisha Chopra, Anna Melnikova, Edouard Millois, Ludwig Gutmann, Miriam Freimer, Hirokazu Shinozaki, Heena Olalde, Kerry Naunton, Shunya Nakane, Ihsan Sengun, Dimos-Dimitrios Mitsikostas, Edina Varga, Juha-Pekka Erälinna, Wolfgang Löscher, Jan De Bleecker, Elena Bravver, Ana Lazaro, Eun Bin Cho, Thomas Cochrane, Jonathan Goldstein, Lisa D. Hobson-Webb, Michaela Tyblova, Angela Marsil, J. Edward Hartmann, Miyuki Morikawa, Karen Zakalik, Claude Desnuelle, Iveta Novakova, Michiaki Koga, Melinda Horvath, Luiz Otavio Maia Gonçalves, Elena Cortes Vicente, Alejandro Tobon Gonzalez, Stanley H. Appel, Brian Minton, Daniele Orrico, Brian Droker, Jacob Kaufman, Erica Coelho, Chafic Karam, Mikko Laaksonen, Katherine Amato, Jinmyoung Seok, Natalia Prando, Pauline Lahaut, Kaori Osakada, Phillipa Lamont, Alexandros Tselis, Daiane da Cruz Pacheco, Joan Højgaard, Hirokazu Shiraishi, Josef Bednarik, Stefania Morino, Mark Levine-Weinberg, Sara-Claude Michon, Yusuke Fukuda, Michael Pulley, Koichi Narikawa, Ricardo Rojas Garcia, Betsy Mosmiller, James Gilchrist, Maria da Penha Morita Ananias, Maryanne Burdette, Shingo Konno, Janelle Butters, Stephan Wenninger, Debbie Davies, Thomas Skripuletz, Mohammad Alsharabati, Katarina Reguliova, Gabor Lovas, Yuichiro Gondo, Miju Shin, HyeLim Lee, Bruno Bezerra Rosa, Michael D. Weiss, Martha Zampaki, Andrea Caramma, Jeffrey V. Rosenfeld, Cigdem Ozen Aydin, Shara Holzberg, Hélène Merle, Olga Zapletalova, Kurt-Wolfram Suehs, Robert P. Lisak, Dale J. Lange, Albert Hietala, Sedat Sen, Elena Giacomelli, Akiyuki Uzawa, Tomás Augusto Suriane Fialho, Matteo Garibaldi, Nadia Sattar, Wai-Kuen Leong, Lindsay Kaplan, Tetsuya Kanai, Jaana Eriksson, Akiko Nagaishi, Khema Sharma, Tamar Gibson, Mohamed Kazamel, Yulia Nesterova, Sascha Alvermann, Murat Terzi, Taylor Darnell, Donna Carnes, Victor Balyazin, John T. Kissel, Waqar Waheed, Jana Junkerova, Kimberly Robeson, Nicholas Vlaikidis, Nicholas Silvestri, Fredrik Piehl, Maurício André Gheller Friedrich, Shun Shimohama, Nuria Vidal, Eleni Kasioti, H. James Jones, Michael K. Hehir, Luiz Augusto da Silva, Dave Watling, Leslie Roberts, Casey Faigle, Caroline Hourquin, Olli Oksaranta, Tomomi Imamura, Shin Hisahara, Dennis Jeffery, Marie-Hélène Soriani, M. Kawai, Chieko Yoshikawa, Roseann Keo, Angela Genge, Michelangelo Maestri Tassoni, Milvia Pleitez, Michael H. Rivner, Maki Jingu, Giorgia Puorro, Andrea Swenson, Saiju Jacob, Carolina Ortea, Shuichiro Suzuki, Marguerite Engel, Ikuko Kamegamori, SangAe Park, Guilhem Sole, Lesly Welsh, Nichole Gallatti, Jakit Gollogly, Daniel Jons, Yasuteru Sano, Takuya Matsushita, Omar Khan, Maria Cristina Gori, Thabata Veiga, Julie Agriesti, Jos Maessen, Sandra Guinrich, Francesca Bevilacqua, Laura Haar, Jordana Gonçalves Geraldo, Justin Y. Kwan, Hidekazu Suzuki, Dai Matsuse, Kelly Jia, Ozlem Tun, Lara Katzin, Yasushi Suzuki, Shannon Lucy, Carlo Antozzi, ANS - Neuroinfection & -inflammation, Neurology, Howard, James F, Utsugisawa, Kimiaki, Benatar, Michael, Murai, Hiroyuki, Barohn, Richard J, Illa, Isabel, Jacob, Saiju, Vissing, John, Burns, Ted M, Kissel, John T, Muppidi, Srikanth, Nowak, Richard J, O'Brien, Fanny, Wang, Jing-Jing, Mantegazza, Renato, Mazia, Claudio Gabriel, Wilken, Miguel, Ortea, Carolina, Saba, Juliet, Rugiero, Marcelo, Bettini, Mariela, Vidal, Gonzalo, Garcia, Alejandra Dalila, Lamont, Phillipa, Leong, Wai-Kuen, Boterhoven, Heidi, Fyfe, Beverly, Roberts, Leslie, Jasinarachchi, Mahi, Willlems, Natasha, Wanschitz, Julia, Löscher, Wolfgang, De Bleecker, Jan, Van den Abeele, Guy, de Koning, Kathy, De Mey, Katrien, Mercelis, Rudy, Wagemaekers, Linda, Mahieu, Delphine, Van Damme, Philip, Smetcoren, Charlotte, Stevens, Olivier, Verjans, Sarah, D'Hondt, Ann, Tilkin, Petra, Alves de Siqueira Carvalho, Alzira, 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Jame, Rosenfeld, Jeffrey, Garcia, Rebekah, Garcia, Sonia, Echevarria, Laura, Pulley, Michael, Aranke, Shachie, Berger, Alan Ro, Shah, Jaimin, Shabbir, Yasmeen, Smith, Lisa, Varghese, Mary, Gutmann, Laurie, Gutmann, Ludwig, Swenson, Andrea, Olalde, Heena, Hafer-Macko, Charlene, Kwan, Justin, Zilliox, Lindsay, Callison, Karen, Disanzo, Beth, Naunton, Kerry, Bilsker, Martin, Sharma, Khema, Reyes, Eliana, Cooley, Anne, Michon, Sara-Claude, Steele, Julie, Karam, Chafic Karam, Chopra, Manisha, Bird, Shawn, Kaufman, Jacob, Gallatti, Nichole, Vu, Tuan, Katzin, Lara, Mcclain, Terry, Harvey, Brittany, Hart, Adam, Huynh, Kristin, Beydoun, Said, Chilingaryan, Amaiak, Droker, Brian, Lin, Frank, Shah, Akshay, Tran, Anh, Akhter, Salma, Malekniazi, Ali, Tandan, Rup, Hehir, Michael, Waheed, Waqar, Lucy, Shannon, Weiss, Michael, Distad, Jane, Downing, Sharon, Strom, Susan, Lisak, Robert, Bernitsas, Evanthia, Khan, Omar, Kumar Sriwastava, Shitiz, Tselis, Alexandro, Jia, Kelly, Bertorini, Tulio, Arnold, Thoma, Henderson, Kendrick, Pillai, Rekha, Liu, Ye, Wheeler, Lauren, Hewlett, Jasmine, Vanderhook, Mollie, Dicapua, Daniel, Keung, Benison, Kumar, Aditya, Patwa, Huned, Robeson, Kimberly, Nye, Joan, Vu, Hong, Howard, J, Utsugisawa, K, Benatar, M, Murai, H, Barohn, R, Illa, I, Jacob, S, Vissing, J, Burns, T, Kissel, J, Muppidi, S, Nowak, R, O'Brien, F, Wang, J, Mantegazza, R, and Bonanno, S

Subjects
Male, 0301 basic medicine, medicine.medical_treatment, Drug Resistance, Adult, Aged, Antibodies, Monoclonal, Humanized, Autoantibodies, Double-Blind Method, Female, Humans, Middle Aged, Myasthenia Gravis, Receptors, Cholinergic, Outcome Assessment (Health Care), Severity of Illness Index, Neurology (clinical), law.invention, Complement inhibitor, 0302 clinical medicine, Randomized controlled trial, law, Monoclonal, Receptors, Clinical endpoint, Humanized, Cholinergic, education.field_of_study, Eculizumab, Autoantibodie, Myasthenia Gravi, Settore MED/26 - NEUROLOGIA, Human, medicine.drug, Meningitides, medicine.medical_specialty, Population, Placebo, Antibodies, 03 medical and health sciences, Internal medicine, medicine, education, business.industry, Surgery, Thymectomy, 030104 developmental biology, business, 030217 neurology & neurosurgery
Abstract

Background Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial. Methods We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II-IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229. Findings Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56·6 [SEM 4·5] vs 68·3 [4·5]; rank-based treatment difference -11·7, 95% CI -24·3 to 0·96; p=0·0698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy. Interpretation The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed. Funding Alexion Pharmaceuticals.

Published
2017

8. Validation of Serum Neurofilaments as Prognostic & Potential Pharmacodynamic Biomarkers for ALS

Author

Rosa Rademakers, Lyle W. Ostrow, Lanyu Zhang, Michael Benatar, Volkan Granit, Joanne Wuu, Carlayne E. Jackson, Richard J. Barohn, Andrea Swenson, Jeffrey Statland, Jacob L. McCauley, Ted M. Burns, Jaya Trivedi, John Ravits, Andrea Malaspina, Lily Wang, Jonathan S. Katz, James B. Caress, and Erik P. Pioro

Subjects
Oncology, 0303 health sciences, medicine.medical_specialty, Neurofilament, business.industry, Operating procedures, Progressive muscular atrophy, medicine.disease, Serum samples, 03 medical and health sciences, 0302 clinical medicine, Sample size determination, Internal medicine, Pharmacodynamics, medicine, Mixed effects, Prognostic biomarker, business, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

ObjectiveIdentify preferred neurofilament assays, and clinically validate serum NfL and pNfH as prognostic and potential pharmacodynamic biomarkers relevant to ALS therapy development.MethodsProspective, multi-center, longitudinal observational study of patients with ALS (n=229), primary lateral sclerosis (PLS, n=20) and progressive muscular atrophy (PMA, n=11). Biological specimens were collected, processed and stored according to strict standard operating procedures (SOPs) 1. Neurofilament assays were performed in a blinded manner by independent contract research organizations (CROs).ResultsFor serum NfL and pNfH measured using the Simoa assay, missing data (i.e. both technical replicates below the lower limit of detection (LLD) was not encountered. For the Iron Horse and Euroimmun pNfH assays, such missingness was encountered in ∼4% and ∼10% of serum samples respectively. Mean coefficients of variation (CVs) for pNfH in serum and CSF were ∼4-5% and ∼2-3% respectively in all assays. Baseline NfL concentration, but not pNfH, predicted the future ALSFRS-R slope and survival.Incorporation of baseline serum NfL into mixed effects models of ALSFRS-R slopes yields an estimated sample size saving of ∼8%. Depending on the method used to estimate effect size, use of serum NfL (and perhaps pNfH) as pharmacodynamic biomarkers, instead of the ALSFRS-R slope, yields significantly larger sample size savings.ConclusionsSerum NfL may be considered a clinically validated prognostic biomarker for ALS. Serum NfL (and perhaps pNfH), quantified using the Simoa assay, have potential utility as pharmacodynamic biomarkers of treatment effect.

Published
2019
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9. Patient Assisted Intervention for Neuropathy: Comparison of Treatment in Real Life Situations (PAIN-CONTRoLS)

Author

Suur Biliciler, Chafic Karam, Alexandru Barboi, Michael K. Hehir, Ghazala Hayat, Paul Twydell, Gil I. Wolfe, Alexandra R. Brown, Pariwat Thaisetthawatkul, Dianna Quan, Moiz Ahmed, Mazen M. Dimachkie, Darryl Heitzman, Alejandro Tobon, Yuebing Li, Andrea Swenson, Jau Shin Lou, William Mallonee, Richard A. Lewis, John T. Kissel, Ted M. Burns, Mark Jacoby, Noah Kolb, Robert M. Pascuzzi, Jaya Trivedi, Tiyonnoh M. Cash, Thomas H. Brannagan, Jeffrey W. Ralph, Vera Bril, Amro M. Stino, Sindhu Ramchandren, Michael Pulley, Christen Kutz, Khema Sharma, Richard J. Barohn, Anza B. Memon, David Saperstein, Matthew Wicklund, Stanley Iyadurai, Navin Verma, Shafeeq Ladha, Gordon Smith, Kim S. Kimminau, Laura Herbelin, Dinesh Pal Mudaranthakam, Byron J. Gajewski, Mark Bazant, Hani Kushlaf, Mamatha Pasnoor, Aiesha Ahmed, Kian Salajegheh, Yessar Hussain, Sara Austin, Omar Jawdat, Tuan Vu, James Wymer, David Walk, and Stephen N. Scelsa

Subjects
medicine.medical_specialty, Randomization, Diabetic neuropathy, business.industry, Pregabalin, Interim analysis, medicine.disease, law.invention, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, chemistry, law, Internal medicine, Neuropathic pain, Medicine, Duloxetine, 030212 general & internal medicine, Neurology (clinical), Nortriptyline, business, 030217 neurology & neurosurgery, medicine.drug
Abstract

Importance Cryptogenic sensory polyneuropathy (CSPN) is a common generalized slowly progressive neuropathy, second in prevalence only to diabetic neuropathy. Most patients with CSPN have significant pain. Many medications have been tried for pain reduction in CSPN, including antiepileptics, antidepressants, and sodium channel blockers. There are no comparative studies that identify the most effective medication for pain reduction in CSPN. Objective To determine which medication (pregabalin, duloxetine, nortriptyline, or mexiletine) is most effective for reducing neuropathic pain and best tolerated in patients with CSPN. Design, Setting, and Participants From December 1, 2014, through October 20, 2017, a bayesian adaptive, open-label randomized clinical comparative effectiveness study of pain in 402 participants with CSPN was conducted at 40 neurology care clinics. The trial included response adaptive randomization. Participants were patients with CSPN who were 30 years or older, with a pain score of 4 or greater on a numerical rating scale (range, 0-10, with higher scores indicating a higher level of pain). Participant allocation to 1 of 4 drug groups used the utility function and treatment’s sample size for response adaptation randomization. At each interim analysis, a decision was made to continue enrolling (up to 400 participants) or stop the whole trial for success (80% power). Patient engagement was maintained throughout the trial, which helped guide the study and identify ways to communicate and disseminate information. Analysis was performed from December 11, 2015, to January 19, 2018. Interventions Participants were randomized to receive nortriptyline (n = 134), duloxetine (n = 126), pregabalin (n = 73), or mexiletine (n = 69). Main Outcomes and Measures The primary outcome was a utility function that was a composite of the efficacy (participant reported pain reduction of ≥50% from baseline to week 12) and quit (participants who discontinued medication) rates. Results Among the 402 participants (213 men [53.0%]; mean [SD] age, 60.1 [13.4] years; 343 White [85.3%]), the utility function of nortriptyline was 0.81 (95% bayesian credible interval [CrI], 0.69-0.93; 34 of 134 [25.4%] efficacious; and 51 of 134 [38.1%] quit), of duloxetine was 0.80 (95% CrI, 0.68-0.92; 29 of 126 [23.0%] efficacious; and 47 of 126 [37.3%] quit), pregabalin was 0.69 (95% CrI, 0.55-0.84; 11 of 73 [15.1%] efficacious; and 31 of 73 [42.5%] quit), and mexiletine was 0.58 (95% CrI, 0.42-0.75; 14 of 69 [20.3%] efficacious; and 40 of 69 [58.0%] quit). The probability each medication yielded the highest utility was 0.52 for nortriptyline, 0.43 for duloxetine, 0.05 for pregabalin, and 0.00 for mexiletine. Conclusions and Relevance This study found that, although there was no clearly superior medication, nortriptyline and duloxetine outperformed pregabalin and mexiletine when pain reduction and undesirable adverse effects are combined to a single end point. Trial Registration ClinicalTrials.gov Identifier:NCT02260388

Published
2021

10. Excellent response to therapeutic plasma exchange in myasthenia gravis patients irrespective of antibody status

Author

Dina Wahib-Khalil, Sharon P. Nations, Laura Kwan, Ravi Sarode, Jaya Trivedi, and Amena Usmani

Subjects
Adult, Male, medicine.medical_specialty, animal structures, Thymoma, medicine.medical_treatment, Late onset, 030204 cardiovascular system & hematology, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Sex Factors, Internal medicine, Myasthenia Gravis, medicine, Humans, Receptors, Cholinergic, Age of Onset, Autoantibodies, biology, Plasma Exchange, business.industry, fungi, Autoantibody, Antibody titer, Receptor Protein-Tyrosine Kinases, Hematology, General Medicine, Middle Aged, medicine.disease, Prognosis, Thymectomy, Myasthenia gravis, Titer, Treatment Outcome, biology.protein, Female, Antibody, business, 030215 immunology
Abstract

INTRODUCTION The primary objective of this study was to assess response to plasma exchange (PLEX) in myasthenia gravis (MG) patients with and without autoantibodies (Ab) to acetylcholine receptor (AChR) or muscle-specific kinase (MuSK). Analysis was also done to determine if correlation existed between sex, early or late onset MG, thymoma, or thymectomy and response to PLEX. MATERIALS AND METHODS Data was analyzed on 58 consecutive MG patients treated with PLEX. Responses were categorized as complete response, clinical improvement requiring maintenance PLEX, or no/minimal response to PLEX. RESULTS Eighty-eight percent (51/58) of patients were Ab-positive; 44 had AChR and 7 had MuSK Ab. Complete response was seen in 26 patients (24 Ab+), 24 remain on maintenance PLEX (19 Ab+), and 2 had no/minimal response (both AChR Ab+). Ab status (P = 0.43), AChR Ab (P = 0.10), MuSK Ab (P = 0.45), early onset MG (P = 0.63), thymoma (P = 0.46), and thymectomy (P = 0.16) were not significantly associated with outcome. Patient sex did show significant association with outcome (P = 0.01), with men more likely to have complete response and women more likely to require maintenance. Late onset MG is significantly associated with higher likelihood of complete response (P = 0.03). Antibody titers declined after PLEX in 83% of patients with complete response, in whom pre- and post-PLEX titers were available (n = 6). CONCLUSIONS In conclusion, our study showed 96% response rate to PLEX in MG; however, only patient gender and late onset MG were significantly associated with treatment response.

Published
2018

11. North America and South America (NA-SA) neuropathy project

Author

Saud Khan, Gil I. Wolfe, Jaya Trivedi, Giseli Quintanilha, Mamatha Pasnoor, Mazen M. Dimachkie, M.R.G. de Freitas, Osvaldo J. M. Nascimento, Laura Herbelin, Richard J. Barohn, and Sharon P. Nations

Subjects
Chagas disease, medicine.medical_specialty, Databases, Factual, Traditional medicine, business.industry, General Neuroscience, Peripheral Nervous System Diseases, General Medicine, Neurological disorder, South America, Familial amyloid neuropathy, medicine.disease, Tertiary care, Amyloid Neuropathy, Peripheral neuropathy, Virus type, Internal medicine, North America, medicine, Humans, Leprosy, business
Abstract

Peripheral neuropathy is a common neurological disorder. There may be important differences and similarities in the diagnosis of peripheral neuropathy between North America (NA) and South America (SA). Neuromuscular databases were searched for neuropathy diagnosis at two North American sites, University of Kansas Medical Center and University of Texas Southwestern Medical Center, and one South American site, Federal Fluminense University in Brazil. All patients were included into one of the six major categories: immune-mediated, diabetic, hereditary, infectious/inflammatory, systemic/metabolic/toxic (not diabetic) and cryptogenic. A comparison of the number of patients in each category was made between North America and South America databases. Total number of cases in North America was 1090 and in South America was 1034 [immune-mediated: NA 215 (19.7%), SA 191 (18%); diabetic: NA 148 (13.5%), SA 236 (23%); hereditary: NA 292 (26.7%), SA 103 (10%); infectious/inflammatory: NA 53 (4.8%), SA 141 (14%); systemic/metabolic/toxic: NA 71 (6.5%), SA 124 (12%); cryptogenic: NA 311 (28.5%), SA 239 (23%)]. Some specific neuropathy comparisons were hereditary neuropathies [Charcot-Marie-Tooth (CMT) cases] in NA 246/292 (84.2%) and SA 60/103 (58%); familial amyloid neuropathy in SA 31/103 (30%) and none in NA. Among infectious neuropathies, cases of human T-lymphotropic virus type 1 (HTLV-1) neuropathy in SA were 36/141(25%), Chagas disease in SA were 13/141(9%) and none for either in NA; cases of neuropathy due to leprosy in NA were 26/53 (49%) and in SA were 39/141(28%). South American tertiary care centers are more likely to see patients with infectious, diabetic and hereditary disorders such as familial amyloid neuropathies. North American tertiary centers are more likely to see patients with CMT. Immune neuropathies and cryptogenic neuropathies were seen equally in North America and South America.

Published
2013

12. Clinical findings in MuSK-antibody positive myasthenia gravis: A U.S. experience

Author

Sharon P. Nations, Gil I. Wolfe, Mazen M. Dimachkie, Richard J. Barohn, Tulio E. Bertorini, Laura Herbelin, Steven Novella, Jaya Trivedi, Jonathan Goldstein, Luis A. Chui, Ronan J. Walsh, Angela Young, Shin Oh, April McVey, Lawrence H. Phillips, Ted M. Burns, Anthony A. Amato, Mamatha Pasnoor, John T. Kissel, Gwendolyn C. Claussen, Tahseen Mozaffar, and Marcel Hungs

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Physiology, medicine.drug_class, medicine.medical_treatment, Severity of Illness Index, Disease-Free Survival, Medical Records, Cellular and Molecular Neuroscience, Atrophy, Physiology (medical), Internal medicine, Myasthenia Gravis, Severity of illness, medicine, Humans, Receptors, Cholinergic, Age of Onset, Child, Aged, Retrospective Studies, Plasma Exchange, biology, Electromyography, business.industry, Remission Induction, Immunoglobulins, Intravenous, Receptor Protein-Tyrosine Kinases, Retrospective cohort study, Middle Aged, Thymectomy, medicine.disease, United States, Myasthenia gravis, Surgery, Treatment Outcome, biology.protein, Prednisone, Corticosteroid, Female, Immunotherapy, Neurology (clinical), Age of onset, Antibody, business
Abstract

We performed a retrospective chart review on 53 muscle-specific kinase antibody (MuSK-Ab)-positive myasthenia gravis (MG) patients at nine university-based centers in the U.S. Of these, 66% were Caucasian, 85% were women, and age of onset was 9-79 years. Twenty-seven patients were nonresponsive to anticholinesterase therapy. Myasthenia Gravis Foundation of America improvement status was achieved in 53% patients on corticosteroids, 51% with plasma exchange, and in 20% on intravenous immunoglobulin (IVIG). Thymectomy was beneficial in 7/18 patients at 3 years. Long-term (> or =3 years) outcome was very favorable in 58% of patients who achieved remission and/or minimal manifestation status. Overall, 73% improved. There was one MG-related death. This survey reinforces several cardinal features of MuSK-Ab-positive MG, including prominent bulbar involvement and anticholinesterase nonresponsiveness. Facial or tongue atrophy was rare. Most patients respond favorably to immunotherapy. The best clinical response was to corticosteroids and plasma exchange, and the poorest response was to IVIG. Long-term outcome is favorable in about 60% of cases.

Published
2010

13. Clinical Review of Muscle-Specific Tyrosine Kinase-Antibody Positive Myasthenia Gravis

Author

Gil I. Wolfe, Shin J. Oh, and Jaya Trivedi

Subjects
medicine.medical_specialty, biology, medicine.diagnostic_test, business.industry, General Medicine, Electromyography, medicine.disease, Myasthenia gravis, Receptor tyrosine kinase, Endocrinology, Neurology, Refractory, Internal medicine, medicine, biology.protein, Neurology (clinical), Repetitive nerve stimulation, Antibody, Abnormality, business, Tyrosine kinase
Abstract

Antibodies to muscle-specific receptor tyrosine kinase (MuSK-Ab) are detected in approximately 40% of generalized acetylcholine receptor antibody (AChR-Ab)-negative myasthenia gravis (MG). Based on a growing number of clinical series, a MuSK-Ab-positive phenotype is emerging. Although these clinical patterns are not wholly distinct from either AChR-Ab-positive or seronegative (both AChR-Ab- and MuSK-Ab-negative) MG, they are still helpful in identifying these patients. Patients with MuSK-Ab-positive MG are predominantly female with more prominent cranial and bulbar involvement and more frequent crises than other populations of people with MG. Disease onset tends to be earlier, generally by the third or fourth decade. The yield of repetitive nerve stimulation with conventional limb muscles is lower in these patients, but at least three-fourths demonstrate decrements in facial-innervated muscles. Similarly, single-fiber electromyography of distal limb muscles tends to have a lower yield of abnormality in patients who are MuSK-Ab-positive than either AChR-Ab-positive or seronegative MG, whereas jitter is increased in nearly all patients who are MuSK-Ab-positive when proximal limb or cranial musculature is studied. Patients who are MuSK-Ab-positive are more likely to display poor tolerance of or a lack of improvement with anticholinesterase agents. Most are managed successfully with immunomodulatory therapies, although a higher proportion of patients with MuSK MG have a refractory course when compared to other generalized populations.

Published
2007

14. Randomized, placebo-controlled trials of dichlorphenamide in periodic paralysis

Author

Antony Amato, Michael P. McDermott, John T. Kissel, Patty C. Smith, Perry B. Shieh, Alan Pestronk, Jeffrey W. Ralph, Hiroshi Mitsumoto, Michael G. Hanna, Valeria A. Sansone, Shree Pandya, Emma Ciafaloni, Giovanni Meola, Brian A. Crum, J. Burge, Richard J. Barohn, Robert C. Griggs, Barbara E. Herr, Jaya Trivedi, Robin Conwit, Rabi Tawil, and Steve C. Cannon

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Dichlorphenamide, Gene mutation, Placebo, Hop (networking), law.invention, Paralyses, Familial Periodic, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Quality of life, Double-Blind Method, law, Internal medicine, medicine, Humans, Adverse effect, Carbonic Anhydrase Inhibitors, business.industry, Periodic paralysis, Middle Aged, medicine.disease, Confidence interval, 030104 developmental biology, Physical therapy, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

Objective: To determine the short-term and long-term effects of dichlorphenamide (DCP) on attack frequency and quality of life in hyperkalemic (HYP) and hypokalemic (HOP) periodic paralysis. Methods: Two multicenter randomized, double-blind, placebo-controlled trials lasted 9 weeks (Class I evidence), followed by a 1-year extension phase in which all participants received DCP. Forty-four HOP and 21 HYP participants participated. The primary outcome variable was the average number of attacks per week over the final 8 weeks of the double-blind phase. Results: The median attack rate was lower in HOP participants on DCP than in participants on placebo (0.3 vs 2.4, p = 0.02). The 9-week mean change in the Physical Component Summary score of the Short Form–36 was also better in HOP participants receiving DCP (treatment effect = 7.29 points, 95% confidence interval 2.26 to 12.32, p = 0.006). The median attack rate was also lower in HYP participants on DCP (0.9 vs 4.8) than in participants on placebo, but the difference in median attack rate was not significant ( p = 0.10). There were no significant effects of DCP on muscle strength or muscle mass in either trial. The most common adverse events in both trials were paresthesia (47% DCP vs 14% placebo, both trials combined) and confusion (19% DCP vs 7% placebo, both trials combined). Conclusions: DCP is effective in reducing the attack frequency, is safe, and improves quality of life in HOP periodic paralysis. Classification of evidence: These studies provide Class I evidence that DCP significantly reduces attack frequency in HOP but lacked the precision to support either efficacy or lack of efficacy of DCP in HYP.

Published
2015

15. Phase 1 safety and pharmacokinetics of the novel enzyme replacement therapy neoGAA in treatment-naïve and alglucosidase alfa-treated late-onset Pompe disease patients

Author

Benedikt Schoser, Philip Van Damme, John Vissing, Kerry Culm-Merdek, Pascal Laforêt, Volker Straub, Shafeeq Ladha, Jaya Trivedi, Loren Pena, Eugen Mengel, Jean Pouget, Peter Young, Raheel Shafi, Alan Pestronk, and Gerard Short

Subjects
medicine.medical_specialty, business.industry, Endocrinology, Diabetes and Metabolism, Late onset, Disease, Enzyme replacement therapy, Biochemistry, Gastroenterology, Therapy naive, Endocrinology, Pharmacokinetics, Internal medicine, Genetics, medicine, business, Molecular Biology, Alglucosidase alfa, medicine.drug
Published
2016

16. Non-dystrophic myotonia: prospective study of objective and patient reported outcomes

Author

Emma Matthews, Jeffrey Statland, Richard J. Barohn, Robert C. Griggs, Dipa L. Raja Rayan, Michael G. Hanna, Stephen C. Cannon, Shannon L. Venance, Jaya Trivedi, Yunxia Wang, Anthony A. Amato, Mohammad Salajegheh, Nina Gorham, Laura Herbelin, Brian N. Bundy, Doreen Fialho, and James C. Cleland

Subjects
musculoskeletal diseases, Adult, Male, medicine.medical_specialty, International Cooperation, Mexiletine, Handgrip myotonia, Myotonic dystrophy, Myotonia, Cohort Studies, Physical medicine and rehabilitation, Chloride Channels, Internal medicine, medicine, Humans, Muscle Strength, NAV1.4 Voltage-Gated Sodium Channel, Exercise, Retrospective Studies, Neurologic Examination, Voltage-Gated Sodium Channel Blockers, CLCN1, Muscle Weakness, biology, Paradoxical myotonia, business.industry, Electrodiagnosis, Muscle weakness, RNA-Binding Proteins, Periodic paralysis, Original Articles, Middle Aged, medicine.disease, Mutation, biology.protein, Quality of Life, Female, Neurology (clinical), medicine.symptom, business, medicine.drug
Abstract

Non-dystrophic myotonias are rare diseases caused by mutations in skeletal muscle chloride and sodium ion channels with considerable phenotypic overlap between diseases. Few prospective studies have evaluated the sensitivity of symptoms and signs of myotonia in a large cohort of patients. We performed a prospective observational study of 95 participants with definite or clinically suspected non-dystrophic myotonia recruited from six sites in the USA, UK and Canada between March 2006 and March 2009. We used the common infrastructure and data elements provided by the NIH-funded Rare Disease Clinical Research Network. Outcomes included a standardized symptom interview and physical exam; the Short Form-36 and the Individualized Neuromuscular Quality of Life instruments; electrophysiological short and prolonged exercise tests; manual muscle testing; and a modified get-up-and-go test. Thirty-two participants had chloride channel mutations, 34 had sodium channel mutations, nine had myotonic dystrophy type 2, one had myotonic dystrophy type 1, and 17 had no identified mutation. Phenotype comparisons were restricted to those with sodium channel mutations, chloride channel mutations, and myotonic dystrophy type 2. Muscle stiffness was the most prominent symptom overall, seen in 66.7% to 100% of participants. In comparison with chloride channel mutations, participants with sodium mutations had an earlier age of onset of stiffness (5 years versus 10 years), frequent eye closure myotonia (73.5% versus 25%), more impairment on the Individualized Neuromuscular Quality of Life summary score (20.0 versus 9.44), and paradoxical eye closure myotonia (50% versus 0%). Handgrip myotonia was seen in three-quarters of participants, with warm up of myotonia in 75% chloride channel mutations, but also 35.3% of sodium channel mutations. The short exercise test showed ≥10% decrement in the compound muscle action potential amplitude in 59.3% of chloride channel participants compared with 27.6% of sodium channel participants, which increased post-cooling to 57.6% in sodium channel mutations. In evaluation of patients with clinical and electrical myotonia, despite considerable phenotypic overlap, the presence of eye closure myotonia, paradoxical myotonia, and an increase in short exercise test sensitivity post-cooling suggest sodium channel mutations. Outcomes designed to measure stiffness or the electrophysiological correlates of stiffness may prove useful for future clinical trials, regardless of underlying mutation, and include patient-reported stiffness, bedside manoeuvres to evaluate myotonia, muscle specific quality of life instruments and short exercise testing.

Published
2013

17. A Quantitative Measure of Handgrip Myotonia in Non-dystrophic Myotonia

Author

Jeffrey Statland, Emma Matthews, L. Dewar, Richard J. Barohn, Karen Findlater, Yunxia Wang, Robert C. Griggs, Jaya Trivedi, Merideth Donlan, Laura Herbelin, Anthony A. Amato, Brian N. Bundy, Shannon L. Venance, Katy Eichinger, Dipa L. Raja Rayan, Shree Pandya, Rhonda McLin, Michael G. Hanna, and William B. Martens

Subjects
musculoskeletal diseases, Adult, Male, medicine.medical_specialty, Physiology, Handgrip myotonia, Article, Sodium Channels, Myotonia, Cellular and Molecular Neuroscience, Young Adult, Chloride Channels, Physiology (medical), Internal medicine, Hand strength, medicine, Humans, Hyperkalemic periodic paralysis, Diagnosis, Computer-Assisted, Longitudinal Studies, Aged, Muscle Weakness, Paradoxical myotonia, Hand Strength, business.industry, Sodium channel, Muscle weakness, Middle Aged, medicine.disease, body regions, Endocrinology, Paramyotonia congenita, Mutation, Cardiology, Exercise Test, Female, Neurology (clinical), medicine.symptom, business
Abstract

Introduction: Non-dystrophic myotonia (NDM) is characterized by myotonia without muscle wasting. A standardized quantitative myotonia assessment (QMA) is important for clinical trials. Methods: Myotonia was assessed in 91 individuals enrolled in a natural history study using a commercially available computerized handgrip myometer and automated software. Average peak force and 90% to 5% relaxation times were compared with historical normal controls studied with identical methods. Results: Thirty subjects had chloride channel mutations, 31 had sodium channel mutations, 6 had DM2 mutations, and 24 had no identified mutation. Chloride channel mutations were associated with prolonged first handgrip relaxation times and warm-up on subsequent handgrips. Sodium channel mutations were associated with prolonged first handgrip relaxation times and paradoxical myotonia or warm-up, depending on underlying mutations. DM2 subjects had normal relaxation times but decreased peak force. Sample size estimates are provided for clinical trial planning. Conclusion: QMA is an automated, non-invasive technique for evaluating myotonia in NDM. Muscle Nerve 46: 482–489, 2012

Published
2012

18. An interactive voice response diary for patients with non-dystrophic myotonia

Author

Jeffrey M, Statland, Yunxia, Wang, Rachel, Richesson, Brian, Bundy, Laura, Herbelin, Joe, Gomes, Jaya, Trivedi, Shannon, Venance, Anthony, Amato, Michael, Hanna, Robert, Griggs, Richard J, Barohn, and Jennifer, Lloyd

Subjects
musculoskeletal diseases, Adult, Male, Weakness, medicine.medical_specialty, Adolescent, Physiology, macromolecular substances, Severity of Illness Index, Medical Records, Article, Myotonia, Cellular and Molecular Neuroscience, Young Adult, Symptom frequency, Physiology (medical), Internal medicine, Interactive voice response, Mexiletine, Severity of illness, Medicine, Humans, Longitudinal Studies, Child, Aged, business.industry, Non dystrophic myotonia, Middle Aged, medicine.disease, Telephone, Multicenter study, Physical therapy, Voice, Female, Neurology (clinical), medicine.symptom, business, medicine.drug
Abstract

Non-dystrophic myotonia (NDM) is caused by mutations in muscle chloride and sodium channels. Currently, there is no standardized instrument for documenting symptom frequency and severity in NDM.Subjects used an automated, interactive, telephone-based voice response diary (IVR) to record frequency and severity of stiffness, weakness, pain, and tiredness once a week for 8 weeks, after their baseline visits.We describe the IVR and report data on 76 subjects for a total of 385 person-weeks. Overall there were 5.1 calls per subject. Forty-eight subjects called in 5 or more times, and 14 called in 8 times. Stiffness was both the most frequent and severe symptom. Warm-up and handgrip myotonia were associated with higher severity scores for stiffness.IVR is a convenient technology to allow patient reporting of repeated and real-time symptom frequency and severity, and it is presently being used in a trial of mexiletine in NDM.

Published
2011

19. Health-related quality-of-life improvements in CIDP with immune globulin IV 10%: the ICE Study

Author

Stanislav Vohanka, Florian P Thomas, Chunqin Deng, Fabio Barroso, Jaya Trivedi, James Caress, Blanka Adamova, Ivana Basta, Giovanni luigi Mancardi, Halina Bartosik-Psujek, Luana Benedetti, Patrizia Dacci, Joab Chapman, Nilo Riva, and Josef Bednarik

Subjects
Adult, medicine.medical_specialty, Adolescent, Placebo, law.invention, Young Adult, Randomized controlled trial, Quality of life, Double-Blind Method, law, Internal medicine, medicine, Humans, Young adult, Social Behavior, Cross-Over Studies, business.industry, Immunoglobulins, Intravenous, Polyradiculoneuropathy, medicine.disease, Crossover study, Confidence interval, Endocrinology, Mental Health, Polyradiculoneuropathy, Chronic Inflammatory Demyelinating, Immune globulin IV, Quality of Life, Neurology (clinical), business
Abstract

Background: Chronic inflammatory demyelinating polyradiculoneuropathy trials have demonstrated the efficacy of IV immunoglobulin vs placebo. However, these trails have not addressed the long-term impact on health-related quality of life (HRQoL). Methods: One hundred seventeen patients in a randomized, double-blind, response-conditional crossover trial received immune globulin IV, 10% caprylate/chromatography purified (IGIV-C [Gamunex®]), or placebo every 3 weeks for up to 24 weeks in the first period (FP). Participants whose inflammatory neuropathy cause and treatment disability score did not improve by ≥1 point received alternate treatment in a 24-week crossover period (CP). In either period, participants who improved and completed treatment were eligible to be randomly reassigned to a blinded 24-week extension phase (EP). HRQoL analyses were conducted using the Short Form-36® (SF-36) and the Rotterdam Handicap Scale (RHS). Results: In the FP, greater improvements in both SF-36 physical and mental component scores were observed with IGIV-C vs placebo, with a significant improvement in the physical component score (difference 4.4 points; 95% confidence interval [CI] 0.7–8.0). Improvements in all SF-36 domains favored IGIV-C vs placebo, with physical functioning, role–physical, social functioning, and mental health reaching significance. Participants receiving IGIV-C experienced a larger improvement in RHS vs those receiving placebo (difference 3.4 points; 95% CI 1.4–5.5; p = 0.001). In the CP, similar general trends were observed. In the EP, mean SF-36 improvements were generally improved or maintained in participants who continued IGIV-C therapy; however, worsening was observed in participants re-randomized to placebo. Conclusions: Long-term therapy with immune globulin IV, 10% caprylate/chromatography purified, improves and maintains health-related quality of life in chronic inflammatory demyelinating polyradiculoneuropathy.

Published
2009

20. Clinical and Electrophysiologic Characterization of Chronic and Critical Ischemic Monomelic Neuropathy after Revascularization: A Case Series (P07.151)

Author

Sharon P. Nations, Jaya Trivedi, Srikanth Muppidi, Nicholas Absalom, and Gil I. Wolfe

Subjects
medicine.medical_specialty, business.industry, medicine.medical_treatment, Sympathetic skin response, Critical limb ischemia, Revascularization, Internal medicine, Anesthesia, medicine, Cardiology, Reflex, Contralateral limb, In patient, Neurology (clinical), medicine.symptom, Prospective cohort study, business, Symptom score
Abstract

Objective: To assess the outcome of chronic and critical ischemic monomelic neuropathy after revascularization. Background Chronic and critical limb ischemia is a known cause of monomelic neuropathy. Although revascularization improves rest pain, objective neuropathic improvement has not been adequately studied in prospective studies. Design/Methods: A prospective study was performed in 9 patients with critical limb ischemia. The contralateral limb was used as a control. Neurologic Symptom Score (NSS – range 0-15, sensory/motor), Neurologic Examination Score (NES – range 0-52, sensory/reflexes/motor), and electrophysiologic data were available for 5 patients at baseline and 6 months post revascularization. Results: The mean improvement in NSS was 6.6/15 (44%) in the revascularized limbs compared to 1.4/15 (9%) in the control limbs (p = 0.052). The mean improvement in NES was 3/52 (6%) in the revascularized limbs compared to 0/52 (0.3%) in the control limbs (p = 0.266). The sural sensory amplitude in the revascularized limbs was unchanged in 2, worsened in 2, and improved in 1 (absent to 7.8 µV). In the control limbs, this response worsened in 2, improved in 2, and was unchanged in 1. Improvement in conduction velocities of the peroneal and tibial motor responses were greater in revascularized than control limbs. Sympathetic skin response (SSR) was absent in three affected limbs at baseline, but were recordable post revascularization in two of these limbs. In the control limbs, SSR was present in 5/5 at baseline and 4/5 at 6 months. Conclusions: Improvement of symptoms, neurologic exam findings, and sympathetic function can be seen following revascularization in patients with chronic critical ischemic monomelic neuropathy. Disclosure: Dr. Absalom has nothing to disclose. Dr. Wolfe has received personal compensation for activities with Eli Lilly & Company, Talecris and Genzyme Corporation as a speaker and/or participant on an advisory board. Dr. Nations has received personal compensation for activities with Hilton Pharmaceuticals. Dr. Nations has received research support from Genzyme Corporation. Dr. Trivedi has nothing to disclose. Dr. Muppidi has nothing to disclose.

Published
2012

22. Clinical and Molecular Characterization of Non-Dystrophic Myotonia (P05.181)

Author

Michael G. Hanna, Shannon L. Venance, Dipa L. Raja Rayan, Jeffrey Statland, Laura Herbelin, Brian N. Bundy, Nina Gorham, Doreen Fialho, Kimberly A. Hart, Jaya Trivedi, Richard J. Barohn, Yunxia Wang, Robert C. Griggs, Anthony A. Amato, and Mohammad Salajegheh

Subjects
musculoskeletal diseases, Weakness, medicine.medical_specialty, CLCN1, biology, business.industry, Non dystrophic myotonia, Myotonia, medicine.disease, Episodic weakness, Mutational analysis, Eye closure myotonia, Internal medicine, biology.protein, Medicine, Neurology (clinical), medicine.symptom, business, Rare disease
Abstract

Objective: To describe genotype-phenotype correlations in non-dystrophic myotonia (NDM). Background NDM are heterogeneous disorders caused by mutations in skeletal muscle sodium (SCN4A) and chloride channel (CLCN1) genes. Although NDMs are distinct, it is at times difficult to distinguish them clinically. Design/Methods: 95 participants with NDM were recruited from 6 centers across the United States, England, and Canada. Mutational and clinical analyses were performed in 93. They were categorized into chloride channel (CLCN1), sodium channel (SCN4A), myotonic dystrophy type 2 (DM2), and unknown mutations. We included DM2 since they clinically present as NDM. We quantitated symptoms and myotonia measurements. Results: Of the 93 subjects reviewed, 29 had CLCN1, 31 SCN4A, and 7 DM2 mutations with 26 as yet unknown. Stiffness was the most prominent symptom in all subtypes and occurred earlier in the SCN (median-5 yrs) vs CLCN (10 yrs) and DM2 (35 yrs) (p=0.0001). Painful myotonia was reported in SCN (25/31), CLCN (16/29), and DM2 (5/7) (p=0.19). Episodic weakness was reported in all subtypes: 23/31 SCN, 12/29 CLCN, and 4/7 DM2. Frequency of fixed weakness was higher in DM2 (6/7) compared to SCN (7/30) and CLCN (9/29) (p=0.012). Muscle hypertrophy was most common in CLCN (21/29) followed by SCN (13/31). DM2 patients did not have hypertrophy. Eye closure myotonia was observed more in SCN (23/31) compared to CLCN (7/29) or DM2 (2/7) (p=0.0005). Grip myotonia warm-up was noted in 20/29 CLCN, 8/31 SCN, and 1/7 DM2 subjects. Paradoxical hand grip & eye closure myotonia was seen in 16/31 SCN. Conclusions: While clinical features can help differentiate various NDM subtypes, mutational analysis is required due to an overlap in the clinical findings in NDM patients. Supported by: NIH/Office of Rare Disease Research Network sponsored Consortium for Clinical Investigations of Neurological Channelopathies (CINCH). Disclosure: Dr. Trivedi has nothing to disclose. Dr. Bundy has nothing to disclose. Dr. Raja Rayan has nothing to disclose. Dr. Salajegheh has nothing to disclose. Dr. Statland has nothing to disclose. Dr. Venance has received personal compensation for activities with Genzyme Corporation. Dr. Wang has nothing to disclose. Dr. Fialho has nothing to disclose. Dr. Hart has nothing to disclose. Dr. Gorham has nothing to disclose. Dr. Herbelin has nothing to disclose. Dr. Amato has received personal compensation for activities with MedImmune, Amgen, and Biogen Idec as a medical advisory board member. Dr. Hanna has nothing to disclose. Dr. Griggs has nothing to disclose. Dr. Barohn has received personal compensation for activities with Talecris Biotherapeutics, Genzyme Corporation and Speakers Bureau. Dr. Barohn has received research support from Alexion Pharmaceuticals.

Published
2012

23. Phase 1 Exploratory Efficacy of the Novel Enzyme Replacement Therapy NeoGAA in Treatment-Naive and Alglucosidase Alfa-Treated Late-Onset Pompe Disease Patients

Author

Loren D.M. Pena, Ans van der Ploeg, Alan Pestronki, Jean Pouget, Shafeeq Ladha, Claude Desnuelle, John Vissing, Kerry Culm-Merdek, Peter Young, Philip Van Damme, Jaya Trivedi, Pascal Laforêt, Gerard Short, Volker Straub, Beth L. Thurberg, Richard Baron, Ozlem Goker-Alpan, Benedikt Schoser, Eugen Mengel, and Barry J. Byrne

Subjects
medicine.medical_specialty, business.industry, Endocrinology, Diabetes and Metabolism, Late onset, Enzyme replacement therapy, Disease, Biochemistry, Gastroenterology, Therapy naive, Endocrinology, Internal medicine, Genetics, medicine, Physical therapy, business, Molecular Biology, Alglucosidase alfa, medicine.drug

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