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1. Safety and tolerability of tegoprubart in patients with amyotrophic lateral sclerosis: A Phase 2A clinical trial.

Author

Steven Perrin, Shafeeq Ladha, Nicholas Maragakis, Michael H Rivner, Jonathan Katz, Angela Genge, Nicholas Olney, Dale Lange, Daragh Heitzman, Cynthia Bodkin, Omar Jawdat, Namita A Goyal, Jeffrey D Bornstein, Carmen Mak, Stanley H Appel, and Sabrina Paganoni

Subjects
Medicine
Abstract

BackgroundThe interaction of CD40L and its receptor CD40 on activated T cells and B cells respectively control pro-inflammatory activation in the pathophysiology of autoimmunity and transplant rejection. Previous studies have implicated signaling pathways involving CD40L (interchangeably referred to as CD154), as well as adaptive and innate immune cell activation, in the induction of neuroinflammation in neurodegenerative diseases. This study aimed to assess the safety, tolerability, and impact on pro-inflammatory biomarker profiles of an anti CD40L antibody, tegoprubart, in individuals with amyotrophic lateral sclerosis (ALS).Methods and findingsIn this multicenter dose-escalating open-label Phase 2A study, 54 participants with a diagnosis of ALS received 6 infusions of tegoprubart administered intravenously every 2 weeks. The study was comprised of 4 dose cohorts: 1 mg/kg, 2 mg/kg, 4 mg/kg, and 8 mg/kg. The primary endpoint of the study was safety and tolerability. Exploratory endpoints assessed the pharmacokinetics of tegoprubart as well as anti-drug antibody (ADA) responses, changes in disease progression utilizing the Revised ALS Functional Rating Scale (ALSFRS-R), CD154 target engagement, changes in pro-inflammatory biomarkers, and neurofilament light chain (NFL). Seventy subjects were screened, and 54 subjects were enrolled in the study. Forty-nine of 54 subjects completed the study (90.7%) receiving all 6 infusions of tegoprubart and completing their final follow-up visit. The most common treatment emergent adverse events (TEAEs) overall (>10%) were fatigue (25.9%), falls (22.2%), headaches (20.4%), and muscle spasms (11.1%). Mean tegoprubart plasma concentrations increased proportionally with increasing dose with a half-life of approximately 24 days. ADA titers were low and circulating levels of tegoprubart were as predicted for all cohorts. Tegoprubart demonstrated dose dependent target engagement associated and a reduction in 18 pro-inflammatory biomarkers in circulation.ConclusionsTegoprubart appeared to be safe and well tolerated in adults with ALS demonstrating dose-dependent reduction in pro-inflammatory chemokines and cytokines associated with ALS. These results warrant further clinical studies with sufficient power and duration to assess clinical outcomes as a potential treatment for adults with ALS.Trial registrationClintrials.gov ID:NCT04322149.

Published
2024
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2. Anti-Sulfoglucuronosyl Paragloboside Antibody

Author

Dongpei Li, Seigo Usuki, Brandy Quarles, Michael H. Rivner, Toshio Ariga, and Robert K. Yu

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons. Although the etiology of ALS is obscure, genetic studies of familiar ALS suggest a multifactorial etiology for this condition. Similarly, there probably are multiple causes for sporadic ALS. Autoimmune-mediated motor neuron dysfunction is one proposed etiology for sporadic ALS. In the present study, anti-glycolipid antibodies including GM1, GD1b, GD3, and sulfoglucuronosyl paragloboside (SGPG) were investigated in the sera of a large number of patient samples, including 113 ALS patients and 50 healthy controls, by means of enzyme-linked immunosorbent assay with affinity parametric complex criterion evaluation and thin-layer chromatography immunooverlay (immuno-TLC). Anti-SGPG antibodies were found in the sera of 13.3% ALS patients (15 out of 113). The highest titer reached 1:1600. The presence of anti-SGPG antibodies in the serum samples was also confirmed by immuno-TLC. Importantly, a multiple logistic regression analysis showed that the presence of anti-SGPG antibody was positively correlated with age ( p

Published
2016
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3. Safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis (the REFALS study): a randomised, double-blind, placebo-controlled phase 3 trial

Author

Michael Pulley, Mikko Kuoppamäki, Carolyn A Young, Jesus S. Mora Pardina, Kumaraswamy Sivakumar, Toni Sarapohja, Michael A. Elliott, Chafic Karam, Sandeep Rana, Orla Hardiman, Nathan P. Staff, Letizia Mazzini, Gabriele Mora, Thomas F. Meyer, Colleen O'Connell, Stéphanie Delstanche, Elham Bayat, Michael D. Weiss, Waqar Waheed, Nenad Mitrovic, Philippe Corcia, Marie-Hélène Soriani, Edward J. Kasarskis, Claudia Caponnetto, Dale J. Lange, Tuan Vu, Leo McCluskey, Berthold Schrank, Angela Genge, Matthew C. Kiernan, Valtteri V Aho, Manu Jokela, Philip Van Damme, Juan F. Vázquez Costa, Maurizio Inghilleri, Wolfgang Löscher, David Schultz, Tero Tapiola, Susanne Petri, Adriano Chiò, Gary L. Pattee, Julian Großkreutz, Ammar Al-Chalabi, Aziz Shaibani, Susan Mathers, Kevin J. Felice, Kimberly Goslin, James Caress, Matthias Boentert, Albert C. Ludolph, Aleksandar Radunovic, Robert D. Henderson, James Wymer, Todd Levine, Jakob Rath, Merrilee Needham, William Camu, Gaurav Guliani, Rune Johansson, Leonard H. van den Berg, Namita Goyal, Mark B. Bromberg, Bjorn Oskarsson, Annie Dionne, Eduardo Locatelli, Brent T. Harris, Suma Babu, Richard Bedlack, John Ravits, Jinsy A. Andrews, Philippe Couratier, Gabriele Siciliano, Hannu Laaksovirta, Kourosh Rezania, Lawrence Korngut, Eduardo Aguera Morales, Peter M Andersen, Eva Farrero Munoz, David Lacomis, Stephen N. Scelsa, Chris Garratt, Matthew Burford, Merit Cudkowicz, Nicholas J. Maragakis, Wendy Johnston, Martin M. Brown, Johannes Prudlo, Justin Y. Kwan, Dominic B. Fee, Senda Ajroud-Driss, Stephen A. Goutman, John Turnbull, Michael H. Rivner, Timothy M. Miller, Jan De Bleecker, Caroline Ingre, Luis Varona, Genevieve Matte, Daragh Heitzman, Robert Untucht, Lorne Zinman, Adam Quick, and Jonathan S. Katz

Subjects
education.field_of_study, medicine.medical_specialty, Supine position, business.industry, Amyotrophic Lateral Sclerosis, Population, Administration, Oral, Levosimendan, Placebo, Treatment Outcome, amyotrophic lateral sclerosis, levosimendan, randomised, double-blind, placebo-controlled trial, Double-Blind Method, Respiratory failure, Internal medicine, Clinical endpoint, Humans, Medicine, Respiratory function, Neurology (clinical), business, Adverse effect, education, Simendan, medicine.drug
Abstract

Summary Background There is an urgent unmet need for new therapies in amyotrophic lateral sclerosis. In a clinical study with healthy volunteers, levosimendan, a calcium sensitiser, was shown to improve neuromechanical efficiency and contractile function of the human diaphragm. We aimed to evaluate the safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis, with a focus on respiratory function. Methods The REFALS study is a randomised, double-blind, placebo-controlled phase 3 trial at 99 amyotrophic lateral sclerosis specialist centres in 14 countries worldwide. People with amyotrophic lateral sclerosis were eligible for participation if they were at least 18 years of age and had a sitting slow vital capacity (SVC) of 60–90% predicted. Participants were randomly assigned (2:1) by interactive web-response system to receive either levosimendan or placebo. The capsules for oral administration were identical in appearance to maintain blinding of participants and investigators. The primary endpoint was the change from baseline in supine SVC at 12 weeks, assessed as the percentage of predicted normal sitting SVC. The key secondary endpoint was the combined assessment of function and survival (CAFS) up to 48 weeks. Analyses were done in the intention-to-treat population, comprising all participants who were randomly assigned. This trial is registered at ClinicalTrials.gov (NCT03505021) and has been completed. An extension study (REFALS-ES; NCT03948178 ) has also been completed, but will be reported separately. Findings Between June 21, 2018, and June 28, 2019, 871 people were screened for the study, of whom 496 were randomly assigned either levosimendan (n=329) or placebo (n=167). Participants were followed up between June 27, 2018 and June 26, 2020, for a median duration of 50·1 (IQR 37·5–51·1) weeks. The median duration of treatment was 47·9 (IQR 26·4–48·1) weeks. Change from baseline in supine SVC at 12 weeks was –6·73% with levosimendan and –6·99% with placebo, with no significant difference between the treatments (estimated treatment difference 0·26%, 95% CI –2·03 to 2·55, p=0·83). Similarly, at week 48, CAFS did not differ between treatment groups (least squares mean change from baseline 10·69, 95% CI –15·74 to 37·12; nominal p value=0·43). The most frequent adverse events were increased heart rate (106 [33%] of 326 receiving levosimendan vs 12 [7%] of 166 receiving placebo), fall (85 [26%] vs 48 [29%]), headache (93 [29%] vs 36 [22%]), and dyspnoea (59 [18%] vs 32 [19%]). 33 (10%) participants allocated levosimendan and 20 (12%) assigned placebo died during the trial, mainly due to respiratory failure or progression of amyotrophic lateral sclerosis. Interpretation Levosimendan was not superior to placebo in maintaining respiratory function in a broad population with amyotrophic lateral sclerosis. Although levosimendan was generally well tolerated, increased heart rate and headache occurred more frequently with levosimendan than with placebo. The possibility of a clinically relevant subgroup of responsive individuals requires further evaluation. Funding Orion Corporation.

Published
2021

4. Effects of mexiletine on hyperexcitability in sporadic amyotrophic lateral sclerosis: Preliminary findings from a small phase <scp>II</scp> randomized controlled trial

Author

Brian J. Wainger, Nazem Atassi, Shafeeq Ladha, Michael D. Weiss, Eric A. Macklin, Matthew C. Kiernan, I-Hweii Amy Chen, Seward B. Rutkove, Stephen A. Goutman, Michael H. Rivner, Maxwell Ma, Courtney E. McIlduff, Steve Vucic, Merit Cudkowicz, Thomas H. Brannagan, Leo H. Wang, Namita Goyal, Matthew B. Harms, Sasha Zivkovic, David Lacomis, Zachary Simmons, and Jeremy M. Shefner

Subjects
Adult, Male, 0301 basic medicine, Physiology, medicine.medical_treatment, Neural Conduction, Mexiletine, 030105 genetics & heredity, Placebo, Article, law.invention, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Double-Blind Method, Randomized controlled trial, law, Physiology (medical), Neuromodulation, Clinical endpoint, Humans, Medicine, Evoked potential, Amyotrophic lateral sclerosis, Aged, Voltage-Gated Sodium Channel Blockers, Electromyography, business.industry, Electrodiagnosis, Amyotrophic Lateral Sclerosis, Middle Aged, Evoked Potentials, Motor, medicine.disease, Transcranial Magnetic Stimulation, Axons, Median Nerve, Transcranial magnetic stimulation, medicine.anatomical_structure, Anesthesia, Cortical Excitability, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, Preliminary Data, medicine.drug
Abstract

Objective To collect preliminary data on the effects of mexiletine on cortical and axonal hyperexcitability in sporadic amyotrophic lateral sclerosis (ALS) in a phase 2 double-blind randomized controlled trial. Methods Twenty ALS subjects were randomized to placebo and mexiletine 300 mg or 600 mg daily for 4 weeks and assessed by transcranial magnetic stimulation and axonal excitability studies. The primary endpoint was change in resting motor threshold (RMT). Results RMT was unchanged with 4 weeks of mexiletine (combined active therapies) as compared to placebo, which showed a significant increase (p=0.039). Reductions of motor evoked potential (MEP) amplitude (p=0.013) and accommodation half-time (p=0.002), secondary outcome measures of cortical and axonal excitability, respectively, were also evident at 4 weeks on mexiletine. Conclusions The relative stabilization of RMT in the treated subjects was unexpected and could be attributed to unaccounted sources of error or chance. However, a possible alternative cause is neuromodulation preventing an increase. The change in MEP amplitude and accommodation half-time supports the reduction of cortical and axonal hyperexcitability with mexiletine. This article is protected by copyright. All rights reserved.

Published
2020

5. Clinical features of LRP4/agrin‐antibody–positive myasthenia gravis: A multicenter study

Author

Ikjae Lee, Mazen M. Dimachkie, Andrea M. Corse, Carlayne E. Jackson, Hongyan Xu, Jerry M. Belsh, J. Americo Fernandes, Mamatha Pasnoor, Tuan Vu, Eroboghene E. Ubogu, James F. Howard, George A. Small, Robert P. Lisak, R. Bhavaraju Sanka, Vanessa Baute, James Caress, Lin Mei, Stephen N. Scelsa, Brandy Quarles, Zachary Simmons, Richard Nowak, Zheng Yu, Richard J. Barohn, Jin-Xiu Pan, Clifton L. Gooch, Michael H. Rivner, and Andrea Swenson

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, clinical features, Physiology, LRP4, neuromuscular transmission disorders, Class iii, 030105 genetics & heredity, Gastroenterology, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Neuromuscular Transmission Disorders, Physiology (medical), Internal medicine, seronegative myasthenia gravis, medicine, Prevalence, Humans, LDL-Receptor Related Proteins, Clinical Research Articles, Autoantibodies, Clinical Research Article, myasthenia gravis, Agrin, biology, business.industry, Middle Aged, Clinical disease, medicine.disease, Myasthenia gravis, United States, Multicenter study, biology.protein, Female, Neurology (clinical), Antibody, Symptom Assessment, business, Standard therapy, agrin, 030217 neurology & neurosurgery
Abstract

Introduction Our aim in this study was to identify the prevalence and clinical characteristics of LRP4/agrin‐antibody–positive double‐seronegative myasthenia gravis (DNMG). Methods DNMG patients at 16 sites in the United States were tested for LRP4 and agrin antibodies, and the clinical data were collected. Results Of 181 DNMG patients, 27 (14.9%) were positive for either low‐density lipoprotein receptor–related protein 4 (LRP4) or agrin antibodies. Twenty‐three DNMG patients (12.7%) were positive for both antibodies. More antibody‐positive patients presented with generalized symptoms (69%) compared with antibody‐negative patients (43%) (P ≤ .02). Antibody‐positive patients’ maximum classification on the Myasthenia Gravis Foundation of America (MGFA) scale was significantly higher than that for antibody‐negative patients (P ≤ .005). Seventy percent of antibody‐positive patients were classified as MGFA class III, IV, or V compared with 39% of antibody‐negative patients. Most LRP4‐ and agrin‐antibody–positive patients (24 of 27, 89%) developed generalized myathenia gravis (MG), but with standard MG treatment 81.5% (22 of 27) improved to MGFA class I or II during a mean follow‐up of 11 years. Discussion Antibody‐positive patients had more severe clinical disease than antibody‐negative patients. Most DNMG patients responded to standard therapy regardless of antibody status.

Published
2020

6. Characterization of LRP4/Agrin Antibodies From a Patient With Myasthenia Gravis

Author

Zheng Yu, Wen Cheng Xiong, Hongyang Jing, Brandy Quarles, Jin-Xiu Pan, Meiying Zhang, Michael H. Rivner, Rangjuan Cao, Lin Mei, Peng Chen, Yue Yu, and Bin Luo

Subjects
medicine.medical_specialty, animal structures, Neuromuscular transmission, Neuromuscular Junction, Neuromuscular junction, Epitope, Antibodies, 03 medical and health sciences, Mice, 0302 clinical medicine, Internal medicine, Myasthenia Gravis, Medicine, Animals, Humans, Agrin, LDL-Receptor Related Proteins, 030304 developmental biology, Acetylcholine receptor, 0303 health sciences, business.industry, Muscle weakness, medicine.disease, Myasthenia gravis, 3. Good health, Compound muscle action potential, medicine.anatomical_structure, Endocrinology, nervous system, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

Background and ObjectiveTo determine whether human anti-LRP4/agrin antibodies are pathogenic in mice and to investigate underpinning pathogenic mechanisms.MethodsImmunoglobulin (Ig) was purified from a patient with myasthenia gravis (MG) with anti-LRP4/agrin antibodies and transferred to mice. Mice were characterized for body weight, muscle strength, twitch and tetanic force, neuromuscular junction (NMJ) functions including compound muscle action potential (CMAP) and endplate potentials, and NMJ structure. Effects of the antibodies on agrin-elicited muscle-specific tyrosine kinase (MuSK) activation and AChR clustering were studied and the epitopes of these antibodies were identified.ResultsPatient Ig-injected mice had MG symptoms, including weight loss and muscle weakness. Decreased CMAPs, reduced twitch and tetanus force, compromised neuromuscular transmission, and NMJ fragmentation and distortion were detected in patient Ig-injected mice. Patient Ig inhibited agrin-elicited MuSK activation and AChR clustering. The patient Ig recognized the β3 domain of LRP4 and the C-terminus of agrin and reduced agrin-enhanced LRP4–MuSK interaction.DiscussionAnti-LRP4/agrin antibodies in the patient with MG is pathogenic. It impairs the NMJ by interrupting agrin-dependent LRP4–MuSK interaction.

Published
2020

7. Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial

Author

Armineuza Evora, Eric A. Macklin, Adel Marei, P. Davila-Pérez, Seward B. Rutkove, Brian J. Wainger, William S. David, Courtney E. McIlduff, James D. Berry, Joan A. Camprodon, Clifford J. Woolf, Bjorn Oskarsson, Nicholas J. Maragakis, Nazem Atassi, Richard A. Lewis, Richard Bedlack, Sean K. Meehan, Evangelos Kiskinis, Shafeeq Ladha, Alvaro Pascual-Leone, Karissa L. Gable, Matthew C. Kiernan, Aura Hurtado, João D. Pereira, Elizabeth A. Mauricio, Zachary Simmons, Divpreet Kaur, Nicolas Phielipp, Sylvia Baedorf Kassis, Robert H. Baloh, Michael D. Weiss, Kevin Eggan, Merit Cudkowicz, Pablo Celnik, David Klements, Peter B. Rosenquist, Lindsay Pothier, Thuong La, Joan Koh, Meghan Hall, Namita Goyal, Sabrina Paganoni, Steve Vucic, Dale J. Lange, Jeremy M. Shefner, Vern C. Juel, Vinay Chaudhry, Stephen A. Goutman, and Michael H. Rivner

Subjects
Male, medicine.medical_treatment, Phenylenediamines, Placebo, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Double-Blind Method, law, Motor system, medicine, Humans, 030212 general & internal medicine, Amyotrophic lateral sclerosis, Aged, Original Investigation, Cerebral Cortex, Motor Neurons, Dose-Response Relationship, Drug, business.industry, Amyotrophic Lateral Sclerosis, Motor neuron, Middle Aged, medicine.disease, Transcranial magnetic stimulation, Clinical trial, medicine.anatomical_structure, Treatment Outcome, Spinal Cord, Anesthesia, Pharmacodynamics, Anticonvulsants, Female, Neurology (clinical), Carbamates, business, 030217 neurology & neurosurgery
Abstract

IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor nervous system. Clinical studies have demonstrated cortical and spinal motor neuron hyperexcitability using transcranial magnetic stimulation and threshold tracking nerve conduction studies, respectively, although metrics of excitability have not been used as pharmacodynamic biomarkers in multi-site clinical trials. OBJECTIVE: To ascertain whether ezogabine decreases cortical and spinal motor neuron excitability in ALS. DESIGN, SETTING, AND PARTICIPANTS: This double-blind, placebo-controlled phase 2 randomized clinical trial sought consent from eligible participants from November 3, 2015, to November 9, 2017, and was conducted at 12 US sites within the Northeast ALS Consortium. Participants were randomized in equal numbers to a higher or lower dose of ezogabine or to an identical matched placebo, and they completed in-person visits at screening, baseline, week 6, and week 8 for clinical assessment and neurophysiological measurements. INTERVENTIONS: Participants were randomized to receive 600 mg/d or 900 mg/d of ezogabine or a matched placebo for 10 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was change in short-interval intracortical inhibition (SICI; SICI(−1) was used in analysis to reflect stronger inhibition from an increase in amplitude) from pretreatment mean at screening and baseline to the full-dose treatment mean at weeks 6 and 8. The secondary outcomes included levels of cortical motor neuron excitability (including resting motor threshold) measured by transcranial magnetic stimulation and spinal motor neuron excitability (including strength-duration time constant) measured by threshold tracking nerve conduction studies. RESULTS: A total of 65 participants were randomized to placebo (23), 600 mg/d of ezogabine (23), and 900 mg/d of ezogabine (19 participants); 45 were men (69.2%) and the mean (SD) age was 58.3 (8.8) years. The SICI(−1) increased by 53% (mean ratio, 1.53; 95% CI, 1.12-2.09; P = .009) in the 900-mg/d ezogabine group vs placebo group. The SICI(−1) did not change in the 600-mg/d ezogabine group vs placebo group (mean ratio, 1.15; 95% CI, 0.87-1.52; P = .31). The resting motor threshold increased in the 600-mg/d ezogabine group vs placebo group (mean ratio, 4.61; 95% CI, 0.21-9.01; P = .04) but not in the 900-mg/d ezogabine group vs placebo group (mean ratio, 1.95; 95% CI, −2.64 to 6.54; P = .40). Ezogabine caused a dose-dependent decrease in excitability by several other metrics, including strength-duration time constant in the 900-mg/d ezogabine group vs placebo group (mean ratio, 0.73; 95% CI, 0.60 to 0.87; P

Published
2020

8. 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. 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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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Michel, Deruelle, Fabienne, Schoser, Benedikt, Wenninger, Stephan, Stangel, Martin, Alvermann, Sascha, Gingele, Stefan, Skripuletz, Thoma, Suehs, Kurt-Wolfram, Trebst, Corinna, Fricke, Karin, Papagiannopoulos, Sotirio, Bostantzopoulou, Sevasti, Vlaikidis, Nichola, Zampaki, Martha, Papadopoulou, Nikoletta, Mitsikostas, Dimos-Dimitrio, Kasioti, Eleni, Mitropoulou, Efstathia, Charalambous, Despoina, Rozsa, Csilla, Horvath, Melinda, Lovas, Gabor, Matolcsi, Judit, Szabo, Gyorgyi, Szabadosne, Brigitta, Vecsei, Laszlo, Dezsi, Livia, Varga, Edina, Konyane, Monika, Gross, Bella, Azrilin, Olga, Greenbereg, Nelly, Bali Kuperman, Hila, Antonini, Giovanni, Garibaldi, Matteo, Morino, Stefania, Troili, Fernanda, Di Pasquale, Antonella, Filla, Alessandro, Costabile, Teresa, Marano, Enrico, Sacca, Francesco, Marsili, Angela, Puorro, Giorgia, Maestri Tassoni, Michelangelo, De Rosa, Anna, Bonanno, Silvia, Antozzi, Carlo, Maggi, Lorenzo, Campanella, Angela, Angelini, Corrado, Cudia, Paola, Pegoraro, 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Mihoko Takada, Yamashita, Yumi, Yoshida, Seiko, Suzuki, Yasushi, Akiyama, Tetsuya, Narikawa, Koichi, Tsukita, Kenichi, Meguro, Fumie, Fukuda, Yusuke, Sato, Miwako, Matsuo, Hidenori, Fukudome, Takayasu, Gondo, Yuichiro, Maeda, Yasuhiro, Nagaishi, Akiko, Nakane, Shunya, Okubo, Yoshinori, Okumura, Meinoshin, Funaka, Soichiro, Kawamura, Tomohiro, Makamori, Masayuki, Takahashi, Masanori, Hasuike, Tomoya, Higuchi, Eriko, Kobayashi, Hisako, Osakada, Kaori, Taichi, Namie, Tsuda, Emiko, Hayashi, Takashi, Hisahara, Shin, Imai, Tomihiro, Kawamata, Jun, Murahara, Takashi, Saitoh, Masaki, Shimohama, Shun, Suzuki, Shuichiro, Yamamoto, Daisuke, Konno, Shingo, Imamura, Tomomi, Inoue, Masashi, Murata, Mayumi, Nakazora, Hiroshi, Nakayama, Ritsu, Ikeda, Yasuko, Ogawa, Miki, Shirane, Maoko, Kanda, Takashi, Kawai, Motoharu, Koga, Michiaki, Ogasawara, Junichi, Omoto, Masatoshi, Sano, Yasuteru, Arima, Hideki, Fukui, Sachie, Shimose, Shigemi, Shinozaki, Hirokazu, Watanabe, Masanori, Yoshikawa, Chieko, van der Kooi, Anneke, de Visser, Marianne, Gibson, Tamar, Maessen, Jo, de Baets, Marc, Faber, Catherine, Keijzers, Maria Johanna, Miesen, Monique, Kostera-Pruszczyk, Anna, Kaminska, Anna, Kim, Byung-Jo, Lee, Chang Nyoung, Koo, Yong Seo, Seok, Hung Youl, Kang, Hoo Nam, Ra, Hyejin, Kim, Byoung Joon, Cho, Eun Bin, Lee, Hyelim, Min, Ju-Hong, Seok, Jinmyoung, Koh, Da Yoon, Kwon, Juyoung, Lee, Jieun, Park, Sangae, Hong, Yoon-Ho, Lim, Jae-Sung, Kim, Miri, Kim, Seung Min, Kim, Yool-hee, Lee, Hyung Seok, Shin, Ha Young, Hwang, Eun Bi, Shin, Miju, Sazonov, Deni, Yarmoschuk, Asya, Babenko, Larisa, Malkova, Nadezhda, Melnikova, Anna, Korobko, Deni, Kosykh, Evgeniya, Pokhabov, Dmitry, Nesterova, Yulia, Abramov, Vladislav, Balyazin, Victor, Casasnovas Pons, Carlo, Alberti Aguilo, Maria, Homedes-Pedret, Christian, Palacios, Natalia Julia, Lazaro, Ana, Diez Tejedor, Exuperio, Fernandez-Fournier, Mireya, Lopez Ruiz, Pedro, Rodriguez de Rivera, Francisco Javier, Salvado Figueras, Maria, Gamez, Josep, Salvado, Maria, Cortes Vicente, Elena, Diaz-Manera, Jordi, Querol Gutierrez, Lui, Rojas Garcia, Ricardo, Vidal, Nuria, Arribas-Ibar, Elisabet, Piehl, Fredrik, Hietala, Albert, Bjarbo, Lena, Lindberg, Christopher, Jons, Daniel, Andersson, Blanka, Sengun, Ihsan, Ozcelik, Pinar, Tuga, Celal, Ugur, Muzeyyen, Boz, Cavit, Altiparmak, Didem, Gazioglu, Sibel, Ozen Aydin, Cigdem, Erdem-Ozdamar, Sevim, Bekircan-Kurt, Can Ebru, Yilmaz, Ezgi, Acar, Nazire Pinar, Caliskan, Yagmur, Efendi, Husnu, Aydinlik, Seda, Cavus, Hakan, Semiz, Cansu, Tun, Ozlem, Terzi, Murat, Dogan, Baki, Onar, Musa Kazim, Sen, Sedat, Cavdar, Tugce Kirba, Norwood, Fiona, Dimitriou, Aikaterini, Gollogly, Jakit, Mahdi-Rogers, Mohamed, Seddigh, Arshira, Maier, Gal, Sohail, Faisal, Sathasivam, Sivakumar, Arndt, Heike, Davies, Debbie, Watling, Dave, Rivner, Michael, Hartmann, J. Edward, Quarles, Brandy, Smalley, Nicole, Amato, Anthony, Cochrane, Thoma, Salajegheh, Mohammed, Roe, Kristen, Amato, Katherine, Toska, Shirli, Wolfe, Gil, Silvestri, Nichola, Patrick, Kara, Zakalik, Karen, Katz, Jonathan, Miller, Robert, Engel, Marguerite, Bravver, Elena, Brooks, Benjamin, Plevka, Sarah, Burdette, Maryanne, Sanjak, Mohammad, Kramer, Megan, Nemeth, Joanne, Schommer, Clara, Juel, Vern, Guptill, Jeffrey, Hobson-Webb, Lisa, Beck, Kate, Carnes, Donna, Loor, John, Anderson, Amanda, Lange, Dale, Agopian, Eliz, Goldstein, Jonathan, Manning, Erin, Kaplan, Lindsay, Holzberg, Shara, Kassebaum, Nicole, Pascuzzi, Robert, Bodkin, Cynthia, Kincaid, John, Snook, Riley, Guinrich, Sandra, Micheels, Angela, Chaudhry, Vinay, Corse, Andrea, Mosmiller, Betsy, Ho, Doreen, Srinivasan, Jayashri, Vytopil, Michael, Ventura, Nichola, Scala, Stephanie, Carter, Cynthia, Donahue, Craig, Herbert, Carol, Weiner, Elaine, Mckinnon, Jonathan, Haar, Laura, Mckinnon, Naya, Alcon, Karan, Daniels, Kevin, Sattar, Nadia, Jeffery, Denni, Mckenna, Kaitlyn, Guidon, Amanda, David, William, Dheel, Christina, Levine-Weinberg, Mark, Nigro, Catherine, Simpson, Ericka, Appel, Stanley H, Lai, Eugene, Lay, Lui, Pleitez, Milvia, Halton, Sharon, Faigle, Casey, Thompson, Lisa, Sivak, Mark, Shin, Susan, Bratton, Joan, Jacobs, Daniel, Brown, Gavin, Bandukwala, Ibrez, Brown, Morri, Kane, Jennifer, Blount, Ira, Freimer, Miriam, Hoyle, J. Chad, Agriesti, Julie, Khoury, Julie, Marburger, Tessa, Kaur, Harpreet, Dimitrova, Diana, Mellion, Michelle, Sachs, George, Crabtree, Brigid, Keo, Roseann, Perez, Ele Kim, Taber, Sandra, Gilchrist, Jame, Andoin, Angela, Darnell, Taylor, Goyal, Neelam, Sakamuri, Sarada, So, Yuen T, Welsh, Lesly Welsh, Bhavaraju-Sanka, Ratna, Tobon Gonzalez, Alejandro, Jones, Floyd, Saklad, Amy, Nations, Sharon, Trivedi, Jaya, Hopkins, Steve, Kazamel, Mohamed, Alsharabati, Mohammad, Lu, Liang, Mumfrey-Thomas, Sandi, Woodall, Amy, Richman, David, Butters, Janelle, Lindsay, Molly, Mozaffar, Tahseen, Cash, Tiyonnoh, Goyal, Namita, Roy, Gulmohor, Mathew, Veena, Maqsood, Fatima, Minton, Brian, Jones, H. 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

9. Phase IIa trial of fingolimod for amyotrophic lateral sclerosis demonstrates acceptable acute safety and tolerability

Author

Alan Gill, Fernando G. Vieira, Michael H. Rivner, Valerie R. Tassinari, Namita Goyal, Nazem Atassi, Daniela L. Grasso, Ericka Simpson, Sabrina Paganoni, James D. Berry, Nicte I. Mejia, Farrah J. Mateen, Eric A. Macklin, Stanley H. Appel, and Steven Perrin

Subjects
0301 basic medicine, medicine.medical_specialty, Randomization, Physiology, Pharmacology, Placebo, Gastroenterology, law.invention, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Randomized controlled trial, law, Physiology (medical), Internal medicine, Fingolimod Hydrochloride, medicine, Adverse effect, business.industry, Fingolimod, 3. Good health, Clinical trial, 030104 developmental biology, Tolerability, Neurology (clinical), business, 030217 neurology & neurosurgery, medicine.drug
Abstract

INTRODUCTION: Immune activation is implicated in ALS progression. Oral fingolimod reduces circulating lymphocytes. The objective of this phase IIa randomized controlled trial was to test the short-term safety, tolerability, and target engagement of fingolimod in ALS. METHODS: Randomization was 2:1 (fingolimod:placebo). Treatment duration was four weeks. Primary outcomes were safety and tolerability. Secondary outcomes included circulating lymphocytes and whole blood gene expression. RESULTS: Thirty participants were randomized; 28 received drug (fingolimod 18; placebo 10). No serious adverse events occurred. Adverse events were similar by treatment arm, as was study discontinuation (2 fingolimod vs. 0 placebo; NS). FEV1 and FEV1/SVC changes were similar in the fingolimod and placebo arms. Circulating lymphocytes decreased significantly in the fingolimod arm (p

Published
2017

10. Long-term effect of thymectomy plus prednisone versus prednisone alone in patients with non-thymomatous myasthenia gravis: 2-year extension of the MGTX randomised trial

Author

Gil I Wolfe, Henry J Kaminski, Inmaculada B Aban, Greg Minisman, Hui-Chien Kuo, Alexander Marx, Philipp Ströbel, Claudio Mazia, Joel Oger, J Gabriel Cea, Jeannine M Heckmann, Amelia Evoli, Wilfred Nix, Emma Ciafaloni, Giovanni Antonini, Rawiphan Witoonpanich, John O King, Said R Beydoun, Colin H Chalk, Alexandru C Barboi, Anthony A Amato, Aziz I Shaibani, Bashar Katirji, Bryan R F Lecky, Camilla Buckley, Angela Vincent, Elza Dias-Tosta, Hiroaki Yoshikawa, Márcia Waddington-Cruz, Michael T Pulley, Michael H Rivner, Anna Kostera-Pruszczyk, Robert M Pascuzzi, Carlayne E Jackson, Jan J G M Verschuuren, Janice M Massey, John T Kissel, Lineu C Werneck, Michael Benatar, Richard J Barohn, Rup Tandan, Tahseen Mozaffar, Nicholas J Silvestri, Robin Conwit, Joshua R Sonett, Alfred Jaretzki, John Newsom-Davis, Gary R Cutter, Gary Cutter, Inmaculada Aban, Michelle Feese, Gil Wolfe, Henry Kaminski, Joshua Sonett, Valeria Saluto, Moises Rosenberg, Valeria Alvarez, Lisa Rey, John King, Helmut Butzkueven, John Goldblatt, John Carey, John Pollard, Stephen Reddel, Nicholas Handel, Brian McCaughan, Linda Pallot, Ricardo Novis, Carlos Boasquevisque, Rubens Morato-Fernandez, Manoel Ximenes, Lineu Werneck, Rosana Scola, Paulo Soltoski, Colin Chalk, Fraser Moore, David Mulder, Lisa Wadup, Michele Mezei, Kenneth Evans, Theresa Jiwa, Anne Schaffar, Chris White, Cory Toth, Gary Gelfand, Susan Wood, Elizabeth Pringle, Jocelyn Zwicker, Donna Maziak, Farid Shamji, Sudhir Sundaresan, Andrew Seely, Gabriel Cea, Renato Verduga, Alberto Aguayo, Sebastian Jander, Philipp Zickler, Michael Klein, Cleo-Aron Weis, Arthur Melms, Felix Bischof, Hermann Aebert, Gerhard Ziemer, Björn Thümler, Thomas Wilhem-Schwenkmezger, Eckhard Mayer, Berthold Schalke, Peter Pöschel, Gisela Hieber, Karsten Wiebe, Alessandro Clemenzi, Vanessa Ceschin, Erino Rendina, Federico Venuta, Stefania Morino, Elisabetta Bucci, Luca Durelli, Alessia Tavella, Marinella Clerico, Giulia Contessa, Piero Borasio, Serenella Servidei, Pierluigi Granone, Renato Mantegazza, Emilia Berta, Lorenzo Novellino, Luisa Spinelli, Masakatsu Motomura, Hidenori Matsuo, Takeshi Nagayasu, Masaharu Takamori, Makoto Oda, Isao Matsumoto, Yutaka Furukawa, Daisuke Noto, Yuko Motozaki, Kazuo Iwasa, Daisuke Yanase, Guillermo Garcia Ramos, Bernardo Cacho, Lorenzo de la Garza, Anne Kostera-Pruszczyk, Marta Lipowska, Hubert Kwiecinski, Anna Potulska-Chromik, Tadeusz Orlowski, Ana Silva, Marta Feijo, António Freitas, Jeannine Heckmann, Andrew Frost, Edward Pan, Lawrence Tucker, Johan Rossouw, Fiona Drummond, Isabel Illa, Jorge Diaz, Carlos Leon, Jiann-Horng Yeh, Hou-Chang Chiu, Yei-San Hsieh, Supoch Tunlayadechanont, Sukasom Attanavanich, Jan Verschuuren, Chiara Straathof, Maarten Titulaer, Michel Versteegh, Arda Pels, Yvonne Krum, M. Isabel Leite, David Hilton-Jones, Chandi Ratnatunga, Maria Farrugia, Richard Petty, James Overell, Alan Kirk, Andrew Gibson, Chris McDermott, David Hopkinson, Bryan Lecky, David Watling, Dot Marshall, Sam Saminaden, Deborah Davies, Charlotte Dougan, Siva Sathasivam, Richard Page, Jon Sussman, John Ealing, Peter Krysiak, Anthony Amato, Mohammad Salajegheh, Michael Jaklitsch, Kristen Roe, Tetsuo Ashizawa, Robert Glenn Smith, Joseph Zwischenberg, Penny Stanton, Alexandru Barboi, Safwan Jaradeh, William Tisol, Mario Gasparri, George Haasler, Mary Yellick, Cedric Dennis, Richard Barohn, Mamatha Pasnoor, Mazen Dimachkie, April McVey, Gary Gronseth, Arthur Dick, Jeffrey Kramer, Melissa Currence, Laura Herbelin, Jerry Belsh, George Li, John Langenfeld, Mary Ann Mertz, Taylor Harrison, Seth Force, Sharon Usher, Said Beydoun, Frank Lin, Steve DeMeester, Salem Akhter, Ali Malekniazi, Gina Avenido, Brian Crum, Margherita Milone, Stephen Cassivi, Janet Fisher, Chad Heatwole, Thomas Watson, James Hilbert, Alexis Smirnow, B. Jane Distad, Michael Weiss, Douglas Wood, Joanna Haug, Raina Ernstoff, Jingyang Cao, Gary Chmielewski, Robert Welsh, Robin Duris, Laurie Gutmann, Gauri Pawar, Geoffrey Marc Graeber, Patricia Altemus, Christopher Nance, Ludwig Gutmann, Carlayne Jackson, Patrick Grogan, John Calhoon, Pamela Kittrell, Deborah Myers, Ghazala Hayat, Keith Naunheim, Susan Eller, Eve Holzemer, Amer Alshekhlee, Jason Robke, Brenda Karlinchak, Jonathan Katz, Robert Miller, Ralph Roan, Dallas Forshew, John Kissel, Bakri Elsheikh, Patrick Ross, Sharon Chelnick, Richard Lewis, Agnes Acsadi, Frank Baciewicz, Stacey Masse, Janice Massey, Vern Juel, Mark Onaitis, James Lowe, Bernadette Lipscomb, Gaby Thai, Jeffrey Milliken, Veronica Martin, Ronnie Karayan, Suraj Muley, Gareth Parry, Sara Shumway, Shin Oh, Gwen Claussen, Liang Lu, Robert Cerfolio, Angela Young, Marla Morgan, Robert Pascuzzi, John Kincaid, Kenneth Kesler, Sandy Guingrich, Angi Michaels, Lawrence Phillips, Ted Burns, David Jones, Cindy Fischer, Michael Pulley, Alan Berger, Harry D'Agostino, Lisa Smith, Michael Rivner, Jerry Pruitt, Kevin Landolfo, Demetric Hillman, Aziz Shaibani, Angelo Sermas, Ross Ruel, Farah Ismail, Mark Sivak, Martin Goldstein, Jorge Camunas, Joan Bratton, Hill Panitch, Bruce Leavitt, Marilee Jones, Srikanth Muppidi, Steven Vernino, Sharon Nations, Dan Meyer, and Nina Gorham

Subjects
0301 basic medicine, Male, medicine.medical_treatment, Edrophonium, law.invention, 0302 clinical medicine, Randomized controlled trial, law, Prednisone, Longitudinal Studies, MGTX Study Group, Thymectomy, 3. Good health, Settore MED/26 - NEUROLOGIA, Editorial Commentary, Treatment Outcome, 6.1 Pharmaceuticals, Female, medicine.drug, Adult, medicine.medical_specialty, Clinical Trials and Supportive Activities, Clinical Sciences, Autoimmune Disease, Article, 03 medical and health sciences, Young Adult, Rare Diseases, Clinical Research, Internal medicine, Myasthenia Gravis, medicine, Humans, Adverse effect, myasthenia gravis, mgtx extension study, Intention-to-treat analysis, Neurology & Neurosurgery, business.industry, Neurosciences, Evaluation of treatments and therapeutic interventions, medicine.disease, Myasthenia gravis, Clinical trial, 030104 developmental biology, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Summary Background The Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone (MGTX) showed that thymectomy combined with prednisone was superior to prednisone alone in improving clinical status as measured by the Quantitative Myasthenia Gravis (QMG) score in patients with generalised non-thymomatous myasthenia gravis at 3 years. We investigated the long-term effects of thymectomy up to 5 years on clinical status, medication requirements, and adverse events. Methods We did a rater-blinded 2-year extension study at 36 centres in 15 countries for all patients who completed the randomised controlled MGTX and were willing to participate. MGTX patients were aged 18 to 65 years at enrolment, had generalised non-thymomatous myasthenia gravis of less than 5 years' duration, had acetylcholine receptor antibody titres of 1·00 nmol/L or higher (or concentrations of 0·50–0·99 nmol/L if diagnosis was confirmed by positive edrophonium or abnormal repetitive nerve stimulation, or abnormal single fibre electromyography), had Myasthenia Gravis Foundation of America Clinical Classification Class II–IV disease, and were on optimal anticholinesterase therapy with or without oral corticosteroids. In MGTX, patients were randomly assigned (1:1) to either thymectomy plus prednisone or prednisone alone. All patients in both groups received oral prednisone at doses titrated up to 100 mg on alternate days until they achieved minimal manifestation status. The primary endpoints of the extension phase were the time-weighted means of the QMG score and alternate-day prednisone dose from month 0 to month 60. Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00294658. It is closed to new participants, with follow-up completed. Findings Of the 111 patients who completed the 3-year MGTX, 68 (61%) entered the extension study between Sept 1, 2009, and Aug 26, 2015 (33 in the prednisone alone group and 35 in the prednisone plus thymectomy group). 50 (74%) patients completed the 60-month assessment, 24 in the prednisone alone group and 26 in the prednisone plus thymectomy group. At 5 years, patients in the thymectomy plus prednisone group had significantly lower time-weighted mean QMG scores (5·47 [SD 3·87] vs 9·34 [5·08]; p=0·0007) and mean alternate-day prednisone doses (24 mg [SD 21] vs 48 mg [29]; p=0·0002) than did those in the prednisone alone group. 14 (42%) of 33 patients in the prednisone group, and 12 (34%) of 35 in the thymectomy plus prednisone group, had at least one adverse event by month 60. No treatment-related deaths were reported during the extension phase. Interpretation At 5 years, thymectomy plus prednisone continues to confer benefits in patients with generalised non-thymomatous myasthenia gravis compared with prednisone alone. Although caution is appropriate when generalising our findings because of the small sample size of our study, they nevertheless provide further support for the benefits of thymectomy in patients with generalised non-thymomatous myasthenia gravis. Funding National Institutes of Health, National Institute of Neurological Disorders and Stroke.

Published
2019

11. ALSUntangled No. 36: Accilion

Author

Gary L. Pattee, Muddasir Quereshi, Paul Wicks, Todd Levine, Chafic Karam, Edor Kabashi, Christen Shoesmith, Jonathan Goldstein, John T. Kissel, Jim Wymer, Fernando G. Vieira, Pamela Kittrell, Carmel Armon, Josep Gamez, Laurie Gutmann, Lisa Kinsley, Gleb Levitsky, Katherine Tindall, Janice Robertson, Yunxia Wang, Emma Fixsen, Carlayne E. Jackson, Stacy A. Rudnicki, Michael Benatar, Robert Bowser, Robin Conwit, Michael J. Strong, Bjorn Oskarsson, Rob Goldstein, Eric J. Sorenson, Alexander Sherman, Neta Zach, Kathy Mitchell, Peter M Andersen, Ahmad Ghavanini, Kristiana Salmon, Richard Bedlack, Nicholas J. Maragakis, Bonnie Gerecke, Jeffrey D. Rothstein, Leo McClusky, Paul E. Barkhaus, Efrat Carmi, Ginna Gonzalez, Jonathan Licht, Steve Perrin, Hiroshi Mitsumoto, Brett M. Morrison, Meraida Polak, Melanie Leitner, Tahseen Mozaffar, Lyle Ostrow, Orla Hardiman, Lorne Zinman, Daniel M. Pastula, Michael H. Rivner, Mazen M. Dimachkie, Steven Nash, Megan Grosso, Ashok Verma, James Heywood, Vivian E. Drory, Erik P. Pioro, Larry Phillips, Gregory T. Carter, Michael D. Weiss, Nazem Atassi, Jeffrey V. Rosenfeld, Khema Sharma, Yvonne Baker, Jon Baker, Christina Fournier, Kevin Boylan, Mark Bromberg, Tulio E. Bertorini, L. P. Rowland, Eric Valor, Sith Sathornsumetee, Rup Tandan, Colin Quinn, Jeremy M. Shefner, James A. Russell, Steve Kolb, Steven Novella, James Caress, Robert G. Miller, Mieko Ogino, George Sachs, Jonathan D. Glass, David Saperstein, Dan Moore, John Ravits, Terry Heiman-Patterson, Dallas Forshew, Catherine Lomen-Hoerth, Daniel MacGowan, Kate Dalton, Merit Cudkowicz, and Noah Lechtzin

Subjects
Risk, 0301 basic medicine, Clinical Trials as Topic, Pathology, medicine.medical_specialty, business.industry, Amyotrophic Lateral Sclerosis, medicine.disease, 03 medical and health sciences, Treatment Outcome, 030104 developmental biology, 0302 clinical medicine, Neurology, medicine, Animals, Humans, Neurology (clinical), Amyotrophic lateral sclerosis, business, 030217 neurology & neurosurgery
Published
2016

12. Muscle-Specific Tyrosine Kinase and Myasthenia Gravis Owing to Other Antibodies

Author

Lin Mei, Mazen M. Dimachkie, Michael H. Rivner, Mamatha Pasnoor, and Richard J. Barohn

Subjects
0301 basic medicine, animal structures, Neuromuscular Junction, Pharmacology, Autoantigens, Article, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, Myasthenia Gravis, medicine, Humans, Receptors, Cholinergic, Cholinesterase, Autoantibodies, Agrin, biology, business.industry, Receptor Protein-Tyrosine Kinases, medicine.disease, Myasthenia gravis, nervous system diseases, 030104 developmental biology, Phenotype, biology.protein, Neurology (clinical), Antibody, business, Tyrosine kinase, 030217 neurology & neurosurgery, Cortactin, Acetylcholine, medicine.drug, Lipoprotein
Abstract

Around 20% of patients with myasthenia gravis are acetylcholine receptor antibody negative; muscle-specific tyrosine kinase antibodies (MuSK) were identified as the cause of myasthenia gravis in 30% to 40% of these cases. Anti MuSK myasthenia gravis is associated with specific clinical phenotypes. One is a bulbar form with fewer ocular symptoms. Others show an isolated head drop or symptoms indistinguishable from acetylcholine receptor-positive myasthenia gravis. These patients usually respond well to immunosuppressive therapy, but not as well to cholinesterase inhibitors. Other antibodies associated with myasthenia gravis, including low-density lipoprotein receptor-related protein 4, are discussed.

Published
2018

13. ALSUntangled: Introducing The Table of Evidence

Author

Hubert Kwieciński, Dan Moore, Gary L. Pattee, Edor Kabashi, Chafic Karam, James Caress, Ashok Verma, Brett M. Morrison, Mieko Ogino, George Sachs, Orla Hardiman, Bonnie Gerecke, Vivian E. Drory, Hiroshi Mitsumoto, Gleb Levitsky, Josep Gamez, James Heywood, Nazem Atassi, Michael D. Weiss, Jeffrey V. Rosenfeld, Colin Quinn, Kathy Mitchell, Robin Conwit, Steven Novella, Mark B. Bromberg, Lewis P. Rowland, Jerry M. Belsh, Michael J. Strong, Todd Levine, Jonathan D. Glass, Yunxia Wang, Carlayne E. Jackson, Jon Baker, Muddasir Quereshi, Melanie Leitner, David Saperstein, Carmel Armon, Leo McClusky, Jonathan Licht, Terry Heiman-Patterson, Dallas Forshew, Laurie Gutmann, Pamela Kittrell, Jonathan Goldstein, Khema Sharma, Alexander Sherman, Efrat Carmi, Tahseen Mozaffar, James A. Russell, Merit Cudkowicz, Meraida Polak, Lorne Zinman, Michael Benatar, Jim Wymer, Christina Fournier, Noah Lechtzin, Eric Valor, Mazen M. Dimachkie, Steve Kolb, Megan Grosso, Katherine Tindall, Gregory T. Carter, Stacy A. Rudnicki, Lyle Ostrow, Eric J. Sorenson, Jeffrey D. Rothstein, Robert Bowser, Bjorn Oskarsson, Rup Tandan, Catherine Lomen-Hoerth, Daniel MacGowan, Peter M Andersen, Kate Dalton, Daniel M. Pastula, Craig Oster, Paul Wicks, Richard Bedlack, Michael H. Rivner, Nicholas J. Maragakis, John Ravits, Erik P. Pioro, Christen Shoesmith, John T. Kissel, Tulio E. Bertorini, Jeremy M. Shefner, Paul E. Barkhaus, Kevin Boylan, Jeff Dietz, Ginna Gonzalez, Sith Sathornsumetee, Larry Phillips, Steven Nash, Robert G. Miller, Janice Robertson, and Lisa Kinsley

Subjects
PubMed, medicine.medical_specialty, Evidence-Based Medicine, Physical medicine and rehabilitation, Neurology, business.industry, Amyotrophic Lateral Sclerosis, Humans, Medicine, Table (landform), Neurology (clinical), business
Published
2014

14. Agrin and low-density lipoprotein-related receptor protein 4 antibodies in amyotrophic lateral sclerosis patients

Author

Lin Mei, Jin-Xiu Pan, Michael H. Rivner, Siyang Liu, Brandy Quarles, Brandi Fleenor, and Chengyong Shen

Subjects
0301 basic medicine, medicine.medical_specialty, animal structures, Physiology, Lower motor neuron, Neuromuscular junction, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, Physiology (medical), Internal medicine, medicine, Amyotrophic lateral sclerosis, Receptor, Agrin, biology, medicine.diagnostic_test, business.industry, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, nervous system, chemistry, Immunoassay, Low-density lipoprotein, biology.protein, Neurology (clinical), Antibody, business, 030217 neurology & neurosurgery
Abstract

Introduction The prevalence and characteristics of agrin and low-density lipoprotein-related receptor protein 4 (LRP4) antibody-positive amyotrophic lateral sclerosis (ALS) patients were studied. Methods We tested 82 ALS patients and 59 controls for agrin and LRP4 antibodies using enzyme-linked immunoassay (ELISA). Results We found that 13.8% of ALS patients had agrin antibodies, and 9.8% had LRP4 antibodies. Women with ALS are twice as likely as men to have antibodies. Agrin-positive ALS patients are younger than agrin-negative ALS patients. Conclusions Antibodies to agrin and LRP4 are found in ALS patients. It must be determined whether these antibodies are pathogenic. Because antibody-positive patients have upper as well as lower motor neuron findings, the antibodies' effects cannot be explained solely by their actions at the neuromuscular junction. A breakdown in interneuronal signaling may be the cause of ALS. Further research is needed to resolve this question. Muscle Nerve, 2016 Muscle Nerve 55: 430-432, 2017.

Published
2016

15. ALSUntangled No. 35: Hyperbaric Oxygen Therapy*

Author

Lisa Kinsley, Christen Shoesmith, Steven Nash, Peter M Andersen, John T. Kissel, Daniel M. Pastula, Josep Gamez, Nicholas J. Maragakis, Michael H. Rivner, Michael D. Weiss, Jeffrey V. Rosenfeld, James A. Russell, Kathy Mitchell, Steve Kolb, Melanie Leitner, Jim Wymer, Larry Phillips, Jon Baker, Jeffrey D. Rothstein, Erik P. Pioro, Katherine Tindall, Khema Sharma, Stacy A. Rudnicki, Jonathan D. Glass, James Caress, Janice Robertson, Meraida Polak, Tulio E. Bertorini, Paul Wicks, Yunxia Wang, Carlayne E. Jackson, L. P. Rowland, Megan Grosso, Bjorn Oskarsson, Carmel Armon, Leo McClusky, David Saperstein, Lorne Zinman, Laurie Gutmann, Gregory T. Carter, Robert Bowser, Gary L. Pattee, Kristiana Salmon, Brett M. Morrison, Richard Bedlack, Fernando G. Vieira, Orla Hardiman, Edor Kabashi, Sith Sathornsumetee, Vivian E. Drory, Jeremy M. Shefner, Emma Fixsen, Robert G. Miller, Steve Perrin, Michael Benatar, Hiroshi Mitsumoto, Alexander Sherman, Colin Quinn, Todd Levine, Neta Zach, Christina Fournier, Jonathan Goldstein, Lyle Ostrow, Mark Bromberg, Terry Heiman-Patterson, Dallas Forshew, Steven Novella, Mieko Ogino, George Sachs, John Ravits, Dan Moore, James Heywood, Merit Cudkowicz, Noah Lechtzin, Catherine Lomen-Hoerth, Daniel MacGowan, Kate Dalton, Ashok Verma, Yvonne Baker, Muddasir Quereshi, Kevin Boylan, Pamela Kittrell, Gleb Levitsky, Eric J. Sorenson, Robin Conwit, Rob Goldstein, Eric Valor, Rup Tandan, Nazem Atassi, Ahmad Ghavanini, Paul E. Barkhaus, Ginna Gonzalez, Efrat Carmi, Tahseen Mozaffar, Chafic Karam, Mazen M. Dimachkie, Michael J. Strong, Jonathan Licht, and Bonnie Gerecke

Subjects
Complementary Therapies, Male, 0301 basic medicine, Mice, Mice, Neurologic Mutants, 03 medical and health sciences, Clinical Trials, Phase II as Topic, 0302 clinical medicine, Hyperbaric oxygen, Animals, Humans, Medicine, Single-Blind Method, Amyotrophic lateral sclerosis, Hyperbaric Oxygenation, Clinical Trials, Phase I as Topic, business.industry, Amyotrophic Lateral Sclerosis, medicine.disease, Disease Models, Animal, Oxidative Stress, Treatment Outcome, 030104 developmental biology, Neurology, Anesthesia, Neurology (clinical), business, 030217 neurology & neurosurgery
Published
2016

16. ALSUntangled 41: 'Eric Is Winning'

Author

Paul E. Barkhaus, Yvonne Baker, Carlayne E. Jackson, Martina Wiedau, Fernando G. Vieira, Michael H. Rivner, Larry Phillips, Stephen J. Kolb, Terry Heiman-Patterson, Kristiana Salmon, Paul Wicks, Richard Bedlack, Eric Valor, John T. Kissel, Gleb Levitsky, Lucie Bruijn, Meraida Polak, Gregory Ringkamp, Mark B. Bromberg, Nicholas J. Maragakis, Carmel Armon, Laurie Gutmann, Michael Benatar, Gregory T. Carter, Kathy Mitchell, Sabrina Paganoni, Jonathan D. Glass, Jeff Rothstein, Tulio E. Bertorini, Lyle Ostrow, and James Caress

Subjects
0301 basic medicine, Aged, 80 and over, Male, medicine.medical_specialty, business.industry, Amyotrophic Lateral Sclerosis, Brain, medicine.disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Physical medicine and rehabilitation, Neurology, Spinal Cord, medicine, Disease Progression, Humans, Neurology (clinical), Amyotrophic lateral sclerosis, Age of Onset, business, 030217 neurology & neurosurgery
Published
2017

17. Screening for lipoprotein receptor-related protein 4-, agrin-, and titin-antibodies and exploring the autoimmune spectrum in myasthenia gravis

Author

Joachim Weis, Kathi Hartmann, Katerina Karagiorgou, John Tzartos, Jörg B. Schulz, Isabell Cordts, Kristl G. Claeys, Nicolas Bodart, Michael H. Rivner, Socrates J. Tzartos, Alain Vigneron, Jens Reimann, Lin Mei, and Philip Van Damme

Subjects
0301 basic medicine, Adult, Male, animal structures, Thymoma, Adolescent, Radioimmunoassay, Thyroiditis, Serology, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Myasthenia Gravis, medicine, Humans, Medical history, Connectin, Receptors, Cholinergic, Agrin, Child, LDL-Receptor Related Proteins, Aged, Autoantibodies, biology, business.industry, Thyroid, Receptor Protein-Tyrosine Kinases, Middle Aged, musculoskeletal system, medicine.disease, Myasthenia gravis, 030104 developmental biology, medicine.anatomical_structure, Neurology, Immunology, biology.protein, Titin, Female, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

In autoimmune myasthenia gravis (MG), the identification of antibodies and characterization of serological subgroups is of great importance for diagnosis and management of the disease. Our aims were to study the frequency of antibodies against lipoprotein-related protein 4 (LRP4), agrin, and titin using the most recent techniques, and to characterize corresponding clinical features and autoimmune diseases (AID) in 100 MG-patients. The antibody frequencies in the 55 AChR-antibody positive patients were 7% LRP4, 5% agrin, 53% titin, and in the 45 AChR-antibody negative patients 2% MuSK, 2% LRP4, 2% agrin, and 27% titin. LRP4-MG presented late-onset age, mild symptoms, good therapeutic response, and no thymic changes. Agrin-MG showed early onset age, mild-to-severe symptoms, and moderate treatment response. The phenotype of titin-MG depended on AChR-antibodies: AChR-antibody negative patients presented with mostly mild limb muscle weakness, whereas AChR-antibody positive patients showed more frequently severe symptoms, including myasthenic crisis, bulbar predominance, and thymoma. Additional AID were detected in 32% of MG-patients, most frequently Hashimoto's thyroiditis (21%). Based on our data, we recommend the detection of LRP4-antibodies for at least AChR-antibody negative MG-patients and titin-antibodies for all MG-patients. We propose taking an accurate medical history for typical symptoms of Hashimoto's thyroiditis in MG-patients.

Published
2017

18. Skeletal muscle oxidative capacity in amyotrophic lateral sclerosis

Author

Michael H. Rivner, Ajay Verma, Melissa L. Erickson, Terence E. Ryan, Kevin K. McCully, and Juan C. Chavez

Subjects
medicine.medical_specialty, medicine.diagnostic_test, Physiology, Skeletal muscle, Magnetic resonance imaging, Anatomy, Motor neuron, Biology, medicine.disease, medicine.disease_cause, Phosphocreatine, Cellular and Molecular Neuroscience, chemistry.chemical_compound, medicine.anatomical_structure, Endocrinology, Myoglobin, chemistry, Physiology (medical), Internal medicine, medicine, Biomarker (medicine), Neurology (clinical), Amyotrophic lateral sclerosis, Oxidative stress
Abstract

Introduction: Mitochondrial dysfunction in the motor neuron has been suspected in amyotrophic lateral sclerosis (ALS). If mitochondrial abnormalities are also found in skeletal muscle, assessing skeletal muscle could serve as an important biomarker of disease progression. Methods: Using 31P magnetic resonance (31P-MRS) and near infrared (NIRS) spectroscopy, we compared the absolute values and reproducibility of skeletal muscle oxidative capacity in people with ALS (n = 6) and healthy adults (young, n = 7 and age-matched, n = 4). Results: ALS patients had slower time constants for phosphocreatine (PCr) and muscle oxygen consumption (mVO2) compared with young, but not age-matched controls. The coefficient of variation for the time constant was 10% (SD = 2.8%) and 17% (SD = 6.2%) for PCr and mVO2, respectively. Conclusions: People with ALS had, on average, a small but not statistically significant, impairment in skeletal muscle mitochondrial function measured by both 31P-MRS and NIRS. Both methods demonstrated good reproducibility. Muscle Nerve 50: 767–774, 2014

Published
2014

19. ALSUntangled No. 29: MitoQ

Author

Muddasir Quereshi, Bjorn Oskarsson, Peter M Andersen, Pamela Kittrell, Mark B. Bromberg, Gleb Levitsky, Richard Bedlack, Nicholas J. Maragakis, Leo McClusky, Michael J. Strong, Robin Conwit, Lewis P. Rowland, Efrat Carmi, Tahseen Mozaffar, Alexander Sherman, Mazen M. Dimachkie, Yunxia Wang, Megan Grosso, Brett M. Morrison, Carlayne E. Jackson, Eric J. Sorenson, Craig Oster, John Ravits, Meraida Polak, Orla Hardiman, Hubert Kwieciński, Terry Heiman-Patterson, Dallas Forshew, Christina Fournier, Jonathan Licht, Dan Moore, Carmel Armon, Gregory T. Carter, Gary L. Pattee, James Heywood, Katherine Tindall, Stacy A. Rudnicki, Edor Kabashi, Laurie Gutmann, Jonathan D. Glass, David Saperstein, Chafic Karam, Kevin Boylan, Daniel M. Pastula, Lorne Zinman, Lisa Kinsley, Eric Valor, Michael H. Rivner, Kathy Mitchell, Neta Zach, James A. Russell, Vivian E. Drory, Melanie Leitner, James Caress, Khema Sharma, Rup Tandan, Colin Quinn, Steven Novella, Ashok Verma, Larry Phillips, Catherine Lomen-Hoerth, Daniel MacGowan, Jim Wymer, Michael Benatar, Kate Dalton, Steve Kolb, Michael D. Weiss, Jeffrey V. Rosenfeld, Nazem Atassi, Robert Bowser, Jon Baker, Merit Cudkowicz, Noah Lechtzin, Jeffrey D. Rothstein, Paul Wicks, Steven Nash, Christen Shoesmith, John T. Kissel, Josep Gamez, Bonnie Gerecke, Hiroshi Mitsumoto, Janice Robertson, Paul E. Barkhaus, Ginna Gonzalez, Mieko Ogino, George Sachs, Todd Levine, Jonathan Goldstein, Jeremy M. Shefner, Tulio E. Bertorini, Robert G. Miller, Sith Sathornsumetee, Lyle Ostrow, Erik P. Pioro, and Jeff Dietz

Subjects
Pathology, medicine.medical_specialty, Ubiquinone, business.industry, Amyotrophic Lateral Sclerosis, Drug Evaluation, Preclinical, medicine.disease, Antioxidants, Disease Models, Animal, Oxidative Stress, Organophosphorus Compounds, Neurology, Animals, Humans, Medicine, Neurology (clinical), Amyotrophic lateral sclerosis, business
Published
2015

20. ALS Untangled No. 20: The Deanna Protocol

Author

Muddasir Quereshi, Pamela Kittrell, Jonathan D. Glass, Efrat Carmi, David Saperstein, Lisa Kinsley, Mark B. Bromberg, Christina Fournier, James Heywood, Eric Valor, Leo McClusky, Rup Tandan, Lyle Ostrow, Eric J. Sorenson, Jim Wymer, Noah Lechtzin, Megan Grosso, Carmel Armon, Todd Levine, Paul E. Barkhaus, Laurie Gutmann, Nazem Atassi, Ginna Gonzalez, Mazen M. Dimachkie, Daniel M. Pastula, Steven Nash, Tahseen Mozaffar, James A. Russell, Robert G. Miller, Hubert Kwieciński, Dan Moore, Michael H. Rivner, Ashok Verma, Craig Oster, John Ravits, Steve Kolb, Jonathan Goldstein, Robert Bowser, Steven Novella, Gregory T. Carter, Michael Benatar, Tulio E. Bertorini, Larry Phillips, Yunxia Wang, Carlayne E. Jackson, Kathy Mitchell, Orla Hardiman, Janice Robertson, Sith Sathornsumetee, Jeffrey D. Rothstein, Melanie Leitner, Lewis P. Rowland, Vivian E. Drory, James B. Caress, Jeremy M. Shefner, Mieko Ogino, George Sachs, Alexander Sherman, Michael J. Strong, Catherine Lomen-Hoerth, Paul Wicks, Erik P. Pioro, Daniel MacGowan, Terry Heiman-Patterson, Kevin B. Boylan, Bjorn Oskarsson, Dallas Forshew, Jonathan Licht, Josep Gamez, Katherine Tindall, Kate Dalton, Gleb Levitsky, Richard Bedlack, Hiroshi Mitsumoto, Gary L. Pattee, Jeff Dietz, Stacy A. Rudnicki, Bonnie Gerecke, Edor Kabashi, Robin Conwit, Peter M Andersen, Nicholas J. Maragakis, Meraida Polak, Michael D. Weiss, Jeffrey V. Rosenfeld, Jon Baker, Christen Shoesmith, John T. Kissel, and Khema Sharma

Subjects
medicine.medical_specialty, business.industry, Amyotrophic Lateral Sclerosis, medicine.disease, Physical medicine and rehabilitation, Neurology, Dietary Supplements, Coconut Oil, Animals, Humans, Plant Oils, Medicine, Nutrition Therapy, Neurology (clinical), Amyotrophic lateral sclerosis, business, Protocol (object-oriented programming)
Published
2013

21. ALSUntangled 38: L-serine

Author

John Ravits, Jonathan D. Glass, David Saperstein, Ahmad Ghavanini, Erik P. Pioro, Efrat Carmi, Tahseen Mozaffar, Bjorn Oskarsson, Steven Nash, Kristiana Salmon, Richard Bedlack, Christina Fournier, Muddasir Quereshi, Pamela Kittrell, Eric J. Sorenson, Michael Benatar, Todd Levine, Jim Wymer, Carmel Armon, Laurie Gutmann, Jonathan Goldstein, Peter M Andersen, Michael D. Weiss, Lisa Kinsley, Paul Wicks, Jeffrey V. Rosenfeld, Ceri Weber, Ashok Verma, Nazem Atassi, Robert G. Miller, Robert Bowser, Josep Gamez, Bonnie Gerecke, Nicholas J. Maragakis, Brett M. Morrison, Megan Grosso, Gary L. Pattee, Orla Hardiman, Janice Robertson, Jon Baker, Edor Kabashi, Gregory T. Carter, Vivian E. Drory, Neta Zach, Merit Cudkowicz, Noah Lechtzin, Colin Quinn, Catherine Lomen-Hoerth, Daniel MacGowan, Terry Heiman-Patterson, Dallas Forshew, Eric Valour, Kate Dalton, Jeremy M. Shefner, James Heywood, Gleb Levitsky, Alexander Sherman, Robin Conwit, Rob Goldstein, Michael J. Strong, Katherine Tindall, Jeffrey D. Rothstein, Stacy A. Rudnicki, James A. Russell, Steve Kolb, Jonathan Licht, Chafic Karam, Steve Perrin, Hiroshi Mitsumoto, Lyle Ostrow, Leo McClusky, Yunxia Wang, Carlayne E. Jackson, Daniel M. Pastula, Michael H. Rivner, Larry Phillips, Rup Tandan, Paul E. Barkhaus, Ginna Gonzalez, Tulio E. Bertorini, L. P. Rowland, Yvonne Baker, Sith Sathornsumetee, Kevin Boylan, Mark Bromberg, Dan Moore, Fernando G. Vieira, Kathy Mitchell, Melanie Leitner, Mazen M. Dimachkie, James Caress, Meraida Polak, Lorne Zinman, Veronica Peschansky, Christen Shoesmith, John T. Kissel, Khema Sharma, Steven Novella, Emma Fixen, Keeli Hope Denson, Mieko Ogino, and George Sachs

Subjects
0301 basic medicine, Risk, Clinical Trials as Topic, Amyotrophic Lateral Sclerosis, L serine, Biology, medicine.disease, Molecular biology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Treatment Outcome, Neurology, medicine, Serine, Humans, Neurology (clinical), Amyotrophic lateral sclerosis, 030217 neurology & neurosurgery
Published
2016

22. Agrin and low-density lipoprotein-related receptor protein 4 antibodies in amyotrophic lateral sclerosis patients

Author

Michael H, Rivner, Siyang, Liu, Brandy, Quarles, Brandi, Fleenor, Chengyong, Shen, Jinxiu, Pan, and Lin, Mei

Subjects
Lipoproteins, LDL, Male, Sex Factors, Amyotrophic Lateral Sclerosis, Age Factors, Humans, Enzyme-Linked Immunosorbent Assay, Female, Agrin, Article, Autoantibodies
Abstract

The prevalence and characteristics of agrin and low-density lipoprotein-related receptor protein 4 (LRP4) antibody-positive amyotrophic lateral sclerosis (ALS) patients were studied.We tested 82 ALS patients and 59 controls for agrin and LRP4 antibodies using enzyme-linked immunoassay (ELISA).We found that 13.8% of ALS patients had agrin antibodies, and 9.8% had LRP4 antibodies. Women with ALS are twice as likely as men to have antibodies. Agrin-positive ALS patients are younger than agrin-negative ALS patients.Antibodies to agrin and LRP4 are found in ALS patients. It must be determined whether these antibodies are pathogenic. Because antibody-positive patients have upper as well as lower motor neuron findings, the antibodies' effects cannot be explained solely by their actions at the neuromuscular junction. A breakdown in interneuronal signaling may be the cause of ALS. Further research is needed to resolve this question. Muscle Nerve, 2016 Muscle Nerve 55: 430-432, 2017.

Published
2016

23. ALSUntangled No. 34: GM604

Author

Yvonne Baker, Alexander Sherman, Gary L. Pattee, Kevin Boylan, Edor Kabashi, Yunxia Wang, Craig Oster, John Ravits, Muddasir Quereshi, Carlayne E. Jackson, Christen Shoesmith, John T. Kissel, Pamela Kittrell, James Heywood, Mieko Ogino, Gleb Levitsky, Bonnie Gerecke, Bjorn Oskarsson, George Sachs, Eric Valor, Kristiana Salmon, Richard Bedlack, Neta Zach, Robin Conwit, Rob Goldstein, Ahmad Ghavanini, Rup Tandan, Fernando G. Vieira, Efrat Carmi, Janice Robertson, Katherine Tindall, James Caress, Megan Grosso, Eric J. Sorenson, Daniel M. Pastula, Michael H. Rivner, Jeffrey D. Rothstein, Stacy A. Rudnicki, Erik P. Pioro, Terry Heiman-Patterson, Dallas Forshew, Lisa Kinsley, Ashok Verma, Paul E. Barkhaus, Ginna Gonzalez, Larry Phillips, Leo McClusky, Jonathan D. Glass, Brett M. Morrison, David Saperstein, Jim Wymer, Jeff Dietz, Catherine Lomen-Hoerth, Tahseen Mozaffar, Gregory T. Carter, Orla Hardiman, Josep Gamez, Vivian E. Drory, Daniel MacGowan, Dan Moore, Colin Quinn, Chafic Karam, Kate Dalton, Tulio E. Bertorini, Nazem Atassi, Robert G. Miller, Peter M Andersen, Robert Bowser, Michael D. Weiss, L. P. Rowland, Michael J. Strong, Jeffrey V. Rosenfeld, Steven Novella, Nicholas J. Maragakis, Michael Benatar, Jeremy M. Shefner, Jon Baker, Jonathan Licht, Kathy Mitchell, Christina Fournier, Mark Bromberg, Mazen M. Dimachkie, Steven Nash, James A. Russell, Paul Wicks, Meraida Polak, Melanie Leitner, Lorne Zinman, Steve Kolb, Noah Lechtzin, Sith Sathornsumetee, Lyle Ostrow, Todd Levine, Jonathan Goldstein, Khema Sharma, Carmel Armon, Laurie Gutmann, and Steve Perrin

Subjects
0301 basic medicine, Compassionate Use Trials, Pathology, medicine.medical_specialty, Drug Evaluation, Preclinical, Pilot Projects, Drug Costs, 03 medical and health sciences, Mice, Mice, Neurologic Mutants, 0302 clinical medicine, Double-Blind Method, Medicine, Animals, Humans, Nerve Growth Factors, Amyotrophic lateral sclerosis, Randomized Controlled Trials as Topic, business.industry, Amyotrophic Lateral Sclerosis, medicine.disease, Peptide Fragments, Rats, Disease Models, Animal, 030104 developmental biology, Treatment Outcome, Neurology, Neurology (clinical), business, Oligopeptides, 030217 neurology & neurosurgery
Published
2016

24. ALSUntangled No. 16: Cannabis

Author

Daniel M. Pastula, Jim Wymer, Michael H. Rivner, Mazen M. Dimachkie, James A. Russell, Steve Kolb, Gary L. Pattee, Muddasir Quereshi, Kathy Mitchell, Noah Lechtzin, Pamela Kittrell, Leo McClusky, Larry Phillips, Melanie Leitner, Hubert Kwieciński, Nicholas Marigakis, Dan Moore, Robert Bowser, Janice Robertson, Yunxia Wang, Carlayne E. Jackson, Todd Levine, James Heywood, Steven Nash, Steven Novella, Carmel Armon, Tahseen Mozaffar, Eric J. Sorenson, Catherine Lomen-Hoerth, Tulio E. Bertorini, Orla Hardiman, Daniel MacGowan, Kate Dalton, Jeremy M. Shefner, Vivian E. Drory, Robert G. Miller, Terry Heiman-Patterson, Dallas Forshew, Megan Grosso, Jonathan Goldstein, John Ravits, Sith Sathornsumetee, George Sachs, Paul Wicks, Jonathan D. Glass, David Saperstein, James Caress, Josep Gamez, Jeffrey D. Rothstein, Hiroshi Mitsumoto, Erik P. Pioro, Jeff Dietz, Michael J. Strong, Lewis P. Rowland, Alexander Sherman, Michael Benatar, Jonathan Licht, Meraida Polak, Michael D. Weiss, Jon Baker, Lisa Kinsley, Katherine Tindall, Stacy A. Rudnicki, Kevin Boylan, Ashok Verma, Robin Conwit, Peter M Andersen, Christen Shoesmith, John T. Kissel, Khema Sharma, Nazem Atassi, Bjorn Oskarsson, Rup Tandan, Richard Bedlack, Ginna Gonzalez, and Bonnie Gerecke

Subjects
medicine.medical_specialty, biology, Cannabinoids, business.industry, Amyotrophic Lateral Sclerosis, Marijuana Smoking, General Medicine, biology.organism_classification, medicine.disease, Neurology, Humans, Immunologic Factors, Medicine, Neurology (clinical), Cannabis, Amyotrophic lateral sclerosis, business, Psychiatry
Published
2012

25. Molecular mimicry: Sensitization of Lewis rats withCampylobacter jejuni lipopolysaccharides induces formation of antibody toward GD3 ganglioside

Author

Keiko Shibata, Robert K. Yu, Michael H. Rivner, Kyoji Taguchi, Toshio Ariga, Stuart A. Thompson, and Seigo Usuki

Subjects
Lipopolysaccharides, Time Factors, Neural Conduction, Fluorescent Antibody Technique, Schwann cell, medicine.disease_cause, Campylobacter jejuni, Article, Nerve conduction velocity, Epitope, Epitopes, Cellular and Molecular Neuroscience, Campylobacter Jejuni Infection, Neurofilament Proteins, Gangliosides, Reaction Time, medicine, Animals, Humans, Evoked Potentials, Immunosorbent Techniques, Inflammation, biology, Electromyography, Chemistry, Molecular Mimicry, Titrimetry, Antibody titer, biology.organism_classification, Molecular biology, Electric Stimulation, Rats, Molecular mimicry, medicine.anatomical_structure, Rats, Inbred Lew, Immunoglobulin G, Antibody Formation, Immunology, Female, Immunization, lipids (amino acids, peptides, and proteins), Chromatography, Thin Layer, Sciatic nerve, Demyelinating Diseases
Abstract

Recently we have reported cases of demyelinating inflammatory neuropathy showing elevated titers of anti-GD3 antibodies, which occurs rarely in Guillain-Barré syndrome. To examine the correlation between the anti-GD3 antibody titer and Campylobacter jejuni infection, we sensitized female Lewis rats with lipopolysaccharides (LPSs) from serotype HS19 of C. jejuni and examined changes in nerve conduction velocity and nerve conduction block (P/D ratio). After 16 weeks of sensitization, animals revealed decreases of nerve conduction velocity and conduction block (P/D ratio) and high titer of anti-GD3 antibodies. These anti-GD3 antibodies also blocked transmission in neuromuscular junctions of spinal cord-muscle cells cocultures. The GD3 epitope was verified to be located on the Schwann cell surface and nodes of Ranvier in rat sciatic nerve. To determine the target epitope for GD3 antibodies in causing nerve dysfunction, the LPS fraction containing the GD3 epitope was purified from the total LPS by using an anti-GD3 monoclonal antibody-immobilized affinity column. Subsequently, chemical analysis of the oligosaccharide portion was performed and confirmed the presence of a GD3-like epitope as having the following tetrasaccharide structure: NeuAcalpha2-8NeuAc2-3Galbeta1-4Hep. Our data thus support the possibility of a contribution of GD3 mimicry as a potential pathogenic mechanism of peripheral nerve dysfunction.

Published
2006

26. AIDP and CIDP having specific antibodies to the carbohydrate epitope (–NeuAcα2–8NeuAcα2–3Galβ1–4Glc–) of gangliosides

Author

Juan Sanchez, Iku Utsunomiya, Toshio Ariga, Robert K. Yu, Michael H. Rivner, Kyoji Taguchi, and Seigo Usuki

Subjects
Male, Carbohydrates, Neuromuscular Junction, Action Potentials, Enzyme-Linked Immunosorbent Assay, Chronic inflammatory demyelinating polyneuropathy, Guillain-Barre Syndrome, Epitope, Epitopes, Antigen, Antibody Specificity, Gangliosides, medicine, Humans, Avidity, Muscle, Skeletal, Chromatography, High Pressure Liquid, Aged, Plasma Exchange, biology, Guillain-Barre syndrome, business.industry, Antibody titer, Middle Aged, medicine.disease, Coculture Techniques, Titer, Polyradiculoneuropathy, Chronic Inflammatory Demyelinating, Spinal Cord, Neurology, Immunology, biology.protein, lipids (amino acids, peptides, and proteins), Neurology (clinical), Antibody, business
Abstract

Anti-ganglioside antibodies were investigated in plasma exchange solutions (PEs) from two patients with acute and chronic inflammatory demyelinating neuropathies (AIDP and CIDP). Both cases show markedly elevated antibody titers against the lacto-series gangliosides, GM3, GD3, and GT3. In the CIDP patient, the IgG antibody titer to GD3 was remarkably elevated (titer, 1:10,000), indicating maximal avidity to the tetrasaccharide epitope (-NeuAcalpha2-8NeuAcalpha2-3Galbeta1-4Glc-). There were also activities toward GM4 and GM2 with the affinity higher to GM4 than to GM2, indicating that the antibody activity was not highly specific. In contrast, the antibody activities in the AIDP patient showed similar avidity to GM3, GD3, and GT3. These two patients are very rare cases that have not previously encountered in GBS. The effects on co-cultured cells of rat spinal cord and muscle differed according to which PE was used. PE from the AIDP patient produced an inhibitory effect (reduction to 26.8%) on the spontaneous muscle action potential of the neuromuscular junction (NMJ), but the PE from the CIDP patient did not. Thus, in AIDP, the common epitope of GM3, GD3, or GT3 may be shared with certain antigens localized in the peripheral nervous system (PNS) and may participate in a component of conduction-related molecules in the NMJ. High titers of anti-GD3 antibody and the distortion of antibody recognition found in CIDP seem to have no immediate effect on electrophysiologic function in the PNS.

Published
2005

27. ALSUntangled 15: Coconut Oil

Author

Meraida Polak, Daniel M. Pastula, Michael H. Rivner, James Heywood, James A. Russell, Todd Levine, Orla Hardiman, Steve Kolb, Kevin Boylan, Michael Benatar, Larry Phillips, Michael J. Strong, Steven Novella, Muddasir Quereshi, Vivian E. Drory, Jonathan Goldstein, Ginna Gonzalez, Jonathan Licht, Noah Lechtzin, Kathy Mitchell, Jim Wymer, Melanie Leitner, Pamela Kittrell, Peter M Andersen, Robert G. Miller, George Sachs, Terry Heiman-Patterson, Dallas Forshew, Lisa Kinsley, Paul Wicks, Robert Bowser, Nazem Atassi, Megan Grosso, Tahseen Mozaffar, Lewis P. Rowland, Michael D. Weiss, Hubert Kwieciński, Dan Moore, Alexander Sherman, Janice Robertson, Catherine Lomen-Hoerth, Jon Baker, Eric J. Sorenson, Daniel MacGowan, Kate Dalton, Bonnie Gerecke, Rup Tandan, Gary L. Pattee, James Caress, Katherine Tindall, Leo McClusky, Stacy A. Rudnicki, Carmel Armon, Khema Sharma, Christen Shoesmith, John T. Kissel, Hiroshi Mitsumoto, Ashok Verma, Nicholas Marigakis, Yunxia Wang, Robin Conwit, Carlayne E. Jackson, Jeremy M. Shefner, Bjorn Oskarsson, Richard Bedlack, Mazen M. Dimachkie, Erik P. Pioro, Jeff Dietz, Steven Nash, Jeffrey D. Rothstein, Josep Gamez, John Ravits, Tulio E. Bertorini, Sith Sathornsumetee, Jonathan D. Glass, and David Saperstein

Subjects
food.ingredient, business.industry, Amyotrophic Lateral Sclerosis, Coconut oil, General Medicine, medicine.disease, food, Neurology, Coconut Oil, medicine, Animals, Humans, Plant Oils, Neurology (clinical), Food science, Amyotrophic lateral sclerosis, business
Published
2012

28. ALSUntangled No. 26: lunasin

Author

Jim Wymer, Christina Fournier, Robert Bowser, Lyle Ostrow, Paul E. Barkhaus, Ginna Gonzalez, Hubert Kwieciński, Dan Moore, Muddasir Quereshi, Catherine Lomen-Hoerth, Daniel MacGowan, Pamela Kittrell, Josep Gamez, Eric J. Sorenson, Kate Dalton, Todd Levine, Eric Valor, Ashok Verma, Tulio E. Bertorini, Mark B. Bromberg, Merit Cudkowicz, Noah Lechtzin, Michael J. Strong, Efrat Carmi, Mazen M. Dimachkie, Rup Tandan, Bjorn Oskarsson, Mieko Ogino, Tahseen Mozaffar, James A. Russell, George Sachs, Jonathan Goldstein, Hiroshi Mitsumoto, Steven Novella, Jonathan Licht, Terry Heiman-Patterson, Dallas Forshew, James Heywood, Richard Bedlack, James Caress, Sith Sathornsumetee, Steve Kolb, Kevin Boylan, Nazem Atassi, Yunxia Wang, Carlayne E. Jackson, Paul Wicks, Gary L. Pattee, Meraida Polak, Chafic Karam, Gleb Levitsky, Lorne Zinman, Craig Oster, Carmel Armon, Edor Kabashi, Robin Conwit, John Ravits, Laurie Gutmann, Janice Robertson, Erik P. Pioro, Brett M. Morrison, Orla Hardiman, Leo McClusky, Vivian E. Drory, Jeff Dietz, Colin Quinn, Jonathan D. Glass, Jeremy M. Shefner, Robert G. Miller, David Saperstein, Michael D. Weiss, Jeffrey V. Rosenfeld, Megan Grosso, Jon Baker, Gregory T. Carter, Kathy Mitchell, Melanie Leitner, Michael Benatar, Bonnie Gerecke, Lisa Kinsley, Khema Sharma, Steven Nash, Christen Shoesmith, John T. Kissel, Jeffrey D. Rothstein, Peter M Andersen, Nicholas J. Maragakis, Katherine Tindall, Stacy A. Rudnicki, Daniel M. Pastula, Michael H. Rivner, Larry Phillips, Lewis P. Rowland, and Alexander Sherman

Subjects
Adult, Male, Pathology, medicine.medical_specialty, business.industry, Amyotrophic Lateral Sclerosis, Anti-Inflammatory Agents, Middle Aged, medicine.disease, Neurology, medicine, Soybean Proteins, Humans, Female, Neurology (clinical), Amyotrophic lateral sclerosis, business, Aged, Phytotherapy, Plant Proteins
Published
2014

29. A new approach to ELISA-based anti-glycolipid antibody evaluation of highly adhesive serum samples

Author

Robert K. Yu, Michael H. Rivner, Seigo Usuki, and Dawn K. O'Brien

Subjects
Immunology, Chronic inflammatory demyelinating polyneuropathy, Enzyme-Linked Immunosorbent Assay, Guillain-Barre Syndrome, Article, Glycosphingolipids, Glycolipid, Antibody Specificity, Predictive Value of Tests, medicine, Immunology and Allergy, Humans, Computer Simulation, Autoantibodies, Models, Statistical, medicine.diagnostic_test, biology, Guillain-Barre syndrome, Chemistry, Amyotrophic Lateral Sclerosis, Autoantibody, Reproducibility of Results, medicine.disease, Myasthenia gravis, Titer, Polyradiculoneuropathy, Chronic Inflammatory Demyelinating, Immunoassay, biology.protein, Chromatography, Thin Layer, Antibody, Hereditary Sensory and Motor Neuropathy, Biomarkers, Protein Binding
Abstract

The enzyme-linked immunosorbent assay (ELISA) is a standard immunoassay used in measuring antibody reactivity (expressed as titers) for glycosphingolipids (GSLs) such as gangliosides and sulfoglycolipids in the sera of patients with Guillain-Barre syndrome (GBS), variants of GBS, and chronic inflammatory demyelinating polyneuropathy (CIDP). In the present study, anti-GSL antibodies were evaluated using a new formula of affinity parametric complex (APC), calculated from limiting-dilution serum assay data, followed by affinity parametric complex criterion (APCC). Using assay results based on APCC, we analyzed serum samples categorized into acute inflammatory demyelinating polyneuropathy (AIDP), acute motor-sensory axonal neuropathy (AMSAN), CIDP, CIDP with myasthenia gravis (MG), and amyotrophic lateral sclerosis (ALS). We were able to determine the affinity strength of antibodies otherwise hidden in the non-specific background activity in highly adhesive serum samples. The thin-layer chromatography (TLC)-immuno-overlay method assured us that this new method is an accurate and reliable way for evaluating anti-GSL antibodies using ELISA serum sample data.

Published
2014

30. The neurophysiology of myofascial pain syndrome

Author

Michael H. Rivner

Subjects
Lidocaine, medicine.diagnostic_test, Electromyography, business.industry, Muscle spindle, Motor nerve, General Medicine, Myofascial pain syndrome, Neurophysiology, medicine.disease, Spinal cord, Nervous System, Anesthesiology and Pain Medicine, medicine.anatomical_structure, Anesthesia, medicine, Animals, Humans, Rabbits, Neurology (clinical), Cervical dystonia, business, Myofascial Pain Syndromes, medicine.drug
Abstract

This article discusses the neurophysiology of myofascial pain syndrome. The local twitch response is a characteristic finding of this condition; it is activated by snapping palpation, pressure, or needle insertion at the trigger point. It is manifested by a burst of activity in the muscle band that contains the activated trigger point. No activity is seen at other muscles bands. Data from experiments with the rabbit indicate that this is a spinal reflex, as it is abolished by transection of the motor nerve innervating the trigger point and infusion of lidocaine. Transection of the spinal cord above the level of the trigger point fails to permanently alter the trigger point response. Needle examination recordings from trigger points show low-voltage spontaneous activity and activity resembling end-plate spikes. This activity is reduced with infusion of phentolamine and local intramuscular infusions of phenoxybenzamine. There are four hypotheses to explain the findings seen at the trigger point. The first is that trigger points are found at the muscle spindle. While this theory may explain the effects of alpha-adrenergic antagonists at the trigger point, it does not fully explain the electromyographic (EMG) findings recorded at the trigger point. The second theory is that trigger points represent hyperactive end-plate regions, as the EMG activity recorded at trigger points resembles that described at the end-plate region. Other theories that either deny the existence of myofascial pain syndrome or believe it represents a focal dystonia are also discussed.

Published
2001

31. Randomized controlled trial of IVIg in untreated chronic inflammatory demyelinating polyradiculoneuropathy

Author

Michael H. Rivner, Peter D. Donofrio, Gareth Parry, Michael E. Shy, Mark B. Bromberg, Robert R. Rice, Rup Tandan, Richard J. Barohn, Richard A. Lewis, Wendy C. King, Miriam Freimer, Yadollah Harati, W. W. Campbell, Charles A. Thornton, M. J. Giuliani, Haikady N. Nagaraja, Jerry R. Mendell, D. M. Simpson, Carlayne E. Jackson, and John T. Kissel

Subjects
Adult, Male, medicine.medical_specialty, Vital capacity, Time Factors, Randomization, Adolescent, Neural Conduction, Placebo, Nerve conduction velocity, law.invention, FEV1/FVC ratio, Double-Blind Method, Randomized controlled trial, law, hemic and lymphatic diseases, medicine, Humans, Aged, Aged, 80 and over, business.industry, Immunoglobulins, Intravenous, Polyradiculoneuropathy, Middle Aged, medicine.disease, Surgery, Peripheral neuropathy, Polyradiculoneuropathy, Chronic Inflammatory Demyelinating, Anesthesia, Female, Neurology (clinical), business
Abstract

Objective: To determine the efficacy of IV immunoglobulin (IVIg) given patients with untreated chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Methods: A randomized, double-blind, multicenter, investigator-initiated study compared IVIg (Aventis Behring LLC, King of Prussia, PA) with placebo (5% albumin). On days 1, 2, and 21, IVIg (1 g/kg) or placebo was given. The primary outcome measure was the change in muscle strength from baseline to day 42, using the average muscle score (AMS). Secondary outcome measures included change from baseline AMS at days 10 and 21, the Hughes’ functional disability scale, forced vital capacity (FVC), and nerve conduction studies (NCS) of four motor nerves (median, ulnar, peroneal, and tibial). Results: The patients (n = 33) were randomized. Of these, 30 (14 women, 16 men, aged 54 ± 20 years, range 13 to 82) received IVIg and 23 were given placebo (12 women, 11 men, aged 50 ± 18 years, range 23 to 73). Baseline AMS values of the groups were similar (IVIg 7.06 ± 1.31 versus placebo 7.28 ± 1.18, p = 0.53). There were two dropouts in placebo group and one in the IVIg group. Mean AMS improved at day 42 comparing IVIg with placebo (0.63 versus −0.1, p = 0.006). Improved strength was seen by day 10. The placebo group lost strength over this same interval. In the IVIg, 11 subjects improved by the functional disability scale; none worsened. This differed ( p = 0.019) from those in the placebo-treated group (two improved, two got worse, remainder unchanged). Forced vital capacity did not improve with IVIg treatment. IVIg improved ulnar motor distal latency ( p = 0.005), tibial distal compound muscle amplitude ( p = 0.003), and peroneal nerve conduction velocity ( p = 0.03). Conclusions: IVIg improves strength in patients with untreated CIDP by day 10 with continued benefit through day 42; more than one third improve by at least a functional grade on a disability scale. This study provides data supporting IVIg as the initial treatment for CIDP.

Published
2001

33. Skeletal muscle oxidative capacity in amyotrophic lateral sclerosis

Author

Terence E, Ryan, Melissa L, Erickson, Ajay, Verma, Juan, Chavez, Michael H, Rivner, and Kevin K, Mccully

Subjects
Adult, Male, Leg, Adolescent, Phosphocreatine, Myoglobin, Amyotrophic Lateral Sclerosis, Age Factors, Phosphorus, Middle Aged, Cohort Studies, Disability Evaluation, Hemoglobins, Oxidative Stress, Young Adult, Oxygen Consumption, Humans, Female, Muscle, Skeletal, Aged
Abstract

Mitochondrial dysfunction in the motor neuron has been suspected in amyotrophic lateral sclerosis (ALS). If mitochondrial abnormalities are also found in skeletal muscle, assessing skeletal muscle could serve as an important biomarker of disease progression.Using 31P magnetic resonance (31P-MRS) and near infrared (NIRS) spectroscopy, we compared the absolute values and reproducibility of skeletal muscle oxidative capacity in people with ALS (n = 6) and healthy adults (young, n = 7 and age-matched, n = 4).ALS patients had slower time constants for phosphocreatine (PCr) and muscle oxygen consumption (mVO2 ) compared with young, but not age-matched controls. The coefficient of variation for the time constant was 10% (SD = 2.8%) and 17% (SD = 6.2%) for PCr and mVO2 , respectively.People with ALS had, on average, a small but not statistically significant, impairment in skeletal muscle mitochondrial function measured by both 31P-MRS and NIRS. Both methods demonstrated good reproducibility.

Published
2013

36. Evoked EMG

Author

Michael H. Rivner

Published
2013

37. Screening for LRP4-, agrin-, and titin-antibodies and exploring the autoimmune spectrum in myasthenia gravis

Author

Alain Vigneron, Michael H. Rivner, Lin Mei, Nicolas Bodart, Kathi Hartmann, Joachim Weis, Isabell Cordts, Jens Reimann, Kristl G. Claeys, Jörg B. Schulz, and Socrates J. Tzartos

Subjects
Agrin, biology, business.industry, medicine.disease, Myasthenia gravis, Neurology, Pediatrics, Perinatology and Child Health, Immunology, biology.protein, Medicine, Titin, Neurology (clinical), Antibody, business, Genetics (clinical)
Published
2016

38. Anti-Sulfoglucuronosyl Paragloboside Antibody

Author

Robert K. Yu, Michael H. Rivner, Brandy Quarles, Toshio Ariga, Seigo Usuki, and Dongpei Li

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Ganglioside, biology, business.industry, General Neuroscience, Sulfoglucuronosyl paragloboside, Disease, Degeneration (medical), medicine.disease, Serology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Immunology, biology.protein, Etiology, Medicine, Neurology (clinical), Amyotrophic lateral sclerosis, Antibody, business, 030217 neurology & neurosurgery
Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons. Although the etiology of ALS is obscure, genetic studies of familiar ALS suggest a multifactorial etiology for this condition. Similarly, there probably are multiple causes for sporadic ALS. Autoimmune-mediated motor neuron dysfunction is one proposed etiology for sporadic ALS. In the present study, anti-glycolipid antibodies including GM1, GD1b, GD3, and sulfoglucuronosyl paragloboside (SGPG) were investigated in the sera of a large number of patient samples, including 113 ALS patients and 50 healthy controls, by means of enzyme-linked immunosorbent assay with affinity parametric complex criterion evaluation and thin-layer chromatography immunooverlay (immuno-TLC). Anti-SGPG antibodies were found in the sera of 13.3% ALS patients (15 out of 113). The highest titer reached 1:1600. The presence of anti-SGPG antibodies in the serum samples was also confirmed by immuno-TLC. Importantly, a multiple logistic regression analysis showed that the presence of anti-SGPG antibody was positively correlated with age ( p

Published
2016

39. Preliminary Findings of High-Dose Thiamine in Dementia of Alzheimer's Type

Author

M. E. Nichols, David W. Loring, Michael H. Rivner, E. E. Moore, Edward Zamrini, Kimford J. Meador, Hernan Posas, and E. E. Thompson

Subjects
Male, medicine.medical_specialty, Disease, Neuropsychological Tests, 03 medical and health sciences, 0302 clinical medicine, Degenerative disease, Double-Blind Method, Alzheimer Disease, Oral administration, Internal medicine, medicine, Humans, Dementia, Single-Blind Method, Thiamine, Aged, Aged, 80 and over, Dose-Response Relationship, Drug, 030214 geriatrics, Electromyography, business.industry, food and beverages, Middle Aged, medicine.disease, Psychiatry and Mental health, Endocrinology, Mechanism of action, Female, Neurology (clinical), Geriatrics and Gerontology, medicine.symptom, Alzheimer's disease, Mental Status Schedule, business, human activities, 030217 neurology & neurosurgery, Acetylcholine, medicine.drug
Abstract

Thiamine is important not only in the metabolism of acetylcholine but also in its release from the presynaptic neuron. Pathologic, clinical, and biochemical data suggest that thiamine deficiency is detrimental to the cholinergic system and that thiamine-dependent enzymes may be altered in Alzheimer's disease. Two previous studies reported contradictory results in patients with dementia of Alzheimer's type treated with 3 g/day of thiamine. In the present study, we examined the effects of 3 to 8 g/day thiamine administered orally. Our results suggest that thiamine at these pharmacologic dosages may have a mild beneficial effect in dementia of Alzheimer's type. The mechanism of the observed effect is unknown, but the findings warrant further investigation, not only for their therapeutic implications but for their possible etiologic clues. In addition, the results suggest long-term carry-over effects that should be considered in the design of future studies.

Published
1993

40. Letters to the editor

Author

Michael H. Rivner, Thomas R. Swift, Barbara O. Crout, W. Trojaborg, A. Moon, B. B. Andersen, N. S. Trojaborg, P. Liam Oey, Jože V. Trontelj, Erik Stålberg, Betty Soliven, Ricardo Maselli, Suat Topaktas, Sefik Dener, Meliha Kenis, Turgay Dalkara, Kieko Genba, Yoshikazu Ugawa, Ichiro Kanazawa, Ichiro Okutsu, Ikki Hamanaka, Toshihiko Yoshida, Masato Morita, Youko Yamanouchi, Koichi Okamoto, Shunsaku Hirai, William Camu, and Michel Billiard

Subjects
Neural Conduction, Cellular and Molecular Neuroscience, Nuclear magnetic resonance, Physiology, business.industry, Body height, Physiology (medical), Medicine, Neurology (clinical), business, Nerve conduction, F wave
Published
1993

41. Steroids are overutilized

Author

Michael H. Rivner

Subjects
medicine.medical_specialty, Physiology, business.industry, medicine.medical_treatment, MEDLINE, Azathioprine, Pharmacology, medicine.disease, Dermatology, Myasthenia gravis, Thymectomy, Cellular and Molecular Neuroscience, Prednisone, Physiology (medical), medicine, Neurology (clinical), business, medicine.drug
Published
2001

42. Letters to the editor

Author

David A. Krendel, Donal A. Costigan, Hernan N. Posas, and Michael H. Rivner

Subjects
Cellular and Molecular Neuroscience, Pathology, medicine.medical_specialty, Expression (architecture), Physiology, business.industry, Physiology (medical), Medicine, Neurology (clinical), Sarcoidosis, business, medicine.disease
Published
1992

43. Frequency of radiculopathies in motor vehicle accidents

Author

Lawrence K. Spitz, Randall L. Braddom, and Michael H. Rivner

Subjects
medicine.medical_specialty, animal structures, Databases, Factual, Physiology, viruses, Population, Poison control, Lumbar vertebrae, complex mixtures, Cellular and Molecular Neuroscience, Lumbar, Physiology (medical), medicine, Humans, Trauma, Nervous System, education, Radiculopathy, Retrospective Studies, education.field_of_study, Lumbar Vertebrae, business.industry, Electrodiagnosis, Accidents, Traffic, hemic and immune systems, medicine.disease, Spinal cord, Surgery, Plexopathy, Motor Vehicles, medicine.anatomical_structure, Anesthesia, Cervical Vertebrae, Neurology (clinical), Radiculopathies, business, Cervical vertebrae
Abstract

This retrospective study compared the frequency of electrodiagnostically confirmed cervical and lumbar radiculopathies in a motor vehicle accident (MVA) population to that of a non-MVA population in 24,651 consecutive initial electrodiagnostic reports. The frequency of cervical radiculopathy was slightly but significantly increased in 8% of the MVA compared to 6% of the non-MVA patients. The frequency of plexopathy was significantly increased in the MVA (3%) compared to the non-MVA patients (2%). The frequency of lumbar radiculopathy was not significantly increased (12% for both groups). Nineteen percent of the MVA patients and 18% of the non-MVA patients had cervical and/or lumbar radiculopathy. This shows that the frequency of cervical and lumbar radiculopathies is low after MVAs. MVA appears to cause a small but significant increase in the frequency of cervical radiculopathy and plexopathy.

Published
2009

44. Letters to the editor

Author

Young Ho Sohn, Ii Nam Sunwoo, Je Geun Chi, Jan Lexell, Charles Taylor, Alberto Priori, Alfredo Berardelli, Maurizio Inghilleri, Giorgio Cruccu, Marina Zaccagnini, Mario Manfredi, A. Palmowski, H. Reichmann, K. V. Toyka, Richard Letz, Fredric E. Gerr, David M. Simpson, Michael H. Rivner, Thomas R. Swift, Barbara O. Crout, and Karen P. Rhodes

Subjects
Cellular and Molecular Neuroscience, Materials science, Human muscle, Physiology, Physiology (medical), Neurology (clinical), Fiber, Fiber density, Biomedical engineering
Published
1991

45. Letters to the editor

Author

P. L. Oey, H. Franssen, R. A. J. A. M. Bernsen, J. H. J. Wokke, M. L. Sales-Luís, M. Galvão, M. Carvalho, G. Sousa, M. M. Alves, R. Serrão, David C. Preston, Eric L. Logigian, David Yarnitsky, Jose L. Ochoa, J. Gert Van, Michael H. Rivner, Thomas R. Swift, Barbara O. Crout, and Karen P. Rhodes

Subjects
Cellular and Molecular Neuroscience, Physiology, business.industry, Physiology (medical), Block (telecommunications), Borrelia Burgdorferi Infection, Medicine, Neurology (clinical), business, Virology
Published
1991

46. Toward more rational nerve conduction interpreations: The effect of height

Author

Michael H. Rivner, B. O. Crout, Thomas R. Swift, and K. P. Rhodes

Subjects
Adult, Adolescent, Physiology, Body height, Neural Conduction, Normal values, Electromyography, Nerve conduction velocity, Cellular and Molecular Neuroscience, Reference Values, Physiology (medical), Reaction Time, Humans, Medicine, In patient, Inverse correlation, Aged, Clinical Trials as Topic, medicine.diagnostic_test, Foot, business.industry, Age Factors, Anatomy, Middle Aged, Body Height, Linear relationship, Neurology (clinical), Skin Temperature, business, Nerve conduction
Abstract

One hundred four normal subjects ranging in age from 17 to 77 years and in height from 115 to 203 cm underwent nerve conduction studies of sural, peroneal, tibial, and median nerves. Foot temperature was measured in each patient. A strong inverse correlation was found between height and sural (r = -0.7104), peroneal (r = -0.6842), and tibial (r = -0.5044) conduction velocities. These correlations were significant at the P less than 0.001 level. Median conduction velocity was not correlated with height. Height was correlated with the distal latencies of all nerves studied (sural r = 0.6518, peroneal r = 0.4583, tibial r = 0.7217, median r = 0.5440). These correlations were significant at the P less than 0.001 level. Age was inversely correlated with both tibial (r = -0.4071) and median (r = -0.3464) nerve conduction velocities but not with sural and peroneal conductions. There were no correlations between distal latencies and age. If the variation in conduction velocity accounted for by the linear relationship with height was removed, then age would be inversely correlated to all conduction velocity measurements with the exception of the sural. Temperature is inversely correlated with the sural (r = -0.2233), peroneal (r = -0.2102), and tibial (r = -0.2710) distal latencies. In all instances, the effects of age and temperature were minor determinants when compared with the effects of height. Diagnostic conclusions made from nerve conduction data without correcting for height may be invalid in patients taller and shorter than normal.(ABSTRACT TRUNCATED AT 250 WORDS)

Published
1990

47. Thymoma: Diagnosis and Management

Author

Michael H. Rivner and Thomas R. Swift

Subjects
medicine.medical_specialty, Thymoma, business.industry, General surgery, Thymus Neoplasms, medicine.disease, Text mining, Neurology, Humans, Medicine, Neurology (clinical), Tomography, X-Ray Computed, business
Published
1990

48. Can we eliminate placebo in ALS clinical trials?

Author

Louis S. Russo, Aron S. Buchman, Wendy Johnston, Peter D. Donofrio, Dawn McGuire, Mark A. Ross, Lawrence H. Phillips, Austin J. Sumner, Janice M. Massey, Michael R. Swenson, Carlayne E. Jackon, Daniel Newman, Scott C. Stromatt, Mark A. Rubin, Lawrence Teitel, Richard J. Barohn, John J. Kelly, Jack H. Petajan, Robert M. Pascuzzi, Andrew Eisen, Wilson W. Bryan, Jessie C. Goodpasture, Rebecca J. Hoagland, Jerry M. Belsh, Carmel Armon, Laurie Gutmann, Richard A. Gan, Steven H. Horowitz, Gareth Parry, Raul N. Mandler, Stephen M. Sergay, Robert G. Miller, James Murphy, and Michael H. Rivner

Subjects
Quality Control, Vital capacity, medicine.medical_specialty, Statistics as Topic, Vital Capacity, Isometric exercise, Placebo, law.invention, Placebos, FEV1/FVC ratio, Randomized controlled trial, Double-Blind Method, law, Medicine, Humans, Nerve Growth Factors, Amyotrophic lateral sclerosis, Muscle, Skeletal, Physical Examination, Randomized Controlled Trials as Topic, Leg, business.industry, Amyotrophic Lateral Sclerosis, medicine.disease, Respiratory Muscles, Clinical trial, Natural history, Treatment Outcome, Research Design, Anesthesia, Physical therapy, Arm, Neurology (clinical), business, Follow-Up Studies, Muscle Contraction
Abstract

Previous studies concluded that the decline in strength in patients with amyotrophic lateral sclerosis (ALS) is a linear function. If so, a patient's natural history might serve as the control, instead of placebo, in a clinical trial.A placebo-controlled ALS clinical trial included a natural history phase, followed by a 6-month treatment phase. Each patient's forced vital capacity (FVC) score and maximal voluntary isometric contraction (MVIC) raw scores were measured monthly, standardized, and averaged into megascores. For 138 patients, the arm, leg, FVC, arm+leg combination, and arm+leg+FVC combination megascore slopes during the natural history phase and during the placebo phase were compared.The mean slope of megascores during the natural history phase and the mean slope during the placebo phase were not different for the arm, leg, and arm+leg megascores, but were different for the FVC and arm+leg+FVC combination megascores.Natural history controls may be useful in ALS exploratory trials that use arm megascore slope as the primary outcome measure. However, there are distinct limitations to the use of natural history controls, so that Phase 3 ALS clinical trials require placebo controls.

Published
2003

50. Influence of age and height on nerve conduction

Author

Michael H. Rivner, Khalid Malik, and Thomas R. Swift

Subjects
Adult, medicine.medical_specialty, Aging, Correlation coefficient, Physiology, Neural Conduction, Normal values, Audiology, Nerve conduction velocity, Correlation, Cellular and Molecular Neuroscience, Sural Nerve, Physiology (medical), Medicine, Response Amplitude, Humans, Neurons, Afferent, Ulnar Nerve, Aged, Retrospective Studies, Aged, 80 and over, Motor Neurons, business.industry, Peroneal Nerve, Regression analysis, Middle Aged, Regression, Body Height, Surgery, Electrophysiology, Neurology (clinical), Nervous System Diseases, business, Nerve conduction
Abstract

Previous studies demonstrated age- and height-related slowing of nerve conduction velocity (NCV) and reduction in nerve response amplitude. Unfortunately, many studies examined discontinuous populations, preventing regression analysis. The correlation coefficients of available studies vary widely, preventing clear conclusions. We retrospectively examined 3969 clinically normal subjects ranging in age from 20 to 95 years from a total of 22,420 electrodiagnostic studies done between 1986 and 1998. The correlation of NCV with height was stronger than with age. Regression equations using both factors account for 12--27% of the variance. Responses were seen in the majority of patients aged 70 years and older, but the percentage of normals who had no response increased with advancing age. Age was strongly inversely correlated with the amplitudes of both sensory and motor responses, accounting for 7--16% of the variance. Regression equations using both height and age improved this correlation, accounting for 7--22% of the variance. Therefore, both height and age must be taken into consideration when normal values are developed.

Published
2001

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