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1. The economic burden of individuals living with generalized myasthenia gravis and facing social determinants of health challenges

Author

Tom Hughes, James F. Howard, Nicholas J. Silvestri, Ashley E. L. Anderson, Mai Sato, Sharon Suchotliff, Jeffrey T. Guptill, and Glenn Phillips

Subjects
myasthenia gravis, social determinants of health, economic burden, mixed methods, patient support, Public aspects of medicine, RA1-1270
Abstract

ObjectiveBetter understanding the impact of social determinants of health (SDOH) barriers from the patient perspective is crucial to improve holistic patient support in generalized myasthenia gravis (gMG), a rare autoimmune disorder with high disease and treatment burden. The objective of this study was to identify economic challenges experienced by individuals living with gMG and SDOH barriers to better address current unmet needs.MethodsAdults (18–75 years) living with gMG and experiencing SDOH barriers in the United States were recruited to a mixed-methods study including qualitative interviews and a web-based quantitative survey. Quotas were implemented to include a balanced spread of baseline demographic categories including insurance type, living environment, and employment status among the study sample. Direct and indirect economic challenges were identified by degree of concern.ResultsThe survey was completed by 38 individuals living with gMG, the majority of whom were enrolled in public insurance and not employed. The most commonly reported major economic concerns were managing funds for emergency care (66%), loss of income (61%), and non-medical expenses (58%), highlighting the diversity of economic challenges. Individuals who were using public insurance plans, living in non-urban environments, and unemployed experienced pronounced challenges around managing non-medical costs and accessing government assistance.ConclusionBoth direct and indirect costs were emphasized as major concerns among individuals living with gMG and SDOH barriers. Increasing access to relevant, personalized, and holistic resources, including care management, should be prioritized to improve disease management and outcomes for individuals living with gMG.

Published
2023
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2. Clinical Significance of Serum Albumin and Implications of FcRn Inhibitor Treatment in IgG-Mediated Autoimmune Disorders

Author

E. Sally Ward, Deborah Gelinas, Erwin Dreesen, Jolien Van Santbergen, Jan Terje Andersen, Nicholas J. Silvestri, Joseph E. Kiss, Darrell Sleep, Daniel J. Rader, John J. P. Kastelein, Els Louagie, Gestur Vidarsson, and Isabel Spriet

Subjects
albumin, autoimmune, FcRn, hypoalbuminemia, IgG, monoclonal antibody, Immunologic diseases. Allergy, RC581-607
Abstract

Serum albumin (SA), the most abundant soluble protein in the body, maintains plasma oncotic pressure and regulates the distribution of vascular fluid and has a range of other important functions. The goals of this review are to expand clinical knowledge regarding the functions of SA, elucidate effects of dysregulated SA concentration, and discuss the clinical relevance of hypoalbuminemia resulting from various diseases. We discuss potential repercussions of SA dysregulation on cholesterol levels, liver function, and other processes that rely on its homeostasis, as decreased SA concentration has been shown to be associated with increased risk for cardiovascular disease, hyperlipidemia, and mortality. We describe the anti-inflammatory and antioxidant properties of SA, as well as its ability to bind and transport a plethora of endogenous and exogenous molecules. SA is the primary serum protein involved in binding and transport of drugs and as such has the potential to affect, or be affected by, certain medications. Of current relevance are antibody-based inhibitors of the neonatal Fc receptor (FcRn), several of which are under clinical development to treat immunoglobulin G (IgG)-mediated autoimmune disorders; some have been shown to decrease SA concentration. FcRn acts as a homeostatic regulator of SA by rescuing it, as well as IgG, from intracellular degradation via a common cellular recycling mechanism. Greater clinical understanding of the multifunctional nature of SA and the potential clinical impact of decreased SA are needed; in particular, the potential for certain treatments to reduce SA concentration, which may affect efficacy and toxicity of medications and disease progression.

Published
2022
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3. Phase <scp>2</scp> trial in acetylcholine receptor antibody‐positive myasthenia gravis of transition from intravenous to subcutaneous immunoglobulin: The <scp>MGSCIg</scp> study

Author

Mamatha Pasnoor, Vera Bril, Todd Levine, Jaya Trivedi, Nicholas J. Silvestri, Milind Phadnis, Hans D. Katzberg, David S. Saperstein, Gil I. Wolfe, Laura Herbelin, Kiley Higgs, Andrew J. Heim, Jeffrey M. Statland, Richard J. Barohn, and Mazen M. Dimachkie

Subjects
Neurology, Neurology (clinical)
Published
2023

5. Testosterone Therapy for Dropped Head Syndrome: A Case Report

Author

Timothy J, Felong, Lucia L, Balos, and Nicholas J, Silvestri

Subjects
Male, Muscle Weakness, Muscular Diseases, Neurology, Neck Muscles, Humans, Testosterone, Syndrome, Neurology (clinical), General Medicine, Middle Aged, Hodgkin Disease
Abstract

Dropped head syndrome (DHS) is an impairment of neck extension resulting in a chin-on-chest deformity. DHS is rarely seen but a major hindrance to daily function in affected patients. DHS has been associated with movement disorders, neuromuscular disorders, and electrolyte and endocrine abnormalities. DHS has also been seen in survivors of Hodgkin lymphoma (HL) years after irradiation. HL survivors are also at risk for endocrine hypogonadism after chemotherapy. We present the case of a 58-year-old male HL survivor with dropped head and limited strength in his atrophic neck extensor muscles. Laboratory testing and imaging, nerve conduction studies, electromyography, and muscle biopsy of the neck extensors revealed myopathic and neurogenic changes. Conservative management was unsuccessful. With a desire to avoid surgical fixation, he asked his primary care physician to check his testosterone levels, which returned as low normal. Within 4 months of starting testosterone therapy, he no longer experienced dropped head.

Published
2022

7. Utilization of MG‐ADL in myasthenia gravis clinical research and care

Author

Srikanth, Muppidi, Nicholas J, Silvestri, Robin, Tan, Kimberly, Riggs, Trevor, Leighton, and Glenn A, Phillips

Subjects
Cellular and Molecular Neuroscience, Psychometrics, Physiology, Physiology (medical), Activities of Daily Living, Myasthenia Gravis, Humans, Neurology (clinical)
Abstract

The Myasthenia Gravis Activities of Living (MG-ADL) scale is an 8-item patient-reported scale that measures myasthenia gravis (MG) symptoms and functional status. The objective of the current review is to summarize the psychometric properties of the MG-ADL and published evidence of MG-ADL use. A targeted literature review for published studies of the MG-ADL was conducted using a database and gray literature search. A total of 48 publications and 35 clinical trials were included. Studies indicated that the MG-ADL is a reliable and valid measure that has been used as an outcome in clinical trials and observational studies to measure MG symptoms and response to treatment. While most often used as a secondary endpoint in clinical trials, its use as a primary endpoint has increased in recent years. The most common MG-ADL endpoint is change in MG-ADL score from baseline, although there has been an increase in the analysis of a responder threshold using the MG-ADL. A new concept of minimal symptom expression (MSE) has emerged more recently. Duration of treatment effect is another important construct that is being increasingly evaluated using the MG-ADL. The use of the MG-ADL as a primary endpoint in clinical trials and in responder threshold analyses to indicate treatment improvement has increased in recent years. MSE using the MG-ADL shows promise in helping to determine success of treatment and may be the aspirational goal of MG treatment for the future once validated, particularly given the evolving treatment landscape in MG.

Published
2022

8. Like a Game of Chess, Every Move Matters: The Role of Antibodies in the Myasthenia Gravis Treatment Landscape

Author

Vera Bril, Nicholas J. Silvestri, and Carolina Barnett-Tapia

Subjects
Myasthenia Gravis, Humans, Receptors, Cholinergic, General Medicine
Abstract

Symptoms and disease pathophysiology of myasthenia gravis (MG) vary considerably with each patient, and their individual preferences and priorities add to the need for individualized treatment of this autoimmune disease. Research in MG has grown substantially in recent years. New treatments have the potential of being both effective and well tolerated, addressing the trade-off of choosing either efficacy or tolerability when selecting treatments. Promising investigational treatments that may become available in the future may allow more patients than ever before to achieve an asymptomatic state, with the ultimate goal being to turn off abnormal antibody production.

Published
2022

10. MPZ-T124M mouse model replicates human axonopathy and suggest alteration in axo-glia communication

Author

Ghjuvan’Ghjacumu Shackleford, Leandro N. Marziali, Yo Sasaki, Nadav I. Weinstock, Alexander M. Rossor, Nicholas J. Silvestri, Emma R. Wilson, Edward Hurley, Grahame J. Kidd, Senthilvelan Manohar, Dalian Ding, Richard J. Salvi, M. Laura Feltri, Maurizio D’Antonio, and Lawrence Wrabetz

Abstract

Myelin is essential for rapid nerve impulse propagation and axon protection. Accordingly, defects in myelination or myelin maintenance lead to secondary axonal damage and subsequent degeneration. Studies utilizing genetic (CNPase-, MAG-, and PLP-null mice) and naturally occurring neuropathy models suggest that myelinating glia also support axons independently from myelin. Myelin protein zero (MPZ or P0), which is expressed only by Schwann cells, is critical for myelin formation and maintenance in the peripheral nervous system. Many mutations in MPZ are associated with demyelinating neuropathies (Charcot-Marie-Tooth disease type 1B [CMT1B]). Surprisingly, the substitution of threonine by methionine at position 124 of P0 (P0T124M) causes axonal neuropathy (CMT2J) with little to no myelin damage. This disease provides an excellent paradigm to understand how myelinating glia support axons independently from myelin. To study this, we generated targeted knock-in P0T124M mutant mice, a genetically authentic model of T124M-CMT2J neuropathy. Similar to patients, these mice develop axonopathy between 2 and 12 months of age, characterized by impaired motor performance, normal nerve conduction velocities but reduced compound motor action potential amplitudes, and axonal damage with only minor compact myelin modifications. Mechanistically, we detected metabolic changes that could lead to axonal degeneration, and prominent alterations in non-compact myelin domains such as paranodes, Schmidt-Lanterman incisures, and gap junctions, implicated in Schwann cell-axon communication and axonal metabolic support. Finally, we document perturbed mitochondrial size and distribution along P0T124M axons suggesting altered axonal transport. Our data suggest that Schwann cells in P0T124M mutant mice cannot provide axons with sufficient trophic support, leading to reduced ATP biosynthesis and axonopathy. In conclusion, the P0T124M mouse model faithfully reproduces the human neuropathy and represents a unique tool for identifying the molecular basis for glial support of axons.

Published
2022

12. Contributors

Author

Annas Aljassem, Bassam A. Bassam, Tulio Bertorini, Aimee Boegle, William W. Campbell, Sonia Caraballo Cartagena, Diana Castro, Vinay Chaudry, Marinos C. Dalakas, Marcus Deschauer, Rima N. El-Abassi, John D. England, Diana M. Escolar, Jonathan Daniel Finder, Christopher Gibbons, Levi M. Hall, Alicia Henriquez, Mohammed K. Ismail, Mark Landau, Maxwell Harris Levy, Thomas E. Lloyd, Catherine Lomen-Hoerth, Carlos A. Luciano, Daniel L. Menkes, Christopher W. Mitchell, William Motley, Pushpa Narayanaswami, Shin J. Oh, Laura Rosow, Jennifer Schramm, Shreesh Shrestha, Nicholas J. Silvestri, Michael Soliman, Michael Spickler, Christopher F. Spurney, Carolina Tesi Rocha, Dorothy Weiss Tolchin, Matthias Vorgerd, William C. Warner, and Saša Živković

Published
2022

13. A Neurologist's Perspective on Thymectomy for Myasthenia Gravis: Current Perspective and Future Trials

Author

Wentao, Mi, Nicholas J, Silvestri, and Gil I, Wolfe

Subjects
Clinical Trials as Topic, Myasthenia Gravis, Humans, Thymectomy
Abstract

The first randomized blinded study of thymectomy in nonthymomatous myasthenia gravis was designed to answer 3 questions: does the combination of prednisone and removal of the thymus gland via extended transsternal thymectomy after 3 years compared with an identical dosing protocol of prednisone alone (1) lead to better disease status for generalized MG patients with antiacetylcholine receptor antibodies, (2) reduce their prednisone requirements, and/or (3) reduce the side-effect burden from medications used to treat the disease? The study demonstrated that thymectomy confers these benefits for patients and sets the stage for inquiries into the benefits of less-invasive approaches to thymic resection.

Published
2019

14. 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

15. Neuromuscular Disease

Author

Gil I. Wolfe, Lucia L. Balos, Edward J. Fine, Carsten G. Bönnemann, and Nicholas J. Silvestri

Published
2019

17. Validation of a simple disease-specific, quality-of-life measure for diabetic polyneuropathy: CAPPRI

Author

William B. Horton, Sarah M. Jones, Carolina Barnett-Tapia, Matthew P. Elliott, Amruta Joshi, Vera Bril, Shruti M. Raja, Karissa L. Gable, Reza Sadjadi, Kelly G. Gwathmey, Noah Kolb, Michael K. Hehir, Gil I. Wolfe, James W. Russell, Nicholas J. Silvestri, Lisa D. Hobson-Webb, A. Gordon Smith, Michelle L. Mauermann, Rebecca Traub, Mark R. Conaway, Rabia Malik, Aziz Shaibani, Jeffrey T. Guptill, and Ted M. Burns

Subjects
Disease specific, Adult, Male, medicine.medical_specialty, Canada, Psychometrics, MEDLINE, 030209 endocrinology & metabolism, Severity of Illness Index, Article, 03 medical and health sciences, 0302 clinical medicine, Quality of life, Diabetic Neuropathies, Severity of illness, Medicine, Humans, Retrospective Studies, business.industry, Reproducibility of Results, Retrospective cohort study, Middle Aged, medicine.disease, United States, Clinical trial, Physical therapy, Quality of Life, Female, Neurology (clinical), business, Polyneuropathy, 030217 neurology & neurosurgery
Abstract

ObjectiveWe studied the performance of a 15-item, health-related quality-of-life polyneuropathy scale in the clinic setting in patients with diabetic distal sensorimotor polyneuropathy (DSPN).MethodsPatients with DSPN from 11 academic sites completed a total of 231 Chronic Acquired Polyneuropathy Patient-Reported Index (CAPPRI) scales during their clinic visits. Conventional and modern psychometric analyses were performed on the completed forms.ResultsConventional and modern analyses generally indicated excellent psychometric properties of the CAPPRI in patients with DSPN. For example, the CAPPRI demonstrated unidimensionality and performed like an interval-level scale.ConclusionAttributes of the CAPPRI for DSPN include ease of use and interpretation; unidimensionality, allowing scores to be summed; adequate coverage of disease severity; and the scale's ability to address relevant life domains. Furthermore, the CAPPRI is free and in the public domain. The CAPPRI may assist the clinician and patient with DSPN in estimating disease-specific quality of life, especially in terms of pain, sleep, psychological well-being, and everyday function. The CAPPRI may be most useful in the everyday clinical setting but merits further study in this setting, as well as the clinical trial setting.

Published
2018

18. Generalized Myasthenia Gravis: Classification, Clinical Presentation, Natural History, and Epidemiology

Author

Michael K, Hehir and Nicholas J, Silvestri

Subjects
Myasthenia Gravis, Humans
Abstract

Myasthenia gravis (MG) is a rare disease, but the most common disorder of the neuromuscular junction. It is the prototypic autoimmune disease most commonly caused by antibodies to the acetylcholine receptor (AChR) leading to characteristic fatigable weakness of the ocular, bulbar, respiratory, axial, and limb muscles. The majority of patients with MG first present with ocular symptoms. Most patients with MG will experience at least 1 exacerbation of symptoms throughout the course of their illness. This article will cover the epidemiology, clinical presentation, classification, and natural history of MG.

Published
2018

20. Neuromuscular Disorders : A Symptoms and Signs Approach to Differential Diagnosis and Treatment

Author

Nicholas J. Silvestri and Nicholas J. Silvestri

Subjects
Neuromuscular diseases--Treatment, Neuromuscular diseases--Diagnosis
Abstract

Neuromuscular Disorders: A Symptoms and Signs Approach to Differential Diagnosis and Treatment is a practical, evidence-based guide to diagnosis and management of neuromuscular disorders for clinicians. Taking a signs and symptoms approach to the myriad of muscle and nerve problems encountered in the clinic or on the wards, the book provides a roadmap for assessing and localizing weakness, pain, and other disease hallmarks, making an accurate diagnosis, and effective management. Neuromuscular Disorders features bulleted outlines for targeted access to key information and is peppered with useful tables and figures for quick reference. Chapters are written by neuromuscular specialists and are structured to cover the history, clinical investigation, differential diagnosis, and treatment for each disorder. Unlike other texts that begin with diagnosis and work backwards, this concise point-of-care reference starts with presenting complaints and findings to guide the reader along the diagnostic pathway. This approach is the foundation of neurologic practice, and this book will be a valued companion for anyone who suspects a neuromuscular pathology in a patient. Key Features A unique, practical reference for clinicians Symptoms and signs approach to the diagnosis and treatment of neuromuscular disorders Delivers the need-to-know information for successfully identifying and treating both common and rare neuromuscular disorders Structured bullet-point format with tables, diagrams, and algorithms for quick access to essential content

Published
2018

21. Acquired Disorders of the Neuromuscular Junction

Author

Nicholas J. Silvestri, Gil I. Wolfe, and Richard J. Barohn

Subjects
medicine.anatomical_structure, business.industry, medicine, business, Neuroscience, Neuromuscular junction
Published
2017

22. Contributors

Author

Gregory S. Aaen, Nicholas Scott Abend, Amal Abou-Hamden, Jeffrey C. Allen, Anthony A. Amato, Catherine Amlie-Lefond, Stephen Ashwal, Russell C. Bailey, James F. Bale, Brenda Banwell, Kristin W. Barañano, A. James Barkovich, Richard J. Barohn, Ute K. Bartels, Brenda Bartnik-Olson, Ori Barzilai, Alexander Bassuk, David R. Bearden, Liat Ben-Sira, Timothy J. Bernard, Elizabeth Berry-Kravis, Lauren A. Beslow, Jaclyn A. Biegel, Lori Billinghurst, Angela K. Birnbaum, Joanna S. Blackburn, Nuala Bobowski, Adrienne Boire, Carsten G. Bönnemann, Sonia L. Bonifacio, Daniel J. Bonthius, Breck Borcherding, Brian R. Branchford, John Brandsema, Kathryn M. Brennan, J. Nicholas Brenton, Amy R. Brooks-Kayal, Lawrence W. Brown, Jeffrey Buchalter, Carol S. Camfield, Peter R. Camfield, Cristina Campoy, Jessica L. Carpenter, Taeun Chang, Vann Chau, Susan N. Chi, Claudia A. Chiriboga, Yoon-Jae Cho, Cindy W. Christian, Nicholas Chrestian, Maria Roberta Cilio, Robin D. Clark, Bruce H. Cohen, Ronald D. Cohn, Anne M. Connolly, Todd Constable, Shlomi Constantini, Jeannine M. Conway, David L. Coulter, Tina M. Cowan, Russell C. Dale, Benjamin Darbro, Basil T. Darras, Jahannaz Dastgir, Linda De Meirleir, Darryl C. De Vivo, Linda S. de Vries, Jeremy K. Deisch, Paul Deltenre, Jay Desai, Maria Descartes, Gabrielle deVeber, Sameer C. Dhamne, Jullianne Diaz, Salvatore DiMauro, William B. Dobyns, Dan Doherty, Elizabeth J. Donner, Nico U.F. Dosenbach, James J. Dowling, James M. Drake, Cecile Ejerskov, Andrew G. Engel, Gregory M. Enns, María Victoria Escolano-Margarit, Iris Etzion, S. Ali Fatemi, Darcy L. Fehlings, Michelle Lauren Feinberg, Donna M. Ferriero, Pauline A. Filipek, Richard S. Finkel, Paul G. Fisher, Kevin Flanigan, Nicholas K. Foreman, Israel Franco, Yitzchak Frank, Douglas R. Fredrick, Hudson H. Freeze, Cristina Fuente-Mora, Joseph M. Furman, Renata C. Gallagher, Catherine Garel, Emily Gertsch, Donald L. Gilbert, Elizabeth E. Gilles, Christopher C. Giza, Carol A. Glaser, Hannah C. Glass, Tracy Glauser, Joseph Glykys, Amy Goldstein, Hernan Dario Gonorazky, Rodolfo Gonzalez, Howard P. Goodkin, John M. Graham, Alexander L. Greninger, Gary Gronseth, Andrea L. Gropman, Richard Grundy, Renzo Guerrini, Nalin Gupta, Jin S. Hahn, Milton H. Hamblin, Abeer J. Hani, Sharyu Hanmantgad, Mary J. Harbert, Chellamani Harini, Andrea M. Harriott, Chad Heatwole, Andrew D. Hershey, Deborah G. Hirtz, Gregory L. Holmes, Barbara A. Holshouser, Kathleen A. Hurwitz, Eugene Hwang, Rebecca N. Ichord, Paymaan Jafar-Nejad, Sejal V. Jain, Lori Jordan, Marielle A. Kabbouche, Joanne Kacperski, Peter B. Kang, Matthias A. Kariannis, Horacio Kaufmann, Harper L. Kaye, Robert Keating, Colin R. Kennedy, Yasmin Khakoo, Adam Kirton, John T. Kissel, Kelly G. Knupp, Bruce R. Korf, Eric H. Kossoff, Sanjeev V. Kothare, Oren Kupfer, W. Curt LaFrance, Beatrice Latal, Steven M. Leber, Jean-Pyo Lee, Ilo E. Leppik, Tally Lerman-Sagie, Jason T. Lerner, Richard J. Leventer, Daniel J. Licht, Uta Lichter-Konecki, Zvi Lidar, Djin Gie Liem, Tobias Loddenkemper, Roger K. Long, Quyen N. Luc, Mark Mackay, Annette Majnemer, Naila Makhani, Gustavo Malinger, David E. Mandelbaum, Stephen M. Maricich, Kiran P. Maski, Mudit Mathur, Dennis J. Matthews, Kelly McMahon, Megan B. DeMara-Hoth, Bryce Mendelsohn, Julie A. Mennella, Laura R. Ment, Eugenio Mercuri, David J. Michelson, Mohamad A. Mikati, Fady M. Mikhail, Steven Paul Miller, Jeff M. Milunsky, Jonathan W. Mink, Ghayda M. Mirzaa, Wendy G. Mitchell, Michael A. Mohan, Payam Mohassel, Mahendranath Moharir, Umrao R. Monani, Michelle Monje Deisseroth, Manikum Moodley, Andrew Mower, Richard T. Moxley, Sabine Mueller, Alysson R. Muotri, Sandesh C.S. Nagamani, Mohan J. Narayanan, Vinodh Narayanan, Ruth D. Nass, Jeffrey L. Neul, Yoram Nevo, Bobby G. Ng, Katherine C. Nickels, Graeme A.M. Nimmo, Michael J. Noetzel, Lucy Norcliffe-Kaufmann, Douglas R. Nordli, Ulrike Nowak-Göttl, Hope L. O'Brien, Joyce Oleszek, Maryam Oskoui, Alex R. Paciorkowski, Roger J. Packer, Seymour Packman, Jose-Alberto Palma, Andrea C. Pardo, Julie A. Parsons, John Colin Partridge, Gregory M. Pastores, Marc C. Patterson, William J. Pearce, Phillip L. Pearl, Melanie Penner, Leila Percival, Marcia Pereira, Stefan M. Pfister, John Phillips, Barbara Plecko, Sigita Plioplys, Annapurna Poduri, Sharon Poisson, Scott L. Pomeroy, Andrea Poretti, Scott W. Powers, Michael R. Pranzatelli, Allison Przekop, Malcolm Rabie, Sampathkumar Rangasamy, Gerald V. Raymond, Alyssa T. Reddy, Rebecca L. Rendleman, Jong M. Rho, Lance H. Rodan, Sarah M. Roddy, Elizabeth E. Rogers, Stephen M. Rosenthal, N. Paul Rosman, M. Elizabeth Ross, Alexander Rotenberg, Robert S. Rust, Cheryl P. Sanchez, Pedro Sanchez, Iván Sánchez Fernández, Tristan T. Sands, Terence D. Sanger, Kumar Sannagowdara, Dustin Scheinost, Mark S. Scher, Nina F. Schor, Isabelle Schrauwen, Michael M. Segal, Syndi Seinfeld, Duygu Selcen, Laurie E. Seltzer, Margaret Semrud-Clikeman, Dennis W. Shaw, Bennett A. Shaywitz, Sally E. Shaywitz, Renée A. Shellhaas, Elliott H. Sherr, Rita D. Sheth, Michael I. Shevell, Shlomo Shinnar, Ben Shofty, Stanford K. Shu, Michael E. Shy, Laura Silveira Moriyama, Nicholas J. Silvestri, Katherine B. Sims, Harvey S. Singer, Nilika Shah Singhal, Craig M. Smith, Edward Smith, Stephen A. Smith, Evan Y. Snyder, Janet Soul, Christy L. Spalink, Karen A. Spencer, Carl E. Stafstrom, Robert Steinfeld, Jonathan B. Strober, Joseph Sullivan, Kenneth F. Swaiman, Kathryn J. Swoboda, Elizabeth D. Tate, William O. Tatum, Ingrid Tein, Kristyn Tekulve, Jeffrey R. Tenney, Elizabeth A. Thiele, Robert Thompson-Stone, Laura Tochen, Laura M. Tormoehlen, Lily Tran, Doris A. Trauner, Sinan O. Turnacioglu, Nicole J. Ullrich, David K. Urion, Guy Van Camp, Michèle Van Hirtum-Das, Clara D.M. van Karnebeek, Lionel Van Maldergem, Adeline Vanderver, Nicholas A. Vitanza, Michael von Rhein, Emily von Scheven, Ann Wagner, Mark S. Wainwright, Melissa A. Walker, John T. Walkup, Laurence Walsh, Lauren C. Walters-Sen, Raymond Y. Wang, Thomas T. Warner, Harry T. Whelan, Geoffrey A. Weinberg, Elizabeth M. Wells, James W. Wheless, Elaine C. Wirrell, Jeffrey H. Wisoff, Nicole I. Wolf, Gil I. Wolfe, F. Virginia Wright, Nathaniel D. Wycliffe, Michele L. Yang, Christopher J. Yuskaitis, Huda Y. Zoghbi, and Mary L. Zupanc

Published
2017

23. International clinimetric evaluation of the MG-QOL15, resulting in slight revision and subsequent validation of the MG-QOL15r

Author

Ted M, Burns, Reza, Sadjadi, Kimiaki, Utsugisawa, Kelly G, Gwathmey, Amruta, Joshi, Sarah, Jones, Vera, Bril, Carolina, Barnett, Jeffrey T, Guptill, Donald B, Sanders, Lisa, Hobson-Webb, Vern C, Juel, Janice, Massey, Karissa L, Gable, Nicholas J, Silvestri, Gil, Wolfe, Gary, Cutter, Yuriko, Nagane, Hiroyuki, Murai, Masayuki, Masuda, Maria Elena, Farrugia, Caroline, Carmichael, Simone, Birnbaum, Jean-Yves, Hogrel, Shahriar, Nafissi, Farzad, Fatehi, Changyi, Ou, Weibin, Liu, and Mark, Conaway

Subjects
Psychometrics, Myasthenia Gravis, Quality of Life, Humans, Retrospective Studies
Abstract

The MG-QOL15 is a validated, health-related quality of life (HRQOL) measure for myasthenia gravis (MG). Widespread use of the scale gave us the opportunity to further analyze its clinimetric properties.We first performed Rasch analysis on1,300 15-item Myasthenia Gravis Quality of Life scale (MG-QOL15) completed surveys. Results were discussed during a conference call with specialists and biostatisticians. We decided to revise 3 items and prospectively evaluate the revised scale (MG-QOL15r) using either 3, 4, or 5 responses. Rasch analysis was then performed on1,300 MG-QOL15r scales.The MGQOL15r performed slightly better than the MG-QOL15. The 3-response option MG-QOL15r demonstrated better clinimetric properties than the 4- or 5-option scales. Relative distributions of item and person location estimates showed good coverage of disease severity.The MG-QOL15r is now the preferred HRQOL instrument for MG because of improved clinimetrics and ease of use. This revision does not negate previous studies or interpretations of results using the MG-QOL15. Muscle Nerve 54: 1015-1022, 2016.

Published
2016

24. Asymptomatic/pauci-symptomatic creatine kinase elevations (hyperckemia)

Author

Nicholas J, Silvestri and Gil I, Wolfe

Subjects
Diagnosis, Differential, Metabolic Diseases, Muscular Diseases, Reference Values, Asymptomatic Diseases, Humans, Creatine Kinase
Abstract

Neuromuscular clinicians are frequently asked to evaluate patients referred for asymptomatic elevations in creatine kinase (CK), a catalytic enzyme that combines creatine and ATP to form phosphocreatine and ADP. This reaction is crucial for cellular energy generation and metabolism. This laboratory finding, often referred to in simplified lexicon as asymptomatic hyperCKemia, continues to generate controversy at several levels, including definition, the extent of evaluation, and the yield of diagnostic testing. In this review, we summarize the literature based on series of patients with asymptomatic hyperCKemia and provide a rational clinical approach to reveal identifiable underlying causes.

Published
2012

26. Contributors

Author

Bassam A. Bassam, Tulio E. Bertorini, William W. Campbell, Vinay Chaudhry, Marinos C. Dalakas, Marcus Deschauer, Diana M. Escolar, Christopher H. Gibbons, Daniel M. Goodenberger, Nivia Hernandez-Ramos, Susan T. Iannaccone, Cristian Ionita, Mohammad K. Ismail, Lisa S. Krivickas, Robert T. Leshner, Yingjun David Li, Thomas E. Lloyd, Catherine Lomen-Hoerth, Carlos A. Luciano, Daniel L. Menkes, Christopher W. Mitchell, Pushpa Narayanaswami, Peter O'Carroll, Shin J. Oh, Nicholas J. Silvestri, Zachary Simmons, Christopher F. Spurney, Matthias Vorgerd, William C. Warner, and Dorothy Weiss

Published
2011

27. A new mouse model of Charcot-Marie-Tooth 2J neuropathy replicates human axonopathy and suggest alteration in axo-glia communication.

Author

Ghjuvan'Ghjacumu Shackleford, Leandro N Marziali, Yo Sasaki, Anke Claessens, Cinzia Ferri, Nadav I Weinstock, Alexander M Rossor, Nicholas J Silvestri, Emma R Wilson, Edward Hurley, Grahame J Kidd, Senthilvelan Manohar, Dalian Ding, Richard J Salvi, M Laura Feltri, Maurizio D'Antonio, and Lawrence Wrabetz

Subjects
Genetics, QH426-470
Abstract

Myelin is essential for rapid nerve impulse propagation and axon protection. Accordingly, defects in myelination or myelin maintenance lead to secondary axonal damage and subsequent degeneration. Studies utilizing genetic (CNPase-, MAG-, and PLP-null mice) and naturally occurring neuropathy models suggest that myelinating glia also support axons independently from myelin. Myelin protein zero (MPZ or P0), which is expressed only by Schwann cells, is critical for myelin formation and maintenance in the peripheral nervous system. Many mutations in MPZ are associated with demyelinating neuropathies (Charcot-Marie-Tooth disease type 1B [CMT1B]). Surprisingly, the substitution of threonine by methionine at position 124 of P0 (P0T124M) causes axonal neuropathy (CMT2J) with little to no myelin damage. This disease provides an excellent paradigm to understand how myelinating glia support axons independently from myelin. To study this, we generated targeted knock-in MpzT124M mutant mice, a genetically authentic model of T124M-CMT2J neuropathy. Similar to patients, these mice develop axonopathy between 2 and 12 months of age, characterized by impaired motor performance, normal nerve conduction velocities but reduced compound motor action potential amplitudes, and axonal damage with only minor compact myelin modifications. Mechanistically, we detected metabolic changes that could lead to axonal degeneration, and prominent alterations in non-compact myelin domains such as paranodes, Schmidt-Lanterman incisures, and gap junctions, implicated in Schwann cell-axon communication and axonal metabolic support. Finally, we document perturbed mitochondrial size and distribution along MpzT124M axons suggesting altered axonal transport. Our data suggest that Schwann cells in P0T124M mutant mice cannot provide axons with sufficient trophic support, leading to reduced ATP biosynthesis and axonopathy. In conclusion, the MpzT124M mouse model faithfully reproduces the human neuropathy and represents a unique tool for identifying the molecular basis for glial support of axons.

Published
2022
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