92 results on '"William S. David"'
Search Results
2. Longitudinal dysphagia assessment in adult patients with nephropathic cystinosis using the Modified Barium Swallow Impairment Profile
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Stacey Sullivan, Natalie Grant, Colleen Hammond, William S. David, Florian Eichler, and Reza Sadjadi
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Adult ,Cellular and Molecular Neuroscience ,Barium ,Physiology ,Physiology (medical) ,Cystinosis ,Humans ,Neurology (clinical) ,Deglutition Disorders ,Deglutition ,Retrospective Studies - Abstract
Nephropathic cystinosis is a lysosomal storage disorder with known myopathic features, including dysphagia. Evaluation of oropharyngeal swallowing physiology can be standardized using the Modified Barium Swallow Impairment Profile (MBSImP), a validated assessment tool used to analyze and rate swallowing across 17 distinct physiologic domains. Our objective was to better characterize swallowing impairments in nephropathic cystinosis using MBSImP analysis.We retrospectively evaluated 40 video fluoroscopic swallowing studies performed at two time points over 1 y in patients with nephropathic cystinosis with various levels of oral and pharyngeal stage dysphagia. Patients completed two self-administered dysphagia outcome measures (the M. D. Anderson Dysphagia Inventory [MDADI] and the 10-item Eating Assessment Tool [EAT-10]).We demonstrated oral stage and pharyngeal stage dysphagia across domains that impacted bolus control, transit, and clearance through both the oral cavity and pharyngeal lumen. Also captured were deficits related to onset and completeness of laryngeal closure that impact airway protection during swallow. There were significant correlations between pharyngeal total score and EAT-10 (r = 0.5, p 0.001) and between oral total score and EAT-10 (r = 0.7, p 0.001), MDADI-e (r = -0.6, p 0.001), MDADI-p (r = -0.5, p 0.001) and MDADI-c (r = -0.6, p 0.001). There were no differences in oral or pharyngeal total scores across the 1-y time span.This study identifies oral and pharyngeal stage dysphagia as crucial to patients with nephropathic cystinosis and paves the path for future studies of treatment targets.
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- 2022
3. Frequency and type of cancers in myotonic dystrophy: A retrospective cross‐sectional study
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Eleonora S. D'Ambrosio, Kathy Chuang, William S. David, Anthony A. Amato, and Paloma Gonzalez‐Perez
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Cellular and Molecular Neuroscience ,Physiology ,Physiology (medical) ,Neurology (clinical) - Published
- 2023
4. Polyneuropathy Quality Measurement Set
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Brian C. Callaghan, Carmel Armon, Vera Bril, Lindsay Colbert, William S. David, David R. Del Toro, Kenneth Fink, Lyell K. Jones, Robert Kleemeier, Leslie C. MacGregor, Amy Bennett, and Anant Shenoy
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Polyneuropathies ,Neurology ,Humans ,Neurology (clinical) ,Quality Improvement - Published
- 2021
5. Parent-of-Origin Effect on the Age at Symptom Onset in Myotonic Dystrophy Type 2
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Paloma Gonzalez-Perez, Eleonora S. D'Ambrosio, Vincent Picher-Martel, Kathy Chuang, William S. David, and Anthony A. Amato
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Neurology (clinical) ,Genetics (clinical) - Abstract
Background and ObjectivesThe existence of clinical anticipation, congenital form, and parent-of-origin effect in myotonic dystrophy type 2 (DM2) remains uncertain. Here, we aimed at investigating whether there is a parent-of-origin effect on the age at the first DM2-related clinical manifestation.MethodsWe identified patients with genetically confirmed DM2 with known parental inheritance from (1) the electronic medical records of our institutions and (2) a systematic review of the literature following the PRISMA 2020 guidelines and recorded their age at and type of first disease-related symptom. We also interrogated the Myotonic Dystrophy Foundation Family Registry (MDFFR) for patients with DM2 who completed a survey including questions about parental inheritance and age at the first medical problem which they related to their DM2 diagnosis.ResultsA total of 26 patients with DM2 from 18 families were identified at our institutions as having maternal (n = 14) or paternal (n = 12) inheritance of the disease, whereas our systematic review of the literature rendered a total of 61 patients with DM2 from 41 families reported by 24 eligible articles as having maternal (n = 40) or paternal (n = 21) inheritance of the disease. Both cohorts were combined for downstream analyses. Up to 61% and 58% of patients had muscle-related symptoms as the first disease manifestation in maternally and paternally inherited DM2 subgroups, respectively. Four patients developed hypotonia at birth and/or delayed motor milestones early in life, and 7 had nonmuscular presentations (2 had cardiac events within the second decade of life and 5 had cataracts), all of them with maternal inheritance. A maternal inheritance was associated with an earlier (within the first 3 decades of life) age at symptom onset relative to a paternal inheritance in this combined cohort, and this association was independent of the patient's sex (OR [95% CI] = 4.245 [1.429–13.820],p= 0.0117). However, this association was not observed in the MDFFR DM2 cohort (n = 127), possibly because age at onset was self-reported, and the information about the type of first symptom or medical problem that patients related to DM2 was lacking.DiscussionA maternal inheritance may increase the risk of an early DM2 onset and of cataracts and cardiovascular events as first DM2 manifestations.
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- 2023
6. Clinical trial readiness study of distal myopathy and dysphagia in nephropathic cystinosis
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Susan E. Thomas, William S. David, Natalie Grant, Maya Doyle, Nicholas Mello, Camille Corre, Stacey Sullivan, Florian Eichler, Reza Sadjadi, and Colleen Hammond
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Adult ,Male ,0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Maximal Respiratory Pressures ,Physiology ,Cystinosis ,Walk Test ,Expiratory Muscle Strength Training ,Timed Up and Go test ,030105 genetics & heredity ,Breathing Exercises ,Young Adult ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Muscular Diseases ,Nephropathic Cystinosis ,Physiology (medical) ,Outcome Assessment, Health Care ,medicine ,Humans ,Muscle Strength ,Patient Reported Outcome Measures ,Respiratory system ,Myopathy ,Clinical Trials as Topic ,Hand Strength ,business.industry ,Respiratory Aspiration ,Middle Aged ,Physical Functional Performance ,Dysphagia ,Distal Myopathies ,Clinical trial ,Female ,Neurology (clinical) ,medicine.symptom ,Deglutition Disorders ,business ,Airway ,030217 neurology & neurosurgery - Abstract
BACKGROUND Nephropathic cystinosis is a lysosomal storage disorder with late-onset systemic complications, such as myopathy and dysphagia. Currently employed outcome measures lack sensitivity and responsiveness for dysphagia and myopathy, a limitation to clinical trial readiness. METHODS We evaluated 20 patients with nephropathic cystinosis in two visits over the course of a year to identify outcomes sensitive to detect changes over time. Patients also underwent an expiratory muscle strength training program to assess any effects on aspiration and dysphagia. RESULTS There were significant differences in the Timed Up and Go Test (TUG) and Timed 25-Foot Walk (25-FW) between baseline and 1-y follow-up (P
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- 2020
7. <scp>COVID</scp> ‐19 in patients with myasthenia gravis
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Lan Zhou, Michelle Kaku, Michaël C. C. Slama, Amanda C. Guidon, Anna M. Cervantes-Arslanian, William S. David, Charlene Ong, and Pria Anand
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0301 basic medicine ,medicine.medical_specialty ,Exacerbation ,Physiology ,medicine.medical_treatment ,Population ,Clinical Neurology ,neuroimmunology ,neuromuscular disorders ,030105 genetics & heredity ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,0302 clinical medicine ,Tocilizumab ,COVID‐19 ,Physiology (medical) ,Internal medicine ,Medicine ,Intubation ,education ,Clinical Research Articles ,Acetylcholine receptor ,Clinical Research Article ,myasthenia gravis ,education.field_of_study ,immunosuppression ,biology ,business.industry ,Immunosuppression ,medicine.disease ,Myasthenia gravis ,chemistry ,biology.protein ,Neurology (clinical) ,Antibody ,business ,030217 neurology & neurosurgery - Abstract
Introduction Coronavirus disease 2019 (COVID‐19) has rapidly become a global pandemic, but little is known about its potential impact on patients with myasthenia gravis (MG). Methods We studied the clinical course of COVID‐19 in five hospitalized patients with autoimmune MG (four with acetylcholine receptor antibodies, one with muscle‐specific tyrosine kinase antibodies) between April 1, 2020‐April 30‐2020. Results Two patients required intubation for hypoxemic respiratory failure, whereas one required significant supplemental oxygen. One patient with previously stable MG had myasthenic exacerbation. One patient treated with tocilizumab for COVID‐19 was successfully extubated. Two patients were treated for MG with intravenous immunoglobulin without thromboembolic complications. Discussion Our findings suggest that the clinical course and outcomes in patients with MG and COVID‐19 are highly variable. Further large studies are needed to define best practices and determinants of outcomes in this unique population.
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- 2020
8. Severe Neurological Toxicity of Immune Checkpoint Inhibitors: Growing Spectrum
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Meghan J. Mooradian, Donald F. Chute, William S. David, Ryan J. Sullivan, Donald P. Lawrence, Divyanshu Dubey, Nathan F. Clement, Kerry L. Reynolds, Amanda C. Guidon, and Justine V. Cohen
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0301 basic medicine ,medicine.medical_specialty ,Combination therapy ,business.industry ,Immune checkpoint inhibitors ,MEDLINE ,Tertiary care ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Neurology ,Toxicity ,medicine ,Neurology (clinical) ,Relapse risk ,Intensive care medicine ,business ,Adverse effect ,030217 neurology & neurosurgery - Abstract
Expanding use of immune-checkpoint inhibitors (ICIs) underscores the importance of accurate diagnosis and timely management of neurological immune-related adverse events (irAE-N). We evaluate the real-world frequency, phenotypes, co-occurring immune-related adverse events (irAEs), and long-term outcomes of severe, grade III to V irAE-N at a tertiary care center over 6 years. We analyze how our experience supports published literature and professional society guidelines. We also discuss these data with regard to common clinical scenarios, such as combination therapy, ICI rechallenge and risk of relapse of irAE-N, and corticosteroid taper, which are not specifically addressed by current guidelines and/or have limited data. Recommendations for management and future irAE-N reporting are outlined. ANN NEUROL 2020;87:659-669.
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- 2020
9. Retrospective analysis of safety and outcomes of rituximab for myasthenia gravis in patients ≥65 years old
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Amanda C. Guidon, Anthony A. Amato, Joome Suh, Christopher T. Doughty, and William S. David
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medicine.medical_specialty ,Physiology ,Cellular and Molecular Neuroscience ,immune system diseases ,Interquartile range ,Prednisone ,Physiology (medical) ,Internal medicine ,Myasthenia Gravis ,medicine ,Humans ,Immunologic Factors ,Adverse effect ,Aged ,Retrospective Studies ,business.industry ,Retrospective cohort study ,medicine.disease ,Myasthenia gravis ,Discontinuation ,Cohort ,Rituximab ,Neurology (clinical) ,business ,medicine.drug - Abstract
INTRODUCTION/AIMS Optimal management of myasthenia gravis (MG) in individuals ≥65 y old is unknown and patient factors may limit therapeutic choices. Safety and efficacy of rituximab in older patients with MG has not been well-studied. METHODS This retrospective study examined 40 patients (14 patients ≥65 y old) treated with rituximab for MG. The primary efficacy outcome was the proportion of patients reaching "Improved" or better on Myasthenia Gravis Foundation of America (MGFA) Post-Intervention Status (PIS) at 12 mo, compared between younger and older patients. RESULTS Ninety-two percent of patients ≥65 y old achieved MGFA PIS Improved or better at 12 mo compared to 69% of those
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- 2021
10. Varied phenotypes and management of immune checkpoint inhibitor-associated neuropathies
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William S. David, Meghan J. Mooradian, Amanda C. Guidon, Justine V. Cohen, Anthony A. Amato, Divyanshu Dubey, Donald P. Lawrence, Ryan J. Sullivan, Kerry L. Reynolds, Nathan F. Clement, and Donald F. Chute
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Adult ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Pain ,Gastroenterology ,Polyneuropathies ,03 medical and health sciences ,0302 clinical medicine ,Adrenal Cortex Hormones ,Modified Rankin Scale ,Internal medicine ,Humans ,Medicine ,Registries ,Adverse effect ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Mononeuritis Multiplex ,Disease Management ,Peripheral Nervous System Diseases ,Retrospective cohort study ,Immunosuppression ,Middle Aged ,medicine.disease ,Genes, cdc ,Phenotype ,030220 oncology & carcinogenesis ,Adenocarcinoma ,Female ,Neurology (clinical) ,business ,Complication ,Meningitis ,Immunosuppressive Agents ,030217 neurology & neurosurgery - Abstract
ObjectiveTo describe the spectrum, clinical course, and management of neuropathies associated with immune checkpoint inhibitors (ICIs).MethodsPatients with ICI-related neuropathy (irNeuropathy) were identified and their clinical characteristics compared to neuropathy attributed to cytotoxic agents.ResultsWe identified 19 patients with irNeuropathies. ICIs included anti-programmed death–1 (PD1), 9; anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA4), 2; and combination of anti-CTLA4 and anti-PD1, 8. Median number of ICI doses prior to neuropathy onset was 4. Rate of neuropathies following ICI therapy was 0.7%. Underlying malignancies included melanoma (n = 15), lung adenocarcinoma (n = 3), and cholangiocarcinoma (n = 1). Neuropathy phenotypes were cranial neuropathies with or without meningitis (n = 7), nonlength-dependent polyradiculoneuropathies with and without cranial nerve involvement (n = 6), small-fiber/autonomic neuropathy (n = 2), ANCA-associated mononeuritis multiplex (n = 1), sensory neuronopathy (n = 1), length-dependent sensorimotor axonal polyneuropathy (n = 1), and neuralgic amyotrophy (n = 1). Immune-related adverse events involving other organ systems were common (58%). Corticosteroid use for management of neuropathy was associated with improvement in median modified Rankin Scale score (1 vs 0, p = 0.001) and Inflammatory Neuropathy Cause and Treatment Disability score (2 vs 0.5, p = 0.012) (Class IV). Significantly higher proportion of irNeuropathies had acute or subacute and nonlength-dependent presentations (p < 0.001) and rate of hospitalization for irNeuropathy was also higher (p = 0.002) compared to toxic neuropathy from chemotherapy.ConclusionNeuropathy is a rare complication of ICIs that often responds to immunosuppression. Recognition of its wide phenotypic spectrum and distinct clinical characteristics and prompt management with corticosteroids may lead to favorable outcomes.
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- 2019
11. Randomized trial of l-serine in patients with hereditary sensory and autonomic neuropathy type 1
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Razina Aziz-Bose, Anne Louise Oaklander, Diane McKenna-Yasek, William S. David, Florian Eichler, Vera Fridman, Eric A. Macklin, Peter Novak, Thorsten Hornemann, Kailey Walsh, Robert H. Brown, Saranya Suriyanarayanan, University of Zurich, and Eichler, Florian
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Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Adolescent ,Neural Conduction ,Serine C-Palmitoyltransferase ,610 Medicine & health ,L serine ,Placebo ,Placebo group ,Article ,law.invention ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Randomized controlled trial ,law ,Surveys and Questionnaires ,Internal medicine ,540 Chemistry ,Hereditary sensory and autonomic neuropathy ,Serine ,medicine ,Humans ,In patient ,Hereditary Sensory and Autonomic Neuropathies ,Adverse effect ,10038 Institute of Clinical Chemistry ,Aged ,Pain Measurement ,Sphingolipids ,business.industry ,Middle Aged ,medicine.disease ,3. Good health ,2728 Neurology (clinical) ,Treatment Outcome ,030104 developmental biology ,Female ,Neurology (clinical) ,Autonomic neuropathy ,business ,Ubiquitin Thiolesterase ,030217 neurology & neurosurgery ,Follow-Up Studies - Abstract
ObjectiveTo evaluate the safety and efficacy of l-serine in humans with hereditary sensory autonomic neuropathy type I (HSAN1).MethodsIn this randomized, placebo-controlled, parallel-group trial with open-label extension, patients aged 18–70 years with symptomatic HSAN1 were randomized to l-serine (400 mg/kg/day) or placebo for 1 year. All participants received l-serine during the second year. The primary outcome measure was the Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNS). Secondary outcomes included plasma sphingolipid levels, epidermal nerve fiber density, electrophysiologic measurements, patient-reported measures, and adverse events.ResultsBetween August 2013 and April 2014, we enrolled and randomized 18 participants, 16 of whom completed the study. After 1 year, the l-serine group experienced improvement in CMTNS relative to the placebo group (−1.5 units, 95% CI −2.8 to −0.1, p = 0.03), with evidence of continued improvement in the second year of treatment (−0.77, 95% CI −1.67 to 0.13, p = 0.09). Concomitantly, deoxysphinganine levels dropped in l-serine-treated but not placebo-treated participants (59% decrease vs 11% increase; p < 0.001). There were no serious adverse effects related to l-serine.ConclusionHigh-dose oral l-serine supplementation appears safe in patients with HSAN1 and is potentially effective at slowing disease progression.Clinicaltrials.gov identifierNCT01733407.Classification of evidenceThis study provides Class I evidence that high-dose oral l-serine supplementation significantly slows disease progression in patients with HSAN1.
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- 2019
12. Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial
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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
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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
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- 2020
13. Comment on COVID-19 in patients with myasthenia gravis: Author response
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Anna M. Cervantes-Arslanian, Lan Zhou, William S. David, Michaël C. C. Slama, Charlene Ong, Michelle Kaku, Pria Anand, and Amanda C. Guidon
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2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,Patients ,Physiology ,business.industry ,SARS-CoV-2 ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Clinical Neurology ,COVID-19 ,medicine.disease ,Virology ,Myasthenia gravis ,Cellular and Molecular Neuroscience ,Physiology (medical) ,Pandemic ,Myasthenia Gravis ,Medicine ,Humans ,In patient ,Neurology (clinical) ,business ,Pandemics - Published
- 2020
14. Selection design phase II trial of high dosages of tamoxifen and creatine in amyotrophic lateral sclerosis
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Eric A. Macklin, Johnny Salameh, Suma Babu, William S. David, Jason Walker, Swati Aggarwal, David A. Schoenfeld, Alan Pestronk, Hong Yu, Michael D. Weiss, Katherine E. Jackson, Zachary Simmons, Laura Simionescu, Merit Cudkowicz, Jeremy M. Shefner, Benjamin Rix Brooks, Paul E. Barkhaus, Nazem Atassi, Katy Mahoney, Elizabeth Simpson, and Mazen M. Dimachkie
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Oncology ,Adult ,Male ,medicine.medical_specialty ,Dose ,Vital Capacity ,Creatine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Double-Blind Method ,Internal medicine ,medicine ,Multiple treatments ,Humans ,Muscle Strength ,Amyotrophic lateral sclerosis ,Selection (genetic algorithm) ,Aged ,business.industry ,Amyotrophic Lateral Sclerosis ,Middle Aged ,medicine.disease ,Design phase ,Tamoxifen ,Neurology ,chemistry ,Sample size determination ,Female ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Objective: To conduct a phase-II trial using a ranking and selection paradigm where multiple treatments are compared with limited sample size and the best is chosen for a subsequent efficacy trial ...
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- 2019
15. 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
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Kazumi Takada, Vladislav Abramov, Seiko Yoshida, Pinar Ozcelik, Carolina Miranda, Jennifer Kane, Kaitlyn McKenna, Natasha Campbell, Sharon P. Nations, Shitiz Kumar Sriwastava, Yuko Fujii, Mayumi Murata, Linda Wagemaekers, Angela Andoin, Mollie Vanderhook, Yoshinori Okubo, Martin Bilsker, Taira Uehara, Vera Bril, Julia Wanschitz, Stanislava Toncrova, Mariela Bettini, Kazumi Futono, Shachie Aranke, Yool-hee Kim, Hiroyuki Murai, Anne Nyrhinen, Vinay Chaudhry, Raffaele Iorio, Takashi Kanda, Brittany Harvey, Francisco Javier Rodriguez de Rivera, Henning Andersen, Marianne de Visser, Miwako Sato, Yasuhiro Maeda, Fabienne Deruelle, Marina Pozo, Adam Hart, Masaki Saitoh, Wladimir Bocca Vieira de Rezende Pinto, Said R. Beydoun, Lindsay Zilliox, Akihiro Mukaino, Cinzia Caserta, Mahi Jasinarachchi, Andrea M. Corse, Nikoletta Papadopoulou, JuYoung Kwon, Fernanda Carrara, Juliet Saba, Masayuki Makamori, Vittorio Frasca, Luciana Souza Duca, Hoo Nam Kang, C. Trebst, Celile Phan, Muzeyyen Ugur, Eduardo Ng, Jonathan McKinnon, Hila Bali Kuperman, David Feder, Judit Matolcsi, Jiri Pitha, Martin Stangel, Kate Beck, Gabriel Paiva, Diego Lopergolo, Katrien De Mey, Hidenori Matsuo, Lucas Eduardo Pazetto, Eugene Lai, Amanda Anderson, Ann D'Hondt, Tetsuya Akiyama, Beverly Fyfe, Bella Gross, Elisabet Arribas-Ibar, Kathy de Koning, Gulmohor Roy, Dmitry Pokhabov, Maria Johanna Keijzers, Nicholas Ventura, Tessa Marburger, John Loor, Ji Eun Lee, Alessandro Filla, Celal Tuga, Stephanie Scala, Rudy Mercelis, Marc H. De Baets, Hisako Kobayashi, Stanislav Vohanka, Ana Paula Macagnan, Ana Carolina Amaral de Andrade, Heike Arndt, Giovanni Antonini, Yumi Yamashita, Gwendal Le Masson, Sonia Garcia, Sarah Verjans, James F. Howard, Zaeem A. Siddiqi, Yuen T. So, Megumi Koga, Exuperio Diez Tejedor, Teresa Costabile, Mihoko Takada Takada, Steve Hopkins, Jonathan S. Katz, Charlene Hafer-Macko, Erica Nogueira Coelho, Hung Youl Seok, Carol Herbert, Yuriko Nagane, Didem Altiparmak, Sachiko Kamakura, Mohammad Sanjak, Caroline Moreau, Jordi Díaz-Manera, Sivakumar Sathasivam, Michael Vytopil, Amelia Evoli, Masakatsu Motomura, Ester Reggio, Guy Van den Abeele, Hélène Zéphir, Asya Yarmoschuk, Jasmine Hewlett, Amy Wilson, Sachie Fukui, Cavit Boz, Iandra Souza, Morgane Gaboreau, Ivana Jurajdova, Sonia Decressac, Yong Seo Koo, Valentina Pegoraro, Seung Min Kim, Benison Keung, Rosana Rocha, Nanna Witting, John Vissing, Elaine Weiner, Ali Malekniazi, Larisa Babenko, Amanda C. Guidon, Gal Maier, Charlotte Smetcoren, Robert M. Pascuzzi, Domenico Marco Bonifati, Yumiko Nakamura, Tamires Cristina Gomes da Silva, Takashi Murahara, Sarah Plevka, Tomoko Tsuda, John C. Kincaid, Arnaud Lacour, Ibrez Bandukwala, Alan R. Berger, Chang Nyoung Lee, Jae-Sung Lim, Vern C. Juel, Tulio E. Bertorini, Valeria Cavalcante Lino, Namie Taichi, Ju-Hong Min, Josep Gamez, Nelly Greenbereg, William S. David, Srikanth Muppidi, Husnu Efendi, Pedro Lopez Ruiz, Baki Dogan, Cansu Semiz, Natalia Julia Palacios, Sharon Downing, Paola Cudia, Daniel Jacobs, Can Ebru Bekircan-Kurt, Takayasu Fukudome, Kristen Roe, Lena Bjarbo, Nicole Kassebaum, Makoto Samukawa, Shizuka Asada, Christina Dheel, Fatima Maqsood, Eun Bi Hwang, Kevin Daniels, Sevim Erdem-Ozdamar, Olivier Stevens, Claudio Mazia, Karan Alcon, Sibel Gazioglu, Keiko Kikutake, Luis Lay, Petra Tilkin, Corrado Angelini, Derrick Blackmore, Kimiaki Utsugisawa, Despoina Charalambous, Tuula Harrison, Kristin Huynh, Huned S. Patwa, Laura Echevarria, Henrique Mohr, Christian Homedes-Pedret, Richard J. Barohn, Byung Jo Kim, Daniel DiCapua, Terry McClain, Debora Dada Martineli Torres, Maria Salvado Figueras, Ana Paula Melo, Riley Snook, Miki Ogawa, Marcelo Annes, Yuka Saito, Isabel Illa, Evanthia Bernitsas, Nicole Smalley, Molly Lindsay, Robert G. Miller, Olga Azrilin, Silvia Bonanno, Evgeniya Kosykh, Marcela Wolfova, Olivier Outteryck, Shirli Toska, Anna Kostera-Pruszczyk, HyeJin Ra, Rup Tandan, Sotirios Papagiannopoulos, Natasha Willlems, Anne Mette Ostergaard Autzen, Meinoshin Okumura, Patrick Vermersch, Sarada Sakamuri, Maria Antonia Alberti Aguilo, Shigemi Shimose, Cynthia Carter, Ira Blount, Lisa Thompson, Maurer Pereira Martins, Richard Nowak, Hyung Seok Lee, Anna Kaminska, Joan Bratton, Nazire Pinar Acar, Junichi Ogasawara, Mohamed Mahdi-Rogers, Teiichiro Mitazaki, Marek Čierny, Craig Donahue, Jaya Trivedi, Neelam Goyal, Gonzalo Vidal, Brandy Quarles, Akiko Kanzaki, Yasuko Ikeda, Tomomi Kobashikawa, Morris Brown, Daisuke Yamamoto, Michel Deneve, Denis Korobko, Beth DiSanzo, Benedikt Schoser, Heidi Boterhoven, Eri Kobayashi, Maoko Shirane, Cristiani Fernanda Butinhao, Eriko Higuchi, Takashi Hayashi, Masanori Takahashi, Anne-Cécile Wielanek-Bachelet, Benjamin Rix Brooks, Emanuela Onesti, Tahseen Mozaffar, Liang Lu, Sevasti Bostantzopoulou, Christophe Vial, Shawn J. Bird, Sandi Mumfrey-Thomas, Julie Khoury, Kara Patrick, Kenichi Tsukita, Yoshiko Sano, Hiroshi Nakazora, David P. Richman, Gavin Brown, Yoon-Ho Hong, Tomohiro Kawamura, Igor Dias Brockhausen, Ye Liu, Acary Souza Bulle Oliveira, Soichiro Funaka, Tomoya Hasuike, Frank Lin, Luis Antonio Querol Gutierrez, Namita Goyal, Elena Pinzan, Michelle Mellion, Silvia Messina, Christopher Lindberg, Csilla Rozsa, J. Chad Hoyle, Yoko Kaneko, Gustavo Duran, Francesco Patti, Arshira Seddigh, Ele Kim Perez, Jayashri Srinivasan, Michael Benatar, Philip Van Damme, Salma Akhter, Daniel Ambrosio, Maria Salvado, Floyd Jones, Mark Sivak, Anneke J. van der Kooi, Karen Callison, Catherine Nigro, Rebekah Garcia, Thomas Arnold, Hideki Arima, Brigid Crabtree, Mary Varghese, Aditya Kumar, Miri Kim, Fanny O'Brien, Naya McKinnon, Lauren Wheeler, Hong Vu, Shunsuke Yoshimura, Masatoshi Omoto, Jeffrey T. Guptill, Maria Gabriele, Francoise Bouhour, Veena Mathew, Ritsu Nakayama, Rosa Hasan, Francesco Saccà, Mohammed Salajegheh, Diana Dimitrova, Alzira Alves de Siqueira Carvalho, Maurizio Inghilleri, George Sachs, Rekha Pillai, Enrico Marano, Monika Konyane, Anh Tran, Seda Aydinlik, Kendrick Henderson, Fumie Meguro, Alexandre Guerreiro, Amaiak Chilingaryan, Tiyonnoh Cash, Jun Kawamata, Julie Steele, Helene Gervais-Bernard, Thomas Harbo, Alejandra Dalila Garcia, Musa Kazim Onar, Sabrina Sacconi, Carlos Casasnovas Pons, Nadezhda Malkova, Denis Sazonov, Mireya Fernandez-Fournier, Karin Fricke, Laurie Gutmann, Amy Saklad, Clara Schommer, Sandra Taber, Fiona Norwood, Tugce Kirbas Cavdar, Monique Miesen, Fernanda Troili, Masanori Watanabe, Ratna Bhavaraju-Sanka, Ted M. Burns, Sari Atula, Faisal Sohail, Barbora Kurkova, Brigitta Szabadosne, Luciana Renata Cubas Volpe, Jane Pedersen, Jing Jing Wang, Masashi Inoue, Antonella Di Pasquale, Megan Kramer, Magda Chmelikova, Mehran Soltani, Tuan Vu, Laura Fionda, Eliz Agopian, Susan Shin, Anthony A. Amato, Lotte Vinge, Hakan Cavus, Gil I. Wolfe, Joan Nye, Delphine Mahieu, Miguel Wilken, Markus Färkkilä, Catherine Faber, Erin Manning, Emiko Tsuda, Rami Massie, Paolo Emilio Alboini, Yasmeen Shabbir, Angela Campanella, Aikaterini Dimitriou, Marcelo Rugiero, Cynthia Bodkin, Gyorgyi Szabo, Sharon Halton, Akshay Shah, Yasuko Maeda, Hans D. Katzberg, Yagmur Caliskan, Jaimin Shah, Katsuhisa Masaki, Valentina Damato, Blanka Andersson, Aline de Cassia Santos, Masahiro Mori, Renato Mantegazza, Misa Shimpo, Joanne Nemeth, Livia Dezsi, Anna De Rosa, Doreen Ho, Julie Moutarde, Efstathia Mitropoulou, Amy Woodall, Angela Micheels, László Vécsei, Byoung Joon Kim, Lisa Smith, Tomihiro Imai, Harpreet Kaur, Lorenzo Maggi, Jane Distad, Anita Mogensen, Ericka Simpson, Anne Cooley, Eliana Reyes, Ha Young Shin, Da Yoon Koh, Stefan Gingele, Susan Strom, Ezgi Yilmaz, Manisha Chopra, Anna Melnikova, Edouard Millois, Ludwig Gutmann, Miriam Freimer, Hirokazu Shinozaki, Heena Olalde, Kerry Naunton, Shunya Nakane, Ihsan Sengun, Dimos-Dimitrios Mitsikostas, Edina Varga, Juha-Pekka Erälinna, Wolfgang Löscher, Jan De Bleecker, Elena Bravver, Ana Lazaro, Eun Bin Cho, Thomas Cochrane, Jonathan Goldstein, Lisa D. Hobson-Webb, Michaela Tyblova, Angela Marsil, J. Edward Hartmann, Miyuki Morikawa, Karen Zakalik, Claude Desnuelle, Iveta Novakova, Michiaki Koga, Melinda Horvath, Luiz Otavio Maia Gonçalves, Elena Cortes Vicente, Alejandro Tobon Gonzalez, Stanley H. Appel, Brian Minton, Daniele Orrico, Brian Droker, Jacob Kaufman, Erica Coelho, Chafic Karam, Mikko Laaksonen, Katherine Amato, Jinmyoung Seok, Natalia Prando, Pauline Lahaut, Kaori Osakada, Phillipa Lamont, Alexandros Tselis, Daiane da Cruz Pacheco, Joan Højgaard, Hirokazu Shiraishi, Josef Bednarik, Stefania Morino, Mark Levine-Weinberg, Sara-Claude Michon, Yusuke Fukuda, Michael Pulley, Koichi Narikawa, Ricardo Rojas Garcia, Betsy Mosmiller, James Gilchrist, Maria da Penha Morita Ananias, Maryanne Burdette, Shingo Konno, Janelle Butters, Stephan Wenninger, Debbie Davies, Thomas Skripuletz, Mohammad Alsharabati, Katarina Reguliova, Gabor Lovas, Yuichiro Gondo, Miju Shin, HyeLim Lee, Bruno Bezerra Rosa, Michael D. Weiss, Martha Zampaki, Andrea Caramma, Jeffrey V. Rosenfeld, Cigdem Ozen Aydin, Shara Holzberg, Hélène Merle, Olga Zapletalova, Kurt-Wolfram Suehs, Robert P. Lisak, Dale J. Lange, Albert Hietala, Sedat Sen, Elena Giacomelli, Akiyuki Uzawa, Tomás Augusto Suriane Fialho, Matteo Garibaldi, Nadia Sattar, Wai-Kuen Leong, Lindsay Kaplan, Tetsuya Kanai, Jaana Eriksson, Akiko Nagaishi, Khema Sharma, Tamar Gibson, Mohamed Kazamel, Yulia Nesterova, Sascha Alvermann, Murat Terzi, Taylor Darnell, Donna Carnes, Victor Balyazin, John T. Kissel, Waqar Waheed, Jana Junkerova, Kimberly Robeson, Nicholas Vlaikidis, Nicholas Silvestri, Fredrik Piehl, Maurício André Gheller Friedrich, Shun Shimohama, Nuria Vidal, Eleni Kasioti, H. James Jones, Michael K. Hehir, Luiz Augusto da Silva, Dave Watling, Leslie Roberts, Casey Faigle, Caroline Hourquin, Olli Oksaranta, Tomomi Imamura, Shin Hisahara, Dennis Jeffery, Marie-Hélène Soriani, M. Kawai, Chieko Yoshikawa, Roseann Keo, Angela Genge, Michelangelo Maestri Tassoni, Milvia Pleitez, Michael H. Rivner, Maki Jingu, Giorgia Puorro, Andrea Swenson, Saiju Jacob, Carolina Ortea, Shuichiro Suzuki, Marguerite Engel, Ikuko Kamegamori, SangAe Park, Guilhem Sole, Lesly Welsh, Nichole Gallatti, Jakit Gollogly, Daniel Jons, Yasuteru Sano, Takuya Matsushita, Omar Khan, Maria Cristina Gori, Thabata Veiga, Julie Agriesti, Jos Maessen, Sandra Guinrich, Francesca Bevilacqua, Laura Haar, Jordana Gonçalves Geraldo, Justin Y. Kwan, Hidekazu Suzuki, Dai Matsuse, Kelly Jia, Ozlem Tun, Lara Katzin, Yasushi Suzuki, Shannon Lucy, Carlo Antozzi, ANS - Neuroinfection & -inflammation, Neurology, Howard, James F, Utsugisawa, Kimiaki, Benatar, Michael, Murai, Hiroyuki, Barohn, Richard J, Illa, Isabel, Jacob, Saiju, Vissing, John, Burns, Ted M, Kissel, John T, Muppidi, Srikanth, Nowak, Richard J, O'Brien, Fanny, Wang, Jing-Jing, Mantegazza, Renato, Mazia, Claudio Gabriel, Wilken, Miguel, Ortea, Carolina, Saba, Juliet, Rugiero, Marcelo, Bettini, Mariela, Vidal, Gonzalo, Garcia, Alejandra Dalila, Lamont, Phillipa, Leong, Wai-Kuen, Boterhoven, Heidi, Fyfe, Beverly, Roberts, Leslie, Jasinarachchi, Mahi, Willlems, Natasha, Wanschitz, Julia, Löscher, Wolfgang, De Bleecker, Jan, Van den Abeele, Guy, de Koning, Kathy, De Mey, Katrien, Mercelis, Rudy, Wagemaekers, Linda, Mahieu, Delphine, Van Damme, Philip, Smetcoren, Charlotte, Stevens, Olivier, Verjans, Sarah, D'Hondt, Ann, Tilkin, Petra, Alves de Siqueira Carvalho, Alzira, Hasan, Rosa, Dias Brockhausen, Igor, Feder, David, Ambrosio, Daniel, Melo, Ana Paula, Rocha, Rosana, Rosa, Bruno, Veiga, Thabata, Augusto da Silva, Luiz, Gonçalves Geraldo, Jordana, da Penha Morita Ananias, Maria, Nogueira Coelho, Erica, Paiva, Gabriel, Pozo, Marina, Prando, Natalia, Dada Martineli Torres, Debora, Fernanda Butinhao, Cristiani, Coelho, Erica, Renata Cubas Volpe, Luciana, Duran, Gustavo, Gomes da Silva, Tamires Cristina, Otavio Maia Gonçalves, Luiz, Pazetto, Lucas Eduardo, Souza Duca, Luciana, Suriane Fialho, Tomás Augusto, Gheller Friedrich, Maurício André, Guerreiro, Alexandre, Mohr, Henrique, Pereira Martins, Maurer, da Cruz Pacheco, Daiane, Macagnan, Ana Paula, de Cassia Santos, Aline, Bulle Oliveira, Acary Souza, Amaral de Andrade, Ana Carolina, Annes, Marcelo, Cavalcante Lino, Valeria, Pinto, Wladimir, Miranda, Carolina, Carrara, Fernanda, Souza, Iandra, Genge, Angela, Massie, Rami, Campbell, Natasha, Bril, Vera, Katzberg, Han, Soltani, Mehran, Ng, Eduardo, Siddiqi, Zaeem, Phan, Celile, Blackmore, Derrick, Vohanka, Stanislav, Bednarik, Josef, Chmelikova, Magda, Cierny, Marek, Toncrova, Stanislava, Junkerova, Jana, Kurkova, Barbora, Reguliova, Katarina, Zapletalova, Olga, Pitha, Jiri, Novakova, Iveta, Tyblova, Michaela, Wolfova, Marcela, Jurajdova, Ivana, Andersen, Henning, Harbo, Thoma, Vinge, Lotte, Mogensen, Anita, Højgaard, Joan, Witting, Nanna, Autzen, Anne Mette, Pedersen, Jane, Färkkilä, Marku, Atula, Sari, Nyrhinen, Anne, Erälinna, Juha-Pekka, Laaksonen, Mikko, Oksaranta, Olli, Eriksson, Jaana, Harrison, Tuula, Desnuelle, Claude, Sacconi, Sabrina, Soriani, Marie-Hélène, Decressac, Sonia, Moutarde, Julie, Lahaut, Pauline, Solé, Guilhem, Le Masson, Gwendal, Wielanek-Bachelet, Anne-Cécile, Gaboreau, Morgane, Moreau, Caroline, Wilson, Amy, Vial, Christophe, Bouhour, Françoise, Gervais-Bernard, Helene, Merle, Hélène, Hourquin, Caroline, Lacour, Arnaud, Outteryck, Olivier, Vermersch, Patrick, Zephir, Hélène, Millois, Edouard, Deneve, 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, Valentina, Pinzan, Elena, Bevilacqua, Francesca, Orrico, Daniele, Bonifati, Domenico Marco, Evoli, Amelia, Alboini, Paolo Emilio, D'Amato, Valentina, Iorio, Raffaele, Inghilleri, Maurizio, Fionda, Laura, Frasca, Vittorio, Giacomelli, Elena, Gori, Maria, Lopergolo, Diego, Onesti, Emanuela, Gabriele, Maria, Patti, Francesco, Salvatore Caramma, Andrea, Messina, Silvia, Reggio, Ester, Caserta, Cinzia, Uzawa, Akiyuki, Kanai, Tetsuya, Mori, Masahiro, Kaneko, Yoko, Kanzaki, Akiko, Kobayashi, Eri, Masaki, Katsuhisa, Matsuse, Dai, Matsushita, Takuya, Uehara, Taira, Shimpo, Misa, Jingu, Maki, Kikutake, Keiko, Nakamura, Yumiko, Sano, Yoshiko, Nagane, Yuriko, Kamegamori, Ikuko, Fujii, Yuko, Futono, Kazumi, Tsuda, Tomoko, Saito, Yuka, Suzuki, Hidekazu, Morikawa, Miyuki, Samukawa, Makoto, Kamakura, Sachiko, Shiraishi, Hirokazu, Mitazaki, Teiichiro, Motomura, Masakatsu, Mukaino, Akihiro, Yoshimura, Shunsuke, Asada, Shizuka, Kobashikawa, Tomomi, Koga, Megumi, Maeda, Yasuko, Takada, Kazumi, Takada, 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
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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.
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- 2017
16. Case 35-2017
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Tracey A. Cho, Michael P. Bowley, William S. David, and Anand S. Dighe
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medicine.medical_specialty ,Weakness ,Gastric bypass ,Gastric Bypass ,Diagnostic Techniques, Neurological ,030209 endocrinology & metabolism ,Electromyography ,Spinal Cord Diseases ,Diagnosis, Differential ,Hypesthesia ,03 medical and health sciences ,0302 clinical medicine ,Evoked Potentials, Somatosensory ,medicine ,Humans ,Vitamin E Deficiency ,Muscle Weakness ,medicine.diagnostic_test ,business.industry ,Diagnostic test ,Vitamin B 12 Deficiency ,General Medicine ,Hypoesthesia ,Middle Aged ,Surgery ,Zinc ,Somatosensory evoked potential ,Anesthesia ,Female ,medicine.symptom ,Deficiency Diseases ,business ,Copper ,030217 neurology & neurosurgery - Abstract
A 57-year-old-woman with a history of gastric bypass presented with hypoesthesia, paresthesia, and weakness in the arms and legs. Studies for somatosensory evoked potentials were consistent with disruption of central conduction. A diagnostic test was performed.
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- 2017
17. Case 19-2017 — A 53-Year-Old Woman with Leg Numbness and Weakness
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John H. Shin, Michael P. Bowley, John C. DeWitt, William A. Mehan, William S. David, and Elizabeth R. Gerstner
- Subjects
Weakness ,medicine.medical_specialty ,Sarcoidosis ,Lumbar vertebrae ,Diagnosis, Differential ,Hypesthesia ,03 medical and health sciences ,0302 clinical medicine ,Leg numbness ,Peripheral Nervous System ,medicine ,Humans ,Tuberculosis ,Cerebrospinal Fluid ,Lumbar Vertebrae ,Muscle Weakness ,Urinary retention ,business.industry ,Brain ,Muscle weakness ,Diagnostic test ,General Medicine ,Hypoesthesia ,Middle Aged ,Magnetic Resonance Imaging ,Surgery ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Saddle anesthesia ,Female ,Lymphoma, Large B-Cell, Diffuse ,medicine.symptom ,Spinal Nerve Roots ,business ,030217 neurology & neurosurgery - Abstract
A 53-year-old woman was admitted to the hospital because of progressive asymmetric hypoesthesia and weakness in the legs. Urinary retention, absence of rectal tone, and saddle anesthesia developed. A diagnostic test was performed.
- Published
- 2017
18. Clinical neurophysiology of lower extremity focal neuropathies
- Author
-
William S, David and Reza, Sadjadi
- Subjects
Lower Extremity ,Nerve Compression Syndromes ,Lumbosacral Plexus ,Humans ,Neuralgia ,Neurophysiology ,Tibial Nerve ,Sciatic Nerve - Published
- 2019
19. Clinical Reasoning: A 15-year-old boy with bilateral wrist pain in the setting of weight loss
- Author
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K. H. Vincent Lau, William S. David, and Reza Sadjadi
- Subjects
musculoskeletal diseases ,Male ,Weakness ,medicine.medical_specialty ,Adolescent ,Brachioradialis ,Wrist pain ,Thumb ,Biceps ,Diagnosis, Differential ,03 medical and health sciences ,0302 clinical medicine ,Weight loss ,Sensation ,Weight Loss ,Medicine ,Humans ,030212 general & internal medicine ,Arthrogryposis ,Muscle Weakness ,business.industry ,Deep Tendon Reflex ,Wrist ,Arthralgia ,body regions ,medicine.anatomical_structure ,Physical therapy ,Neurology (clinical) ,medicine.symptom ,business ,Hereditary Sensory and Motor Neuropathy ,030217 neurology & neurosurgery - Abstract
A 15-year-old previously healthy boy was referred for further evaluation of wrist pain. Right and left wrist pain started 2 years ago and got significantly worse in the setting of intentional 25-pound weight loss over 6 months. He also had numbness in the 4th and 5th digits of his left hand for the last 3 months. Neurologic examination was notable for weakness of both thumb abduction, finger abduction, and flexion of 4th and 5th digits on the left. There was decreased sensation to pinprick in palms, as well as trace deep tendon reflexes at biceps, triceps, and brachioradialis.
- Published
- 2019
20. Clinical neurophysiology of lower extremity focal neuropathies
- Author
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Reza Sadjadi and William S. David
- Subjects
medicine.medical_specialty ,Physical medicine and rehabilitation ,business.industry ,medicine ,MEDLINE ,Neurophysiology ,Clinical neurophysiology ,business - Published
- 2019
21. Clinical myopathy in patients with nephropathic cystinosis
- Author
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Susan E. Thomas, Florian Eichler, Natalie Grant, Maya Doyle, Camille Corre, Rachel Duong, Reza Sadjadi, Colleen Hammond, Stacey Sullivan, and William S. David
- Subjects
0301 basic medicine ,Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Psychometrics ,Physiology ,Cystinosis ,030105 genetics & heredity ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Young Adult ,0302 clinical medicine ,Nephropathic Cystinosis ,Physiology (medical) ,medicine ,Humans ,Respiratory function ,In patient ,Myopathy ,Muscle, Skeletal ,Muscle contracture ,Neurologic Examination ,Muscle Weakness ,business.industry ,Muscle weakness ,Extremities ,Middle Aged ,Hand ,Dysphagia ,Respiratory Function Tests ,Transplantation ,Distal Myopathies ,Treatment Outcome ,Female ,Neurology (clinical) ,Self Report ,medicine.symptom ,business ,Deglutition Disorders ,030217 neurology & neurosurgery - Abstract
Background Nephropathic cystinosis is a lysosomal storage disorder. Patient survival years after renal transplantation has revealed systemic complications including distal myopathy and dysphagia. Methods We evaluated 20 adult patients with nephropathic cystinosis using patient-reported and clinical outcome measures. Standard motor measures, video fluoroscopy swallow studies, and tests of respiratory function were performed. We also used Rasch analysis of an initial survey to design a 16-item survey focused on upper and lower extremity function, which was completed by 31 additional patients. Results Distal myopathy and dysphagia were common in patients with nephropathic cystinosis. Muscle weakness ranges from mild involvement of intrinsic hand muscles to prominent distal greater than proximal weakness and contractures. Conclusions In addition to further characterization of underlying dysphagia and muscle weakness, we propose a new psychometrically devised, disease specific, functional outcome measures for distal myopathy in patients with nephropathic cystinosis.
- Published
- 2018
22. A randomized controlled trial of methotrexate for patients with generalized myasthenia gravis
- Author
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David Saperstein, J. Aziz Shaibani, Carlayne E. Jackson, Namita Goyal, Mazen M. Dimachkie, Tahseen Mozaffar, Jianghua He, Ted M. Burns, Vera Bril, William S. David, Sharon P. Nations, Mamatha Pasnoor, Andrea Swenson, Ericka Simpson, Bakri Elsheikh, Michael Benatar, Richard J. Barohn, Michael Pulley, Laura Herbelin, Jeffrey Rosenfeld, James F. Howard, Mara L. Becker, John T. Kissel, Jeffrey Statland, Matthew Wicklund, Annabel K. Wang, and Robert Pazcuzzi
- Subjects
030203 arthritis & rheumatology ,medicine.medical_specialty ,business.industry ,medicine.disease ,Placebo ,Article ,Myasthenia gravis ,law.invention ,Clinical trial ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,Prednisone ,law ,Internal medicine ,Severity of illness ,medicine ,Methotrexate ,Neurology (clinical) ,Adverse effect ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Objective: To determine the steroid-sparing effect of methotrexate (MTX) in patients with symptomatic generalized myasthenia gravis (MG). Methods: We performed a 12-month multicenter, randomized, double-blind, placebo-controlled trial of MTX 20 mg orally every week vs placebo in 50 acetylcholine receptor antibody–positive patients with MG between April 2009 and August 2014. The primary outcome measure was the prednisone area under the dose-time curve (AUDTC) from months 4 to 12. Secondary outcome measures included 12-month changes of the Quantitative Myasthenia Gravis Score, the Myasthenia Gravis Composite Score, Manual Muscle Testing, the Myasthenia Gravis Quality of Life, and the Myasthenia Gravis Activities of Daily Living. Results: Fifty-eight patients were screened and 50 enrolled. MTX did not reduce the month 4–12 prednisone AUDTC when compared to placebo (difference MTX − placebo: −488.0 mg, 95% confidence interval −2,443.4 to 1,467.3, p = 0.26); however, the average daily prednisone dose decreased in both groups. MTX did not improve secondary measures of MG compared to placebo over 12 months. Eight participants withdrew during the course of the study (1 MTX, 7 placebo). There were no serious MTX-related adverse events. The most common adverse event was nonspecific pain (19%). Conclusions: We found no steroid-sparing benefit of MTX in MG over 12 months of treatment, despite being well-tolerated. This study demonstrates the challenges of conducting clinical trials in MG, including difficulties with recruitment, participants improving on prednisone alone, and the need for a better understanding of outcome measure variability for future clinical trials. Classification of evidence: This study provides Class I evidence that for patients with generalized MG MTX does not significantly reduce the prednisone AUDTC over 12 months of therapy.
- Published
- 2016
23. Construction and validation of the chronic acquired polyneuropathy patient-reported index (CAP-PRI): A disease-specific, health-related quality-of-life instrument
- Author
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Vera Bril, Michael K. Hehir, Thomas H. Brannagan, Margaret Adler, Mark R. Conaway, William S. David, Eduardo Ng, Karissa L. Gable, Jennifer Dineen, Lisa D. Hobson-Webb, Carolina Barnett, Amruta Joshi, Jeffrey T. Guptill, Ted M. Burns, Esther Byun, Reza Sadjadi, and Kelly G. Gwathmey
- Subjects
Male ,medicine.medical_specialty ,Psychometrics ,Physiology ,Chronic inflammatory demyelinating polyneuropathy ,Statistics, Nonparametric ,Article ,Polyneuropathies ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Physical medicine and rehabilitation ,Quality of life ,Surveys and Questionnaires ,Physiology (medical) ,medicine ,Humans ,Prospective Studies ,030212 general & internal medicine ,Prospective cohort study ,Retrospective Studies ,Rasch model ,business.industry ,Reproducibility of Results ,Retrospective cohort study ,medicine.disease ,Clinical trial ,Quality of Life ,Physical therapy ,Female ,Patient-reported outcome ,Neurology (clinical) ,business ,Polyneuropathy ,030217 neurology & neurosurgery - Abstract
Introduction: Generic health-related quality-of-life (HRQOL) patient-reported outcome measures have been used in patients with chronic immune-mediated polyneuropathies. We have created a disease-specific HRQOL instrument. Methods: The chronic acquired polyneuropathy patient-reported index (CAP-PRI) was developed and validated in multiple steps. Items were initially generated through patient and specialist input. The performance of the preliminary 20 items was analyzed via a prospective, 5-center study involving chronic immune-mediated polyneuropathy patients. Results: Data analysis suggested modification to a 15-item scale with 3 response categories rather than 5. The final CAP-PRI was validated in another prospective, 5-center study. The CAP-PRI appeared to be a unidimensional outcome measure that fit the Rasch model in our multicenter cohort. It correlated appropriately with outcome measures commonly used in this patient population. Conclusions: The CAP-PRI is a simple disease-specific HRQOL measure that appears to be useful for clinical care and possibly also for clinical trials. Muscle Nerve 54: 9-17, 2016.
- Published
- 2015
24. Editorial by concerned physicians: Unintended effect of the orphan drug act on the potential cost of 3,4-diaminopyridine
- Author
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Mark B. Bromberg, Miriam Freimer, Nizar Chahin, Laurie Gutmann, Mohammad Salajegheh, Kelly G. Gwathmey, Tyler A. Webb, David P. Richman, Aziz Shaibani, Guillermo Solorzano, Elliot L. Dimberg, Janice M. Massey, Rabi Tawil, James Gilchrist, Michael Benatar, Jeffrey A. Allen, Anthony J. Windebank, Summer Gibson, William J. Litchy, Yuebing Li, Amanda C. Guidon, James A. Russell, Vern C. Juel, William S. David, Shafeeq Ladha, Tahseen Mozaffar, Shawn J. Bird, David Saperstein, Chafic Karam, Noah Kolb, Gordon Smith, Gil I. Wolfe, W. David Arnold, Nicholas E. Johnson, Eric L. Logigian, John C. Kincaid, Duygu Selcen, Annabel K. Wang, Matthew N. Meriggioli, Andrew G. Engel, Pariwat Thaisetthawatkul, Lyle Ostrow, Yuen T. So, Jau Shin Lou, Michael K. Hehir, Eric J. Sorenson, P. James B. Dyck, George Sachs, Julie Khoury, Namita Goyal, Jeffrey T. Guptill, Jinny Tavee, Robert M. Pascuzzi, Jeffrey A. Cohen, Michael D. Weiss, Ted M. Burns, Yadollah Harati, Peter D. Donofrio, Jayashri Srinivasen, Perry B. Shieh, Daniel G Larriviere, Mark A. Ferrante, Sidney M. Gospe, Kathleen D. Kennelly, John T. Kissel, Clifton L. Gooch, Carlayne E. Jackson, Dmitri Gorelov, Nicholas Silvestri, Katherine Ruzhansky, Daniel J L Macgowen, Joon Shik Moon, Jonathan Goldstein, Robert G. Miller, Devon I. Rubin, Karissa L. Gable, Richard J. Barohn, Charles A. Thornton, Emma Ciafaloni, C. Michel Harper, Sarah M. Jones, Ricardo A. Maselli, J. Rob Singleton, Michelle M Mauermann, Brian A. Crum, James F. Howard, Erik R. Ensrud, Sami Khella, Mark A. Ross, Lisa D. Hobson-Webb, Sharon P. Nations, Stephen N. Scelsa, Katherine D. Mathews, Henry J. Kaminski, Andrea M. Corse, Amanda Peltier, Anthony A. Amato, Richard A. Lewis, Steven Vernino, Richard Nowak, Eduardo A De Sousa, Ludwig Gutmann, Benn E. Smith, Brent P. Goodman, David Lacomis, and Jaya Trivedi
- Subjects
medicine.medical_specialty ,Physiology ,business.industry ,Potassium channel blocker ,medicine.disease ,Orphan drug ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Physiology (medical) ,Orphan Drug Production ,Environmental health ,Neuromuscular junction disease ,medicine ,030212 general & internal medicine ,Neurology (clinical) ,Intensive care medicine ,business ,030217 neurology & neurosurgery ,medicine.drug - Published
- 2015
25. IDENTIFICATION OF DISTINCT PATIENT CLUSTERS WITH HETEROGENEOUS CLINICAL PROFILES INCLUDING TIMELINE TO DIAGNOSIS, CO-MORBIDITIES AND ECHOCARDIOGRAPHIC FEATURES AMONG PATIENTS WITH 99MTC-PYROPHOSPHATE POSITIVE TRANSTHYRETIN AMYLOID CARDIOMYOPATHY (ATTR-CM)
- Author
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Gregory D. Lewis, Ahmed Tawakol, Alexander Camacho, Neyat Fiseha, Nasrien E. Ibrahim, Reza Sadjadi, Frederick L. Ruberg, Hanna K. Gaggin, Cian P. McCarthy, William S. David, James L. Januzzi, Asher Bean, Michael T. Osborne, Austin Nguonly, and Andrew Abboud
- Subjects
Pathology ,medicine.medical_specialty ,biology ,business.industry ,99mTc-Pyrophosphate ,Early detection ,Transthyretin ,biology.protein ,Medicine ,Identification (biology) ,Co morbidity ,Cardiology and Cardiovascular Medicine ,business ,Amyloid cardiomyopathy - Abstract
Transthyretin amyloid cardiomyopathy (ATTR-CM) presents with heterogeneous clinical manifestations, making early detection and diagnosis challenging. A new approach may be needed to identify affected patients. A random sample of 46 patients with grade 2 or 3 positive 99mTc-Pyrophosphate scans and
- Published
- 2020
26. CARE TRAJECTORY AND EARLY CLINICAL FEATURES AMONG PATIENTS WITH 99MTC-PYROPHOSPHATE POSITIVE TRANSTHYRETIN AMYLOID CARDIOMYOPATHY (ATTR-CM)
- Author
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Cian P. McCarthy, Frederick L. Ruberg, Hanna K. Gaggin, William S. David, James L. Januzzi, Andrew Abboud, Asher Bean, Gregory D. Lewis, Alexander Camacho, Nasrien E. Ibrahim, Ahmed Tawakol, Reza Sadjadi, Michael T. Osborne, Austin Nguonly, and Neyat Fiseha
- Subjects
medicine.medical_specialty ,Transthyretin ,biology ,business.industry ,Internal medicine ,99mTc-Pyrophosphate ,Cardiology ,biology.protein ,Medicine ,Cardiology and Cardiovascular Medicine ,business ,Amyloid cardiomyopathy ,Flag (geometry) - Abstract
Transthyretin amyloid cardiomyopathy (ATTR-CM) may be more common than previously thought and is often underdiagnosed. We sought to evaluate traditionally accepted “red flag” clinical features with novel methods. We identified a random sample of 46 patients with a grade 2 or 3 positive 99mTc
- Published
- 2020
27. Reducing sample size requirements for future ALS clinical trials with a dedicated electrical impedance myography system
- Author
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William S. David, Eric A. Macklin, Seward B. Rutkove, Michael Benatar, James B. Caress, Jose L. Bohorquez, Jeremy M. Shefner, and Michael S. Cartwright
- Subjects
Oncology ,Adult ,Male ,medicine.medical_specialty ,0206 medical engineering ,Vital Capacity ,02 engineering and technology ,Muscle Strength Dynamometer ,Article ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Electric Impedance ,Medicine ,Humans ,Amyotrophic lateral sclerosis ,Muscle, Skeletal ,Aged ,Electrical impedance myography ,business.industry ,Amyotrophic Lateral Sclerosis ,Myography ,Middle Aged ,medicine.disease ,Evoked Potentials, Motor ,020601 biomedical engineering ,Clinical trial ,Neurology ,Sample size determination ,Sample Size ,Disease Progression ,Biomarker (medicine) ,Female ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Cohort study - Abstract
OBJECTIVE: In this longitudinal multicenter cohort study, we evaluated the potential of a dedicated electrical impedance myography (EIM) device to assess ALS progression and the system’s basic reproducibility and diagnostic accuracy. METHODS: Forty-six ALS patients underwent up to 5 sequential measurements of multiple muscles over a period of 8 months at 2-month intervals using the mView EIM device (Myolex, Inc). Standard measures of disease status were also obtained. A group of 30 healthy volunteers and 30 ALS-mimics were evaluated once to determine if the technique could assist with initial diagnosis. Several electrode arrays and EIM outcomes were assessed. RESULTS: EIM tracked ALS progression; power analyses suggested a 5.2-fold reduction in sample size requirements compared to ALSFRS-R by utilizing 50 kHz phase value from the muscle with the greatest EIM decline in each subject. This progression rate correlated to total ALSFRS-R progression, with R=0.371, p=0.021. Reproducibility was high, with both intra- and inter-rater intraclass correlation coefficients for individual muscles mostly greater than 0.90. The mean 50 kHz phase distinguished between ALS patients and healthy controls (area-under-curve 0.78, 95% confidence intervals (CIs) 0.68,0.89), but not between mimics and ALS patients (area-under-curve 0.60, 95% CIs 0.47,0.73). CONCLUSIONS: While limited in its specificity to identify ALS versus disease mimics, these results support the hypothesis that single-muscle EIM can serve as a convenient, repeatable, and powerful outcome measure in ALS clinical trials.
- Published
- 2018
28. Randomized, double-blind, placebo-controlled trial of arimoclomol in rapidly progressive SOD1 ALS
- Author
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Joanne Wuu, William S. David, David A. Schoenfeld, Michael Benatar, Merit Cudkowicz, Nazem Atassi, and Peter M. Andersen
- Subjects
Adult ,Male ,0301 basic medicine ,Neurologi ,SOD1 ,Placebo-controlled study ,Pharmacology ,Arimoclomol ,Hydroxylamines ,Severity of Illness Index ,Article ,law.invention ,Double blind ,03 medical and health sciences ,chemistry.chemical_compound ,Superoxide Dismutase-1 ,0302 clinical medicine ,Double-Blind Method ,Randomized controlled trial ,law ,Heat shock protein ,Humans ,Medicine ,In patient ,Aged ,business.industry ,Amyotrophic Lateral Sclerosis ,Middle Aged ,Survival Analysis ,3. Good health ,Neuroprotective Agents ,Treatment Outcome ,030104 developmental biology ,Tolerability ,chemistry ,Neurology ,Disease Progression ,Female ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
ObjectiveTo examine the safety and tolerability as well as the preliminary efficacy of arimoclomol, a heat shock protein co-inducer that promotes nascent protein folding, in patients with rapidly progressive SOD1 amyotrophic lateral sclerosis (ALS).MethodsThis was a double-blind, placebo-controlled trial in which patients with rapidly progressive SOD1-mutant ALS were randomized 1:1 to receive arimoclomol 200 mg tid or matching placebo for up to 12 months. Study procedures were performed using a mix of in-person and remote assessments. Primary outcome was safety and tolerability. Secondary outcome was efficacy, with survival as the principal measure. Additional efficacy measures were the rates of decline of the Revised ALS Functional Rating Scale (ALSFRS-R) and percent predicted forced expiratory volume in 6 seconds (FEV6), and the Combined Assessment of Function and Survival (CAFS).ResultsThirty-eight participants were randomized. Thirty-six (19 placebo, 17 arimoclomol) were included in the prespecified intent-to-treat analysis. Apart from respiratory function, groups were generally well-balanced at baseline. Adverse events occurred infrequently, and were usually mild and deemed unlikely or not related to study drug. Adjusting for riluzole and baseline ALSFRS-R, survival favored arimoclomol with a hazard ratio of 0.77 (95% confidence interval [CI] 0.32–1.80). ALSFRS-R and FEV6 declined more slowly in the arimoclomol group, with treatment differences of 0.5 point/month (95% CI −0.63 to 1.63) and 1.24 percent predicted/month (95% CI −2.77 to 5.25), respectively, and the CAFS similarly favored arimoclomol.ConclusionsThis study provides Class II evidence that arimoclomol is safe and well-tolerated at a dosage of 200 mg tid for up to 12 months. Although not powered for therapeutic effect, the consistency of results across the range of prespecified efficacy outcome measures suggests a possible therapeutic benefit of arimoclomol.Clinicaltrials.gov identifierNCT00706147.Classification of evidenceThis study provides Class II evidence that arimoclomol is safe and well-tolerated at a dosage of 200 mg tid for up to 12 months. The study lacked the precision to conclude, or to exclude, an important therapeutic benefit of arimoclomol.
- Published
- 2018
29. Abstract 14
- Author
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Marco Visaggio, Gem Runyan, William S. David, Robert W. Redmond, Jane M. Tsui, Reiner B. See, Mark A. Randolph, Ian L. Valerio, Jonathan M. Winograd, and Marek A. Hansdorfer
- Subjects
Non human primate ,business.industry ,Peripheral nerve ,Medicine ,Surgery ,business ,Neuroscience - Published
- 2019
30. Natural history and biomarkers in hereditary sensory neuropathy type 1
- Author
-
William S. David, Vera Fridman, Florian Eichler, Elise A. Johnson, Robert H. Brown, Jessica Pan, Anne Louise Oaklander, and Peter Novak
- Subjects
Adult ,Male ,Weakness ,medicine.medical_specialty ,Pathology ,peripheral neuropathy ,Adolescent ,small fiber neuropathy ,Physiology ,Neural Conduction ,Neurogenetics ,Gastroenterology ,Young Adult ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Charcot-Marie-Tooth Disease ,Physiology (medical) ,Internal medicine ,Hereditary sensory and autonomic neuropathy ,medicine ,Humans ,Hereditary Sensory and Autonomic Neuropathies ,SPTLC1 ,neurogenetics ,skin biopsy ,Research Articles ,Aged ,Retrospective Studies ,Skin ,030304 developmental biology ,0303 health sciences ,medicine.diagnostic_test ,business.industry ,Data Collection ,Sensory loss ,Middle Aged ,medicine.disease ,Peripheral neuropathy ,Skin biopsy ,Biomarker (medicine) ,Female ,Neurology (clinical) ,medicine.symptom ,hereditary neuropathy ,business ,Biomarkers ,030217 neurology & neurosurgery - Abstract
Introduction: Hereditary sensory and autonomic neuropathy type 1 (HSAN1) is most commonly caused by missense mutations in SPTLC1. In this study we mapped symptom progression and compared the utility of outcomes. Methods: We administered retrospective surveys of symptoms and analyzed results of nerve conduction, autonomic function testing (AFT), and PGP9.5-immunolabeled skin biopsies. Results: The first symptoms were universally sensory and occurred at a median age of 20 years (range 14–54 years). The onset of weakness, ulcers, pain, and balance problems followed sequentially. Skin biopsies revealed universally absent epidermal innervation at the distal leg with relative preservation in the thigh. Neurite density was highly correlated with total Charcot-Marie-Tooth Examination Score (CMTES; r2 = −0.8) and median motor amplitude (r2 = −0.75). Conclusions: These results confirm sensory loss as the initial symptom of HSAN1 and suggest that skin biopsy may be the most promising biomarker for future clinical trials. Muscle Nerve, 2015 Muscle Nerve 51: 489–495, 2015
- Published
- 2015
31. Case 3-2015
- Author
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William S. David, Jessica J. Kraeft, David C. Hooper, and Elizabeth S. Temin
- Subjects
Diplopia ,medicine.medical_specialty ,Abdominal pain ,business.industry ,Diagnostic test ,General Medicine ,Surgery ,medicine.anatomical_structure ,Case records ,Tongue ,medicine ,Proximal weakness ,medicine.symptom ,Presentation (obstetrics) ,General hospital ,business - Abstract
A 60-year-old woman was admitted to the hospital because of abdominal pain, dyspnea, and diplopia. Several hours after presentation, she was unable to phonate clearly or protrude the tongue, and proximal weakness of the arms and legs developed. A diagnostic test was performed.
- Published
- 2015
32. Evidence-based guideline summary: Diagnosis and treatment of limb-girdle and distal dystrophies: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine
- Author
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William S. David, Gary S. Gronseth, Matthew Wicklund, Anthony A. Amato, Duygu Selcen, Erik R. Ensrud, Michael D. Weiss, Elizabeth M. Raynor, Richard J. Barohn, Gregory T. Carter, Robert C. Griggs, and Pushpa Narayanaswami
- Subjects
medicine.medical_specialty ,Pediatrics ,education.field_of_study ,Neurology ,Muscle biopsy ,medicine.diagnostic_test ,business.industry ,Population ,Evidence-based medicine ,medicine.disease ,Pulmonary function testing ,Transplantation ,Special Article ,Physical therapy ,Medicine ,Neurology (clinical) ,Muscular dystrophy ,Differential diagnosis ,business ,education - Abstract
Objective: To review the current evidence and make practice recommendations regarding the diagnosis and treatment of limb-girdle muscular dystrophies (LGMDs). Methods: Systematic review and practice recommendation development using the American Academy of Neurology guideline development process. Results: Most LGMDs are rare, with estimated prevalences ranging from 0.07 per 100,000 to 0.43 per 100,000. The frequency of some muscular dystrophies varies based on the ethnic background of the population studied. Some LGMD subtypes have distinguishing features, including pattern of muscle involvement, cardiac abnormalities, extramuscular involvement, and muscle biopsy findings. The few published therapeutic trials were not designed to establish clinical efficacy of any treatment. Principal recommendations: For patients with suspected muscular dystrophy, clinicians should use a clinical approach to guide genetic diagnosis based on clinical phenotype, inheritance pattern, and associated manifestations (Level B). Clinicians should refer newly diagnosed patients with an LGMD subtype and high risk of cardiac complications for cardiology evaluation even if they are asymptomatic from a cardiac standpoint (Level B). In patients with LGMD with a known high risk of respiratory failure, clinicians should obtain periodic pulmonary function testing (Level B). Clinicians should refer patients with muscular dystrophy to a clinic that has access to multiple specialties designed specifically to care for patients with neuromuscular disorders (Level B). Clinicians should not offer patients with LGMD gene therapy, myoblast transplantation, neutralizing antibody to myostatin, or growth hormone outside of a research study designed to determine efficacy and safety of the treatment (Level R). Detailed results and recommendations are available on the Neurology® Web site at Neurology.org.Neurology® 2014;83:1453–1463
- Published
- 2014
33. Seeking a measure of clinically meaningful change in ALS
- Author
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Raymond R. Goetz, Merit Cudkowicz, Hiroshi Mitsumoto, Jonathan S. Katz, William S. David, Jonathan D. Glass, Judith G. Rabkin, Stanley H. Appel, Martin McElhiney, Dallas A. Forshew, Robert G. Miller, and Ericka Simpson
- Subjects
Adult ,Aged, 80 and over ,Male ,Alsfrs r ,Amyotrophic Lateral Sclerosis ,Middle Aged ,Severity of Illness Index ,Statistics, Nonparametric ,Young Adult ,Treatment Outcome ,Quality of life (healthcare) ,Caregivers ,Neurology ,Activities of Daily Living ,Respondent ,Quality of Life ,Humans ,Female ,sense organs ,Neurology (clinical) ,skin and connective tissue diseases ,Psychology ,Aged ,Follow-Up Studies ,Clinical psychology - Abstract
We sought to identify a method to assess 'clinically meaningful change' perceived by patients, caregivers and clinical raters in relation to changes in ALSFRS-R scores at three-month intervals. In this five-site study, 81 patient-caregiver dyads were interviewed at baseline, three, and six months to assess changes in ALSFRS-R in relation to perceived occurrence of change, its magnitude and impact. Ratings by patients, caregivers and clinical raters were analyzed over three-month intervals within and between respondent groups. We found that patients, clinical raters, and caregivers agreed about 80% of the time about whether change occurred, and in what direction, on each of three visits. The perceived magnitude of change for the four domains measured by the ALSFRS-R was correlated with ratings of impact within respondent groups and across time. We also found moderate associations between changes in ALSFRS-R domain scores and judgments of symptom impact as rated by patient, caregiver and clinical rater. Independent measures (Quality of Life, Goal Assessment Scaling) showed no consistent correlations with ALSFRS-R change scores. In conclusion, the use of scales to assess the perceived magnitude and impact of change corresponding with the domains of the ALSFRS-R may be a step towards understanding of the clinical meaning of changes in that measure.
- Published
- 2014
34. Quality improvement in neurology: Distal symmetric polyneuropathy quality measures
- Author
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Gary M. Franklin, William S. David, Rebecca J. Swain-Eng, Richard Dubinsky, Gina Gjorvad, Benn E. Smith, Thomas H. Brannagan, and John D. England
- Subjects
medicine.medical_specialty ,education.field_of_study ,Pediatrics ,Weakness ,Neurology ,business.industry ,Population ,Prevalence ,Peripheral Nervous System Diseases ,Sensory loss ,medicine.disease ,Impaired glucose tolerance ,Special Article ,Peripheral neuropathy ,Diabetes mellitus ,Physical therapy ,Humans ,Medicine ,Neurology (clinical) ,medicine.symptom ,business ,education ,Quality of Health Care - Abstract
Peripheral neuropathy is a common neurologic disorder, affecting 2% to 8% of the population1–3 in population-based studies with confirmation by neurologist examination. These prevalence numbers are remarkably stable across developed countries.4 In 1999, 8.6% of Medicare beneficiaries had neuropathy as a primary or secondary diagnosis, and the cost of treatment was estimated at $3.5 billion (Consumer Price Index adjusted to 2013 $4.9 billion), which did not include outpatient medications.5 Peripheral neuropathy has many causes and varies in regard to its clinical manifestations and severity. Distal symmetric polyneuropathy (DSP) is the most common pattern of peripheral neuropathy generally and the most common phenotype of neuropathy due to diabetes. Reported prevalence rates of DSP among diabetic patients range from 15% to 37% across large population-based studies, and the prevalence among those with impaired glucose tolerance has been reported to be 11%.4,6 DSP can result in weakness, sensory loss, pain, autonomic dysfunction, gait impairment, falls, disability, and impaired quality of life.7,8
- Published
- 2014
35. In vivo measurement of PDE10A enzyme occupancy by positron emission tomography (PET) following single oral dose administration of PF-02545920 in healthy male subjects
- Author
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Ottavio V. Vitolo, Patrik Fazio, Nahid Amini, Marielle Delnomdedieu, Nabil Al-Tawil, Adam Ogden, Per Stenkrona, Sangram Nag, Sridhar Duvvuri, Anton Forsberg, Christer Halldin, William S. David, Ching-Ray Yu, and Andrea Varrone
- Subjects
0301 basic medicine ,Adult ,Male ,Fluorine Radioisotopes ,Phthalimides ,Pharmacology ,Medium spiny neuron ,Models, Biological ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Radioligand Assay ,0302 clinical medicine ,In vivo ,Radioligand ,medicine ,Humans ,Quinazolinones ,medicine.diagnostic_test ,Chemistry ,Phosphoric Diester Hydrolases ,Phosphodiesterase ,Binding potential ,Middle Aged ,Corpus Striatum ,030104 developmental biology ,Tolerability ,Positron emission tomography ,Positron-Emission Tomography ,Quinolines ,Pyrazoles ,PDE10A ,030217 neurology & neurosurgery - Abstract
Phosphodiesterase 10A (PDE10A) is an enzyme highly enriched in the striatal medium spiny neurons. It is involved in the regulation of cytoplasmic levels of cAMP and cGMP and signaling within the basal ganglia. This study with PDE10A radioligand [18F]MNI-659 was designed to measure the enzyme occupancy of PF-02545920 in 8 healthy male volunteers (48 ± 4 years) after a single oral dose (10 mg or 20 mg) and to evaluate safety and tolerability. Arterial blood sampling was performed to obtain a metabolite-corrected plasma input function for the quantification of [18F]MNI-659 binding to PDE10A. The occupancy of PF-02545920 was calculated with two different methods: In Method 1, [18F]MNI-659 enzyme occupancy was calculated from the estimates of binding potential, using the cerebellum as a reference region; in Method 2, occupancy was estimated from the slope of the revised Lassen's plot. Serum concentrations of PF-02545920 were measured to determine the relationship between concentration and occupancy. Based on Method 1, striatal PDE10A occupancy increased with increasing PF-02545920 dose: 14–27% at 10 mg dose (N = 4) and 45–63% at 20 mg dose (N = 3). Comparable occupancies were observed using Lassen's plot Method 2: 10 mg: 14–37%; 20 mg: 46–55%. The relationship between exposure and occupancy was best described using an Emax model. The serum concentration associated with 50% occupancy was estimated to be 93.2 ng/mL. Single oral doses of 10 mg or 20 mg of PF-02545920 were safe and well tolerated in healthy male volunteers [NCT# 01918202].
- Published
- 2016
36. A standardized clinical evaluation of phenotypic diversity in diabetic polyneuropathy
- Author
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Joachim Scholz, James P. Rathmell, William S. David, Jenna L. Wells, Naomi S. Shin, Stephen Perros, Simon Tate, David A. Chad, Alithia C. Broderick, Shuang Wang, John B. Davis, and Charles J. DiMaggio
- Subjects
0301 basic medicine ,Male ,Pain Threshold ,medicine.medical_specialty ,Analgesic ,Statistics as Topic ,Physical examination ,Type 2 diabetes ,Severity of Illness Index ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Threshold of pain ,Severity of illness ,medicine ,Humans ,Pain Measurement ,Principal Component Analysis ,medicine.diagnostic_test ,business.industry ,Middle Aged ,medicine.disease ,030104 developmental biology ,Anesthesiology and Pain Medicine ,Phenotype ,Neurology ,Diabetes Mellitus, Type 2 ,ROC Curve ,Hyperalgesia ,Neuropathic pain ,Neuralgia ,Female ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Diabetic polyneuropathy (DPN) is a major cause of neuropathic pain and a frequent target condition in analgesic treatment trials. Differences in the clinical symptoms and signs associated with DPN suggest distinct pathophysiological mechanisms underlying nerve damage and dysfunction that are likely to have therapeutic relevance. The aim of this study was to develop a tool for the bedside assessment of painful neuropathies such as DPN that captures the diversity of phenotypes. Sixty-one patients with type 2 diabetes and painful neuropathy, 19 patients with painless DPN, 25 patients with type 2 diabetes but no clinical evidence of neuropathy, and 20 healthy control subjects completed a structured interview (47 items) and a standardized physical examination (39 items). After analyzing critical features of pain and painless symptoms and examining the outcome of physical tests of sensory function, we determined principal components of the phenotypic variance among patients. Increased sensitivity to mechanical or thermal stimuli and, to a lesser extent, the sensory quality of pain or paresthesia were the most discriminating elements of DPN phenotypes. Correlation patterns of symptoms and signs indicated the involvement of functionally distinct nerve fiber populations. We combined interview questions and physical tests identifying these differences in a shortened assessment protocol that we named Standardized Evaluation of Pain and Somatosensory Function (StEPS). The protocol StEPS generates a phenotypic profile of patients with neuropathy. Separate intensity ratings for spontaneous painful symptoms and pain evoked by standard stimuli support a detailed documentation of neuropathic pain and its response to analgesic treatment.
- Published
- 2016
37. Electrical impedance myography as a biomarker to assess ALS progression
- Author
-
Mary Lou Watson, Shiva Gautam, Pushpa Narayanaswami, Khema Sharma, Judy Warder, Michael Benatar, Sharon Usher, Jeremy M. Shefner, Lora Clawson, Ted M. Burns, Elizabeth M. Raynor, Michael S. Cartwright, Seward B. Rutkove, Nicholas J. Maragakis, Namita Goyal, James B. Caress, and William S. David
- Subjects
Adult ,Male ,medicine.medical_specialty ,Time Factors ,Adolescent ,Phases of clinical research ,Article ,Young Adult ,Physical medicine and rehabilitation ,Internal medicine ,Electric Impedance ,medicine ,Humans ,Treatment effect ,Amyotrophic lateral sclerosis ,Muscle, Skeletal ,Survival rate ,Aged ,Aged, 80 and over ,Clinical Trials as Topic ,Electrical impedance myography ,business.industry ,Amyotrophic Lateral Sclerosis ,Myography ,General Medicine ,Middle Aged ,medicine.disease ,Survival Rate ,Clinical trial ,Neurology ,Multicenter study ,Disease Progression ,Cardiology ,Biomarker (medicine) ,Female ,Neurology (clinical) ,business - Abstract
Electrical impedance myography (EIM), a non-invasive, electrophysiological technique, has preliminarily shown value as an ALS biomarker. Here we perform a multicenter study to further assess EIM's potential for tracking ALS. ALS patients were enrolled across eight sites. Each subject underwent EIM, handheld dynamometry (HHD), and the ALS Functional Rating Scale-revised (ALSFRS-R) regularly. Techniques were compared by assessing the coefficient of variation (CoV) in the rate of decline and each technique's correlation to survival. Results showed that in the 60 patients followed for one year, EIM phase measured from the most rapidly progressing muscle in each patient had a CoV in the rate of decline of 0.62, compared to HHD (0.82) and the ALSFRS-R (0.74). Restricting the measurements to the first six months gave a CoV of 0.55 for EIM, 0.93 for HHD, and 0.84 for ALSFRS-R. For both time-periods, all three measures correlated with survival. Based on these data, a six-month clinical trial designed to detect a 20% treatment effect with 80% power using EIM would require only 95 patients/arm compared to the ALSFRS-R, which would require 220 subjects/arm. In conclusion, EIM can serve as a useful ALS biomarker that offers the prospect of greatly accelerating phase 2 clinical trials.
- Published
- 2012
38. Electrodiagnostic Evaluation of Lower Extremity Mononeuropathies
- Author
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Vera Fridman and William S. David
- Subjects
medicine.medical_specialty ,medicine.diagnostic_test ,Electromyography ,business.industry ,Mononeuropathies ,Lower limb ,Mononeuropathy ,Physical medicine and rehabilitation ,Lower Extremity ,medicine ,Humans ,Neurology (clinical) ,business ,Nerve conduction ,Foot (unit) ,Needle electromyography - Abstract
This article discusses the anatomy of lower limb mononeuropathies and reviews the general approach to evaluating patients in the electrodiagnostic laboratory with suspected mononeuropathies of the lower limb. Through illustrative cases of patients presenting with a floppy foot, buckling knee, or painful foot, the approaches using nerve conduction studies and needle electromyography are reviewed, and the pattern of findings of peroneal, tibial, sciatic, femoral, and obturator neuropathies is shown.
- Published
- 2012
39. Case 7-2012
- Author
-
E. Tessa Hedley-Whyte, David A. Chad, Avinash Kambadakone, and William S. David
- Subjects
medicine.medical_specialty ,Weakness ,Leg weakness ,medicine.diagnostic_test ,business.industry ,Physical examination ,General Medicine ,body regions ,Decreased reflexes ,Case records ,Physical therapy ,Medicine ,General hospital ,medicine.symptom ,business - Abstract
A 79-year-old man was admitted to the hospital because of pain and weakness in the legs. He had multiple chronic medical problems and took numerous medications, with no recent changes. Examination revealed leg weakness and decreased reflexes.
- Published
- 2012
40. Multipoint incremental motor unit number estimation as an outcome measure in ALS
- Author
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L. Simionescu, Michael Benatar, William S. David, Nicholas J. Maragakis, Seward B. Rutkove, James B. Caress, Khema Sharma, Ted M. Burns, Jeremy M. Shefner, and Mary Lou Watson
- Subjects
Adult ,Male ,medicine.medical_specialty ,Time Factors ,Adolescent ,Action Potentials ,Physical examination ,Electromyography ,Severity of Illness Index ,Disability Evaluation ,Young Adult ,Physical medicine and rehabilitation ,Outcome Assessment, Health Care ,Severity of illness ,medicine ,Humans ,Motor unit number estimation ,Amyotrophic lateral sclerosis ,Aged ,Aged, 80 and over ,Motor Neurons ,medicine.diagnostic_test ,Amyotrophic Lateral Sclerosis ,Reproducibility of Results ,Articles ,Repeatability ,Middle Aged ,medicine.disease ,Electric Stimulation ,Motor unit ,Sample size determination ,Female ,Neurology (clinical) ,Psychology ,Follow-Up Studies - Abstract
Background: Improved outcome measures are necessary to reduce sample size and increase power in amyotrophic lateral sclerosis (ALS) clinical trials. Motor unit number estimation (MUNE) is a potentially attractive tool. MUNE methods previously employed in multicenter trials exhibited excessive variability and were prone to artifact. Objective: To evaluate a modification of standard incremental MUNE in a multicenter natural history study of subjects with ALS. Methods: Fifty healthy subjects were evaluated twice and 71 subjects with ALS were studied repeatedly for up to 500 days. Side and nerve studied was based on clinical examination findings. Nerves were stimulated at 3 specified locations and 3 increments were obtained at each location. Average single motor unit action potential (SMUP) amplitude was calculated by adding the amplitude of the third increment at each location and dividing by 9; SMUP was divided into maximum CMAP amplitude to determine the MUNE. Results: Test-retest variability was 9% in normal subjects. Average MUNE for normal subjects was 225 (±87), and was 41.9 (±39) among subjects with ALS at baseline. Subjects with ALS showed clear decrements over time, with an overage rate of decline of approximately 9% per month. SMUP amplitude increased with time in a fashion consistent with the known pathophysiology of ALS. Conclusion: Multipoint incremental MUNE has a number of attributes that make it attractive as an outcome measure in ALS and other diseases characterized by motor unit loss. It can be rapidly performed on any EMG machine and has repeatability and rates of decline that favorably compare to other previously described methods.
- Published
- 2011
41. Validation of an incremental motor unit number estimation technique in rabbits
- Author
-
Namita Goyal, Laura E. Baldassari, William S. David, Francis P. Henry, and Robert W. Redmond
- Subjects
Reproducibility ,Correlation coefficient ,Human studies ,Physiology ,business.industry ,Intraclass correlation ,Anatomy ,Cellular and Molecular Neuroscience ,Physiology (medical) ,Quantitative assessment ,Medicine ,Motor unit number estimation ,Neurology (clinical) ,Poor correlation ,business ,Nuclear medicine ,Histological correlation - Abstract
Motor unit number estimation (MUNE) allows for quantitative assessment of functional motor units in a nerve. Several techniques have been applied to human studies. Although MUNE has been performed in animals to study neurological disorders, reproducibility has not been addressed. We analyzed the test–retest reproducibility of an incremental MUNE technique in rabbits and performed histological correlation. A peroneal MUNE was performed in 9 rabbits on two occasions separated by 30 days. MUNE was then performed on 18 rabbits prior to euthanize. A count of total fibers and a second count of large myelinated fibers were performed on nerve cross-sections. Test–retest reproducibility revealed an intraclass correlation coefficient (ICC) of 0.75. The average test–retest relative difference was 26.6%. Comparison of MUNE and histomorphometrical counts revealed a correlation coefficient (r) of 0.21 (total fiber counts) and 0.27 (large fibers). Although incremental MUNE has a high degree of reproducibility in rabbits, there is poor correlation with histological fiber counts. Muscle Nerve, 2010
- Published
- 2010
42. Electrical impedance myography correlates with standard measures of Als severity
- Author
-
Namita Goyal, Michael Benatar, William S. David, Elizabeth M. Raynor, Ted M. Burns, James B. Caress, Mary Lou Watson, Pushpa Narayanaswami, Judy Warder, Nicholas J. Maragakis, Seward B. Rutkove, Michael S. Cartwright, Jeremy M. Shefner, and Khema Sharma
- Subjects
medicine.medical_specialty ,Electrical impedance myography ,Alsfrs r ,Physiology ,business.industry ,medicine.disease ,Cellular and Molecular Neuroscience ,Physical medicine and rehabilitation ,Muscle nerve ,Disease severity ,Single muscle ,Physiology (medical) ,medicine ,Physical therapy ,Motor unit number estimation ,Neurology (clinical) ,Amyotrophic lateral sclerosis ,business ,Whole body - Abstract
Introduction: Electrical impedance myography (EIM) can be used to assess amyotrophic lateral sclerosis (ALS) progression. The relationship between EIM values and standard assessment measures, however, is unknown. Methods: EIM 50 kHz phase data from 60 subjects who participated in a longitudinal natural history study of ALS were correlated with handheld dynamometry (HHD), the ALS Functional Rating Scale-Revised (ALSFRS-R) score, and motor unit number estimation (MUNE). Results: Moderate strength correlations between EIM parameters and HHD were observed for both whole-body and individual upper and lower extremity values. Similarly, moderate strength correlations were observed between EIM and ALSFRS-R upper and lower extremity subscores, but not total ALSFRS-R scores. MUNE correlated significantly with single muscle EIM data but not with whole body or upper or lower extremity values. Conclusions: These results support the concept that EIM can serve as a meaningful measure of disease severity in ALS. Muscle Nerve 49:441–443, 2014
- Published
- 2013
43. Phase II/III randomized trial of TCH346 in patients with ALS
- Author
-
Andrea M. Corse, François Vingerhoets, Nigel Leigh, Michael Swash, Terry Heiman-Patterson, Vincenzo Silani, Sanjay Kalra, Robert M. Pascuzzi, Dirk Sauer, Andrew Eisen, Merit Cudkowicz, Andrew J. Waclawik, Walter G. Bradley, Michael J. Strong, Orla Hardiman, Albert C. Ludolph, William Camu, Neil R. Cashman, Stanley H. Appel, Hiroshi Mitsumoto, Charles Krieger, Erik P. Pioro, Hans E. Neville, H. Pohlmann, Mark B. Bromberg, John Turnbull, Carlayne E. Jackson, Reinhard Dengler, Richard J. Barohn, Vincent Meininger, William S. David, Angela Genge, Thomas F. Meyer, M. de Visser, Jean P. Hubble, Adriano Chiò, Robert G. Miller, Jeremy M. Shefner, E. Vernotica, Darlene R. Moore, Alain Destée, L. H. van den Berg, Robert L. Sufit, Michael C. Graves, John T. Kissel, Jeffrey V. Rosenfeld, and Lucette Lacomblez
- Subjects
medicine.medical_specialty ,business.industry ,Treatment comparison ,Placebo ,medicine.disease ,Pulmonary function testing ,law.invention ,Surgery ,Secondary outcome ,Randomized controlled trial ,law ,Rating scale ,Internal medicine ,medicine ,In patient ,Neurology (clinical) ,Amyotrophic lateral sclerosis ,business - Abstract
Background: TCH346 exerts antiapoptotic effects by binding to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and blocking the apoptotic pathway in which GAPDH is involved. Apoptosis is considered to be a key pathogenic mechanism in neurodegenerative diseases including ALS. Methods: Patients were randomly assigned in a double-blind fashion to receive either placebo or one of four doses of TCH346 (1.0, 2.5, 7.5, or 15 mg/day) administered orally once daily for at least 24 weeks. The primary outcome measure was the rate of change in the revised ALS functional rating scale (ALSFRS-R). The trial design included a 16-week lead-in phase to determine each patient9s rate of disease progression. The between treatment comparison was adjusted for the individual pretreatment rates of progression. The study was powered to detect a 25% reduction in the rate of decline of the ALSFRS-R as compared with placebo. Secondary outcome measures included survival, pulmonary function, and manual muscle testing (MMT). Results: Five hundred ninety-one patients were enrolled at 42 sites in Europe and North America. There were no differences in baseline variables. There were no significant differences between placebo and active treatment groups in the mean rate of decline of the ALSFRS-R or in the secondary outcome measures (survival, pulmonary function, and MMT). Conclusion: The trial revealed no evidence of a beneficial effect of TCH346 on disease progression in patients with ALS.
- Published
- 2007
44. Quality improvement in neurology: Muscular dystrophy quality measures
- Author
-
Michelle Mellion, John D. England, David Q.-H. Wang, Jodi Wolff, William S. David, Jianguo Cheng, Gina Gjorvad, Christopher F. Spurney, Benn E. Smith, Richard Dubinsky, Pushpa Narayanaswami, Frederic Shapiro, and Jonathan D. Finder
- Subjects
Genetics ,medicine.medical_specialty ,Pathology ,Heterogeneous group ,Neurology ,Quality management ,business.industry ,Genetic heterogeneity ,fungi ,food and beverages ,medicine.disease ,Phenotype ,Quality Improvement ,Muscular Dystrophies ,Special Article ,hemic and lymphatic diseases ,Practice Guidelines as Topic ,medicine ,Humans ,Neurology (clinical) ,Muscular dystrophy ,business - Abstract
The muscular dystrophies (MDs) are a heterogeneous group of genetically determined myopathies. Identification of underlying genetic defects has demonstrated that MDs exhibit significant phenotypic and genetic heterogeneity. One genetic mutation can lead to a variety of phenotypes while different genetic mutations can manifest similar phenotypes; therefore MDs are challenging to diagnose.
- Published
- 2015
45. Radiculopathies and Neuropathies
- Author
-
William S David and Kathy Chuang
- Subjects
medicine.medical_specialty ,Physical medicine and rehabilitation ,business.industry ,Medicine ,business ,Radiculopathies - Abstract
“Radiculopathies” are disorders of nerve roots, whereas “neuropathies” are disorders of the peripheral nerve. These disorders may involve single roots or nerves, multiple roots or nerves, and even other aspects of the nervous system. This chapter reviews the anatomy and pathophysiology of the peripheral nervous system; the general approach to radiculopathies and neuropathies, including clinical manifestations and localization, diagnostic studies, and treatment; radiculopathies, including anatomy, cervical radiculopathy, lumbosacral radiculopathy, thoracic radiculopathy, and cauda equina syndrome; and neuropathies, including mononeuropathies and polyneuropathies. Tables describe the innervation of select nerve roots and peripheral nerves, differences between root and nerve lesions, commonly used neuropathic pain medications, distinctive patterns of neuropathy with limited differential diagnoses, differential diagnosis of demyelinating polyneuropathy, drugs that may cause polyneuropathy, and neuropathies associated with diabetes mellitus. Figures show the anatomy of a spinal segment, nerve fascicles, ultrasound images of the median nerve, magnetic resonance imaging of the lumbosacral spine, the Spurling maneuver, and physical examination maneuvers for lumbosacral radiculopathies. This chapter contains 6 highly rendered figures, 8 tables, 77 references, and 5 MCQs.
- Published
- 2015
46. Case records of the Massachusetts General Hospital. Case 3-2015. A 60-year-old woman with abdominal pain, dyspnea, and diplopia
- Author
-
William S, David, Elizabeth S, Temin, Jessica J, Kraeft, and David C, Hooper
- Subjects
Diagnosis, Differential ,Radiography, Abdominal ,Dyspnea ,Electromyography ,Diplopia ,Humans ,Botulism ,Female ,Middle Aged ,Nervous System Diseases ,Abdominal Pain - Published
- 2015
47. List of Contributors
- Author
-
Hasan O. Akman, Felicia B. Axelrod, Jonathan Baets, Alan H. Beggs, Carsten G. Bönnemann, Kathryn M. Brennan, Robert H. Brown, Kate Bushby, Stirling Carpenter, Wendy Chung, Emma Ciafaloni, Pedro D.S.C. Ciarlini, Thomas O. Crawford, Basil T. Darras, William S. David, Umberto De Girolami, Darryl C. De Vivo, Feza Deymeer, Salvatore DiMauro, James J. Dowling, Hacer Durmus, Andrew G. Engel, Elizabeth C. Engle, Hans H. Goebel, Padraic J. Grattan-Smith, Michela Guglieri, Debra Guntrum, Judith G. Hall, Veronica Hinton, Susan T. Iannaccone, H. Royden Jones, Karin Jurkat-Rott, Peter B. Kang, Horacio Kaufmann, Petra Kaufmann, Werner Klingler, Louis M. Kunkel, Frank Lehmann-Horn, Kerry H. Levin, Wendy K.M. Liew, Deirdre Logan, Stephen M. Maricich, Jennifer A. Markowitz, Wilson Marques, Thornton B.A. Mason, Andrew McKeon, Hugh J. McMillan, Caroline C. Menache-Starobinski, Jerry R. Mendell, Eugenio Mercuri, Payam Mohassel, Umrao R. Monani, Jacqueline Montes, Manikum Moodley, Richard T. Moxley, Francesco Muntoni, Kathryn N. North, Anders Oldfors, Maryam Oskoui, Robert A. Ouvrier, Lauren M. Pachman, Massimo Pandolfo, Carmen Paradas, Marc C. Patterson, Alan K. Percy, Matthew Pitt, David Pleasure, Susana Quijano-Roy, Francis Renault, Louise R. Rodino-Klapac, Manuel Roig-Quilis, David P. Roye, Reinhardt Rüdel, Barry S. Russman, Monique M. Ryan, Ai Sakonju, Harvey B. Sarnat, William A. Scott, Alan R. Seay, Piraye Serdaroglu-Oflazer, Navil F. Sethna, Evan D. Sheha, Michael E. Shy, Jemeen Sreedharan, Nancy E. Strauss, Rabi Tawil, Ingrid Tein, Jennifer A. Tracy, Bjarne Udd, Silvère M. van der Maarel, Angela Vincent, Joseph J. Volpe, Jo M. Wilmshurst, Nanfang Xu, Eppie M. Yiu, and Huda Y. Zoghbi
- Published
- 2015
48. Infectious or Acquired Motor Neuron Diseases
- Author
-
William S. David, Manikum Moodley, and Alan R. Seay
- Subjects
business.industry ,Tetanus ,viruses ,Poliovirus ,Motor neuron ,medicine.disease ,medicine.disease_cause ,Virology ,Poliomyelitis ,medicine.anatomical_structure ,Post-polio syndrome ,Immunology ,Hopkins syndrome ,Medicine ,Rabies ,business ,Acute Poliomyelitis - Abstract
The infectious or acquired motor neuronopathies are a heterogeneous group of disorders in which motor neuron degeneration or dysfunction produces the predominant manifestation of weakness while the sensory system is clinically spared. The most common disorders seen in children include acute poliomyelitis, vaccine associated poliomyelitis, asthma associated poliomyelitis syndrome (Hopkins syndrome), rabies, and tetanus. Viruses other than the poliovirus rarely cause the poliomyelitis syndrome including other enteroviruses (coxsackie, echo viruses), herpes virus family, adenovirus, HIV, and West Nile virus. Virologic and serologic techniques are necessary to isolate, identify, and differentiate these viruses. The pathogenesis of most acquired motor neuron disorders is poorly understood and the treatment is mainly symptomatic and supportive. This chapter is enhanced by clinical vignettes that describe the salient historical and clinical presentations and laboratory findings of the prototype disorders leading to motor neuronopathies.
- Published
- 2015
49. High-frequency chest wall oscillation in ALS: An exploratory randomized, controlled trial
- Author
-
Terry Heiman-Patterson, Noah Lechtzin, Hiroshi Mitsumoto, Brian Becker, Dale J. Lange, Cynthia S. Davey, William S. David, and Deborah F. Gelinas
- Subjects
Male ,Vital capacity ,medicine.medical_specialty ,Time Factors ,medicine.medical_treatment ,Vital Capacity ,Severity of Illness Index ,law.invention ,FEV1/FVC ratio ,Double-Blind Method ,Randomized controlled trial ,law ,medicine ,Humans ,Respiratory function ,Chest wall oscillation ,Aged ,High-Frequency Chest Wall Oscillation ,Capnography ,Chi-Square Distribution ,medicine.diagnostic_test ,business.industry ,Respiration ,Amyotrophic Lateral Sclerosis ,Bayes Theorem ,Middle Aged ,Chest Wall Oscillation ,Respiratory Function Tests ,Treatment Outcome ,Anesthesia ,Quality of Life ,Physical therapy ,Breathing ,Female ,Neurology (clinical) ,business - Abstract
Objectives: To evaluate changes in respiratory function in patients with ALS after using high-frequency chest wall oscillation (HFCWO). Methods: This was a 12-week randomized, controlled trial of HFCWO in patients with probable or definite ALS, an Amyotrophic Lateral Sclerosis Functional Rating Scale respiratory subscale score ≤11 and ≥5, and forced vital capacity (FVC) ≥40% predicted. Results: We enrolled 46 patients (58.0 ± 9.8 years; 21 men, 25 women); 22 used HFCWO and 24 were untreated. Thirty-five completed the trial: 19 used HFCWO and 16 untreated. HFCWO users had less breathlessness ( p = 0.021) and coughed more at night ( p = 0.048) at 12 weeks compared to baseline. At 12 weeks, HFCWO users reported a decline in breathlessness ( p = 0.048); nonusers reported more noise when breathing ( p = 0.027). There were no significant differences in FVC change, peak expiratory flow, capnography, oxygen saturation, fatigue, or transitional dyspnea index. When patients with FVC between 40 and 70% predicted were analyzed, FVC showed a significant mean decrease in untreated patients but not in HFCWO patients; HFCWO patients had significantly less increased fatigue and breathlessness. Satisfaction with HFCWO was 79%. Conclusion: High-frequency chest wall oscillation was well tolerated, considered helpful by a majority of patients, and decreased symptoms of breathlessness. In patients with impaired breathing, high-frequency chest wall oscillation decreased fatigue and showed a trend toward slowing the decline of forced vital capacity.
- Published
- 2006
50. Treatment of sporadic inclusion body myositis with bimagrumab
- Author
-
Namita Goyal, Estelle Lach-Trifilieff, Jens Praestgaard, Brian Tseng, William S. David, Mohammad Salajegheh, Anne-Ulrike Trendelenburg, Anthony A. Amato, Steven A. Greenberg, Kumaraswamy Sivakumar, Didier Laurent, Ronenn Roubenoff, and David J. Glass
- Subjects
Adult ,Male ,medicine.medical_specialty ,Neuromuscular disease ,Activin Receptors, Type II ,Smad2 Protein ,Biology ,Placebo ,Antibodies, Monoclonal, Humanized ,Gastroenterology ,Article ,Myositis, Inclusion Body ,Double-Blind Method ,Internal medicine ,medicine ,Humans ,Immunologic Factors ,Smad3 Protein ,Phosphorylation ,Antibodies, Blocking ,Muscle, Skeletal ,Bimagrumab ,Right Thigh ,Aged ,Aged, 80 and over ,Antibodies, Monoclonal ,Activin receptor ,Neuromuscular Diseases ,Organ Size ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,Pathophysiology ,Endocrinology ,Treatment Outcome ,Thigh ,Lean body mass ,Exercise Test ,Female ,Neurology (clinical) ,Inclusion body myositis - Abstract
Objective: To study activin signaling and its blockade in sporadic inclusion body myositis (sIBM) through translational studies and a randomized controlled trial. Methods: We measured transforming growth factor β signaling by SMAD2/3 phosphorylation in muscle biopsies of 50 patients with neuromuscular disease (17 with sIBM). We tested inhibition of activin receptors IIA and IIB (ActRII) in 14 patients with sIBM using one dose of bimagrumab (n = 11) or placebo (n = 3). The primary outcome was the change in right thigh muscle volume by MRI at 8 weeks. Lean body mass, strength, and function were secondary outcomes. Twelve of the patients (10 bimagrumab, 2 placebo) participated in a subsequent 16-week observation phase. Results: Muscle SMAD2/3 phosphorylation was higher in sIBM than in other muscle diseases studied ( p = 0.003). Eight weeks after dosing, the bimagrumab-treated patients increased thigh muscle volume (right leg +6.5% compared with placebo, p = 0.024; left leg +7.6%, p = 0.009) and lean body mass (+5.7% compared with placebo, p = 0.014). Subsequently, bimagrumab-treated patients had improved 6-minute walking distance, which peaked at 16 weeks (+14.6%, p = 0.008) compared with placebo. There were no serious adverse events; the main adverse events with bimagrumab were mild acne and transient involuntary muscle contractions. Conclusions: Transforming growth factor β superfamily signaling, at least through ActRII, is implicated in the pathophysiology of sIBM. Inhibition of ActRII increased muscle mass and function in this pilot trial, offering a potential novel treatment of sIBM. Classification of evidence: This study provides Class I evidence that for patients with inclusion body myositis, bimagrumab increases thigh muscle volume at 8 weeks.
- Published
- 2014
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