Suitability of external controls for drug evaluation in Duchenne muscular dystrophy

OBJECTIVE: To evaluate the suitability of real-world data (RWD) and natural history data (NHD) for use as external controls in drug evaluations for ambulatory Duchenne muscular dystrophy (DMD). METHODS: The consistency of changes in the 6-minute walk distance (Δ6MWD) was assessed across multiple clinical trial placebo arms and sources of NHD/RWD. Six placebo arms reporting 48-week Δ6MWD were identified via literature review and represented 4 sets of inclusion/exclusion criteria (n = 383 patients in total). Five sources of RWD/NHD were contributed by Universitaire Ziekenhuizen Leuven, DMD Italian Group, The Cooperative International Neuromuscular Research Group, ImagingDMD, and the PRO-DMD-01 study (n = 430 patients, in total). Mean Δ6MWD was compared between each placebo arm and RWD/NHD source after subjecting the latter to the inclusion/exclusion criteria of the trial for baseline age, ambulatory function, and steroid use. Baseline covariate adjustment was investigated in a subset of patients with available data. RESULTS: Analyses included ∼1,200 patient-years of follow-up. Differences in mean Δ6MWD between trial placebo arms and RWD/NHD cohorts ranged from -19.4 m (i.e., better outcomes in RWD/NHD) to 19.5 m (i.e., worse outcomes in RWD/NHD) and were not statistically significant before or after covariate adjustment. CONCLUSIONS: We found that Δ6MWD was consistent between placebo arms and RWD/NHD subjected to equivalent inclusion/exclusion criteria. No evidence for systematic bias was detected. These findings are encouraging for the use of RWD/NHD to augment, or possibly replace, placebo controls in DMD trials. Multi-institution collaboration through the Collaborative Trajectory Analysis Project rendered this study feasible

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

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

NEUROMUSCULAR CASE STUDIES

In this unique book, Dr. Bertorini guides you through more than 100 cases that demonstrate the diagnosis and management of a wide range of common and rare neuromuscular disorders. No other reference boasts such a large array of clinical studies devoted to all areas of this broad topic! Each case study reviews the etiologies, pathogenesis, differential diagnosis, and management of a particular disorder, helping you not only recognize its presentation, but also determine a diagnosis and the best treatment plans for your patients. You₂ll also find expert guidance on the basic mechanisms of neuromuscular disorders, clinical examination, and diagnostic tests--including EMG, muscle biopsy, genetic testing, and more. More than 100 detailed case studies explore both common and rare neuromuscular disorders and the treatment protocols for each, equipping you with the knowledge you need to confidently manage any challenge. Each case includes a summary of important points or highlights of the study. Case studies are arranged either by complaint or by diagnosis so that you can successfully manage your patients with or without an initial diagnosis. Comprehensive coverage of EMGs and nerve conduction studies and other diagnostic tests, including muscle and nerve biopsies and genetic testing, helps you accurately diagnose nerve, muscle, and neuromuscular transmission disorders. Detailed discussions of treatment plans and commonly used drugs enhance your management of autoimmune disorders, painful neuropathy, dysautonomia, and other neuromuscular disorders. A reader-friendly format takes you step by step through the diagnosis and treatment of neuromuscular disorders, from the basic anatomy and physiology of the nerve and muscle through to clinical evaluation, diagnostic testing, and therapy. More than 350 high-quality illustrations, including full-color patient photographs, biopsies, and EMG tracings, make complex concepts easier to understand and apply.Includes bibliographical references and index.Chapter 1 Neuromuscular Anatomy and Function -- Chapter 2 Neurological Evaluation and Ancillary Tests -- Chapter 3 Therapy in Neuromuscular Diseases -- Case 1 Carpal Tunnel Syndrome in an Elderly Woman Likely from Rheumatoid Arthritis and the Use of a Walker -- Case 2 A Uremic Patient with a Shunt-Related Ischemic Monomelic Neuropathy Later Diagnosed with Carpal Tunnel Syndrome from Beta-2 Microglobulin Accumulation -- Case 3 A Diabetic with Peripheral Neuropathy and Carpal Tunnel Syndrome Who Later Developed Dysautonomia -- Case 4 Martin Gruber and Anastomosis and Carpal Tunnel Syndrome -- Case 5 Traumatic Median Neuropathy at the Elbow Mimicking Anterior Interossei Syndrome -- Case 6 Pronator Teres Syndrome -- Case 7 Ulnar Entrapment at the Elbow -- Case 8 Ulnar Neuropathy at the Wrist from a Ganglion Cyst -- Case 9 Focal Myositis Causing Radial Neuropathy -- Case 10 Musculoskeletal Neuropathy from Compression During Positioning for Back Surgery -- Case 11 Acute Brachial Neuritis -- Case 12 Lower Trunk Plexopathy and Horner's Syndrome from Lymphoma -- Case 13 Radiation Plexopathy -- Case 14 Suprascapular Neuropathy -- Case 15 C6 Radiculopathy with Motor Deficits from Herpes Zoster -- Case 16 C5 Radiculopathy from a Ruptured Disc -- Case 17 C7 Radiculopathy from a Herniated Disc -- Case 18 L4 Radiculopathy from a Disc Herniation and Peroneal Entrapment -- Case 19 S1 Radiculopathy -- Case 20 L5 Radiculopathy and an Accessory Peroneal Nerve -- Case 21 L2 Radiculopathy from Tumor Invasion -- Case 22 Demylinating Lumbosacral Radiculoneuropathy in a Diabetic -- Case 23 Cauda Equina Syndrome from Spinal Stenosis -- Case 24 Sciatic Neurofibroma Mimicking Tarsal Tunnel Syndrome -- Case 25 Femoral Neuropathy from a Hematoma from Angiography -- Case 26 Carcinomatous Lumbosacral Plexopathy -- Case 27 Meralgia Paresthetica -- Case 28 Lumbosacral Ependymoma Mimicking a Motor Neuron Disease -- Case 29 Acute Facial Neuropathy -- Case 30 Neurosarcoidosis Presenting with Bilateral Vi and Vii Nerve Palsies -- Case 31 A Patient with Als Presenting with Head Drop -- Case 32 Man in the Barrel Syndrome -- Case 33 Benign Focal Amyotrophy or Monomelic Amyotrophy -- Case 34 Post-Myelopathy Amyotrophy -- Case 35 Tethered Cord Syndrome Causing Muscle Pseudohypertrophy from Partial Denervation -- Case 36 Kennedy₂s Disease -- Case 37 Machado-Joseph Disease -- Case 38 Infantile Spinal Muscular Atrophy -- Case 39 Guillain Barř Syndrome with Central Demyelination -- Case 40 Acute Inflammatory Polyneuropathy in an HIV Positive Person -- Case 41 Miller Fisher Syndrome -- Case 42 Ciguatera Poisoning -- Case 43 Acute Quadriplegic Polyneuropathy from Porphyria -- Case 44 Critical Illness Myopathy -- Case 45 Pernicious Anemia Presenting with Hand Numbness in a Patient with Cervical Spondylosis -- Case 46 Pernicious Anemia Manifesting with Weakness and Abnormal Gait -- Case 47 Chronic Inflammatory Demyelinating Polyneuropathy -- Case 48 Chronic Inflammatory Demyelinating Polyneuropathy with Asymmetric Presentation in a Patient with a Monoclonal Gammopathy -- Case 49 Purely Motor Chronic Inflammatory Demyelinating Polyneuropathy -- Case 50 Subacute Inflammatory Demyelinating Polyneuropathy in a Diabetic -- Case 51 Demyelinating Neuropathy Associated with MAG Antibodies -- Case 52 Hereditary Demyelinating Polyneuropathy with Multiple Sclerosis -- Case 53 Inflammatory Polyneuropathy after Bariatric Surgery -- Case 54 Diabetic Amyotrophy -- Case 55 Diabetic Amyotrophy/Mononeuritis Multiplex in the Upper Extremities -- Case 56 Diabetic Muscle Infarct -- Case 57 Uremic Neuropathy -- Case 58 (A) Demyelinating Charcot-Marie-Tooth Disease (B) Axonal Charcot-Marie-Tooth Disease -- Case 59 Hereditary Polyneuropathy with Liability to Pressure Palsy Presenting with Bilateral Median Neuropathy after Snow Skiing -- Case 60 Hereditary Neuropathy with Liability to Pressure Palsy Presenting with a Footdrop -- Case 61 Mononeuritis Multiplex from Vasculitic Neuropathy -- Case 62 Vasculitic Neuropathy from Rheumatoid Arthritis -- Case 63 Wegener's Granulomatosis and Peripheral Neuropathy -- Case 64 Neurolymphomatosis Presenting with Mononeuritis Multiplex -- Case 65 Paraneoplastic Ganglioneuritis -- Case 66 Familial Amyloid Neuropathy -- Case 67 Amiodarone Neuropathy -- Case 68 Myasthenia Gravis Presenting with Difficulty Swallowing -- Case 69 Familial Myasthenia Gravis with Recurrence after Thymectomy -- Case 70 Eaton Lambert Myasthenic Syndrome Secondary to Small Cell Carcinoma of the Lung -- Case 71 Eaton Lambert Myasthenic Syndrome in a Patient with Hypothyroidism and Later Uterine Carcinoma -- Case 72 Slow Channel Congenital Myasthenic Syndrome -- Case 73 Hypokalemic Periodic Paralysis -- Case 73 Thyrotoxic Periodic Paralysis -- Case 74 Becker's Muscular Dystrophy Presenting with Large Muscles -- Case 75 A Manifest Carrier of Muscular Dystrophy -- Case 76 Distal Muscular Dystrophy from Dysferlin Deficiency -- Case 77 Oculopharyngeal Muscular Dystrophy -- Case 78 Facioscapulohumeral Muscular Dystrophy -- Case 79 Merosin Deficient Congenital Muscular Dystrophy -- Case 80 Central Core Disease Manifesting with Progressive Weakness in an Adult -- Case 81 Mitochondrial Disease Manifests as Progressive External Ophthalmoplegia Mimicking Myasthenia Gravis -- Case 82 Mitochondrial Myopathy with Prominent Neck Lipoma -- Case 83 Rhabdomyolysis in a Patient with Myophosphorylase Deficiency -- Case 84 Adult Onset Acid Maltase Deficiency -- Case 85 Myoglobinuria from a Viral Infection as the First Manifestation of Carnitine Palmitoyltransferase (Cpt) Deficiency in An Adult -- Case 86 Proximal Weakness from Beta-2 Microglobulin Accumulation in a Uremic Patient -- Case 87 Hypothyroid Myopathy -- Case 88 Hypoparathyroid Myopathy -- Case 89 Dermatomyositis in a Mother and Her Son -- Case 90 Polymyositis and Myoadenylate Deaminase Deficiency (Double Trouble?) -- Case 91 Inclusion Body Myositis -- Case 92 Inclusion Body Myositis in a Young HIV Positive Person -- Case 93 Eosinophilic Fascitis -- Case 94 Bent Spine Syndrome -- Case 95 A Case of Stiff Person Syndrome and Myasthenia Gravis -- Case 96 Cramp Fasciculation Syndrome from a Chronic, Predominantly Motor Neuronopathy -- Case 97 Myotonic Congenita -- Case 98 Schwartz-Jampel Syndrome -- Case 99 Tetany -- Case 100 Proximal Myotonic Myopathy -- Case 101 Acquired Rippling Muscle Disease.In this unique book, Dr. Bertorini guides you through more than 100 cases that demonstrate the diagnosis and management of a wide range of common and rare neuromuscular disorders. No other reference boasts such a large array of clinical studies devoted to all areas of this broad topic! Each case study reviews the etiologies, pathogenesis, differential diagnosis, and management of a particular disorder, helping you not only recognize its presentation, but also determine a diagnosis and the best treatment plans for your patients. You₂ll also find expert guidance on the basic mechanisms of neuromuscular disorders, clinical examination, and diagnostic tests--including EMG, muscle biopsy, genetic testing, and more. More than 100 detailed case studies explore both common and rare neuromuscular disorders and the treatment protocols for each, equipping you with the knowledge you need to confidently manage any challenge. Each case includes a summary of important points or highlights of the study. Case studies are arranged either by complaint or by diagnosis so that you can successfully manage your patients with or without an initial diagnosis. Comprehensive coverage of EMGs and nerve conduction studies and other diagnostic tests, including muscle and nerve biopsies and genetic testing, helps you accurately diagnose nerve, muscle, and neuromuscular transmission disorders. Detailed discussions of treatment plans and commonly used drugs enhance your management of autoimmune disorders, painful neuropathy, dysautonomia, and other neuromuscular disorders. A reader-friendly format takes you step by step through the diagnosis and treatment of neuromuscular disorders, from the basic anatomy and physiology of the nerve and muscle through to clinical evaluation, diagnostic testing, and therapy. More than 350 high-quality illustrations, including full-color patient photographs, biopsies, and EMG tracings, make complex concepts easier to understand and apply.Print version record.Elsevie

Progressive amyotrophy as a late complication of myelopathy

A delayed syndrome of progressive weakness has been described in survivors of paralytic poliomyelitis — ‘‘Post-Polio Muscular Atrophy (PPMA)’’. One proposed etiology is a drop-out of motor neurons due to increased metabolic demands of an enlarged motor unit territory. We report a patient with slowly progressive lower extremity weakness 20 years after recovery from an episode of myelopathy involving the lower lumbar and sacral segments of the spinal cord. Delayed progressive amyotrophy may complicate any significant injury to anterior horn cells

La Neuropatía Diabética. Consideraciones clínicas y Neuropatológicas

Fragmento La Diabetes Mellitus es una enfermedad muy común; así por ejemplo se considera que en los Estados Unidos existen 3 millones de personas que la sufren. Es conocida desde tiempos muy remotos ya que los Papiros de Ebers la mencionan 3.500 años antes de Cristo.

Selective paraspinal muscle amyotrophy

A 56-year-old female presented with mild low back pain. Examination revealed severe, selective atrophy of the thoracic and lumbar paraspinal muscles. Fibrillations were seen in the paraspinal muscles on EMG. Limb EMG was normal. Biopsy of the gluteus maximus was normal. Paraspinal muscle biopsy revealed neurogenic features. Atrophy of the thoracic and lumbar paraspinal muscles was noted on magnetic resonance imaging. This patient has selective amyotrophy of the thoracic and lumbar paraspinal muscles. This may be an addition to the spectrum of ‘benign focal amyotrophy’. The differential diagnosis of paraspinal muscle weakness is discussed.  2000 Elsevier Science B.V. All rights reserved

Dr. Aníbal Zambrano: un médico peruano con corazón de oro

The objective of the article is to describe and analyze the life trajectory and the humanitarian contributions of Dr. Zambrano, a physician who graduated from San Fernando Medical school, and was president of the Center for Medical Students at a politically critical time in public university education. He emigrated to the United States in 1970, in the context of sociopolitical crisis in Peru and the world, where he became a renowned internist and cardiologist at St. Luke’s Hospital. Despite the distance, he maintained a close relationship with Peru, organizing multiple medical missions for underserved populations, training medical personnel, and providing technological implementation to Cajamarca Regional Hospital. In 2011, the Educational Medical Center was inaugurated in Chincha, with Zambrano being one of the leaders for its construction. Despite suffering from a disabling illness, he dedicated until the last days of his life, providing help for those most in need. His life trajectory shows us an example of commitment to Peru and practice of Medicine committed to solidarity and the development of Medicine in his country of origin.El objetivo del artículo es describir y analizar la trayectoria de vida y las contribuciones humanitarias del Dr. Zambrano, médico egresado de la Escuela de Medicina de San Fernando, quién fue presidente del Centro de Estudiantes de Medicina en una época políticamente álgida en la educación universitaria pública. Emigró a los Estados Unidos en 1970, bajo el contexto de crisis sociopolítica económica en el Perú y en el mundo, donde se convirtió en un renombrado médico internista y cardiólogo del St. Luke’s Hospital. A pesar de su lejanía, mantuvo un lazo estrecho con el Perú organizando múltiples misiones médicas para el beneficio de poblaciones vulnerables, capacitación al personal médico e implementación tecnológica del Hospital Regional de Cajamarca. En 2011 se inauguró el Centro Médico Educativo en Chincha, siendo Zambrano uno de los líderes para su construcción. A pesar de padecer una enfermedad invalidante dedicó hasta los últimos días de su vida a brindar ayuda a los más necesitados. Su trayectoria de vida nos muestra un ejemplo de compromiso con el Perú y de un ejercicio de la medicina comprometida con la solidaridad y el desarrollo de la medicina en su país de origen

Dropped head presentation of mitochondrial myopathy

Dropped head secondary to weakness of the neck extensor has been reported in a wide assortment of neuromuscular disorders. Infrequently, dropped head can be the first sign of disease. We describe two patients with dropped head as the presenting manifestation of mitochondrial myopathy. In both patients, serum lactate was elevated and muscle biopsy showed mitochondrial proliferation. Mitochondrial myopathy should be considered in the differential diagnosis of dropped head syndrome, particularly when other, more common causes such as myasthenia gravis, polymyositis, and amyotrophic lateral sclerosis have been excluded by appropriate laboratory and electrophysiological studies. Copyright © 2003 by Lippincott Williams & Wilkins

Spinocerebellar degeneration and slow saccades in three generations of a kinship: clinical and electrophysiologic findings

Four members of a family with spinocerebellar degeneration and slow saccadic eye movements are described. Detailed electrophysiological studies revealed abnormalities of neurological pathways not apparent clinically. The patients had slow saccades as mesasured electrophysiologically, as well as absence of rapid eye movements (REM) despite REM stages of sleep. These studies suggest that although saccadic eye movement and REM are mediated through the pontine paramedian reticular formation, other characteristics of REM sleep are not necessarily mediated through the same neurons