Atlas of neuromuscular diseases : a practical guideline [Third ed.] 9783030634483, 3030634485

Table of contents :
Acknowledgments
Abbreviations
Contents
Contributors
1: Tools
1.1 New Developments in Neuromuscular Disease
1.2 The Patient with Neuromuscular Disease
1.3 History and General Physical Examination
1.4 Neuromuscular Clinical Phenomenology
1.4.1 Motor Function
1.4.2 Abnormal Muscle Movements
1.4.3 Reflex Testing
1.4.4 Muscle Tone
1.4.5 Sensory Symptoms
1.5 Sensory Qualities
1.5.1 Myalgia and Pain
1.5.2 Neuropathic Pain
1.5.3 Autonomic Function
1.5.4 Gait, Coordination
1.5.5 Clinical Pitfalls
1.6 NCV/EMG/Autonomic Testing and Miscellaneous Electrophysiology
1.6.1 Motor and Sensory NCV Studies
1.6.2 EMG
1.6.3 EMG Techniques
1.7 Laboratory Tests
1.7.1 Autoimmune Testing in Neuromuscular Transmission and Muscle Disorders
1.8 Genetic Testing (see Chap. 3)
1.9 Neuroimaging Techniques: MR and Ultrasound (see Chap. 2)
1.10 Tissue Diagnosis: Muscle/Nerve/Skin Biopsy
1.10.1 Nerve Biopsy
1.10.2 Muscle Biopsy
1.11 Neuromuscular Approaches to Quality of Life
Further Readings
2: Imaging
2.1 Introduction
2.2 Ultrasound
2.2.1 What Can be Seen with Ultrasound
2.2.2 Pathological Patterns Identified by Ultrasound
2.2.3 Ultrasound Equipment
2.2.4 Safety and Contraindications of the Use of Ultrasound
2.2.5 Problems with Ultrasound
2.2.6 Ultrasound in Daily Clinical Practice
2.3 Magnetic Resonance Imaging
2.3.1 Equipment
2.3.2 Safety and Contraindications
2.3.3 MR Neurography
2.3.4 MRI of Skeletal Muscle
2.3.5 The Strengths of MRI in Imaging Neuromuscular Diseases
2.3.6 The Weaknesses of MRI in Imaging Neuromuscular Diseases
2.4 Computed Tomography
2.4.1 Safety and Contraindications
2.5 X-Ray Imaging
References
3: Genetic Testing in Neuromuscular Diseases
3.1 Introduction
3.2 The Genetic Basis of Neuromuscular Diseases
3.3 Next-Generation Sequencing
3.3.1 Gene Panels
3.3.2 Exome Sequencing
3.3.3 Genome Sequencing
3.4 Interpretation of Genetic Testing Results
3.5 Diagnostic Reassessment and Periodic Data Reanalysis
3.6 Limitations of Genomic Testing
3.7 Secondary (Actionable) Findings
3.8 Conclusion and Future Perspectives
References
4: New Neuromuscular Therapies
4.1 Introduction
4.2 New Treatment Strategies
4.2.1 ASOs
4.2.2 Exon-Skipping ASOs
4.2.3 RNA Interference Therapy
4.2.4 Genome Editing
4.2.5 Gene Replacement Therapy
4.2.6 Enzyme Replacement Therapy
4.2.7 Protein Expression/Activity Modulation
4.2.8 Antioxidant Therapies
4.2.9 Targeted Biologic Immunotherapies
4.3 Looking Ahead
References
5: Principles of Peripheral Nerve Surgery
5.1 Defining the Problem
5.2 Timing of Nerve Repair
5.3 Restoration of Nerve Continuity
5.3.1 End-to-End Coaptation (Direct Nerve Repair)
5.3.2 Nerve Grafting
5.4 End-to-Side Coaptation
5.5 Nerve Transfer
5.6 Neurolysis
5.7 Conclusions
References
Further Readings
6: Principles of Nerve and Muscle Rehabilitation
6.1 Principles
6.2 Outcome Measurement
6.3 Rehabilitation Treatment
6.3.1 Exercise and Medical Training
6.3.2 Occupational Therapy and Splints
6.3.3 Orthotic Devices
6.3.4 Neural Plasticity
6.3.5 Surgery
6.3.6 Physical Interventions as a Part of Rehabilitation
6.3.7 Treatment Options for Autonomic Symptoms
6.4 Mononeuropathies
6.4.1 Median Neuropathy
6.4.2 Ulnar Neuropathy
6.4.3 Femoral Neuropathy
6.4.4 Peroneal Neuropathy
6.4.5 Tibial Neuropathy
6.4.6 Plexopathies
6.5 Polyneuropathies
6.6 Myopathies
References
Further Readings
7: Chronic Pain in Peripheral Neuropathy
7.1 Neuropathic Pain Mechanisms
7.2 Clinical Approach and Treatments to Neuropathic Pain
7.2.1 Diagnosis
7.2.2 Common Patterns of Peripheral Neuropathic Pain (Fig. 7.3)
7.2.3 Pharmacological Treatments Options
7.2.4 Opioids
7.2.5 Non-pharmacologic Treatments of Neuropathic Pain
Further Readings
8: Cranial Nerves
8.1 Introduction
8.2 Olfactory Nerve
8.3 Optic Nerve
8.4 Oculomotor Nerve
8.5 Trochlear Nerve
8.6 Trigeminal Nerve
8.7 Abducens Nerve
8.8 Facial Nerve
8.9 Acoustic Nerve
8.10 Vestibular Nerve
8.11 Glossopharyngeal Nerve
8.12 Vagus Nerve
8.13 Accessory Nerve
8.14 Hypoglossal Nerve
8.15 Oral Cavity
8.15.1 Ventral Part and Closure
8.15.2 Middle Part, Oral Cavity, and Tongue
8.15.3 Posterior Part, Gag, and Swallowing
8.16 CNs and Painful Conditions: A Checklist
8.17 CN Examination in Coma (Table 8.8)
8.18 Pupil
8.18.1 Anatomy and Conditions Associated with Pupillary Dysfunction
8.19 Multiple and Combined Oculomotor Nerve Palsies (Table 8.9)
Further Readings
9: Radiculopathies
9.1 Cervical Radicular Symptoms
9.2 Thoracic Radicular Nerves
9.3 Lumbar and Sacral Radiculopathy
9.4 Cauda Equina Syndrome
Further Readings
Thoracic
Lumbar
Cauda
10: Plexopathies
10.1 Introduction
10.2 Cervical Plexus and Cervical Spinal Nerves
10.2.1 Infectious
10.3 Brachial Plexus
10.4 Thoracic Outlet Syndromes (TOS)
10.4.1 True Neurogenic TOS
10.4.2 Arterial TOS
10.4.3 Venous TOS
10.4.4 Disputed Neurogenic TOS
10.4.5 Others
10.5 Lumbosacral Plexus
10.5.1 Diagnosis
Further Readings
11: Mononeuropathies
11.1 Introduction
11.2 Mononeuropathies: Upper Extremities
11.2.1 Axillary Nerve
11.2.2 Musculocutaneous Nerve
11.2.3 Cutaneous Nerves of the Shoulder and Upper Arm
11.2.4 Nerves around the Elbow
11.2.5 Median Nerve
11.2.6 Ulnar Nerve
11.2.7 Radial Nerve
11.2.8 Cutaneous Forearm Nerves
11.2.9 Digital Nerves of the Hand
11.3 Truncal Mononeuropathies
11.3.1 Phrenic Nerve
11.3.2 Dorsal Scapular Nerve
11.3.3 Suprascapular Nerve
11.3.4 Subscapular Nerve (Inferior Scapular Nerve)
11.3.5 Long Thoracic Nerve
11.3.6 Thoracodorsal Nerve
11.3.7 Innervation of the Shoulder
11.3.8 Pectoral Nerve
11.3.9 Thoracic Spinal Nerves
11.3.10 Intercostobrachial Nerve
11.3.11 Around the Breast
11.3.12 Abdominal Walls and their Innervation
11.3.13 Iliohypogastric Nerve
11.3.14 Ilioinguinal Nerve
11.3.15 Genitofemoral Nerve
11.3.16 Superior and Inferior Gluteal Nerves
11.3.17 Cluneal Nerves
11.3.18 Pudendal Nerve
11.4 Mononeuropathies: Lower Extremities
11.4.1 Obturator Nerve
11.4.2 Neurology and the Hip
11.4.3 Femoral Nerve
11.4.4 Saphenous Nerve
11.4.5 Lateral Femoral Cutaneous Nerve
11.4.6 Posterior Cutaneous Femoral Nerve
11.4.7 Sciatic Nerve
11.4.8 Around the Knee
11.4.9 Peroneal Nerve
11.4.10 Tibial Nerve (Posterior Tibial Nerve)
11.4.11 Posterior Tarsal Tunnel Syndrome
11.4.12 Anterior Tarsal Tunnel Syndrome
11.4.13 Sural Nerve
11.4.14 Nerves of the Foot
11.4.15 Interdigital Neuroma and “Neuritis” (Morton’s Neuroma)
11.5 Peripheral Nerve Tumors
References
Further Readings
Shoulder
Upper Extremities
Truncal Mononeuropathies
Lower Extremities
Peripheral Nerve Tumors
12: Polyneuropathies
12.1 Introduction
12.1.1 Anatomical Distribution
12.1.2 Clinical Syndromess
12.2 Metabolic Diseases
12.2.1 Diabetic Distal Symmetric Polyneuropathy
12.2.2 Diabetic Autonomic Neuropathy
12.2.3 Diabetic Cranial Mononeuropathy and Diabetic Radiculoplexus Neuropathy
12.2.4 Distal Symmetric Polyneuropathy of Renal Disease
12.3 Neuropathies Associated with Paraproteinemias
12.3.1 Multiple Myeloma Neuropathy
12.3.2 Monoclonal Gammopathy of Undetermined Significance (MGUS)
12.3.3 Demyelinating Neuropathy Associated with Anti-MAG Antibodies
12.3.4 Waldenström’s Macroglobulinemia
12.3.5 POEMS Syndrome
12.3.6 AL and TTR Amyloid Neuropathy
12.4 Vasculitides
12.4.1 Nonsystemic Vasculitic Neuropathy
12.4.2 Vasculitic Neuropathy, Systemic
12.4.3 Sjögren’s Neuropathy
12.5 Infectious Neuropathies
12.5.1 Human Immunodeficiency Virus-1 Neuropathy
12.5.2 Herpes Zoster Neuropathy
12.5.3 Lyme Disease (Neuroborreliosis)
12.5.4 Leprosy
12.6 Inflammatory Neuropathies
12.6.1 Guillain–Barré Syndrome (GBS) - Acute Inflammatory Demyelinating Polyneuropathy (AIDP) Subtype
12.6.2 GBS—Acute Motor Axonal Neuropathy (AMAN) Subtype
12.6.3 GBS—Acute Motor and Sensory Axonal Neuropathy (AMSAN) Subtype
12.6.4 GBS—Miller Fisher Syndrome Subtype
12.6.5 Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) [Typical]
12.6.6 Multifocal Motor Neuropathy (MMN)
12.6.7 Multifocal Asymmetric Demyelinating Acquired Sensorimotor Neuropathy (MADSAM)
12.7 Nutritional Neuropathies
12.7.1 Cobalamin Neuropathy
12.7.2 Post-Gastroplasty Neuropathy
12.7.3 Pyridoxine Neuropathy
12.7.4 Strachan’s Syndrome
12.7.5 Thiamine Neuropathy
12.7.6 Tocopherol Neuropathy
12.8 Drugs, Industrial Agents, and Metals
12.8.1 Alcohol Polyneuropathy
12.8.2 Other Drug-Induced Neuropathies
12.8.3 Toxic Neuropathies: Industrial Agents
12.8.4 Toxic Neuropathies: Metals
12.9 Critical Illness Neuropathy
12.10 Hereditary Neuropathies
12.10.1 Hereditary Motor and Sensory Neuropathies: Charcot–Marie–Tooth Disease
12.10.2 Hereditary Neuropathy with Liability to Pressure Palsy (HNPP)
12.10.3 Hereditary Neuralgic Amyotrophy
12.10.4 Hereditary Sensory Autonomic Neuropathies
12.10.5 Distal Hereditary Motor Neuropathies (d-HMN)
12.10.6 Porphyria
12.11 Cancer and Neuropathy
12.11.1 Paraneoplastic Neuropathies
12.11.2 Neuropathies in Lymphoma and Leukemia
12.11.3 Polyneuropathy and Chemotherapy
12.11.3.1 Platinum Compounds
12.11.3.2 Taxanes
12.11.3.3 Epothilones
12.11.3.4 Vinca Alkaloids
12.11.3.5 Proteasome Inhibitors
12.11.3.6 Thalidomide and Lenalidomide
12.11.3.7 Hybrid Therapies
12.12 Cryptogenic Sensory Peripheral Neuropathy
Further Readings
13: Neuromuscular Transmission: Endplate Disorders
13.1 Introduction
13.2 Myasthenia Gravis
13.3 Congenital Myasthenic Syndromes
13.4 Lambert–Eaton Myasthenic Syndrome (LEMS)
13.5 Botulism
13.6 Neuromyotonia (Isaacs’ Syndrome)
Further Readings
Myasthenia Gravis
Congenital Myasthenic Syndromes
Lambert-Eaton Myasthenic Syndrome (LEMS)
Botulism
Neuromyotonia (Isaacs’ Syndrome)
14: Muscle and Myotonic Diseases
14.1 Introduction
14.1.1 Electrophysiology
14.1.2 Muscle Histology and Immunohistochemistry
14.1.3 Molecular Genetics in Muscle Disease
14.1.4 Clinical Phenotypes of the Inherited Myopathies
14.1.5 Therapy for Neuromuscular Diseases
14.2 Polymyositis (PM) and Dermatomyositis
14.3 Inclusion Body Myositis (IBM)
14.4 Immune-Mediated Necrotizing Myopathy (IMNM)
14.5 Connective Tissue Diseases (CTDs) in “Overlap” Myositis (OM)
14.6 Viral Myopathies
14.7 Toxic Myopathies
14.8 Critical Illness Myopathy (CIM)
14.9 Myopathies Associated with Endocrine/Metabolic Disorders and Carcinoma
14.10 Duchenne Muscular Dystrophy (DMD)
14.11 Becker Muscular Dystrophy (BMD)
14.12 Myotonic Dystrophy (DM)
14.13 Limb-Girdle Muscular Dystrophy (LGMD)
14.14 Oculopharyngeal Muscular Dystrophy (OPMD)
14.15 Facioscapulohumeral Muscular Dystrophy (FSHD)
14.16 Emery–Dreifuss Muscular Dystrophy (EDMD)
14.17 Distal Myopathies
14.18 Congenital Myopathies
14.19 Mitochondrial Myopathies
14.20 Glycogen Storage Diseases (GSDs)
14.21 Defects of Fatty Acid Oxidation and the Carnitine Shuttle System (DFAOCSS)
14.22 Myotonia Congenita
14.23 Paramyotonia Congenita
14.24 Hyperkalemic Periodic Paralysis (HyperPP)
14.25 Hypokalemic Periodic Paralysis (HypoPP)
References
Duchenne Muscular Dystrophy
Myotonic Dystrophy (DM)
Limb-Girdle Muscular Dystrophy (LGMD)
Emery-Dreifuss Muscular Dystrophy (EDMD)
Distal Myopathies
Further Readings
Polymyositis (PM) and Dermatomyositis
Inclusion Body Myositis (IBM)
Immune-Mediated Necrotizing Myopathy (IMNM)
Connective Tissue Diseases (CTDs) in “Overlap” Myositis
Viral Myopathies
Duchenne Muscular Dystrophy
Becker Muscular Dystrophy
Myotonic Dystrophy (DM)
Limb-Girdle Muscular Dystrophy (LGMD)
Oculopharyngeal Muscular Dystrophy (OPMD)
Facioscapulohumeral Muscular Dystrophy (FSHD)
Congenital Myopathies
Mitochondrial Myopathies
Glycogen Storage Diseases
Defects of Fatty Acid Oxidation and the Carnitine Shuttle System
Toxic Myopathies
Critical Illness Myopathy
Myopathies Associated with Endocrine/Metabolic Disorders and Carcinoma
Myotonia Congenita and Paramyotonia Congenita
Hyperkalemic and Hypokalemic Periodic Paralysis
15: Motor Neuron Diseases
15.1 Amyotrophic Lateral Sclerosis (ALS)
15.2 Spinal and Bulbar Muscular Atrophy (SBMA, Kennedy Syndrome)
15.3 Spinal Muscular Atrophies (SMA)
15.4 Poliomyelitis and Post-Polio Syndrome (PPS)
Further Readings
Amyotrophic Lateral Sclerosis
Spinal and Bulbar Muscular Atrophy (SBMA, Kennedy Syndrome)
Spinal Muscular Atrophies (SMA)
Poliomyelitis and Post-Polio Syndrome (PPS)
16: Autonomic Neuropathies
16.1 Introduction
16.2 Anatomy
16.2.1 Common Autonomic CNS Structures
16.2.2 Sympathetic Nervous System
16.2.3 Parasympathetic Nervous System
16.2.4 Enteric Nervous System
16.3 History Taking and Bedside Tests
16.3.1 Autonomic Testing
16.3.2 Cardiovascular Reflex Tests
16.3.3 Sudomotor Tests
16.4 Autonomic Syndromes
16.4.1 Orthostatic Hypotension (OH)
16.4.2 Diabetic Autonomic Neuropathy
16.4.3 Supine Hypertension (SH)
16.4.4 Reflex Syncope
16.4.5 Postural Orthostatic Tachycardia Syndrome (POTS)
Reference
Further Readings
General Disease Finder
Index

Citation preview

Eva L. Feldman · James W. Russell  Wolfgang N. Löscher · Wolfgang Grisold  Stefan Meng

Atlas of Neuromuscular Diseases A Practical Guideline Third Edition

123

Atlas of Neuromuscular Diseases

Eva L. Feldman • James W. Russell Wolfgang N. Löscher • Wolfgang Grisold Stefan Meng

Atlas of Neuromuscular Diseases A Practical Guideline Third Edition

Eva L. Feldman Department of Neurology University of Michigan Ann Arbor, MI USA

James W. Russell Department of Neurology University of Maryland Baltimore Baltimore, MD USA

Wolfgang N. Löscher Department of Neurology Medical University Innsbruck Innsbruck, Tirol Austria

Wolfgang Grisold Ludwig Boltzmann Institute for Experimental und Clinical Traumatology Vienna Austria

Stefan Meng Department of Radiology and Center for Anatomy and Cell Biology Hanusch Hospital and Medical University of Vienna Vienna Austria

ISBN 978-3-030-63448-3    ISBN 978-3-030-63449-0 (eBook) https://doi.org/10.1007/978-3-030-63449-0 © Springer Nature Switzerland AG 2021 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

In memory of Veronika Grisold, a shining light in our lives whom we will always love and cherish. Her brilliance lives permanently in our hearts, and her radiance will never leave our souls.

Acknowledgments

We are very grateful for our colleagues who contributed chapters to previous editions of our book, including Drs. Thomas Cheng, Anne Louise Oaklander, Tatjana Paternostro-Sluga, Michael Quittan, Robert Schmidhammer, and Walter Struhal. There is a common saying, “the third time is a charm,” and that is how we feel about this new third edition of our book. We welcome back colleagues who again joined us in writing this third edition, two of whom are now editors, Drs. Wolfgang Löscher and Stefan Meng. As neuromuscular diseases develop rapidly, we have added chapters on genetics, imaging, and new therapies in addition to updating the previous chapters, including new advances in diagnosis and therapies. Our new collaborators have provided chapters and material that add extra dimensions to the book. Drs. Gregor Kasprian, Martin Krenn, and Hannes Platzgummer from the Medical University of Vienna, Drs. Lindsey Zilliox and Peter Jin from the University of Maryland, Drs. Brian Callaghan, Stacey (Sakowski) Jacoby, Masha Savelieff, and Amro Stino from the University of Michigan, and Dr. David Bennett from Oxford University not only enhanced the content of our book, but also enhanced the experience of writing the third edition. We hope that our readers will find this new edition useful, and that it will help in both clinical practice and to enhance the understanding of neuromuscular diseases. Mrs. Jeanette Schulz, who was responsible for art in previous editions, is unfortunately no longer with us. For this edition, we thank Ms. Carolin Holzhuber, who added new figures and introduced a modern art style. We wish to acknowledge our spouses, Dr. Neal Little, Dr. Maria Grisold, Monica Tschernitz, Katharina Meng, and Jane Russell, for their constant support and understanding. We tested the old adage that “patience is a virtue” for a third time with each of them. We also thank our children, who have become young adults between our first edition in 2005 and today: Drs. Laurel and John Roberts and Scott Roberts JD (Eva Feldman); Drs. Anna and Simon Grisold and Thomas Grisold (Wolfgang Grisold); Maja and Leo Meng (Stefan Meng); and Kelly Ann, Richard, and Catherine Russell (James Russell). They all grew up in the world of neurology and lent enthusiasm and encouragement to our careers. Mentors and colleagues have been influential in our lives and this book. We acknowledge the late Drs. P.K. Thomas (London, UK) and Jack Griffin (Baltimore, USA) for their enduring influences in our careers. We thank Dr. James Albers, former Director of Neuromuscular Disease, and all current members of this Division, from the University of Michigan and the University of Maryland; and the members of the Neuromuscular Division of the Kaiser Franz Josef Hospital in Vienna, especially Dr. Elisabeth Lindeck Pozza and the late Dr. Peter Hitzenberger. We would like to thank Dr. Stacey (Sakowski) Jacoby for her expert editorial assistance and attention to detail. We deeply appreciate the endless hours she spent ensuring every word, every figure, and every figure legend are error-free.

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Finally, we each care for patients, who inspire us, and work with trainees, who challenge us. This book is our way of thanking them for all they do and have done for us. We are forever grateful. Eva L. Feldman, MD, PhD Wolfgang Grisold, MD Wolfgang Löscher, MD Stefan Meng, MD James Russell, MD

Acknowledgments

Abbreviations

AAN American Academy of Neurology AASN Acute autonomic and sensory neuropathy AAV Adeno-associated virus Ab Antibody ABER Abduction and external rotation ACE Angiotensin-converting enzyme Ach Acetylcholine AchR Acetylcholine receptor ACMG American College of Medical Genetics and Genomics ACNES Anterior cutaneous nerve entrapment syndrome AD Autosomal dominant ADL Activities of daily living AHRQ Agency for Healthcare Research and Quality AIDP Acute inflammatory demyelinating polyneuropathy AIDS Acquired immunodeficiency syndrome AL Acquired light chain ALIF Anterior lumbar interbody fusion ALS Amyotrophic lateral sclerosis AMAN Acute motor axonal neuropathy AMSAN Acute motor and sensory axonal neuropathy ANA Antinuclear antibody ANS Autonomic nervous system APP Acute paralytic poliomyelitis AR Autosomal recessive ASO Antisense oligonucleotide AV Arteriovenous AZT Azidothymidine BMD Becker muscular dystrophy BOLD Blood-Oxygen-Level Dependent imaging BVAS Birmingham Vasculitis Activity Scale BUN Blood urea nitrogen CADD Combined Annotation Dependent Depletion c-ANCA Cytoplasmic antineutrophil cytoplasmic antibody CAR Cancer-associated retinopathy CATD Carnitine acylcarnitine translocase deficiency CCD Central core disease CDC Centers for Disease Control and Prevention CFD Congenital fiber-type disproportion CIDP Chronic inflammatory demyelinating polyneuropathy CIM Critical illness myopathy CINM Critical illness neuromyopathy CIP Critical illness polyneuropathy ix

x

CIPN Chemotherapy-induced peripheral neuropathy CISP Chronic inflammatory sensory polyradiculoneuropathy CISS Constructive interference in steady state CK Creatine kinase CMAP Compound muscle action potential CMFA Continuous muscle fiber activity CMS Congenital myasthenic syndromes CMT Charcot–Marie–Tooth CMV Cytomegalovirus CN Cranial nerve CN1A Cytosolic 5’-nucleotidase 1A CNM Centronuclear myopathy CNS Central nervous system CNV Copy number variation CoQ10 Coenzyme Q10 CPEO Chronic progressive external opthalmoplegia CPT2 Carnitine palmitoyltransferase 2 deficiency CRD Complex repetitive discharge CRISPR Clustered regularly interspaced short palindromic repeats CRP C-reactive protein CRPS Complex regional pain syndrome CSF Cerebrospinal fluid CSPN Cryptogenic sensory polyneuropathy CSS Carotid sinus syncope CT Computed tomography CTD Connective tissue disease CTS Carpal tunnel syndrome D Dominant DADS Distal acquired demyelinating sensorimotor DAN Diabetic autonomic neuropathy DBM Distal desmin body myofibrillar myopathy DFAOCSS Defects of fatty acid oxidation and the carnitine shuttle system dHMN Distal hereditary motor neuropathy DLRPN Diabetic lumbosacral radiculoplexus neuropathy DM Myotonic dystrophy DMD Duchenne muscular dystrophy DMPK Dystrophia myotonica protein kinase DPN Diabetic distal symmetric polyneuropathy DRG Dorsal root ganglia DRPN Diabetic radiculoplexus neuropathy dsDNA Double-stranded DNA DSP Distal symmetric polyneuropathy DTI Diffusion tensor imaging EBV Epstein–Barr virus EDMD Emery–Dreifuss muscular dystrophy EDX Electrodiagnostic medicine EFNS European Federation of Neurological Societies EFSUMB European Federation of Societies for Ultrasound in Medicine and Biology EGPA Eosinophilic granulomatosis with polyangiitis ELISA Enzyme-linked immunosorbent assays EMG Electromyogram ENA Extractable nuclear antigen ENT Ear, nose, and throat

Abbreviations

Abbreviations

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ERT Enzyme replacement therapy esASO Exon-skipping antisense oligonucleotide ESR Erythrocyte sedimentation rate ETF Electron transfer flavoprotein ETFDH Electron transfer flavoprotein dehydrogenase EU European Union fALS Familial amyotrophic lateral sclerosis FAO Fatty acid oxidation FAP Familial amyloid polyneuropathy FDA Food and Drug Administration FISH Fluorescent in situ hybridization FOSMN Facial onset sensory and motor neuropathy FSHD Facioscapulohumeral dystrophy FTD Frontotemporal dementia FUS Fused in sarcoma G6Pase Glucose-6-phosphatase G6PT Glucose-6-phosphate transporter GBS Guillain–Barré syndrome GI Gastrointestinal GM1 Gangliosidosis-1 GPA Granulomatous polyangiitis GSD Glycogen storage disease H&E Hematoxylin and eosin HbA1c Hemoglobin A1c HDL High-density lipoprotein HGMD Human Gene Mutation Database HIV Human immunodeficiency virus HLA Human leukocyte antigen HMGCR Hydroxy-3-methylglutaryl-CoA reductase HMSN Hereditary motor and sensory neuropathy HNA Hereditary neuralgic amyotrophy HNPP Hereditary neuropathy with liability to pressure palsy HR Homologous recombination HSAN Hereditary sensory and autonomic neuropathy HSP Hereditary spastic paraplegia HTLV Human T-cell lymphotropic virus HyperPP Hyperkalemic periodic paralysis HypoPP Hypokalemic periodic paralysis IASP International Association for the Study of Pain IBM Inclusion body myositis ICF International Classification of Functioning, Disability, and Health ICI Immune checkpoint inhibitors ICP Intracranial pressure ICU Intensive care unit IENF Intraepidermal nerve fiber IHC Immunohistochemistry IL Interleukin IM Intramuscular IMNM Immune-mediated necrotizing myopathy IU International units IV Intravenous IVIG Intravenous immunoglobulin KSS Kearns–Sayre Syndrome

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LACD Long-chain acyl-CoA dehydrogenase LDM Laing distal myopathy LEMS Lambert–Eaton myasthenic syndrome LGMD Limb-girdle muscular dystrophy LHON Leber’s hereditary optic neuropathy LIF Lumbar interbody fusion LLIF Lateral lumbar interbody fusion LMN Lower motor neuron LMNA Lamin A/C LRP4 Low-density lipoprotein receptor-related protein 4 LSM Lipid storage myopathy LUMA Transmembrane protein 43 MAD Multiple acyl-CoA dehydrogenation deficiency MADSAM Multifocal asymmetric demyelinating sensorimotor acquired polyneuropathy MAG Myelin-associated glycoprotein MCAD Medium-chain acyl-CoA dehydrogenase MCD Multi or minicore disease MCDT Mixed connective tissue disorder MDM Markesbery (type II) distal myopathy MELAS Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke-like episodes MEP Maximal expiratory pressure MERRF Myoclonic epilepsy with ragged-red fibers MG Myasthenia gravis MGFA Myasthenia Gravis Foundation of America MGUS Monoclonal gammopathy of undetermined significance MHC Major histocompatibility complex MIDM Miyoshi distal myopathy MLF Medial longitudinal fasciculus MMF Mycophenolate mofetil MMN Multifocal motor neuropathy MPA Microscopic polyangiitis MPNST Malignant peripheral nerve sheath tumor MR Magnetic resonance MRC Medical Research Council MRI Magnetic resonance imaging MS Multiple sclerosis mtDNA Mitochondrial DNA MTX Methotrexate MU Motor unit MUAP Motor unit action potentials MuSK Muscle-specific kinase NCS Nerve conduction studies NCV Nerve conduction velocity NDM Nonaka distal myopathy NF1, NF2 Neurofibromatosis 1 or 2 NGS Next-generation sequencing NHEJ Non-homologous end junction NLSDI Neutral lipid storage disease with ichthyosis NLSDM Neutral lipid storage disease with myopathy NM Nemaline myopathy NMJ Neuromuscular junction NMT Neuromuscular transmission NNT Number needed to treat

Abbreviations

Abbreviations

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nOH Neurogenic orthostatic hypotension NSAID Nonsteroidal anti-inflammatory drug NSVN Non-systemic vasculitic neuropathy OH Orthostatic hypotension OLIF/ATP Oblique lumbar interbody fusion/anterior to psoas OM Overlap myositis OPMD Oculopharyngeal muscular dystrophy PAN Polyarteritis nodosa p-ANCA Perinuclear anti-neutrophil cytoplasmic antibody PCD Primary systemic carnitine deficiency: carnitine transporter defect PCR Polymerase chain reaction PEG Percutaneous endoscopic gastrostomy PET Positron emission tomography PHN Postherpetic neuralgia PLIF Posterior lumbar interbody fusion PM Polymyositis PMM Primary mitochondrial myopathy PMS Postmastectomy syndrome PNS Peripheral nervous system PO By mouth POEMS Polyneuropathy, Organomegaly, Endocrinopathy, M-spike protein, Skin changes POTS Postural orthostatic tachycardia syndrome PPARα Peroxisome proliferator-activated receptor α PPS Post-polio syndrome Q Daily; once daily QHS Once nightly QLQ-CIPN 20 Quality-of-life questionnaire for chemotherapy-induced peripheral neuropathy QOD Every other day QSART Quantitative sudomotor axon reflex test QST Quantitative sensory testing R Recessive RA Rheumatoid arthritis RAN Repeat-associated non-AUG RF Rheumatoid factor RFS Radiation fibrosis syndrome RISC RNA-Induced silencing complex RNAi RNA Interference RNS Repetitive nerve stimulation ROM Range of motion RT Radiation therapy RyR Ryanodine receptor sALS Sporadic amyotropic lateral sclerosis SBMA Spinal and bulbar muscular atrophy SCLC Small cell lung cancer SCN4A Skeletal muscle sodium channel SDH Succinate dehydrogenase SEP Somatosensory evoked potential SFEMG Single fiber electromyography sgRNA Single guide RNA SH Supine hypertension siRNA Small interfering RNA

xiv

SLE Systemic lupus erythematosus SMA Spinal muscular atrophy SNAP Sensory nerve action potential SNR Signal-to-noise ratio SNRI Serotonin reuptake inhibitor SOD1 Cu2+/Zn2+ superoxide dismutase SOF Superior orbital fissure SRP Signal recognition particle SSA Anti-Sjögrens syndrome antigen A antibody SSB Anti-Sjögrens syndrome type B antibody SSc Systemic sclerosis SSRT Sympathetic skin response test STIR Short tau inversion recovery SVN Systemic vasculitic neuropathy TALE Transcription activator-like effector TALEN Transcription activator-like effector nuclease TARDBP Gene for TAR DNA-binding protein of 43 kDa TCA Tricyclic antidepressant TCS Tethered cord syndrome TDP-43 TAR DNA-binding protein of 43 kDa TENS Transcutaneous electrical nerve stimulation TFP Trifunctional protein TID Three times daily TIND Treatment-induced neuropathy of diabetes TK2d Thymidine kinase 2 deficiency TLIF Transforaminal lumbar interbody fusion TLOC Transient loss of consciousness TOS Thoracic outlet syndrome TPMT Thiopurine methyltransferase TRI Transient radicular irradiation TTR Transthyretin TTS Tarsal tunnel syndrome UMN Upper motor neuron US Ultrasound USA The United States of America VEGF Vascular endothelial growth factor VGCC Voltage-gated calcium channel VGKC Voltage-gated potassium channel VGSC Voltage-gated sodium channel VLACD Very long-chain acyl-CoA dehydrogenase deficiency VUS Variants of uncertain significance WDM Welander (type I) distal myopathy WHO World Health Organization ZF Zinc finger ZFN Zinc finger nuclease

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1 Tools�����������������������������������������������������������������������������������������������������������������������������   1 1.1 New Developments in Neuromuscular Disease���������������������������������������������������   1 1.2 The Patient with Neuromuscular Disease �����������������������������������������������������������   3 1.3 History and General Physical Examination���������������������������������������������������������   4 1.4 Neuromuscular Clinical Phenomenology �����������������������������������������������������������   4 1.4.1 Motor Function ���������������������������������������������������������������������������������������   4 1.4.2 Abnormal Muscle Movements�����������������������������������������������������������������   6 1.4.3 Reflex Testing �����������������������������������������������������������������������������������������   8 1.4.4 Muscle Tone���������������������������������������������������������������������������������������������   8 1.4.5 Sensory Symptoms ���������������������������������������������������������������������������������   8 1.5 Sensory Qualities�������������������������������������������������������������������������������������������������  10 1.5.1 Myalgia and Pain�������������������������������������������������������������������������������������  10 1.5.2 Neuropathic Pain�������������������������������������������������������������������������������������  11 1.5.3 Autonomic Function �������������������������������������������������������������������������������  11 1.5.4 Gait, Coordination�����������������������������������������������������������������������������������  11 1.5.5 Clinical Pitfalls����������������������������������������������������������������������������������������  11 1.6 NCV/EMG/Autonomic Testing and Miscellaneous Electrophysiology �������������  11 1.6.1 Motor and Sensory NCV Studies�������������������������������������������������������������  11 1.6.2 EMG���������������������������������������������������������������������������������������������������������  13 1.6.3 EMG Techniques�������������������������������������������������������������������������������������  14 1.7 Laboratory Tests���������������������������������������������������������������������������������������������������  14 1.7.1 Autoimmune Testing in Neuromuscular Transmission and Muscle Disorders �������������������������������������������������������������������������������������������������  15 1.8 Genetic Testing (see Chap. 3) �����������������������������������������������������������������������������  16 1.9 Neuroimaging Techniques: MR and Ultrasound (see Chap. 2)���������������������������  16 1.10 Tissue Diagnosis: Muscle/Nerve/Skin Biopsy�����������������������������������������������������  16 1.10.1 Nerve Biopsy�������������������������������������������������������������������������������������������  16 1.10.2 Muscle Biopsy�����������������������������������������������������������������������������������������  16 1.11 Neuromuscular Approaches to Quality of Life���������������������������������������������������  17 Further Readings�����������������������������������������������������������������������������������������������������������  17 2 Imaging �����������������������������������������������������������������������������������������������������������������������  19 2.1 Introduction���������������������������������������������������������������������������������������������������������  19 2.2 Ultrasound�����������������������������������������������������������������������������������������������������������  19 2.2.1 What Can be Seen with Ultrasound���������������������������������������������������������  19 2.2.2 Pathological Patterns Identified by Ultrasound���������������������������������������  19 2.2.3 Ultrasound Equipment�����������������������������������������������������������������������������  21 2.2.4 Safety and Contraindications of the Use of Ultrasound��������������������������  21 2.2.5 Problems with Ultrasound�����������������������������������������������������������������������  22 2.2.6 Ultrasound in Daily Clinical Practice �����������������������������������������������������  22 2.3 Magnetic Resonance Imaging�����������������������������������������������������������������������������  22 2.3.1 Equipment �����������������������������������������������������������������������������������������������  22 xv

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2.3.2 Safety and Contraindications�������������������������������������������������������������������  23 2.3.3 MR Neurography�������������������������������������������������������������������������������������  23 2.3.4 MRI of Skeletal Muscle���������������������������������������������������������������������������  25 2.3.5 The Strengths of MRI in Imaging Neuromuscular Diseases�������������������  25 2.3.6 The Weaknesses of MRI in Imaging Neuromuscular Diseases���������������  25 2.4 Computed Tomography���������������������������������������������������������������������������������������  25 2.4.1 Safety and Contraindications�������������������������������������������������������������������  25 2.5 X-Ray Imaging�����������������������������������������������������������������������������������������������������  25 References���������������������������������������������������������������������������������������������������������������������  25 3 Genetic Testing in Neuromuscular Diseases�������������������������������������������������������������  27 3.1 Introduction���������������������������������������������������������������������������������������������������������  27 3.2 The Genetic Basis of Neuromuscular Diseases���������������������������������������������������  27 3.3 Next-Generation Sequencing�������������������������������������������������������������������������������  28 3.3.1 Gene Panels���������������������������������������������������������������������������������������������  28 3.3.2 Exome Sequencing����������������������������������������������������������������������������������  30 3.3.3 Genome Sequencing �������������������������������������������������������������������������������  30 3.4 Interpretation of Genetic Testing Results�������������������������������������������������������������  31 3.5 Diagnostic Reassessment and Periodic Data Reanalysis�������������������������������������  32 3.6 Limitations of Genomic Testing �������������������������������������������������������������������������  32 3.7 Secondary (Actionable) Findings �����������������������������������������������������������������������  32 3.8 Conclusion and Future Perspectives �������������������������������������������������������������������  32 References���������������������������������������������������������������������������������������������������������������������  33 4 New Neuromuscular Therapies���������������������������������������������������������������������������������  35 4.1 Introduction���������������������������������������������������������������������������������������������������������  35 4.2 New Treatment Strategies �����������������������������������������������������������������������������������  35 4.2.1 ASOs �������������������������������������������������������������������������������������������������������  35 4.2.2 Exon-Skipping ASOs�������������������������������������������������������������������������������  36 4.2.3 RNA Interference Therapy�����������������������������������������������������������������������  38 4.2.4 Genome Editing���������������������������������������������������������������������������������������  39 4.2.5 Gene Replacement Therapy���������������������������������������������������������������������  41 4.2.6 Enzyme Replacement Therapy ���������������������������������������������������������������  42 4.2.7 Protein Expression/Activity Modulation�������������������������������������������������  42 4.2.8 Antioxidant Therapies�����������������������������������������������������������������������������  42 4.2.9 Targeted Biologic Immunotherapies�������������������������������������������������������  43 4.3 Looking Ahead�����������������������������������������������������������������������������������������������������  43 References���������������������������������������������������������������������������������������������������������������������  43 5 Principles of Peripheral Nerve Surgery �������������������������������������������������������������������  45 5.1 Defining the Problem�������������������������������������������������������������������������������������������  45 5.2 Timing of Nerve Repair���������������������������������������������������������������������������������������  45 5.3 Restoration of Nerve Continuity�������������������������������������������������������������������������  45 5.3.1 End-to-End Coaptation (Direct Nerve Repair) ���������������������������������������  45 5.3.2 Nerve Grafting�����������������������������������������������������������������������������������������  47 5.4 End-to-Side Coaptation���������������������������������������������������������������������������������������  48 5.5 Nerve Transfer�����������������������������������������������������������������������������������������������������  49 5.6 Neurolysis �����������������������������������������������������������������������������������������������������������  49 5.7 Conclusions���������������������������������������������������������������������������������������������������������  51 References���������������������������������������������������������������������������������������������������������������������  51 6 Principles of Nerve and Muscle Rehabilitation�������������������������������������������������������  53 6.1 Principles�������������������������������������������������������������������������������������������������������������  53 6.2 Outcome Measurement ���������������������������������������������������������������������������������������  53 6.3 Rehabilitation Treatment�������������������������������������������������������������������������������������  55

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6.3.1 Exercise and Medical Training ���������������������������������������������������������������  55 6.3.2 Occupational Therapy and Splints�����������������������������������������������������������  56 6.3.3 Orthotic Devices �������������������������������������������������������������������������������������  56 6.3.4 Neural Plasticity���������������������������������������������������������������������������������������  56 6.3.5 Surgery�����������������������������������������������������������������������������������������������������  57 6.3.6 Physical Interventions as a Part of Rehabilitation�����������������������������������  57 6.3.7 Treatment Options for Autonomic Symptoms�����������������������������������������  58 6.4 Mononeuropathies�����������������������������������������������������������������������������������������������  58 6.4.1 Median Neuropathy���������������������������������������������������������������������������������  58 6.4.2 Ulnar Neuropathy������������������������������������������������������������������������������������  58 6.4.3 Femoral Neuropathy �������������������������������������������������������������������������������  59 6.4.4 Peroneal Neuropathy�������������������������������������������������������������������������������  59 6.4.5 Tibial Neuropathy �����������������������������������������������������������������������������������  59 6.4.6 Plexopathies���������������������������������������������������������������������������������������������  59 6.5 Polyneuropathies�������������������������������������������������������������������������������������������������  59 6.6 Myopathies�����������������������������������������������������������������������������������������������������������  60 References���������������������������������������������������������������������������������������������������������������������  60 7 Chronic Pain in Peripheral Neuropathy�������������������������������������������������������������������  63 7.1 Neuropathic Pain Mechanisms ���������������������������������������������������������������������������  63 7.2 Clinical Approach and Treatments to Neuropathic Pain�������������������������������������  64 7.2.1 Diagnosis�������������������������������������������������������������������������������������������������  64 7.2.2 Common Patterns of Peripheral Neuropathic Pain (Fig. 7.3) �����������������  64 7.2.3 Pharmacological Treatments Options �����������������������������������������������������  66 7.2.4 Opioids�����������������������������������������������������������������������������������������������������  66 7.2.5 Non-pharmacologic Treatments of Neuropathic Pain�����������������������������  66 Further Readings�����������������������������������������������������������������������������������������������������������  67 8 Cranial Nerves�������������������������������������������������������������������������������������������������������������  69 8.1 Introduction���������������������������������������������������������������������������������������������������������  69 8.2 Olfactory Nerve���������������������������������������������������������������������������������������������������  69 8.3 Optic Nerve ���������������������������������������������������������������������������������������������������������  70 8.4 Oculomotor Nerve�����������������������������������������������������������������������������������������������  72 8.5 Trochlear Nerve���������������������������������������������������������������������������������������������������  74 8.6 Trigeminal Nerve�������������������������������������������������������������������������������������������������  75 8.7 Abducens Nerve���������������������������������������������������������������������������������������������������  80 8.8 Facial Nerve���������������������������������������������������������������������������������������������������������  83 8.9 Acoustic Nerve�����������������������������������������������������������������������������������������������������  87 8.10 Vestibular Nerve���������������������������������������������������������������������������������������������������  88 8.11 Glossopharyngeal Nerve �������������������������������������������������������������������������������������  89 8.12 Vagus Nerve���������������������������������������������������������������������������������������������������������  90 8.13 Accessory Nerve �������������������������������������������������������������������������������������������������  92 8.14 Hypoglossal Nerve�����������������������������������������������������������������������������������������������  93 8.15 Oral Cavity�����������������������������������������������������������������������������������������������������������  96 8.15.1 Ventral Part and Closure �������������������������������������������������������������������������  96 8.15.2 Middle Part, Oral Cavity, and Tongue�����������������������������������������������������  96 8.15.3 Posterior Part, Gag, and Swallowing�������������������������������������������������������  96 8.16 CNs and Painful Conditions: A Checklist�����������������������������������������������������������  96 8.17 CN Examination in Coma (Table 8.8)�����������������������������������������������������������������  97 8.18 Pupil���������������������������������������������������������������������������������������������������������������������  98 8.18.1 Anatomy and Conditions Associated with Pupillary Dysfunction ���������  98 8.19 Multiple and Combined Oculomotor Nerve Palsies (Table 8.9)�������������������������  98 Further Readings����������������������������������������������������������������������������������������������������������� 100

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9 Radiculopathies����������������������������������������������������������������������������������������������������������� 103 9.1 Cervical Radicular Symptoms����������������������������������������������������������������������������� 103 9.2 Thoracic Radicular Nerves���������������������������������������������������������������������������������� 106 9.3 Lumbar and Sacral Radiculopathy����������������������������������������������������������������������� 109 9.4 Cauda Equina Syndrome������������������������������������������������������������������������������������� 114 Further Readings����������������������������������������������������������������������������������������������������������� 116 10 Plexopathies����������������������������������������������������������������������������������������������������������������� 119 10.1 Introduction������������������������������������������������������������������������������������������������������� 119 10.2 Cervical Plexus and Cervical Spinal Nerves����������������������������������������������������� 119 10.2.1 Infectious����������������������������������������������������������������������������������������������� 120 10.3 Brachial Plexus ������������������������������������������������������������������������������������������������� 120 10.4 Thoracic Outlet Syndromes (TOS) ������������������������������������������������������������������� 130 10.4.1 True Neurogenic TOS ��������������������������������������������������������������������������� 130 10.4.2 Arterial TOS������������������������������������������������������������������������������������������� 131 10.4.3 Venous TOS������������������������������������������������������������������������������������������� 131 10.4.4 Disputed Neurogenic TOS��������������������������������������������������������������������� 131 10.4.5 Others����������������������������������������������������������������������������������������������������� 131 10.5 Lumbosacral Plexus������������������������������������������������������������������������������������������� 132 10.5.1 Diagnosis����������������������������������������������������������������������������������������������� 136 Further Readings����������������������������������������������������������������������������������������������������������� 136 11 Mononeuropathies ����������������������������������������������������������������������������������������������������� 139 11.1 Introduction������������������������������������������������������������������������������������������������������� 139 11.2 Mononeuropathies: Upper Extremities ������������������������������������������������������������� 139 11.2.1 Axillary Nerve��������������������������������������������������������������������������������������� 139 11.2.2 Musculocutaneous Nerve����������������������������������������������������������������������� 143 11.2.3 Cutaneous Nerves of the Shoulder and Upper Arm������������������������������� 144 11.2.4 Nerves around the Elbow����������������������������������������������������������������������� 145 11.2.5 Median Nerve����������������������������������������������������������������������������������������� 145 11.2.6 Ulnar Nerve������������������������������������������������������������������������������������������� 153 11.2.7 Radial Nerve ����������������������������������������������������������������������������������������� 158 11.2.8 Cutaneous Forearm Nerves������������������������������������������������������������������� 162 11.2.9 Digital Nerves of the Hand ������������������������������������������������������������������� 162 11.3 Truncal Mononeuropathies ������������������������������������������������������������������������������� 163 11.3.1 Phrenic Nerve����������������������������������������������������������������������������������������� 163 11.3.2 Dorsal Scapular Nerve��������������������������������������������������������������������������� 165 11.3.3 Suprascapular Nerve ����������������������������������������������������������������������������� 165 11.3.4 Subscapular Nerve (Inferior Scapular Nerve)��������������������������������������� 166 11.3.5 Long Thoracic Nerve����������������������������������������������������������������������������� 167 11.3.6 Thoracodorsal Nerve����������������������������������������������������������������������������� 169 11.3.7 Innervation of the Shoulder������������������������������������������������������������������� 170 11.3.8 Pectoral Nerve��������������������������������������������������������������������������������������� 173 11.3.9 Thoracic Spinal Nerves������������������������������������������������������������������������� 174 11.3.10 Intercostobrachial Nerve����������������������������������������������������������������������� 175 11.3.11 Around the Breast ��������������������������������������������������������������������������������� 175 11.3.12 Abdominal Walls and their Innervation������������������������������������������������� 176 11.3.13 Iliohypogastric Nerve����������������������������������������������������������������������������� 178 11.3.14 Ilioinguinal Nerve ��������������������������������������������������������������������������������� 179 11.3.15 Genitofemoral Nerve����������������������������������������������������������������������������� 180 11.3.16 Superior and Inferior Gluteal Nerves����������������������������������������������������� 181 11.3.17 Cluneal Nerves��������������������������������������������������������������������������������������� 181 11.3.18 Pudendal Nerve������������������������������������������������������������������������������������� 182

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11.4 Mononeuropathies: Lower Extremities������������������������������������������������������������� 184 11.4.1 Obturator Nerve������������������������������������������������������������������������������������� 184 11.4.2 Neurology and the Hip��������������������������������������������������������������������������� 185 11.4.3 Femoral Nerve��������������������������������������������������������������������������������������� 186 11.4.4 Saphenous Nerve����������������������������������������������������������������������������������� 188 11.4.5 Lateral Femoral Cutaneous Nerve��������������������������������������������������������� 188 11.4.6 Posterior Cutaneous Femoral Nerve ����������������������������������������������������� 189 11.4.7 Sciatic Nerve����������������������������������������������������������������������������������������� 189 11.4.8 Around the Knee ����������������������������������������������������������������������������������� 194 11.4.9 Peroneal Nerve��������������������������������������������������������������������������������������� 195 11.4.10 Tibial Nerve (Posterior Tibial Nerve) ��������������������������������������������������� 197 11.4.11 Posterior Tarsal Tunnel Syndrome��������������������������������������������������������� 200 11.4.12 Anterior Tarsal Tunnel Syndrome��������������������������������������������������������� 202 11.4.13 Sural Nerve ������������������������������������������������������������������������������������������� 202 11.4.14 Nerves of the Foot��������������������������������������������������������������������������������� 203 11.4.15 Interdigital Neuroma and “Neuritis” (Morton’s Neuroma)������������������� 203 11.5 Peripheral Nerve Tumors����������������������������������������������������������������������������������� 205 References��������������������������������������������������������������������������������������������������������������������� 209 12 Polyneuropathies��������������������������������������������������������������������������������������������������������� 215 12.1 Introduction������������������������������������������������������������������������������������������������������� 215 12.1.1 Anatomical Distribution������������������������������������������������������������������������� 216 12.1.2 Clinical Syndromess ����������������������������������������������������������������������������� 217 12.2 Metabolic Diseases ������������������������������������������������������������������������������������������� 218 12.2.1 Diabetic Distal Symmetric Polyneuropathy������������������������������������������ 218 12.2.2 Diabetic Autonomic Neuropathy����������������������������������������������������������� 220 12.2.3 Diabetic Cranial Mononeuropathy and Diabetic Radiculoplexus Neuropathy ��������������������������������������������������� 221 12.2.4 Distal Symmetric Polyneuropathy of Renal Disease����������������������������� 222 12.3 Neuropathies Associated with Paraproteinemias����������������������������������������������� 222 12.3.1 Multiple Myeloma Neuropathy������������������������������������������������������������� 222 12.3.2 Monoclonal Gammopathy of Undetermined Significance (MGUS)���������������������������������������������������������������������������� 223 12.3.3 Demyelinating Neuropathy Associated with Anti-MAG Antibodies��������������������������������������������������������������������������� 224 12.3.4 Waldenström’s Macroglobulinemia������������������������������������������������������� 224 12.3.5 POEMS Syndrome��������������������������������������������������������������������������������� 224 12.3.6 AL and TTR Amyloid Neuropathy ������������������������������������������������������� 225 12.4 Vasculitides ������������������������������������������������������������������������������������������������������� 226 12.4.1 Nonsystemic Vasculitic Neuropathy ����������������������������������������������������� 226 12.4.2 Vasculitic Neuropathy, Systemic����������������������������������������������������������� 228 12.4.3 Sjögren’s Neuropathy���������������������������������������������������������������������������� 230 12.5 Infectious Neuropathies������������������������������������������������������������������������������������� 230 12.5.1 Human Immunodeficiency Virus-1 Neuropathy ����������������������������������� 230 12.5.2 Herpes Zoster Neuropathy��������������������������������������������������������������������� 231 12.5.3 Lyme Disease (Neuroborreliosis) ��������������������������������������������������������� 232 12.5.4 Leprosy ������������������������������������������������������������������������������������������������� 233 12.6 Inflammatory Neuropathies������������������������������������������������������������������������������� 234 12.6.1 Guillain–Barré Syndrome (GBS) - Acute Inflammatory Demyelinating Polyneuropathy (AIDP) Subtype ��������������������������������� 234 12.6.2 GBS—Acute Motor Axonal Neuropathy (AMAN) Subtype����������������� 234 12.6.3 GBS—Acute Motor and Sensory Axonal Neuropathy (AMSAN) Subtype ������������������������������������������������������������������������������� 235

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12.6.4 GBS—Miller Fisher Syndrome Subtype����������������������������������������������� 236 12.6.5 Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) [Typical]��������������������������������������������������������� 237 12.6.6 Multifocal Motor Neuropathy (MMN) ������������������������������������������������� 240 12.6.7 Multifocal Asymmetric Demyelinating Acquired Sensorimotor Neuropathy (MADSAM)�������������������������������� 240 12.7 Nutritional Neuropathies����������������������������������������������������������������������������������� 241 12.7.1 Cobalamin Neuropathy ������������������������������������������������������������������������� 241 12.7.2 Post-Gastroplasty Neuropathy��������������������������������������������������������������� 241 12.7.3 Pyridoxine Neuropathy ������������������������������������������������������������������������� 241 12.7.4 Strachan’s Syndrome����������������������������������������������������������������������������� 242 12.7.5 Thiamine Neuropathy ��������������������������������������������������������������������������� 242 12.7.6 Tocopherol Neuropathy������������������������������������������������������������������������� 242 12.8 Drugs, Industrial Agents, and Metals����������������������������������������������������������������� 243 12.8.1 Alcohol Polyneuropathy ����������������������������������������������������������������������� 243 12.8.2 Other Drug-Induced Neuropathies��������������������������������������������������������� 243 12.8.3 Toxic Neuropathies: Industrial Agents��������������������������������������������������� 245 12.8.4 Toxic Neuropathies: Metals������������������������������������������������������������������� 246 12.9 Critical Illness Neuropathy ������������������������������������������������������������������������������� 248 12.10 Hereditary Neuropathies ����������������������������������������������������������������������������������� 248 12.10.1 Hereditary Motor and Sensory Neuropathies: Charcot–Marie–Tooth Disease��������������������������������������������������������������� 248 12.10.2 Hereditary Neuropathy with Liability to Pressure Palsy (HNPP) ������������������������������������������������������������������������� 252 12.10.3 Hereditary Neuralgic Amyotrophy ������������������������������������������������������� 253 12.10.4 Hereditary Sensory Autonomic Neuropathies��������������������������������������� 254 12.10.5 Distal Hereditary Motor Neuropathies (d-HMN) ��������������������������������� 254 12.10.6 Porphyria����������������������������������������������������������������������������������������������� 254 12.11 Cancer and Neuropathy������������������������������������������������������������������������������������� 255 12.11.1 Paraneoplastic Neuropathies����������������������������������������������������������������� 255 12.11.2 Neuropathies in Lymphoma and Leukemia������������������������������������������� 256 12.11.3 Polyneuropathy and Chemotherapy������������������������������������������������������� 257 12.12 Cryptogenic Sensory Peripheral Neuropathy����������������������������������������������������� 260 Further Readings����������������������������������������������������������������������������������������������������������� 260 13 Neuromuscular Transmission: Endplate Disorders������������������������������������������������� 263 13.1 Introduction������������������������������������������������������������������������������������������������������� 263 13.2 Myasthenia Gravis��������������������������������������������������������������������������������������������� 263 13.3 Congenital Myasthenic Syndromes������������������������������������������������������������������� 269 13.4 Lambert–Eaton Myasthenic Syndrome (LEMS)����������������������������������������������� 269 13.5 Botulism������������������������������������������������������������������������������������������������������������� 271 13.6 Neuromyotonia (Isaacs’ Syndrome) ����������������������������������������������������������������� 271 Further Readings����������������������������������������������������������������������������������������������������������� 272 14 Muscle and Myotonic Diseases���������������������������������������������������������������������������������� 275 14.1 Introduction������������������������������������������������������������������������������������������������������� 275 14.1.1 Electrophysiology ��������������������������������������������������������������������������������� 275 14.1.2 Muscle Histology and Immunohistochemistry ������������������������������������� 276 14.1.3 Molecular Genetics in Muscle Disease������������������������������������������������� 276 14.1.4 Clinical Phenotypes of the Inherited Myopathies��������������������������������� 276 14.1.5 Therapy for Neuromuscular Diseases��������������������������������������������������� 276 14.2 Polymyositis (PM) and Dermatomyositis��������������������������������������������������������� 277 14.3 Inclusion Body Myositis (IBM)������������������������������������������������������������������������� 279 14.4 Immune-Mediated Necrotizing Myopathy (IMNM)����������������������������������������� 280

Contents

xxi

14.5 Connective Tissue Diseases (CTDs) in “Overlap” Myositis (OM)������������������� 281 14.6 Viral Myopathies����������������������������������������������������������������������������������������������� 282 14.7 Toxic Myopathies����������������������������������������������������������������������������������������������� 283 14.8 Critical Illness Myopathy (CIM)����������������������������������������������������������������������� 285 14.9 Myopathies Associated with Endocrine/Metabolic Disorders and Carcinoma� 286 14.10 Duchenne Muscular Dystrophy (DMD) ����������������������������������������������������������� 286 14.11 Becker Muscular Dystrophy (BMD)����������������������������������������������������������������� 289 14.12 Myotonic Dystrophy (DM) ������������������������������������������������������������������������������� 290 14.13 Limb-Girdle Muscular Dystrophy (LGMD)����������������������������������������������������� 291 14.14 Oculopharyngeal Muscular Dystrophy (OPMD)����������������������������������������������� 293 14.15 Facioscapulohumeral Muscular Dystrophy (FSHD)����������������������������������������� 294 14.16 Emery–Dreifuss Muscular Dystrophy (EDMD)����������������������������������������������� 296 14.17 Distal Myopathies ��������������������������������������������������������������������������������������������� 298 14.18 Congenital Myopathies ������������������������������������������������������������������������������������� 298 14.19 Mitochondrial Myopathies��������������������������������������������������������������������������������� 301 14.20 Glycogen Storage Diseases (GSDs)������������������������������������������������������������������� 302 14.21 Defects of Fatty Acid Oxidation and the Carnitine Shuttle System (DFAOCSS) ����������������������������������������������������������������������������� 304 14.22 Myotonia Congenita������������������������������������������������������������������������������������������� 306 14.23 Paramyotonia Congenita����������������������������������������������������������������������������������� 307 14.24 Hyperkalemic Periodic Paralysis (HyperPP)����������������������������������������������������� 308 14.25 Hypokalemic Periodic Paralysis (HypoPP)������������������������������������������������������� 309 References��������������������������������������������������������������������������������������������������������������������� 310 15 Motor Neuron Diseases����������������������������������������������������������������������������������������������� 313 15.1 Amyotrophic Lateral Sclerosis (ALS)��������������������������������������������������������������� 313 15.2 Spinal and Bulbar Muscular Atrophy (SBMA, Kennedy Syndrome)��������������� 315 15.3 Spinal Muscular Atrophies (SMA) ������������������������������������������������������������������� 315 15.4 Poliomyelitis and Post-Polio Syndrome (PPS) ������������������������������������������������� 318 Further Readings����������������������������������������������������������������������������������������������������������� 319 16 Autonomic Neuropathies ������������������������������������������������������������������������������������������� 321 16.1 Introduction������������������������������������������������������������������������������������������������������� 321 16.2 Anatomy������������������������������������������������������������������������������������������������������������� 321 16.2.1 Common Autonomic CNS Structures��������������������������������������������������� 321 16.2.2 Sympathetic Nervous System ��������������������������������������������������������������� 321 16.2.3 Parasympathetic Nervous System��������������������������������������������������������� 323 16.2.4 Enteric Nervous System������������������������������������������������������������������������� 323 16.3 History Taking and Bedside Tests��������������������������������������������������������������������� 323 16.3.1 Autonomic Testing��������������������������������������������������������������������������������� 323 16.3.2 Cardiovascular Reflex Tests������������������������������������������������������������������� 324 16.3.3 Sudomotor Tests������������������������������������������������������������������������������������� 325 16.4 Autonomic Syndromes��������������������������������������������������������������������������������������� 325 16.4.1 Orthostatic Hypotension (OH)��������������������������������������������������������������� 325 16.4.2 Diabetic Autonomic Neuropathy����������������������������������������������������������� 327 16.4.3 Supine Hypertension (SH)��������������������������������������������������������������������� 327 16.4.4 Reflex Syncope ������������������������������������������������������������������������������������� 328 16.4.5 Postural Orthostatic Tachycardia Syndrome (POTS)���������������������������� 329 Reference ��������������������������������������������������������������������������������������������������������������������� 329 General Disease Finder������������������������������������������������������������������������������������������������������� 331 Index������������������������������������������������������������������������������������������������������������������������������������� 343

Contributors

David Bennett  Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK Brian C. Callaghan  Department of Neurology, University of Michigan, Ann Arbor, MI, USA Eva L. Feldman  Department of Neurology, University of Michigan, Ann Arbor, MI, USA Wolfgang Grisold  Ludwig Boltzmann Institute for Experimental und Clinical Traumatology, Vienna, Austria Peter Jin  Department of Neurology, University of Maryland, Baltimore, MD, USA Gregor Kasprian  Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria Martin Krenn  Department of Neurology, Medical University of Vienna, Vienna, Austria Wolfgang N. Löscher  Department of Neurology, Medical University Innsbruck, Innsbruck, Tirol, Austria Stefan Meng  Department of Radiology and Center for Anatomy and Cell Biology, Hanusch Hospital and Medical University of Vienna, Vienna, Austria Tatajana Paternostro-Sluga  Department of Physical Medicine and Rehabilitation, Danube Hospital, Vienna Hospital Association, Vienna, Austria Hannes  Platzgummer Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria Michael Quittan  Karl Landsteiner Institute for Remobilisation and functional Health, Vienna, Austria James W. Russell  Department of Neurology, University of Maryland Baltimore, Baltimore, MD, USA Stacey A. Sakowski  Department of Neurology, University of Michigan, Ann Arbor, MI, USA Masha G. Savelieff  Department of Neurology, University of Michigan, Ann Arbor, MI, USA Robert  Schmidhammer  Millesi Center-Competence Center for Peripheral Nerve Surgery, Brachial Plexus, and Reconstructive Surgery, Vienna, Austria Amro Maher Stino  Department of Neurology, University of Michigan, Ann Arbor, MI, USA Walter  Struhal Department for Neurology, University Clinic Tulln, Karl Landsteiner University of Health Sciences, Tulln, Austria Lindsay A. Zilliox  Department of Neurology, University of Maryland, Baltimore, MD, USA Veterans Administration Maryland Healthcare System, University of Maryland, Baltimore, MD, USA

xxiii

1

Tools

About the Atlas  Several important diagnostic tools are necessary for the proper evaluation of a patient with a suspected neuromuscular disorder. Each individual chapter in this book is headed by a “tool bar,” indicating the usefulness of various diagnostic tests for the particular condition discussed in the chapter. For example, genetic testing is necessary for the diagnosis of hereditary neuropathy and hereditary myopathy, while NCV and EMG tests can be important but are less specific. Conversely, NCV and EMG are the predominant diagnostic tools for a local entrapment neuropathy like carpal tunnel syndrome. Imaging is now a standard tool in diagnosing certain nerve and muscle disorders, particularly nerve entrapments and myopathies, respectively. Some conditions will require tissue biopsy although this is becoming increasingly less common, as genetic testing is more common. The evaluation of a patient’s symptoms, in particular pain, is increasingly important, as are assessments of a patient’s quality of life and disability. In Europe, the International Classification of Functioning, Disability, and Health (ICF) (www.who.int) is used as a metric for a patient’s overall function. In the United States, a patient’s overall functional status can be assessed using one of many “tools” within the National Institutes of Health Tool Box (www.ninds.nih.gov).

1.1

 ew Developments in Neuromuscular N Disease

The first edition of this book was published in 2004, the second edition in 2014. In the ensuing years, several new developments changed our approach to patients with neuromuscular disorders. In the authors’ opinion, the most important change is that the idea of “evidence-based medicine” is now widely accepted. The Cochrane Collaboration (www.cochrane.org), the European Federation of Neurological Societies (EFNS)

Contributions by Eva L. Feldman and Wolfgang Grisold

(www.efns.org), and the American Academy of Neurology (AAN) (www.aan.com) all provide unbiased systematic reviews of treatment paradigms with evidence-based recommendations. Increasingly, freely available sources such as the Directory of Open Access Journals (www.doaj.org) and PubMed Central (www.ncbi.nlm.nih.gov/pubmed) are used, which enable rapid and commonly unrestricted access to new medical information. These changes are reflected in updated content in the third edition of this atlas. The clinical methodology of the examination of the patient with neuromuscular disease has remained unchanged and is based on a detailed case history and a systematic neuromuscular examination. The number of antibody-associated and immune-mediated neuromuscular disorders is growing. The number of newly identified neuromuscular genetic disorders has increased dramatically and continues to evolve on a monthly basis. Open access websites, including Gene Reviews (www.ncbi.nlm.nih.gov/sites/GeneTests/review) and the Neuromuscular Home Page (neuromuscular.wustl. edu), provide up-to-date genetic and clinical information for the practitioner and information on how to attain appropriate genetic testing. As whole genome sequencing also becomes available and affordable, clinical pathways in several genetic diseases can change. Another major ongoing change since 2014 is the increasing use of imaging to assess the integrity of peripheral nerves and muscles. Ultrasound imaging of peripheral nerves and muscles routinely provides the initial assessment of tissue integrity and is the mainstay of neuromuscular imaging. MRI is now also commonly used to assess the integrity of nerve roots, the brachial or lumbosacral plexus, and individual peripheral nerves. MRI of muscle is increasingly employed and identifies changes in muscle integrity, including muscle tears, edema, fatty infiltration, hematomas, and tumors. MR tractography is also currently under development for use in the peripheral nervous system Figs. 1.1–1.3. Driven by technology, increases in resolution and precision support the visualization of tracts as well as DRG.  Ultrasound techniques have also improved and are

© Springer Nature Switzerland AG 2021 E. L. Feldman et al., Atlas of Neuromuscular Diseases, https://doi.org/10.1007/978-3-030-63449-0_1

1

1 Tools

2

a

b 2

1

Fig. 1.1 (a) The axon (1) is surrounded by layers of Schwann cell cytoplasm (2) and membranes. The Schwann cell cytoplasm is squeezed into the outer portion of the Schwann cell leaving the plasmalemma of the Schwann cell in close apposition. These layers of Schwann cell membrane contain specialized proteins and lipids and are known as the

myelin sheath. (b) Peripheral axons are surrounded by as series of Schwann cells. The space between adjacent Schwann cells is called nodes of Ranvier (asterisk). The nodes contain no myelin but are covered by the outer layers of the Schwann cell cytoplasm. The area covered by the Schwann cell is known as the internode

Fig. 1.2  A peripheral nerve consists of bundles of axons surrounded by and embedded in a collagen matrix. The outer connective tissue covering is called the epineurium. The inner connective tissue that divides the axons into bundles is called the perineurium. The innermost layer of connective tissue surrounding the individual axons is called the endoneurium. Blood vessels and connective tissue cells such as macrophages, fibroblasts, and mast cells are also contained within the peripheral nerve. The arrow indicates an enlarged view of an individual axon and its surrounding Schwann cells. A node of Ranvier, the space between adjacent Schwann cells, is depicted as the narrowing of the sheath surrounding the axon. Each internode is formed by a single Schwann cell

1.2 The Patient with Neuromuscular Disease

3

used as a precise concomitant tool in nerve lesions, visualizing peripheral nerves to the fascicular level. In addition, nerve movements and the relation with adjacent structures can be well demonstrated, which may identify dynamic changes of function. Genetic testing is now in widespread use in neuromuscular disease. In parallel, major revelations have also occurred on the therapeutic level, where new therapies influence and even cure some genetic neuromuscular disorders.

1.2

 he Patient with Neuromuscular T Disease

The evaluation of a patient with neuromuscular disease includes a thorough clinical history, duration of the present illness, past medical history, social history, family history, and details about the patient’s occupation, behaviors, and habits. The clinical history and temporal development of symptoms provide essential information to the practitioner. The types of symptoms (motor, sensory, coordination, autonomic, and pain) and how these symptoms affect the patient’s activities of daily living can supply essential information required for a correct diagnosis. The history is followed by a classical clinical neurological examination, which assesses signs of muscle weakness, reflex and sensory abnormalities, coordination, and autonomic changes, as well as information about pain and impairment. The clinical examination is of utmost importance for several reasons. The findings will correlate with the patient’s symptoms, and the distribution of the signs (e.g., muscle atrophy in muscle disease) can give important clues to the precise diagnosis. Documentation of the course of signs and symptoms will be useful in monitoring disease progression and may guide therapeutic decisions. Documentation of the progression of neuromuscular disease (especially chronic diseases) should not be limited to changes measured by the ancillary tests described later in this

Fig. 1.3  Sensory information is relayed from the periphery toward the central nervous system through special sensory neurons. These are pseudounipolar neurons located within the dorsal root ganglia along the spinal cord. Mechanical, temperature, and noxious stimuli are transduced by special receptors in the skin into action potentials that are transmitted to the sensory neuron. The direction of the sensory system (arrow). This neuron then relays the impulse to the dorsal horn of the spinal cord. Motor information is relayed from the central nervous system to the muscles by the alpha motor neurons. These multipolar neurons are located within the ventral or anterior horn of the spinal cord gray matter. Impulses from the motor cortex travel down the spinal cord to the motor neurons. The motor neuron relays this impulse to the muscle inducing muscle contraction and movement

4

1 Tools

section. Depending upon the disease, assessments of muscle strength [e.g., Medical Research Council (MRC) scale] and sensation (e.g., vibration threshold, Semmes-­Weinstein filaments, two-point discrimination, warm–cold discrimination), patterns of atrophy, and reflex changes are useful. Digital imaging, video clips, and photographs of patients provide a precise documentation of the patient’s function and are suggested when possible. The diagnostic hypothesis is developed on the basis of history and clinical exam and can be confirmed by additional diagnostic testing. These same tests are used, in conjunction with newer quality of life scales, to monitor the impact of therapies on the disease course. Standard electrophysiological tests include NCV, EMG, and repetitive nerve stimulation. Complete blood counts, blood chemistries including creatine kinase, vitamin levels, serological markers of inflammation, specific antibody levels, and genetic testing are frequently required to secure a precise diagnosis. Other quantitative clinical assessments are employed when required, including autonomic function testing (Ewing test battery) and quantitative sensory testing (QST). Both neuroimaging with ultrasound and/or MRI, and, if indicated nerve or muscle biopsy, are used to confirm specific diagnoses. The following description of diagnostic tools is intended to be a brief overview, with reference to specific chapters that will provide more detail. As outlined above, since a large proportion of neuromuscular disease is known to have a hereditary etiology, ­molecular testing approaches play an increasingly important role in their diagnostic workup. While most patients with neuromuscular disease remained undiagnosed only a decade ago, the recent implementation of next-generation sequencing methods has significantly enhanced the genetic-diagnostic yield. Given the enormous molecular heterogeneity of many genetic neuromuscular diseases, broad and unbiased testing approaches (i.e., comprehensive gene panels or exome sequencing) seem to be most appropriate. With Chap. 3 “Genetic Testing in Neuromuscular Diseases,” this book aims to provide clinically relevant details about genetic-­ diagnostic aspects in neuromuscular diseases, delineating the key mutational mechanisms and focusing on modern genetic testing methods and their implications. In view of the emerging genotype-guided treatments in the field of neuromuscular medicine, this knowledge will be of utmost importance in future years, and new therapeutic approaches are now discussed in Chap. 4 “New Neuromuscular Therapies.”

1.3

 istory and General Physical H Examination

The detailed neurological, general medical, family, and social history, as discussed above, is essential and must be completed in a systematic manner. Upon completion, each

patient should undergo a basic general physical examination. This should begin with a general inspection of the skin (identifying rashes, papules, birthmarks such as café au lait spots, hyperpigmentation, hypertrichosis, or other dermatological abnormalities) and the musculoskeletal system (detecting kyphosis, scoliosis, pes cavus, atrophy, hypertrophy, or any abnormal muscle movements). General inspection is followed by assessments of blood pressure and pulse and examination of cardiopulmonary function. Depending on the clinical history, a more thorough general examination may be required; for example, assessments including but not limited to the thyroid, abdomen, and lymph nodes can provide clinical information that may be required for specific neuromuscular diagnoses.

1.4

Neuromuscular Clinical Phenomenology

In addition to the classical concept of the distribution of sensory, motor, and autonomic functions, further anatomic concepts need to be considered: 1. Sklerotoma: Bones, joints, and periosteum are segmentally innervated, and the distribution does not correspond the usual dermatomal distribution. This can be important for local pain syndromes, and also for referred pain. 2. Angiosoma: This concept describes the vascularization of tissue. Angiosomas are vessel specific parts of the body. Peripheral nerves and muscle usually traverse several angiosomas. A practical example is the plastic and ­reconstructive “flap” surgery, where skin, vessels, and adjacent tissue are selected according to this principle. 3. Fascia not only serve as the origin and final pathway for some muscles, but they are also densely innervated.

1.4.1 Motor Function Motor dysfunction is one of the most prominent features of neuromuscular disease. The patient’s symptoms may include weakness, fatigue, muscle cramps and pain, atrophy, and abnormal muscle movements like fasciculations or myokymia. Weakness often results in disability, depending on the muscle groups involved. Depending on the onset and progression, weakness may be acute and debilitating (as in the acquired inflammatory neuropathies) or may remain discrete for a long time. As a rule, lower extremity weakness is noticed earlier due to difficulties in climbing stairs or walking. The distribution of weakness is characteristic for some diseases, and proximal and distal weaknesses are generally associated with different etiologies. Fluctuation of muscle weakness is often a sign of neuromuscular junction disorders.

1.4 Neuromuscular Clinical Phenomenology

5

a

b

T2

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1 T4 T5 T1 T1

L1

T10 2

L1 C6

C8

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C6 C7C8

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C7 4 5

3

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L5

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5 S1

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Fig. 1.4 (a) 1 Axillary nerve, 2 superficial radial nerve, 3 median nerve, 4 ulnar nerve, 5 femoral nerve, 6 saphenous nerve, and 7 peroneal nerve. On the right side of the body, the segmental innervation is

marked. (b) 1 Axillary nerve, 2 superficial radial nerve, 3 ulnar nerve, 4 cutaneous femoris posterior nerve, and 5 sural nerve

Weakness and atrophy should be precisely assessed in mononeuropathies because the site of the lesion can be pinpointed by mapping the locations of functional and nonfunctional nerves leaving the main nerve trunk. Partial lesions of proximal nerves can also result in a distinct peripheral pattern (e.g., in proximal lesions of the sciatic nerve, the peroneal nerve fibers are more vulnerable) Fig. 1.4. Muscle strength can be evaluated clinically by manual and functional testing. Typically, the British MRC scale is used. This simple grading gives a good general impression, and most patients fall between grades 3 and 5 (3 = sufficient force to hold against gravity, 5 = maximal muscle force). A composite MRC scale can be used for longitudinal assessment of disease. Quantitative assessment of muscle power is more difficult because a group of muscles is usually involved

in the disease, and single muscles cannot be assessed individually. Handgrip strength can be measured by a dynamometer and provides a quantitative measure of muscle strength that can be followed over time. Fatigability is present in many neuromuscular disorders. It can be objectively noted in neuromuscular transmission disorders like myasthenia gravis (e.g., ptosis time) and is also present in neuromuscular diseases like amyotrophic lateral sclerosis, muscular dystrophies, and metabolic myopathies, where it is exacerbated by activity. Muscle wasting can be generalized or focal (Figs. 1.5, 1.6 and 1.7) and may be difficult to assess in infants and obese patients. Asymmetric weakness is usually noted earlier, in particular, in the intrinsic muscles of the hand and foot. Muscle wasting may also occur secondary to immobilization

6

1 Tools

a

(e.g., casting for fractures or persistent joint deformities in rheumatoid arthritis) and in wasting due to malnutrition or tumor cachexia and sarcopenia caused by cancers. Muscle hypertrophy is much rarer than atrophy and may be generalized, as in myotonia congenita, or localized, as in the “pseudohypertrophy” of the calf muscles in some types of muscular dystrophy and glycogen storage diseases or other myotonias. Focal hypertrophy is even rarer and may occur in muscle tumors, focal myositis, amyloidosis, or infection. Finally, ruptured muscles may mimic a local hypertrophy during contraction.

b

1.4.2 Abnormal Muscle Movements Abnormal muscle movements can be the hallmark of a neuromuscular condition and should be observed at rest, during and after contraction, and after mechanical stimulation such as percussion.

Fig. 1.5 (a) Hemangioma in the fourth and fifth finger and palm. (b) Multiple neurofibromas in NF1

a

b

• Fasciculations are brief asynchronous twitches of muscle fibers usually apparent at rest. They may occur in healthy individuals after exercise or after caffeine or other stimulant intake. Cholinesterase inhibitors or theophylline can provoke fasciculations. Fasciculations are often associated with motor neuron diseases (amyotrophic lateral sclerosis; ALS) and spinal muscular atrophy (SMA), but can also occur in polyneuropathies, and appear localized in radiculopathies. Contraction fasciculations appear during muscle contraction and are common in ALS.

c

Fig. 1.6  Features of myopathy. (a) Hyperlordosis and scapular winging, (b) proximal weakness of shoulder girdle, (c) shortening of Achilles tendon

1.4 Neuromuscular Clinical Phenomenology

7

a

•

b

•

•

• c

• Fig. 1.7  Time course of a patient with a progressive axonal neuropathy. Follow-up over 8 years. (a) At the onset, atrophy of the first interosseus can be noted. (b) 5 years later increasing atrophy. (c) 8 years later severe atrophy, in particular of all intrinsic hand muscles of the left hand, had developed

Ultrasound easily detects fasciculations and can be used to assess the tongue and other muscles. Fasciculations are also easily identified on EMG. • Myokymia is defined as involuntary, repeated, worm-like contractions that can be clearly seen under the skin (“a

•

bag of worms”). EMG shows abundant activity of single or grouped, normal-appearing muscle unit potentials and is different from fasciculations. Myokymia is rare and appears in neuromuscular disease with “continuous muscle fiber activity,” such as in Isaacs’ Syndrome and in central nervous system disease (e.g., brain stem glioma). Myokymia may be a sequelae of radiation injury to the peripheral nerves, most frequently seen in radiation plexopathies of the brachial or lumbosacral plexus. Neuromyotonia, or continuous muscle fiber activity (CMFA), is rare. It results in muscle stiffness and a myotonic appearance of movements after contraction. Rarely, bulbar muscles can be involved, resulting in a changed speech pattern. The condition can be idiopathic and can appear on a toxic basis (e.g., gold therapy) or on an autoimmune basis. Myoedema occurs after percussion of a muscle and results in a ridge-like mounding of the muscle, lasting 1–3 s. It is a rare finding and can be seen in hypothyroidism and cachexia. Rippling muscle is a self-propagating rolling or rippling of muscle that can be elicited by passive muscle stretch. It is an extremely rare phenomenon. Percussion can induce mounding of the muscle (mimicking myoedema). The rippling muscle movement is associated with electrical silence in EMG. Myotonia occurs when a muscle is unable to relax after voluntary contraction and is caused by repetitive depolarization of the muscle membrane. Myotonia is well characterized by EMG. It occurs in myotonic dystrophies and congenital myotonias. Action myotonia is most commonly observed. The patient is unable to relax the muscles after a voluntary action (e.g., handgrip). This phenomenon can last up to 1  min, but is usually shorter (10–15  s). Action myotonia diminishes after repeated exercise (warm-up phenomenon), but may conversely worsen in paramyotonia congenita. Percussion myotonia can be seen in all affected muscles, but most often the thenar eminence, forearm extensors, anterior tibialis muscle, or the tongue are examined. The relaxation is delayed, and a local dimple caused by the percussion appears, lasting about 10 s. Pseudoathetosis is a characteristic of deafferentation and loss of position sense. Fine motor tasks are impaired or markedly slowed and result in a writhing and undulating movement pattern of outstretched fingers, aggravated with eye closure. Pseudoathetosis appears in sensory neuropathies and neuronopathies, posterior column degeneration, and tabes dorsalis. Painful legs and moving toes: Length-dependent distal neuropathies may be associated with moving toes. This sign may be due to large-fiber sensory loss and has been observed in cisplatinum-induced neuropathies and other acquired neuropathies.

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• Neuropathic tremor resembles orthostatic tremor and has a frequency of 3–6 Hz. It occurs rarely in association with demyelinating neuropathies or hereditary neuropathies. • Muscle cramps are painful involuntary contractions of a part or the whole muscle. At the site of the contraction, a palpable mass can be felt. EMG reveals bursts of motor units in an irregular pattern. Cramps often occur in the calves and can be relieved by stretching. Cramps may occur in metabolic conditions (electrolyte changes), motor neuron disease, some myopathies, and some types of polyneuropathy.

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a

1.4.3 Reflex Testing The long reflex arc tested by the deep tendon reflex is useful for neuromuscular diagnosis. The reflex arc measures both the large-fiber sensory and motor divisions of the local segment tested. Reflexes do not measure small-fiber function and are normal in isolated small-fiber neuropathies. The quality of the reflex provides information on the central nervous system input to the local segment (e.g., exaggerated, brisk, normal, or diminished). In polyneuropathies, reflex changes are symmetrical, and ankle reflexes are routinely diminished or absent, while more proximal reflex arcs remain intact until later in the disease progression. Asymmetric reflexes suggest focal pathology which can occur at the spinal cord, nerve root, or peripheral nerve level. Reflexes in myopathies are frequently diminished but preserved until late stages of the disease. Exaggerated and brisk reflexes in combination with weakness and atrophy are suggestive of a combined lesion of lower and upper motor neurons, as in ALS. Reflexes may also be absent at rest and reappear after contraction or repeated tapping (“facilitation”) as seen characteristically in the Lambert–Eaton syndrome. In summary, reflexes are useful to identify both widespread and local loss of nerve function and in combination with long tract signs, reflexes yield important diagnostic information.

b

c

1.4.4 Muscle Tone Muscle tone is an important issue in motor neuron diseases, where it can be increased in ALS and decreased in SMAs. Muscle tone is assessed in parallel with reflexes.

1.4.5 Sensory Symptoms Sensory disturbances signal disease of the peripheral nerve or DRG and include a spectrum of positive and negative phenomena. Importantly, the symptoms and signs are frequently classified as originating from small or large fibers. By definition, small fibers are unmyelinated sensory axons while large fibers are thinly myelinated or fully myelinated sensory axons. Small fibers carry the sensory modalities of pain and temperature

Fig. 1.8 (a) Weinstein filaments, (b) simple test for temperature discrimination, (c) Greulich “star” for two-point discrimination

while large fibers relay information on vibration and proprioception. Both fiber types are involved in touch. The patient is asked to provide a precise description and boundaries of sensory loss (or paresthesias). Reports of permanent, undulating, or ictal (transient) loss of sensations should be recorded. In radiculopathies, the sensory loss is rarely expressed through the whole dermatome but often confined to distal areas (Figs. 1.8–1.10).

1.4 Neuromuscular Clinical Phenomenology

a

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b

c

Fig. 1.9 (a) Vibration can be assessed with a Rydel-Seiffer tuning fork, (b) position sense, (c) or vibrometer that allows quantitative assessment of vibration threshold

a

b

Fig. 1.10 (a) Small fiber, testing by thermal threshold. The finger is put on a device, which changes temperature. The patient is requested to report changes of temperature or pain. (b) Vibration threshold can be assessed electronically and displayed on the screen

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1.5

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Sensory Qualities

entrapment, tarsal tunnel syndrome, pronator compression, medial plantar neuropathy, superficial peroneal neuropathy, • Negative symptoms are numbness, loss of feeling, per- thoracic outlet syndrome, cervical radiculopathies, periphception, and even anesthesia. eral neuropathies, cervical plexus injuries, lateral femoral • Positive symptoms are paresthesias, pins and needles, tin- cutaneous nerve entrapment, traumatic prepatellar neuroma, gling, dysesthesias (uncomfortable feelings), or hyper- bowler’s thumb, and peripheral nerve lesions. pathia (painful perception of a non-painful stimulus). QST includes testing of small fibers by cooling, and large Inadequate hyperpathia can result in allodynia. Pruritus fibers by vibration threshold and is increasingly used in occurs rarely. neuropathies. Distribution of Sensory Symptoms: The distribution of The type of sensory disturbance gives a clue to the affected sensory symptoms in peripheral neurology typically follows fibers. Loss of temperature and pain perception point to as segmental (radicular) or peripheral nerve distribution. small-fiber loss, whereas large-fiber loss manifests itself in Patchy and “atypical” sensory distributions are rare and can loss of vibration perception and position sense (Table 1.1). occur in Wartenberg’s neuritis, sarcoid, and leprosy. The distribution of the sensory symptoms can follow a Small-Fiber Neuropathy: Small fibers can be affected peripheral nerve (mononeuropathy), a single root (radicu- predominately in some types of neuropathy, especially early lopathy), or, in most polyneuropathies, a stocking glove dis- in the course of the disease. In small-fiber neuropathy, clinitribution. The sensory trigeminal nerve distribution can cal assessment of a patient reveals diminished pain, thermal suggest a lesion of a branch (e.g., numb chin syndrome) or a and light touch perception, but intact vibratory and position ganglionopathy (i.e., DRG injury). Maps of dermatomes and sense. While conventional NCV studies are normal, a skin peripheral nerve distributions can be used to distinguish and punch biopsy allows quantification of intraepidermal nerve classify the pattern found. A patchy distribution is much fiber (IENF) density. IENF density is decreased in small-­ rarer and can occur in the rare sensory neuritis of Wartenberg fiber neuropathies. and in leprosy and sarcoid. Raynaud’s Phenomenon: Occurs in connective tissue Transient sensory symptoms can be elicited by local pres- disease and has also been reported in peripheral autoimmune sure on a nerve, resulting in neurapraxia. In patients who conditions and as a late effect in chemotherapy-induced neuhave a history of repeated numbness and weakness in single ropathies. It is characterized by a discoloration of fingers and nerve distribution, a hereditary neuropathy with pressure toes and is caused by an exaggerated sympathetic response palsy (HNPP) should be considered. Some transient sensory causing vasoconstriction. changes are characteristic but difficult to assess, such as periOther Types of Sensory/Pain Distribution: In contrast oral sensations in hypocalcemia or hyperventilation. to radiating pain, referred pain projects into remote cutaneA characteristic sign of sensory neuropathy is the Tinel-­ ous zones. These areas are sensitive to touch sometimes Hoffmann sign, which is a distally radiating sensation resulting in allodynia and hyperalgesia. A common examspreading in the direction of a percussed nerve. It is believed ple is an “ice cream headache” where pain from the throat to be a sign of reinnervation by sensory fibers, but may also and palate are referred to the sinus. Other examples include occur in a normal peripheral nerve when vigorously tapped. pain in the left shoulder/arm in myocardial infarction and The Tinel-Hoffmann sign has been described in carpal pain in the right tip of the scapula in gallbladder pain tunnel syndrome, cubital tunnel syndrome, radial nerve (Kehr’s sign).

1.5.1 Myalgia and Pain

Table 1.1  Sensory qualities Sensory quality Light touch Pressure Pain Temperature Vibration Position sense Two-point discrimination

Method Brush, examiner’s finger tips Semmes-Weinstein filaments Pin prick Temperature threshold devices Tuning fork Greulich device

Fiber type All types Small and large fibers— Quantification possible Small fibers Small fibers Large fibers Large fibers Large fibers

Myalgia (muscle pain) occurs in neuromuscular diseases in several settings. It can occur at rest (polymyositis) and may be the leading symptom in polymyalgia rheumatica and also toxic conditions (e.g., treatment with taxanes or gemcitabine). Focal muscle pain in association with exercise-­ induced ischemia is observed in occlusive vascular disease. Local, often severe, pain is the hallmark of compartment syndrome occurring after exercise or ischemia. Exercise-­ induced muscle pain in association with muscle cramps can be seen in metabolic disease.

1.6 NCV/EMG/Autonomic Testing and Miscellaneous Electrophysiology

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1.5.2 Neuropathic Pain

1.5.5 Clinical Pitfalls

The definition and characterization of neuropathic pain is essential for an accurate diagnosis of several neuromuscular disorders and is discussed in Chap. 7.

There is normal variation in human anatomy that can influence aspects of both the clinical examination and results obtained from electrodiagnostic testing and imaging. For example, there are several anatomic variations of the peripheral nervous system, including a pre- and postfixed brachial plexus and a median to ulnar anastomosis, termed a Martin Gruber anastomosis. In addition, while myotomes and dermatomes reflect radicular segmental innervation, anatomic studies show a significant degree of overlap among innervation patterns. Finally, myotome and dermatome patterns do not consider the innervation patterns of bone and joints, which can also be a source of pain and may make clinical diagnoses challenging.

1.5.3 Autonomic Function Autonomic signs and symptoms are often neglected and include loss of sweating leading to skin changes, orthostatic hypotension, tachyarrhythmias, ileus, urinary retention, impotence, incontinence, and pupillary abnormalities. In amyloidosis, autonomic neuropathy is frequently the presenting problem. In some polyneuropathies and mononeuropathies, autonomic involvement is documented by skin changes at examination. The dry, anhydrotic skin in diabetic neuropathy is a good example. Skin changes in peripheral nerve lesions can include pale, dry, and glossy skin and changes of the nail beds. The methods suggested for testing include RR variation testing, the sympathetic skin response, and other components of the Ewing test battery. Autonomic function is discussed in more detail in Chap. 16.

1.5.4 Gait, Coordination A patient’s gait can be a definite clue to the cause of the neuromuscular disease. Proximal weakness (if symmetric) causes a waddling gait. Unilateral pelvic tilt toward the swinging leg is caused by weakness of contralateral hip abductors. Hyperextension of the knee may be compensatory for quadriceps weakness. If proximal weakness has progressed, hip flexion can be replaced by circumduction of the hyperextended knee. Distal neuropathies often include weakness of the peroneal muscles, resulting in a steppage gait. Loss of position sense due to large-fiber damage results in sensory ataxia, with a broad-based gait and worsening of symptoms with eyes closed (Romberg’s sign). Combinations of neuropathies and posterior column degeneration are observed in vitamin B12 deficiency. Transient gait disturbances may point to spinal claudication and also rarely to spinal arteriovenous malformations. Deformities of the joints (Charcot joints, Charcot osteoarthropathy) can involve foot joints, the knee, and even the hip and the vertebral column. The clubfoot can be a clue to neuropathies or impaired sensory function, which can cause serious complications including spontaneous fractures, infections, osteomyelitis, and necrosis, as well as neuropathic arthropathy and pain.

1.6

NCV/EMG/Autonomic Testing and Miscellaneous Electrophysiology

1.6.1 Motor and Sensory NCV Studies Motor NCV Studies: Motor nerve conduction studies are one of the basic investigations in peripheral neurology. A peripheral nerve is stimulated at one or more points to record a compound action potential (CMAP) from a muscle innervated by this nerve. Both sensory and motor fibers are stimulated. The amount of time between the stimulation and muscle response (distal latency) includes the conduction time along the myelinated axon as well as the unmyelinated axonal endings and the neuromuscular transmission time. The difference in distal latency between two points of stimulation is used to calculate the NCV in m/s. The amplitude of the CMAP in the muscle reflects the number of innervated muscle fibers. This method can discriminate between axonal and demyelinating neuropathies and correlates well with morphological findings. NCV can be used to locate the site of entrapment in mononeuropathies. Local slowing, local impulse blockade, and decreased or absent CMAPs with stimulation proximal and distal of a lesion can be observed. Several techniques are used to detect these changes, including stimulation at different sites, comparison of conduction properties in adjacent nerves (median/ulnar), and the “inching” technique. While the measurement of motor nerves at the extremities is methodologically easy, the measurement of NCVs of proximal nerve segments is problematic. For some proximal motor nerves, like the long thoracic and femoral nerves, only the distal latencies can be assessed with certainty. Age, height, and temperature are also important factors in all motor NCV studies (Fig. 1.11).

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Fig. 1.11 (a) Motor nerve conduction (median nerve), (b) sensory nerve conduction, with near-nerve needle electrodes (sural nerve)

Sensory NCV Studies: Unlike motor conduction, where a terminal branch and synapse contribute to latency, no synapse exists between the stimulating site and recording site in a sensory nerve. Sensory nerve conduction (SNAPs) can be measured in myelinated axons in both the orthodromic and the antidromic direction. This means that stimulation of the main (mixed) nerve trunk results in a signal at the distal sensory nerve, or conversely stimulation of the distal sensory branch, yields a signal at the nerve trunk. The studies can be done with surface recordings or recording with needle electrodes using a near-nerve technique. Antidromic techniques with surface recording are commonly used. Near-nerve recordings are time-consuming but are able to pick up even low signals and allow the assessment of several fiber populations conducting at different velocities (dispersion), which may be necessary for diagnosis in sensory neuropathies. Sensory responses are more sensitive to temperature than motor responses in regard to conduction velocity, but not to nerve action potential amplitude. Warming of the extremity provides optimal readings; if this is not possible, correction factors exist for suboptimal recordings, but provide less useful information. Radiculopathies do not affect the sensory potentials, as the DRG, which lies within or outside the neural foramen, is usually not affected. This can be useful if electrophysiology is needed to distinguish between radiculopathy and plexopathy or neuropathy. Late responses (F wave, M wave) are techniques to obtain information about the proximal portions of the nerve and nerve roots. This is important because few studies permit access to proximal parts of the PNS. • The A wave (axon reflex) is a small amplitude potential of short latency (10–20  ms) and high persistence, usually

•

•

•

•

•

•

elicited by submaximal stimulation. It is generated by normal or pathologic axon branching. It may occur in neuropathies, possibly due to sprouting. The F wave is an antidromic/orthodromic motor response and can be generated from any motor nerve. It has a variable latency and amplitude and can be confused with A waves. It is clinically used to evaluate proximal portions of the nerves. The H reflex is an orthodromic sensory/orthodromic motor response and is usually obtained in the L5/S1 portion, evaluating an S1 radiculopathy. The blink reflex and the masseteric reflex are used in the evaluation of cranial nerve and brain stem function. Primary and secondary homo- and contralateral responses reveal reflex patterns in the brainstem. The masseteric reflex is induced by tapping on the chin and results in a response in the masseteric muscle. Reflex testing of deep tendon reflexes can be performed with a “trigger” hammer to elicit the reflex arc and an EMG from the respective muscle. The latencies vary between 20 and 30 ms for the polysynaptic stretch reflex, depending on the size of the person examined. In clinical practice, this technique is rarely used, although it measures an extensive sensorimotor loop. Proximal nerve stimulation studies are more difficult than the “standard” NCV studies. Proximal stimulation can be performed near-nerve with electrical or magnetic ­stimulation. The proximal parts of nerves like the long thoracic, phrenic, spinal accessory, suprascapular, axillary, musculocutaneous, femoral, and sciatic nerves can be evaluated by this method. Repetitive nerve stimulation is most commonly used to investigate the function of the neuromuscular junction. A train of stimuli is given to a peripheral nerve in a defined frequency. The resulting CMAP’s amplitude and area are

1.6 NCV/EMG/Autonomic Testing and Miscellaneous Electrophysiology

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recorded and measured. Repetitive nerve stimulation variable duration, depending on the method of assessment allows a distinction between pre- and postsynaptic trans(concentric needle, monopolar, or single-fiber technique), mission disorders. Myasthenia gravis (MG) is usually and depend on the muscle and the age of the patient. At detected at 3  Hz low-frequency stimulation, whereas mild contraction, the duration is usually in the range high-frequency stimulation (20 Hz) leads to an incremenbetween 5 and 15 ms, has up to four phases, and has an tal response in the Lambert–Eaton myasthenic syndrome amplitude maximum of 1–3  mV.  For the assessment of (LEMS). Although this technique is extremely useful, MUAP potentials, duration is more constant and reliable nonspecific decremental and incremental responses can than amplitude. also be observed in other conditions. Maximum contraction produces overlapping MUAPs, • Evoked responses, in particular somatosensory-evoked called an interference pattern in normal conditions. The responses, allow measurement of central structures, like spectrum of pathologic conditions ranges from individual the posterior columns and central nervous system pathMUAPs firing in neurogenic conditions to a full interferways, and provide additional insight into the peripheral-­ ence pattern with low-amplitude MUAPS in myopathies. central conduction properties. • Magnetic stimulation techniques are usually performed Types of pathological discharges: with a coil and can be used to measure central conduction time as a parameter for central motor function. • Fasciculations resemble MUAPs in configuration, but Stimulation at the vertebral column and in proximal have an irregular discharge pattern. They may be linked nerve segments allows measurement of these difficult-towith a visible or palpable muscle twitch. They can be approach segments. benign or occur as part of any neuromuscular condition and are notably increased in ALS. • CRDs (“bizarre high-frequency discharges”) are caused 1.6.2 EMG by groups of adjacent muscle fibers discharging with ephaptic spread from one fiber to another. They are usuEMG is the basic method to study skeletal muscle function. ally seen in chronic neurogenic and myopathic disease In Europe, concentric needle electrodes are mainly used, processes. They typically begin and end abruptly and while in the United States mainly monopolar needles in comhave a frequency of 5–100  Hz. The frequency does not bination with surface reference electrodes are used. change and contrasts with the waning and waxing pattern Three different steps of evaluation of the electrical activof myotonia. ity are usually taken: • Myotonic discharges are induced by mechanical provocation (needle, percussion). They are independent, repeti• Insertional activity is created by small movements of the tive discharges of muscle fibers at rates of 20–80 Hz. The needle electrode and results in amorphous discharges amplitude and frequency wane characteristically. The with short durations. It is usually increased in neuropathic sound is often compared to a “dive bomber.” They occur processes, but is difficult to quantify, and often labeled in myotonic dystrophy, myotonia congenita, paramyoto“irritability.” Strictly speaking, pathologic conditions like nia congenita, hyperkalemic periodic paralysis, acid maltmyotonia, neuromyotonia, myokymia, and complex ase deficiency, and myotubular myopathy. repetitive discharges (CRDs) belong in this category, but • Neuromyotonia are bursts of multiple spikes, dischargare usually considered spontaneous activity by the neuroing in high frequency (up to 300  Hz). The frequency muscular practitioner. remains constant, but the amplitude slowly decreases. • Activity at rest (spontaneous activity): A normal musSometimes groups of normal-appearing MUAPs are cle has no spontaneous activity, other than at the end called neuromyotonia, but may also be classified as plate region. The end plate region has typical short myokymia. negative spikes. Potentials generated from single mus- • Myokymia are bursts of motor unit potentials (resembling cle fibers are called fibrillations and positive sharp normal MUAPS) and appear in groups separated by interwaves. More complex discharges from the motor unit vals of silence. The frequency of the spikes is 5–60 Hz. are fasciculations, myokymia, neuromyotonia, and the They may appear focal or generalized. Focal myokymia is discharges of muscle cramps and tetany. CRDs stem often associated with radiation damage. from electrically linked muscle fibers, firing in a syn- • Cramp discharges are involuntary muscle discharges, chronous pattern. consisting of multiple MUAPs that originate from an • Voluntary activity: Voluntary innervation generates motor involuntary tetanic contraction. The discharge rate is unit action potentials (MUAP). These MUAPs have a between 20 and 150 Hz.

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1.6.3 EMG Techniques • Quantitative EMG: Usually, 20 MUAPs are analyzed for this technique. Automated or semiautomated methods are available on most EMG machines. Decomposition techniques can extract single MUAPs from an interference pattern. For analysis of the interference pattern, a turn amplitude system is available in most programs. Quantitative EMG is the backbone of EMG studies and is performed with monopolar and concentric needle electrodes. • Single-fiber (SF) EMG is performed with a special needle (SFEMG-needle), a special filter setting, and special analysis programs. The SFEMG technique permits the study of the fiber density and the time relationship between discharges of fibers. This allows measurement of the “jitter,” which depends on the functional state of the neuromuscular transmission. These studies can be used for disorders of neuromuscular transmission, but also provide insight into the stability of the neuromuscular system (reinnervation, denervation). • Special EMG applications: –– Diaphragmatic EMG. –– Tongue or eye EMG. –– Sphincteric EMG. –– EMG of the vocal cords (also monitoring of thyroid surgery). –– Intraoperative techniques. –– Surface EMG. –– Polygraphy (usually surface EMG) to monitor or detect complex functions (e.g., sleep, gait, startle reactions). How to Interpret EMG: The interpretation of EMG is based on activity at rest, spontaneous activity, characteristics of MUAPs, and the pattern at maximum contraction. The concept of EMG is based on the fact that diseases of the neuromuscular system often induce changes in the architecture of the motor unit, which induces morphologic changes and the changes of electrical activity observed in EMG.  The EMG is used to show normal, myopathic, and neurogenic activity. Specific (or almost specific) phenomena can appear, as well as evidence of denervation, reinnervation, and acute or stable conditions. EMG is considered an electrophysiological “extension” of the neurological examination, and results should be interpreted in conjunction with the patient’s clinical history, examination, and ancillary test results. The specific patterns of abnormality found with needle EMG are subsequently described in the individual disease chapters. NCV and EMG are generally considered to be safe procedures and are in routine clinical practice. General hygienic principles need to be followed, and the use of disposable

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needles is highly recommended and in nearly all settings, mandatory. Generally, the risk of a precisely placed EMG needle is low although iatrogenic side effects have been reported for both EMG and NCV. The risk in patients with anticoagulants or on antiplatelet medication is also low although electromyographers frequently avoid paraspinal EMG in the ­anticoagulated patient. Paraspinal and diaphragm EMG also have the risk of pneumothorax. The ground cable should not traverse the body and always remain on the same side as the EMG apparatus.

1.7

Laboratory Tests

Complete blood count and blood chemistries are routinely obtained on most patients presenting for diagnosis. Different neuromuscular disorders mandate more specialized serological testing, which is discussed in each chapter under the individual disorders. Unfortunately, there are no Class A studies available to define the spectrum of laboratory tests needed for the most common neuromuscular disorder: polyneuropathy. A fasting blood glucose, B12 level, and serum immunoelectrophoresis have the highest diagnostic yield. One important laboratory test is the measurement of creatine kinase (CK). This single, reliable test is usually associated with myopathies, rather than neurogenic disorders. However, transient CK elevation is also observed after exercise, muscle trauma, surgery, seizures, and acute psychosis. Asymptomatic CK elevations occur more often in people of African descent with large muscle mass. The syndrome of idiopathic hyperCKemia is a persistent CK elevation without a definable neuromuscular disease. The CSF is often studied in polyneuropathies, particularly in acute and chronic inflammatory neuropathies, and in radiculopathies. Often, inflammatory or cellular responses can be ruled out by a normal CSF white blood cell count, and elevated protein levels remain the only insignificant finding. Elevated CSF white blood cells suggest other inflammatory or infectious etiologies (Table 1.2). Immunologic studies: Autoantibodies have been described in several disease entities, like polyneuropathies, disorders of the neuromuscular junction, paraneoplastic disease, and muscle disease. The antibodies can be detected by immunofluorescence methods, ELISA, Western blotting, radioimmunoassays, thin layer chromatography, and immunofixation electrophoresis. Autoantibodies and Immune Polyneuropathies: In the most frequently occurring conditions, like acute or chronic inflammatory demyelinating polyneuropathies (AIDP, CIDP) no constant autoantibody pattern is found. There is a high frequency of anti-GM1 ganglioside antibodies in multifocal motor neuropathy with conduction block (80%). The

1.7 Laboratory Tests

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Table 1.2  Radiculitis and CSF findings Infection Borreliosis, Lyme disease Herpes zoster HIV seroconversion CMV-radiculitis Syphilis

Cell count Up to 200/μl 300/μl

8/μl 8/μl Early: 25–2000/μl IgG>> Late: May be normal Brucellosis 15–700/μl cells West Nile fever Pleocytosis Protein elevation Central European tick 60–2000/μl encephalitis

Cell type Lymphocytic, lymphomonocytic, many activated lymphocytes Lymphocytic Polymorphonuclear cells Mixed cell population Lymphomonocytic cell count

Clinical manifestation Cranial nerve: VII, meningoradicular syndrome Monoradicular (also myotomal) lesions GBS, CIDP Cauda equina syndrome Painful polyneuropathy

Other tests Antibody detection by ELISA, immunoblotting, PCR Serology Serology Specific test

Tabes dorsalis Lymphocytes, granulomatous meningitis Lymphocytic cell distribution

CN: VII, lumbar radiculopathies polyradiculopathies GBS-like polyneuropathy

Lymphocytes: 20–60% lymphocytes and 40–80% PMN

Radiculitis, myelitis, poliomyelitis-like, CN

anti-myelin-associated glycoprotein (MAG) neuropathy is a typical syndrome with MAG positivity in 50–70%. The GQ1b antibody is recorded in 95% of patients with the rare Miller–Fisher syndrome. There are several antibodies described associated with different neuropathies. These include IgM antibodies (GalC, GalNAc-GD1a, Galop, GD1a, GD1b, GM1 ganglioside, MAG, neurofilaments, SGPG, sulfatide, and tubulin) or IgG antibodies (gangliosides as GM1, GD1b, GQ1b, GT1a, GD1a). In most cases, the role and frequency of occurrence for these antibodies is not certain. In vasculitic neuropathies, c-ANCA and p-ANCA antibodies can be found. In paraneoplastic sensory neuropathies, the association with anti-Hu antibodies (or amphiphysin antibodies) is common. In Sjögren’s syndrome, IgG against SS-A and SS-B has been described. However, most of these autoantibodies seem to be an epiphenomenon, rather than a pathologic cause for the neuropathy. Paraproteinemia can occur without pathological significance or point to hematologic diseases like multiple myeloma, Waldenstrom’s disease, osteosclerotic myeloma, or lymphoma. Electrophoresis, immunofixation, and often bone marrow biopsies are needed, often in addition to skeletal X-ray and nerve biopsies. This is discussed in detail in Chap. 12.

1.7.1 Autoimmune Testing in Neuromuscular Transmission and Muscle Disorders The prototypes of neuromuscular junction disorders are MG and LEMS. The pathology of MG is localized to the postsynaptic membrane. In the majority of patients (in particular with generalized MG – about 90%), antibodies against the

Antibody testing

acetylcholine receptor (AchR) can be detected. The yield in ocular MG is lower (60–70%). There is a poor correlation between antibody titers and disease severity, but they have a high specificity for MG. About 10% of patients with typical generalized MG are seronegative for AchR antibodies; a percentage of these individuals have antimuscarinic (MUSK) antibodies although there are patients with MG who have neither antibodies. Striational antibodies lack specificity for MG, but may be helpful in thymoma detection. Other autoantibodies against proteins like titin and the ryanodine receptor (RyR) may point to epitopes in a thymoma (see Chap. 13). In LEMS, a presynaptic disorder, there are calcium channel autoantibodies directed against the P/Q type channels. These autoantibodies are detected in nearly 100% of patients with LEMS.  Antibodies against the N-type channel are detected in 74% of LEMS patients. LEMS is most commonly associated with small-cell lung cancer. Serum from patients with small-cell lung cancer is also positive for antibodies against intracellular antigens, including SOX and HU, present in 60% and 30% of patients, respectively (see Chap. 13). Autoantibodies to ganglionic acetylcholine receptors resulting in autonomic dysfunction have been described. Autoantibodies have been described in syndromes with increased muscle activity, such as rippling muscle syndrome and neuromyotonia. Neuromyotonia can be caused by an antibody against voltage-gated potassium channels at the paranodal and terminal regions of myelinated axons of peripheral nerves. The acquired type of rippling muscle disease has been described in association with thymoma and an antibody against RyR. In various types of myositis, antibodies like anti-Jo 1, anti-PL 7, anti-PL 12, anti-OJ, anti-EJ, and anti-KS, and sev-

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eral others such as SRP and MI-2, are described. While some of these antibodies may help to predict disease course, prognosis, and response to therapy, the pathogenic role of these antibodies is not well understood.

1.8

Genetic Testing (see Chap. 3)

Genetic testing is an important tool in the diagnosis of neuromuscular diseases, and since the first and second editions of this book in 2004 and 2016, respectively, the field has grown tremendously. Several techniques are presently available, and with the advent of exome sequencing, it is likely that the number of identified genetic disorders will continue to increase at an even more accelerated pace.

1.9

Neuroimaging Techniques: MR and Ultrasound (see Chap. 2)

MRI has become the method of choice for many conditions although CT remains superior in the imaging of bones and calcified structures. Ultrasound is a fast and inexpensive application with the additional ability to display dynamic processes (e.g., movement of peripheral nerves and of muscles such as the diaphragm).

1.10 T  issue Diagnosis: Muscle/Nerve/Skin Biopsy Nerve and muscle biopsy are important tools in the diagnosis of neuromuscular disease. Precise clinical, electrophysiological, and laboratory diagnostics must be done and assessed before a biopsy is done. The biopsy must be taken from the correct tissue. A neuropathologist experienced in processing samples of the neuromuscular system should be involved, and optimal tissue processing by the most current methods must be applied. There is rarely an acute indication for biopsy, except in the suspicion of peripheral nerve vasculitis, neoplastic infiltration, or florid polymyositis. The number of nerve biopsies performed on patients is decreasing due to the increased power of genetic testing as well as the sufficiency of clinical and immunological criteria for some diseases like CIDP and multifocal motor neuropathy (MMN). Imaging studies are becoming increasingly important as a precursor to biopsy. Particularly in muscle disease, imaging allows estimation of the pattern of distribution of the disease in various muscles. In patients with considerable muscle atrophy and fatty replacement, imaging helps in the selection of the muscle to be biopsied.

1.10.1 Nerve Biopsy The sural nerve is the most frequently biopsied nerve. Some schools prefer the superficial peroneal nerve or the radial nerve, and biopsies from other nerves such as the pectoral nerves can also be obtained. The nerve should be fixed in formalin, prepared for electron microscopy, and a special segment should be kept ready if nerve teasing is indicated. Immunologic studies can be best obtained on a frozen section. More materials may be necessary in cases of vasculitis. The histologic examination includes hematoxylin-eosin sections, staining for myelin, and special stains depending on the clinical case. A morphometric analysis can be used to define the population of myelinated fibers, which is bimodal in the normal nerve. Plastic-embedded sections and preparations for teased fibers should be available. The analysis of the biopsy can distinguish between axonal pathology, demyelination, regeneration, inflammation, and rare affections such as neoplastic involvement or deposition of amyloid. Several complications have been reported although generally nerve biopsy is safe. Skin punch biopsy allows an estimation of intraepidermal nerve fiber density as a measure of epidermal innervation. It is the diagnostic tool of choice in small-fiber neuropathy.

1.10.2 Muscle Biopsy Muscle tissue can be examined by several histologic techniques, including light microscopy, electron microscopy, and histochemistry. Immunohistochemistry uses available antibodies to detect immunologic alterations or defined structures. Molecular diagnosis and studying the cytoskeleton and its interaction with the sarcolemma, extracellular matrix, and transmembrane proteins has been applied in the diagnosis of dystrophies. There is a list of myopathies that warrant a biopsy, either for morphological, molecular, or biochemical analysis. However, with the advent of whole exome sequencing, this list grows shorter. In clinical practice, a biopsy is often performed to discover or confirm inflammatory conditions (dermato-, polymyositis, inclusion body myositis), structural abnormalities, and finding additional morphologic indications of neuromuscular disease. Simultaneous muscle and nerve biopsies are recommended in cases of suspected vasculitic neuropathies. The likelihood of detecting inflammatory changes is higher by using both techniques together (Fig. 1.12).

Further Readings

17

a

b

c

d

Fig. 1.12  Tissue diagnosis is often important in neoplastic nerve disease. Lymphoma: (a) small lymphoma infiltration in a nerve fascicle, (b) diffuse cranial nerve infiltration, (c) dorsal root ganglion with sparse lymphocytic infiltration, (d) cranial nerve invasion in a more patchy fashion

1.11 Neuromuscular Approaches to Quality of Life Quantification of function, impairment, disability, treatment outcome, and quality of life are parameters which require thorough, statistically valid, efficient, sensitive, and specific methods. These instruments are prerequisites for clinical studies and outcome measures, and the elected methodology may contribute significantly to the result of a study. As discussed in the beginning of this chapter, European physicians use the ICF as a metric to assess a patient’s overall function while American physicians are using a standardized National Institutes of Health Tool Box (www.ninds.nih.gov) for specific neuromuscular diseases. These newer metrics employ components of older but well-standardized motor, sensory, spasticity, respiratory, and disability scales. Pain scales are now more widely used in assessing the level of a patient’s

discomfort and monitoring success of therapeutic interventions. A new addition to the field of neuromuscular disease is the emphasis on quality of life as both a patient-centered outcome and a measure of disease efficacy. Specific quality of life-outcome tools are now available for neuropathies, myopathies, and motor neuron diseases.

Further Readings AAEM Quality Assurance Committee (2001) Literature review of the usefulness of repetitive nerve stimulation and single fiber EMG in the electrodiagnostic evaluation of patients with suspected myasthenia gravis or Lambert Eaton myasthenic syndrome. Muscle Nerve 24:1239–1247 Anonymous (2001) American Association of Electrodiagnostic Medicine. AAEM: glossary of terms in electrodiagnostic medicine. Muscle Nerve 24(Suppl 10):S1–S49

18 Arguello L, Sanchez-Montes C, Mansilla-Vivar R, Artes J, Preito M, Alonso-Lazaro N, Satorres-Paniagua C, Pnos-Beltran V (2020) Diagnostic yield of endoscopic ultrasound with fine-needle aspiration in pancreatic systic lesions. Gastroenterol Hepatol 43(1): 1–8 Burns TM, Graham CD, Rose MR et al (2012) Quality of life and measures of quality of life in patients with neuromuscular disorders. Muscle Nerve 46:9–25 Daube JR, Rubin DI (2009) Needle electromyography. Muscle Nerve 39(2):244–270 Gilhus NE (2016) Myasthinia gravis. N Engl J Med 375(26):2570–2581 Greenberg SA (2003) The history of dermatome mapping. Arch Neurol 60(1):126–131 Gwathmey KG, Pearson KT (2019) Diagnosis and management of sensory polyneuropathy. BMJ 365:I1108 Katirji B, Kaminski HJ, Ruff RL (eds) (2013) Neuromuscular disorders in clinical practice, 2nd edn. Springer-Verlag, New York Inc. Khan S, Zhou L (2012) Characterization of non-length-dependent small-fiber sensory neuropathy. Muscle Nerve 45:86–91 Kline DG, Hudson AR (1995) Nerve injuries. WB Saunders, Philadelphia, PA Lauria G, Hsieh ST, Johansson O et  al (2010) European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. Eur J Neurol 17(7):903–912 Merkies IS, Schmitz PI, van der Meché FG et  al (2000) Reliability and responsiveness of a graduated tuning fork in immune mediated polyneuropathies. The Inflammatory Neuropathy Cause and Treatment (INCAT) Group. J Neurol Neurosurg Psychiatry 68: 669–671

1 Tools Moon HS, Kim YD, Song BH et  al (2010) Position of dorsal root ganglia in the lumbosacral region in patients with radiculopathy. Korean J Anesthesiol 59:398–402 Moriishi JK, Otani K, Tanaka IS (1989) The intersegmental anastomoses between spinal nerve roots. Anat Rec 224(1):110–116 Preston DC, Shapiro B (2013) Electromyography and neuromuscular disorders: clinical-electrophysiologic correlations, 3rd edn. Elsevier Saunders, London; New York Pullman SL, Goodin DS, Marquinez AI et al (2000) Clinical utility of surface EMG: report of therapeutics and technology assessment subcommittee of the American Academy of Neurology. Neurology 55:171–177 Rutkove SB (2001) Effects of temperature on neuromuscular electrophysiology. Muscle Nerve 24:867–882 Schliack H (1969) Segmental innervation and the clinical aspects of spinal nerve roots syndromes. In: Vinken PJ, Bruyn GW (eds) Handbook of clinical neurology, vol 2. North Holland Publishing, Amsterdam/New York, pp 157–177 Siao P, Kaku M (2019) A clinician’s approach to peripheral neuropathy. Semin Neurol 39(5):519–530 Suarez GA, Chalk CH, Russell JW et  al (2001) Diagnostic accuracy and certainty from sequential evaluations in peripheral neuropathy. Neurology 57:1118–1120 Taylor GI, Palmer JH (1987) The vascular territories (angiosomes) of the body: experimental study and clinical applications. Br J Plast Surg 40(2):113–141 Thurston TJ (1982) Distribution of nerves in long bones as shown by silver impregnation. J Anat 134(4):719–728 Walters J (2017) Muscle hypertrophy and pseudohypertrophy. Pract Neurol 17(5):369–379 WB Saunders (1986) Aids to the examination of the peripheral nervous system. WB Saunders, London

2

Imaging

2.1

Introduction

Direct nerve imaging is an important complementary diagnostic modality and aids in the diagnosis of a peripheral nerve injury, including injury secondary to trauma (Amrami et al. 2008). Direct nerve imaging is also an important prerequisite to localize anatomical structures prior to nerve biopsy. These same statements hold true for muscle, where imaging has become an essential part of diagnosis and treatment paradigms (Ohana et al. 2014). The best imaging modalities for nerves and muscles are MRI and ultrasound (Fig. 2.1). CT and conventional radiographs may also be used, especially to depict bony structures or calcified pathologies, but both fail to depict peripheral nerve morphology. In the visualization of muscle parenchyma CT is clearly inferior when compared to MRI.

2.2

Ultrasound

Since early descriptions of the visualization of peripheral nerves (Fornage 1988), ultrasound hardware, examination protocols, and knowledge of specific findings have been advancing at an increasingly fast pace. The ultrasound examination of nerves can change the diagnostic and therapeutic management after NCS and EMG in over 42% of cases (Padua et al. 2012). Peripheral nerve injuries provide a good example: when electrophysiological examination shows a conduction block after trauma, it is not possible to further distinguish between an axonotmesis (an injury to the axon but the coverings of the peripheral nerve are intact) or a neurotmesis (an injury where the peripheral nerve is completely divided). Here, ultrasound can detect the potential transection of the nerve so the decision whether nerve surgery is necessary can be made immediately after the trauma (Hollister et al. 2012).

Contributions by Stefan Meng, Gregor Kasprian, Hannes Platzgummer

2.2.1 What Can be Seen with Ultrasound In the ultrasound examination of nerves, it is a standard procedure to scan the nerve in a longitudinal and transverse plane. In the latter, we can see the nerve as a round structure surrounded by a hyperechoic rim, which represents the outer epineurium, and many hypoechoic dots inside the nerve— the fascicles. The hyperechoic area between the fascicles corresponds to the inner epineurium (Fig. 2.2). In a longitudinal view, fascicles are depicted as hypoechoic stripes. We can track a single fascicle within a nerve over a long distance and recognize branching and merging of fascicles. A sensitive Doppler mode depicts the vascular architecture within the nerve as well as the flow spectrum within the above-­ mentioned intraneural blood vessels. Muscle ultrasound is already well established in the diagnosis of musculoskeletal disorders. Fascicles of muscle fibers are depicted as hypoechoic stripes with surrounding hyperechoic perimysium and epimysium. Tendon tissue forming within the muscle is hyperechoic. Muscle contractions can be visualized in real-time, recorded, and measured (Pillen et al. 2016). With ultrasound we can also assess various structures around nerves and muscles which may contribute to a patient’s symptoms, e.g., bony spurs, osteosynthetic screws, foreign bodies, tumors, scar tissue formation, hematoma, and cysts, for example. An additional increasingly important feature of ultrasound is that we can use this method to guide needles to specific structures, e.g., injection cannula to reach a specific nerve either for verification or in a therapeutic approach, or EMG needle probes.

2.2.2 P  athological Patterns Identified by Ultrasound Pathological states of a nerve vary widely in appearance.

© Springer Nature Switzerland AG 2021 E. L. Feldman et al., Atlas of Neuromuscular Diseases, https://doi.org/10.1007/978-3-030-63449-0_2

19

20

2 Imaging

a

b

c

d

Fig. 2.1  Axial (a) and longitudinal (b) high resolution ultrasound images of the median nerve, showing a tumorous swelling (arrows). Axial T2-weighted sequence (c) and sagittal STIR sequence (d) depict-

a

ing the neurogenic mass (arrows) of the median nerve. After resection, histology showed the typical appearance of a median nerve ancient Schwannoma

b

Fig. 2.2  Ultrasound scan of a peripheral nerve. Transversal (a) and longitudinal (b) scan of the median nerve (arrowheads) at the distal forearm. Note the fine hypoechoic stripe (arrows) which represent one fascicle

There may be a discontinuity of the entire nerve or of one or more fascicles after a cutting injury or in traumatic ruptures (Fig. 2.3). Other pathologies may present themselves as a round- or spindle-shaped swelling. These swellings may be

short or affect long segments of the nerve. In some cases, these swellings can be found along the entire course of the nerve or multiple nerves, e.g., these can be found in inflammatory diseases or as a sequela of a traction lesion. As very

2.2 Ultrasound

21

phies, inflammatory myopathies, congenital myopathies, and motor neuron diseases (e.g., SMA and ALS). Finally, ultrasound of muscles can also facilitate diagnosis in peripheral neuropathies (Pillen et al. 2016).

2.2.3 Ultrasound Equipment

Fig. 2.3  Nerve transection. Complete transsection of the radial nerve (arrowheads) in the spiral groove after a stabbing injury. Longitudinal ultrasound scan of the distal stump. Humerus (asterisks). Note the fold back of the distal nerve stump

Fig. 2.4  Myopathy. Ultrasound of the ventral flexors show structural disarray of muscle tissue (arrows)

sensitive probes are available, changes of intraneural ­vascularity can be visualized, which may be a part of an inflammatory process. Tumor or tumor-like alterations may be very small and only detectable with very high-frequency ultrasound probes. Conversely, huge tumors may surpass the field of view, even of abdominal ultrasound probes. During movements of the body nerves, change their position in longitudinal and transverse planes. In some entrapment pathologies, this movement can be substantially reduced (Meng et al. 2015). In muscles, we can recognize changes of echogenicity and size (Fig. 2.4). In some cases, edema in the muscle tissue can be detected with ultrasound; however, MRI is by far more sensitive. The superior temporal resolution of muscle ultrasound allows the detection and recording of muscle movements. Ultrasound can be used in muscular dystro-

Although data sheets and image settings of different clinical ultrasound systems may be similar, image characteristics and image quality are different. Most current ultrasound probes do not work with one single frequency, but have a broad spectrum of frequencies. The final image is then composed of image data from various frequencies preselected by an integrated algorithm. The examiner can only indirectly change this composition. In general, a high transducer frequency leads to high spatial resolution, but also to a small penetration depth. Conversely, a low transducer frequency has a low spatial resolution, but a better depiction of structures which are deep in the body. Most abdominal probes use low frequencies within a range of 2–8 MHz, which allows only a rough depiction of large nerves, such as the sciatic nerve in the posterior thigh. Probes for the Doppler examination of the carotid artery are around 9 MHz and show a better image of deep lying nerves. High resolution probes, which should be the first choice in neuromuscular ultrasound, are above 10 MHz, and ideally above 14 MHz. Very high resolution probes with frequencies over 20 MHz may be used for cutaneous nerves. Probes with 50  MHz or more have a limited spectrum of applications as the depth of view is confined to a shallow region mostly in or closely under the skin. Even if raw image data could be identical between two ultrasound systems, image post-processing alters the image and shows an optimized “photoshopped” version of the raw image. This post-processing is increasingly important, as it strongly improves the image and thus facilitates visualization of the pathology. However, in the same way it can also mask or hide the pathology, so ultrasound of neuromuscular structures requires some technical understanding. Finally, one has to acknowledge that individual pattern recognition varies, e.g., some examiners detect most pathologies with “hard images” (high contrast, hard edges, small dynamic range with only a few shades of grey), and some prefer a “soft image” with a larger dynamic range (low contrast, soft edges, large dynamic range with many different shades of grey).

2.2.4 S  afety and Contraindications of the Use of Ultrasound Generally, diagnostic ultrasound is considered a safe modality. There is no ionizing radiation.

22

Ultrasound waves, however, have the potential to produce biological effects in the body, as they may slightly heat the tissue or lead to cavitations, in which small amounts of gas are produced in liquid or solid body regions. As the long-­ term consequences of these effects are not known, it is advised that diagnostic ultrasound only be performed by trained health care providers. Please see related statements by the U.S. Food and Drug Administration (FDA; www.fda.gov/radiation-emitting-products/medical-imaging/ultrasound-imaging) and the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB; www.efsumb.org/blog/archives/885).

2.2.5 Problems with Ultrasound Ultrasound has two major problems. The first problem is based on the physical properties of ultrasound. It is not possible to see past gas or bone tissue. For example, with ultrasound the brachial plexus can be assessed with ease and accuracy, but the lumbar and sacral plexus are hidden behind the pelvic bones and gas-filled intestines. Deep lying structures can only be visualized with lower frequencies, and thus with a lower spatial resolution, which impedes the examination of deep lying small nerves or small pathological changes. The second problem arises with the way the patient is examined. Ultrasound is strongly examiner-dependent, and recorded ultrasound images do not have the same quality as a live examination. In the case of a second opinion, the examination would have to be performed again, with the limitation of being performed under potentially different circumstances at a different time point. This can present a problem with clinical diagnoses as well as the use of ultrasound as a research tool.

2.2.6 Ultrasound in Daily Clinical Practice The general versatility of ultrasound also allows ultrasound-­ guided procedures to be easily integrated into clinical practice. In addition to standard EMG, ultrasound allows precise placement of EMG needles into the targeted muscle or muscle segment under image guidance. In the same way, botulinum toxin can be injected into the appropriate muscles with superior precision, ease, and avoidance of critical structures. With ultrasound guidance, corticosteroids can be applied precisely around nerves in a conservative therapeutic attempt. Similarly, tiny amounts (34 repeats) in the gene DMPK Expansion of a CCTG repeat within a complex repeat motif (usually several thousand repeats, up to 11,000) GCG trinucleotide expansion in the gene PABPN1 (>10 repeats)

Contraction of D4Z4 repeat array (chromosome 4) (FSHD1), hypomethylation of D4Z4 repeat array due to a heterozygous variant in SMCHD1 (FSHD2) Non-dystrophic myotonias Usually due to ion channel mutations in chloride (CLCN1) and sodium channels (SCN4A) Limb-girdle muscular dystrophies Genetic heterogeneity (genes encoding calpain, (LGMD) sacroglycan, dysferlin, etc.), >30 loci known Distal myopathies Genetic heterogeneity, e.g., Udd myopathy (TTN gene), hereditary inclusion body myopathy (VCP gene) Congenital myasthenic Multiple neuromuscular junction-related genes syndromes (CMS) implicated (most commonly CHRNE, COLQ, DOK7) Mitochondrial disorders Clinically and genetically heterogeneous, e.g., CPEO, MERRF, LHON, etc. with systemic, PNS and CNS manifestations Charcot–Marie–tooth disease 1 Duplications of PMP22 gene in 70% of cases (demyelinating) (CMT1A) Deletions of PMP22 gene Hereditary neuropathy with liability to pressure palsies (HNPP) Charcot–Marie–tooth disease 2 Genetic heterogeneity, approximately 30% due to (axonal) variants in MFN2 gene Hereditary sensory and High genetic heterogeneity autonomic neuropathy (HSAN) Hereditary transthyretin Heterozygous pathogenic variants in TTR gene amyloidosis Familial amyotrophic lateral 20–30% intronic C9orf72 expansions, other genes: sclerosis (fALS) FUS, SOD1, TARDBP, etc. Spinal muscular atrophy (SMA) Classical form due to homozygous deletions of SMN1 gene (SMN2 acts as modulator of clinical severity); other forms are rare and genetically heterogeneous (e.g., BICD2, ATP7A, CHCHD10) Hemizygous CAG trinucleotide expansion (>35 Spinal and bulbar muscular repeats) in AR (androgen receptor) gene atrophy (SBMA) = Kennedy’s disease Hereditary spastic paraparesis Enormous genetic heterogeneity (>80 loci) with a (HSP) variety of underlying biological mechanisms

Inheritance/additional information X-linked inheritance, usually only males affected, gene therapy in early stages X-linked inheritance, onset later in life and milder disease course than in DMD AD inheritance, repeat expansion may be missed by NGS-based tests AD inheritance, repeat expansion may be missed by NGS-based tests AD (12–17 repeats) or AR (11 repeats) inheritance, may even be detected by NGS given the limited length AD/digenic inheritance

AD and AR inheritance, Mexiletine as targeted treatment AD (LGMD1) and AR (LGMD2) forms AD and AR forms

AD and AR forms, available targeted treatment approaches (fluoxetine, quinidine, beta-adrenergic agonists) Maternally inherited mtDNA, but also large number of mitochondrial genes within nuclear genome Classical CMT1A = AD inheritance, sometimes de novo mutations AD inheritance

Mostly AD inheritance, NGS useful as a first-tier diagnostic approach AD, AR, X-linked forms, rare AD inheritance, targeted treatment with tafamidis (TTR-stabilizing drug), gene therapies In most cases, AD inheritance, overlap with FTD, C9orf72 expansions not detectable by NGS SMN1-related SMA = AR inheritance, may be missed by NGS approaches because of pseudogene SMN2, gene therapy X-linked inheritance, only males affected, complete penetrance with >38 repeats All types of inheritance observed (NGS-based approaches useful early in diagnostic pathway), clinical pure (only spasticity), or complex/ complicated forms (with additional CNS or PNS symptoms)

AD autosomal dominant, ALS amyotrophic lateral sclerosis, AR autosomal recessive, CNS central nervous system, CPEO Chronic progressive external ophthalmoplegia, FTD frontotemporal dementia, LHON Leber’s hereditary optic neuropathy, MERRF myoclonic epilepsy with ragged-­ red fibers, mtDNA mitochondrial DNA, NGS next-generation sequencing, PNS peripheral nervous system

30

3  Genetic Testing in Neuromuscular Diseases

Table 3.2  Comparison of different next-generation sequencing applications (gene panels, exome and genome sequencing) Gene panels Targeting a predefined set of disease genes depending on phenotype (sometimes whole-exome is sequenced and only analysis is targeted) Best coverage (read depth) of target regions, sometimes using additional technologies: Sanger sequencing, CNV array, repeat detection, etc.) Lower sequencing costs

Exome sequencing Sequencing of virtually all coding regions (1–2%) at comparably high coverage

Genome sequencing Extensive, more uniform but lower coverage of whole genome

Results in very large Exon-intron datasets (data storage boundaries are problem) often covered as well (intronic splice-site variants)

Not all exons are Largest part of sufficiently covered sequences (intronic, intergenic), but very difficult to interpret Best detection rate of May not detect Lower rate of VUS/ repeat expansions, structural variants fewer interpretation complex structural (CNVs) difficulties variation (most CNVs involving coding regions can be detected) Reanalysis and Reanalysis and Does not account for detection of novel detection of novel atypical phenotypes, disease genes possible no novel disease genes disease genes possible can be detected Largest number of No secondary Large number of (actionable) findings VUS and secondary VUS and secondary findings (may be findings complemented by transcriptomics/ proteomics)

CNV copy number variation, VUS Variants of uncertain significance

appropriate coverage of missed exons, Southern blots to account for repeat expansions, or microarrays for the analysis of structural variation (CNVs). So far, several studies have addressed the clinical utility of comprehensive gene panels in neuromuscular disorders, resulting in variable diagnostic hit rates between 20 and 30%, mainly depending on the panel design, the selected patient population and the investigated phenotype (Beecroft et al. 2020; Winder et al. 2020).

3.3.2 Exome Sequencing Exome sequencing, sometimes referred to as whole-exome sequencing, is a type of NGS that is confined to the coding regions, which together make up approximately 1–2% of the entire human genome. This approach is based on the idea that the vast majority of Mendelian diseases (at least 80%) is

secondary to pathogenic variation in exons. In theory, exome sequencing has the potential to directly confirm more than 5000 phenotypically and genetically heterogeneous conditions with one single test. It is thus widely considered as the current technology of choice for the diagnosis of monogenic neurological disorders (Rexach et  al. 2019). When well-­ selected neurological patients with presumably monogenic conditions are properly identified and analyzed using exome sequencing, a molecular diagnosis can be established in up to 40% (Srivastava et al. 2014). Such an unbiased analysis of virtually all 20,000 genes accounts for unexpected genetic etiologies that are easily missed by narrowly targeted panel designs. Therefore, the diagnostic yield of exome sequencing may be higher when compared to gene panels (Krenn et al. 2020). Significantly increased diagnostic hit rates observed in consanguineous populations reflect the additional influence of patient selection on the testing outcome (Fattahi et al. 2017).

3.3.3 Genome Sequencing While gene panels and exomes are already routinely used in the standard workup for Mendelian conditions, the use of genome sequencing is still largely limited to research settings. Aside from an enormous volume of sequence data that needs to be stored, one major difficulty is the abundance of variants that require analyses. Deep intronic variants represent a major challenge for interpretation, as their functional impact is often unknown and difficult to predict. One evolving method to better appreciate these variants is the complementary use of transcriptome sequencing, which is a powerful tool to enhance outcomes by detecting defects that result in aberrant splicing or differential gene expression. In one study specifically focusing on neuromuscular phenotypes, transcriptome sequencing yielded genetic diagnoses in 35% of previously unsolved families (Cummings et  al. 2017). When compared to exome sequencing, whole-genome-­ wide data show a less deep but more uniform coverage across the coding regions. Another theoretical advantage of genome sequencing is the increased sensitivity to detect structural variants (CNVs) and exactly define the breakpoints of deletions. Taken together, all different applications of genomic testing have their advantages and drawbacks, and at the moment, no clear guidelines exist regarding which test to use as a first-­ tier approach. However, there is overall increasing evidence for the cost-effectiveness of broad genomic approaches (such as exome and genome sequencing) early in the diagnostic pathway, when compared to more narrow types of testing (Schofield et al. 2017). Figure 3.1 illustrates a principal sug-

3.4 Interpretation of Genetic Testing Results

31

Genetic diagnostics in neuromuscular diseases

Specific phenotype

Unspecific phenotype

Multiple genes Gene panel (depending on phenotype)

Single gene/variant

if negative Targeted diagnostics (e.g., single gene, CNV microarray, repeats)

if negative if negative

Exome/Genome sequencing (may detect novel disease genes, yields unpredictable findings)

Fig. 3.1  Suggested workflow for the selection of next-generation sequencing applications in neuromuscular disorders

gestion for genetic-diagnostic decision-making that needs to be modified depending on local conventions, general availability, and most importantly, the specific phenotype in question.

3.4

Interpretation of Genetic Testing Results

Exome sequencing may detect around 25,000 and genome sequencing five million variants per sample, and this long list of variants needs to be narrowed down to differentiate potentially disease-relevant variants from the large amount of benign background variation. To this end, specific analysis pipelines are used, which may slightly differ between laboratories. In a first step, a significant number of variants may be filtered out because of insufficient sequencing quality, high frequencies in the general population (as reflected by ExAC, gnomAD databases) or the lack of consequences on a protein level (i.e., synonymous variants with no changes of the amino acid sequence). This filtering already reduces the number of variants to a few hundred in a step-by-step manner. In addition, family genotype data may help to assess pathogenicity, either if a certain variant is shared between multiple affected family members (familial segregation) or if it occurs de novo.

The strict clinical-genetic guidelines of the American College of Medical Genetics and Genomics (ACMG) are widely accepted for the classification of genetic variants in a diagnostic setting (Richards et al. 2015). According to different strands of genetic, phenotypic, and bioinformatic evidence, variants are classified into five different categories: (1) pathogenic, (2) likely pathogenic, (3) variant of uncertain significance (VUS), (4) likely benign, and (5) benign. Only cases with pathogenic and likely pathogenic variants (in keeping with the expected pattern of inheritance) are considered as diagnostic variants, if compatible with the expected mode of inheritance. Variants may also be considered pathogenic, if they have already reliably been reported as disease causing in other families. Useful references for previously described disease-­ related mutations are the Human Gene Mutation Database (HGMD) (Stenson et al. 2017) and ClinVar (Landrum et al. 2018). Although such repositories can be extremely helpful, the reported variant assessments need to be considered with caution since misclassifications are not uncommon. Another frequently encountered problem is the classification of very rare and previously undescribed missense variants in candidate or disease genes because their disease-causing effect may only be proven by additional experiments. In these cases, computational in silico prediction tools such as PolyPhen-2 and/or Combined Annotation Dependent Depletion (CADD) score may be useful to pre-

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3  Genetic Testing in Neuromuscular Diseases

dict the impact of a variant on a protein level, e.g., based on evolutionary conservation and/or structural and biochemical changes of amino acid substitutions. Nonetheless, one must be cautious not to overinterpret rare variants that do not fulfill the strict criteria for pathogenicity since this may have significant implications for genetic counseling. Therefore, these variants often remain classified as VUS in a diagnostic report.

3.5

Diagnostic Reassessment and Periodic Data Reanalysis

It is increasingly acknowledged that the interpretation and classification of variants should not be limited to the assessment of a genetic-diagnostic testing laboratory. Instead, recent data support an interdisciplinary setting involving geneticists, clinicians (e.g., neuromuscular specialists) and bioinformaticians within the framework of clinical-genetic boards to discuss the possible impact of detected variants. In many cases, uncertain variants need to be re-evaluated by clinicians, followed by focused re-phenotyping or complementary diagnostic testing (laboratory tests, functional investigations, additional neuroimaging, and family genotyping). This may eventually allow a more precise classification of initial genetic-diagnostic results, as it has been specifically demonstrated for genetic neuromuscular diseases (Krenn et  al. 2020). Furthermore, in contrast to predefined gene panels, the more comprehensive exome or genome datasets offer the opportunity for a periodic reanalysis. This has the potential to further enhance the diagnostic testing outcomes, as the knowledge about genetic variants is constantly expanding and novel disease genes are being discovered at a rapid pace (Wenger et al. 2017).

3.6

Limitations of Genomic Testing

Although currently available NGS applications represent a great advancement in comparison to previous types of genetic testing, more than 50% of patients still remain undiagnosed even in thoroughly selected cohorts. One can argue that some of these genetically unresolved cases may indeed display an acquired or polygenic etiology. However, there are also some inherent limitations of NGS, indicating that some genetic diagnoses may simply be missed. First, conventional short-read NGS (i.e., using short DNA fragments of usually  IgG > IgA. Diagnosis: Laboratory: Immunofixation electrophoresis reveals a gammopathy of significance. If there is clinical suspicion for a paraproteinemic syndrome, further testing can be pursued, including urine immunofixation electrophoresis as well as free light chain testing, which depends on the heavy or light chain subtype. Of IgM MGUS neuropathies, for example, half develop antibodies to myelin-associated glycoprotein (MAG), and this should be tested for when there is a concordant clinical phenotype (demyelination on nerve testing, ataxia, weakness, and sensory loss on exam). Electrophysiology: Neurophysiologic pattern depends on the monoclonal gammopathy, with IgM-associated distal acquired demyelinating sensorimotor (DADS) showing demyelination, whereas IgG-associated neuropathies are axonal. Imaging: A skeletal survey should be done to evaluate for lytic lesions in the setting of a monoclonal gammopathy of undetermined significance. Differential Diagnosis: A true MGUS-associated neuropathy is a diagnosis of exclusion and should only come after more concerning paraproteinemias are excluded, such as multiple myeloma, IgM anti-MAG-associated DADS neuropathy, amyloid neuropathy, or POEMS associated neuropathy. Therapy: IgG monoclonal gammopathies associated with a CIDP-like picture frequently respond to immunosuppression and plasmapheresis. Other monoclonal gammopathies are less responsive, even in the presence of a CIDP-like pattern.

Table 12.4  Approach to the evaluation of a patient with a monoclonal protein identified in conjunction with peripheral neuropathy Monoclonal gammopathy subtype IgM kappa or lambda

IgA or IgG, lambda Any type including light chain only

Plasma cell disorder MGUS

Peripheral neuropathy phenotype Length-dependent, sensory predominant, demyelinating Similar to IgM-MGUS Waldenström neuropathy with more common macroglobulene-­ axonal involvement mia POEMS syndrome Sensory and motor, demyelinating more than axonal, polyradiculoneuropathy Amyloidosis Length-dependent (or polyradiculoneuropathy) sensory and motor, axonal

Autonomic involvement −

Systemic symptoms −

−

Yes

Hemoglobin, platelet count, IgM levels, β2-microglobulin

+

Yes

+++

Yes

Platelet count (thrombocytosis, vascular endothelial growth factor (VEGF), endocrine studies) 24-h urine total protein, complete blood count, creatinine, alkaline phosphatase, troponin, brain natriuretic peptide, or N-terminal pro-brain natriuretic peptide levels

Helpful laboratory markers MAG antibodies

Reproduced with permission from Stino AM, Naddaf E, Dyck PJ, Dyck PJB.  Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP)—Diagnostic pitfalls and treatment approach of CIDP in Medical Practice, Muscle Nerve, In Press

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12 Polyneuropathies

12.3.3  Demyelinating Neuropathy Associated with Anti-MAG Antibodies Genetic testing

NCV/EMG ++

Laboratory ++

Imaging

Biopsy

Anatomy/Distribution: Demyelination occurs in sensory and motor nerves, with disproportionate involvement of nerve terminals. Symptoms: Symptoms of ascending numbness and ataxia progress slowly over months to years. Pain is usually minimal. Clinical Syndrome/Signs: Gait disorders occur in 50% of patients. Intention tremor may develop late in disease. Weakness is usually minimal at disease onset, but can become severe with disease progression. Sensory loss is symmetric. Pathogenesis: Anti-MAG IgM antibodies result in complement deposition on peripheral nerve myelin with minimal cellular infiltration compared to other inflammatory neuropathies, leading to widening of nerve myelin lamellae and resultant impairment in NCV. Diagnosis: Laboratory: IgM M-spike protein is present in all patients. Anti-MAG IgM antibody is positive, and titer can quantify level, although it is not a useful measure of disease severity. Electrodiagnostic Studies: Prolonged distal latencies, slowed sensory and motor NCVs without conduction block, and prolonged F waves are seen. Imaging: None. Nerve biopsy: Electron microscopy demonstrates widening of myelin lamellae. Therapy: There are currently no approved therapies, although there are small studies showing some efficacy with rituximab. Prognosis: This is a progressive disorder that frequently results in falls in the elderly secondary to severe sensory loss; motor function remains much more intact than sensory function, which is the common underlying cause of physical disability.

12.3.4  Waldenström’s Macroglobulinemia Associated with chronic lymphocytic leukemia or lymphoma. Symptoms: Large-fiber sensory function is lost and there may be a tremor. Signs: The disease presents as a sensorimotor neuropathy with a predilection for large-fiber involvement. It is difficult to distinguish from MGUS, and MGUS may evolve into Waldenström’s over time. Pathogenesis: There is likely an autoimmune attack against peripheral nerves. Diagnosis: Skeletal survey is normal. Laboratory studies can show IgM monoclonal gammopathy, IgM antibodies to

MAG, GM1, sulfatide, GD1a, or GD1b. Bone marrow and/or lymph node biopsy may be abnormal. Nerve studies show comparable axonal loss between IgM MGUS neuropathy and Waldenstrom neuropathy although there is less demyelination than in IgM MGUS. Therapy: Chemotherapy, intravenous immunoglobulin (IVIG), and plasmapheresis can be effective. Prognosis: Neuropathy can often be arrested or improved with treatment.

12.3.5  POEMS Syndrome POEMS syndrome stands for polyneuropathy, organomegaly, endocrinopathy, M-component, and skin lesions (Fig. 12.6). POEMS syndrome is also called osteosclerotic myeloma, with sclerotic lesions often involving the vertebral column and long bones, but not the skull. A polyneuropathy resembling CIDP occurs and papilledema has been described. Symptoms: Large-fiber sensory function is lost and the condition can be rapidly progressive, leading to severe distal and proximal weakness, and sometimes to respiratory compromise. Signs: The disease presents as a predominantly demyelinating sensorimotor neuropathy with a predilection for large-­ fiber involvement, although there are key differences from CIDP. Non-neurologic manifestations are equally important, including leg swelling, papilledema, and rapidly progressing proximal weakness. Pathogenesis: POEMS syndrome is a paraneoplastic disorder occurring in the setting of an underlying plasma cell neoplasm. Vascular endothelial growth factor (VEGF) plays a major role in increasing vascular endothelial permeability and contributing to pathogenesis. Diagnosis: Laboratory: Immunofixation electrophoresis often shows a combined IgA or IgG lambda monoclonal gammopathy although the lambda spike is quite low. VEGF level elevation further confirms the diagnosis. Endocrine lab changes as well as the presence of thrombocytosis are all helpful findings supportive of the diagnosis of POEMS. Electrophysiology: Although demyelinating like CIDP, there is disproportionate axonal injury on NCS, with demyelination typically being more uniform. Imaging: Skeletal survey often shows sclerotic lesions although PET imaging may be needed  to identify such lesions. Nerve Biopsy: Nerve biopsies do not show the typical onion-bulbing seen in CIDP, but rather axonal degeneration and epineurial neovascularization. Bone marrow histopathology shows λ-restricted monoclonal gammopathy, plasma cell rimming around lymphoid aggregates, and megakaryocytic hyperplasia.

12.3  Neuropathies Associated with Paraproteinemias

a

225

c

b

Fig. 12.6  An autopsy from a patient with POEMS syndrome. (a) A DRG, normal nerve cells. (b) Paravertebral small spinal nerve: loss of myelinated fibers with the remaining myelin sheath stained with anti-IgG (arrow). (c) Myelinated motor nerve roots

Therapy: Therapy consists of systemic chemotherapy often in combination with stem cell transplantation. Prognosis: Proper treatment significantly alters the natural history of disease and can arrest neuropathy progression. If left untreated, prognosis is guarded, and the disease is fatal.

12.3.6  AL and TTR Amyloid Neuropathy Genetic testing ++

NCV/EMG ++

Laboratory +++

Imaging ++

Biopsy +++

Amyloidosis involves the excessive generation and deposition of insoluble fibrillary proteins in β-pleated sheets in various organ systems. There are numerous forms, including acquired light chain (AL) amyloidosis, familial amyloidosis, secondary amyloidosis (associated with chronic inflammation and infection), and beta-2-microglobulin amyloidosis (seen in chronic renal failure). In this section, AL amyloid polyneuropathy and familial amyloid polyneuropathy (FAP) will be discussed. Of the various forms of familial amyloidosis, we will focus our discussion on transthyretin (TTR)associated amyloid neuropathy, which is the most common subtype. Epidemiology: Acquired amyloid neuropathy is found in about 20% of patients with primary AL amyloidosis, 10% of whom can have multiple myeloma. It generally affects patients ages 50–80 with a 2:1 male to female predilection. FAP due to TTR mutations is endemic in Portugal, Sweden, and Japan. Sporadic cases are rare but found worldwide.

Apolipoprotein A-1 FAP is rare; gelsolin FAP is almost exclusively found in individuals of Finnish descent. Anatomy and Pathophysiology: In AL amyloidosis, the bone marrow produces excessive light chain antibodies (kappa or lambda) that are misfolded and cannot be broken down, and which deposit in numerous organ systems. In TTR amyloidosis, the liver produces mutated TTR protein that causes unstable tetramers, which subsequently dissociate into monomers then oligomers and then fibrils. The most common pathogenic mutation worldwide is the Val30Met mutation (Portugal, Sweden, Japan), while in African Americans in the United States, the most common mutation is the Val122Ile. Congo red staining identifies amyloid deposition in various tissues (Fig.  12.7). Amyloid distribution is multifocal and is found in the endoneurium and capillary walls. Amyloid can also be seen on electron microscopy. Laser microdissection mass spectroscopy can differentiate hereditary from acquired amyloidosis. Immunolabeling with anti-TTR antibodies confirms the diagnosis of TTR amyloidosis. Currently available genetic sequencing and deletion/duplication testing can evaluate for TTR amyloidosis. Symptoms: In AL neuropathy, neuropathic pain in the distal  legs is typical. Orthostatic intolerance, impotence, bladder dysfunction, and reduced sweating are common. Weight loss also occurs. In TTR-FAP, early-onset (third to fourth decade) patients report discomfort and neuropathic pain in the feet. Symptoms

226

Fig. 12.7  Peripheral nerve amyloidosis. The biopsy shows a congo red-stained section with evidence of birefringence in amyloid deposits within endoneurial vessels

progress and extend more proximally within months, and numbness and weakness develop. Postural hypotension, impotence, bladder dysfunction, weight loss, and gastrointestinal dysfunction are early symptoms. Late-onset (sixth to eighth decade) TTR-FAP is commonly less painful with mild autonomic symptoms and a slower progression. Signs: In both acquired AL and hereditary TTR amyloid, temperature and pain sensation are impaired. With disease progression, vibration and light touch perception are also impaired and distal weakness develops. Weight loss, macroglossia, organomegaly, and cardiomyopathy are found in AL. With regard to TTR amyloidosis, rare subtypes present with multifocal neuropathy of upper limbs or ataxia. Carpal tunnel syndrome occurs disproportionately in TTR families. Extraneurological manifestations in TTR amyloidosis frequently include restrictive cardiomyopathy and ocular opacities. Causes: Primary acquired amyloidosis is caused by overproduction of monoclonal immunoglobulin light chains. While multiple genetic variants cause FAP, TTR is by far the most common. Within TTR, the Val30Met accounts for most mutations in Portugal and Sweden (two hotspots) and for approximately 50% of mutations worldwide. Among African American, the Val122Ile mutation is the most common. Diagnosis: Laboratory: For the workup of suspected AL amyloid, monoclonal light chain gammopathy can be detected on both serum and urine testing. IgG is more frequent than IgA and IgM, and lambda light chains are more frequent than kappa light chains. For suspected hereditary TTR amyloid, in addition to the above serum and urine-based testing, serum-based full-gene sequencing, and deletion/duplication analysis testing of the TTR gene is now commercially available, and is an integral part of the diagnostic workup, especially prior to initiating gene-targeted therapies. Electrophysiology: At early stages (especially small-fiber neuropathy predominant), NCS can be normal. After a few

12 Polyneuropathies

months, SNAPs are reduced or absent. CMAPs can also be reduced. NCVs are normal or slightly reduced. Carpal tunnel syndrome (CTS) is frequently found. Imaging: Technetium-99 m pyrophosphate imaging demonstrates 100% specificity and 97% specificity at distinguishing TTR from AL amyloid, and a 92% specificity in diagnosing TTR amyloid. MRI cardiac imaging is also helpful at evaluating for both AL and TTR amyloid and shows diffuse and irregular hyperenhancement of myocardium that is usually circumferential and subendocardial. Nerve and other tissue biopsy: The presence of a monoclonal gammopathy and demonstration of amyloid in liver, nerve, abdominal fat, rectal mucosa, gingival, and/ or salivary gland biopsy suggests AL amyloidosis, although low-grade MGUS can also be found in FAP. The diagnosis of AL amyloid can be challenging due to frequent negative tissue biopsy, but clinical suspicion should be the guide. Genetic analysis of the TTR gene is appropriate to diagnose most cases of FAP, with tissue and serology-based diagnosis now less needed. Differential Diagnosis: Other causes of rapidly progressive axonal neuropathies with small-fiber and autonomic involvement should be considered. Therapy: AL amyloidosis is treated with chemotherapy and stem cell transplantation. For TTR-FAP, liver transplantation had been the only available treatment. Recently, antisense oligonucleotide and RNA interference therapy gained approval for the treatment of TTR amyloidosis in both the United States and Europe. Inotersen is an antisense oligonucleotide that targets mRNA and pre-mRNA in the nucleus for degradation via splicing interference. Patisiran operates in the cytosol by targeting mRNA for destruction and also by impeding ribosomal translation. Inotersen is given subcutaneously once weekly, but carries some thrombocytopenic risk. Patisiran is administered every 3 weeks intravenously and carries little adverse event risk. Tafamidis, a selective TTR tetramer stabilizer, is also approved in both the United States and Europe for the treatment of TTR amyloidosis, and slows neuropathy progression. Treatment of neuropathic pain follows the standard treatment guidelines.

12.4 Vasculitides 12.4.1  Nonsystemic Vasculitic Neuropathy Genetic testing

NCV/EMG ++

Laboratory +

Imaging +

Biopsy ++

Distribution/Anatomy: Both sensory and motor fibers are affected in individual peripheral nerve and cranial nerve distributions.

12.4 Vasculitides

Symptoms: The symptoms in vasculitic neuropathy are dependent on which nerve(s) are affected. As a class, this neuropathy is usually painful and patients experience both sensory loss and weakness in multiple named nerves (85% of cases). Motor deficits are quite severe and sudden in onset, with patients reporting abrupt onset wrist or foot drop. Fifteen percent of patients present with a symmetric polyneuropathy. Clinical Syndrome/Signs: Examination reveals sensory loss and weakness in affected peripheral or cranial nerves (multiple mononeuropathies, see Fig.  12.8) and, rarely, a stocking–glove pattern of sensory loss and weakness. Most commonly, there is dense, focal, asymmetric weakness on exam, manifesting in a nerve (rather than myotomal) distribution (e.g., fibular nerve foot drop, radial nerve wrist drop, ulnar nerve claw hand). Diagnosis: Laboratory: The serological markers of vasculitis depend on whether it is systemic or non-systemic. In non-systemic vasculitic neuropathy, which only affects peripheral nerves  (and not other end organs), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are often elevated, but may be the only abnormal lab findings noted. One should, however, also test for renal function, hepatic function, chronic hepatic viral levels, cryoglobulinemia, cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA), perinuclear antineutrophil cytoplasmic antibodFig. 12.8 Anatomical patterns of multiple mononeuropathies in vasculitis

227

ies (p-ANCA), antinuclear antigen (ANA), and extractable nuclear antigen (ENA) to exclude a more systemic vasculitic process. Electrophysiology: A multiple mononeuropathy distribution of nerve injury, manifest with asymmetric low-­amplitude SNAPs and/or CMAPs, is helpful. Of note, side-to-side comparison studies of affected and unaffected limbs should be done to secure the diagnosis. Pseudo-conduction block may be seen, which is reflective of ongoing incomplete axonal degeneration. It should not be mistaken for demyelinating conduction block, as seen in demyelinating neuropathies. Imaging: MRI of individual nerves (i.e. sciatic nerve) can be helpful, particularly in imaging deep nerves that are inaccessible via ultrasound, such as the sciatic nerve, and can reveal increased T2-weighted signal. Nerve Biopsy: Consensus criteria were developed in 2010 by the Peripheral Nerve Society to diagnose definite vasculitic neuropathy on  nerve biopsy. In general, vessel wall inflammation plus damage is necessary to diagnose definite vasculitis, and is classified as either active or chronic, depending on the presence of lesions. There is evidence of epineurial arteriole or venule inflammation and necrosis in multiple sites, producing axonal loss, frequently in a central fascicular pattern. In addition, predominantly axonal damage coupled with perivascular inflammation or other signs of vascular damage can be used to establish the diagnosis. The

228

diagnosis also varies by the size of the vessel involved— small (microvasculitis), medium sized, or large vessel. The diagnostic yield of nerve biopsy depends on the nerve biopsied, and in general, a combined nerve and muscle biopsy should be obtained. Often, the superficial fibular nerve is combined with the extensor digitorum brevis, or the sural nerve with the medial gastrocnemius. Differential Diagnosis: Other more widespread disorders that affect multiple named nerves, such as more systemic vasculitis or infectious neuropathies, need to be excluded. Furthermore, the multiple mononeuropathy phenotype, especially if painless, should prompt consideration for multifocal motor neuropathy (MMN), hereditary neuropathy with liability to pressure palsy (HNPP), and motor neuron disease. In addition, one should exclude multiple entrapment mononeuropathies. Therapy: Treatment consists of steroids combined with steroid-sparing immunosuppressive agents. While predni-

Fig. 12.9  Hand in a patient with vasculitis. There is atrophy of small hand muscles with vasculitic changes at the nail beds

Fig. 12.10  Sural nerve biopsy from a patient with isolated peripheral nerve vasculitis. Infiltration of a perineurial vessel wall by multiple inflammatory cells including lymphocytes and macrophages (black

12 Polyneuropathies

sone monotherapy is often adequate, some advocate combinining steroids with a steroid-sparing agent from disease onset, such as pulsed intravenous or oral cyclophosphamide, to yield maximal improvemenet and lessen risk of future relapse. Prognosis: With treatment, the disorder frequently stabilizes, yielding a good prognosis.

12.4.2  Vasculitic Neuropathy, Systemic Genetic testing −

NCV/EMG ++

Laboratory ++

Imaging

Biopsy ++

Distribution/Anatomy: As with non-systemic vasculitic neuropathy, systemic vasculitic neuropathy also typically  assumes a multiple mononeuropathy distribution of injury, but can also involve nerve roots, and plexus. Symptoms: Proximal and distal weakness, pain, and sensory loss occur in a multifocal distribution. Clinical Syndrome/Signs: Systemic vasculitic neuropathy may affect isolated nerves (45% of cases), overlapping nerves (40%), or cause symmetric peripheral neuropathy (15%). Patients typically present with a mixture of motor and sensory signs (Fig. 12.9). Associated signs of systemic ­vasculitic disease include fever, weight loss, anorexia, rash, arthralgia, GI, lung, or renal disease. Usually, the neuropathy presents in patients that have already been diagnosed with a specific vasculitis, although it may also be the presenting complaint. Pathogenesis: Several immune-mediated mechanisms have been identified that lead to the destruction of vessel walls and subsequent ischemic necrosis of axons (Figs. 12.10 and 12.11). Primary and systemic diseases that can cause vasculitic neuropathy are presented in Tables 12.5 and 12.6.

arrows). There is also evidence of pink fibrin deposits consistent with the presence of fibrinoid necrosis (white arrows)

12.4 Vasculitides

229

Fig. 12.11  Dorsal root ganglion biopsy from a patient with severe sensory ataxia due to dorsal root ganglionitis. There are clusters of inflammatory cells (white arrow) surrounding the dorsal root ganglion neurons (black arrows). Many of the neurons show evidence of degeneration

Diagnosis: Laboratory: Findings in conjunction with systemic disease could include elevated ESR, CRP, ANA, ENA, p- or c-ANCA, cryoglobulins. In addition, hepatitis B, hepatitis C, HIV-1, and/or Lyme serology should be tested in the appropriate setting. Electrophysiology: The pattern of findings is similar to that seen in non-systemic vasculitic neuropathy. Imaging: Findings are not unlike that seen in non-­systemic vasculitic neuropathy. Of note, however, MRI can also be used to evaluate for CNS vasculitic disease (strokes, cerebrovascular vasculitis) as well as secondary processes that can mimic vasculitic neuropathy (nerve root, plexus, or peripheral nerve neurolymphomatosis). Nerve biopsy: Muscle and nerve biopsies reveal T-cell and macrophage invasion, with necrosis of blood vessels. Differential Diagnosis: The differential approach is like that seen with non-systemic vasculitic neuropathy, namely any process that can produce a multiple mononeuropathy picture. In addition, attention should be given to diabetic radiculoplexus neuropathy and non-diabetic radiculoplexus neuropathy, neurolymphomatosis, and more widespread CNS disease, which can occur in systemic vasculitis.

Table 12.5  Overview of primary systemic vasculitides

Polyarteritis nodosa (PAN)

Histopathology Necrotizing vasculitis, mixed infiltrate

Microscopic polyangitis (MPA) Eosinophilic granulomatosis with polyangitis (EGPA)

Necrotizing vasculitis, mixed infiltrate Necrotizing vasculitis, mixed infiltrate with eosinophils

Granulomatosis with polyangiitis (GPA)

Necrotizing vasculitis, granulomas

Other organs clinically Vessels affected involved Small to Skin, joints, kidney medium

Arterioles, capillaries Small and medium arteries, arterioles Small and medium arteries, arterioles

Laboratory studies Elevated ESR, leukocytosis, anemia, thrombocytosis, rheumatoid factor (RF) in 30%, hepatitis B in 30%, low complement in 25% Kidney, joints, skin, lungs, GI Elevated ESR, ANCA, RF in up to 50%

Lungs in nearly all, asthma in Elevated eosinophils in all, elevated up to 75%, sinusitis, rhinitis, ESR, elevated IgE, ANCA, RF skin, GI, joints, heart Sinopulmonary changes in up ANCA in 90%, elevated ESR, anemia, thrombocytosis, RF to 95%, lung changes, kidneys, eyes, skin

Table 12.6  Overview of common secondary systemic vasculitides Histopathology Rheumatoid arthritis Necrotizing vasculitis at all levels. Nerve infarction at watershed zones (mid-sciatic nerve) Sjogren’s Epineurial vascular inflammation, with occasional necrotizing epineurial vasculitis Sarcoidosis

Hepatitis C and cryoglobulinemia

Epineurial granulomas and perineuritis, lymphocytic necrotizing vasculitis Patchy, fascicular axonopathy with endoneurial damage.

Vessels affected Small to medium

Other organs clinically involved Purpura, nodules, alveolar hemorrhage, glomerulonephritis, stroke

Mirovasculitis Exocrine glands, sicca (dry eyes, dry mouth)

Any vessel size

Skin, eyes, liver, lymph nodes

Laboratory studies RF, anti-cyclic citrullinated peptide (CCP) elevation; anemia; elevated CRP and sedimentation rate Minor salivary gland shows lymphocytic infiltrate Anti-Sjögren’s-syndrome-related antigen A (anti-SSA), anti-Sjögren’s syndrome type B antibodies (anti-SSB) Calcium and angiotensin-converting enzyme (ACE) may be elevated

Large arteriole Purpura, glomerulonephritis, 50% of patients with hepatitis C have leg ulcers, arthritis, sicca mixed essential cryoglobulinemia (types II and III). C4 complement is low, RF elevated

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Therapy: Aggressive treatment of systemic disease is often warranted in systemic vasculitic neuropathy, usually consisting of cyclophosphamide for 3–6 months, and often in combination with corticosteroids. Cyclophosphamide should be instituted for moderate to advanced granulomatous polyangitis (GPA), microscopic polyangitis (MPA), eosinophilic granulomatosis with polyangitis (EGPA), or polyarteritis nodosa (PAN) with organ-threatening vasculitic involvement, whereas for milder cases of GPA and MPA, methotrexate can be used as a steroid-sparing agent instead. Of note, rituximab can also be used in lieu of cyclophosphamide as a first-line inductive agent for GPA and MPA, and also has efficacy in cryoglobulinemic vasculitis and vasculitis associated with rheumatoid arthritis. Of note, no large-­scale randomized controlled clinical trials exist, and most treatment efficacy data is based on large case series and meta-analyses. Methotrexate can also be used as induction therapy in combination with corticosteroids for mild ANCA-­associated vasculitic neuropathy. For patients with non-­systemic vasculitic neuropathy or systemic vasculitic neuropathy that is progressing despite steroid monotherapy, steroid-sparing therapy should be added. Plasma exchange should be instituted for ANCA-associated vasculitis with alveolar hemorrhage or glomerulonephritis, as well as for hepatitis B-associated PAN and hepatitis C-associated cryoglobulinemic vasculitis. Treatments for hepatitis B include pegylated interferon-alpha and tenofovir. Hepatitis C-associated cryoglobulinemic vasculitis is treated with pegylated interferon alpha and ribavirin. Rituximab can often also be combined with antiviral therapy, although data is not based on randomized controlled clinical trials. For HIV-associated vasculitic neuropathy, corticosteroid monotherapy (rather than combination therapy with a sparing agent) is preferred, given risk of infection. Prognosis: Therapy can lead to improvement, but there can be a fixed deficit. Pain symptoms often respond quickly, but importantly, this is not necessarily a marker for resolution of the disorder itself. ESR, CRP, and the Birmingham Vasculitis Activity Scale, in addition to thorough examination, can be used to track disease activity.

12 Polyneuropathies

Signs: The disease presents with disproportionate sensory involvement and does not typically affect motor fibers as aggressively as other autoimmune connective tissue conditions. Non-neurologic manifestations are equally important, particularly the presence of sicca (dry eyes, dry mouth), as well as other symptoms or signs of exocrine gland dysfunction (nasal congestion, dry hacking cough, abdominal pain after fatty meals). Pathogenesis: Sjögren’s involves the lymphocytic cell infiltrate of peripheral nerves, often the dorsal root ganglia, leading to significant ataxia. It can also affect  the posterior spinal column, leading to a combined myeloneuropathy picture. Diagnosis: Laboratory: Anti-Ro and Anti-La antibodies are helpful, but have low sensitivity, and a negative test does not exclude the condition. Additional helpful lab tests include ESR and CRP. Electrophysiology: While nerve studies may show the classic length-dependent sensory or sensorimotor pattern, a sensory  neuronopathy phenotype manifests with global or length-independent reduction or complete loss of SNAPs with relative sparing of motor fibers. Imaging: MR imaging of the spinal cord, when appropriate, can often reveal a posterior tractopathy. Nerve and other tissue biopsy: Nerve biopsies show perivascular inflammatory infiltrates and necrotizing vasculitis, with a predominance of axonal degeneration over demyelination. Minor lip salivary gland biopsy shows lymphocytic infiltrate. Therapy: Data regarding immunosuppressant therapy for Sjögren’s-associated neuropathy is mixed, with some suggestion that drugs like IVIG, prednisone, or rituximab may be of benefit in some patients.

12.5 Infectious Neuropathies 12.5.1  Human Immunodeficiency Virus-1 Neuropathy Genetic testing −

NCV/EMG +

Laboratory +

Imaging −

Biopsy −

Epidemiology: Prevalence data about HIV-related neuropathies vary widely, but it is generally estimated that approximately 50% of HIV-positive patients have evidence of DSP, Sjögren’s is often classified as a  vasculitic neuropathy, the most common form of neuropathy, on clinical examinaalthough it has unique features that warrant a separate tion. Older age and severe disease increase the risk discussion. of DSP. Other forms are rare. The various types of neuropaSymptoms: Sjögren’s can present with a length-­ thy are linked to the stage of HIV infection: HIV-GBS and dependent small-fiber neuropathy, a length-dependent large-­ HIV-CIDP occur mainly in the early phase when patients are fiber neuropathy, or a length-independent sensory otherwise asymptomatic. Vasculitic multiple mononeuropaneuronopathy or ganglionopathy. It often also involves auto- thy typically is a disease of the early symptomatic phase of nomic fibers. HIV.  DSP occurs in the late phase of HIV infection.

12.4.3  Sjögren’s Neuropathy

12.5  Infectious Neuropathies

Antiretroviral toxic neuropathy begins within weeks to months after initiation of treatment with nucleoside analog reverse transcriptase inhibitors. An autonomic neuropathy is more frequent in HIV patients at later stages of the disease. Anatomy and Pathophysiology: DSP is a dying-back axonopathy with the occasional presence of macrophage and lymphocytic infiltration; HIV-infected macrophages are reported in the dorsal root ganglia. Skin biopsies in DSP and antiretroviral toxic neuropathy show reduced intraepidermal nerve fiber densities. Symptoms: Painful burning dysesthesias in a stocking, and later, in a stocking–glove distribution are the leading symptoms in DSP and antiretroviral toxic neuropathy. Lower extremity pain may be so severe that patients cannot walk or tolerate acral  contact with bedding. Symptoms in GBS, CIDP, and vasculitic multiple mononeuropathy in the setting of HIV infection are similar to the idiopathic syndromes. Orthostatic hypotension and diarrhea can result from autonomic neuropathy. Signs: In DSP and antiretroviral toxic neuropathy, allodynia and small  greater than  large-fiber sensory loss are found on clinical examination together with absent ankle reflexes. Signs may seem mild compared to the pain experienced by the patient. Weakness is uncommon. GBS, CIDP, and mononeuritis multiplex present with typical signs. Causes: The pathophysiology of HIV neuropathy is poorly understood but is likely immune-mediated. Antiretroviral toxic neuropathy is secondary to drug-induced mitochondrial dysfunction. Diagnosis: The diagnosis rests upon the known diagnosis of HIV infection, its treatment, and the typical clinical picture. Laboratory: No neuropathy-specific tests exist once HIV has been diagnosed. Other causes of neuropathy should be excluded. Electrophysiology: In DSP and antiretroviral toxic neuropathy, SNAPs are decreased or absent. Motor NCVs are generally normal with the exception of mildly prolonged F-wave latencies. GBS, CIDP, and mononeuritis multiplex present with typical electrophysiological findings. Imaging: None. Differential Diagnosis: DSP and antiretroviral toxic neuropathy are clinically similar. The only feature to differentiate the two neuropathies is the initiation of treatment with nucleoside analog reverse transcriptase inhibitors weeks to a few months before symptom onset. Therapy: Pain control is frequently required for DSP and antiretroviral toxic neuropathy. If drug treatment is discontinued secondary to antiretroviral toxic neuropathy, the symptoms can continue to worsen (known as coasting). HIV-­GBS and -CIDP are treated as non-HIV-GBS and -CIDP with immunomodulatory treatment with IVIG or plasmapheresis.

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12.5.2  Herpes Zoster Neuropathy Genetic testing −

NCV/EMG −

Laboratory +

Imaging −

Biopsy −

Epidemiology: The incidence of herpes zoster in the United States between 1945 and 2003 was between 1.2 and 6.5 cases/1000 person years. Its incidence increases with increasing age. A large proportion of patients with herpes zoster develop post-herpetic neuralgia. Anatomy and Pathophysiology: After infection with varicella zoster virus in childhood, the neurotropic virus becomes latent in the dorsal root, cranial nerve, and/or autonomic ganglia. Virus reactivation causes shingles within one to three dermatomes. Post-herpetic neuralgia may result from chronic ganglionitis. Symptoms: Burning, stabbing neuropathic pain in a dermatomal distribution is the first symptom. Hypesthesia and allodynia develop and are followed by the typical rash. Weakness occurs in 1–30% of affected individuals, more frequently if lumbosacral dermatomes are affected. The Ramsay Hunt syndrome, herpes oticus, is characterized by facial weakness, a painful ear, and vesicles in the ear. Signs: Hypesthesia and allodynia are present in the affected dermatomes with weakness occurring in a radicular pattern with corresponding absent reflexes. Post-herpetic neuralgia  is characterized by allodynia, hyperalgesia, and hypesthesia in affected areas. Causes: Reactivation of varicella zoster virus causes acute herpes zoster and chronic vasculitis, and central reorganization is implicated in post-herpetic neuralgia. Diagnosis: Skin rash in a dermatomal distribution and CSF findings defines acute herpes zoster. Post-herpetic neuralgia is often diagnosed in the setting of previous herpes zoster and dermatomal neuropathic pain. Laboratory: In acute herpes zoster, CSF shows a mononuclear pleocytosis and PCR confirms the varicella zoster virus infection. In post-herpetic neuralgia, affected areas of the skin have reduced intraepidermal nerve fiber densities. Electrophysiology: Sensory NCVs are normal. In cases with weakness, signs of de- and re-innervation can be found on EMG.  QST reveals impaired small- and large-fiber function. Imaging: None. Differential Diagnosis: Before the typical rash develops, other causes of radicular pain must be considered. In patients with facial palsy, the pain and vesicles in the ear distinguish it from other causes of facial nerve palsy, such as idiopathic or Lyme disease. Therapy: Valacyclovir (1000 mg TID for 7 days) and famciclovir (500  mg TID for 7  days) are used to treat acute herpes zoster. Topical high-concentration capsaicin patches are used to treat post-herpetic neuralgia. Vaccination with a live, attenuated zoster vaccine reduces

232

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the incidence of herpes zoster and PHN although it is less effective with increasing age.

12.5.3  Lyme Disease (Neuroborreliosis) Genetic testing −

NCV/EMG −

Laboratory +

Imaging −

Biopsy −

Epidemiology: In the United States, most cases of Lyme disease occur in north-eastern and north-central states. In several European regions, Lyme disease is endemic. The epidemiology depends on the distribution of infection in vector ticks. Anatomy and Pathophysiology: Erythema migrans is caused by local spreading of Borrelia in the skin. An immune response is triggered that can result in neurological and systemic manifestations. Lymphocytic infiltration is present in affected tissues. Symptoms: The earliest stage of Lyme disease (Stage 1) develops 7–10 days after a tick bite and is characterized by the unique skin rash (erythema migrans) and mild constitutional symptoms. 10–20% of these patients develop neurological manifestations, typically 4–6  weeks after the tick bite. This neuroborreliosis (Stage 2, Bannwarth syndrome) is characterized by radicular pain and weakness, headache, and cranial nerve palsies (Fig.  12.12). Some patients develop asymmetric oligoarthritis, cardiac impairment, and myositis, along with CNS impairment 6  months after the tick bite (Stage 3). Fig. 12.12 Abdominal weakness in Lyme disease: This patient had a protruding abdomen due to abdominal weakness (a), he was unable to do sit ups (b), the MRI (c) showed atrophy of the rectus abdominis muscles (arrows). Lyme borreliosis with involvement of thoracic nerve roots was identified as the etiology

a

Signs: The radiculitis frequently affects thoracolumbar spinal roots. Besides sensory symptoms in affected areas, weakness can be seen in the form of bulging of the abdominal wall. Facial nerve palsy frequently is bilateral; other nerves, e.g., trigeminal, optic, vestibulocochlear, and oculomotor nerves, are less commonly affected. Profound CNS symptoms are probably rare, and the relationship to Lyme borreliosis has recently been questioned. Sensory neuropathies are found in acrodermatitis chronica atrophicans. Causes: Lyme disease is caused by infection with the spirochete Borrelia burgdorferi. The infection is transmitted by bites from the Ixodes dammini, scapularis, and pacificus tick species. Three genospecies exist and their occurrence varies between the United States and Europe, which may account for the variation of clinical presentations between these countries. Diagnosis: Clinical picture, CSF pleocytosis, and detection of intrathecal antibody production against Borrelia confirm the diagnosis. A history of tick bite and erythema migrans can be missing in up to 50% of cases with confirmed neuroborreliosis. Laboratory: CSF shows a mild lymphomonocytic pleocytosis in neuroborreliosis. Antibody detection in serum commonly leads to false-positive results in up to 30% of healthy individuals in endemic areas. Antibody detection in CSF is specific, and the combination of CSF and serum antibody titers is used to calculate an antibody index. PCR of blood and CSF can be used in difficult cases.

b

c

12.5  Infectious Neuropathies

233

Electrophysiology: In radiculitis, SNAPs are normal. In cases with weakness, signs of de- and reinnervation are present on EMG. In cases with neuropathy, SNAPs are reduced or absent. Imaging: None. Differential Diagnosis: Unilateral facial nerve palsy needs to be distinguished from idiopathic Bell’s palsy. Therapy: Isolated facial nerve palsy can be treated with oral or intravenous antibiotics; meningitis, radiculitis, and other neurological manifestations are treated with intravenous antibiotics. Oral doxycycline (200 mg daily) and intravenous ceftriaxone (2  g daily) are typically used for 2–3 weeks. Doxycycline is contraindicated in pregnancy and lactation and in children below 8 years of age. In these cases, amoxicillin is the drug of choice.

12.5.4  Leprosy Genetic testing −

NCV/EMG +/−

Laboratory +

Imaging −

Biopsy +

Epidemiology: Leprosy is one of the most common treatable neuropathies in several Asian, South American, and African countries. Although the incidence of leprosy has decreased over the last decade, the World Health Organization (WHO) reported nearly a quarter of a million new cases in 2018 from 127 countries. Anatomy and Pathophysiology: Infection with M. leprae results in a destructive inflammatory immune response. Early lepromatous disease involves infection of Schwann cells with minimal inflammatory response. Later, increased inflammation may lead to axonal damage with episodes of demyelination and remyelination. Based on the immunological status of the patient, leprosy is classified as tuberculoid, lepromatous, or borderline. In tuberculoid leprosy, the immune response is robust and only a few lesions without mycobacteria are detectable. In leproa

matous leprosy, patients are anergic toward M. leprae and show multiple lesions containing bacteria. Symptoms: Numbness and weakness affecting individual peripheral and cranial nerves is often reported. Signs: Leprous neuropathy is characterized by sensory loss in a patchy distribution. Lepromatous disease is extensive, with loss of temperature and pain occurring in the forearms, legs, ears, and dorsum of the hands and feet (Fig. 12.13). Cranial nerve damage can lead to facial damage, including iritis, alopecia, and changes in eyelid and forehead skin. Tuberculoid leprosy involves only a few skin lesions with accompanying local sensory loss. Several nerves, typically the greater auricular and/or radial cutaneous, are enlarged. Causes: Infection with Mycobacterium leprae causes severe disease in patients with an impaired cell-mediated immunity (lepromatous cases) or benign disease in patients with intact immunity (tuberculoid cases). The transmission of M.  Leprae is not completely understood, but person-to-­ person infections via airborne droplets are believed to be the main route of infection. Diagnosis: Typical clinical picture and detection of acid fast bacilli in skin smears or biopsies secure the diagnosis. PCR can be used to detect M. Leprae DNA in biopsies. Laboratory: No accepted serological test to diagnose or monitor leprosy is currently available. Promising are assays to detect PGL-1 antibodies although the test is not definite. Electrophysiology: NCV and EMG show axonal damage of affected nerves with decreased or absent SNAPs and CMAPs; NCVs can be mildly slowed. Imaging: None. Differential Diagnosis: Multiple mononeuropathies. Therapy: The WHO recommends treating patients with paucibacillary disease (tuberculosis and borderline leprosy) with dapsone and rifampicin (rifampin) for 6 months. Those with multibacillary disease (lepromatous leprosy) should be treated with dapsone, rifampicin, and clofazimine for

b

Fig. 12.13 (a) Leprosy in a patient who served with the foreign legion in North Africa. He has mutilated hands and toes and ulcers on the dorsum of his foot. (b) An axial ultrasound scan of the ulnar nerve

(arrows) in the ulnar groove. Note the swelling of some fascicles in the nerve while other remain thin

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12  months. Cases of treatment-induced reactions require quick diagnosis and treatment with high-dose steroids until the reaction subsides.

12.6 Inflammatory Neuropathies 12.6.1  Guillain–Barré Syndrome (GBS) - Acute Inflammatory Demyelinating Polyneuropathy (AIDP) Subtype Genetic testing

NCV/EMG +++

Laboratory ±

Imaging +

Biopsy +

Distribution/Anatomy: Acute inflammatory radiculoneuropathies, most classically manifesting as the AIDP subtype of GBS, cause demyelination of peripheral nerves and nerve roots, leading to a combined radiculoneuropathy picture, with combined proximal and distal weakness. Symptoms: Classic AIDP, the most common GBS subtype, presents with rapidly progressing bilateral (but not necessarily symmetric) ascending weakness. Paresthesias are reported early on, but weakness is the predominant feature. Patients sometimes report back pain, and often have notable appendicular pain as well. Of note, craniobulbar symptoms such as dysphagia, dyspnea, dysarthria, diplopia, as well as autonomic symptoms are often present and suggestive of the condition. Clinical Syndrome/Signs: Weakness develops over a course of hours or days. Proximal weakness is more severe. Reflexes are reduced or absent, usually at the time of presentation. Cranial nerve involvement occurs in half of patients. One-third of patients need respiratory support. Numerous types of autonomic dysfunction are possible (Fig. 12.14). Pathogenesis: Eighty percent of patients have an antecedent event (infection, surgery, and trauma). Two-thirds of patients have a prior respiratory or GI viral infection (especially CMV) 1–4  weeks before the onset of symptoms. Campylobacter jejuni infection is the most commonly associated bacterial infection with AIDP.  Research suggests a complex interaction of humoral and cell-mediated immunity events that lead to complement deposition on myelin. Diagnosis: Laboratory: CSF protein is elevated, with no increase in cells, in the majority of cases. Low serum sodium may develop and can portend more serious prognosis, as can low serum albumin. GM1 and GD1a antibodies help identify axonal variants of GBS. Electrophysiology: Per the Hadden criteria, to diagnose AIDP electrophysiologically, motor NCV should be less than 90% of the lower limit of normal in two or more motor nerves, with distal latency exceeding 110% of the upper limit of normal in two or more motor nerves. There is evidence of unequivocal temporal dispersion or conduction block on proximal stimulation, consisting of a proximal–distal ampli-

tude ratio 8  weeks), gait instability, and large fiber predominant sensory loss. Patients do not typically report pain, as is seen with GBS. Clinical Syndrome/Signs: Exam reveals symmetric, proximal, and distal weakness with large-fiber modality sensory loss and areflexia although distal motor deficits are usually more severe. The course may be progressive, monophasic, or relapsing. Any age group may be affected. Autonomic dysfunction, respiratory involvement, and pain are not common, and should prompt consideration for alternate diagnoses. Some cranial nerve involvement, mainly cranial nerve VII, can occur. Diabetes has been postulated as a risk factor the development of CIDP, although epidemiologic data have been mixed in this regard. Nevertheless, patients with CIDP in the setting of diabetes often develop greater disability due to later referrals and mis-attribution of pathology to diabetes alone. It is important that stringent clinical and electrodiagnostic criteria be used in the diagnosis of CIDP in patients with diabetes, as the diagnosis of CIDP is often overmade due to nonspecific electrophysiologic changes in such patients. Pathogenesis: Thirty percent of patients have an antecedent event (viral infection, immunization, and surgery). CIDP is an acquired idiopathic autoimmune disorder, with elements of both cell-mediated and humoral immunity. Recently, nodopathy subtypes have been described, ­involving IgG4-mediated targeting of the nodal and paranodal regions. Diagnosis: Laboratory: No good biomarkers currently exist to diagnose typical CIDP.  CSF protein elevation is helpful, although CSF cell count can also be elevated with >10 WBC/m3. Serum and urine protein immunofixation electrophoresis are important to exclude paraproteinemic

neuropathy mimickers. Newly identified serological tests can now identify CIDP subtypes that involve node-directed pathology, the so-called nodopathies. Of these, anti-­contactin 1 and anti-neurofascin-155 are the most well described (Fig. 12.16). Contactin-1 presents with rapidly progressive, GBS-like weakness, with disproportionate axonal injury, while neurofascin-155 patients have significant ataxia on exam. Electrophysiology: The EFNS CIDP electrodiagnostic criteria are the gold standard of diagnosis, wherein patients must have features of demyelination in at least two motor nerves to be deemed definite for CIDP. NCV is 130% of the upper limit of normal in two or more motor nerves. There is evidence of unequivocal temporal dispersion or conduction block on proximal stimulation, consisting of a proximal–distal amplitude ratio 130% of the upper limit of normal in one or more nerves. Imaging: MR imaging of nerve roots and plexus may show hypertrophy or enhancement, which can be particularly helpful in advanced CIDP or sensory variant CIDP (chronic inflammatory sensory demyelinating radiculoneuropathy) (Fig.  12.17). Ultrasound evaluation of the brachial plexus and peripheral nerves is also helpful, and can even demonstrate focal areas of signal change concordant with conduction block. Bone survey or scan is useful to exclude paraproteinemias, such as multiple myeloma, when an M spike is present. Biopsy: The presence of patchy onion-bulbing on nerve biopsies is a unique finding in CIDP, different from the uniform onion-bulbing seen in CMT. Furthermore, this finding helps distinguish CIDP from such mimickers as POEMS syndrome, which does not show onion bulbing. In addition, nerves may show inflammatory infiltrate, with focal myelin loss on teased fiber analysis (Fig. 12.18). Differential Diagnosis: The differential diagnosis for typical CIDP is wide. However, any presentation that varies from a symmetric, painless, chronically progressive (>8  weeks), proximal and distal distribution sensorimotor demyelinating neuropathy pattern with areflexia should prompt evaluation for disease mimickers or CIDP variants. Thus, one should exclude such conditions as GBS or acute-­ onset CIDP nodopathy subtypes (contactin-1 and neurofascin-­155) that present in 4  weeks or less; length-dependent neuropathies (diabetes, B12); sensory ganglionopathies (paraneoplastic, Sjoegren’s, chronic inflammatory sensory polyneuropathy); conditions that present with upper limb, asymmetric onset deficits (multifocal motor neuropathy multifocal acquired demyelinating asymmetric sensory and motor neuropathy (MADSAM), brachial plexopathy); or neuropathies with significant, rapidly progressive pain (vas-

238

Fig. 12.16  Schematic illustration of the node of Ranvier in the PNS. CASPR1 contactin-associated protein 1, CNTN1 contactin-1, Kv potassium channel, Nav sodium channel, NF neurofascin, NrCAM Neuronal

12 Polyneuropathies

cell adhesion molecule. (Reprinted from Neurochemistry International, Volume 130, Kira et al. Anti-neurofascin autoantibody and demyelination, Pages 104360, Copyright 2019, with permission from Elsevier)

Fig. 12.17  Axial ultrasound scan of the median nerve (arrows) in the upper arm with diffuse fascicle swelling in CIDP

culitic neuropathy or amyloid). Furthermore, one must exclude paraproteinemic neuropathies that often look like CIDP, but do not respond to standard treatments, such as anti-MAG IgM DADS neuropathy or POEMS syndrome. Also, demyelinating CMT (CMT1A in particular) can be confused with CIDP, but often features other findings (lifelong history of motor weakness, pes cavus, or family history) that distinguish it. Furthermore, it is worthwhile to recog-

Fig. 12.18  Sural nerve biopsy from a patient with chronic inflammatory demyelinating polyneuropathy showing variation in myelin thickness in the presence of multiple onion bulbs (white arrow), suggestive of patchy onion-bulbing. This is consistent with an acquired  chronic de- and re-myelinating process

12.6  Inflammatory Neuropathies

239

nize  the different atypical CIDP variants, as not all are equally responsive to standard CIDP therapies (Fig. 12.19). Therapy: • IVIG can be administered in various forms. The 1 g/kg IV Q 3 weekly dosing was chosen in the landmark Intravenous Immune Globulin for the Treatment of Chronic Inflammatory Demyelinating Polyradiculoneuropathy (ICE) trial protocol, which definitively established the efficacy of IVIG. However, more frequent (weekly or Q 2 weekly) lower dose (0.4–0.5  g/kg dosing) IVIG is also equally effective, and may be worth considering in those failing Q 3 weekly dosing, as more frequent, lower-dose IVIG treatment regimens lead to less peak-to-trough IgG level fluctuations. • Prednisone is given 1 mg/kg per day, up to a maximum 100 mg/day. Once the patient is stable or improved, the prednisone is tapered to an every other day dosage by

approximately 10% at 4 weekly intervals. The dose should be maintained at a steady state if the patient relapses. • Recent studies have focused on pulsed corticosteroid delivery. The Intravenous Immunoglobulin versus Intravenous Methylprednisolone for CIDP (IMC) trial showed that intravenous methylprednisolone given in the form of 0.5 g daily for 4 days, once per month, was efficacious. The Pulsed High-Dose Dexamethasone versus Standard Prednisolone Treatment for CIDP (PREDICT) trial showed that monthly dexamethasone administered in the form of 40 mg daily for 4 days, once per month, was favorable to daily oral prednisolone (both in terms of time to disease remission and adverse events). • Plasma exchange can be administered intermittently for outpatients failing IVIG or corticosteroids. It can also be used for induction for relapsing patients who are admitted

Fig. 12.19  Variants of CIDP: clinical and electrophysiological hallmarks of CIDP subtypes. Motor deficits are drawn in red, sensory deficits in green and sensorimotor in brown color. Classical CIDP presents often with proximal and distal sensorimotor deficits. Demyelination should be present as defined by the the EFNS/PNS criteria. “Distal acquired demyelinating symmetric neuropathy” (DADS) shows typically distal symmetrical, sensory, or sensorimotor symptoms and is often associated with abnormally increased distal motor latencies (dmL). Patients with Lewis-Sumner syndrome (LSS) - or MADSAM display multifocal distributed sensory and motor symptoms, and nerve conduction studies frequently show conduction blocks. Pure sensory and motor CIDP show exclusively sensory or motor deficits and may

have normal respective nerve conduction studies. Chronic immune sensory polyradiculopathy (CISP) is restricted to sensory nerve roots only. CANOMAD (chronic ataxic neuropathy associated with ophthalmoplegia, IgM paraprotein, cold agglutinins, and disialosyl antibodies) presents as chronic ataxic neuropathy associated with oculomotor and/or bulbar symptoms. CIDP, chronic inflammatory demyelinating polyneuropathy; EFNS/PNS, European Federation of Neurological Societies and the Peripheral Nerve Society; NCV, nerve conduction velocity. (Reprinted from Journal of Neurology, Neurosurgery & Psychiatry, Chronic inflammatory demyelinating polyneuropathy: update on diagnosis, immunopathogenesis and treatment, Lehmann et  al., 90, 981– 987, 2019, with permission from BMJ Publishing Group LTD)

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to the hospital. It is often combined with IV methylprednisolone. • In resistant individuals, cyclophosphamide or rituximab may be considered. Rituximab is particularly efficacious in the CIDP nodopathy subtypes—contactin-1 and neurofascin-155. Prognosis: The chance for recovery is generally good with most patients showing response to therapy. The course may be relapsing, especially when treatment is inadequate. Treatment may be required for years to prevent relapses.

12.6.6  Multifocal Motor Neuropathy (MMN) Genetic testing

NCV/EMG +++

Laboratory +

Imaging +/−

Biopsy −

Anatomy/Distribution: Paranodal demyelination and Wallerian degeneration of motor nerves. Symptoms: MMN is characterized by asymmetric progressive weakness in the distribution of peripheral nerves without sensory symptoms. Weakness worsens in the cold. Clinical Syndrome/Signs: Exam reveals asymmetric, predominantly distal weakness without sensory loss in the distribution of individual terminal nerve branches. Finger extensor weakness and wrist or foot drop are frequent initial signs. MMN starts in the legs in 20–30% of cases, but is most suggested by upper limb onset. Weakness is greater than atrophy initially, and fasciculations are not uncommon. The course typically is progressive. Over time, muscle atrophy develops. Cranial nerve involvement is rare. The disease develops before the age of 50 years in approximately 80% of patients and affects more men than women. Pathogenesis: Dysfunction of the nodes of Ranvier leads to conduction failure and weakness. It is not a truly demyelinating disorder although it is often classified as a CIDP variant. IgM antibodies against GM1 gangliosides are probably pathogenic and MMN is believed to be an autoimmune disorder. Diagnosis: Laboratory: IgM antibodies against GM1 gangliosides are present in 20–85% and CSF protein is   hands. Tendon reflexes are diminished or absent (hyporeflexia). Sensory: Pan-modal reduction, allodynia, pain (dull or lancinating). Autonomic: Hyperhidrosis, cardiac vagal impairment, esophageal dysmotility.

243

Cranial Nerves: Vagal nerve  involvement, leading to a hoarse voice. Special Association: Proximal neuropathy with cranial nerve involvement, including a toxic alcoholic-nutritional amblyopia. Mononeuropathies Due to Pressure Palsies: Radial nerve, peroneal nerve, sciatic nerve, brachial plexus lesions—all due to excessive applied pressure at entrapment sites. Causes: Alcoholic neuropathy is difficult to separate from nutritional neuropathy, particularly thiamine deficiency neuropathy. Incidence is 9–30% of hospitalized alcoholics. Occurs after several years of consuming at least 100 mg alcohol daily. Women are more susceptible. Chronic alcohol intake leads to malnutrition and vitamin deficiencies. Pathophysiology: Axonal degeneration with loss of large and small myelinated fibers in autonomic, sensory, and motor nerves. Pathophysiology is unknown but is often associated with nutritional deficiency. Diagnosis: Electrophysiology and  laboratory testing (liver function panel, transketolase studies, B1, B12, methylmalonic acid, folate, magnesium, phosphorous). SNAPs may be absent or reduced with a variable degree of motor nerve involvement. Differential Diagnosis: Other toxic axonal neuropathies should be considered. Whenever an alcoholic neuropathy is suspected by history, a complete screen for nutritional and micronutrient deficiencies (referenced above) should be pursued. Therapy: Abstinence, multivitamin replacement, pain control therapy, and management of autonomic orthostatic hypotension. Prognosis: Depends on duration and severity of symptoms. No regeneration seen in nerve biopsies in 17 patients after 2 years. Autonomic neuropathy reduces life expectancy.

12.8.2  Other Drug-Induced Neuropathies Genetic testing –

NCV/EMG ++

Laboratory –

Imaging –

Biopsy –

Epidemiology: A variety of drugs can cause neuropathies, some frequently and others rarely. The incidence of drug-­induced neuropathies varies depending on the drug and dose used and also on patient characteristics such as underlying peripheral nerve disease and genetic polymorphisms. Anatomy and Pathophysiology: Most drug-induced neuropathies affect peripheral nerve axons in a length-­ dependent pattern and cause a distal symmetric, axonal dying-back neuropathy. Sensory fibers are generally more

244

vulnerable than motor fibers, and thus sensory symptoms dominate. The “coasting” phenomenon—worsening of the neuropathy up to 1 year after the drug has been discontinued—has been described for chemotherapeutic agents. Symptoms: Paresthesias and dysesthesias in the feet and later in the hands are present. Neuropathic pain is frequent. If the motor nerves are affected, foot drop and hand weakness can develop. The onset typically is gradual over weeks to months. Signs: Distal large- and/or small-fiber sensory loss and areflexia are found in the majority of cases. Atrophy of intrinsic foot muscles and, at later stages, dorsiflexor weakness can occur. Signs of autonomic involvement can be

12 Polyneuropathies

found in some forms. Table 12.8 lists features of selected or frequent drug-induced neuropathies. Causes: See Table  12.8 for a list of drugs that cause neuropathies. Diagnosis: The diagnosis rests upon a close temporal relationship between symptom onset and exposure as well as stabilization or improvement after cessation of the drug. Also, other causes should be excluded. Nerve biopsies usually show nonspecific signs of axonal degeneration and occasionally disruption of myelin. Electrophysiology: In typical sensory-predominant neuropathy, routine motor nerve conduction studies are normal or show low CMAPs. SNAPs are reduced or absent. EMG

Table 12.8  Specific features or relevant drug-induced neuropathies (alphabetical order) Drug Amiodarone

Features of neuropathy Amiodarone is a level III cardiac antiarrhythmic that has a variable incidence and poor correlation of associated toxic peripheral neuropathy with dose. However, neuropathy risk appears to increase with higher dose and longer duration of treatment. Affected individuals develop a subacute to chronic sensorimotor distal symmetric neuropathy. Predominant motor and GBS-like presentations have been reported. The neuropathy is at least partially reversible after dose reduction or drug discontinuation, typically taking no more than 3 months. Autonomic neuropathy with orthostatic hypotension can also occur. Tremor, ataxia, and myopathy are possible additional features. Electrophysiology shows demyelinating or axonal features. Sural nerve biopsy shows lamellated inclusion bodies Colchicine Colchicine is an anti-gout medication that functions by preventing microtubule assembly, thus blocking cell mitosis. It often produces neuropathy in patients with at least mild chronic renal insufficiency. A subacute to chronic progressive distal sensory neuropathy in combination with proximal myopathic weakness develops. Percussion and grip myotonia can occur. NCV show distal axonal sensory neuropathy and EMG of proximal muscles demonstrates myopathic features and occasionally myotonic discharges. CPK is mildly to significantly elevated. The myopathy resolves after drug withdrawal; symptoms and signs of the sensory neuropathy remain. Nerve biopsy shows axonal loss, while muscle biopsy shows vacuolar changes, with lysosomal and autophagic vacuole accumulation Dapsone Dapsone is an antimicrobial agent that also has anti-inflammatory properties and is used for such varied purposes as pneumocystis pneumonia and dermatitis herpetiformis. The neuropathy is rare and usually occurs after long-term and high-dose use. It is a predominantly distal motor neuropathy of lower and upper limbs. Reflexes are typically normal. NCV show low-amplitude CMAPs and normal SNAPs. Spontaneous activity and motor unit loss is seen on EMG. After dapsone discontinuation, the neuropathy dramatically improves within months to a year Disulfiram Disulfiram is an inhibitor of the enzyme acetaldehyde dehydrogenase, which is used to treat alcohol dependence. Dose-­ dependent neuropathy after several months of treatment has been reported, and it is under-recognized given the tendency to attribute neuropathy to alcohol in patients with chronic alcohol use. It progresses faster than alcoholic neuropathy. Distal axonal symmetric large- and small-fiber sensory and later sensory and motor neuropathy develop of the lower, and at later stages, upper extremities. NCV show axonal sensory and motor neuropathy. Recovery after drug withdrawal is slow and frequently incomplete. Sural nerve biopsy samples show neurofilamentous changes, with carbon disulfide being implicated as a potential culprit. Optic neuritis can also occur Etanercept and Tumor necrosis factor-α blockers are used in the treatment of autoimmune conditions such as rheumatoid arthritis, Crohn’s infliximab disease, ulcerative colitis, and ankylosing spondylitis, and work by suppressing the pro-inflammatory TNF-α molecule. Substantial data now show that TNF-α blockers themselves trigger chronic and acute inflammatory demyelinating neuropathies, in the form of CIDP and AIDP, as well as miller fisher syndrome, MMN, and axonal sensorimotor polyneuropathies. The neuropathies develop after 6 months to 2 years after treatment. NCV show signs of acquired demyelination. Drug withdrawal improves only some neuropathies, and standard immune neuropathy therapy (steroids, IVIG) should be prescribed as appropriate. Nerve biopsy suggests both T cell and humoral-mediated targeting of myelin as well as vasculitic injury Isoniazid Isoniazid functions to inhibit mycobacterial cell wall formation and is used in the treatment or prevention of tuberculosis. Isoniazid treatment results in pyridoxine (B6) deficiency, which is responsible for a sensory predominant large- and small-­ fiber neuropathy, which can be quite painful. Burning feet are an early complaint. Weakness and atrophy can develop at later stages. The neuropathy is prevented by the intake of 10–50 mg pyridoxine/day. However, pyridoxine treatment does not affect the recovery once neuropathy has developed. Furthermore, care should be taken not to over-treat with pyridoxine, which itself can cause a toxic neuropathy. Linezolid Linezolid is an antimicrobial that inhibits bacterial growth by inhibiting protein synthesis. Its association with painful sensory predominant length-dependent peripheral neuropathy is frequently described. Some patients also develop optic neuropathy. While the optic neuropathy resolves with drug discontinuation, the peripheral neuropathy is generally considered irreversible although there are cases of reversibility. NCS show a length-dependent axonal sensory or sensorimotor axonal peripheral neuropathy. Some patients may have a pure small-fiber neuropathy

12.8  Drugs, Industrial Agents, and Metals

245

Table 12.8 (continued) Drug Metronidazole

Nitrofurantoin

Nucleoside analogs

Pyridoxine abuse

Features of neuropathy Metronidazole is an antimicrobial that disrupts nucleic acid synthesis only in anaerobic organisms. It is a well-recognized cause of reversible peripheral neuropathy. Autonomic neuropathy is also a described sequelae. NCS may show reduction in distal SNAPs or be completely normal, suggesting a predilection for small fibers. Cumulative exposure of >42 g over >4 weeks portends a nearly 18% risk of development, while in those receiving a lesser doses, the risk is quite low. Drug discontinuation often leads to symptom resolution in most patients Nitrofurantoin is a synthetic antimicrobial often used in the treatment of urinary tract infections, mainly to target such organisms as Escherichia coli. Distal symmetric sensory neuropathy, oftentimes preferentially targeting small fibers, is reported. In such patients, skin biopsies show particular morphologic changes with clustered terminal nerve swellings, sometimes without nerve fiber degeneration Antiviral nucleoside analogs competitively bind with reverse transcriptase to inhibit early phase viral replication in HIV1 and HIV2. Nucleoside analog-associated neuropathy represents a dose-dependent and painful sensory axonal neuropathy and can be challenging to distinguish from HIV-related painful neuropathy although its onset is usually more abrupt and painful. It has small-fiber sensory predilection although large-fiber sensory loss is also common, presenting with reduced or absent SNAPs. The incidence of neuropathy varies by the specific drug (10% for stavudine, 1% for didanosine). Prompt withdrawal allows for improvement although coasting can occur High-dose pyridoxine (B6) intake causes a pure sensory neuropathy at 500 mg daily, neuropathy develops after several years; at 1000 mg, after several months. Toxic pyridoxine neuropathy is most commonly resultant from excessive supplementation, whether directly or through indirect supplementation, such as energy drinks. Doses >50 mg per day are generally advised against to avoid risk of toxic neuropathy, unless indicated for medical reasons (such as isoniazid use). Distal symmetric foot numbness and gait ataxia can be followed by large-fiber sensory loss in the hands. NCV show a sensory axonal neuropathy, while motor studies are normal. Following drug withdrawal, coasting can occur, which is followed by a slow recovery

Table 12.9  Drugs associated with neuropathy (drugs that frequently cause neuropathies are in bold text) Cardiovascular drugs Amiodarone Clofibrate Perhexiline Propafenone Statins

CNS drugs Chlorprothixene Glutethimide Phenelzine Phenytoin

Antibiotics, antiviral drugs Chloroquine Chloramphenicol Dapsone Ethambutol Fluoroquinolones Isoniazid Linezolid Metronidazole Nitrofurantoin Nucleoside analogs Sulfasalazine

can show polyphasic, medium- to high-amplitude, and long-­ duration motor unit action potentials when motor fibers are involved. Demyelinating forms show nonuniform slowing of motor NCV, temporal dispersion, and conduction block. Imaging: None. Laboratory: CPK can be mildly elevated in all forms of neuropathies. Differential Diagnosis: See Table 12.1. Therapy: Discontinuation of the causative medication is the only known treatment. Symptomatic treatment for neuropathic pain and motor symptoms can be offered when necessary (Table 12.9).

12.8.3  Toxic Neuropathies: Industrial Agents Genetic testing –

NCV/EMG ++

Laboratory –

Imaging –

Biopsy –

Miscellaneous drugs Allopurinol Colchicine Cyclosporin A Dichloroacetate Disulfiram Etanercept Gold Hydralazine Infliximab Interferons alpha 2a and 2b Leflunomide Penicillamine Pyridoxine abuse Tacrolimus

Epidemiology: Toxic neuropathies caused by industrial agents are rare in developed countries. A causal relationship has been established for some industrial agents (Table 12.10). Anatomy and Pathophysiology: Toxic industrial agents usually affect nerve axons in a length-dependent pattern and cause a distal symmetric, axonal dying-back neuropathy. Sensory fibers are generally more affected than motor fibers and thus sensory symptoms dominate. Symptoms: Numbness, paresthesias, and dysesthesias in a stocking or stocking-and-glove-like distribution are reported. Neuropathic pain can occur. Systemic symptoms are frequent (Table 12.10). Signs: Distal large and/or small-fiber sensory loss and areflexia are found in the majority of cases. Atrophy of intrinsic foot muscles and dorsiflexion weakness can occur. Table 12.10 lists specific features of some agents. Causes: See Table  12.10 for a list of industrial agents which cause neuropathies.

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Table 12.10  Features of neuropathies caused by industrial agents Morphology and neurophysiology Large-fiber loss; Paranodal Acrylamide accumulation of neurofilaments, tubulovesicular profiles, and degeneration of mitochondria. There is reduction in bidirectional anterograde and retrograde transport. Cerebellar Purkinje cell loss causes cerebellar ataxia. NCS: Axonal. Low SNAPs and CMAPs In animals, causes axonal Headache, depression, Carbon disulfide Depending on exposure, degeneration with giant dizziness, memory either mild sensory or fusiform axonal swellings and impairment; progressive length-­ accumulation of 10 nm extrapyramidal signs in dependent sensorimotor neurofilaments severe intoxication. neuropathy One-third of patients NCS: Distal slowing of continue to have sensory and later motor NCV, symptoms and signs of with prolonged latencies. neuropathy 10 years after Denervation on EMG in distal exposure muscles Focal axonal accumulation of Hexacarbons Distal symmetrical subacute Hyperhidrosis and blue 10 nm neurofilaments; discoloration of hands or slowly progressive and feet can occur in glue Paranodal demyelination and sensory motor neuropathy; myelin retraction sniffers. Spasticity and prolonged exposure can result in weakness of hands loss of color vision can be NCS: In mild cases, NCV can found and feet. Autonomic be normal but with clinical symptoms can occur. progression, significant NCV Coasting is typically seen slowing occurs and lasts from 1 to 4 months Can produced a delayed After weeks to months, Organophosphates Initial symptoms are ongoing neuropathy. signs of corticospinal cramping and calf pain, tract dysfunction become Characterized by a dying-back numbness, burning, and evident in some patients axonal degeneration in both tingling feet. Progressive central and peripheral nerve distal weakness in legs more fibers after exposure due to than arms develops and targeting of the neuropathy proximal muscles target esterase enzyme (particularly pelvic muscles) may become involved, along NCS: Low amplitude or with a high steppage gait, absent SNAPs and CMAPs. ataxia, and confusion EMG can initially show denervation Neuropathy Distal symmetric sensory neuropathy; sensory ataxia. Autonomic neuropathy can develop

Other features Dysarthria, hallucinations, weight loss, memory loss, as well as skin rash, and peeling of skin on hands

Diagnosis: The diagnosis rests upon a known exposure to an industrial agent that is known to cause peripheral neuropathy, and upon a typical clinical picture and specific systemic features. Thus, it is almost entirely predicated upon the history. Electrophysiology: SNAPs are reduced or absent. Motor NCV are normal or show low CMAPs. EMG can show polyphasic, medium- to high-amplitude, long-duration MUAPs when motor fibers are involved. Demyelinating forms show nonuniform slowing of motor NCV, temporal dispersion, and conduction block. Imaging: None. Laboratory: CPK can be mildly elevated in all forms of neuropathies.

Source Monomeric acrylamide for production of polyacrylamide; intoxication is via skin contact and, to a lesser degree, inhalation of the monomer

Used in the manufacture of viscose rayon, cellophane, pesticide production, and in chemical labs. Main route of intoxication is by inhalation

Used in industrial solvents and cleansers and household glues. Commonly due to intentional inhalation of glues (glue sniffing)

Common in insecticides, petroleum additives, plastic modifiers, fuel additives, lubricants. All are acetylcholinesterase inhibitors and cause organophosphate-­ induced delayed neurotoxicity 7–21 days after exposure

Differential Diagnosis: Other causes of neuropathy (see Table 12.1). Therapy: Removal of the offending agent stops progression of neuropathy, and recovery depends on the extent of axonal damage. Symptomatic treatment for neuropathic pain and motor symptoms can be offered when necessary.

12.8.4  Toxic Neuropathies: Metals Genetic testing −

NCV/EMG ++

Laboratory ++

Imaging −

Biopsy −

Epidemiology: Increased exposure to metals can be present in industrial and agricultural workers. Metal intoxications

12.8  Drugs, Industrial Agents, and Metals

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are seen in attempted suicide and homicide and rarely after consumption of contaminated traditional herbal medicine. Anatomy and Pathophysiology: All metals cause widespread damage and not only to the PNS. In the PNS, metals primarily result in axonal degeneration. The most common metals affect distinct anatomical structures (Table 12.11). Symptoms: Symptoms depend on the disease-causing metal. Occasionally systemic symptoms predominate (see Table 12.11). Signs: Signs depend on the disease-causing metal (Fig.  12.21). Lead is commonly associated with an upper limb motor neuropathy, mercury with pure sensory features, and thallium and arsenic with sensorimotor neuropathy. See Table 12.11 for associated symptoms. Causes: See Table  12.11 for a list of relevant metals which cause neuropathies. Diagnosis: The diagnosis rests upon known exposure to a given metal, with a typical clinical picture, specific systemic features, and evidence of increased body content of the specific metal. Electrophysiology: Signs of axonal degeneration are found. Depending on the metal and the phenotype, CMAPs and/or SNAPs are reduced or absent. NCV can be mildly slowed. In motor predominant forms, EMG shows signs of denervation and reinnervation. Imaging: None. Laboratory: Heavy metals can be detected in urine but 24  h urine sampling may be necessary. Lead and mercury can be measured in serum, but mercury measurements are unreliable (see Table 12.11).

Differential Diagnosis: Other causes of neuropathy (see Table 12.1). Therapy: Removal of the offending agent stops progression of neuropathy, and recovery depends on the extent of axonal damage. Chelating agents have been used in lead, arsenic, and mercury neuropathy to increase excretion. While this seems beneficial in lead and arsenic neuropathy, little is known about its efficacy in mercury neuropathy. Intravenous EDTA, penicillamine, British anti-Lewisite, and dimercaprol have been used. Symptomatic treatment for neuropathic pain and motor symptoms can be offered when necessary.

Fig. 12.21  Mees lines (white arrow) at the nail bed in a case of arsenic poisoning and polyneuropathy (Courtesy Dr. Freymueller, Hermagor, Austria)

Table 12.11  Features of neuropathies caused by metals Neuropathy 5–30 days after exposure: Distal symmetric sensory > motor; burning painful paresthesias in hands and feet. With high doses, can produce an AIDP-like neuropathy. Autonomic neuropathy can develop Lead Motor neuropathy of arms > legs. Finger and wrist extensors preferentially affected. Asymmetric atrophy and fasciculations occur. Minimal sensory signs and symptoms. Tendon reflexes are reduced or absent Mercury Mild distal sensory neuropathy with paresthesias. GBS-like neuropathy is reported in children Thallium Painful distal symmetric sensory neuropathy. Severe cases show distal > proximal weakness. Proximal reflexes relatively preserved. Cranial nerve involvement and ptosis. Autonomic neuropathy can develop

Arsenic

Other features Acute gastrointestinal illness with abdominal pain and vomiting before neuropathy. Hypotension, renal failure, CNS symptoms. Chronic exposure: Mees lines and arsenic exfoliative dermatitis

Laboratory Increased urine excretion; aplastic anemia, pancytopenia; increased arsenic in nails and hair; increased protein without pleocytosis in CSF

Anemia, abdominal pain, and constipation are typically present. Nephropathy and gout can be found. Children typically present with encephalopathy

Increased urine excretion; increased serum levels; microcytic and hypochromic anemia; red cells can show a basophilic stippling due to ribosomal clustering Increased urine excretion

Anorexia, gingivitis, hypersalivation. Personality change, ataxia, dysarthria, head and limb tremor Nausea, abdominal pain, and diarrhea within hours after acute intoxication. Neuropathy develops after 1–2 days. Alopecia develops 2 weeks after intoxication. With increased exposure: Behavioral changes, anxiety, psychosis, tremor, and ataxia. Nephropathy, anemia, abnormal liver function tests

Increased urine excretion; increased protein without pleocytosis may be seen in CSF

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12 Polyneuropathies

12.9 Critical Illness Neuropathy Genetic testing

NCV/EMG ++

Laboratory ±

Imaging −

12.10 Hereditary Neuropathies Biopsy ±

Anatomy/Distribution: Length-dependent axonal degeneration of motor and sensory nerves without signs of demyelination is often seen. In the majority of cases, concomitant damage to muscle is seen, and the condition is referred to as critical illness neuromyopathy or critical illness weakness. Symptoms: Symmetric weakness and sensory loss in awake patients, often noted after prolonged intensive care unit stays, upon awakening from coma, or upon failing to wean from ventilation. Clinical Syndrome/Signs: Exam reveals symmetric, distal > proximal weakness and atrophy, and large-fiber sensory loss. Phrenic nerve involvement is not uncommon. Pathogenesis: Steroid, sedative, and paralytic use in a ventilator-dependent patient as well as sepsis, multiorgan failure, and the presence of a systemic inflammatory response syndrome are risk factors for the development of critical illness neuromyopathy. Immune activation and increased vascular permeability, inflammation, edema, and hypoxia are thought to result in nerve damage. Diagnosis: Laboratory: CPK elevation can alert the clinician to the presence of a concomitant myopathy although its often normal if nerve only is involved or only slightly elevated. Electrophysiology: Low-amplitude motor and sensory compound action potentials are very suggestive. Prolonged duration CMAPs are suggestive of muscle involvement. NCV are normal or slightly reduced. EMG shows widespread denervation. Direct muscle stimulation can differentiate between critical illness neuropathy and myopathy. Biopsy: Axonal degeneration of motor and sensory fibers and denervation atrophy. Myopathic changes are frequently seen in the muscle, with loss of thick filaments. Differential Diagnosis: Whereas GBS, myasthenia, and inflammatory myopathy patients often come to the ICU with weakness, critical illness neuromyopathypatients most commonly arrive in the ICU without a neuromuscular disorder, but then develop critical illness neuromyopathy with prolonged hospitalization. Therapy: No specific therapy exists. Reduction of paralytic, sedative, and steroid exposure is helpful. Early treatment of sepsis and strict glucose control might reduce the incidence and severity of critical illness neuromyopathy. Early rehabilitation and patient mobilization are important. Prognosis: Functional outcome is generally good although it is common that some degree of weakness may persist.

12.10.1  Hereditary Motor and Sensory Neuropathies: Charcot–Marie–Tooth Disease Genetic testing +++

NCV/EMG ++

Laboratory ±

Imaging +

Biopsy +

Epidemiology: Hereditary motor and sensory neuropathy or Charcot–Marie–Tooth disease (CMT) is the most common form of inherited neuropathy with an estimated prevalence of 1:2500. The disease usually starts in the first or second decade of life, but severe early-onset and mild late-onset variants are described. CMT may be inherited in an autosomal dominant, autosomal recessive, or X-linked condition, but de novo mutations frequently occur. Demyelinating forms of CMT are more frequent than axonal forms (Fig. 12.22). Anatomy and Pathophysiology: Depending on the subtype, the disease primarily affects either the axon or the myelin sheath. However, impairments of Schwann cell— axonal interactions, axonal transport, and protein trafficking—are also implicated in CMT.  The pathophysiology depends on the genetic defect and, to date, there are more than 45 CMT-causing genes. In the most frequent form, CMT 1A, a PMP22 duplication, results in an increased peripheral myelin protein 22 (PMP22) expression with abnormal Schwann cell differentiation, onion bulb formation, and secondary axonal dysfunction. Symptoms: In CMT1A, the “classic” presentation is a patient with weak ankle  dorsiflexion, clumsiness of gait, often preventing participation in sports, and recurrent calluses secondary to foot deformities. Over time, many patients experience weakness and clumsiness of their hands. The complaint of numbness is not typical for CMT1A, and commonly symptoms of pain are musculoskeletal in nature resulting from foot deformities and altered biomechanics. Rarer forms of CMT are associated with additional specific features that result in specific symptoms (Table 12.12). Signs: Characteristic foot deformities with a high arch (pes cavus), hammertoes secondary to atrophy of intrinsic foot muscles, weakness of ankle dorsiflexion leading to a steppage gait, absent ankle reflexes, and pan-modal sensory impairment in the feet constitute the “classic” signs of CMT1A (Fig. 12.23). Over time, a patient experiences atrophy and weakness of the hand muscles with sensory impairment as well. CMT1A and primarily axonal forms of CMT, designated CMT2 (see Table  12.12), are difficult to distinguish by clinical signs and symptoms alone, although reflexes may be retained in CMT2. Additional features such as optic atrophy, proximal weakness, scoliosis, tremor, vocal cord palsy, hearing loss, Adie’s pupil, or neuromyotonia can

12.10  Hereditary Neuropathies Fig. 12.22  The effects demyelination and axonal damage on myelinated axons. (a) A single neuron and its axon, which has five myelin internodes that are separated by nodes of Ranvier. (b) In an inherited demyelinating neuropathy, two myelin internodes have been lost, leaving demyelinated segments that will usually be remyelinated. Even though demyelination is the primary pathology, axonal degeneration (see c) is a common, long-term consequence. (c) In an inherited axonal neuropathy, the distal part of the axon has degenerated (dashed region), and the myelin sheaths that formerly surrounded the degenerated region have disappeared as a secondary consequence of the axonal degeneration. (Reprinted from J Clin Invest, Volume 121, Issue 12, Scherer SS, The debut of a rational treatment for an inherited neuropathy? pp. 4624–4627, Copyright 2011, with permission from the American Society for Clinical Investigation)

249

a Healthy peripheral neuron

Cell body

Node of Ranvier

Schwann cell Axon terminal

Internode

Axon

b Inherited demyelinating neuropathy Schwann cell defect leads to demyelination and subsequent axonal degeneration

Demyelination

c Inherited axonal neuropathy Neuron/axon defect impairs axon function

occur and may be specific in some forms of CMT (see Table 12.12). Causes: CMT is caused by mutations in an increasingly expanding number of genes. The most relevant genes are PMP22, MPZ, GJB1, and MFN2. Diagnosis: The diagnosis of CMT is based on the classic clinical picture, family history, and exclusion of other ­etiologies, especially in de novo or atypical cases. Further classification is based on NCV and mode of inheritance: demyelinating forms are classified as CMT 1 when inheritance is autosomal dominant and as CMT 4 when inheritance is autosomal recessive. CMT 2 and AR-CMT 2 denote dominant and recessive axonal CMT; CMTX is X-chromosomal inherited. The diagnosis can be made by appropriate genetic testing. Recent studies indicate that four genes account for more than 90% of all molecular CMT diagnoses. The PMP22 duplication is the most frequent cause of CMT 1, and muta-

tions in the GTPase mitofusin-2 (MFN2) are the most frequent cause of CMT 2. Of note, PMP22 deletion is responsible for hereditary neuropathy with liability to pressure palsy (HNPP). The following algorithm for the genetic diagnosis of CMT has been proposed (Fig. 12.24). In cases with specific associated features, testing is guided by these features (see Table 12.12). Laboratory: Appropriate genetic testing (discussed above). As per Fig. 12.24, if ulnar (or median) NCV is in the demyelinating range, PMP22 testing is reasonable to evaluate for CMT1A. If NCV are not demyelinating or if PMP 22 testing is negative, one should go directly to a  Next Generation sequence panel testing. CSF protein can be elevated in CMT. Electrophysiology: NCS are essential in classifying CMT and in guiding genetic testing. In demyelinating CMT (CMT 1 and 4), median motor NCV are 38 m/s, and an intermediate form of CMT  is defined by median motor NCV between 25 and 45  m/s. SNAPs are absent or quite low in most cases of advanced CMT1 and 2. In CMT1A, in spite of slowed NCVs, there is no temporal dispersion or block of CMAPs, i.e., the slowing is uniform. In CMTX, NCS can show nonuniform slowing, temporal dispersion, and conduction block, mimicking acquired autoimmune neuropathy. Imaging: MR and ultrasound: Nerve and nerve root enlargements can be seen (Fig. 12.25), but these findings are not specific to CMT, as they can also be seen in acquired demyelinating conditions, such as CIDP. Nerve biopsy: Diffuse onion-bulbing is seen in CMT1A, which differentiates it from the patchy pattern seen in CIDP (Fig. 12.26). Nerve biopsy is now rarely done, however. Differential Diagnosis: Differential diagnoses include other inherited neurologic disorders that are present in early life. The spinocerebellar ataxias and leukodystrophies can be distinguished by the presence of cranial nerve, cer-

ebellar, and long tract signs that are not found in CMT. Hereditary neuropathy with liability to pressure palsies (HNPP), secondary to PMP22 deletion, may resemble CMT.  However, the history of pressure palsies and extremely prolonged distal latencies in the presence of mild slowing of motor NCV, identifies the disorder as HNPP, as does the asymmetric presentation. In inflammatory demyelinating neuropathies, the clinical presentation is usually more rapid, while electrodiagnostic studies are usually asymmetric and often demonstrate  temporal dispersion, conduction block. Finally, inherited myopathies and SMA show no impairment of sensory function, unlike CMT. However, pure motor CMT (also called distal hereditary motor neuropathy or distal SMA) often requires NCV to distinguish it from classic, or CMT. Therapy: To date, no drug therapy is available. Physical therapy, orthotics, and occasional surgery are available treatment options. The major goal of treatment is to retain optimal function throughout the course of the patient’s life.

252

12 Polyneuropathies

a

b

c

d

Fig. 12.23  Physical findings in a patient with CMT. (a, b) Claw hands. (c) Atrophy in the lower legs with particular thinning of distal muscles. (d) Foot deformities with hammer toes, pes cavus, and plantar and heal callus formation

12.10.2  Hereditary Neuropathy with Liability to Pressure Palsy (HNPP) Epidemiology: The prevalence of HNPP varies greatly by population studied and testing modality, with estimates ranging from 1 to 10 per 100,000, but it is generally much lower than CMT1A. Anatomy and pathophysiology: HNPP presents with focal weakness and sensory loss, typically due to repeated trauma and pressure at entrapment sites (carpal tunnel, cubital tunnel, spiral groove, fibular head). PMP22 deletion leads to loss of membrane stabilization and loss of axonal excitability. Symptoms: In HNPP, repeat episodes of transient weakness and numbness in isolated peripheral nerve distributions are reported. Age of onset is generally ~25  years. Patients report focal weakness, such as wrist drop or foot drop, after applied pressure, such as crossing one’s leg, resting on

one’s  elbow, or sports (such as swimming or wrestling). Patients also report paresthesias, pins and needles, and may have had recurrent failed prior entrapment surgeries (carpal tunnel, cubital tunnel). Signs: Exam shows weakness in distribution of individual nerves, along with corresponding sensory loss. Diagnosis: Laboratory: Genetic testing shows PMP22 deletion. Electrophysiology: NCV show distal latency prolongation particularly in the median and fibular nerves, with focal slowing mostly confined to entrapment sites. Imaging: The role of ultrasound imaging in HNPP does show enlargement at entrapment sites, yet in isolation, is insufficient to diagnose the condition. Nerve biopsy: Teased fibers reveal tomacula formation at sites of trauma (Fig.  12.27) although this is now rarely needed in light of genetic testing.

12.10  Hereditary Neuropathies

253

HEREDITARY NEUROPATHY SUSPECTED CLINICALLY -pes cavus? -hammertoes? -bilateral symmetric foot drop without pain or positive sensory symptoms -delayed motor milestones

Perform EMG/NCS (include at least one upper limb to evaluate median or ulnar motor nerve conduction velocity)

CV < 38m/s

CV > 38m/s

Targeted PMP22 DELETION/DUPLICATION testing (CMT1A) If NEGATIVE

CMT PANEL FULL-GENE SEQUENCING – DELETION/DUPLICATION ANALYSIS via NEXT GENERATION SEQEUENCING TECHNOLOGY

If NEGATIVE

WHOLE EXOME SEQUENCING

Fig. 12.24  An algorithmic approach to the diagnostic evaluation of hereditary neuropathy

Fig. 12.25 Lesser occipital nerve (arrowheads) ultrasound in CMT. Note the inconsistent swelling of the nerve throughout the segment shown

12.10.3  Hereditary Neuralgic Amyotrophy Anatomy and Pathophysiology: Hereditary neuralgic amyotrophy is a genetic condition that involves repeated episodes of pain and weakness involving the brachial plexus.

Fig. 12.26 Sural nerve biopsy from a patient with HMSN III (Dejerine–Sottas disease). The biopsy shows severe demyelination with thinly myelinated fibers and formation of multiple onion bulbs (arrows)

Symptoms: Patients present with repeat episodes of shoulder pain and weakness involving the brachial plexus. Surgery, infection, and pregnancy can trigger these episodes.

254

12 Polyneuropathies Table 12.13  Distal hereditary motor neuropathies

Fig. 12.27  Hereditary neuropathy with liability to pressure palsies (HNPP). A teased fiber preparation from a patient with HNPP.  The myelin shows a large sausage-shaped myelin enlargement (tomaculum – little sausage)

Weakness can be transient but usually persists to some degree with the onset of symptoms starting between 10 and 30  years of age. 75% of patients report at least a second attack, typically described as shoulder pain, which lasts up to 3  weeks on average. 70–90% of patients recover strength within 2 years. Signs: Patients exhibit weakness, typically proximally, and in the distribution of affected nerves. In addition, other nerves can be involved, presenting with such findings as scapular winging and phrenic nerve palsy. Other systemic features that suggest HNA include hypotelorism, short stature, small facies, and syndactyly. Diagnosis: Laboratory: Genetic testing often shows an autosomal dominant pathogenic variant or duplication in the SEPTIN9 gene. Electrophysiology: NCS often reveals a brachial plexopathy pattern of injury, most often involving the upper trunk. Imaging: MRI reveals hyperintensity and thickening of the brachial plexus. Therapy: Steroids may be of benefit when instituted in the acute phase to improve pain and recovery. Physical rehabilitation should be instituted, as well as behavioral counseling.

12.10.4  Hereditary Sensory Autonomic Neuropathies Hereditary sensory autonomic neuropathies represent a diverse group of genetic disorders that preferentially target small somatic fibers and autonomic fibers. They can also involve large-fiber sensory (and sometimes motor) fibers as well. Of the five major subtypes (I-V), type I is unique in that it is the only autosomal dominant subtype and the only subtype that can present beyond infancy or childhood. Hereditary sensory autonomic neuropathy should be suspected in the presence of a history of pain insensitivity, alacrima,  ulceration, bone deformities, and fractures.

Gene Specific feature Genetics of most frequent distal hereditary motor neuropathies (dHMN) HMN HSPB1 Adult-onset leg weakness; arms 2B affected later in the disease course HMN GARS Onset in hands (thenar and first dorsal 5A interosseous); legs affected a few years later; pyramidal signs rare HMN BSCL2 Most frequent form. Early hand weakness 5C (thenar more and affected earlier than first dorsal interosseous); distal leg weakness; brisk reflexes in legs; muscle tone in legs can be increased. Plantar response flexor. Allelic to SPG 17 and congenital lipodystrophy, type 2

OMIM #

608634 600794

600794

12.10.5  Distal Hereditary Motor Neuropathies (d-HMN) Distal hereditary motor neuropathies (Table 12.13) encompass a heterogeneous group of length-dependent motor neuropathies that may often overlap with CMT type 2 (axonal type). Although the disease selectively targets motor nerves, it predominantly affects only distal muscles, in contrast to typical SMA, which has both proximal and distal weakness.

12.10.6  Porphyria Genetic testing ++

NCV/EMG ++

Laboratory ++

Imaging

Biopsy

Anatomy/Distribution: Porphyria causes axonal degeneration with some regions of demyelination. Symptoms: Patients typically present with debilitating abdominal pain, changes in urine color, constipation, and vomiting. Neuropathy usually follows the abdominal signs by several days and resembles AIDP, with pain and potentially asymmetric weakness. Clinical Syndrome/Signs: CNS disturbances can precede neuropathy, including agitation, psychosis, seizures, and eventually coma. Weakness can involve the face and respiratory muscles. Autonomic dysfunction is common. In some forms of porphyria, skin blisters can accompany an acute attack. Attacks can be precipitated by hepatotoxic drugs, fasting, stress, and alcohol. Pathogenesis: Porphyria is rare and caused by disruption of heme biosynthesis. Subtypes of porphyria result from dysfunction of each of the enzymes in the heme synthetic pathway, but only the subtypes that involve liver enzymes cause neuropathy. These subtypes are porphobilinogen synthase deficiency, acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria.

12.11  Cancer and Neuropathy

Diagnosis: Electrodiagnosis shows predominately motor impairment. The primary diagnostic tool for an acute attack is a rapid urine test for porphobilinogen. Genetic testing is useful for exact diagnosis and family counseling. Differential Diagnosis: AIDP does not involve such intense abdominal pain. Changes in urine color should raise suspicion for porphyria. Poisoning by lead, arsenic, or thallium can appear similar to porphyria and even cause an increase in urine porphobilinogen. To test for acute intermittent porphyria, one should check urine alanine and porphobilinogen, urine porphyrins, and red blood cell porphyrins, preferably during or as close as possible to an attack. In acute intermittent porphyria, urine alanine, porphobilinogen, and porphyrins are all elevated, while red blood cell porphyrins are normal. Therapy: The most important treatment for an acute attack is IV heme, with attention to carbohydrate and fluid maintenance. Hyponatremia may occur and needs to be corrected. Any precipitating drugs should be withdrawn. Pain and vomiting should be treated. CNS disturbances can be difficult to treat, although antiepileptic drugs may help control seizures. In the long term, prevention is the best therapy. Drugs that can precipitate attacks should be avoided. Some porphyria can be triggered by hormonal changes during menstruation, and these cases can be very difficult to control. Prognosis: Heme therapy is very effective at preventing attacks although mortality may still be as high as 10%. Most patients recover on the whole, but severe neuropathy may remain because of the axonal degeneration.

12.11 Cancer and Neuropathy 12.11.1  Paraneoplastic Neuropathies Genetic testing NCV/EMG Laboratory Imaging Biopsy Other ++ ++

Paraneoplastic neuropathies are a heterogeneous group of neuropathies that can affect the peripheral nerves (sensory, sensory/motor) or the dorsal root ganglion neuron  (DRG) (sensory ganglionopathy/neuronopathy)  and can be associated with posterior column degeneration. Some neuropathies are associated with antineuronal antibodies, in particular anti-Hu or anti-CRMP5. Paraneoplastic neuropathies in cancer patients can also be part of a multifocal paraneoplastic encephalomyelitis complex (PEM). The most frequent type of paraneoplastic neuropathy is subacute sensory neuronopathy. Nerve vasculitis is rarely associated with paraneoplastic syndromes. Demyelinating neuropathies occur in association with lymphoma and Hodgkin’s disease. Anatomy/Distribution: Although sensory ganglionopathy is an anatomically defined entity characterized by inflam-

255

mation of the DRG and additional posterior column degeneration, the anatomy is less well defined for other less-­ characterized paraneoplastic neuropathies (Fig. 12.28). Symptoms: Sensory neuronopathy (“Denny-Brown’s syndrome”) is characterized by subacute development of sensory neuropathy, with ataxia, and pseudoathetoid movements of the upper extremities and ataxia of the lower extremities. Autonomic neuropathies can cause GI symptoms (e.g., pseudo-obstruction), sexual dysfunction, urine retention, dry eyes, dry mouth, pupillary non-reactivity, and orthostatic hypotension. Care should be taken to ensure adequate antibody–phenotype correlation, as false-positive tests can be problematic. Clinical Syndrome: Sensory neuronopathy often presents acutely with the onset of painful asymmetric severe sensory loss with sensory ataxia. Loss of manual dexterity and the ability to stand with severe gait ataxia usually follows. Signs: Sensory neuronopathy is characterized by  asymmetric disease onset, areflexia, ataxia, pseudoathetoid movements, and pain. Motor involvement is atypical, but can occur. Sensory neuronopathy occurs typically before the diagnosis of the cancer. DSP, with a glove and stocking-like distribution, is usually very mild and subclinical. Pathogenesis: The pathogenesis of paraneoplastic neuropathies is unclear but is believed to be the result of numerous onconeuronal autoantibodies associated with cancer, the most prominent being anti-Hu. A sensorimotor type of neuropathy has been associated with anti-CV2 antibodies. Anti-­ CRMP5 is associated with a subacute painful sensory neuronopathy or sensorimotor neuropathy, sometimes in the setting of optic neuritis, encephalitis, and myelopathy. Demyelinating forms are more likely associated with lymphoma and Hodgkin’s disease. Diagnosis: The diagnosis of paraneoplastic neuropathies is based on the case history and clinical presentation. NCV often reveals absent SNAPs. Anti-Hu antibodies, especially in cases of lung cancer, may be detectable; other onconeuronal antibodies as CV2 or CRMP 5 are also now commercially testable. Differential Diagnosis: The syndrome of sensory neuronopathy is not exclusively paraneoplastic, but may also be idiopathic or associated with Sjögren’s syndrome. The sensory variant of CIDP (chronic inflammatory sensory ­polyradiculoneuropathy; CISP) should also be considered in the differential. In the course of cancer, chemotherapy-induced neuropathy is a common possibility, and concomitant metabolic diseases, malnourishment, and weight loss should be excluded. Therapy: No established therapies other than treating the cancer are available for the treatment of sensory neuronopathy, paraneoplastic sensorimotor polyneuropathy, and autonomic neuropathy. Immunomodulatory therapies have been

256

12 Polyneuropathies

a

b

c

d

Fig. 12.28  Paraneoplastic ganglionopathy. (a–c) Dorsal root ganglion (DRG) pathology. (a, b) Examples of an inflammatory paraneoplastic ganglionitis (arrows). (b) An infiltrate that is immunostained for T-cells (arrow). (c) Rare example of neoplastic infiltration of a DRG by lym-

suggested and include steroids, IVIG, plasmapheresis, and immunosuppression, albeit with limited evidence. Symptomatic treatment can be useful. Demyelinating neuropathies of the GBS and CIDP type need treatment according to the current standard of practice. Vasculitic neuropathy can be treated with steroids and immunosuppression (which may be part of the cancer therapy).

phoma cells (arrows) of a Burkitt-like lymphoma. This patient had additional meningeal infiltration. (d) Paraneoplastic ganglionopathy in a patient with small cell lung cancer. Chest CT shows enlargement of the mediastinal lymph nodes

Hodgkin’s  lymphoma. There is a strong association with immune neuropathies, namely CIDP, which often is treatment-­refractory to standard immune neuropathy therapies (IVIG, corticosteroids). Multiple cranial nerves and nerve roots can be involved in lymphoma with CSF spread. Neurolymphomatosis and neuroleukemiosis are quite rare, but are still important to keep in the differential, and involve direct cranial nerve, nerve root, or plexus infiltration. Symptoms: Symptoms depend on the distribution and 12.11.2  Neuropathies in Lymphoma extent of nerve involvement, although patients often report a and Leukemia significant degree of weakness or disability that progressively worsens and/or remains refractory to standard treatGenetic testing NCV/EMG Laboratory Imaging Biopsy Other ments (as in CIDP). + ++ + + Diagnosis: Laboratory: There is hematologic and bone In general, lymphoma- and leukemia-associated neuropa- marrow evidence of lymphoma and/or leukemia as expected. thies most commonly result from chemotherapy, which are CSF analysis reveals an elevated protein and neoplastic cells, highlighted in detail in the subsequent chemotherapy-­ if there is nerve root involvement. induced peripheral neuropathy section. Secondly, lymphoma Electrophysiology: Multiple axonal mononeuropathies is more commonly associated with peripheral neuropathy with low or absent SNAPs and CMAPs and denervation in than leukemia, and of the lymphomas, non-Hodgkin’s lym- innervated myotomes are seen. If there is primary nerve root phoma is more commonly associated with neuropathy than infiltration, needle examination reveals anterior and poste-

12.11  Cancer and Neuropathy

a

257

b

Fig. 12.29  Sural nerve biopsy from a patient with lymphoma. (a) Infiltration of the peripheral nerve by collections of B cells, with disruption of normal sural nerve architecture (arrows). (b) Disruption of myelin, with myelin splaying and partial loss of myelin (arrow)

rior (paraspinal muscles) myotome denervation. In CIDP-­ like cases, there is symmetric demyelination. Imaging: MRI of the craniospinal axis is required in suspected cases of neoplastic polyradiculopathy. PET scanning of the plexus and peripheral nerves can reveal areas of tumor deposition. Increasingly, ultrasound of peripheral nerves is used to examine the nerve plexus and peripheral nerves and can show nerve thickening and nerve enlargement. Nerve Biopsy: There is direct infiltration of nerve, resulting in axonal loss and the presence of tumor deposits in the nerve (Fig. 12.29). Disorders that can affect multiple named nerves or nerve roots, such as vasculitis or infectious neuropathies, need to be excluded, and histological studies are required to distinguish between inflammatory and neoplastic cells. Therapy: Treatment either by chemo- or immuno-­therapy can be helpful. Rarely, surgery is performed to remove local metastasis or a shunt is placed for chemotherapy directed at meningeal and/or root involvement. Therapy is dependent on the etiology and includes symptomatic treatment for sensory neuropathies, immunomodulatory treatment in CIDP, and antineoplastic treatment in cases of neurolymphomatosis. No recommended therapies other than treating the cancer are available for sensorimotor polyneuropathies and autonomic syndromes. For sensory neuropathies and neuronopathies, immunomodulatory therapies have been suggested and range from steroids to IVIG, plasmapheresis, and immunosuppression, all without strong evidence. Symptomatic treatment can be useful. Demyelinating neuropathies of the GBS and CIDP type need treatment according to the current standard of practice. Vasculitic neuropathy can be treated with steroids and immunosuppression (which may be part of the cancer therapy). Prognosis: While the prognosis is dependent on the type of cancer, in general, peripheral nervous system involvement is a poor prognostic factor suggesting the final stages of the disease.

12.11.3  Polyneuropathy and Chemotherapy Genetic testing –

NCV/EMG +

Laboratory –

Imaging –

Biopsy –

Chemotherapy-induced polyneuropathies (CIPN) are usually dose dependent and may resolve after termination of the chemotherapy. Increasingly, CIPN is recognized as a late effect in long-term cancer survivors. Acute effects of chemotherapy occur predominately in oxaliplatin treatment. Little is known about the influence of pre-existing polyneuropathies on the development of CIPN (except for  hereditary sensorimotor neuropathies) and the toxicity of chemotherapy drug combinations. Additionally, biological agents such as antibodies, interferons, cytokines, and vaccines are used in cancer therapy and may have a risk of inducing polyneuropathies. Pathogenesis: The pathogenesis of drug-induced neuropathy is dependent on the substance used and varies with different classes of drugs. For example, platinum drugs target the DRG, vinca alkaloids act on tubulin, and the taxanes and epothilones induce excessive tubulin polymerization. The mechanism of proteasome inhibitor toxicity  on the peripheral nervous system has not been fully elucidated. Most recently, the emergence of immune checkpoint inhibitors has been of great interest, and may follow more of a vasculitic etiopathology rather  than a true toxicity. Acute, Cumulative, and Late Effects: The evaluation of peripheral neuropathy in patients receiving potentially neurotoxic chemotherapeutic agents needs to be approached systematically. First, one must establish if the drug is indeed neurotoxic. Second, route of administration is of importance and impacts toxicity level. Third, drug dose matters, as some toxic neuropathies are dose-dependent in severity, or develop only in the setting of a certain threshold of drug received. In this regard, the concept of acute, cumulative, and late toxic effects is of great importance.

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12 Polyneuropathies

As the number of cancer survivors increases, persistent CIPN is reducing their quality of life and resulting in significant morbidity. Common persistent problems are sensory neuropathy, neuropathic pain syndromes, muscle cramps and fasciculations, altered smell and taste, and vestibular dysfunction. CIPN can have long-term effects in cancer survivors and can significantly impact the patient’s quality of life. Clinical Distribution: Most neuropathies caused by chemotherapeutic agents are symmetric and length dependent, with a stocking–glove distribution of sensory loss. Distal weakness (lower extremities) rarely occurs. Cranial nerves are usually not involved, except in acute oxaliplatin toxicity where patients experience cold-induced face and throat pain. Clinically, the development of distal sensory symptoms (numbness or paresthesias) can be used as a clinical sign of neurotoxicity. Although CIPN is generally described within the context of large-fiber sensory loss, small-fiber loss is often seen, mainly in the setting of taxane use. The newly described checkpoint inhibitors also cause AIDP or CIDP patterns with rapid or ascending proximal distribution weakness. Symptoms: Most CIPN are sensory. Tingling or numbness in the feet or fingers is often an early sign. Also “positive” sensory symptoms occur, including paresthesias, dysesthesias, tingling, itching and burning, tight, stabbing, sharp (lightening like), or aching pain. Not all CIPN is painful, although a sizeable number is, for which neuropathic

pain medications are available. Sensory loss in the feet and legs can cause sensory ataxia and gait disorders. Loss of sensation in the hands is often perceived as “clumsiness.” Myalgias have been described with gemcitabine and taxane therapies. Signs: Diminished sensory perception for touch, pinprick, and vibration is seen. Ankle reflexes are often absent. Finger-to-nose, knee-to-shin, and Romberg testing  are often  abnormal. Weakness is rarely a feature (except with some cases of vinca alkaloids and bortezomib treatment). Raynaud’s syndrome has been observed in long-term survivors. Even with drug withdrawal, signs may continue to progress, a phenomenon known as “coasting.” Prevention: To date, preventative treatment with vitamins, antioxidants, and growth factors and other drugs, as well a cooling of the extremities, prior to or at the time of chemotherapy has not prevented the onset and progression of CIPN. Symptomatic Treatment: Neuropathic pain treatment is required with anticonvulsants, antidepressants, in severe cases opioids and also topical local anesthetics. Physical and occupational therapy are helpful to compensate for loss of proprioception and increase function. Drugs Used for Chemotherapy: There are a large number of drugs used for chemotherapy. Some of the biological agents currently in use are also reported to have neurotoxic effects in individual cases (Table  12.14). The main sub-

Table 12.14  Drugs used for chemotherapy Drug Cisplatin

Cumulative dose 300–400 mg/m2

Carboplatin Oxaliplatin Vincristine

600 mg/m2 800 mg/m2 5–15 mg/m2

Paclitaxel Cabazitaxel

200 mg/m2 Neuropathy risk does not appear to be related to cumulative dose although CNS toxicity may be dose-dependent 400–600 mg/m2 120 mg/m2 1–1.3 mg/m2

Docetaxel Ixabepilone Bortezomib

Thalidomide Lenalidomide Brentuximab Immune checkpoint inhibitors

20 g (total) Neuropathy risk does not appear to be related to cumulative dose 23% increase risk for every 100 mg dose increase Neuropathy risk does not appear to be related to cumulative dose

Immediate (acute) effects

Other effects Coasting, can produce sensory ganglionopathy with sensory ataxia Coasting

Acute toxicity. Cold dependent

Acute toxicity likely (distal pain)

Acute toxicity likely (distal pain)

Cranial and peripheral nerve mononeuropathies, autonomic neuropathy, myopathy Myalgias, myopathy

Similar to taxanes Painful, and risk is reduced through subcutaneous administration Rarely demyelinating Poor reversibility

Can produce a CIDP-like picture although rare Produces numerous neuropathies Acute toxicity common and can manifest with varied neuromuscular complications, including CIDP and AIDP phenotypes

12.11  Cancer and Neuropathy

stances causing chemotherapy-induced neuropathies are platinum compounds, vinca alkaloids, taxanes, bortezomib, and thalidomide. Toxicity is dose dependent and cumulative; acute effects occur in oxaliplatin and possibly in taxanes.

12.11.3.1 Platinum Compounds • Cisplatin: The neuropathy is predominantly sensory with complaints of distal numbness or paresthesias with sensory ataxia and a positive L'hermitte’s sign. Patients often develop a sensory ganglionopathy/neuronopathy, as the DRG is not protected by the blood–nerve barrier, and particularly susceptible to platinum-based compounds. Coasting is also a unique feature. Many patients experience residual neuropathic pain after improvement in their neuropathy. Ototoxicity can result in hearing loss and dizziness. • Carboplatin: In higher cumulative doses than cisplatin, carboplatin also produces a sensory neuropathy similar to cisplatin. • Oxaliplatin: 80% of patients develop an acute effect of cold-induced paresthesias and dysesthesias in the throat, mouth, face, and hands. The symptoms settle a few days after the infusion is completed. The dose-related sensory neurotoxicity resembles cisplatin-induced neuropathy. Oxcarbazepine is modestly effective as a prophylactic agent.

259

Weakness is mild or absent with rare reports of proximal muscle weakness. Myalgias and arthralgias can also  occur with paclitaxel therapy. Electrophysiology: Testing reveals reduced or absent sensory nerve action potentials in a length-dependent fashion. Sensory symptoms also occur even in the absence of nerve conduction study findings, suggesting that for some patients, CIPN is small-fiber predominant, which can be further confirmed on intraepidermal nerve fiber density testing.

12.11.3.3 Epothilones Ixabepilone is a semisynthetic microtubule-stabilizing agent used often in the treatment of breast cancer, and often combined with capecitabine. It produces a dose-dependent neuropathy. Clinical Features: Epothilone can produce a mild to moderate, length-dependent, sensory-predominant peripheral neuropathy, with symptoms of numbness, paresthesias, and dysesthesias. Drug discontinuation leads to prompt reversal of neuropathy. Electrophysiology: Testing reveals an axonal distal length-­ dependent sensory neuropathy.

Clinical Features: Early symptoms are painful paresthesias of the hands (particularly the fingers) and feet. Of note, cisplatinum is known to produce a sensory ganglionopathy. Weakness can occur in wrist extensors and toe extensors. Rarely, patients experience autonomic dysfunction or cranial nerve mononeuropathies. Electrophysiology: NCS show axonal neuropathy with reduced or absent SNAPs with mildly reduced NCVs. In cisplatinum-associated neuropathy, the damage is often length-independent.

12.11.3.4 Vinca Alkaloids Vinca alkaloids bind tubulin and arrest its polymerization into microtubules in rapidly dividing cells. This mechanism of action also inhibits anterograde and retrograde axonal transport, producing a dose-related sensorimotor neuropathy. Vincristine and vindesine have more severe neurotoxicity compared with vinblastine and vinorelbine. Clinical Features: Early symptoms are painful paresthesias of the hands (particularly the fingers) and feet. Weakness can occur in wrist extensors and toe dorsiflexors. Rarely, patients experience autonomic dysfunction or cranial nerve mononeuropathies. Electrophysiology: Testing shows evidence of a sensory predominant length-dependent axonal neuropathy.

12.11.3.2 Taxanes Paclitaxel (Taxol), cabazitaxel, and docetaxel (Taxotere) are widely used alone or in combination with other agents for the treatment of breast, ovarian, lung, and other cancers. Paclitaxel produces a more severe neuropathy than docetaxel. The combination of carboplatin (a platinum-based agent) and paclitaxel (or Cabazitaxel) together seems to be particularly toxic. Clinical Features: Sensory symptoms are dose-related, although less so for cabazitaxel. Both drugs induce loss of sensation, paresthesias, or allodynia in the feet and hands. Proprioceptive sensory loss can result in gait ataxia.

12.11.3.5 Proteasome Inhibitors Bortezomib is a polycyclic derivative of boronic acid that inhibits the mammalian 26S proteasome. Carfilzomib is a new proteasome inhibitor in current clinical trials with reportedly less neurotoxic side effects. Clinical Features: The neuropathy is dose related and cumulative although it is less toxic when given subcutaneously. It is predominantly sensory, distal, and length dependent. It often causes neuropathic pain and autonomic neuropathy with postural hypotension probably due to small-­ fiber involvement. Neuropathy occurs in 37–44% of patients receiving this drug.

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Electrophysiology: Electrophysiological changes demonstrate axonal loss with low or absent SNAPs.

12.11.3.6 Thalidomide and Lenalidomide Thalidomide has been used in the treatment of multiple myeloma, Waldenström’s macroglobulinemia, myelodysplastic syndromes, and acute myeloid leukemia. Clinical Features: The neuropathy is predominantly sensory and develops in 20–40% of patients. The frequency of neuropathy increases with age and the cumulative dose. Lenalidomide (alpha-3-aminophthalimidoglutarimide) is an analog of thalidomide that is significantly  less neurotoxic, if at all. Also, pomalidomide, a newer analog, is designed to be less neurotoxic. Electrophysiology: Demonstrate axonal neuropathy with reduced or absent SNAPs. 12.11.3.7 Hybrid Therapies Brentuximab: Brentuximab vedotin is an antineoplastic agent used in the treatment of Hodgkin’s and non-Hodgkin’s lymphoma, which uses a combined antibody-drug delivery mechanism. The antibody targets CD30 protein on tumor cell surfaces, whereupon drug (auristatin) is then released into the cell. Clinical Features: The drug produces an axonal length-­ dependent sensorimotor neuropathy, which can occasionally be aggressive. A sizeable number develop a demyelinating picture. Most patients attain at least partial recovery with drug discontinuation. Electrophysiology: Most develop an axonal sensorimotor neuropathy, although some develop a demyelinating electrophysiologic picture (CIDP). Trastuzumab: Trastuzumab is a monoclonal antibody directed against HER2-receptor-positive breast and gastric cancers. There are limited studies that describe the onset of neuropathy when trastuzumab is combined with taxane therapy. Immune checkpoint inhibitors: Immune checkpoint inhibitors are a new class of antineoplastic agents, with application in the treatment of advanced stage melanoma and lung carcinoma, among others. They can lead to neuromuscular toxicity, affecting muscle, neuromuscular junction, and nerve. Clinical Features: Among its neuropathic toxic effects, immune checkpoint inhibitors produce length-dependent axonal sensorimotor neuropathies, length-independent demyelinating polyradiculoneuropathies (such as AIDP and CIDP), and cranial neuropathies. Pathophysiologically, the neuropathy is thought to be inflammatory rather than toxic,

12 Polyneuropathies

and thus responsive to such therapies as IVIG or steroids. Molecular mimicry involving tumor antigen and compact myelin ganglioside is thought to underlie neuropathy development. Patients not infrequently have superimposed myopathic or neuromuscular junctional deficits as well. Electrophysiology: Immune checkpoint inhibitors often produce a demyelinating neuropathy, with evidence of conduction block at non-entrapment sites. In addition, a significant percenteage develop an axonal neuropathy.

12.12 C  ryptogenic Sensory Peripheral Neuropathy CSPN is a diagnosis of exclusion and refers to length-­ dependent distal symmetric sensory predominant large or small-fiber polyneuropathy that presents in the absence of an established or known cause  of neuropathy. While there is a  growing association between CSPN and metabolic syndrome, there still remains a sizeable number of patients who have no identifiable underlying secondary cause to their polyneuropathy. CSPN usually occurs in patients older than age 50 years.

Further Readings Adams D, Koike H, Slama M, Coelho T (2019) Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease. Nat Rev Neurol 15(7):387–404 Adams D, Lozeron P, Lacroix C (2012) Amyloid neuropathies. Curr Opin Neurol 25(5):564–572 Callaghan B, Feldman E (2013) The metabolic syndrome and neuropathy: therapeutic challenges and opportunities. Ann Neurol 74(3):397–403 Collins MP, Hadden RD (2017) The nonsystemic vasculitic neuropathies. Nat Rev Neurol 13(5):302–316 Dimachkie MM, Barohn RJ, Katz J (2013) Multifocal motor neuropathy, multifocal acquired demyelinating sensory and motor neuropathy, and other chronic acquired demyelinating polyneuropathy variants. Neurol Clin 31(2):533–555 Donofrio PD (2017) Guillain-Barré syndrome. Continuum (Minneap Minn) 23(5, Peripheral Nerve and Motor Neuron Disorders):1295–1309 Dyck PJ, Windebank AJ (2002) Diabetic and nondiabetic lumbosacral radiculoplexus neuropathies: new insights into pathophysiology and treatment. Muscle Nerve 25(4):477–491 Dyck PJB, Tracy JA (2018) History, diagnosis, and management of chronic inflammatory demyelinating polyradiculoneuropathy. Mayo Clin Proc 93(6):777–793 Feldman EL, Callaghan BC, Pop-Busui R, Zochodne DW, Wright DE, Bennett DL, Bril V, Russell JW, Viswanathan V (2019) Diabetic neuropathy. Nat Rev Dis Primers 5(1):41 Gwathmey KG, Burns TM, Collins MP, Dyck PJ (2014) Vasculitic neuropathies. Lancet Neurol 13(1):67–82

Further Readings Hammond N, Wang Y, Dimachkie MM, Barohn RJ (2013) Nutritional neuropathies. Neurol Clin 31(2):477–489 Hehir MK, Logigian EL (2014) Infectious neuropathies. Continuum (Minneap Minn) 20(5 Peripheral Nervous System Disorders):1274–1292 Jones MR, Urits I, Wolf J, Corrigan D, Colburn L, Peterson E, Williamson A, Viswanath O (2020) Drug-induced peripheral neuropathy: a narrative review. Curr Clin Pharmacol 15(1):38–48 Lawson VH, Arnold WD (2014) Multifocal motor neuropathy: a review of pathogenesis, diagnosis, and treatment. Neuropsychiatr Dis Treat 10:567–576 London Z, Albers JW (2007) Toxic neuropathies associated with pharmaceutic and industrial agents. Neurol Clin 25(1):257–276 Mauermann ML (2014) Paraproteinemic neuropathies. Continuum (Minneap Minn) 20(5 Peripheral Nervous System Disorders):1307–1322

261 Rossor AM, Evans MR, Reilly MM (2015) A practical approach to the genetic neuropathies. Pract Neurol 15(3):187–198 Rudnicki SA, Dalmau J (2005) Paraneoplastic syndromes of the peripheral nerves. Curr Opin Neurol 18(5):598–603 Sindic CJ (2013) Infectious neuropathies. Curr Opin Neurol 26(5):510–515 Staff NP, Grisold A, Grisold W, Windebank AJ (2017) Chemotherapy-­ induced peripheral neuropathy: a current review. Ann Neurol 81(6):772–781 van Alfen N (2011) Clinical and pathophysiological concepts of neuralgic amyotrophy. Nat Rev Neurol 7(6):315–322 Vural A, Doppler K, Meinl E (2018) Autoantibodies against the node of Ranvier in seropositive chronic inflammatory demyelinating polyneuropathy: diagnostic, pathogenic, and therapeutic relevance. Front Immunol 9:1029

Neuromuscular Transmission: Endplate Disorders

13

13.1 Introduction Neuromuscular transmission disorders are classified into pre- and postsynaptic disorders. The Lambert–Eaton myasthenic syndrome (LEMS) is a presynaptic disorder and can be observed as an autoimmune or a paraneoplastic condition. Acquired autoimmune myasthenia gravis (MG) is the most frequent of the postsynaptic neuromuscular transmission disorders. Since the last edition of the Neuromuscular Atlas II, new antibodies against neuromuscular junction structures have been developed and new evidence-based treatments have emerged. Similarly, diagnostic and treatment options for congenital myasthenia have increased over the years.

13.2 Myasthenia Gravis Genetic testing −

NCS/EMG ++

Laboratory ++

Imaging ++

Biopsy −

Epidemiology: The prevalence and incidence of MG have increased over the years, especially in elderly men. Current estimates are 0.17–1.04/100,000 for incidence and 0.3– 20/100,000 for prevalence. MuSK-Ab-positive MG more commonly affects women (between 1% and 10%). Coexisting autoimmune diseases are frequent in MG with Grave’s disease, Hashimoto disease and rheumatoid arthritis being the most common. Autoimmune diseases occur more often in female and seronegative patients. Anatomy and Pathophysiology: In AchR-Ab-positive MG, the number of AchR is reduced, their function partially blocked, AchR turnover is increased and complement is activated. If untreated, the endplate becomes structurally damaged. MuSK is necessary for AchR clustering, but the pathophysiology of MuSK-Ab MG is incompletely understood. Low-density lipoprotein receptor-related protein 4 (LRP4) antibodies disrupt the LRP4–agrin interaction Contributions by Wolfgang N. Löscher

Fig. 13.1  Schematic representation of neuromuscular junction membrane proteins and structures relevant to the pathophysiology of NMT disorders. NMT neuromuscular junction transmission, VGSC voltage-­ gated sodium channel, VGCC voltage-gated calcium channel, Ach acetylcholine, LRP4 low-density lipoprotein receptor-related protein 4, MuSK muscle-specific kinase

thereby inhibiting agrin-induced MuSK activation and AchR clustering. Antibodies against AchR and LRP4 belong predominantely to the IgG1 subclass, while those against MuSK belong to the IgG4 subclass. LRP4-Ab can be found in AchR-Ab (8%) and MusK-Ab-positive (15%) cases (see Fig. 13.1). Symptoms: Use-dependent weakness and increased fatigability. Initial complaints are frequently double vision secondary to eye movement abnormalities, “droopy” eyelids (ptosis), difficulties chewivng and swallowing, softening of voice when speaking over prolonged periods of time, shortness of breath or increased fatigability of arms or legs with prolonged use. Typically, these symptoms fluctuate and worsen during the day. The disease fluctuates over weeks or months and severe exacerbations (“myasthenic crisis”) can occur (Fig. 13.2). Signs: Extraocular muscle weakness and ptosis are often asymmetrical and fluctuating (Fig. 13.3). Speech may

© Springer Nature Switzerland AG 2021 E. L. Feldman et al., Atlas of Neuromuscular Diseases, https://doi.org/10.1007/978-3-030-63449-0_13

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13  Neuromuscular Transmission: Endplate Disorders

Fig. 13.2  Generalized MG. (a) Bilateral ptosis. (b) Attempted gaze to the right. Only right eye abducts partially. (c) Proximal weakness upon raising the arms. (d) Holding the arms and fingers extended, the extensor muscles weaken and finger drop occurs

Fig. 13.3  Ptosis and eye movement abnormalities in MG.  Uni- and often bilateral ptosis occur. The eye movements are often severely affected. In this case, downward gaze is reduced on the right

Fig. 13.4  Triple furrowed tongue: this patient suffered about 20 years from MG. Despite modern and intensive treatment, the bulbar symptoms were never completely controlled. The tongue shows “tripled furrowed tongue” atrophy

13.2  Myasthenia Gravis

265

become nasal during prolonged talking and swallowing may be impaired. Neck extensor weakness is rare but neck flexor weakness is common. When breathing is impaired, it is most impaired in the supine position. In the extremities, weakness and fatigability usually affect proximal muscles. MuSK-Ab-positive MG tends to present with bulbar and respiratory symptoms and signs, and myasthenic crises are frequent. MuSK-positive patients can develop facial myopathy and tongue atrophy (Fig. 13.4), which can be seen on MRI. LRP4-Ab-positive MG tends to be mild, with a disease onset of 33–42 years of age in men. Myasthenic Crisis: Severe impairment of respiration, bulbar function and severe generalized weakness; mechanical ventilation is frequently necessary. Myasthenic crises can be triggered by various drugs (see drug-induced MG) and infections; it affects 10–15% of patients during the course of their disease. MG crises are more frequent in MuSK-Ab-positive MG. Classification and Scores: Myasthenia was previously classified according to Osserman. Recently, MG is classified according to antibody status, age of onset and the presence or absence of thymoma (Table  13.1) and in addition, MG is classified according to the MG Foundation of America classification (Table  13.2), which takes disease severity into account.

Table 13.2  Classification of MG according to the Myasthenia Gravis Foundation of America (MGFA) Class I Class II   IIa

Any ocular muscle weakness; may have weakness of eye closure, all other muscle strength is normal Mild weakness affecting other than ocular muscles; may also have ocular muscle weakness of any severity Predominantly affecting the limb, axial muscles or both; may also have lesser involvement of oropharyngeal muscles   IIb Predominantly affecting oropharyngeal and respiratory muscles or both; may also have lesser or equal involvement of the limb, axial muscles or both Class Moderate weakness affecting other than ocular muscles; may III also have ocular muscle weakness of any severity   IIIa Predominantly affecting the limb, axial muscles or both; may also have lesser involvement of oropharyngeal muscles   IIIb Predominantly affecting oropharyngeal and respiratory muscles or both; may also have lesser or equal involvement of the limb, axial muscles, or both Class Severe weakness affecting other than ocular muscles; may IV also have ocular muscle weakness of any severity   IVa Predominantly affecting the limb, axial muscles or both; may also have lesser involvement of oropharyngeal muscles   IVb Predominantly affecting oropharyngeal and respiratory muscles or both; may also have lesser or equal involvement of the limb, axial muscles or both Class Defined by intubation, with or without mechanical V ventilation, except when employed during routine postoperative management. The use of a feeding tube without intubation places the patient in class IVb

Table 13.1  Subtypes of myasthenia

Early onset

Percentage of MG 20–25

Age 40 7.5 mg prednisone equivalent is expected, prophylaxis with calcium (1000–1500  mg/day) and vitamin D (400–800  IU/day) should be started. In postmenopausal woman, bisphosphonates are approved to treat steroid-induced osteoporosis.

268

When long-term steroid treatment is necessary or remission is incomplete, additional immunosuppression is used. Azathioprine: This is a steroid-sparing drug, but an effect is not seen before 6–12 months. Before azathioprine can be started, a thiopurine methyltransferase (TPMT) level must be checked; if the patient is TPMT deficient, the drug cannot be started, as the patient will not be able to metabolize azathioprine, which belongs to the class of thiopurines. The daily dose is 2.5 mg/kg; when effective, the dose can be reduced to 1 mg/kg. After prolonged periods of steroid-­ free complete remission, azathioprine can be stopped. Relapses are possible. Monitor WBC, RBC, and liver function. In most responders, mean corpuscular volume increases with treatment. Side effects include flu-like reactions, arthralgia, rarely severe bone marrow suppression, opportunistic infections and lymphoma. The risk for malignancies is increased. If allopurinol is taken concomitantly, reduce azathioprine dose to 25% to avoid severe adverse events. Mycophenolate mofetil (MMF): While not superior to placebo in two randomized controlled trials, this drug is frequently used in North America if azathioprine is not tolerated. MMF seems to be beneficial in MuSK-positive MG when standard treatment does not work. The daily dose is 1 g twice a day. Intravenous gamma globulin: Is usually begun as a steroid sparing agent or when a combination of steroids and azathioprine or MMF are not providing sufficient clinical recovery. Usual starting dose is 1  g/kg body weight given either twice monthly or monthly, after a loading dose of 2 g/ kg body weight over 2–5 days. Methotrexate: Methotrexate can also be used. The dose is 7.5–25 mg once weekly. Before treatment, a chest X-ray is necessary and regular monitoring of WBC, RBC, and renal and liver function during treatment. Side effects include nausea, vomiting, oral ulcerations, itching, exanthema, rarely severe bone marrow suppression, opportunistic infections, and lymphoma. Methotrexate must not be used without birth control in men and women. Strict birth control has to be maintained for six additional months after termination of treatment. Cyclosporin A and tacrolimus: These drugs have been effective in smaller studies. Cyclosporin is given at a daily dose of 2.5 mg/kg (maximum 3–4 mg/kg/day) and tacrolimus at 3–5  mg/day. Side effects include tremor, hirsutism, headache, anemia, hypertension, renal insufficiency, and increased risk of malignancies. Cyclophosphamide: Has been used to treat single cases. Hemorrhagic cystitis may complicate treatment. Rituximab: Rituximab can be used in patients who do not respond to standard treatment, but seems to be more effective in MuSK-positive than in AchR-Ab-positive MG. Typically, 1000 mg rituximab i.v. is given twice with 2 weeks between

13  Neuromuscular Transmission: Endplate Disorders

treatments, but other dosing regimens have been used (500 mg; 375 mg/m2). Further treatments are based on B-cell count and clinical symptoms. Serious side effects are rare, but some cases with progressive multifocal leukoencephalopathy have been reported. Eculizumab: This drug has recently been approved for treatment-refractory cases. Preceeding treatment, patients have to be vaccinated against Neisseria meningitides or have to take antibiotics until a vacination has been performed. Eculizumab is given intravenously at 1200 mg every second week after a 4 weeks run-in phase. While experience with the drug is still in early stages, there are patients who were previously treatment resistant who are reported to respond to therapy. Thymectomy: A recent well done clinical trial showed a benefit of thymectomy in select MG patients. Thymectomy is recommended in patients with AchR-Ab-positive generalized MG between the age of 18 and 65  years. When performed within 2–5 years of disease onset, treatment outcome is better, less steroids and additional immunosupressants and less hospitalizations are necessary. It also doubles the likelihood of remission. Robot-assisted thymectomy is as effective and better tolerated than transsternal thymectomy. There are no data to support the use of thymectomy in ocular MG, even in the presence of AchR-Abs. At present, thymectomy is not recommended in MuSK-­ positive MG, and its use in double-seronegative and LRP4-­ Ab-­positive MG is controversial. Treatment of Myasthenic Crisis: Standard ICU treatment and care are mandatory. Disease-specific treatments of equal efficacy are plasma exchange, immunoadsorption, and intravenous immunoglobulin. The number of plasma exchanges or immunoadsorptions depends on the individual response; 3–8 treatments are usually necessary. Treatments every other day seem to be as effective as daily treatments. A singe course of IVIG at 1 g/kg/day is also helpful during a crisis. Myasthenia and Pregnancy: Pregnancy has no predictable effect on MG; symptoms can worsen, improve, or remain unchanged. If worsening occurs, this is more likely during the first trimester or the first month postpartum. Men and women of childbearing age should avoid immunosuppressant treatment when possible. Of the common drugs used, only methotrexate is associated with a high risk for fetal malformations and therefore must not be used in both men and women of childbearing age. During pregnancy, methotrexate and MMF should be avoided. Other immunosuppressive drugs have a potential risk for fetal development, but when necessary, potential benefits outweigh the risk (classes C and D; FDA classification). If patients who are treated with immunosuppressants get pregnant, treatment with azathioprine, cyclosporine, tacrolimus, cyclophosphamide, rituximab, and eculizumab might be continued when necessary although rituximab and

13.4  Lambert–Eaton Myasthenic Syndrome (LEMS)

269

eculizumab are not recommended due to the lack of data. Table 13.3  Congenital myasthenic syndromes Rituximab can cause B-cell depetion in neonates. Steroids, Presynaptic defects Defect in choline acetyltransferase pyridostigmine, IVIG, and plasma exchange are safe in Paucity of synaptic vesicles and reduced quantal release pregnancy. Congenital Lambert–Eaton-like syndrome Vaginal delivery is usually safe, and Cesarean section Reduced quantal Ach release should be reserved for obstetric indications. The frequency Synaptic basal lamina Endplate acetylcholinesterase deficiency of obstetric complications, e.g., premature amniorrhexis, is defects β2 (LAMB2) deficiency only marginally increased. Postsynaptic defects Primary AchR deficiency with or without Breastfeeding is safe in patients treated with pyridostigkinetic abnormalities   Reduced expression due to mutations in mine or steroids although it is recommended to postpone AchR α, β, δ, and e subunits breastfeeding for 4 h after steroid intake. High doses of ace  Reduced expression due to rapsyn tylcholinesterase inhibitors may produce gastrointestinal mutations disorders in the neonate.   Reduced expression due to plectin Women with immunosuppression other than steroids deficiency Primary AchR kinetic abnormality with or should not breastfeed as immunosuppressants may also prowithout deficiency duce immunosuppression in the neonate.   Slow-channel syndrome Neonatal Myasthenia: Approximately 10–20% of infants   Fast-channel syndrome born to myasthenic mothers develop transient weakness due   Sodium channel congenital myasthenic to passive transfer of IgG antibodies across the placenta. syndrome Typical signs are weak cry, hypotonia, and respiratory and   Agrin mutations   MuSK mutations feeding difficulties. Symptoms last a few weeks. Neonatal Centronuclear myopathies MG has been reported in a few neonates born to MuSK-Ab-­ Presynaptic and postsynaptic defects Familial limb-girdle myasthenia—Dok-7 positive mothers. mutations Congenital arthrogryposis has rarely been described when Familial limb-girdle myasthenia with the transferred antibodies have a high affinity to the fetal acetubular aggregates—GFPT1mutations tylcholine receptor.

13.3 Congenital Myasthenic Syndromes Genetic testing ++

NCS/EMG +

Laboratory −

Imaging −

Biopsy +

Congenital myasthenic syndromes are genetic disorders of the neuromuscular junction. Inheritance is recessive in most cases, but dominant forms do occur. Congenital myasthenic syndromes are classified by the site of the neuromuscular junction at which the defect occurs. Mutations in various genes have been described in about a third of the patients (Table 13.3). Approximately 50% of mutations affect genes coding for the AchR (CHRNE, CHRNA1, CHRNB1, CHRND), followed my mutations is genes essential for endplate formation and function (DOK7 and RAPSN, ~15% each). COLQ mutations cause deficiency of acetylcholinesterase at the endplate. Congenital myasthenic syndromes present in infancy or early childhood, but later manifestations are possible. It should be suspected in infants and children with hypotonia, underdeveloped muscles and unexplained weakness, weakness affecting cranial nerves and repeated episodes of respiratory insufficiency and episodic apneas. Some congenital myasthenic syndromes also cause myopathy and facial deformities. Adult cases mimicking limb girdle muscular

dystrophy have been reported. Autoantibodies are not present, but a decremental response is frequently seen with low-­ frequency repetitive stimulation. After-discharges are seen in slow-channel syndromes. Treatment depends on the genetic defect and the underlying mechanism. Pyridostigmine is helpful in some subtypes, while deleterious in others. Other drugs used are 3,4-­ diaminopyridine, ephedrine, salbutamol, albuterol, fluoxetine, and quinidine.

13.4 Lambert–Eaton Myasthenic Syndrome (LEMS) Genetic testing −

NCS/EMG ++

Laboratory ++

Imaging ++

Biopsy −

Epidemiology: LEMS is rare. It usually occurs in midlife and is associated with small cell lung cancer (SCLC) in 50–60% of patients; other malignancies are rarer. One to three percent of patients with SCLC have LEMS. Anatomy and Pathophysiology: Antibodies to the presynaptic P/Q-type VGCC impair calcium influx, which reduces the number of acetylcholine vesicles released per action potential. Antibodies to the N-type VGCC can also be found, but their contribution to the clinical symptoms probably is small.

270

Symptoms: Proximal leg and arm weakness; distal muscles can also be affected but bulbar and ocular signs are rare and mild. Symptoms of autonomic dysfunction, e.g., dry mouth and eyes, impotence, constipation, impaired sweating, and orthostatic hypotension, are frequent. LEMS may precede cancer detection by several years. Signs: Proximal weakness and diminished or absent tendon reflexes. Following a brief sustained exercise of 10  s, strength may improve and tendon reflexes may reappear. Orthostatic hypotension can be detected bedside with the Schellong test. Some patients show signs of cerebellar dysfunction, and anti-Hu-Ab can also be found in these patients. Causes: LEMS is caused by antibodies against the P/Q-­type VGCC in approximately 85% of patients. It is a paraneoplastic disorder in about 50%, mostly associated with SCLC. In non-tumor LEMS, there is a strong association with HLA-B8, a female preponderance, and approximately 25% of these patients have autoimmune disorders such as thyroid disease, pernicious anemia, celiac disease, and vitiligo. Diagnosis: Typical symptoms and signs, the characteristic electrophysiological findings, and antibody tests. Electrophysiology: Routine NCS show low-amplitude CMAP. Sensory NCS and EMG are usually normal. Repetitive low-frequency nerve stimulation results in a decremental response similar to MG. The diagnostic yield of stimulation of distal nerve-muscle pairs is higher. High-­ frequency stimulation of >20  Hz results in an increase of Fig. 13.7 (a) Decremental response in the abductor digiti minimi muscle after 3 Hz repetitive stimulation of the ulnar nerve. (b) Responses to single stimulation of the ulnar nerve at the wrist recorded from the abductor digiti minimi muscle. Left: CMAP at rest. Right: CMAP immediately after a 10-s maximum voluntary contraction. s—seconds

13  Neuromuscular Transmission: Endplate Disorders

CMAP amplitude. Alternatively, a single stimulation should be performed before and after a 10-s maximum voluntary contraction. A postexercise amplitude increase of >60% is diagnostic. Acetylcholinesterase inhibitors should be withheld 12 h prior to testing (Fig. 13.7). Imaging: CT of the thorax is mandatory in patients with LEMS; when the CT scan is normal, bronchoscopy and PET are optional in selected cases. If no tumor is found, follow-up with CT scans should be performed every 6  months for at least 4 years. Laboratory: Antibodies to the P/Q-type VGCC are found in approximately 85%. The antibody titer does not correlate with disease severity or tumor presence. SOX1-antibodies have been found in paraneoplastic but not in non-tumor LEMS. Anti-Hu antibodies have been found in LEMS in combination with a paraneoplastic cerebellar syndrome. Differential Diagnosis: MG, other neuromuscular transmission disorders, myopathy, polyneuropathy. Therapy: Treatment of the tumor also improves LEMS in SCLC.  Symptomatic treatment includes 3–4 diaminopyridine up to 20 mg t.i.d. Side effects are paresthesias and rarely seizures. Pyridostigmine can improve weakness in some patients. Immunosuppressive treatments should be considered (steroids, azathioprine, rituximab, plasma exchange, and immunoglobulin) if other treatment fails.

13.6  Neuromyotonia (Isaacs’ Syndrome)

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Prognosis: In paraneoplastic LEMS, the prognosis depends on the disease-causing neoplasm, but remission may occur after successful cancer treatment. Survival was longer in SCLC-LEMS than in SCLC patients without LEMS (median of 17 vs 7 months). In non-tumor LEMS, sustained treatment usually is necessary, but life expectancy is not shortened.

13.5 Botulism Genetic testing −

NCS/EMG ++

Laboratory +

Imaging −

Biopsy −

Epidemiology: Botulism is rare, with an average of 145 cases per year in the United States. Sixty five percent of these cases are infantile botulism, 15% food-borne and 20% wound botulism. Anatomy and Pathophysiology: Botulinum toxin is produced by the Gram-positive anaerobic spore-forming bacillus Clostridium botulinum. Several strains exist (A–G) and produce immunologically distinct toxins with the same mode of action. The toxins cleave SNARE proteins, which are necessary for the release of presynaptic Ach vesicles. As a consequence, the number of Ach vesicles released per action potential is reduced and a presynaptic neurotransmission disorder and autonomic symptoms develop. The incubation period is 12–36 h. Symptoms: Diffuse weakness of proximal, extraocular and bulbar muscles, including altered speech, difficulties swallowing, and double vision. The weakness typically is of a descending pattern. Photophobia, nausea, constipation, or diarrhea and symptoms of postural hypotension occur. Signs: Bilateral symmetric ptosis, extraocular muscle weakness with fixed dilated pupils, facial weakness, and progressive bulbar weakness. Dysarthria and dysphagia, proximal weakness, and respiratory insufficiency develop. Tendon reflexes are absent. Signs of autonomic failure include fixed dilated pupils, hypohidrosis and hypotension, alterations in resting heart rate and urinary retention. Ileus may develop. Causes: Botulinum toxin is produced by Gram-positive anaerobic spore-forming bacilli. Four forms of botulism exist, classified according to the mode of exposure (Table 13.4). Table 13.4  Types of botulism Food-­ borne Neonatal

Caused by ingestion of food contaminated with toxin, mostly home-preserved food Ingestion of organism by infants 2  days after toxin ingestion. Electrophysiology: Routine motor NCS show low-­ amplitude compound muscle action potential (CMAP) in affected muscles. Sensory NCS and EMG are normal. Repetitive low-frequency nerve stimulation results in a decremental response similar to MG in some patients. High-­ frequency stimulation of >20  Hz results in an increase of CMAP amplitude. Single stimulations performed before and after a 10-s maximum voluntary contraction show postexercise facilitation. These abnormal responses are only found in some muscles. Imaging: None. Laboratory: Detection of the toxin in serum, stool, food, or anaerobic samples from wounds by ELISA has largely replaced the mouse inoculation test. Samples should be taken as early as possible. Differential Diagnosis: Guillain–Barré syndrome (ascending paralysis), Miller Fisher syndrome, MG, tick paralysis. Therapy: Supportive ICU care is the mainstay of treatment. A heptavalent botulinum antitoxin is available should be administered as early as possible and is also cost-­effective. Surgical debridement and antibiotics in wound botulism. For the treatment of neonatal botulism, a human botulism immune globulin is available. Prognosis: Supportive intensive care treatment has decreased mortality to 3–5%. Recovery from weakness, shortness of breath, and fatigability may require 1 year or more.

13.6 Neuromyotonia (Isaacs’ Syndrome) Genetic testing −

NCS/EMG ++

Laboratory ++

Imaging ++

Biopsy −

Epidemiology: Neuromyotonia is rare. The cramp-­ fasciculation syndrome is described as a forme fruste of neuromyotonia, Morvan syndrome is characterized by neuromyotonia, dysautonomia, sleep disturbances, and personality changes. All three are within the spectrum of peripheral nerve hyperexcitability syndromes. Anatomy and Pathophysiology: Antibodies to voltage-­ gated potassium channels (VGKC) in one-third. These antibodies do not directly bind to the VGKC but to proteins associated with the VGKC (LGI1 and CASPR2). The exact mode of action is debated. Symptoms: Muscle twitching, cramps, and muscle stiffness. Distal muscles are usually more affected; trunk, pharynx, tongue, and face can also be involved. Excessive sweating is frequent. The combination of these symptoms

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with severe autonomic dysfunction, disordered sleep, and behavioral changes has been termed Morvan syndrome. Signs: Muscle twitching, myokymia, and muscle hypertrophy; muscle relaxation is delayed, weakness is rare, and tendon reflexes are normal or decreased. Causes: Neuromyotonia is an autoimmune disorder with antibodies to VGKC in about one-third of cases. A paraneoplastic form has been described in association with lung and thymus neoplasms and Hodgkin’s lymphoma. Neuromyotonia can precede the tumor be several years. Neuromyotonia is also seen in patients taking d-penicillamine. Diagnosis: Typical symptoms and signs and electrophysiological findings. Antibody tests are only positive in some patients. Electrophysiology: Routine motor and sensory NCS are normal, but repetitive F waves can be observed in cramp-­ fasciculation syndrome. Needle EMG shows fasciculations, doublets, triplets, or multiplets and high-frequency (up to 300 Hz) neuromyotonic discharges. Motor unit action potentials are normal. Imaging: Thorax CT is mandatory and PET scan is optional in selected cases. If no tumor is found, follow-up with CT scans should be performed every 6  months for at least 4 years. Laboratory: VGKC-Abs are found in less than one-third; AchR-Ab can also be found. Differential Diagnosis: Polyneuropathies, focal myokymia, or neuromyotonia in multifocal motoneuropathy and radiation injury to nerves/plexus, motor neuron disease. Therapy: Immunosuppressive treatments (plasma exchange, intravenous immunoglobulin, and steroids) can be used, but plasma exchange seems to be more efficient. Rituximab has been used occasionally. Symptomatic treatment with sodium channel-blocking agents (carbamazepine, phenytoin, or mexiletine) usually is successful. Prognosis: In paraneoplastic neuromyotonia, the prognosis depends on the related neoplasm, but improvement may occur with successful cancer treatment. Neuromyotonia in patients with previous thymoma is rare but may indicate tumor recurrence. In non-tumor neuromyotonia, sustained treatment usually is necessary, but life expectancy is not shortened.

Further Readings Myasthenia Gravis Burns TM (2010) History of outcome measures for myasthenia gravis. Muscle Nerve 42:5–13 Di Stefano V, Lupica A, Rispoli MG et  al (2020) Rituximab in AChR subtype of myasthenia gravis: systematic review. J Neurol Neurosurg Psychiatry 91:392–395

13  Neuromuscular Transmission: Endplate Disorders Gilhus NE, Owe JF, Hoff JM, Romi F, Skeie GO, Aarli JA (2011) Myasthenia gravis: a review of available treatment approaches. Autoimmune Dis 2011:847393 Gronseth GS, Barohn R, Narayanaswami P (2020) Practice advisory: Thymectomy for myasthenia gravis (practice parameter update). Neurology. https://doi.org/10.1212/WNL.0000000000009294 Guptill JT, Sanders DB (2010) Update on muscle-specific tyrosine kinase antibody positive myasthenia gravis. Curr Opin Neurol 23:530–535 Jacob S, Viegas S, Lashley D, Hilton-Jones D (2009) Myasthenia gravis and other neuromuscular junction disorders. Pract Neurol 9:364–371 Jaretzki A, Barohn RJ, Ernstoff RM, Kaminski HJ, Keesey JC, Penn AS, Sanders DB (2000) Myasthenia gravis: recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Neurology 55(1):16–23 Muppidi S, Utsugisawa K, Benatar M et al (2019) Long-term safety and efficacy of eculizumab in generalized myasthenia gravis. Muscle Nerve 60:14–24. https://doi.org/10.1002/mus.26447. Pasnoor M, Wolfe GI, Nations S, Trivedi J, Barohn RJ, Herbelin L, McVey A, Dimachkie M, Kissel J, Walsh R, Amato A, Mozaffar T, Hungs M, Chui L, Goldstein J, Novella S, Burns T, Phillips L, Claussen G, Young A, Bertorini T, Oh S (2010) Clinical findings in MuSK-antibody positive myasthenia gravis: a U.S. experience. Muscle Nerve 41:370–374 Safa H, Johnson DH, Trinh VA et al (2019) Immune checkpoint inhibitor related myasthenia gravis: single center experience and systematic review of the literature. J Immunother Cancer 7:319 Spillane J, Beeson DJ, Kullmann DM (2010a) Myasthenia and related disorders of the neuromuscular junction. J Neurol Neurosurg Psychiatry 81:850–857 Vincent A (2006) Immunology of disorders of neuromuscular transmission. Acta Neurol Scand 113(Suppl 183):1–7

Congenital Myasthenic Syndromes Alseth EH, Maniaol AH, Elsais A, Nakkestad HL, Tallaksen C, Gilhus NE, Skeie GO (2011) Investigation for RAPSN and DOK-7 mutations in a cohort of seronegative myasthenia gravis patients. Muscle Nerve 43:574–577 Engel AG (2012) Current status of the congenital myasthenic syndromes. Neuromuscul Disord 22:99–111 Harper CM (2004) Congenital myasthenic syndromes. Semin Neurol 24:111–123 Palace J, Lashley D, Bailey S, Jayawant S, Carr A, Mcconville J, Robb S, Beeson D (2012) Clinical features in a series of fast channel congenital myasthenia syndrome. Neuromuscul Disord 22:112–117 Schara U, Lochmüller H (2008) Therapeutic strategies in congenital myasthenic syndromes. Neurotherapeutics 5:542–547 Vanhaesebrouck AE, Beeson D (2019) The congenital myasthenic syndromes. Curr Opin Neurol 32:696–703

Lambert-Eaton Myasthenic Syndrome (LEMS) Hatanaka Y, Oh SJ (2008) Ten-second exercise is superior to 30-second exercise for post-exercise facilitation in diagnosing Lambert-Eaton myasthenic syndrome. Muscle Nerve 37:572–575 Lipka AF, Boldingh MI, van Zwet EW et al (2020) Long-term follow­up, quality of life, and survival of patients with Lambert-Eaton myasthenic syndrome. Neurology 94:e511–e520 Petty R (2007) Lambert Eaton myasthenic syndrome. Pract Neurol 7:265–267 Spillane J, Beeson DJ, Kullmann DM (2010b) Myasthenia and related disorders of the neuromuscular junction. J Neurol Neurosurg Psychiatry 81:850–857

Further Readings Titulaer MJ, Wirtz PW, Kuks JB, Schelhaas HJ, van der Kooi AJ, Faber CG, van der Pol WL, de Visser M, Sillevis Smitt PA, Verschuuren JJ (2008) The Lambert-Eaton myasthenic syndrome 1988–2008: a clinical picture in 97 patients. J Neuroimmunol 201–202:153–158 Titulaer MJ, Maddison P, Sont JK, Wirtz PW, Hilton-Jones D, Klooster R, Willcox N, Potman M, Sillevis Smitt PA, Kuks JB, Roep BO, Vincent A, van der Maarel SM, van Dijk JG, Lang B, Verschuuren JJ (2011) Clinical Dutch-English Lambert-Eaton Myasthenic syndrome (LEMS) tumor association prediction score accurately predicts small-cell lung cancer in the LEMS.  J Clin Oncol 29: 902–908

Botulism Anderson DM, Kumar VR, Arper DL et al (2019) Cost savings associated with timely treatment of botulism with botulism antitoxin heptavalent product. PLoS One 14:e0224700. https://doi.org/10.1371/ journal.pone.0224700 Dembek ZF, Smith LA, Rusnak JM (2007) Botulism: cause, effects, diagnosis, clinical and laboratory identification, and treatment modalities. Disaster Med Public Health Prep 1:122–134 Spillane J, Beeson DJ, Kullmann DM (2010c) Myasthenia and related disorders of the neuromuscular junction. J Neurol Neurosurg Psychiatry 81:850–857

273 Zhang JC, Sun L, Nie QH (2010) Botulism, where are we now? Clin Toxicol 48:867–879

Neuromyotonia (Isaacs’ Syndrome) Gastaldi M, De Rosa A, Maestri M et al (2019) Acquired neuromyotonia in thymoma-associated myasthenia gravis: a clinical and serological study. Eur J Neurol 26:992–999 Hart IK, Maddison P, Newsom-Davis J, Vincent A, Mills KR (2002) Phenotypic variants of autoimmune peripheral nerve hyperexcitability. Brain 125:1887–1895 Löscher WN, Wanschitz J, Reiners K, Quasthoff S (2004) Morvan’s syndrome: clinical, laboratory, and in  vitro electrophysiological studies. Muscle Nerve 30:157–163 Merchut MP (2010) Management of voltage-gated potassium channel antibody disorders. Neurol Clin 28:941–959 Rubio-Agusti I, Perez-Miralles F, Sevilla T, Muelas N, Chumillas MJ, Mayordomo F, Azorin I, Carmona E, Moscardo F, Palau J, Jacobson L, Vincent A, Vilchez JJ, Bataller L (2011) Peripheral nerve hyperexcitability: a clinical and immunologic study of 38 patients. Neurology 76:172–178 Serratrice G, Serratrice J (2011) Continuous muscle activity, Morvan’s syndrome and limbic encephalitis: ionic or non ionic disorders? Acta Myol 30:32–33

14

Muscle and Myotonic Diseases

14.1 Introduction Since the first publication of this book nearly two decades ago, there has been tremendous advances in the molecular genetics of muscle disease. One might posit the question, why would you then still need a clinical atlas? Despite significant advances in technology, correct diagnosis and expression of that diagnosis to a patient requires a trained, highly observant and knowledgable neuromuscular clinician. The neuromuscular clinician has to not only use clinical judgment but also has to understand the strengths and weaknesses of muscle electrophysiology, pathology, and genetics to differentiate between an ever-increasing number of complex disorders of muscle. Understanding the interface between the genetics of each muscle disease and the pathophysiology is critical. Better understanding of the molecular biology of inherited muscle disease is leading to improved therapy that the neuromuscular clinician will be expected to administer and monitor.

sarcomere into A and I bands (Fig.  14.1). Myosin is composed of light and heavy meromyosin and acts as an ATPase, hydrolyzing ATP. Actin filaments comprise actins, troponins, and tropomyosin. ATPase hydrolysis in the presence of calcium ions activates the troponin–tropomyosin system and permits sliding of actin on myosin filaments as predicted by the “sliding filament theory.” The force generated by a muscle is critically dependent on the length and the number of cross bridges between the filaments. Electrodiagnosis is useful in diagnosing the myopathies. Firstly, it helps distinguish between primarily myopathic and neurogenic disorders; secondly, it allows the distribution of the myopathy to be determined; and finally, it gives some information about severity and prognosis. Although electromyography can distinguish broad types of myopathic disorders, it cannot diagnose the specific myopathy. This requires analysis of the muscle

14.1.1 Electrophysiology Although the use of electrophysiology has often been supplanted in diagnosis of certain myopathies by genetic testing, electrophysiology allied with the clinical examination is critical in focusing the clinical differential diagnosis, in determining which muscles are affected and the degree of muscle injury. The basis of the motor system is the motor unit, which consists of the anterior horn cell, axon, muscle membrane, and muscle fiber and is the final common pathway leading to activation of the muscle. Electromyography allows us to determine if the abnormality of the motor unit points to a disorder of the axon, muscle membrane, or muscle fiber and allows accurate diagnosis. Striated muscle is made up of interdigitating thick filaments comprising myosin, and thin filaments comprising actin, and dividing the Contributions by James W. Russell, Lindsay A. Zilliox and Peter Jin

I SA

T tubules Z

A H Z

Sarcoplasmic reticulum (SR)

Lateral sac of SR

Fig. 14.1  Human skeletal muscle showing the gross and microscopic structure. The sarcoplasmic reticulum (SR) is an intracellular membrane system. The T tubules are invaginations of the sarcolemma and communicate with the extracellular space. Ultrastructurally, several components of the muscle can be identified. The sarcomere (SA) represents the space between the Z-discs. The A band comprises thick filaments of myosin, with an overlap of actin at the edges. The H band represents pure myosin, with a thickening in the center called the M-line. The I band, on either side of the Z-line, comprises thin filaments. The Z-disc helps to stabilize the actin filaments

© Springer Nature Switzerland AG 2021 E. L. Feldman et al., Atlas of Neuromuscular Diseases, https://doi.org/10.1007/978-3-030-63449-0_14

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pathology often coupled with biochemical and genetic analysis. Furthermore, some myopathies show evidence of both myopathic and neurogenic types of motor units, for example, the inflammatory myopathies and disorders of fatty acid metabolism.

14.1.2 Muscle Histology and Immunohistochemistry The second critical diagnostic evaluation in myopathic disorders is the muscle biopsy. Regular histology may diagnose many of the disorders listed in the following sections and can recognize distinct histological patterns such as those seen in dermatomyositis or some infective or toxic myopathies. However, increasingly specific immunohistochemical studies are needed to make an accurate diagnosis. Biochemical tests may reveal significant enzyme abnormalities that would otherwise be missed. However, even the most astute muscle pathologist is dependent on accurate clinical information to decide which of the numerous biochemical studies are most appropriate. Pathological evaluation of muscle is often performed even where genetic analysis is available because it provides information about the severity of the disease, ­characterizes the presence or absence of a specific protein, and provides a clinical correlate for an available treatment.

14.1.3 Molecular Genetics in Muscle Disease Characterizing the molecular genetics of muscle has become increasingly important in understanding the pathogenesis of myopathy. Considerable progress has been made since the first edition of this book in identifying new genetic mechanisms, in clarifying previously known genetic disorders, and in developing gene-related approaches to therapy. Most gene defects have been described in the following chapters and are extensively reviewed in the selected references for each section. Even the presence of a specific gene mutation may produce widely varying biochemical changes in the muscle due to the presence of gene-modifying effects. Unfortunately, the cost and commercial availability of genetic studies have made it imperative that the clinician use consummate diagnostic skills to define the type and extent of testing. Thus, clinical judgment still remains important in differentiating the various myopathies and in determining which genetic testing is most appropriate for the individual patient. This often requires that the neuromuscular specialist work closely with a clinical geneticist. It is critical that neuromuscular clinicians understand that while a genetic diagnosis may be regarded as the “gold standard,” like the actual gold standard, genetic testing currently has critical flaws. These flaws affect both the technology and the interpretation of the results. For

14  Muscle and Myotonic Diseases

example, the application of (whole-)exome sequencing or next-generation sequencing technologies are commonly used in commercial testing and have resulted in the generation of many variants of uncertain significance that years or even decades later may be determined to be pathogenic or benign. Clearly, this is highly problematic for the patient and clinician at the time of diagnosis. Furthermore, this technology tells us nothing about RNA expression and mutations in the intronic regions of the genes that are not sequenced. Thus, certain genetic defects such as deletions or duplications or repeats cannot be identified with these techniques. For example, myotonic dystrophy type 1 (caused by increased repeat length in the DMPK gene) or Duchenne muscular dystrophy (with a deletion or duplication in the DMD gene) cannot be diagnosed or differentiated using the currently available next-generation sequencing technologies. Newer techniques such as RNA-sequencing (RNA-seq or transcriptomics) and whole genome sequencing will most probably be applied in routine diagnostics in the future.

14.1.4 Clinical Phenotypes of the Inherited Myopathies As indicated in Sect. 14.1.3 above, the genetic diagnosis of the inherited myopathies is complex. The clinical phenotype can help the clinician to focus genetic testing for inherited myopathies (Table 14.1).

14.1.5 Therapy for Neuromuscular Diseases There have been considerable advances in therapy since the first edition of this atlas and there is considerable interest in drug development for many disorders of muscle. Within the scope of this atlas, we have described in each section therapies that are approved for use in humans by government regulatory agencies and have provided recent comprehensive refences that describe current pharmacotherapeutic research. Unfortunately, for many reasons those promising therapies may not achieve regulatory approval. The mainstay of treatment for inflammatory myopathies remains corticosteroids and immunosuppressive therapies. Prednisone is still effective for Duchenne muscular dystrophy (DMD) but Deflazacort has recently been introduced and is as effective as prednisone but increases survival by up to 15 years, thus significantly altering the natural course of the illness. Other medication have been approved by regulatory agencies based on targeting specific gene mutations and are disease modifying in a much smaller subset of DMD. Eteplirsen targets a confirmed mutation of DMD amenable to exon 51 skipping. Goldarn is approved for the treatment of DMD with a confirmed mutation amenable to exon 53 skipping. Ataluren is

14.2 Polymyositis (PM) and Dermatomyositis Table 14.1  Inherited Myopathies Categorized by Phenotype Muscle contractures Glycogen metabolism (McCardle), LGMD early in presentation (1G, 2A, D5), Emery–Dreifuss, Fukuyama, Ullrich Distal > Proximal Distal myopathies, myotonic dystrophies, weakness centronuclear myopathy, myofibrillar myopathy, phosphorylase B kinase deficiency, debrancher deficiency Asymmetric FSHD, McLeod syndrome, McArdle’s, acid weakness maltase deficiency (adult onset), LGMD (2B, 2 J, 2 L) Scapuloperoneal FSHD, Emery–Dreifuss, acid maltase weakness deficiency, nemaline, scapuloperoneal Prominent neck Isolated neck extensor weakness, carnitine extensor weakness deficiency, FSHD, myotonic dystrophies Ptosis without Myotonic dystrophies, nemaline, myofibrillar ophthalmoparesis (desmin subtype), central core myopathy Ptosis with Centronuclear, mitochondrial, oculopharynophthalmoparesis geal, oculopharyngodistal myopathy Pompe, acid maltase deficiency, Clinical and centronuclear, myofibrillar myopathy electrodiagnostic myotonia McArdle’s, phosphofructokinase deficiency, Muscle pain and lipid storage disorders, Becker, mitochondrial cramping with myopathy exercise Pompe disease, muscular dystrophies, LGMD Respiratory insufficiency early in (2I, 2C-F), myofibrillar, oculopharyngodistal, nemaline, mitochondrial myopathy presentation Cardiac arrhythmias Andersen–Tawil syndrome, Emery–Dreifuss, Kearns–Sayre syndrome, LGMD (B, 2C-F, 2G) Congestive heart Acid maltase, carnitine deficiency, Duchenne, failure Becker, Emery–Dreifuss, myotonic dystrophies, limb-girdle (1B, 2C-F, 2G), nemaline myopathy X-linked inheritance Becker, Duchenne, Emery–Dreifuss, McLeod syndrome Autosomal dominant Central core myopathy, FSHD, LGMD, inheritance oculopharyngeal, myotonic dystrophies, paramyotonia congenita, myotonia congenita (Thomsen), periodic paralysis Autosomal recessive LGMD, metabolic myopathies, myotonia inheritance congenita (Becker) Adulthood Centronuclear, distal myopathies, lipid presentation storage diseases, acid maltase deficiency, debrancher deficiency, phosphorylase kinase deficiency, nemaline, myotonic dystrophies, FSHD, Becker, LGMD, Emery–Dreifuss, scapuloperoneal FSHD facioscapulohumeral muscular dystrophy, LGMD limb-girdle muscular dystrophy

approved for the treatment of DMD nonsense mutations in ambulatory patients aged 2 years and older and can be given orally. In Pompe disease, enzyme replacement therapy (ERT) slows progression and may stabilize the disease in late-onset Pompe disease and improve function in infantile-onset Pompe disease. However, use of ERT in severely affected patients and asymptomatic patients is less clear. The adverse effects of these medications is described in the specific section.

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14.2 Polymyositis (PM) and Dermatomyositis Genetic testing NCV/NCV/EMG Laboratory Imaging Biopsy ++ ++ + +++ −

Distribution: Weakness generally involves neck flexor and proximal muscles symmetrically. Time Course: Progresses over months. Age of Onset: PM, typically fourth decade; dermatomyositis, bimodal frequency at 5–15 and 45–65 years of age. Clinical Syndrome: PM and dermatomyositis are acquired idiopathic inflammatory myopathies. They affect women more than men. The most common presenting features are subacute proximal weakness, neck flexor weakness, and myalgia. In both diseases, dysphagia can be present at disease onset and worsen over the disease course. Dermatomyositis is clinically distinguished from PM by specific dermatologic findings, namely heliotrope rash (purple or red patches in a symmetric periorbital distribution with or without associated edema), Gottron’s papules (purple or red raised and palpable rash occurring on extensor surface of joints of fingers), and Gottron’s sign (purple or red flat and non-palpable rash over extensor surfaces of joints). Other dermatologic findings that are seen in both PM and dermatomyositis (but more common in dermatomyositis) are Raynaud’s phenomenon, mechanic’s hands (dry and cracked skin on the palm), joint calcinosis, and dilated capillaries at the base of fingernails. Interstitial lung disease, which occurs in a third of patients, can lead to progressive dyspnea. There is an increased risk for malignancy, more so in dermatomyositis (Figs. 14.2 and 14.3). Pathogenesis: Whereas PM and dermatomyositis are clinically distinguished based on dermatologic findings, they are histopathologically distinct and likely represent two different diseases. In other words, dermatomyositis is not simply PM with a rash. In PM, histopathology demonstrates endomysial inflammation mainly with CD8+ T cells, expression of MHC-1 complex, and the absence of fascicular atrophy. In dermatomyositis, there is perimysial and perifascicular inflammation with an absence of CD8+ T cells, perivascular inflammation with microangiopathy, perifascicular atrophy, and occasional muscle necrosis. The exact pathophysiologic trigger for these diseases remain unclear. There may be a genetic component with predisposing HLA alleles. Diagnosis: Muscle biopsy is the diagnostic test of choice in both dermatomyositis and PM. Serum creatine kinase levels are at least 5–10 times normal (often greater than 50 times normal). Nerve conduction is generally normal. Needle EMG is nonspecific and may demonstrate findings of muscle membrane irritability with positive waves and fibrillation potentials along with early recruitment and small-amplitude, short-duration, polyphasic motor units. Muscle MRI may

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14  Muscle and Myotonic Diseases

a

b

Fig. 14.2 (a) MRI—abnormal high T2 signal in the hamstring muscles in the posterior compartment of the thigh bilaterally, which is fairly symmetric. (b) Polymyositis showing inflammatory infiltration of muscle fibers

a

b

Fig. 14.3  Dermatomyositis. (a) Typical perifascicular atrophy (arrowhead) and perivascular inflammation (arrow). (b) CD20 (B-cell) immunostaining in perivascular infiltrate (arrow)

show increased T2 signal and contrast enhancement in inflamed muscle and is useful for muscle biopsy planning. Various myositis-related antibodies have not only been associated with dermatomyositis and PM but also with certain clinical features. Sixty percent of patients with dermatomyositis or PM will test positive for a myositis-related antibody. Large testing panels for these antibodies are available, but the clinical usefulness of these tests requires further study. They may be helpful in identifying patients at increased risk for certain phenotypes, but they are not a substitute for muscle biopsy for diagnosis. Anti-SRP has been associated with higher risk for dysphagia and malignancy. Anti-Jo-1 has been associated with higher risk for interstitial lung disease. Anti-Mi-2 has been associated with a lower risk for interstitial lung disease and malignancy along with better response to treatment. Differential Diagnosis: Toxic, endocrine, or metabolic myopathy, muscular dystrophy, inclusion body myositis, neuromuscular junction disorders, polymyalgia rheumatica.

Therapy: Glucocorticoids are the mainstay of treatment. Initial therapy is often started with prednisone 1 mg/kg daily or an equivalent glucocorticoid. In severe cases or those not responsive to this initial therapy, intravenous pulse dose steroids between 500  mg and 1  g for 3  days have been used. Eventual steroid dose reduction generally requires slow tapering and adding a steroid-sparing agent. First-line therapies are methotrexate and azathioprine. Mycophenolate and cyclophosphamide are also used in those with refractory disease. Rituximab has been shown to be particularly effective in patients with anti-Jo-1 and anti-Mi-2 antibodies. IVIG has limited data for use and the benefit is often short-lived. Prognosis: The prognosis is generally good with most patients showing response to therapy. About one-third of patients will have a monophasic disease, one-third will have a relapsing-remitting course, and one-third will have a chronic progressive course. Patients who develop interstitial lung disease and malignancy will have a poorer prognosis. In general, the prognosis is worse in dermatomyositis compared to PM.

14.3 Inclusion Body Myositis (IBM)

14.3 Inclusion Body Myositis (IBM) Genetic testing NCV/NCV/EMG Laboratory Imaging Biopsy ++ + ++ +++ −

Distribution: Weakness involves quadriceps, forearm flexor, and foot extensor muscles. Time Course: Progresses over years. Age of Onset: Affects males greater than females typically in the sixth decade. Clinical Description: The typical phenotype is a slowly progressive weakness and wasting usually first in quadriceps followed by forearm finger flexor muscles. Some patients may initially present with finger flexor weakness or bulbar symptoms with lower extremity weakness occurring later. The distal phalanx flexors of the thumb and fingers are especially affected, and the hand intrinsic muscles are frequently spared in early stages. Other described patterns of weakness include mild to moderate facial muscle weakness and paraspinal muscle weakness that can present as dropped head. Dysphagia occurs in about half of patients and can predate limb weakness by up to 10  years. Respiratory dysfunction can manifest as sleep disordered breathing due to weakness of oropharyngeal muscles and orthopnea due to diaphragmatic weakness. Pathogenesis: Histopathology demonstrates findings of both autoimmunity and degeneration. Autoimmunity findings include CD8+ T-cell lymphocytic endomysial infiltrate with invasion of non-necrotic muscle fibers and upregulation of MHC-1 antigens. Degenerative findings include deposition of abnormal protein (amyloid precursors, tau, and alpha synuclein) and rimmed vacuoles. Early on in the disease, markers of autoimmunity are more severe whereas later in its course the markers of degeneration are more prominent. The relation between these two processes is unknown. The rea-

a

279

son for why IBM does not respond to immunotherapy similar to other autoimmune myopathies is speculated to be due to the invasion of highly differentiated T cells that are resistant to apoptosis due to escaping typical immune regulatory checkpoints. Most cases of IBM are sporadic. Occasionally, the disease has been associated with HIV, human T-cell lymphotropic virus (HTLV), and Sjögren’s syndrome. Rare cases of families with an autosomal recessive or dominant pattern of inheritance have been described, but a distinct gene mutation has not been identified. Genetic susceptibility studies have found strong associations between IBM and various HLA groups, particularly HLA-DRB1*03:01 and HLA-B*08:01. Diagnosis: Diagnosis is largely made on clinical grounds based on age of onset, affected muscle groups, and slow rate of progression. Muscle biopsy remains the definitive diagnostic procedure (Fig. 14.4). Early on in the disease process, however, biopsy may not demonstrate all of the classic histopathologic findings of IBM. NCS are generally normal but reduced sensory nerve action potentials and slowing of motor conduction velocities have been described in some series. EMG findings are nonspecific. Affected muscles frequently demonstrate abnormal spontaneous activity with fibrillations and positive sharp waves. Rarely, myokymia and myotonia can be seen. Volitional motor units show typical myopathic features of early recruitment with short-duration and polyphasic motor units; however, large and long-duration motor units can be mixed in as well. Muscle imaging can be helpful in diagnosis for patients who cannot undergo biopsy or in whom the target of biopsy is not clear. MRI of the forearm can demonstrate atrophy and STIR hyperintensity that is predominantly found in the flexor digitorum profundis (FDP) with relative sparing of the flexor digitorum superficialis (FDS) and extensor muscles of the

b

Fig. 14.4 (a) Modified Gomori’s trichrome stain showing a rimmed vacuole (white arrow) in patient with inclusion body myositis. (b) SMI31 (40×) stain showing cytoplasmic inclusions (black arrow)

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forearm. In the lower limb, a similar pattern of abnormal signal is found in the quadriceps with relative sparing of the hamstring and adductor groups. Ultrasound can also identify these patterns of preferentially affected muscles, which show increased echogenicity. About one-third of patients have been shown to have serum antibodies to cytosolic 5′-nucleotidase 1A (anti-­ CN1A). The presence of anti-CN1A may be helpful in distinguishing IBM from other idiopathic inflammatory myopathies. The antibody, however, is not specific and present in patients with other autoimmune diseases including systemic lupus erythematosus and Sjögren’s syndrome. Serum studies may also reveal elevated markers of muscle breakdown such as creatine kinase (2–5 times above upper limit of normal), but these are nonspecific. Differential Diagnosis: Motor neuron disease, polymyositis, distal myopathy, and muscular dystrophy. Therapy: Unlike other inflammatory myopathies, immunosuppression therapy has not been shown to be effective in IBM. Lack of efficacy has been shown in trials of azathioprine, methotrexate, prednisone, alemtuzumab, and etanercept. The use of IVIG remains controversial with multiple studies showing no long-term benefit while some studies have shown specific benefit in improving dysphagia. An open-label trial of exercise alone has shown benefit in maintenance of strength and improvement in quality of life. Prognosis: Survival is usually unaffected. Weakness is progressive and debilitating with the majority of individuals requiring assistive devices within 5–10  years. The greatest rate of decline is often in quadriceps strength. Male sex and older age of onset are associated with faster progression and more severe disability.

14.4 Immune-Mediated Necrotizing Myopathy (IMNM) Genetic testing NCV/NCV/EMG Laboratory Imaging Biopsy ++ ++ + +++ −

Distribution: Severe proximal muscle weakness. Time Course: Acute to subacute. Age of Onset: Bimodal distribution. More common in those greater than 60 years of age with a smaller subset in those around 40 years of age. Clinical Syndrome: IMNM (also known as necrotizing autoimmune myopathy) is an idiopathic inflammatory myopathy distinguished by its histologic namesake of necrotic muscle tissue. The clinical syndrome is proximal muscle weakness. Extramuscular manifestations are generally rare compared to other inflammatory myopathies. Three subtypes have been identified based on the presence

14  Muscle and Myotonic Diseases

of autoantibodies. The most common is hydroxy-3methylglutaryl-­CoA reductase (HMGCR) antibody which is more typically found in older individuals. Signal recognition particle (SRP) antibody is associated with more severe weakness and atrophy, higher likelihood of respiratory and oropharyngeal weakness, and worse response to immunotherapy. The antibody negative subtype (negative for HMGCR and SRP antibodies) is associated with higher association with connective tissue diseases, higher risk for malignancy, and higher association with extramuscular manifestations such as interstitial lung disease, arthritis, and skin changes. Statin exposure is a known risk for developing the disease, but it is generally associated only with the HMG-CoA subtype. Pathogenesis: Histopathology demonstrates distinguishing features of muscle necrosis and muscle cell regeneration. Similar to other myositis, there is also upregulation of MHC-1 complex and deposition of membrane attack complex on sarcolemma of non-necrotic muscle fibers. These findings along with the associated autoantibodies suggest an immune-mediated etiology of the disease. The disease does not improve with statin therapy, which suggests that it is not caused by statin toxicity. Instead, statin exposure may lead to a breakdown of immunotolerance to the native HMGCR protein via aberrant processing of the protein or binding to the protein and changing its conformation. The disease trigger in non-statin-exposed patients is less clear. The cause of necrosis is also unclear. In vitro studies have shown that anti-­ HMGCR and anti-SRP antibodies themselves may be toxic to muscle. Diagnosis: Muscle biopsy is the diagnostic test of choice. There is, however, known overlap even in histopathologic findings among inflammatory myopathies. While muscle necrosis is the hallmark of IMNM, it is also seen in a small percentage of patients with anti-Jo-1 dermatomyositis. Diagnosis of IMNM therefore is based on a combination of clinical findings, biopsy, and the presence of autoantibodies. Muscle MRI can be helpful for biopsy guidance to identify affected muscles with edema and fatty infiltrate. Creatine kinase (CK) is significantly elevated similar to other inflammatory myopathies. Unlike dermatomyositis, and PM, however, tracking CK elevations has been shown to be useful to trend disease state. CK elevations may also precede other symptoms and lead to an initial diagnosis of benign hyperCKemia before weakness manifests. EMG findings are similar to other inflammatory myopathies. Affected muscles demonstrate features of muscle membrane irritability with positive waves and fibrillation potentials. Volitional units are myopathic with early recruitment pattern, short duration, and polyphasic morphology. Differential Diagnosis: Polymyositis, dermatomyositis, toxic myopathy, and metabolic myopathy.

14.5 Connective Tissue Diseases (CTDs) in “Overlap” Myositis (OM)

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Treatment: Corticosteroids are first-line treatment. Second-line treatments include methotrexate, azathioprine, and IVIG.  Other immunosuppressants that have been used include mycophenolate, tacrolimus, and cyclophosphamide. Many patients require multiple immunosuppression agents before there is treatment response. It is not uncommon for patients to require three immunosuppression agents. IVIG may be specifically more helpful in the anti-HMGCR subtype. The anti-SRP subtype is notably treatment resistant compared to other forms. Rituximab has been shown to have specific benefit in the anti-SRP subtype. Prognosis: Prognosis varies among patients. After treatment for 2  years, approximately 50% of patients are independent whereas 50% will have persistent weakness requiring assistance in day-to-day activities. The treatment response is overall worse compared to that of dermatomyositis and PM. Younger age of onset and anti-SRP antibody are associated with worse prognosis.

stitial lung disease, calcinosis, mechanic’s hands, and esophageal dysmotility. Cutaneous findings are rare. The main associated antibodies are anti-Ku and anti-PM-SCl. Myositis is much less common in other CTDs, but is seen in a small percentage (~5–10%) of cases in systemic lupus erythematous (SLE), rheumatoid arthritis (RA), and mixed connective tissue disorder (MCTD). Sjögren syndrome-associated myositis is rare. As a whole, OM have a different clinical course compared to dermatomyositis and PM. In OM, there is more extramuscular involvement, particularly in respiratory and esophageal problems. Dysphagia and dyspnea are typically more common in OM.  Patient’s with OM have been shown to be at higher risk of severe infections, which is a major cause of mortality. Pathogenesis: The pathogenesis of myositis with CTD is poorly understood and is likely heterogeneous. Muscle biopsy findings are similar to that of polymyositis and demonstrate endomysial inflammation mainly with CD8+ T cells and expression of MHC-1 complex. The presence of associated autoantibodies are suggestive of a humoral response. It is unclear why only a small percentage of patients with the same CTD will develop myositis. Diagnosis: Diagnosis is dependent on a combination of muscle biopsy findings consistent with myositis (Fig. 14.5), clinical features of CTD, and autoantibody testing. Serum CK levels are often very high (up to 15 times normal) similar to other inflammatory myopathies. Autoantibodies that are most commonly associated are anti-Pm-Scl, anti-Ku, and anti-U1RNP. EMG demonstrates findings similar to other inflammatory myopathies with irritability noted on spontaneous activity via the presence of positive waves and fibrillation potentials along with volitional units that are myopathic with early recruitment pattern, short duration, and polyphasic morphology. Differential Diagnosis: dermatomyositis, IBM, PM, and other causes of weakness, for example, polyneuropathy or mononeuritis multiplex. Therapy: Due to the heterogeneous nature of the disease, guidance on treatment for OM is limited. Treatment ­decisions are heavily guided by the underlying CTD. Corticosteroids are the mainstay of therapy. Similar to dermatomyositis and PM, methotrexate, azathioprine, cyclophosphamide, and IVIG are the most commonly used second-­line therapies. Prognosis: Response to treatment is variable. Anti-Ku is associated with higher likelihood for a monophasic course with good response to treatment. Poorer prognosis is seen with older age of onset, treatment refractory CTD, and the presence of pulmonary hypertension.

14.5 C  onnective Tissue Diseases (CTDs) in “Overlap” Myositis (OM) Genetic tests −

EMG +++

Laboratory +++

Imaging +

Biopsy +++

Distribution/Anatomy: Proximal muscles are more commonly involved. Time Course: Variable. Age of Onset: Most common in third to fifth decade. Clinical Syndrome: OM is a heterogeneous group of disorders defined by the presence of myositis that generally affects proximal muscles in conjunction with either an associated diagnosis of a CTD or clinical features of a CTD. Such features include Raynaud’s phenomenon, arthritis, interstitial lung disease, and skin rashes. Myositis may present before any evidence of a CTD. These disorders are a heterogeneous group with considerable overlap with dermatomyositis and polymyositis. Historically, all of these diseases were considered under an umbrella group of inflammatory myopathies, but current knowledge suggests that they are separate disease entities. Similar to how dermatomyositis is not simply polymyositis with a rash, overlap myositis is unlikely polymyositis with a CTD. Similar to diseases such as dermatomyositis, there are subdivisions among overlap myositis diseases based on antibody associations with distinctive phenotypic associations. The most common overlap syndrome is systemic sclerosis (SSc), where myositis is seen in up to 40% of patients. The associated CTD features are Raynaud’s, arthritis, inter-

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a

b

Fig. 14.5  Myositis in mixed connective tissue disease. (a) In the hematoxylin and eosin (H&E) stained section, there is an inflammatory response. (b) CD3 (T-cell) staining of the inflammatory response

14.6 Viral Myopathies Genetic testing −

NCV/EMG ++

Laboratory +++

Imaging +

Biopsy +++

Distribution/Anatomy: The distribution is variable depending on the type of infection. Time Course: Is variable depending on the type of infection. Age of Onset: Any age. Clinical Syndrome: Influenza-induced myositis is characterized by severe pain, tenderness, and swelling that usually affects the calf muscles but may also affect thigh muscles. Myalgia is common and starts 1  week after the onset of the influenza infection and persists for another 2–3 weeks. The disorder is usually self-limiting; however, in rare cases, it may be severe with myoglobinuria and a risk of renal failure. Coxsackie virus infection is characterized by a widespread acute myositis that may be severe and may be associated with myoglobinuria. Epidemics of Coxsackie virus infection tend to occur during the summer and fall. In children aged 5–15 years, there may be a self-limiting acute inflammatory myopathy. Infection is usually caused by Coxsackie virus group B. Affected patients may complain of muscle aching, which is often exacerbated by exercise. Weakness, if it occurs, may be minimal. The symptoms usually resolve within 1–2 weeks. Bornholm’s disease is associated with severe pain and tenderness in the muscles of the chest, back, shoulders, or abdomen and may be associated with a more severe Coxsackie B5 infection. The HIV and

HTLV may be associated with a variety of myopathic manifestations. HIV-associated myopathy in commonly encountered in clinical practice and represents a spectrum of underlying pathology. HIV-infected patients may develop one of the following manifestations: • An HIV-associated myopathy that resembles polymyositis. • A retroviral myopathy, which resembles mitochondrial myopathy. • AIDS-associated cachexia with muscle wasting. • Opportunistic infections and tumor formation within muscle. • A myopathy resembling nemaline myopathy. • An HIV-associated vasculitis. With HIV-associated nemaline rods, the CK is often very high, and there may be evidence of muscle fiber necrosis. HIV may also be associated with a necrotizing myopathy with proximal weakness. Pyomyositis and lymphoma may also develop in the muscle and may be associated with painful limb swelling. A variety of organisms have been associated with the pyomyositis including cryptococcus, CMV, Mycobacterium avium intracellular (MAI), and toxoplasma. HIV, a wasting disease, is associated with fatigue and evidence of type II atrophy (Fig. 14.6). Pathogenesis: The specific mode of muscle injury depends on the particular pathogen. Several of the viral infections, including HIV, may cause myositis by increasing the release of cytokines and interferons. Viral infections

14.7 Toxic Myopathies

a

283

b

c

Fig. 14.6 (a) HIV myopathy. Proximal arm atrophy and bilateral scapular winging in a patient with HIV myopathy. (b) Pyomyositis with marked neutrophil inflammation (arrows). The muscle fibers are tex-

tureless and have no nuclei, features consistent with acute fiber necrosis. (c) H&E. Inflammatory response dispersed between several fibers (white arrows)

may also cause perivascular, perimysial, or endomysial inflammation. Diagnosis: CK may be normal or mildly elevated. EMG shows evidence of focal or more diffuse muscle damage that is characterized by increased insertional activity or with “myopathic” polyphasic motor unit potentials. It is important to note that in many cases the changes may be focal. MRI studies may show evidence of a focal myositis depending on the specific pathogen. The muscle biopsy changes depend on the specific pathogen. In general, the features are similar to those observed in polymyositis. In certain disorders such as HIV, nemaline rods may be observed. Differential Diagnosis: Many of the causes of viral myositis resemble one another and determining the specific cause may require the culture of the organism, specific antibody testing, and muscle biopsy with special staining. The differential diagnosis includes (1) polymyositis, (2) dermatomyositis, and (3) mitochondrial myopathies. Therapy: Many causes of viral myositis are self-limiting. HIV-induced myopathy responds to retroviral therapy and some retroviral therapies can cause myopathy. These medications are not specific for the myopathy and are discussed further in the references. HIV polymyositis is similar to the disease in non-HIV patients and may improve with corticosteroids or other immunosuppressive medications.

Prognosis: The prognosis depends on the specific cause of the myositis. For a non-HIV-related viral syndrome, the prognosis is usually good. Where there is HIV infection or opportunistic infection, the prognosis is usually worse.

14.7 Toxic Myopathies Genetic testing +

NCV/EMG +++

Laboratory +

Imaging +

Biopsy +++

Distribution/Anatomy: Usually proximal muscles are involved but there may be more diffuse distribution. Time Course: The time course is variable, depending on the type of toxic agent, but is often subacute. Age of Onset: Can occur at any age. Clinical Syndrome: The clinical presentation of toxic myopathy is heterogeneous and requires a high degree of suspicion to diagnose. There may be an acute episode with rhabdomyolysis or the disorder may develop over months or even years. The signs and symptoms include a focal myopathy, acute painful or painless weakness, chronic painful or painless weakness, myalgia alone, or CK elevation alone. In severe cases, there may be inflammation, myalgia, and myoglobinuria. In mitochondrial or vacuolar damage, the myalgia is usually painless. The most common iatrogenic causes are statin and fibrate cholesterol-lowering medications, but

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there is a wide range of etiologies for toxic myopathies. The toxic myopathies can be divided into several etiological groups including: necrotic myopathies, myopathies with type II fiber atrophy, vacuolar myopathies, myopathies with mitochondrial abnormalities, inflammatory myopathies, and myofibrillar myopathies. Necrotic myopathies may be due to acute alcohol exposure, amiodarone, chloroquine, cocaine, emetine, clofibrate, heroin, combined neuromuscular-blocking agents and steroids, perhexiline, and statins (HMGCR inhibitors). Meta-­ analysis indicates that the highest risk of rhabdomyolysis occurs with atorvastatin and the lowest risk with fluvastatin, whereas there is an intermediated risk with simvastatin, lovastatin, and pravastatin. There is an increased risk of rhabdomyolysis with the coadministration of a statin and a fibrate drug, which is especially true of gemfibrozil. The risk of a toxic myopathy due to statins is dose dependent and several disorders may predispose to statin-induced injury, including undiagnosed congenital myopathies, myasthenia gravis, and inflammatory myopathies. Genetic factors may contribute to the susceptibility to statin myopathy susceptibility. The most important genetic variant is the SLCO1B1 gene that encodes the organic anion-transporting polypeptide (OATP1B1) hepatic transporter for statins. In rare cases, an immune-­ mediated necrotizing myopathy can occur due to statin therapy. These cases present clinically in the same manner as toxic necrotizing myopathies, but when the statin medication is stopped the myopathy does not improve and treatment with immunomodulatory therapy is required. Antibodies against HMG-CoA reductase are detectable in the serum of patients with statin-associated immune-mediated necrotizing myopathy are very specific. Another cause of muscle injury in necrotic myopathies is crush injuries that occur in comatose or motionless patients who are taking drugs for addiction. Steroids may also cause a myopathy with type II fiber atrophy due to a variety of mechanisms that include protein suppression and abnormalities of glycolysis. In the vacuolar myopathies, there is accumulation of autophagic (lysosomal) vacuoles. This is observed with amiodarone, chloroquine, colchicine, and vincristine and amphotericin. Mitochondrial defects are seen with anti-HIV agents that inhibit nucleoside or nucleotide reverse transcriptase and deplete mitochondrial DNA. The resulting accumulation of abnormal mitochondria results in formation of “ragged-red fibers.” Azidothymidine (AZT) is associated with mitochondrial changes and sometimes with inflammation. Similar changes are seen with clevudine and statins. Clevudine may cause a slow progressive proximal myopathy with mitochondrial DNA depletion. An inflammatory toxic myopathy with similar clinical features to dermatomyositis may be seen with HMG-CoA reductase inhibitors (as discussed under necrotizing myopathies), d-penicillamine, phenytoin, procainamide, hydralazine, l-dopa, streptokinase, and immune checkpoint inhibitors.

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Myofibrillar myopathy is seen with emetine and acute quadriplegic myopathy. Pathogenesis: A range of mechanisms have been described in toxic myopathies and are described as part of the clinical grouping above. Diagnosis: CK levels are variable ranging from normal, with steroid myopathies, to very high with rhabdomyolysis. On EMG, there may be increased insertional activity in inflammatory and vacuolar myopathies but is usually normal in type II fiber atrophy. The motor units range from small short-duration action potentials typical of myopathy to ­polyphasic motor unit action potentials similar to those seen in dermatomyositis. Various changes may be observed in the muscle biopsy including necrosis, vacuolar changes, mitochondrial defects, and inflammatory changes (Fig. 14.7). Differential Diagnosis: PM, dermatomyositis, IBM, muscular dystrophy, mitochondrial myopathies. Therapy: There is no specific treatment for most toxic myopathies. Early recognition of a potential toxin and removal of the toxin are essential in limiting the muscle injury. In most cases, where statins are implicated and are discontinued, symptoms improve, and there is recovery over a period of 2–3 months. If there is no improvement, serologic testing for antibodies against HMG-CoA reductase or a muscle biopsy should be considered to determine the presence of a necrotizing autoimmune myopathy or an inflammatory myopathy, which should be treated with corticosteroids or immunosuppressive medication. Coenzyme Q10 supplementation may help. If other cholesterol-lowering medications cannot be used or are ineffective, then a gradual rechallenge with a lower risk statin, e.g., rosuvastatin may be attempted.

Fig. 14.7  Colchicine myopathy showing a vacuolar myopathy with numerous autophagic subsarcolemmal vacuoles of varying sizes (arrows)

14.8 Critical Illness Myopathy (CIM)

285

Prognosis: This is varied depending on the degree of muscle injury. Where the toxic exposure is recognized and the toxin removed, the prognosis is usually good.

14.8 Critical Illness Myopathy (CIM) Genetic testing −

NCV/EMG ++

Laboratory +

Imaging −

Biopsy +++

Distribution/Anatomy: CIM is usually more severe in proximal muscles. Time Course: Time course is variable but usually develops over days to months. Age of Onset: May develop at any age. More common in older patients. Clinical Syndrome: The classic presentation is symmetric weakness in the setting of an intubated and critically ill patient. Muscle atrophy is common. The diagnosis is prompted most often due to inability to liberate the patient from the ventilator in spite of correction of other causes of respiratory failure. The same population of patients who develop CIM are also at risk of developing critical illness polyneuropathy (CIP) and many patients have features of both (aka critical illness polyneuromyopathy). The major risk factors for developing either syndrome are septic shock, multiorgan failure, septic encephalopathy, acute respiratory distress syndrome, and hyperglycemia. Previous studies demonstrated that glucocorticoid and neuromuscular blockade usage increased the risk for developing CIP and CIM, but subsequent analyses and studies have not corroborated these findings. Pathogenesis: Given the strong association with sepsis and multiorgan failure, it is hypothesized that both CIP and CIM are the result of systemic inflammation. There is increased vascular permeability secondary to inflammatory cytokines, microcirculation dysfunction, hyperglycemia, and hypoalbuminemia. Vascular permeability may lead to muscle necrosis in two ways. For one, local tissue edema can impede diffusion of oxygen and nutrients to nerve and muscle and lead to energy failure. Secondly, vascular permeability allows for toxins to enter muscle and nerve tissue. On histopathology, there is preferential loss of thick filaments and myosin which suggest breakdown of the primary contractile mechanism (Fig.  14.8). There is also sodium channel dysfunction which can lead to muscles becoming inexcitable. There can be findings of a necrotizing myopathy which may be secondary to energy failure. A cachectic myopathy can also be appreciated with evidence of type II muscle fiber loss. Diagnosis: Muscle biopsy provides the clearest diagnostic evidence, but it is not routinely used due to its invasiveness and the increased risk of the procedure in the

Fig. 14.8  H&E stain shows marked fiber atrophy with disruption of contractile elements (arrows) in a subpopulation of fibers

critically ill patient. The diagnosis is most commonly made through a combination of excluding other possible causes of weakness in critical illness and electrophysiologic testing. NCS can show motor conductions with reduced compound muscle action potential (CMAP) amplitudes and prolonged CMAP durations. The study, however, is often limited due to the limb edema, hypothermia, and ICU electrical interference. Needle EMG is often only useful for activity at rest as volitional activity is not elicitable. There is generally the presence of abnormal spontaneous activity with fibrillation and positive wave potentials in affected muscles. If volitional activity is generated, there may be a myopathic pattern with early recruitment with short and polyphasic motor units. Similar to NCS, the needle EMG may be limited by electrical interference. Use of a sterile uncoated needle ground electrode can help reduce interference. Direct muscle stimulation is another potential diagnostic test. It is mainly useful to distinguish CIP an CIM. In CIP, direct electrical stimulation to a muscle causes muscle contraction as the nerve impulse bypasses the affected nerve. In CIM, direct electrical stimulation to a muscle will result in no contraction. Muscle ultrasound may be a useful auxiliary test for diagnosis. Affected muscles may demonstrate muscle atrophy and loss of architecture. This finding, however, is not specific for CIM. CK levels are generally mildly elevated or normal. The exception to this is if there is a necrotizing myopathy, in which case the CK will be severely elevated. Differential Diagnosis: Critical illness polyneuropathy, neuromuscular junction defects, inflammatory myopathies, muscular dystrophy, previously undiagnosed motor neuron disease.

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Therapy: There is no specific targeted therapy. There is moderate quality evidence from two large trials that intensive insulin therapy reduces CIM, and high-quality evidence that it reduces the duration of mechanical ventilation. However, very strict aggressive targeted blood glucose control with insulin to 80–110 mg/dL has been shown to increase mortality. Early mobilization and physical therapy is frequently implemented but studies have shown mixed results for long-term benefit. Electrical stimulation therapy of muscle has been shown to decrease muscle atrophy but is not correlated with significant improvements in strength. IVIG and corticosteroids have been studied in a randomized control trials and did not show benefit. Prognosis: Development of CIM is associated with prolonged ICU stay, prolonged hospitalization, and increased 1-year mortality that is independent of the underlying systemic illness. While the distinction between CIP and CIM does not change clinical management, it can be helpful for prognostication. Overall CIM has a better prognosis than CIP. The majority of CIM patients will have complete recovery in 6 months and overall will recover more quickly and more completely than CIP patients. Recovery of strength can continue as far as 2 years after diagnosis, after which there is a plateau in progress.

14.9 Myopathies Associated with Endocrine/Metabolic Disorders and Carcinoma Genetic testing −

NCV/EMG ++

Laboratory +++

Imaging +

Biopsy ++

Distribution/Anatomy: Variable; however, proximal muscles are most usually affected. Time Course: Most of these myopathies progress slowly although thyrotoxicosis-induced myopathy is rapid. Age of Onset: Any age although most are observed in adults. Clinical Syndrome: Hypothyroidism may be associated with a painful myopathy that can simulate polymyalgia or polymyositis. Severely hypothyroid children develop weakness, slow movements, and striking muscle hypertrophy. Thyrotoxicosis may be associated with muscle atrophy and weakness, a progressive extraocular muscle weakness, ptosis, periodic paralysis, myasthenia gravis, spastic paraparesis and bulbar palsy (similar to amyotrophic lateral sclerosis), hypoparathyroidism-related tetany, muscle spasm, and occasionally weakness. Hyperparathyroidism results in proximal weakness, muscle atrophy, hyperreflexia, and fasciculations. Severe vitamin D deficiency is associated with proximal muscle weakness and myalgias. Cushing syndrome may cause muscle atrophy and weakness. Acromegaly may be associated with mild proxi-

Fig. 14.9 High-magnification H&E shows acute segmental fiber necrosis or myolysis in a diabetic patient (arrowheads)

mal weakness. Diabetic amyotrophy may be associated with muscle necrosis (Fig. 14.9) or inflammation although usually diabetes is not associated with myopathy. Hypoglycemia may be associated with muscle atrophy. Chronic renal failure may cause proximal weakness or rhabdomyolysis. Muscle may be affected as part of a paraneoplastic syndrome or by direct invasion with leukemias and lymphomas. Pathogenesis: The pathogenesis depends on the specific muscle disorders indicated above. Diagnosis: Biochemistry helps determine the specific metabolic defect. The CK is usually normal. The EMG results are dependent on the specific disorder but may show “myopathic changes.” In hypo- and hyperthyroidism, the muscle biopsy is often normal. In hyperparathyroidism and acromegaly, there may be type II fiber atrophy. Inflammation and muscle infarction may be observed in diabetic amyotrophy. Inflammation may occur in carcinomatous or paraneoplastic myopathy. Differential Diagnosis: Other metabolic myopathies, polymyositis, dermatomyositis, inclusion body myositis. Therapy: The therapy of the underlying endocrinopathy often leads to improvement of the myopathy. Prognosis: This is dependent on the specific disorder but is usually good for the endocrine disorders.

14.10 Duchenne Muscular Dystrophy (DMD) Genetic testing +++

NCV/EMG +

Laboratory +

Imaging ++

Biopsy +

Distribution: Usually affects proximal muscles and spares the face. Time Course: Progressive disorder with gradual onset. Age of Onset: Usually around age 3–5 years though sometimes earlier.

14.10 Duchenne Muscular Dystrophy (DMD)

Clinical Syndrome: DMD is the most common form of muscular dystrophy affecting 1:3500 male infants. DMD starts with symmetric proximal greater than distal weakness in the arms and legs. Infants may have generalized hypotonia and be described as “floppy.” By 6–9 years they characteristically exhibit a positive Gower’s sign, and by 10–12 years, without treatment, patients often fail to walk. They frequently have calf hypertrophy, muscle fibrosis, contractures in the lower extremities, and scoliosis of the spine. However, the major determinant of morbidity is progressive respiratory insufficiency and forced vital capacity declines progressively after loss of ambulation. In general, the average IQ of affected children is reduced compared to the general population to approximately 85. Some patients (20%) may have more severe cognitive impairment. Other features include a retinal abnormality with night blindness and a cardiomyopathy that develops by the mid-teens. In DMD, cardiac conduction defects, resting tachycardia, and cardiomyopathy are frequently encountered. Mitral valve prolapse and pulmonary hypertension may also be seen. The clinical progression is altered by treatment as described below. Pathogenesis: DMD is caused by a mutation of the dystrophin gene at locus Xp21, located on the short arm of the X chromosome. In the absence of dystrophin, there is loss of membrane integrity that leads to fiber degeneration and exhaustion of regenerative capacity that leads to fibrosis and fatty replacement of muscle. Deletions of DMD exons result in nonfunctional dystrophin. However, if exons adjacent to the section of deletions are skipped then a semi-functional dystrophin can be generated that is associated with a better clinical outcome than the absolute absence of dystrophin (similar to Becker muscular dystrophy; BMD). Thus, drugs that skip exons to restore the reading frame and produce truncated dystrophin may have therapeutic benefit. These medications are designed to target specific exons that are most common in order to help the greatest number of people, for example, 14% of the mutations in DMD are amendable to exon 51 skipping therapy (see therapy below). Diagnosis: Genetic testing of the dystrophin gene is the mainstay of diagnosis and is commercially available. Genetic testing typically shows exonic or multiexonic deletions in about 65–70%, duplication in 5–10%, or missense mutations that generate stop codons may be observed in a small percentage of DMD patients. One-third of DMD cases are de novo. Carrier testing should always be considered for mothers of DMD boys although it is not required in the setting of a clear X-linked history consistent with an obligate carrier status. Germline mosaicism can occur in 10% of mothers with negative DNA tests, thus genetic counseling should be provided and address the risk of germline mosaicism in mothers with negative DNA tests. The reading frame rule is accurate approximately 90% of the time. However, because

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there are exceptions in genetic mutations, diagnosis of DMD or Becker muscular dystrophy (BMD) depends on the clinical picture, presentation age, phenotype, and results of dystrophin expression studies. In the majority of patients, the CK is typically very high, usually over 5000. NCS are usually normal. Membrane instability in the form of positive sharp waves and fibrillation potentials is commonly seen. Short-duration polyphasic motor unit action potentials, mixed with normal and long-­ duration units, are noted in the affected muscles. Recent MRI studies suggest that the anterior compartment of the lower leg may be preferentially involved in this disease relative to the posterior compartment muscles, with good correlation to muscle histology. Biopsy usually shows variation in muscle fiber size, an increase in endomysial connective tissue, increased myopathic grouping, necrotic fibers, hypercontracted fibers, and evidence of degeneration and regeneration of muscle fibers (Fig.  14.10). Inflammatory cells can also be seen. Dystrophin is also found to be absent by immunohistochemical staining or Western blotting of muscle from DMD patients. Differential Diagnosis: BMD, inflammatory myopathies, spinal muscular atrophy, congenital myopathy, limb-­ girdle muscular dystrophy (LGMD). Therapy: Corticosteroids are thought to reduce inflammation and are the current standard of care in DMD. Prednisone improves pulmonary function, delays cardiomyopathy, prolongs the ability to walk by a few years, reduces falling, and reduces the need for scoliosis surgery in patients with DMD. The doses used are usually 0.75 mg/kg/ day as a starting dose and then changing to a weekly dose of 5–10 mg/kg. Several medications have been tested in clinical trials for DMD, the following are currently FDA approved: (1) Deflazacort is as effective as prednisone but increases survival by up to 15 years. Deflazacort, 0.9 mg/kg/day, significantly improves muscle strength and is associated with less weight gain compared with prednisone but otherwise has similar side effects to other corticosteroids. (2) Eteplirsen is a phosphorodiamidate morpholino oligomer and was the first disease-modifying drug approved for DMD. Eteplirsen is given intravenously at a dose of 30  mg/kg per week to patients with a confirmed mutation of DMD amenable to exon 51 skipping. A onetime intramuscular injection of 0.9 mg of eteplirsen into the extensor digitorum brevis muscle increased dystrophin expression by 11–21% and after 36 months improved the 6-minute walk test significantly. A serious adverse effect of Eteplirsen is hypersensitivity, but the most common adverse events are headache, pain due to the procedure, and proteinuria. (3) Golodirsen 30  mg/kg intravenously per week is approved for the treatment of DMD patients who have a confirmed mutation amenable to exon 53 skipping (about 8%). Similar to Eteplirsen, hypersensitivity is also a serious adverse effect, but the most com-

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a

b

c

d

Fig. 14.10  Duchenne muscular dystrophy. (a) On H&E staining, considerable fiber-type variation, including an occasional hypertrophic fiber (arrow) and fibrosis with fatty infiltration (arrow heads), is noted.

(b) Also, on H&E staining, lymphocytic infiltrates are demonstrated (arrow). (c) Normal dystrophin staining. (d) Loss of dystrophin staining in DMD

mon adverse effects are headache, pyrexia, and gastrointestinal symptoms. Ataluren is approved in the European economic area for the treatment of DMD nonsense mutations in ambulatory patients aged 2  years and older. Ataluren is an oral agent that suppresses nonsense mutations in genetic diseases in a similar way as aminoglycosides. Ataluren treatment increases expression of full-length ­dystrophin protein in muscle cells containing the premature stop codon mutation for DMD. The most common adverse effects are vomiting, diarrhea, nausea, headache, and abdominal pain. Numerous other treatments are in various stages of clinical development and are described in the review by Grages et al. 2020 in the bibliography. Nonsurgical treatment of contractures consists of night splints and daytime passive stretch. Surgical treatment of contractures consists of early contracture release, Achilles tenotomy, and posterior tibial tendon transfer followed by early ambulation. Scoliosis may require back bracing. Spinal fusion may be required where there is respiratory compro-

mise. According to Hart and McDonald (1998), fusion should be used before the curvature is greater than 30° and vital capacity is less than 35% of predicted. Patients with cardiomyopathy and pulmonary hypertension may be helped by angiotensin-converting enzyme inhibitors, beta blockers, and supplemental oxygen. Digoxin may be used in selected patients. Carriers should also be checked for cardiac defects. Respiratory compromise may require portable positive pressure ventilation. Patients with DMD are at risk of pulmonary infections and should be vaccinated for pneumonia and influenza. Prophylactic antibiotics should be used for dental and surgical procedures in patients with mitral valve prolapse. Low-impact aerobic exercise can help maintain strength, mobility, and general health. Prognosis: Due mainly to improved cardiac and respiratory care, coupled with newer therapies outlined above, life expectancy is increasing. Survival into young adulthood and even having children is more common. Many with DMD typically are unable or have difficulty walking by their teen-

14.11 Becker Muscular Dystrophy (BMD)

289

age years and have a cardiomyopathy by the late teens. Death normally occurs from respiratory or cardiac failure.

14.11 Becker Muscular Dystrophy (BMD) Genetic testing +++

NCV/EMG +

Laboratory +

Imaging ++

Biopsy +

Distribution/Anatomy: Usually affects proximal muscles and spares the face. Time Course: Progressive disorder with gradual onset. Age of Onset: Usually around age 10–12 years though a later presentation is not uncommon. Age of onset of weakness is very variable. Clinical Syndrome: BMD is another X-linked dystrophinopathy that in general is much milder than DMD with later clinical onset. Patients may have difficulty walking by their late teens. There is clearly an overlap with DMD and thus the concept of “intermediate muscular dystrophy” be useful to describe boys who walk past age 12 years but stop walking by age 15  years. Thus, the classification of BMD may be reserved for patients who lose ambulation after the age of 15 years. BMD often causes calf pain, cramps, and myalgias. Weakness is present in approximately 20% of affected patients, typically in proximal > distal muscles and often effecting the quadriceps and hamstring muscles preferentially. Patients may have no symptoms. In general, the severity and onset age correlate with muscle dystrophin levels. As with DMD, affected subjects may have calf muscle hypertrophy and contractures in the lower extremities. Patients with BMD often have a cardiomyopathy as part of the muscle weakness syndrome or may have an isolated dilated cardiomyopathy. Carriers for BMD must also be monitored as they can also develop cardiomyopathy. Pathogenesis: Most BMD patients have a frameshift mutation (>95%) although 30% may have a new mutation. Mutational analysis of blood samples can lead to the diagnosis of a dystrophinopathy in around 95% of cases. Dystrophin is reduced in BMD although to a lesser extent than DMD. The mechanism of muscle degeneration is similar in both. Dystrophin links the cytoskeleton to the extracellular matrix, through the transmembrane dystroglycan protein and its associated protein complex that includes the sarcoglycans. Dystrophin binds to cytoskeletal actin via its N-terminal actin-binding domain 1 and to β-dystroglycan via its C-terminal domain. In the absence of dystrophin, the muscle membrane is susceptible to damage and muscle fiber deterioration occurs, resulting in cycles of regeneration and degeneration that result in fibrosis and fatty replacement of muscle. Diagnosis: Genetic testing remains the definitive test for diagnosing BMD. Genetic testing of the dystrophin gene is

commercially available and typically shows exonic or ­multiexonic deletions in about 80%, duplication in 5–10%, or missense mutations that generate stop codons may be observed in a small percentage of BMD patients. In the majority of patients, the CK is typically very high, usually over 5000. NCS are usually normal. Membrane instability in the form of positive sharp waves and fibrillation potentials is commonly seen. Short-duration polyphasic motor unit action potentials, mixed with normal and long-­ duration units, are noted in the affected muscles. MRI study often demonstrates focal muscle enlargement and edema, especially observed on T2- and T1-weighted images with gadolinium, in more severely affected patients. T2 signal and lipid fraction correlate to longitudinal progression of disease, raising the possibility that MRI may become a robust outcome measure for clinical trials. Muscle biopsy may still be required in selected cases. Biopsy usually shows variation in muscle fiber size, an increase in endomysial connective tissue, increased myopathic grouping, necrotic muscle fibers, and evidence of degeneration and regeneration of muscle fibers. These histopathologic changes are not specific (similar changes may be seen in other muscular dystrophies and in particular, the LGMDs), diagnosis from muscle biopsy depends on analysis of dystrophin expression. Diagnosis using immunohistochemistry or immunofluorescent analysis of muscle sections or by immunoblot of muscle homogenates is required. Immunohistochemistry or immunofluorescence is performed using antibodies directed toward the N-terminal, the central rod, and the C-terminal domains. The use of rod domain antibodies alone may be misinterpreted as dystrophin absence if an internally truncated BMD-associated protein lacks the epitope toward which the antibody is directed. Figure 14.11 shows the absence of dystrophic staining.

Fig. 14.11 Becker’s muscular dystrophy. Immunohistochemistry demonstrates variable reduction of dystrophin

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Differential Diagnosis: Spinal muscular atrophy (SMA), congenital myopathy, myofibrillar myopathy, limb-girdle muscular dystrophy. Therapy: As with DMD, there may be a role for prednisone therapy in more severely affected subjects and should be personalized in each case. Deflazacort’s primary indication is for DMD. Management of the side effects of corticosteroids is a significant challenge. The treatment of contractures, cardiac, and pulmonary disease follows the outlines for DMD. Early treatment of cardiomyopathy with ACE inhibitors is recommended and severe cases may require referral for cardiac transplantation. Management includes multidisciplinary care with physiotherapy to reduce joint contractures and prolong walking. Many subjects have mild symptoms and do not require therapy. Prognosis: Unlike DMD, the prognosis for BMD patients is highly variable. Some patients become unable to walk as a teenager while others continue to ambulate throughout life. The 10-m walk test (time to walk 10 m) has prognostic value: a time of greater than 12 sec predicts wheelchair use within 1 year in 100% of patients. Restrictive lung disease may ultimately require noninvasive ventilation but is a challenge to predict. Some patients may become candidates for cardiac transplant as well. Despite the variability, patients usually die in the fourth or fifth decade of life. With some alleles, variation within families is seen, some may have minimal weakness or cramp-myalgia, whereas others are entirely asymptomatic into their eighth decade. In BMD, cognition is generally spared although isolated cognitive impairment has been reported.

14.12 Myotonic Dystrophy (DM) Genetic testing +++

NCV/EMG ++

Laboratory −

Imaging +

Biopsy +

Distribution/Anatomy: Affects both distal and proximal muscles, as well as many other organ systems. Time Course: Slowly progressive disorder. Age of Onset: Variable age of onset. Clinical Syndrome: There is considerable phenotypic variation within families. Usually, symptomatic weakness begins in the hands and at the ankles and usually follows years of myotonia. Facial muscle weakness with prominent mouth puckering, weak eye closure, and external ocular muscle weakness is common. Myotonia may be demonstrated in the thenar eminence or tongue. Frequently affected organs include skeletal muscles, the cardiac conduction system, the brain, peripheral nerve, smooth muscles, and lens. Respiratory failure is the most common cause of death in DM and is correlated with CTG repeat size and may occur in the absence of significant muscle weakness. The respiratory dysfunction is due to a combination of skeletal muscle weak-

ness and central nervous system dysfunction. Patients with DM1 may not be aware of respiratory failure and respiratory parameters must be monitored even in the absence of obvious symptomatology (supine evaluation is more sensitive for restrictive lung disease). Cardiomyopathy is less common in DM but cardiac conduction abnormalities occur in a majority of patients with DM1. In DM1, cardiac conduction abnormalities range from asymptomatic PR interval prolongation to complete heart block and correlate with repeat expansion size. Progression of cardiac conduction abnormalities is usually slow but is variable. Cardiac-related involvement is the second most common source of mortality in DM1 (approx. 30% of deaths). In later years, cognitive impairment, hypersomnolence, hyperglycemia with insulin insensitivity, and cataracts may be prominent. Cognitive dysfunction affecting visuospatial and executive function is present in almost all DM1 and approximately 60% of DM2 patients and is ­associated with size of the CTG expansion and with worsening in quality of life. Peripheral neuropathy is present in both DM1 and DM2 in about 10–15% of patients on the basis of NCS, but is clinically mild. Where the expansion is small ( distal weakness, myotonia, and white matter hyperintensity on the brain MRI. Pathogenesis: DM1 is an autosomal dominant disease due to an expanded CTG repeat expansion of the dystrophia myotonica-protein kinase gene (DMPK) on chromosome 19. DM2 is related to an expansion of the CCTG repeat expansion of the CNBP (ZNF9) gene on chromosome 3q21. In both DM1 and DM2, there is an RNA toxic gain-of-function in which RNA repeats form nuclear foci resulting in sequestration of RNA-binding proteins and result in dysregulated splicing of premessenger RNA.  Recently, repeat-associated non-AUG (RAN) translation has gained attention and the DM1 disease mechanism could be related to a combination of RNA toxic gain-of-function and toxicity of RAN proteins. Diagnosis: Genetic evaluation has supplanted other tests in the diagnosis of DM. DNA testing using PCR or Southern blotting is available to measure the size of the unstable CTG repeat in blood or tissue DNA.  Each test should be interpreted with care: a small myotonic dystrophy repeat may be missed by Southern blotting techniques, while a larger repeat may be missed by PCR methods. Serum CK is often normal. If the EMG is abnormal, it shows a minimal increase in insertional activity in affected muscles. Myotonic discharges may be seen in distal muscles in particular and may be increased by cooling the muscle. The muscle biopsy in both DM1 and DM2 is similar but nonspecific and shows type I fiber atrophy, central nuclei, atrophied fibers mixed with

14.13 Limb-Girdle Muscular Dystrophy (LGMD)

291

• • • • Fig. 14.12  Myotonic dystrophy. H&E section shows atrophied fibers (small arrows), mixed with hypertrophied fibers (arrowhead), numerous centrally migrated nuclei, and a slight increase in endomysial connective tissue (large arrow)

hypertrophied fibers, and a slight increase in endomysial connective tissue (Fig. 14.12). Ringbinden, characterized by peripheral myofilaments wrapped perpendicularly around the center of a fiber may be seen but are not pathognomonic of DM.  Electron microscopy shows sarcoplasmic masses and dilation of the terminal cisternae of the sarcoplasmic reticulum. MRI and PET may be useful in detecting brain lesions. The PET may show decreased glucose utilization. Differential Diagnosis: The clinical manifestations of DM are very variable, and thus the disorder may remain undiagnosed without a family history. Other conditions to be considered are myotonia congenita and cold-induced myotonia (paramyotonia). Therapy: There is no specific therapy for DM. New therapy development has focused on reversal of the spliceopathy and strategies have included small molecule therapeutics, antisense oligonucleotide (ASO)-based therapy, and genome editing targeting either the expanded DNA, RNA, or altered downstream signaling pathways. For detailed recommendations on clinical management of DM1, see the reference by Ashizawa et al. 2018. The following are useful in management of DM: • A randomized, double-blind, placebo-controlled trial did show mexiletine 200–600 mg/day to be effective in reducing clinical myotonia in patients with DM1 without any significant adverse events. However, mexiletine does have proarrhythmic potential, and use is contraindicated in second- or third-degree AV block. Lamotrigine, another sodium channel blocker, and ranolazine, which increases slow inactivation of sodium channels, may be effective for the treatment of myotonic dystrophy. • Monitoring the EKG for gradual widening of the PR interval (>0.22 ms). This provides a warning for impend-

•

ing heart block and the need for further electrophysiologic testing. An elective pacemaker may be necessary if the patient has an atrioventricular block or bradycardia. If the patient has ventricular fibrillation, an intracardiac defibrillator may be necessary. In contrast to DM1, the frequency and severity of involvement of the cardiac system are less in DM2. Diabetes should be controlled with diet, oral hypoglycemics, or insulin. Modafinil may be used for hypersomnolence, but there is no strong trial evidence supporting use of modafinil. Cataracts and blepharoptosis may require surgical treatment. Assessment for pharyngoesophageal dysfunction may prevent aspiration. Cognitive impairment and personality disorders require a combined approach with medication and psychological support.

Prognosis: DM shows variable progression, even in members of the same family. Earlier onset usually implies a rapid and severe disorder. Although survival to the fifth decade is common, survival beyond 65  years is rare. The most frequent causes of death are pneumonia and cardiac arrhythmias.

14.13 L  imb-Girdle Muscular Dystrophy (LGMD) Genetic testing +++

NCV/EMG ++

Laboratory +

Imaging +

Biopsy ++

Distribution: Can affect the pelvic girdle or pectoral girdle muscles but spares the face. Time Course: Forms that begin in childhood tend to progress more rapidly than those that appear in late adolescence or adulthood, which may have a more gradual and milder course. Age of Onset: Can occur in childhood, especially autosomal recessive forms, or in adulthood, especially autosomal dominant subtypes. Clinical Syndrome: LGMD is a very heterogeneous disorder, where the clinical presentation depends on the gene defect. Age of onset is variable and depends on the specific cause of the LGMD.  At least 30 subtypes of LGMD have been described and are divided into categories based on whether the pattern of inheritance is autosomal dominant (D) or autosomal recessive (R). The LGMD are further subdivided as follows according to the new classification system (see Straub et al. 2018): LGMD, inheritance (R or D), order of discovery (number), affected protein (See Table  14.2). The autosomal recessive forms are more severe and start

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Table 14.2  Proposed new nomenclature for LGMD compared to the previous nomenclature Old name LGMD 1F LGMD 1G LGMD 1I LGMD 2A LGMD 2B LGMD 2C LGMD 2D LGMD 2E LGMD 2F LGMD 2G LGMD 2H LGMD 2I LGMD 2 J LGMD 2 K LGMD 2 L LGMD 2 M LGMD 2 N LGMD 2O LGMD 2P LGMD 2Q LGMD 2S LGMD 2 T LGMD 2 U LGMD 2Z Bethlem myopathy recessive Bethlem myopathy dominant Laminin α2-related muscular dystrophy POMGNT2-related muscular dystrophy

Gene TNP03 HNRNPDL CAPN CAPN DYSF SGCG SGCA SGCB SGCD TCAP TRIM32 FKRP TTN POMT1 ANO5 FKTN POMT2 POMGnT1 DAG1 PLEC TRAPPC11 GMPPB ISPD POGLUT1 COL6A1, COL6A2, COL6A3 COL6A1, COL6A2, COL6A3 LAMA2 POMGNT2

Proposed new nomenclature LGMD D2 TNP03-related LGMD D3 HNRNPDL-related LGMD D4 calpain3-related LGMD R1 calpain3-related LGMD R2 dysferlin-related LGMD R5 γ-sarcoglycan-related LGMD R3 α-sarcoglycan-related LGMD R4 β-sarcoglycan-related LGMD R6 δ-sarcoglycan-related LGMD R7 telethonin-related LGMD R8 TRIM 32-related LGMD R9 FKRP-related LGMD R10 titin-related LGMD R11 POMT1-related LGMD R12 anoctamin5-related LGMD R13 Fukutin-related LGMD R14 POMT2-related LGMD R15 POMGnT1-related LGMD R16 α-dystroglycan-related LGMD R17 plectin-related LGMD R18 TRAPPC11-related LGMD R19 GMPPB-related LGMD R20 ISPD-related LGMD R21 POGLUT1-related LGMD D5 collagen 6-related LGMD D5 collagen 6-related LGMD R23 laminin α2-related LGMD R24 POMGNT2-related

Based on Straub V, Murphy A, Udd B; LGMD workshop study group (2018)

early in life, whereas the autosomal dominant forms are milder and start later. The weakness is progressive, and eventually all muscles in the body are affected. Generally, though, it is slow in its progression. It occurs approximately equally in both sexes. In approximately 50%, weakness begins in the pelvic girdle musculature (the Leyden and Möbius type) and then spreads to the pectoral musculature, and in the other 50% (the Erb type), the weakness begins with the pectoral girdle musculature. Facial muscles are uninvolved in LGMD until the patient is severely disabled from limb weakness. Pseudohypertrophy of calf muscles is unusual. Muscle tendon reflexes are preserved in the early stages but are lost as the disease progresses. As the disease progresses, there may be respiratory failure associated with axial weakness and scoliosis. Specific phenotypes may be dependent on the gene mutation. According to genetic analysis on a large LGMD cohort, the LGMD phenotype is primarily driven by pathogenic variants in one of the following genes: CAPN3, DYSF, FKRP, and ANO5. Under the new definition Emery–Dreifuss muscular dystrophy (EDMD), rippling muscle disease, and myofibrillar myopathy have been removed from the list of LGMDs. Pathogenesis: LGMD is a heterogeneous disorder with a wide range of molecular defects. Table  14.2 indicates the

new nomenclature for confirmed LGMD. Uncertain cases or those described only in a single family have been excluded. Diagnosis: The serum CK in LGMD is usually elevated especially in the autosomal recessive forms, but a normal CK does not exclude the diagnosis. Electrodiagnostic testing typically demonstrates findings that support a myopathy but are otherwise nonspecific. MRI may play a role in distinguishing among the LGMDs. A recent study suggested that LGMD R9 FKRP related has characteristic MRI changes most prominent in the posterior and adductor thigh muscles, with relative sparing of the gluteal and calf muscles. LGMD R1 calpain3 related shows similar involvement of the posterior and adductor thigh muscles but also the medial gastrocnemius and soleus muscles. LGMD R2 dysferlin related has variable involvement of posterior and anterior thigh muscles. LGMD R3 α-sarcoglycan related demonstrates prominent involvement of the anterior > posterior thigh muscles. The muscle biopsy is also nonspecific and depends on the particular type of LGMD. In general, there are a wide range of degenerative changes seen, including fiber splitting, ring fibers, and lobulated fibers. Individual muscle fibers can also show hyalinization, vacuolation, and necrosis. Other changes include an increase in connective tissue with nesting of muscle fibers, and muscle atrophy as seen in LGMD R5

14.14 Oculopharyngeal Muscular Dystrophy (OPMD)

293

on the type, although they are usually less severe than in the dystrophinopathies. Affected patients may develop a cardiac arrhythmia or sometimes congestive cardiac failure.

14.14 O  culopharyngeal Muscular Dystrophy (OPMD) Genetic testing +++

Fig. 14.13  LGMD R5 γ-sarcoglycan-related (LGMD2C). H&E staining shows fiber size variation, hypertrophic fibers (large arrows), limited inflammatory infiltrate (small arrow), and increased fibrosis (arrowhead)

γ-sarcoglycan related (Fig. 14.13). Regenerating fibers with prominent nucleoli and basophilic sarcoplasm are often seen. Rarely, mononuclear cellular infiltrates are seen near necrotic muscle fibers, especially in calpainopathies, sarcoglycanopathies, and dysferlinopathies. Available genetic testing for LGMD can be obtained by searching the NCBI Genetic Testing Registry (the current registry still uses the old LGMD nomenclature – see Table 14.2). Differential Diagnosis: Facioscapulohumeral dystrophy, myotonic dystrophy, myofibrillar myopathy, Duchenne and Becker muscular dystrophies. Therapy: No specific therapy is known for any form of LGMD at this time. Corticosteroids may be useful in the treatment of LGMD R13 Fukutin related (LGMD2M). In LGMD, R3 α-sarcoglycan-related (LGMD2D) robust alpha-­ sarcoglycan gene expression is seen following intramuscular or isolated limb intravascular infusion gene (SGCA) transfer. Future therapies will have to target the specific molecular defect. The treatment of contractures, cardiac, and pulmonary disease follows the outlines for DMD. Genetic counseling is complex in LGMD due to the heterogeneity of the disease. Prognosis: LGMD is a progressive disorder although the rate of progression depends on the type. Autosomal recessive LGMD usually progresses rapidly, with inability to walk in late childhood and death in early adulthood. In contrast, autosomal dominant LGMD, even of childhood onset, is usually very slowly progressive. Respiratory involvement may occur later in the disease depending on the specific type of LGMD.  This may result in pneumonia and early death. Myocardial changes may also occur in LGMD, depending

NCV/EMG ++

Laboratory +

Imaging +

Biopsy ++

Distribution: OPMD causes ptosis and affects pharyngeal muscles, extraocular muscles, and proximal limb muscles. Time Course: The condition is very slowly progressive in most cases. Age of Onset: Presents in the fourth to sixth decade most frequently with ptosis. Clinical Syndrome: Autosomal dominant OPMD is more common than the autosomal recessive form. Patients hypercontract the frontalis muscle and retroflex the head so they have a characteristic looking up posture. Patients often have incomplete extraocular muscle paralysis and a superior field defect that disappears when the eyelids are elevated. Dysphagia and tongue weakness are other early symptoms and may result in repeated episodes of aspiration and may lead to aspiration pneumonia. Laryngeal weakness may result in dysphonia. Weakness in the limbs is usually mild, although it may vary, and usually affects proximal muscles with distal muscles later becoming weak in more severe cases. Mild neck weakness also occurs. Strict clinical diagnostic criteria for dominant OPMD have been shown to have 100% specificity for many patients: • A positive family history of OPMD. • At least one palpebral fissure at rest smaller than 8 mm (or previous blepharoplasty). • A swallowing time greater than 7 s when asked to drink 80 ml of ice-cold water. Pathogenesis: Mutation of the PABPN1 gene (GCN)(n)/ polyalanine mutations. PABPN1 acts as a nuclear to cytosolic shuttle for mRNA. Mutated PABPN1 is an inefficient transporter and results in cell death. Patients with OPMD with longer PABPN1 expansion are on average diagnosed at an earlier age than patients with a shorter expansion confirming that polyalanine expansion size plays a role in OPMD, with an effect on disease severity and progression. One potential mechanism is that PABPN1 accumulates on the inner membrane of mitochondria and reduces expression of OXPHOS complexes in mouse muscle fibers and may therefore reduce mitochondrial function. Diagnosis: Genetic testing is highly useful in diagnosis and if clearly abnormal, other testing is usually not required. A short GCG repeat expansion in the poly (A) binding pro-

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Prognosis: Depends on the degree of pharyngeal and esophageal involvement and thus the risk of aspiration.

14.15 Facioscapulohumeral Muscular Dystrophy (FSHD) Genetic testing +++

NCV/EMG +

Laboratory −

Imaging −

Biopsy +

Distribution: FSHD has a worldwide prevalence of 2–7/100,000 individuals and affects the face, scapula and proximal shoulder girdle, and the lower extremities in a peroneal distribution. Time Course: Slow progression with a normal life span. Age of Onset: Across the life span. Fig. 14.14  H&E section with a prominent rimmed vacuole (small Clinical Syndrome: There is considerable variability in arrow) and a mixture of atrophied (large arrow) and hypertrophied presentation and rates of progression of FSHD ranging fibers with central nuclei (arrowheads) across the life span. The clinical presentation is similar is tein nuclear 1 (PABPN1) gene can be detected in both the FSHD1 and FSHD2 but may vary considerably irrespective autosomal dominant and recessive forms of OPMD. PCR is of the genetics both between and within families. Although required to establish the carrier status of an individual. The FSHD does not typically shorten the life span, it can result in test has a sensitivity and specificity greater than 99%. Genetic significant morbidity and approximately 20% of people older testing for targeted mutation analysis, sequencing, carrier than 50 years of age will require a wheelchair. Penetrance in status, and prenatal testing is available. Serum CK is usually women is believed to be lower than in men and generally normal or mildly elevated. Needle EMG is nonspecific and women are diagnosed at an older age and are often less shows myopathic and polyphasic motor unit potentials simi- severely affected. The following support a diagnosis of lar to most myopathies. On muscle biopsy, there is evidence FSHD: onset of weakness affecting the facial muscles or of variation in fiber diameter, and the presence of atrophic, shoulder girdle muscles, with asymmetric muscle involveangulated, hypertrophic, or segmented muscle fibers ment, abdominal weakness, retinal vasculopathy, or hearing (Fig. 14.14). Rimmed cytoplasmic vacuoles and internuclear loss in early-onset FSHD. The following would not support inclusions (15–18  nm in diameter) are characteristically a diagnosis of FSHD: ptosis or extraocular muscle involveseen. Filaments in nuclei are often tubular and form tangles ment, with lingual involvement or difficulty swallowing, and palisades. These contain mutant PABPN1 protein, ubiq- prominent contractures, cardiomyopathy. Winging of the scapulae is a prominent feature and is not uitin, proteasome components, and poly(A)-RNA. Rimmed related to position. The pectoral muscles are often poorly vacuoles are seen in all biopsies but are not numerous. Differential Diagnosis: Centronuclear or myotubular developed and there is frank pectus excavatum. The scapula myopathy, mitochondrial myopathies, oculopharyngodistal weakness means that the arms cannot be raised to shoulder level even though strength in the supraspinati, infraspinati, or myopathy. Therapy: Nutritional support is important because the deltoids may be normal. However, the hands maintain funcdysphagia worsens prognosis. Pharyngoesophageal sphinc- tion. The deltoid is often preserved, and the trapezius can ter abnormalities may benefit from cricopharyngeal myot- appear bunched due to selective involvement of the lower omy if the lower esophageal sphincter is intact. Surgical part of the muscle (polyhill appearance). The biceps and tricorrection of the ptosis (resection of the levator palpebral ceps are often wasted with preservation of distal forearm aponeurosis or frontal suspension of the eyelids) is appropri- muscles (Popeye arms). In the legs, there is distal muscle ate if orbicularis oculi strength is sufficient to allow closure weakness resulting in a scapuloperoneal syndrome of the eyelids after surgery. Recently, it has been shown that (Fig. 14.15). Other symptoms include difficulty with whisthe treatment of a mouse model of OPMD with an adeno-­ tling, closing the eyelids, and weakness of the abdominal associated virus-based gene therapy combining complete muscles with a positive Beevor’s sign. The reflexes may be knockdown of endogenous PABPN1 and its replacement by either preserved or absent if muscle weakness is severe. a wild-type PABPN1 substantially reduced the amount of About 20% of adults lose the ability to walk and are in insoluble aggregates, decreased muscle fibrosis, reverted wheelchairs although in general most adult patients retain muscle strength to the level of healthy muscles, and normal- mobility. In addition to the musculature, FSHD may be associated with hearing impairment in about 16% and retinopaizes the muscle transcriptome.

14.15 Facioscapulohumeral Muscular Dystrophy (FSHD)

a

295

b

c

d

Fig. 14.15 (a–c) Patients with FSHD. There is prominent scapular winging, bilateral ptosis, and facial weakness. (d) Lobulated type I fibers (white arrows) that are smaller than the type II fibers (succinic dehydrogenase)

thy including Coats’ disease rarely occurs, approximately 8% require noninvasive ventilatory support due to restrictive respiratory involvement, but the heart usually only shows

benign changes. Approximately 10–30% of all familial cases are asymptomatic. Sporadic cases are more likely to have onset in childhood or infancy and have a more severe course.

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Hearing impairment and retinopathy are more common in childhood-onset FSHD. With DNA diagnosis, it is apparent that the presentation of FSHD may be atypical with a facial-­ sparing scapuloperoneal myopathy, distal myopathy, asymmetric arm weakness, or limb-girdle muscular dystrophy. Pathogenesis: FSHD is an autosomal dominant disorder but up to 30% of mutations can be spontaneous. FSHD is due to two genetically distinct types that converge to a common downstream pathway in the expression of the toxic protein DUX4. FSHD is caused by expression of DUX4 located on the D4Z4 macrosatellite repeat array on chromosome 4q35, a gene expressed in the germline but usually repressed in somatic tissue. In 95% of patients (FSHD1), there is a large deletion in the D4Z4 macrosatellite repeat array at 4q35 with 1–10 repeats whereas non-affected individuals possess 11–150 repeats. Each D4Z4 unit contains a DUX4gene. Synthesis of the DUX4 transcription factor DUX4 is thought to cause disease through a toxic gain-of-function mechanism and may target several genes that inhibit myogenesis, sensitize cells to oxidative stress, and induces muscle atrophy. In FSHD2, there is a deletion-independent mechanism but, similar to FSHD1, there is hypomethylation and epigenetic depression in the same region of chromosome 4q. FSHD1 is dominantly inherited and FSHD2 shows digenic inheritance, with about 80% of patients also having a mutation in the SMCHD1 gene. Diagnosis: If clinically suspected, the next diagnostic step is genetic testing. Commercial testing for a D4Z4 contraction using Southern blot after double digestion with EcoRI/BlnI yields a sensitivity of 93% and specificity of 98%. If Southern blot testing is negative (no contraction of D4Z4 repeats), then determination of the presence of at least one A allele and very low methylation (less than 20%) confirms a diagnosis of FSHD2. Serum CK is normal or mildly elevated. On EMG, there are usually a mixture of small, short duration, and larger polyphasic motor unit potentials. Muscle biopsy shows lobulated type I fibers, with isolated angular and necrotic fibers. Moderate endomysial connective tissue proliferation may be observed. The biopsy may show variation in severity and may include clusters of inflammatory cells (40%). Muscle biopsy and EMG are not needed if genetic testing is abnormal. Differential Diagnosis: Spinal muscular atrophy, inflammatory myopathy, limb-girdle muscular dystrophy, mitochondrial myopathy, Emery–Dreifuss muscular dystrophy, Dawidenkow’s syndrome of scapuloperoneal neuropathy. Therapy: No medication significantly alters the disease. However, epigenetic regulators of the disease locus may be therapeutic targets for FSHD because most would not globally modify the genome and altering their expression or activity should allow correction of the underlying defect. The following may be helpful: assistive devices through physical and occupational therapy, low-intensity aerobic

14  Muscle and Myotonic Diseases

exercise, range of motion exercises, pain therapy, baseline pulmonary function repeated yearly, ventilator support for hypoventilation, cardiac screening if symptomatic (rare), baseline dilated eye examination for potentially reversible retinal vascular involvement, lubricants to prevent scleral drying, ankle/foot orthoses, surgical fixation of the scapula to the chest wall for arm range of motion, children with FSHD should be screened for hearing deficits as this can affect learning and language development, adults should be screened if symptomatic. Prognosis: FSHD is usually slowly progressive and survival is normal. Over 50% of patients continue working. Less than 10% need a wheelchair. The risk of becoming wheelchair bound is bimodal with a peak in the second decade for patients with the more severe infantile form and mostly, only about 20% over the age of 50 years will require a wheelchair for some portion of the day. Although cardiac defects may occur, these are invariably benign and medical complications are few.

14.16 E  mery–Dreifuss Muscular Dystrophy (EDMD) Genetic testing +++

NCV/EMG +

Laboratory −

Imaging +

Biopsy +

Distribution: EDMD is a rare muscular dystrophy with a pooled prevalence of 0.39 per 100,000 but is important to diagnose due to frequent life-threatening cardiac complications. Its distribution is variable but often affects the limb-girdle. Time Course: Usually slow progression with cardiac disease determining life span. Age of Onset: Variable from infancy to early adulthood and depends on the gene type. Clinical Syndrome: In EDMD, the classic clinical syndrome consists of early contractures, progressive muscle weakness and atrophy, and cardiac abnormalities. The contractures frequently emerge in the first decade of life that affect limbs but also the neck can lead to dysphagia. Difficulty with walking or running begins early. Muscle weakness and atrophy become evident by the second or third decade. The weakness commonly present affects the proximal arms (biceps and triceps) with relative sparing of the deltoids and infraspinatus and distal legs (predominantly the peroneal muscles) with sparing of the thighs and intrinsic foot muscles. Neck weakness is common, scapular winging is common, but facial muscles are spared. Cardiac complications are common and start in the second decade, may precede significant muscle weakness, and may exceed 60% in patients over 50 years: Complications include atrial and ventricular tachyarrhythmias, and cardiomyopathy. EDMD1

14.16 Emery–Dreifuss Muscular Dystrophy (EDMD)

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female carriers have an increased risk of developing cardiac complications, including conduction abnormalities and sudden cardiac death even if no significant neuromuscular symptoms. The seven types of EDMD and the individual variances in clinical presentation by gene mutation is described in Heller et  al. (2020) Muscle Nerve 61(4):436– 448 (see references). In general, while there are specific differences in the genotype–phenotype correlations, there is also considerable overlap. Pathogenesis: The exact pathogenesis is of EDMD is unknown. It is thought to be due to a structural or functional defect of one or more proteins comprising the nuclear that may affect protein importation into the nucleus. In EDMD, there are at least seven subtypes and the following genes have been implicated in associated genes include EMD, LMNA, SYNE1, SYNE2, FHL1, TMEM43, SUN1, SUN2, and TTN, encoding emerin, lamin A/C, nesprin-1, nesprin-2, FHL1, transmembrane protein 43 (LUMA), SUN1, SUN2, and titin, respectively. Mutations in LMNA and EMD are the most common genetic causes accounting for around 40% of cases. Diagnosis: Genetic testing is now the gold standard for diagnosis of EDMD and relies on next-generation sequencing technology often supplemented by specific deletion– duplication testing for slightly larger mutations such as exon-level deletions. EMG findings in EDMD are consistent with a myopathy with increased spontaneous activity, low-­ amplitude, short-duration motor unit action potentials, and early recruitment patterns. However, as with other dystrophic muscle diseases, apparent “neurogenic changes” may be interspersed. Skeletal muscle imaging can be a helpful adjunctive tool and distinct patterns of muscle involvement may be seen on muscle imaging studies in the setting of

EDMD, sometimes suggesting specific disease subtypes. Muscle CT imaging can differentiate EDMD from collagen VI-related myopathies as both present with significant contractures. In Bethlem or Ullrich myopathy, fatty infiltration was more likely to be seen in the rectus femoris, while posterior thigh muscles were more prominently infiltrated in EDMD. Muscle biopsies findings are not specific to EDMD and demonstrate dystrophic or other myopathic features, including a variation in muscle fiber size, a marked increase in internal nuclei, and, occasionally, a mild increase in endomysial connective tissue and necrotic fibers. In EDMD1, the anti-emerin antibody (Fig.  14.16) shows the absence of staining of the inner nuclear membrane, but in EDMD2 staining for laminin A/C (LMNA) is normal but LUMA staining may be reduced in EDMD2 and 7. Differential Diagnosis: Collagenopathies (Ullrich congenital muscular dystrophy), Bethlem myopathy, arthrogryposis multiplex congenita. Therapy: In EDMD, management is supportive as there are currently no disease-modifying therapies available. It is important to monitor patients closely in a multidisciplinary clinic, especially for potential cardiac complications and management follows the guidelines outlined for DMD. Contractures depending on severity may be treated by stretching, surgical interventions (such as elongation of the Achilles tendon for ankle contractures). Procedures often need to be repeated to maintain benefit and last longer if performed completion of growth. Respiratory dysfunction is generally not a prominent component of EDMD. Prognosis: This is highly dependent on the severity and nature of the cardiac defects and to some extent on the genetic mutation.

Fig. 14.16 (a) H&E section showing marked variability of fiber diameters (large arrows), increased internal nuclei (small arrow). (b) Immunostaining for emerin negative (no nuclear staining). The severe dystrophic changes and loss of emerin staining supports Emery–

Dreifuss muscular dystrophy. Images were kindly provided by Dr. Monika Hofer from Oxford University Hospitals, NHS Foundation Trust, UK

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14.17 Distal Myopathies Genetic testing +++

NCV/EMG ++

Laboratory −

Imaging −

Biopsy ++

Distribution: Characteristically affects distal leg or arm/ hand muscles depending on the specific disease. Time Course: Slowly progressive and usually limited to distal muscles. Age of Onset: May present in childhood but typically is seen in early adulthood to middle age. Clinical Syndrome: The distal myopathies represent a genetically heterogeneous group of disorders with shared clinical features. Welander (type I) distal myopathy (WDM) affects finger and hand extensors and later flexors may be affected. Cold sensation may be decreased distally. Markesbery (type II) distal myopathy (MDM) affects tibial muscles early, with foot drop developing later. MDM is usually milder than WMD and many patients remain asymptomatic. Nonaka distal myopathy (NDM) progresses to significant weakness of anterior tibial and then posterior compartment muscles within 10–15 years. Cardiomyopathy and conduction block may occur in some patients. Miyoshi distal myopathy (MIDM) causes progressive weakness of the posterior gastrocnemius muscles and results in difficulty standing on toes. Other distal muscles may be affected. Laing distal myopathy (LDM) begins in the neck flexors and anterior leg muscles, followed by finger extensor weakness, and ending with shoulder girdle weakness. Distal desmin body myofibrillar myopathy (DBM) is similar to other distal myopathies, but cardiomyopathy and conduction defects are common.

Pathogenesis: The genetic and molecular pathogenesis is described in Milone and Liewluck (2019). Diagnosis: CK is usually minimally elevated except in MIDM where it may be >100 times normal. On EMG, there may be “myopathic units” in distal muscles. WDM shows variation in fiber size, fiber splitting, and rimmed vacuoles along with filamentous inclusions (15–18  nm; Fig.  14.17). Characteristically, there is loss of Aδ fibers on the sural nerve biopsy. Rimmed vacuoles are seen in MDM and NDM, but usually not MIDM. There may be immunostaining for desmin in DBM. Genetic testing is available for several distal myopathies. Available genetic testing for distal myopathies can be obtained by searching the NCBI Genetic Testing Registry. Differential Diagnosis: HMSN (Charcot–Marie–Tooth disease), SMA, FSHD, IBM, nemaline myopathy. Therapy: There is no medical treatment although more severely affected patient may benefit from orthotics. Cardiac complications in DBM and NDM may require use of a pacemaker. Prognosis: Variable  – worse in DBM and MIDM than WDM and MDM.

14.18 Congenital Myopathies Genetic testing +

NCV/EMG ++

Laboratory +

Imaging ++

Biopsy +++

Distribution/Anatomy: Congenital myopathies refer to a heterogeneous group of genetic muscle disorders characterized by early-onset muscle weakness, hypotonia, and devel-

Fig. 14.17 (a) H&E section of an uncharacterized distal myopathy showing a rimmed vacuole (small arrow), degenerating fiber (arrowhead), and minimal inflammation (large arrow). (b) Ubiquitin immunostaining of a rimmed vacuole (arrow)

14.18 Congenital Myopathies

opmental delay. They are further classified into core myopathies, centronuclear myopathies, nemaline myopathies, and congenital fiber-type disproportion based on the characteristic pathologic features found in muscle biopsies. Central core disease (CCD) is generalized or limited to upper or lower limbs. In multi or minicore disease (MCD), nemaline myopathy (NM), and centronuclear myopathy (CNM), all muscle types including the face may be affected. Congenital fiber-type disproportion (CFD) may affect any muscle mass; subjects often have a thin face and body. Time Course: Variable. In CCD, progression is slow. In MCD, spinal rigidity becomes a significant feature restricting head mobility. In NM, the progression of the disease is variable depending on the type. In CNM, the progression is more severe in the infantile form and milder in later onset forms. Childhood- and adult-onset CFD develops insidiously, whereas neonatal disease progresses more rapidly and infants may die from respiratory failure. Age of Onset: In CCD, 20% of patients present between 0 and 5 years, 30% between 6 and 20 years, 30% between 21 and 40 years, and 15% over 40 years. MCD usually presents in the first year of life; however, approximately 10% of cases present in adulthood. CFD and CNM may present at any age. Clinical Syndrome: Consists of the following groups: • Myopathies with protein accumulations. Examples include NM where there are accumulations of Z-line proteins called nemaline rods and variants such as zebra body myopathy. Myosin storage (hyaline body) is associated with accumulations of myosin thick filaments. • Myopathies with cores. The cores are regions devoid of oxidative activity. They are a feature of CCD and MCD. • Myopathies with central nuclei: examples include autosomal and X-linked (myotubular) forms of CNM. • Myopathies with fiber size variation: examples include CFD characterized by selective atrophy of type I fibers. CCD: Presents with slowly progressive muscle weakness. There is generalized weakness in 40% of patients, or the disease may be limited to the upper or lower limbs. Rarely the face is involved, and strength may be normal in 15% of cases. Muscle atrophy and decreased reflexes occur in 50% of subjects. Other associations are kyphoscoliosis or lordosis, foot deformities, congenital hip dislocations, contractures, hypertrophic cardiomyopathy, and arrhythmias. There is also an association between central core disease and ryanodine receptor gene abnormalities associated with malignant hyperthermia. MCD: The infant presents with hypotonia and delayed motor development. Cleft palate or arthrogryposis may be seen. Minimal proximal and distal weakness may be present. The facial muscles are not involved. The deep tendon reflexes are reduced. Despite hypotonia, patients may have a rigid

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spine and kyphoscoliosis that may progress in late childhood. Approximately 20% of patients have ophthalmoplegia. NM: There are several types including congenital forms that vary in severity: severe infantile, intermediate congenital, typical congenital, and juvenile (Fig.  14.18a–c). The infantile form is rapidly fatal. Infants have severe hypotonia, facial diplegia, failure to thrive secondary to inability to suck, respiratory complications, hypotonia, depressed deep tendon reflexes, proximal weakness, bulbar weakness, respiratory impairment, and ophthalmoplegia. Patients are thin due to reduced muscle bulk and facial weakness. In contrast, the adult form may only present with weakness in the seventh decade. Most patients have progressive weakness although occasionally weakness improves over time. CNM: In the infantile form, often referred to as myotubular myopathy, affected subjects may have a large head, with a narrow face, and long digits. Subjects often develop severe hypotonia, weakness of proximal and distal muscles, ophthalmoplegia, and ptosis. They may also develop severe hypotonia, proximal and distal muscle weakness, respiratory insufficiency, ophthalmoplegia, and ptosis. Subjects may become respirator dependent. Older patients with CNM develop weakness of proximal and distal muscles coupled with kyphoscoliosis, pes equinovarus, leg cramps, ophthalmoplegia, facial, and scapular weakness. There appears to be an association between myasthenic syndrome and CNM. CFD: There is prominent facial weakness with ptosis, variable external ophthalmoplegia, and pharyngeal muscle weakness. Patients often have a generalized loss of muscle mass including the tongue. Tendon reflexes are often reduced. Congenital contractures, scoliosis, and foot deformities are present in a minority. Cardiomyopathy is rare. Pathogenesis: This is evolving and complex. There is diverse clinical variability associated with the genes responsible for congenital myopathies and pathogenic proteins may be associated with a wide spectrum of disease ranging from a severe neonatal course with early death to mildly affected adults with late-onset disease. Pathogenesis is related to the affected protein and gene. Some that have been described up to this time are indicated below. CCD and MCD: Several proteins and mutations in genes have been identified: ryanodine receptor 1 (RYR1), selenoprotein N (SEPN1), filamentous α-actin (ACTA1), titin (TTN), β-myosin heavy chain (MYH7). NM: Several proteins and mutations in genes have been identified: filamentous α-actin (ACTA1), alpha tropomyosin(slow) (TPM3), nebulin (NEB), cofilin-2 (CFL2), troponin T1(slow) (TNNT1), β-tropomyosin (TPM2), α-tropomysin(slow) (TPM3), kelch repeat and BTB (POZ) domain containing 13 (KBTBD13), kelch-like family member 40 (KLHL40), kelch-like family member 41 (KLHL41), and leiomodin 3 (LMOD3).

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a

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b

d

c

e

f

g

h

i

Fig. 14.18  Congenital myopathies. Nemaline myopathy (NM): (a) Distal leg atrophy. (b) Atrophy of the proximal arm muscles, neck muscles, and weakness of the facial muscles. (c) Bilateral hand wasting. (d) Collection of red nemaline rods (arrows) on Gömöri trichrome stain. (e) EM-nemaline rod inclusion (arrows). (f) Central core disease (CCD). Red central cores with trichrome and eosin staining (arrowheads). (g)

CFD: Several proteins and mutations in genes have been identified: filamentous α-actin (ACTA1), selenoprotein N (SEPN1), alpha tropomyosin(slow) (TPM3), β-tropomyosin (TPM2), ryanodine receptor 1 (RYR1), β-myosin heavy chain (MYH7). CNM: Several proteins and mutations in genes have been identified: myotubularin MTM1), dynamin 2 (DNM2), bridging integrator 1 (BIN1), ryanodine receptor 1 (RYR1), titin (TTN), myotubularin-related protein 14 (MTMR14), coiledcoil domain-containing protein 78 (CCDC78), and striated muscle preferentially expressed protein kinase (SPEG).

Multicore disease  – multiple cores (arrowheads) using an NADHtetrazolium reductase stain. (h) Centronuclear myopathy (CNM). Adultonset subject with red stained central nuclei (arrowheads) seen in small type I fibers (arrows). (i) Centronuclear myopathy. NADH-tetrazolium reductase showing small type I fibers (arrows) and central nuclei with mitochondria arranged like spokes in a wheel (arrowheads)

Other recognized genetic/pathological types are: • Core-rod myopathy: ryanodine receptor 1: (RYR1), nebulin (NEB), kelch repeat and BTB (POZ) domain containing 13 (KBTBD13), and cofilin-2 (CFL2). • Myosin Storage Myopathy: β-myosin heavy chain (MYH7). • Cap Myopathy: β-tropomyosin (TPM2), α-tropomysin(slow) (TPM3), and filamentous α-actin (ACTA1). • Zebra Body Myopathy: filamentous α-actin (ACTA1). • Distal Myopathy with no Rods: nebulin (NEB).

14.19 Mitochondrial Myopathies

Diagnosis: There are more than 20 genes pathogenetic for congenital myopathies. Each gene can be associated with multiple histopathologic abnormalities in the myofibers, and these may change with time. Furthermore, each distinct pathologic feature can be caused by multiple different genes. As the clinical phenotypes are highly diverse, accurate diagnosis requires a systematic approach that includes the clinical evaluation, EMG, and muscle imaging to help select the appropriate site for muscle biopsy as well as targeted next-­ generation gene sequencing. The serum CK is usually normal or slightly elevated. A fivefold elevation of serum CK would be likely due to a muscular dystrophy or other muscle disorder. NCS are usually normal. EMG may be normal or there may be an increase in insertional activity in affected muscles, along with short-duration motor unit action potentials typical of myopathy. MRI can differentiate between different forms of congenital myopathy by identifying patterns of selective muscle involvement associated with specific genetic abnormalities (See Carlier RY 2019). Composite imaging and heatmaps are improving the specificity of this diagnostic tool. Most congenital myopathies can be diagnosed using light microscopy. Immunohistochemistry is rarely needed. EM is indicated to clarify the light microscopy. Muscle biopsy shows the following features: CCD: There is variation in muscle fiber size and the presence of “cores,” in muscle with reduced or absent oxidative enzyme activity. The cores run along the long axis of the muscles and sometimes the whole length of the muscle fiber. There may be an increase in the RYR 1 protein in the core (Fig. 14.18f, g). MCD: Light microscopy may show normal muscle fiber architecture or slight variation in muscle fiber size. Numerous unstructured cores are observed and there is an abundance of central nuclei. NM: Diagnosis depends on the finding of nemaline rods in the muscle biopsy (Fig. 14.18d, e). CFD: There is a predominance of small myofibers, usually type I, with the remaining hypertrophic fibers being type II, particularly IIb. CNM: (Fig. 14.18h, i). The muscle biopsy shows the presence of central nuclei, central pallor of the fibers on ATPase. Type I fibers are predominant and small in many affected patients. Available genetic testing for congenital myopathies can be obtained by searching the NCBI Genetic Testing Registry. Differential Diagnosis: Muscular dystrophies, myotonic dystrophies, metabolic myopathies, spinal muscular atrophy, and congenital myasthenic syndromes. Therapy: At present, only supportive treatment is available. Management should be by a multidisciplinary team. Children should be monitored for respiratory, swallowing, and speech problems. Some children may require noninva-

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sive ventilation. In patients where there is prominent respiratory involvement (SEPN1) prophylactic pneumococcal and influenza vaccinations are indicated. Cardiac disease is a rare primary presentation of some congenital myopathies (TTN, MYH7, rarely ACTA1). Patients with asymptomatic congenital myopathies should be screened by a cardiologist every 2 years and tested performed as needed. Scoliosis and joint contractures should be checked at each visit. Regular aerobic exercise may be helpful. In RYR1, risks for malignant hyperthermia should be addressed, for example, anesthetics associated with malignant hyperthermia should be avoided. Prognosis: CCD – slow progression of weakness with a good prognosis in most except for the severe neonatal form. Virtually, all affected subjects are at risk of developing malignant hyperthermia and this is increased by certain general anesthetics. Some patients may suffer from cardiac conduction defects. In NM, CNM, and CFD, the prognosis depends on the severity of the initial disorder.

14.19 Mitochondrial Myopathies Genetic testing ++

NCV/EMG +

Laboratory +

Imaging –

Biopsy +++

Distribution/Anatomy: Primary mitochondrial myopathy (PMM) may affect any muscles but usually proximal muscles or facial muscles are affected. Time Course: Slowly progressive in most cases. Age of Onset: May occur at any age ranging from infancy to middle age. Clinical Syndrome: PMM is fairly common in practice but often unrecognized. The majority of patients will present with isolated myopathy that is frequently associated with myalgia and fatigue. The syndromes described below are less common. In rearrangements of mtDNA or point mutations, symptoms are often mild or absent. mtDNA deletions cause more severe symptoms. The most common and mildest variant is chronic progressive external ophthalmoplegia syndrome (CPEO), in which clinical signs and symptoms develop during adulthood, are slowly progressive and are initially limited to the eyelids and eye muscles (Fig 14.19a). This is then followed by oropharyngeal weakness (dysphagia and dysarthria) and proximal weakness (neck flexors, shoulders, and hips). A more severe variant is Kearns–Sayre Syndrome (KSS), which is characterized by significant multisystem involvement starting usually in the second decade, and which includes cardiac conduction defects, diabetes mellitus, cerebellar ataxia, retinitis pigmentosa, and multifocal neurodegeneration. Proximal muscle weakness is almost invariably present. Primary mitochondrial myopathy is often accompanied by multiorgan dysfunction with variable failure to thrive, developmental delay, dementia, encephalomy-

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a

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b

c

Fig. 14.19 (a) Muscle weakness resulting in bilateral ptosis and ocular divergence. (b) Ragged-red fiber (arrow) is present on a Gömöri’s trichrome preparation. (c) EM demonstrates a large collection of morpho-

logically abnormal mitochondria, some of which contain “parking lot” paracrystalline inclusions (arrow)

opathy, stroke-like episodes, seizures, ataxia, optic atrophy, sensorineural hearing loss, cardiomyopathy, diabetes, hepatopathy, nephropathy, and peripheral neuropathy. In children, PMM can present as floppy infant syndrome. Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke-like episodes (MELAS) is characterized by encephalopathy, seizures, headaches, stroke-like episodes (usually before 40  years), dementia, hearing impairment, gastrointestinal symptoms, muscle weakness, exercise intolerance, peripheral neuropathy, and diabetes. In infancy, there may be failure to thrive. Myoclonic epilepsy with ragged-red fibers (MERRF) often starts during infancy with myoclonus followed by generalized epilepsy, progressive ataxia, weakness, and dementia. Other findings may include short stature, optic atrophy, pigmentary retinopathy, hearing loss, lipomatosis, and cardiac involvement (in particular Wolff–Parkinson– White syndrome). Primary coenzyme Q10 (CoQ10) deficiencies include weakness, exercise intolerance, encephalopathy, hypotonia, seizures, dystonia, cerebellar ataxia, epilepsy, stroke-like episodes, spasticity, intellectual disability, peripheral neuropathy, sensory neural hearing loss, hypertrophic cardiomyopathy, retinopathy, and optic atrophy. Isolated mitochondrial complex III deficiency is associated with sporadic myopathy, exercise intolerance, occasional myoglobinuria, and occasional multisystem involvement. Thymidine kinase 2 deficiency (TK2d  Mitochondrial DNA Depletion Syndrome 2) has three main phenotypes depending on the age of presentation of symptoms. The infantile-onset form is characterized by myopathy with respiratory failure. Some patients have encephalopathy, seizures, dysarthria, and dysphagia. The childhood-onset presentation shows proximal limb weakness and respiratory compromise. The late-onset form (after age 12  years) is ­associated with bulbar weakness, limb myopathy, variable respiratory muscle weakness, progressive external ophthalmoplegia, dysphagia, and dysarthria. Pathogenesis: Impaired oxidative phosphorylation and toxic damage to the mitochondrial respiratory chain due to mutations in the mitochondrial and/or nuclear genome. Diagnosis: CK values may be mildly elevated, and there may be elevation in serum lactic acid levels. In most cases,

the EMG is normal or shows mildly “myopathic” motor unit action potentials. In general, most muscle fibers show evidence of typical ragged-red fibers on trichrome or more specific succinate dehydrogenase (SDH) staining (Fig. 14.19b, c). Genetic testing in serum or muscle is extremely helpful in differentiating the specific mitochondrial disorder. Differential Diagnosis: Other metabolic myopathies, congenital myopathies, muscular dystrophies, myasthenic syndromes. Therapy: There are no specific pharmacological treatments. Mitochondrial enzyme supplements including coenzyme Q, creatine, carnitine, vitamin B2, arginine, and alpha lipoic acid may be used. Aerobic and, perhaps, strength training improve function and muscle metabolism in some patients. It is critical that cardiac function is carefully monitored, in particular in KSS. In the MOTOR trial, Omaveloxolone 160 mg was well tolerated, but did not lead to change in the peak cycling exercise workload (primary endpoint) or the in 6-minute walk test distance (secondary endpoint) but lowered heart rate and lactate production during submaximal exercise, consistent with improved mitochondrial function and submaximal exercise tolerance. In a non-controlled study, deoxypyrimidine monophosphate bypass therapy demonstrated safety and improved survival in early-onset TK2d patients. Nicotinamide riboside is effective in animal studies but data from human studies is pending. Prognosis: Usually good but depends on the specific mitochondrial disorder as described above.

14.20 Glycogen Storage Diseases (GSDs) Genetic testing +++

NCV/EMG ++

Laboratory +

Imaging +

Biopsy +++

Distribution: Usually affects the limbs but may also affect respiratory and cardiac muscles and the central nervous system. Time Course: Variable depending upon the subtype. Glycogen storage diseases can be mildly progressive and episodic or more dramatic in progression.

14.20 Glycogen Storage Diseases (GSDs)

Age of Onset: Variable depending upon the subtype. Glycogen storage diseases can begin in infancy, early childhood, adolescence, or, less commonly, adulthood. Clinical Syndrome: GSD is a group of disorders in which patients present generally with either exercise intolerance or progressive weakness. Forms in which exercise intolerance occurs include GSDV, VII, and VIII–XIII. GSDV (McArdle disease). GSDX occurs almost exclusively in blacks, and heterozygotes may also have exercise intolerance. Forms of GSD associated with progressive weakness include GSDI–IV. GSDI (von Gierke disease) is characterized by growth retardation, hypoglycemia, hepatomegaly, kidney enlargement, hyperlipidemia, hyperuricemia, and lactic acidemia. Deficiencies in glucose-6-phosphatase (G6Pase) and glucose-6-phosphate transporter (G6PT) cause GSDIa and GSDIb. GSDIb patients also suffer from chronic neutropenia and functional deficiencies of neutrophils and monocytes, resulting in recurrent bacterial infections as well as ulceration of the oral and intestinal mucosa. GSDII (acid maltase deficiency) consists of three subtypes: • Infantile onset with cardiomegaly and heart failure, liver disease, weakness, and hypotonia. • Childhood onset with proximal symmetrical weakness with enlarged muscles due to glycogen accumulation, with respiratory failure. • Adult onset with fatigue early in the disease, followed by proximal weakness, and eventually respiratory failure. Respiratory failure may be the presenting feature in 30% of patients. GSDIII (debrancher deficiency) is more common in men than women (~3:1) and has three subtypes: • An infantile form associated with deposition in muscle and liver, with hypoglycemia, recurrent seizures, severe cardiomegaly, and hepatomegaly. • A childhood form associated with hypoglycemia, seizures, growth retardation, weakness, liver dysfunction, and hepatomegaly. • An adult form develops in the third to sixth decade and is slowly progressive. It is associated with muscle weakness and wasting, fatigue and myalgia, exercise intolerance, respiratory failure, milder cardiomyopathy, hepatic dysfunction, and sometimes an axonal neuropathy. GSDIV (brancher deficiency), prevalent especially in Ashkenazi Jews, is associated with myopathy, cardiomyopathy, and liver disease. In addition, the brain and spinal cord can be affected, resulting in progressive involvement of the upper and lower motor neurons, sensory loss, sphincter problems, and dementia, often mimicking motor neuron disease. Other rarer forms of GSD are described in the references.

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Pathogenesis: GSDs are a group of predominantly autosomal recessive disorders with the exception of phosphorylase b kinase deficiency (GSDIX) and phosphoglycerate kinase 1 deficiency, which are X-linked recessive disorders. GSDI is caused by deficiencies in the activity of the G6Pase system consisting of two membrane proteins that work in concert to maintain glucose homeostasis, G6PT (11q23) and G6Pase (17q21). Deficiencies in G6Pase and G6PT cause GSDIa and GSDIb, respectively. GSDII is an autosomal recessive disorder due to deficiency of l acid a-1,4-­ glucosidase. GSDIII results from nonsense, small deletions or insertions, or splice site changes on chromosome 1p21. In GSDV, there is a deficiency of muscle phosphorylase A, resulting in impaired ATP generation from aerobic and anaerobic glycolysis. GSDVII is due to a deficiency of 6-phosphofructokinase. Other listed enzyme deficiencies and gene mutations resulting in defects of glycogen storage include the following: GSDXII, aldolase A, 16q22; GSDXIII, b enolase, 17pter; GSDXI, lactate dehydrogenase, 11p15; GSDIX, phosphoglycerate kinase, Xq13; GSDX, phosphoglycerate mutase, 7p12; and GSDVIII, phosphorylase b kinase, Xq12. Diagnosis: CK is often normal between episodes of exercise intolerance or elevated for those forms of GSD causing progressive weakness. In GSDII and III, EKG abnormalities can often be seen. The ischemic forearm test shows an insufficient rise in venous lactate, but is nonspecific for the GSD, relies on patient compliance, and may have complications such as myoglobinuria. GSDVII is associated with a compensated hemolytic anemia. Electrophysiologic testing is sometimes helpful. NCS are usually normal; however, in GSDIII there is often evidence of an axonal neuropathy. On needle EMG, during contractures, the muscle is electrically silent in GSD. There is an increase in insertional activity in distal muscles, along with short-duration motor unit action potentials typical of myopathy. Myotonic discharges may be observed, and in GSD II there may be a mixture of myotonic and complex repetitive discharges observed especially in paraspinal muscles. In adults with GSD II, recent studies suggest that muscle MRI may demonstrate early involvement of the adductor magnus and semimembranosus muscles with later involvement of the long head of the biceps femoris, semitendinosus, and anterior thigh muscles and selective sparing of the sartorius, rectus, parts of the vastus lateralis, and gracilis muscles even in advanced stages. On muscle biopsy, GSDI and II are characterized by prominent PAS-positive lysosomal vacuoles with enlargement of muscle fibers (Fig. 14.20). There is little muscle fiber degeneration. Electron microscopy shows glycogen in cytoplasm with membrane-bound, autophagic vacuoles. In GSDIII, GSDV, and GSDVII, there can be subsarcolemmal and intermyofibrillar vacuoles though often muscle architecture is normal in GSD V and VII. In GSDV and VII, routine immunohistochemistry reveals decreased or

304

a

14  Muscle and Myotonic Diseases

b

c

Fig. 14.20 (a) Subsarcolemmal vacuoles (arrows) that are PAS positive in GSDII. (b) Arrows indicating muscle glycogen in GSDV. (c) High-magnification H&E. There are numerous subsarcolemmal vacu-

oles (large arrows) in addition to fiber size variation, a few central nuclei (small arrow), and regenerating fibers (arrowhead)

absent staining of muscle fibers for myophosphorylase A and phosphofructokinase, respectively, though partial reductions of phosphofructokinase to 20% of normal may be artifactual due to the lability of the enzyme in incorrectly handled fresh frozen muscle. Enzyme analysis from muscle (and dried blood spot analysis for acid maltase levels for GSDII) is often the key to making a diagnosis of any GSD, showing substantial deficiencies of specific enzymes. Genetic testing is commercially available for GSDI–VII, X, and XI and can help confirm the diagnosis of GSD. Differential Diagnosis: Carnitine palmitoyltransferase II deficiency, limb-girdle muscular dystrophy, congenital myopathy, polymyositis, mitochondrial myopathy. Therapy: Prevention is the mainstay of therapy. GSD patients in general must not perform strenuous exercise to prevent rhabdomyolysis. Patients should avoid precipitating a muscle energy crisis with heavy sustained activity while promoting moderate intermittent exercise. In GSDVII, patients should avoid high-carbohydrate meals that exacerbate the “out-of-wind” phenomenon as well as eat frequent small meals. Sucrose loading in GSDV patients prior to exercise may improve aerobic exercise based on a recent study. These patients also benefit from carbohydrate-rich diets. GSD myopathy patients consume at least 1.2 g protein/kg/ day to maintain muscle mass. There may also be a role for pyridoxine supplementation. ERT is now available for the infantile and late-onset forms of GDSII, having been shown to significantly modify the course of the disease. ERT initiation is recommended in symptomatic late-onset Pompe disease patients for a period of 1–2  years until there is stabilization or improvement of the disease. Use of ERT in pre-symptomatic and severely affected patients is controversial. Adverse effects are mainly related to immune-mediated infusion reactions. Prognosis: In GSDII (infantile form), death occurs before 1  year of age, and in the childhood form, before 25  years. ERT has significantly altered the prognosis of GSDII.  In infantile GSDIII, death occurs before 4 years though patients with the childhood and adult forms survive longer.

GSDV has a normal life expectancy. In other forms of GSD, life expectancy may be normal unless severe myoglobinuria and muscle necrosis occur.

14.21 D  efects of Fatty Acid Oxidation and the Carnitine Shuttle System (DFAOCSS) Genetic testing ++

NCV/EMG +

Laboratory +++

Imaging −

Biopsy +

Carnitine shuttle defects include: carnitine palmitoyl transferase 2 deficiency (CPT2), primary systemic carnitine deficiency: carnitine transporter defect (PCD), carnitine acylcarnitine translocase deficiency (CATD). Disorders of fatty acid oxidation (FAO) include: very-long-chain acyl-­ CoA dehydrogenase deficiency (VLACD), long-chain acyl-­ CoA dehydrogenase (LACD), trifunctional protein (TFP), multiple acyl-CoA dehydrogenation deficiency (MAD), and medium-chain acyl-CoA dehydrogenase (MCAD) are discussed in this section. Distribution: In most cases of CPT2, there is no weakness. Proximal weakness is seen in PCD, VLCAD, and MAD. Time Course: CPT2 may have an acute onset, whereas other forms of PCD and VLCAD produce more chronic myopathic symptoms. Age of Onset: Depends on the specific disease. Most cases of CPT2 start between 6 and 20 years, PCD before 7 years of age, and VLCAD can occur in infants or adults. Clinical Syndrome: The phenotype is heterogeneous. Constant or progressive muscle weakness with or without metabolic crisis is often seen in lipid storage myopathy (LSM) patients. In contrast, recurrent provoked rhabdomyolysis usually occurs in patients with disorders affecting intramitochondrial fatty acid transport and β-oxidation, such as deficiencies of CPT2 and VLCAD.  In infantile-onset patients, the clinical manifestations are similar between lipid

14.21 Defects of Fatty Acid Oxidation and the Carnitine Shuttle System (DFAOCSS)

disorders and include hypotonia, encephalopathy, hepatomegaly, and cardiomyopathy. In CPT2, there are at least three different phenotypes: a myopathic form with juvenile–adult onset; an infantile form with hepatic, muscular, and cardiac involvement; and a lethal neonatal form with developmental abnormalities. Adult patients develop pain, stiffness, and tightness of the muscles although they do not get muscular cramps or second-wind phenomena. CPT2 is frequently associated with myoglobinuria that develops after prolonged fasting, low-carbohydrate high-fat diets, exercise, infection, cold exposure, and general anesthesia. In most patients, strength is normal. CPT2 deficiency is more common in males (6:1) with females having milder disease. In CPT2, here is a good correlation between genotype, metabolic dysfunction, and phenotype. VLCAD is clinically similar to CPT2 deficiency. PCD may be asymptomatic or may be more severe. In children, PCD is associated with cardiomyopathy and myopathy and, in infants, with recurrent acute episodes of hypoglycemic encephalopathy with hypoketonemia. MAD has a heterogeneous presentation with (1) neonatal onset forms having hypotonia, hepatomegaly, nonketotic hypoglycemia, metabolic acidosis, and early death, and (2) milder and/or later onset forms with proximal myopathy, hepatomegaly, and episodic metabolic crisis that can be lethal. Both forms may have cardiomyopathy. The clinical presentation, inheritance, and acylcarnitine profile of disorders of fatty acid oxidation and the carnitine shuttle system are presented in Table 14.3. Pathogenesis: Fatty acid oxidation in the mitochondrial matrix is a major source of energy in muscle, and defects in this system usually lead to acute rhabdomyolysis in provoking conditions such as infection, fasting, and prolonged exercise. Patients with an FAO disorder are expected to have an increased glucose demand because they have a diminished capacity to generate ATP from fatty acids and ketones. CPT2 is associated with a mutation of p.S113L in more than 50% of mild late-onset patients. There are at least 20 CPT2 gene mutations. PCD is usually associated with nonsense mutations of the genes encoding OCTN2, a high-affinity sodium-­ dependent carnitine transporter and SLC22A5, an organic cation transporter. Secondary carnitine deficiency may be due to mitochondrial disorders, renal failure, muscular dystrophy, chronic myopathy, and liver failure. VLCAD catalyzes the long-chain fatty acyl-CoA that has been incorporated into the mitochondrial CPT2. Therefore, the clinical features of VLCAD deficiency are very similar to CPT2 deficiency. VLCAD is due to a defect of the ACADVL gene and is associated with at least 60 mutations. MAD is caused by the defects in electron transfer flavoprotein (ETF) and many are associated with mutations in the electron transfer flavoprotein-­dehydrogenase (ETFDH) gene.

305

Table 14.3  Defects of fatty acid oxidation and the carnitine shuttle system Metabolic disorder Clinical features Carnitine shuttle defects PCD Hypotonia, muscle weakness (MW), fatigue, cardiomyopathy (CM) CPT2 MW, rhabdomyolysis (RM), CM, hepatomegaly, hypoglycemia CATD Muscle damage, CM, arrhythmias, hepatomegaly, hypoglycemia FAO pathway defects VLCAD MW, CM,RM, deficiency hypoketotic hypoglycemia (HH), hepatic syndrome (HS) LCAD MW sudden death, RM, deficiency HS, HH, cardiomyopathy, retinopathy TFP Sudden death, HS, HH, deficiency CM, RM, peripheral neuropathy MAD MW, CM, HH, RM, deficiency respiratory dysfunction, encephalopathy, acidosis MCAD MW, exercise deficiency intolerance, RM

Acylcarnitine Inheritance profile AR

↓ C0, C2

AR

↑ C16, C18, C18:1

AR

↑ C16, C18, C18:1

AR

↑ C14:1, C14:2, C14, C12:1

AR

↑ OH-C16, OH-C18:1, OH-C18:2

AR

↑ OH-C16, OH-C18:1, OH-C18:2 Complex ↑ in variable chain lengths

AR

AR

↑ C6, C8, C10, C12

MW muscle weakness, CM cardiomyopathy, RM rhabdomyolysis, HH hypoketotic hypoglycemia, HS hepatic syndrome, FAO fatty acid oxidation

Diagnosis: Introduction of tandem mass spectrometry is the first test of choice, and it is also the method by which neonatal screening for these disorders is performed (the acylcarnitine profile is described in Table 14.3). It is assumed that an abnormal acylcarnitine profile reflects the intramitochondrial accumulation of acyl-CoAs and as such the substrate of the deficient enzyme in vivo. Rapid confirmation of a particular suspected enzyme deficiency can be performed in lymphocytes. If an enzyme is deficient, subsequent genomic analysis of the encoding gene should be done to identify the underlying molecular defect. Cultured fibroblasts can also be used for diagnostics via enzyme analysis and via acylcarnitine profiling after fatty acid loading. In CPT2, VADC, and MAD, the CK is normal between episodes of myoglobinuria. In CPT2 and VADC, carnitine is usually normal but decreased in MAD. During episodes of rhabdomyolysis, CK is high in all the disorders of free fatty acid metabolism. Diagnosis of CPT2 and VLCAD relies on showing an elevation of

306

long-chain acylcarnitines. In PCD, free carnitine and all acylcarnitine species are usually severely reduced. However, as the plasma carnitine level can occasionally be normal in PCD, carnitine transport studies in fibroblasts may also be used to confirm the diagnosis. Secondary carnitine deficiency shows decreased free carnitine levels but elevated specific species of acylcarnitine should be excluded. MAD shows increased urinary organic acid profiles, plasma carnitine, and acylcarnitines and reduced respiratory chain enzymes. Mutation analysis of ETF enzymes may be diagnostic for MAD. In all disorders of fatty acid metabolism, EMG is often normal or shows minimal evidence of myopathy between episodes of myoglobinuria. Available genetic testing can be obtained by searching the NCBI Genetic Testing Registry. Muscle pathology is often not diagnostically helpful. In CPT2, the muscle biopsy is normal with the exception of a decrease in CPT activity. In VLCAD, the muscle biopsy is normal with no increase in lipid droplets, but immunohistochemistry may show decreased VLCAD.  There are increased lipid droplets in muscle fibers often close to enlarged mitochondrial in PCD, MAD, and neutral lipid storage disease with icthyosis (NLSDI) or with myopathy (NLSDM). Differential Diagnosis: Other disorders of fatty acid metabolism, glycogen storage diseases, other metabolic myopathies, mitochondrial myopathies. Therapy: The treatment for CPT2 deficiency consists of a high-carbohydrate low-fat diet with frequent and regularly scheduled meals. A long-chain fat-restricted diet with medium-chain triglyceride supplementation is recommended. Bezafibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist can increase intracellular carnitine and may be a potential treatment. Bezafibrate restores normal fatty acid oxidation in muscle in mild CPT2 deficiency and may improve physical activity. However, its use is unproven in clinical trials. PCD responds to carnitine supplementation (100–400 mg/ kg per day) and may improve cardiomyopathy and other organ damage. Patients with VLCAD are treated with a high-­ carbohydrate, low-fat diet, with or without supplementation with medium-chain triglyceride oil (less effective than with CPT2), riboflavin, or l-carnitine. In MAD, riboflavin supplementation (100–400  mg/day) markedly improves clinical symptoms, particularly with ETFDH mutations and in the later onset form. Carnitine and CoQ10 supplementation may be useful where there is secondary carnitine or CoQ10 deficiency, respectively. Prognosis: In later onset CPT2 and treated PCD, prognosis is usually good. In VLCAD and MAD, prognosis depends on the disorder type.

14  Muscle and Myotonic Diseases

14.22 Myotonia Congenita Genetic testing +++

NCV/EMG +++

Laboratory +

Imaging −

Biopsy +

Distribution/Anatomy: Can affect the limbs as well as the face. Time Course: Mild progression with gradual onset. Some patient may develop fixed weakness later in life. Age of Onset: Usually begins in infancy or early childhood, but onset may be as late as the third or fourth decade of life. Clinical Syndrome: Myotonia congenita is a hereditary neuromuscular disorder typified by difficulty with muscle relaxation, often affecting both limb and facial muscles. The condition can be inherited either in autosomal dominant or recessive fashion. The autosomal dominant form of myotonia congenita, also known as Thomsen’s disease, presents with myotonia beginning in infancy that is usually mild, though approximately 50% of patients may have percussion myotonia. The myotonia (Fig. 14.21a, b) is associated with fluctuations and may worsen with cold, hunger, fatigue, and emotional upset. Muscle hypertrophy is seen in many patients (Fig.  14.21c, d). Patients may report a “warm-up” phenomenon, in which the myotonia decreases after repeated muscle contractions. Muscle strength is usually normal. In the autosomal recessive form, also known as Becker’s disease, the condition presents later in life, usually in early childhood, and patients may also have a “warm-up” phenomenon. The disease is more severe than Thomsen’s, and although strength is usually normal in childhood, there is often mild distal weakness in older individuals. In addition, individuals with Becker’s disease may have transient attacks of weakness brought on by movement after rest. Pathogenesis: Both Thomsen’s and Becker’s disease is due to a defect of the skeletal muscle chloride channel (CLCN1) gene localized on chromosome 7q35 and are usually due to missense mutations. Impaired chloride conductance causes cation conductance after depolarization and spontaneous triggering of action potentials, leading to prolonged muscle contraction. Diagnosis: The CK is typically normal though occasionally it can be mildly elevated. Electrophysiologic testing is of great value in assisting in the diagnosis. Short exercise testing (repeated single supramaximal stimulation of a motor nerve, typically ulnar, over a minute after 10 s of exercise) can demonstrate a decrement that repairs with repeated tests. Cooling does not affect the nerve response. On needle EMG, myotonic discharges are abundant, especially in distal muscles. In Becker’s disease, there may be a “warm-up” effect with fewer myotonic discharges after maximal contraction.

14.23 Paramyotonia Congenita

307

a

c

d

b

Fig. 14.21 (a) Myotonia congenita with muscle myotonia in the hypothenar muscle. (b) Myotonic discharges on EMG. (c) Increased muscle bulk in the arms and chest in a patient with Thomsen’s disease. (d) Hypertrophy of the extensor digitorum brevis muscle

Muscle biopsy is often unremarkable or demonstrates nonspecific changes. In more severe cases, there may be increased fiber diameter variation, internalization of nuclei, and vacuolation. Genetic testing for mutations of the CLCN1 gene is commercially available. Differential Diagnosis: Paramyotonia congenita, myotonic dystrophy, hyperkalemic periodic paralysis. Therapy: Medications that primarily block skeletal muscle sodium channels may potentially help stabilize the muscle membrane and control myotonia. Some of these medications include the following: mexiletine (150– 1000 mg/day), quinine (200–1200 mg/day), phenytoin (300– 400 mg/day), procainamide (125–1000 mg/day), tocainide, carbamazepine, ranolazine and acetazolamide (125– 1000  mg/day). Procainamide and tocainamide are rarely used because of concerns with bone marrow suppression. Patients should avoid certain medications that can aggravate

myotonia: depolarizing muscle relaxants, adrenaline, beta-­ adrenergic agonists, propranolol, and colchicine. Prognosis: Overall, most patients with myotonia congenita have a good prognosis. However, in some patients, the myotonia can be severely disabling when untreated. The prognosis for Thomsen’s disease is especially benign, with mild progression over many years. Patients with Becker’s myotonic dystrophy may develop significant persistent weakness later in life.

14.23 Paramyotonia Congenita Genetic testing +++

NCV/EMG +++

Laboratory +

Imaging −

Biopsy +

Distribution: Can affect the proximal and distal limbs as well as the face and neck.

308

Time Course: Mild progression with gradual onset. Some patients may develop fixed weakness later in life. Age of Onset: Usually begins in late adolescence can begin earlier, even in infancy. Clinical Syndrome: Paramyotonia congenita is a hereditary neuromuscular disorder typified by difficulty with muscle relaxation and transient weakness. Many patients with myotonia exhibit minimal to no symptoms at all. In more severely affected subjects, myotonia may affect both proximal and distal muscles. The disorder may present at any age, most commonly in late adolescence. Weakness can occur, usually beginning in late adolescence, although myotonia may present earlier, often in infancy. Myotonia is often worse in the cold and with exercise and may affect the face, neck, and upper extremities (Fig. 14.22). Episodic weakness may occur after exercise or cold exposure or may occur spontaneously. The weakness usually lasts for a few minutes but may extend to several days. Older patients with paramyotonia congenita may develop permanent muscle weakness. Myotonia is usually paradoxical in that it worsens with exercise, in comparison to myotonia congenita. Pathogenesis: Paramyotonia congenita is an autosomal dominant disorder associated with a gain-of-function mutation of the skeletal muscle sodium channel (SCN4A) gene on chromosome 17q23. At least 11 missense mutations have been described. Disruption of fast inactivation of sodium channels in this disorder is thought to lead to leakage of sodium ions into the muscle fibers, causing more persistent depolarization and producing myotonia. Diagnosis: The CK is typically normal though occasionally it can be mildly elevated. Electrophysiologic testing is of great value in assisting in the diagnosis. Short exercise testing (repeated single supramaximal stimulation of a motor nerve, typically ulnar, over a minute after 10 s of exercise) can demonstrate a decrement that becomes greater with repeated tests and even more so with cooling. Long exercise testing (repeated single supramaximal stimulation over 45 min after 5 min of exercise) also shows an early decrement in the response that can persist throughout the testing. On needle EMG, myotonic discharges are abundant, especially in distal muscles. With cooling, the myotonic dis-

Fig. 14.22  Myotonia of the hand in a patient with cold-induced myotonia (Von Eulenburg’s disease). The patient is trying to open his hand

14  Muscle and Myotonic Diseases

charges may initially worsen, but with prolonged cooling there is usually muscle paralysis, and the discharges disappear. Muscle biopsy is often unremarkable or demonstrates nonspecific changes. In some areas, there may be subsarcolemmal vacuoles. Genetic testing for mutations of the SCN4A gene is commercially available and can help confirm the diagnosis. Differential Diagnosis: Myotonia congenital, myotonic dystrophy, hyperkalemic periodic paralysis. Therapy: Medications that primarily block skeletal muscle sodium channels may potentially help stabilize the muscle membrane and control myotonia. Some of these medications include the following: mexiletine (150– 1000 mg/day), quinine (200–1200 mg/day), phenytoin (300– 400 mg/day), procainamide (125–1000 mg/day), tocainide, carbamazepine, lamotrigine, ranolazine, and acetazolamide (125–1000  mg/day). Procainamide and tocainamide are rarely used because of concerns with bone marrow suppression. Patients should try to avoid sudden exposure to very cold weather and avoid sudden heavy physical activity. In addition, potassium-rich food may trigger myotonia and patients may need to regulate their potassium intake. Some patients may benefit from acetazolamide or thiazide diuretics. Prognosis: Overall, most patients with par amyotonia congenita have a good prognosis with few limitations. However, in some patients, the myotonia can be severely disabling when untreated. Some patients may also develop significant persistent weakness later in life.

14.24 H  yperkalemic Periodic Paralysis (HyperPP) Genetic testing +++

NCV/EMG +++

Laboratory +

Imaging −

Biopsy +

Distribution: Proximal muscles symmetrically. Time Course: Flaccid, episodic weakness. Age of Onset: Usually in the first decade and progresses slowly over several decades. Clinical Syndrome: There is episodic skeletal muscle weakness that lasts up to 2 h that can involve varying patterns of monomelic weakness, hemiparesis, or quadriparesis that generally spares bulbar muscles. Reflexes can be reduced. The episodes occur most commonly in the morning due to the fasted state and can also be triggered by potassium-­ rich food, exposure to cold, emotional stress, rest after exercise, and alcohol. Patients have attacks of varying intervals that can vary between daily and months apart. In between attacks, most patients return to normal strength. Half of patients report inter-attack myotonia or muscle stiffness. Although the disease is episodic, up to 80% of patients over 60 years old will have some degree of permanent weakness

14.25 Hypokalemic Periodic Paralysis (HypoPP)

and up to one-tird of patients will develop a chronic progressive myopathy later in life. Compared to its sister disease hypokalemic periodic paralysis, the attacks of weakness are more frequent and shorter. Pathogenesis: In all forms of periodic paralysis, there is episodic abnormal depolarization of the muscle sarcolemma that ultimately leads to voltage-gated sodium channel inactivation and reduced muscle fiber excitability. In HyperPP, there is a mutation in the SCNA4A sodium channel resulting in a gain-of-function that leads to impaired inactivation and produces an aberrant sodium ion current that leads to depolarization-­induced muscle paralysis. The mutation is inherited in an autosomal dominant fashion. Sporadic mutations have been reported, but the incidence is unknown. Diagnosis: Genetic testing for SCN4A mutations (T704M and M1592V) is the diagnostic test of choice. During an attack, serum potassium may be mildly elevated. Although the namesake is “hyperkalemic” periodic paralysis, patients often have borderline normokalemia. Most patients will have a potassium level  >  4.5  mEq/L during the attack. A prolonged exercise nerve conduction test can be both specific and sensitive for diagnosis. In this test, a baseline CMAP at rest is established. Next, the patient performs isometric exercise the tested muscle for 5 min. Afterwards, the patient is asked to relax completely and a CMAP is recorded every 1–2  min for 40–60  min. In patients with hyperkalemic or hypokalemic periodic paralysis, there should be a 40% decrement in CMAP amplitude. Needle EMG may show signs of muscle membrane irritability, namely positive sharp waves and myotonia especially during an attack. The motor unit potentials are normal early in the disease. Late in the disease, volitional units may show a myopathic pattern. Differential Diagnosis: Paramyotonia congenital, hypokalemic periodic paralysis, acetazolamide-responsive myotonia congenital, thyrotoxic periodic paralysis, Andersen–Tawil syndrome. Treatment: In hyperkalemic periodic paralysis, many of the attacks are short lived and do not require acute treatment. During an acute attack, carbohydrate ingestion and mild exercise (walking) may improve the weakness. Beta-2-­ agonist inhalation therapy (e.g., salbutamol) may also shorten attacks. Use of anhydrase inhibitors may help prevent attacks. The most commonly used agents are acetazolamide and dichlorphenamide. Only dichlorphenamide has been studied in randomized control trials which demonstrated reductions in both severity and frequency of attacks. Lifestyle modifications can help in attack prevention. Exercise should be preceded by warm-up and followed by gradual cooling down. Consulting a professional dietician can be helpful to assist patients in avoiding excessive consumption of potassium, avoiding fasting, and eating regular meals. Use of acetazolamide or thiazide diuretics may help

309

prevent further attacks. Unpublished reports suggest a good response to dichlorphenamide in single cases. Prognosis: Most patients have a good prognosis with return to normal function in between attacks. With age, however, permanent weakness becomes more common and a small subset of patients will develop a progressive myopathy.

14.25 H  ypokalemic Periodic Paralysis (HypoPP) Genetic testing +++

NCV/EMG +

Laboratory ++

Imaging −

Biopsy +

Distribution: Symmetric, legs greater than arms. Time Course: Acute episodes of flaccid weakness, approximately 25% experience degenerative myopathy of limbs over years. Age of Onset: Teenage years. Clinical Syndrome: In contrast to hyperkalemic periodic paralysis, the hypokalemic variant is associated with less frequent attacks that are longer and more severe. Similarly, limb muscles are involved with sparing of the bulbar muscles. Reflexes can be reduced during attacks. Episodes are typically triggered by carbohydrate-rich meals, high salt meals, alcohol, and rest after exercise. The first attack occurs most commonly between age 15 and 35 years. Attack frequency can be daily to monthly. Unlike the hyperkalemic variant, myotonia is not present except sometimes in the eyelids. Pathogenesis: Two genetic mutations can lead to the phenotype: CACNA1S (type 1, 70–80% of cases) and SCN4A (type 2, 10–20% of cases). The reason why two completely different ion channel mutations produce the same phenotype is due to both mutations leading to an anomalous leakage of current that produces susceptibility to paradoxical muscle depolarization in the setting of low extracellular potassium. The inheritance pattern is autosomal dominant. Sporadic mutations have been reported but the incidence is unknown. Diagnosis: Genetic testing for mutations in SCN4A on 17q23.3 and CACNA1S on 1q32.1 is the diagnostic test of choice. During an attack, serum potassium is usually 40% decrement (see section on hyperkalemic periodic paralysis). Needle EMG should not show myotonia and is generally normal except late in the disease when a myopathic motor unit pattern can develop. Thyrotoxic periodic paralysis can closely resemble hypoPP with long-duration attacks of weakness with low serum potassium, and a detailed thyroid function panel should be sent in all patients. Differential Diagnosis: Thyrotoxic periodic paralysis, HyperPP (comparison in Table  14.4), Andersen–Tawil syndrome.

310

14  Muscle and Myotonic Diseases

Table 14.4  Comparison of hyper- and hypokalemic periodic paralysis (APs action potentials) Features Precipitating factors

HyperPP Potassium, cooling, rest after strenuous exercise, fasting, stress Attack severity Mild to severe Duration of 1–4 h attack NCS During an attack, short exercise results in transient increase in CMAP. In between attacks, there is decrement on long exercise testing. EMG Myotonic discharges Mix of autonomous APs Consequence and Na channel of depolarization inactivation Mutation SCN4A 50–70% Therapy

HypoPP Rest after exercise, high-carbohydrate meal, glucose Severe Hours to days During an attack, short exercise results in transient increase in CMAP. In between attacks, there is decrement on long exercise testing. Na channel inactivation prevents APs

CACNA1S 75%, SCN4A 10–15% Potassium, Mild exercise, carbohydrates; thiazides, acetazolamide acetazolamide

References Duchenne Muscular Dystrophy Grages SM, Bell M, Berlau DJ (2020) New and emerging pharmacotherapy for duchenne muscular dystrophy: a focus on synthetic therapeutics. Expert Opin Pharmacother 21(7):841–851 Hart DA, McDonald CM (1998) Spinal deformity in progressive neuromuscular disease. Phys Med Rehab Clin N America 9:213–232

Myotonic Dystrophy (DM) Ashizawa T, Gagnon C, Groh WJ et  al (2018) Consensus-based care recommendations for adults with myotonic dystrophy type 1. Neurol Clin Pract 8(6):507–520

Limb-Girdle Muscular Dystrophy (LGMD) Straub V, Murphy A, Udd B, LGMD Workshop Study Group (2018) 229th ENMC international workshop: limb girdle muscular dystrophies—nomenclature and reformed classification Naarden, the Netherlands, 17–19 March 2017. Neuromuscul Disord 28(8):702–710

Emery-Dreifuss Muscular Dystrophy (EDMD) Therapy: Potassium supplementation is the treatment of choice in acute attacks. Oral potassium is often sufficient unless the patient is unable to take medication by mouth. Excessive correction of potassium should be avoided. Whereas there is an abnormally low extracellular potassium concentration, the total body potassium is normal. Overaggressive potassium supplementation may lead to toxic levels of total body potassium and result in cardiac emergencies. Medications administered in glucose solutions should be avoided as it can worsen weakness. For maintenance therapy, daily oral potassium supplementation of 40–80 mEQ two to three times a day can often decrease the severity and frequency of attacks. Potassiumsparing diuretics such as spironolactone may also provide benefit. Paradoxically, carbonic anhydrase inhibitors such as acetazolamide and dichlorphenamide may benefit some patients with hypoPP.  Patients with hypoPP due to the SCN4A mutation, however, may be less responsive to carbonic anhydrase inhibitor therapy and may even be worsened by it. Similar to hyperPP, lifestyle modification and trigger avoidance are important treatments. Exercise should be preceded by warm-­up and followed by gradual cooling down. High-carbohydrate meals and alcohol should be avoided. Prognosis: Similar to hyperPP, the prognosis is usually good with return to normal function between attacks. A small portion of patients will develop a progressive myopathy late in the disease.

Heller SA, Shih R, Kalra R, Kang PB (2020) Emery-Dreifuss muscular dystrophy. Muscle Nerve 61(4):436–448

Distal Myopathies Milone M, Liewluck T (2019) The unfolding spectrum of inherited distal myopathies. Muscle Nerve 59(3):283–294

Further Readings Polymyositis (PM) and Dermatomyositis Clark K, Isenberg DA (2018) A review of inflammatory idiopathic myopathy focusing on polymyositis. Eur J Neurol 25(1):13–23 Dobloug C, Garen T, Bitter H et  al (2015) Prevalence and clinical characteristics of adult polymyositis and dermatomyositis; data from a large and unselected Norwegian cohort. Ann Rheum Dis 74(8):1551–1556 Li S, Ge Y, Yang H et  al (2019) The spectrum and clinical significance of myositis-specific autoantibodies in Chinese patients with idiopathic inflammatory myopathies. Clin Rheumatol 38(8):2171–2179 Lundberg IE, Tjärnlund A, Bottai M et  al (2017) 2017 European league against rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups. Ann Rheum Dis 76(12):1955–1964 Mandel DE, Malemud CJ, Askari AD (2017) Idiopathic inflammatory myopathies: a review of the classification and impact of pathogenesis. Int J Mol Sci 18(5):1084

References

Inclusion Body Myositis (IBM) Greenberg SA (2019) Inclusion body myositis: clinical features and pathogenesis. Nat Rev Rheumatol 15(5):257–272 Needham M, Mastaglia FL (2016) Sporadic inclusion body myositis: a review of recent clinical advances and current approaches to diagnosis and treatment. Clin Neurophysiol 127(3):1764–1773

Immune-Mediated Necrotizing Myopathy (IMNM) Allenbach Y, Mammen AL, Benveniste O, et  al (2018) 224th ENMC international workshop: Clinico-sero-pathological classification of immune-mediated necrotizing myopathies Zandvoort, the Netherlands, 14–16 October 2016. Neuromuscul Disord 28(1):87–99 Lim J, Rietveld A, De Bleecker JL et al (2019) Seronegative patients form a distinctive subgroup of immune-mediated necrotizing myopathy. Neurol Neuroimmunol NeuroInflamm 6(1):e513 Pinal-Fernandez I, Casal-Dominguez M, Mammen AL (2018) Immune-­ mediated necrotizing myopathy. Curr Rheumatol Rep 20(4):21 Watanabe Y, Uruha A, Suzuki S et al (2016) Clinical features and prognosis in anti-SRP and anti-HMGCR necrotising myopathy. J Neurol Neurosurg Psychiatry 87(10):1038–1044

Connective Tissue Diseases (CTDs) in “Overlap” Myositis

311 McDonald CM, Campbell C, Torricelli RE, Finkel RS, Flanigan KM, Goemans N et al (2017) Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 390(10101):1489–1498

Becker Muscular Dystrophy Angelini C, Marozzo R, Pegoraro V (2019) Current and emerging therapies in Becker muscular dystrophy (BMD). Acta Myol 38(3):172–179 Thangarajh M (2019) The dystrophinopathies. Continuum (Minneap Minn) 25(6):1619–1639 Waldrop MA, Flanigan KM (2019) Update in Duchenne and Becker muscular dystrophy. Curr Opin Neurol 32(5):722–727

Myotonic Dystrophy (DM) LoRusso S, Weiner B, Arnold WD (2018) Myotonic dystrophies: targeting therapies for multisystem disease. Neurotherapeutics 15(4):872–884 Thornton CA, Wang E, Carrell EM (2017) Myotonic dystrophy: approach to therapy. Curr Opin Genet Dev 44:135–140

Limb-Girdle Muscular Dystrophy (LGMD)

Fredi M, Cavazzana I, Franceschini F (2018) The clinico-serological spectrum of overlap myositis. Curr Opin Rheumatol 30(6):637–643 Nuño-Nuño L, Joven BE, Carreira PE et al (2019) Overlap myositis, a distinct entity beyond primary inflammatory myositis: a retrospective analysis of a large cohort from the REMICAM registry. Int J Rheum Dis 22(8):1393–1401

Chu ML, Moran E (2018) The limb-girdle muscular dystrophies: is treatment on the horizon? Neurotherapeutics 15(4):849–862 Mendell JR, Chicoine LG, Al-Zaidy SA et al (2019) Gene delivery for limb-girdle muscular dystrophy type 2D by isolated limb infusion. Hum Gene Ther 30(7):794–801 Nallamilli BRR, Chakravorty S, Kesari A et al Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients. Ann Clin Transl Neurol 5(12):1574–1587

Viral Myopathies

Oculopharyngeal Muscular Dystrophy (OPMD)

Llyoyd TE, Pinal-Fernandez I, Michelle EH et al (2017) Overlapping Doki T, Yamashita S, Wei FY et al (2019) Mitochondrial localization features of polymyosistis and inclusion body myositis in HIV-­ of PABPN1  in oculopharyngeal muscular dystrophy. Lab Investig infected patients. Neurology 88(15):1454–1460 99(11):1728–1740 Prior DE, Song N, Cohen JA (2018) Neuromuscular diseases associ- Malerba A, Klein P, Bachtarzi H et al (2017) PABPN1 gene therapy for ated with human immunodeficiency virus infection. J Neurol Sci oculopharyngeal muscular dystrophy. Nat Commun 8:14848 387:27–36 Richard P, Trollet C, Stojkovic T et  al (2017) Correlation between Robinson-Papp J, Simpson DM (2009) Neuromuscular diseases associPABPN1 genotype and disease severity in oculopharyngeal muscuated with HIV-1 infection. Muscle Nerve 40:1043–1053 lar dystrophy. Neurology 88(4):359–365

Duchenne Muscular Dystrophy Griggs RC, Miller JP, Greenberg CR, Fehlings DL, Pestronk A, Mendell JR et al (2016) Efficacy and safety of deflazacort vs prednisone and placebo for Duchenne muscular dystrophy. Neurology 87(20):2123–2131 Mendell JR, Goemans N, Lowes LP, Alfano LN, Berry K, Shao J et al (2016) Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. Ann Neurol 79(2):257–271

Facioscapulohumeral Muscular Dystrophy (FSHD) Himeda CL, Jones PL (2019) The genetics and epigenetics of Facioscapulohumeral muscular dystrophy. Annu Rev Genomics Hum Genet 20:265–229 Statland JM, Tawil R (2016) Facioscapulohumeral muscular dystrophy. Continuum 22(6):1916–1931 Sacconi S, Briand-Suleau A, Gros M et al (2019) FSHD1 and FSHD2 form a disease continuum. Neurology 92(19):e2273–e2285

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Congenital Myopathies

Critical Illness Myopathy

Carlier RY, Quijano-Roy S (2019) Myoimaging in congenital myopathies. Semin Pediatr Neurol 29:30–43 Claeys KG (2020) Congenital myopathies: an update. Dev Med Child Neurol 62(3):297–302 Mah JK, Joseph JT (2016) An overview of congenital myopathies. Continuum 22(6):1932–1953 Phadke R (2019) Myopathology of congenital myopathies: bridging the old and the new. Semin Pediatr Neurol 29:55–70

Hermans G, De Jonghe B, Bruyninckx F, Van den Berghe G (2014) Interventions for preventing critical illness polyneuropathy and critical illness myopathy. Cochrane Database Syst Rev (1):CD006832 Kramer CL (2017) Intensive care unit–acquired weakness. Neurol Clin 35(4):723–736 Vanhorebeek I, Latronico N, Van den Berghe G (2020) ICU-acquired weakness. Intensive Care Med 46(4):637–653

Mitochondrial Myopathies

Myopathies Associated with Endocrine/ Metabolic Disorders and Carcinoma

de Barcelos IP, Emmanuele V, Hirano M (2019) Advances in primary mitochondrial myopathies. Curr Opin Neurol 32(5):715–721 Madsen KL, Buch AE, Cohen BH et al (2020) Safety and efficacy of omaveloxolone in patients with mitochondrial myopathy: MOTOR trial. Neurology 94(7):e687–e698

Katzberg HD, Kassardjian CD (2016) Toxic and endocrine myopathies. Continuum 22(6):1815–1828 Michelle EH, Mammen AL (2015) Myositis mimics. Curr Rheumatol Rep 17(10):63

Glycogen Storage Diseases

Myotonia Congenita and Paramyotonia Congenita

Ellingwood SS, Cheng A (2018) Biochemical and clinical aspects of glycogen storage diseases. J Endocrinol 238(3):R131–R141 Tarnopolsky MA (2016) Metabolic myopathies. Continuum 22(6):1829–1851

Defects of Fatty Acid Oxidation and the Carnitine Shuttle System El-Gharbawy A, Vockley J (2018) Inborn errors of metabolism with myopathy: defects of fatty acid oxidation and the carnitine shuttle system. Pediatr Clin N Am 65(2):317–335 Houten SM, Violante S, Ventura FV, Wanders RJ (2016) The biochemistry and physiology of mitochondrial fatty acid β-oxidation and its genetic disorders. Annu Rev Physiol 78:23–44

Toxic Myopathies Doughty CT, Amato AA (2019) Toxic myopathies. Continuum 25(6):1712–1731 Mastaglia FL, Needham M (2012) Update on toxic myopathies. Curr Neurol Neurosci Rep 12:54–61

George AL Jr, Crackower MA, Abdalla JA et al (1993) Molecular basis of Thomsen’s disease (autosomal dominant myotonia congenita). Nat Genet 3:305–310 Nojszewska M, Lusakowska A, Gawel M et  al (2019) The needle EMG findings in myotonia congenita. J Electromyogr Kinesiol 49:102362 Ptácek LJ, George AL Jr, Barchi RL et al (1992) Mutations in an S4 segment of the adult skeletal muscle sodium channel cause paramyotonia congenita. Neuron 8(5):891–897 Taminato T, Mori-Yoshimura M, Miki J et  al (2020) Paramyotonia congenita with persistent distal and facial muscle weakness: a case report with literature review. J Neuromuscul Dis 7(2):193–201

Hyperkalemic and Hypokalemic Periodic Paralysis Fialho D, Griggs RC, Matthews E (2018) Periodic paralysis. Handb Clin Neurol 148:505–520 Statland JM, Fontaine B, Hanna MG, Johnson NE (2018) Review of the diagnosis and treatment of periodic paralysis. Muscle Nerve 57(4):522–530

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Motor Neuron Diseases

15.1 Amyotrophic Lateral Sclerosis (ALS) Genetic testing + in familial ALS

NCS/EMG ++

Laboratory −

Imaging +

Biopsy −

Epidemiology: The incidence of ALS is 1.5–2.5/100,000; prevalence 4–6/100,000. Mean age of onset is between 58 and 63 years; men are slightly more affected. The disease is sporadic in most cases, but approximately 15% are familial (fALS). Anatomy and Pathophysiology: Loss of upper (UMNs) and lower motor neurons (LMNs) occurs and is seen on autopsy. TAR DNA-binding protein of 43  kDa (TDP-43)positive ubiquitinated cytoplasmatic inclusions are found in motor neurons in sporadic ALS; the pathology is slightly different in some forms of fALS. Inclusions can also be found in frontotemporal lobes. Glutamate excitotoxicity and free radical formation have been implicated in the pathophysiology of ALS.  Aberrant RNA metabolism, impaired protein homeostasis affecting autophagy and proteasome function, mitochondrial abnormalities, autophagy, disrupted axonal transport, sodium-­ potassium ion pump dysfunction, insufficient release of neurotrophic factors by astroglia, and TDP-43 aggregates may play a role in triggering ALS. Symptoms: Progressive focal painless weakness and atrophy without any sensory symptoms. Cramps and fasciculations are frequent. In patients with bulbar onset, speech is affected first and dysphagia develops later. Head drop and dyspnea are rare initial symptoms, but a small percentage of patients present with isolated severe dyspnea. Dyspnea usually is worse in the supine position, and symptoms of nocturnal hypoxia, e.g., morning headache, daytime sleepiness, and lack of concentration, can develop. Generalized spasticity in the absence of clear LMN weakness and loss of handedness are symptoms of predominant UMN disease. Extraocular movements, bladder and bowel function, and sensation are spared. Obvious frontotemporal dementia (FTD) develops in 5–15% of patients; 20–50% demonstrate Contributions by Wolfgang N. Löscher and Stacey A. Sakowski

behavioral and/or cognitive impairment as reported by caregivers and detected on detailed cognitive and neuropsychological assessment. Signs: Signs of UMN and LMN dysfunction are evident in several body regions, e.g., the combination of weakness, atrophy, fasciculations, increased muscle tone, exaggerated reflexes, and pathological reflexes. Disease onset is spinal in about two-thirds and bulbar in the remainder. Bulbar symptoms include tongue atrophy, dysarthria, and later on dysphagia and drooling. The masseter reflex is exaggerated. Hand weakness typically shows a “split-hand” pattern, with greater weakness in the radial aspect of the hand. Signs of FTD include pathological laughing and crying, impaired judgement, and other deficits of executive function of language or personality. The disease is progressive, and approximately 50% of patients die within 3  years of symptom onset; only about 20% survive 5–10 years. Table 15.1 lists features and prognosis of ALS subgroups. Table 15.1  Subtypes of sporadic ALS Classic ALS Progressive muscular atrophy Flail arm/flail leg syndrome Progressive bulbar palsy Respiratory

Primary lateral sclerosis UMN predominant ALS

Typical features Prognosis UMN and LMN; FTD in app 5–15% Poor Progressive LMN Relatively poor Progressive LMN syndrome in the arms/legs. Confided to arms/legs for at least 1 year after symptom onset Bulbar onset and no other symptoms for at least 6 months after symptom onset Respiratory signs and symptoms at onset, only minor bulbar or spinal signs in the first 6 months Absence of LMN signs for at least 4 years after disease onset Pure UMN syndrome for 3 years but signs of LMN in the fourth year

Relatively good Very poor

Extremely poor Good Relatively good

FTD frontotemporal dementia, LMN lower motor neuron, UMN upper motor neuron

© Springer Nature Switzerland AG 2021 E. L. Feldman et al., Atlas of Neuromuscular Diseases, https://doi.org/10.1007/978-3-030-63449-0_15

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Causes: ALS is mostly sporadic. The cause remains unknown. ALS is familial in approximately 15%. fALS is currently diagnosed in cases with a first or second-degree relative also affected with ALS or patients who present at a young age, or with a family history of early dementia. Most known fALS-­ causing genes are inherited in an autosomal dominant trait with variable penetrance. Clinically, fALS is indistinguishable from sporadic ALS in most cases. A hexanucleotide repeat expansion in C9ORF72 causes approximately 20% of fALS. This same mutation can cause FTD and a variety of other neurodegenerative disorders, making the family history an extremely important component of the patient’s history. Mutations in Cu2+/Zn2+ superoxide dismutase (SOD1), fused in sarcoma (FUS), and TAR DNA-binding protein (TARDBP) cause approximately 10%, 5%, 5%, respectively. There is a clear overlap with FTD in C9ORF72, FUS, and TARDBP fALS. Mutations in known ALS-causing genes can be found in approximately 5% of sporadic ALS.

Diagnosis: Diagnostic criteria depend on the number of body regions showing signs of UMN and LMN dysfunction. Four regions (bulbar, cervical, thoracic, and lumbar) are defined. The revised El Escorial criteria have been replaced by the Awaji-Shima criteria(Table 15.2, Figs. 15.1 and 15.2). Electrophysiology: NCS exclude other disorders, especially multifocal motor neuropathy (MMN) with conduction block. In ALS, motor NCS can show low-amplitude CMAPs. Sensory NCS are normal although minor abnormalities can be seen in the lower limbs in elderly patients. EMG demonstrates evidence of LMN degeneration. Complex fasciculations, fibrillations, and sharp waves, and unstable and chronic neurogenic motor unit action potentials (MUAPs) are accepted (Awaji-Shima criteria). At least two muscles in arms and legs representing different mytomes (nerve roots) and one thoracic paraspinal muscle should be

Table 15.2 Awaji-Shima criteria (LMN affected clinically or electrophysiologically) Clinically possible ALS UMN and LMN in 1 region Or UMN in 2 regions Or LMN signs above UMN signs

Clinically probable ALS UMN and LMN in 2 regions

Clinically definite ALS UMN and LMN in 3 regions

LMN lower motor neuron, UMN upper motor neuron

a

Fig. 15.1  Tongue atrophy is a striking feature in motor neuron disease. The atrophy is usually symmetric

b

Fig. 15.2  Atrophy of the (a) hands and (b) legs. This patient started with asymmetric proximal weakness of the lower extremities. One year later, the atrophy had progressed. This patient had fALS (SOD1 mutation)

15.3 Spinal Muscular Atrophies (SMA)

studied. Bulbar muscles should be studied when clinically indicated. Transcranial magnetic stimulation does not reveal ALS-specific findings. Imaging (MRI, CT Scan, Ultrasound): Ultrasound is better at detecting fasciculations than EMG, especially in the tongue. At present, MRI is not recommended to diagnose or monitor ALS.  In some cases, MRI can demonstrate T2-weighted hyperintense signals in the corticospinal track. Imaging is necessary to exclude ALS-mimicking disorders. Laboratory: Erythrocyte sedimentation rate; full blood count; glucose, urea, and electrolyte analysis; renal, liver, and thyroid function; B12 and antinuclear antibody (ANA) measurements; rheumatoid factor test; and serum protein electrophoresis and immunofixation should be obtained to exclude other causes. CSF and serum neurofilament light chain and phosphorylated neurofilament heavy chain are promising diagnostic and prognostic biomarkers. In atypical or young cases, CSF analysis, hexosaminidase A and B, HTLV-1 testing, and urine heavy metal screening are included. Genetic testing is performed in suspected fALS. Differential Diagnosis: Depending on the phenotype: cervical myelopathy, Hirayama disease, spinal muscular atrophy (SMA), spinal and bulbar muscular atropshy (SBMA), poliomyelitis and post-polio syndrome (PPS), hexosaminidase A deficiency, MMN, heavy metal poisoning, hereditary spastic paraplegia, hereditary motor neuropathies, HIV myeloradiculoneuropathy, subacute combined degeneration, inclusion body myositis, hyperparathyroidism. Therapy: Riluzole 100  mg daily is safe and probably prolongs survival by about 2–3  months in patients with ALS.  Liver function monitoring is needed during riluzole treatment. Edaravone was approved in the United States, but not in Europe. It is given intravenously for 14  days in the first month, then for 10 days/month. Percutaneous endoscopic gastrostomy (PEG) tube should be started early in the course of the disease, as should noninvasive ventilation. Early PEG and early noninvasive ventilation both extend life span and improve quality of life. Anticholinergic antidepressants, anticholinergic drugs, and botulinum toxin injections in salivary glands to treat sialorrhea. Cannabinoids, mexiletin, physiotherapy, muscle relaxants, anticonvulsants, and opioids to treat cramps, musculoskeletal pain, and spasticity. Braces, ambulatory support, and communication devices. Benzodiazepines and opioids to alleviate respiratory distress and anxiety. A multidisciplinary treatment approach is recommended and the standard of care in North America is provided by multidisciplinary clinics.

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15.2 S  pinal and Bulbar Muscular Atrophy (SBMA, Kennedy Syndrome) Genetic testing +++

NCS/EMG +

Laboratory +

Imaging −

Biopsy −

Epidemiology: SBMA is a rare X chromosome-inherited adult-onset motor neuron disease. Anatomy and Pathophysiology: CAG repeat expansion of the androgen receptor on the X chromosome. A toxic gain of function is suspected. Age of disease onset is inversely linked to the size of the expansion. Symptoms: Initial symptoms are hand tremor and proximal leg weakness. Nasal speech and dysphagia at later stages. Median onset of tremor is around 35  years, weakness at 45 years, dysarthria at 50 years, and dysphagia at 55 years of age. Fifty percent of patients are wheelchair bound at 61 years. Survival is minimally reduced compared to controls. Signs: Proximal leg and, to a lesser degree, arm weakness, nasal speech, tongue atrophy, and dysphagia. Fasciculations in tongue and face; perioral fasciculations are typical. Tendon reflexes are reduced or absent, and a postural tremor of the hands is frequently observed. Gynecomastia is seen in approximately 50% and testicular atrophy in some (Figs. 15.3). Causes: CAG repeat expansion of the androgen receptor on the X chromosome. Repeat length is between 40 and 60 repeats. Diagnosis: Genetic testing when SBMA is suspected. Muscle and nerve biopsies are not recommended. Electrophysiology: Routine motor NCS are normal or show low-amplitude compound muscle action potential (CMAP). Sensory nerve action potentials (SNAPs) of the sural nerve are reduced or absent. EMG shows high-­ amplitude, long-duration motor unit action potentials. Grouped discharges can be seen. Imaging: None. Laboratory: CK is elevated ( bulbar; can be focal with rapid spreading; fasciculations; areflexia; eventually atrophy develops; urinary retention; blood pressure instability; cardiac arrhythmias; constipation; increased or decreased sweating New weakness; new atrophy in some usually later during the disease; dysphagia and respiratory dysfunction

Electrophysiology: Sensory NCS are normal in APP and PPS. CMAP is low in amplitude when recorded from affected muscles. EMG in APP initially shows reduced MUAP recruitment and spontaneous activity in the form of fibrillations and positive sharp waves after 2–3 weeks. Over time, reinnervation results in polyphasic and enlarged MUs. In PPS, polyphasic and very enlarged MUAPs are found; single-fiber EMG studies show increased fiber density and increased jitter and blocking. Imaging: In APP, inflammation of the anterior horn can be seen on spinal MRI. Laboratory: Virus can be detected in stool and throat cultures during the first 2–3 weeks in APP. A fourfold or greater increase in serum antibody titers in repeated measurements is also considered diagnostic. CSF in APP shows a polymorphonuclear and later lymphocytic pleocytosis. CSF protein is slightly to moderately elevated. In PPS, CK can be mildly elevated. Differential Diagnosis: The differential diagnosis of APP includes Guillain–Barré syndrome, acute transverse myelitis, botulism, tick paralysis, neuromuscular junction disease, and myopathies. The differential of PPS includes adult SMAs, LMN variant of ALS, spinal stenosis, MMN, inflammatory myopathy, and heavy metal toxicity. Therapy: Treatment of APP is symptomatic. Early physical therapy is recommended to prevent deformities. Assistive devices and orthopedic surgery can be necessary. In PPS, a comprehensive management program which includes management of pain, fatigue, dysphagia, respira-

Further Readings

a

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b

c

Fig. 15.6  PPS: with polio in early infancy. (a, b) Foot deformity reveals early onset. (c) Often involvement of the lower limbs is asymmetric; in this case, the right calf is more atrophic than the left

tory dysfunction, and psychosocial difficulties is recommended. Proper exercise, avoidance of overuse, and assistive devices are helpful.

Miller RG, Mitchell JD, Moore DH (2012) Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev (Online) 3:CD001447 Rothstein JD (2017) Edaravone: a new drug approved for ALS.  Cell 171(4):725

Further Readings

Spinal and Bulbar Muscular Atrophy (SBMA, Kennedy Syndrome)

Amyotrophic Lateral Sclerosis Brenner D, Weishaupt JH (2019) Update on amyotrophic lateral sclerosis genetics. Curr Opin Neurol 32(5):735–739 Brent JR, Franz CK, Coleman JM 3rd, Ajroud-Driss S (2020) ALS: management problems. Neurol Clin 38(3):565–575 Chiò A, Mazzini L, Mora G (2020) Disease-modifying therapies in amyotrophic lateral sclerosis. Neuropharmacology 167:107986 Goutman SA, Savelieff MG, Sakowski SA, Feldman EL (2019) Stem cell treatments for amyotrophic lateral sclerosis. Expert Opin Investig Drugs 28(6):525–543 Masrori P, Van Damme P (2020) Amyotrophic lateral sclerosis: a clinical review. Eur J Neurol. https://doi.org/10.1111/ene.14393

Atsuta N, Watanabe H, Ito M, Banno H, Suzuki K, Katsuno M, Tanaka F et al (2006) Natural history of spinal and bulbar muscular atrophy (SBMA): a study of 223 Japanese patients. Brain 129(Pt 6):1446–1455 Chahin N, Klein C, Mandrekar J, Sorenson E (2008) Natural history of spinal-bulbar muscular atrophy. Neurology 70(21):1967–1971 Katsuno M, Banno H, Suzuki K, Takeuchi Y, Kawashima M, Yabe I, Sasaki H et al (2010) Efficacy and safety of leuprorelin in patients with spinal and bulbar muscular atrophy (JASMITT study): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol 9(9):875–884

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Rhodes LE, Freeman BK, Auh S, Kokkinis AD, La Pean A, Chen C, Lehky TJ et al (2009) Clinical features of spinal and bulbar muscular atrophy. Brain 132(Pt 12):3242–3251 Weydt P, Sagnelli A, Rosenbohm A, Fratta P, Pradat PF, Ludolph AC, Pareyson D (2016) Clinical trials in spinal and bulbar muscular atrophy—past, present, and future. J Mol Neurosci 58(3):379–387

Wadman RI, van der Pol WL, Bosboom WM, Asselman FL, van den Berg LH, Iannaccone ST, Vrancken AF (2020) Drug treatment for spinal muscular atrophy types II and III. Cochrane Database Syst Rev 1(1):CD006282 Wee CD, Kong L, Sumner CJ (2010) The genetics of spinal muscular atrophies. Curr Opin Neurol 23(5):450–458

Spinal Muscular Atrophies (SMA)

Poliomyelitis and Post-Polio Syndrome (PPS)

Finkel RS, Mercuri E, Darras BT et al (2017) Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med 377:1723–1732 Mendell JR, Al-Zaidy S, Shell R et  al (2017) Single-dose gene-­ replacement therapy for spinal muscular atrophy. N Engl J Med 377:1713–1722 Mercuri E, Darras BT, Chiriboga CA et  al (2018) Nusinersen versus sham control in later-onset spinal muscular atrophy. N Engl J Med 378:625–635 Ramdas S, Servais L (2020) New treatments in spinal muscular atrophy: an overview of currently available data. Expert Opin Pharmacother 21(3):307–315 Wadman RI, van der Pol WL, Bosboom WM, Asselman FL, van den Berg LH, Iannaccone ST, Vrancken AF (2019) Drug treatment for spinal muscular atrophy type I.  Cochrane Database Syst Rev 12(12):CD006281

Boonyapisit K, Shapiro BE, Trojan DA, Cashman NR (2002) Poliomyelitis and postpoliomyelitis syndrome. In: Katirji B, Kaminski HJ, Preston DC, Ruff RL, Shapiro BE (eds) Neuromuscular disorders in clinical practice. Butterworth-Heinemann, Boston, pp 403–416 Koopman FS, Uegaki K, Gilhus NE, Beelen A, de Visser M, Nollet F (2011) Treatment for postpolio syndrome. Cochrane Database Syst Rev (Online) 2:CD007818 Lo JK, Robinson LR (2018a) Postpolio syndrome and the late effects of poliomyelitis. Part 1. Pathogenesis, biomechanical considerations, diagnosis, and investigations. Muscle Nerve 58(6):751–759 Lo JK, Robinson LR (2018b) Postpolio syndrome and the late effects of poliomyelitis. Part 2. Treatment, management, and prognosis. Muscle Nerve 58(6):760–769 Trojan DA, Cashman NR (2005) Post-poliomyelitis syndrome. Muscle Nerve 31(1):6–19

Autonomic Neuropathies

16.1 Introduction The autonomic nervous system (ANS) controls the synergistic action of all visceral organs in the human body to achieve homeostasis. ANS diseases lead to dysfunction of blood pressure, heart rate, sudomotor function, digestion, urinary function, and sexual function. ANS disorders can have a central or peripheral etiology and may be widespread or focal. The approach to each patient should be uniform with the goal to localize the autonomic involvement (sympathetic, parasympathetic, central, or peripheral disease), identify a common autonomic syndrome (orthostatic hypotension, autonomic neuropathy, postural orthostatic tachycardia syndrome, reflex syncope), and to treat treatable diseases. To achieve this aim, a comprehensive history, appropriate autonomic tests, and laboratory tests are necessary.

16.2 Anatomy The anatomy of the ANS is complex, with CNS centers serving specific integrative tasks and a spinal and peripheral organization into sympathetic, parasympathetic, and enteric ANS.

16.2.1 Common Autonomic CNS Structures Several CNS structures coordinate autonomic afferents and efferents. The insular cortex represents the primary viscerosensory cortex and is organized in a viscerotropic pattern. It is the primary area for pain and temperature projection and controls sympathetic and parasympathetic output. The anterior cingulate modulates autonomic activation due to motivation and goal-directed behavior, the amygdala is responsible for integrated autonomic and emotional responses. The hypothalamus orchestrates organ function: Contributions by Walter Struhal and James W Russell

16

neuroendocrine control by the periventricular zone, homeostasis, including thermo- and osmoregulation, food intake, reproduction by the medial zone, and arousal and behavior (sleep-wake cycle, feeding, reward responses) by the lateral zone. Several areas are involved in integration of autonomic, somatic, and nociceptive information, especially the periaqueductal gray and the parabrachial nucleus. An important relay station for taste and visceral afferents as well as all medullary reflexes for circulation, respiration, and gastrointestinal function is the nucleus of solitary tract. Vessel constriction, cardiac function, and respiration are controlled by the ventrolateral medulla.

16.2.2 Sympathetic Nervous System CNS: Sympathetic preganglionic neurons originate in the T1 to L2 spinal cord levels, primarily in the intermediolateral nucleus (Fig.  16.1). Neurons are small myelinated fibers organized in functional units, each responsible for specific organ functions. PNS: Preganglionic cholinergic neurons project to two types of ganglia: prevertebral and paravertebral ganglia. Neurons originating in prevertebral ganglia (celiac, superior, and inferior mesenteric ganglia) innervate the abdominal and pelvic organs and vessels. Paravertebral ganglia innervate all other tissues. The primary neurotransmitter for all preganglionic neurons is acetylcholine (Ach), and for postganglionic neurons is norepinephrine except for neurons innervating sweat glands that are also cholinergic, i.e., Ach. Main functions: • Blood pressure regulation. • Thermoregulation. • Cardiovascular and metabolic responses to exercise, stress, and emotion. Typical reflex tests: Noradrenergic sympathetic ANS:

© Springer Nature Switzerland AG 2021 E. L. Feldman et al., Atlas of Neuromuscular Diseases, https://doi.org/10.1007/978-3-030-63449-0_16

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Fig. 16.1  Neuroanatomical organization of the peripheral ANS. Red: sympathetic preganglionic fibers. Green: Sympathetic postganglionic fibers. Blue: parasympathetic preganglionic fibers. Yellow: parasympathetic postganglionic fibers. Circles: ganglionic organization. (Reprinted

• Blood pressure dynamics during the Valsalva maneuver or on standing. • Plasma catecholamines.

16  Autonomic Neuropathies

with permission from Struhal W, Lahrmann H, Fanciulli A, Wenning GK, Eds (2017) Bedside Approach to Autonomic Disorders: A Clinical Tutor. Springer, https://www.springer.com/de/book/9783319051420)

Cholinergic sympathetic ANS (sudomotor function): • Quantitative Sudomotor Axon Reflex Test (QSART). • Sympathetic skin response test (SSRT).

16.3 History Taking and Bedside Tests

16.2.3 Parasympathetic Nervous System CNS: Cranial nerves III, VII, IX main nuclei and functions: Edinger–Westphal nucleus—pupil constrictor and ciliary body (III), superior salivatory nucleus— lacrimal glands and skull sinuses as well as nasal cavity (VII), inferior salivatory nucleus—parotid gland (IX). Cranial nerve X: nerve fibers originate from the dorsal nucleus and the ventrolateral portions of nucleus ambiguus; innervation of the heart (mainly fibers from nucleus ambiguus), respiratory tract and gastrointestinal tract (mainly fibers from the dorsal nucleus), terminating at the flexura coli sinistra. Sacral preganglionic output arises from the sacral preganglionic nucleus located in the lateral gray matter of segments S2-S4. PNS: Cranial nerves III, VII, IX, X as well as the sacral output synapse to postganglionic cholinergic fibers in ganglia close to the target tissues. Primary neurotransmitter for all pre- and postganglionic fibers is Ach. Main functions: Vagus nerve: • Beat-to-beat heart rate control. • Esophageal motility, gastric relaxation and evacuation, and gastrointestinal peristalsis. Sacral neurons: • Micturition, defecation, penile erection. Typical reflex tests: • Heart rate variability during deep breathing, Valsalva.

16.2.4 Enteric Nervous System A huge number of autonomic nerve fibers from two plexuses innervate the intestines: the myenteric plexus (from the pharyngoesophageal junction to the anal sphincter) and the submucosal plexus (small and large intestines). Main function: Coordinated peristalsis and secretion. Typical tests: • Colon transit time.

16.3 History Taking and Bedside Tests A detailed history is of crucial importance. Many patients with cardiovascular autonomic diseases report transient loss of consciousness (TLOC). TLOC is defined as an

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apparent loss of consciousness with a rapid onset, a short duration, and a spontaneous and complete recovery. The examiner should gather information from as many events as possible from the patient and if possible, an eyewitness to distinguish TLOC from other causes of falls including epileptic spells. In addition, the examiner should inquire if symptoms occur in an upright position and cease in a lying position; these symptoms should include dizziness, lightheadedness, visual disturbances, headache, nausea, pallor, or evidence of epilepsy. Symptoms might be aggravated in the early morning (due to nocturia), by a carbohydrate meal, menstruation, or prolonged standing. Most patients with autonomic neuropathies, do not have TLOC but may have presyncopal symptoms. Sudomotor involvement is a frequent feature of autonomic peripheral neuropathy and may be focal (e.g., socks still wet after training?) or generalized (e.g., severe heat intolerance). Gastrointestinal symptoms may be present, for example, constipation or diarrhea, abdominal cramps, postprandial symptoms. The presence of incontinence and sexual dysfunction should be documented. Validated autonomic scores provide a standardized system to document and quantify the presence of autonomic symptoms. A careful history and examination focused on autonomic dysfunction may be supplemented with an office or bedside standing test to assess for symptomatic orthostatic dysregulation. A common protocol is the Schellong test, but for sake of time, this protocol can be modified. Initial measurements are taken after the patient has tested supine for 5–10 min. Steady-state blood pressure and pulse measurements in the supine position are critical as a starting point for further analysis. The patient then stands and blood pressure and pulse are measured immediately upon standing and then at least every second minute for up to 10  min. Critical time point measurements are at 1, 3, and 5 min after standing. To further evaluate patients with autonomic neuropathies, standardized testing should be performed in an autonomic laboratory.

16.3.1 Autonomic Testing Standardized autonomic tests that are performed in most autonomic function testing laboratories are discussed below. Autonomic testing should be performed in a temperature controlled room (23  °C). Laboratory assistants should be well trained and a physician, experienced in autonomic testing, should be present in the room or closely available. Noise or other stress factors (e.g., full bladder) should be avoided. If possible, medications that significantly affect autonomic function should be discontinued prior to testing in order to allow adequate washout of the drug and its effects on the ANS.

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16.3.2 Cardiovascular Reflex Tests

16  Autonomic Neuropathies

repeated. Typical evaluations include the expiratory/inspiratory ratio or heart rate range (maximum-minimum) over five The patient is usually placed in a supine position for 30 min consecutive intervals. This test is a valuable tool for measurto obtain a steady state. The heart rate is measured employ- ing parasympathetic vagal activity. Valsalva maneuver: The patient is asked to blow into a ing a 3 channel ECG, respiration by a piezo-belt or a nose-­ tube. The air pressure should be measured and maintained at mouth temperature sensor, blood pressure by noninvasive about 40 mmHg for 15 s. A small air leak ensures an open beat-to-beat measurement (volume-clamp technique). Autonomic testing should obtain beat-to-beat blood pressure glottis. The Valsalva reaction is divided into four phases measurements, in order to obtain important real-time data on (Fig. 16.2). Heart rate changes are evaluated employing the Valsalva ratio (highest heart rate during the Valsalva maneuautonomic function. Deep breathing: Typically, the heart rate is measured at 6 ver divided by the lowest heart rate following the maneuver). breaths per minute (5  s inspiration and 5  s expiration) for The Valsalva ratio reflects parasympathetic vagal function. 80–90  s. After a waiting period of 2  min, the test may be Blood pressure recovery during late phase II (IIb) primarily

Fig. 16.2  Valsalva maneuver; (I) mechanical: compression of the vena cava with decreased venous return to the heart leads to increased cardiac output, (II) reduced blood flow to the heart due to increased intrathoracic pressure with compensatory heart rate increase (parasympathetic reaction) in early phase II (IIa) and blood pressure increase in late phase II (IIb) (sympathetic reaction), (III) mechanical: dilatation of the vena cava due to sudden intrathoracic pressure fall, and (IV) compensatory blood pressure increase due to latency in sympathetic response and sympathetic outburst in phase III

16.4 Autonomic Syndromes

325

is controlled by sympathetic α-adrenergic control, and the phase IV blood pressure overshoot by sympathetic β-adrenergic control. Tilt table: After reaching a steady-state blood pressure and pulse, patients are tilted to an angle between 60° and 80° for a period of time depending on the suspected autonomic syndrome (e.g., orthostatic hypotension 10 min, reflex syncope for 45  min). After a modest decrease in systolic and diastolic blood pressure during the first minute, the blood pressure response should stabilize for the remainder of the test period. Recordings are made of any symptoms and/or blood pressure and heart rate abnormalities.

16.3.3 Sudomotor Tests Sudomotor testing evaluates disorders of sweating (hypo- or hyperhidrosis) and their distribution (focal or generalized). Evaluation of sudomotor function can provide early diagnosis of small-fiber neuropathy and is used to provide a measure of cholinergic sympathetic function. The sympathetic skin response (SSRT) can be used to assess the skin sympathetic response but is relatively insensitive and poorly reproducible. In contrast, the QSART is a reproducible test to assess postganglionic cholinergic sympathetic function. The thermoregulatory sweat test provides a subjective global assessment of cholinergic sympathetic function. The QSART and SSRT are discussed below: QSART: This test measures postganglionic axon-reflex mediated sweat production in a small restricted area of the skin over time. The neural pathway consists of the postganglionic sympathetic sudomotor axon. To stimulate the reflex, Ach is applied on the skin and follows an electric potential into the skin (iontophoresis). The axon terminal M3 muscarinic receptors are activated by Ach intradermally and trigger an action potential. The action potential travels antidromically, reaches a branch point, and travels orthodromic to release Ach from the nerve terminal. Quantitative sweat production in microliters is recorded at four defined sites in the forearm, proximal leg, distal leg, and dorsal foot (Fig. 16.3–16.5). SSRT: This measure of electrodermal activity provides a surrogate marker of sympathetic cholinergic sudomotor activity. An arousal stimulus (electric, acoustic, deep breath) induces a change in skin potential, which is usually recorded from the palms and soles of the feet. In sympathetic dysfunction, SSRTs are reported as absent in all or in one channel or 50% amplitude reduction or prolonged latencies compared to normal values. Although this test is very easy to perform and integrated in many commercial EMG devices, there are serious limitations: (1) habituation, (2) high intra- and interindividual variability, (3) the SSRT declines with age.

Fig. 16.3  QSART: local quantitative measurement of sudomotor function employing multicompartmental sweat capsules (white capsules) and iontophoresis of acetylcholine into the skin (electrodes)

16.4 Autonomic Syndromes 16.4.1 Orthostatic Hypotension (OH) OH is a common, yet underdiagnosed disorder. Untreated OH can increase the risk of falls and contributes to morbidity, disability, or even death because of the potential risk of injury. OH may be the first sign of autonomic dysfunction. OH may be worsened by age, medication, or dehydration. If autonomic neurotransmission causes OH, the diagnosis is neurogenic OH (nOH). Typical prodromal symptoms can be reported by the patient (lightheadedness, visual disturbances, and/or pain in the suboccipital and paracervical regions known coat hanger pain). For a patient to experience a prodrome, the blood pressure reduction must be noticed and remembered by the patient. Especially in the elderly patient, prodromal symptoms may not be reported in OH. Red flags in history: • Symptoms occurring soon after standing up. • In connection with initiation or dose change of autonomic medication. • During prolonged standing in crowded or hot places. • Presence of autonomic neuropathy. • After eating or after exertion. Criteria: Classical OH: Reduction of blood pressure of 20 mmHg systolic, or 10 mmHg diastolic, or below an absolute systolic value of 90  mmHg from a lying to standing position (Fig. 16.6b). Office tests for classical OH: Active standing test for 5 min.

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16  Autonomic Neuropathies

Fig. 16.4  Healthy 31-year-old male. A steady-state resting sweat production is reached. After starting iontophoresis (first triangle), the sweat production increases (red: left arm; green, blue, yellow: left leg) and then decreases to baseline after stopping iontophoresis (second triangle)

Fig. 16.5  An 82-year-old male with diabetic polyneuropathy. In this patient, there is a small-fiber neuropathy showing a pathologic “hung up” response in the upper extremity (red tracing, probably an equivalent

of spontaneous activity in axonal damage in somatic motor nerves). There is no response from the three capsules in the lower extremity (green, blue, and yellow tracings)

16.4 Autonomic Syndromes

a

b

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• Stand up slowly. • Physical counter maneuvers immediately at the onset of presyncopal symptoms: leg crossing with tension of the thigh, buttock, and calf muscles (party position), bending over, squatting. • Eventually elastic stockings (at least 30–40 mmHg ankle counterpressure) and abdominal compression bands. • Liberal intake of salt (if there is no cardiac counterindication). • Individualized exercise training (swimming, aerobics, if possible, cycling and walking). Things to avoid:

c

d

• Hot environments including hot baths, showers, sauna. • Carbohydrate-rich meals if the blood pressure drops after eating. • Lying flat—supine hypertension (SH) may be a severe problem either resulting from medication or being part of the disease. Patients should not be treated with plasma expansion (see below) after 18:00 and should sleep with the head of the bed elevated (20-30 cm). Pharmacological treatment: Long acting: • Fludrocortisone is a glucocorticoid that acts as a plasma expander (3.5 h half-life, 1–2 days duration of effect). Short-acting:

Fig. 16.6 (a) Normal autonomic testing, (b) OH, (c) marked heart rate increase in POTS, (d) heart rate and blood pressure decrease due to reflex syncope; first yellow line: beginning of tilt, second yellow line: end of tilt; blue trace: breathing, white trace: heart rate, upper red trace systolic blood pressure, lower red trace diastolic blood pressure

Bedside criteria for nOH: blunted rise in heart rate of 40 years) is typically carotid sinus syncope (CSS), provoked by external pressure to the anterior neck region or head movements. Red flags for reflex syncope:

• Mild SH: systolic BP 140–159 mmHg or diastolic BP values of 90–99 mmHg. • Moderate SH: systolic BP 160–179  mmHg or diastolic BP 100–109 mmHg. • Severe SH: systolic BP values of ≥180 mmHg or diastolic BP values of ≥110 mmHg.

16.4.4 Reflex Syncope Reflex syncope predominantly is found in younger healthy female patients. The autonomic nervous system is structurally intact; syncope is secondary to an “overshooting” of the ANS.  Reflex syncope is due to a vasodepressor response

• A long history of syncope (it is rare that the patient seeks medical advice after the first episode of reflex syncope). • Syncope following an unpleasant event (optic, acoustic, olfactory, or pain). • Syncope during standing in crowded, hot places. • During head movements. • Strong sweating during or after syncope. • During swallowing, micturition, defecation. Criteria: (Pre-) syncope combined with marked blood pressure decrease (eventually including heart rate decrease)

Reference

(Fig.  16.6d); CSS: asystole >3  s, blood pressure reduction >50 mmHg during carotid sinus massage. Office tests for reflex syncope: An active standing test might sometimes provoke a reflex syncope but cannot be regarded as standard test. Autonomic tests for reflex syncope: • Deep breathing, Valsalva, tilt table test for 45–60  min, which might include provocatory tests (e.g., venous puncture). • Carotid sinus massage in patient where carotid sinus syncope is suspected. Treatment: The primary aim of therapy is prevention of syncope and injury and increase of life quality. Nonpharmacological treatment is of major importance: • • • • • • •

Avoidance of situations typically leading to syncope. Early recognition of prodromal symptoms. Early initiation of countermeasures. Prevention of triggers if possible. Moderate exercise. Increase fluid intake. Liberal salt intake.

16.4.5 Postural Orthostatic Tachycardia Syndrome (POTS) POTS is not an entity but caused by different pathophysiologic pathways. These include hypovolemic, hyperadrenergic, immune mediated, mast cell activation, and partial sympathetic neuropathy mechanisms. POTS might be primary or secondary. Secondary POTS is commonly associated with chronic diseases (diabetes mellitus, amyloidosis, sarcoidosis, paraneoplastic syndromes, Lupus, Sjogren’s Syndrome, or other vasculitis syndromes) or either drug or toxin ingestion (alcohol, heavy metal poisoning, chemotherapy). Primary POTS is divided into partial dysautonomic or hyperadrenergic POTS.  Important differential diagnoses include inappropriate sinus tachycardia syndrome or chronic fatigue syndrome. Syncope is common in POTS patients but is not obligatory. Red flags for POTS in history: a great variety of symptoms including: • • • • • •

Tachycardia. Fatigue. Lightheadedness. Tremor. Anxiety. Visual blurring.

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• • • •

Exercise intolerance. Cognitive impairment. Gastrointestinal upset. Headache.

All symptoms have in common that they cease during rest and occur during circumstances of orthostatic challenge. Criteria: Heart rate increase of 30/min or above 120/min from lying to standing within 10 min (Fig. 16.6c) without a blood pressure decrease fulfilling the criteria of orthostatic hypotension (see above); and a minimum history of symptoms of 3 months. Office tests: Standing test for 10  min might prove the diagnosis of POTS. Autonomic testing: Deep breathing, Valsalva, tilt table test for 10  min, catecholamines (hyperadrenergic POTS?), QSART (small-fiber involvement in partial dysautonomic POTS?) Treatment: Treatment of POTS is often complex and is best left to an expert well experienced with this syndrome. It is essential to try out nonpharmacological treatment first. Nonpharmacological treatment: • Increased hydration, increased salt intake. • Individualized exercise training (swimming, aerobics, if possible, cycling and walking). Pharmacological treatment: Pharmacotherapy may include midodrine, fludrocortisone, pyridostigmine, nonselective beta-blockers, clonidine, selective serotonin reuptake inhibitors, as well as droxidopa. The patient has to be informed that all those therapies only have limited evidence supporting their use.

Reference Struhal W, Lahrmann H, Fanciulli A, Wenning GK (eds) (2017) Bedside approach to autonomic disorders: a clinical tutor. Springer. https:// www.springer.com/de/book/9783319051420

Further Readings Arnold AC, Ng J, Raj SR (2018) Postural tachycardia syndrome—diagnosis, physiology, and prognosis. Auton Neurosci 215:3–11 Brignole M, Moya A, de Lange FJ, Deharo JC, Elliott PM, Fanciulli A, Fedorowski A, Furlan R, Kenny RA, Martin A, Probst V, Reed MJ, Rice CP, Sutton R, Ungar A, van Dijk JG, E. S. C. S. D. Group (2018) 2018 ESC guidelines for the diagnosis and management of syncope. Eur Heart J 39(21):1883–1948 Bryarly M, Phillips LT, Fu Q, Vernino S, Levine BD (2019) Postural orthostatic tachycardia syndrome: JACC Focus Seminar. J Am Coll Cardiol 73(10):1207–1228 Fanciulli A, Jordan J, Biaggioni I, Calandra-Buonaura G, Cheshire WP, Cortelli P et al (2018) Consensus statement on the definition of

330 neurogenic supine hypertension in cardiovascular autonomic failure by the American Autonomic Society (AAS) and the European Federation of Autonomic Societies (EFAS): endorsed by the European Academy of Neurology (EAN) and the European Society of Hypertension (ESH). Clin Auton Res 28(4):355–362 Hilz M, Thijs RD, Struhal W, Rocha I, Lahrmann H (2011) Diagnosing autonomic nervous system disorders—existing guidelines and future perspectives. Eur Neurol Rev 6(1)

16  Autonomic Neuropathies Low AL, Benarroch E (2008) Clinical autonomic disorders. LWW Norcliffe-Kaufmann L, Palma JA, Kaufmann H (2018) A validated test for neurogenic orthostatic hypotension at the bedside. Ann Neurol 84(6):959–960 Zilliox L, Peltier AC, Wren PA, Anderson A, Smith AG, Singleton JR, Feldman EL, Alexander NB, Russell JW (2011) Assessing autonomic dysfunction in early diabetic neuropathy: the survey of autonomic symptoms. Neurology 76(12):1099–1105

General Disease Finder

This overview will help to find neuromuscular disease patterns in the different sections. Addison’s disease: Cushing’s disease: steroid myopathy, general muscle weakness CN: VII CMV: polyradiculomyelopathy Herpes zoster: radiculitis Immune Reconstitution Inflammatory Syndrome (IRIS) Infections: aspergillus, candida, CMV, cryptococcus, histoplasma, HSV, TBC, toxoplasmosis, varicella Myopathies: inflammatory, treatment related Neoplastic: lymphoma (direct nerve and muscle invasion) Neurotoxicity of drug treatment Polyneuropathies: inflammatory, immune mediated, treatment related Syphilitic radiculopathy Treatment related: polyneuropathy/myopathy Zidovudine Acute necrotizing myopathy and myoglobinuria Chronic proximal weakness Compartment syndromes (prolonged compression) CN: recurrent nerve Hypokalemic paralysis Mononeuropathy—radial nerve (compression) Myoglobinuria Myopathy Optic nerve (methanol and adultered alcohol) Polyneuropathy (distal, rarely proximal, rarely ulcers) Small fiber neuropathy Periodic paralysis Tetanic muscles Amyloidoma (trigeminal root) Autonomic involvement Chronic inflammatory diseases, rheumatoid diseases, osteomyelitis CN: V, VII, and other CN Deposition of acute phase plasma protein, serum amyloid A Deposition of immunoglobulin light chains in tissue Familial amyloid polyneuropathies Gelsolin type Mononeuropathy: Carpal tunnel syndrome Muscle amyloid—“muscle amyloidosis” Painful neuropathy Polyneuropathy, painful, hearing loss Primary amyloidosis (AL) Secondary or reactive amyloidosis (AA) Sensorimotor neuropathy Transthyretin Cobalamin deficiency, vitamin B12 polyneuropathy Lead poisoning polyneuropathy Pure red cell anemia: autoimmune disease associated with myasthenia gravis Thalassemia: muscle cramps, myalgia, muscle atrophy

© Springer Nature Switzerland AG 2021 E. L. Feldman et al., Atlas of Neuromuscular Diseases, https://doi.org/10.1007/978-3-030-63449-0

Adrenal dysfunction AIDS

Alcohol

Aldosteronism Amyloid

Anemia

331

332 Addison’s disease: Cushing’s disease: steroid myopathy, general muscle weakness Cardiac bypass operations: nerve stretch, hypothermia, phrenic nerve lesions Local: drug toxicity, local hematoma, vasoconstriction, needle injury, infection, extravasation Lower extremity (30%): mononeuropathies of peroneal, sciatic, or femoral nerves Malignant hyperthermia Malpositioning Neuromuscular transmission disorders induced by muscle relaxants Regional: Epidural or spinal anesthesia may cause cauda equina lesions Tourniquet palsy Upper extremity (70%): mononeuropathies of brachial, radial, ulnar, or median nerves Brachial artery: median nerve Cerebral angiography: femoral nerve lesions Femoral nerve lesion in inguinal arterial puncture or hematoma Peripheral: Axillary or femoral artery puncture (brachial plexus and femoral nerve) Acute intensive care myopathy Eosinophilic syndrome Mononeuropathies Myopathy steroids Demyelinating polyneuropathy Sensory polyneuropathy Autoimmune adverse events CIDP Focal damage; sacral plexus Inflammatory myopathies MG Polyneuropathy Facial nerve lower branch Horner syndrome Hypoglossal nerve Vagal recurrent nerve Antineoplastic treatment-­associated polyneuropathy:  Acute neurotoxicity; oxaliplatin  Cumulative toxicity  Bortezomibe  Epithelons  Platinum derivatives (Cisplatinum Carboplatin, Oxaliplatin)  Suramin  Taxanes  Thalidomide  Vinca alkaloids Car T cell therapy CN: optic nerve CN: meningeal carcinomatosis, base of the skull metastasis, nerve infiltrations, radiation injury Immune checkpoint inhibitors Immune therapies Induction or reactivation MG (ICI) Malignant peripheral nerve sheath tumors (MPNST) Mantle field radiation Mononeuropathies (pressure, toxic, extravasation, following operations), rarely infiltration or metastasis. CTS in paraproteinemia and amyloidosis Myopathies: cachexia, dermatomyositis/polymyositis, ICI myositis, necrotizing myopathy, neuromyotonia, amyloid deposition, sarcopenia, type 2 fiber atrophy, lymphoid infiltration, rarely muscle metastasis Neuromuscular transmission: MG and thymoma, LEMS and (lung) cancer Plexopathies (brachial, lumbar, sacral). Polyneuropathies: treatment related (CIPN), rarely autoimmune, paraneoplastic, rarely infiltrative Radiation: Early, delayed, and late effects Radiation fibrosis syndrome Radiculopathies (meningeal carcinomatosis, compression or infiltration of roots, multiple spinal metastasis), cauda equina syndrome Steroid myopathy Targeted therapies

General Disease Finder Adrenal dysfunction Anesthesia

Angiography

Asthma

Biliary cirrhosis Bone marrow transplant

Carotid surgery

Cancer

General Disease Finder Addison’s disease: Cushing’s disease: steroid myopathy, general muscle weakness Carotid surgery—see temporary aortic occlusion (surgery) CN: recurrent laryngeal nerve palsy Drug treatment: cholesterol lowering drugs Embolism-compartment syndrome Intermittent claudication Ischemic neuropathy, angiopathic neuropathies Mononeuropathy: femoral nerve lesion (ruptured aneurysm, aortic surgery)  Obturator nerve: hematoma in psoas muscle Monomelic neuropathy Muscle hemorrhage: hemophiliacs, anticoagulants: retroperitoneal, buttock, arm, calf Myopathy, cramps and cholesterol-­lowering agents (benzafibrate, clofibrate, fenofibrate, gemfibrozil, lovastatin, nicotinic acid, pravastatin simvastatin) Nerve compression by hematoma (femoral nerve, lumbar plexus, sciatic nerve) Neuropathy by fistula—hemodialysis and mononeuropathies Radiculopathies: compression of L4, 5 and S1, 2 by terminal aorta  Ischemic monomelic: predominately sensory with causalgia like pain Venous occlusion—phlegmasia cerulea dolens Compartment syndromes Cranial nerve lesions Critical illness myopathies Critical illness neuropathy Mononeuropathies (malpositioning, pressure palsy) Rhabdomyolysis Steroid myopathy Thick filament myopathy Drug-induced myopathy: acute hypokalemic paralysis, necrotizing myopathy, subacute and chronic myopathies, ischemic injury during surgery Hip and joint surgery: sciatic, femoral nerve lesions Hypothermia: polyneuropathy Injection into nerves Intramuscular injections Knee surgery: peroneal nerve, ramus infrapatellaris, and cutaneous nerves Mononeuropathies Mononeuropathies due to body position: plexus, radial, ulnar, median, peroneal, femoral nerve lesions Muscle Nerve blockade Neuromuscular blocking agents Neuromuscular transmission: drug-induced MG Postoperative apnea, malignant hyperthermia Postoperatively: GBS Radiation Shoulder surgery Spinal anesthesia: adhesive arachnoiditis, abscess, epidural hemorrhage, nerve roots, paraplegia, sensory loss Spinal cord and nerve plexus (brachial, lumbar, and sacral plexus) mononeuropathies Surgical trauma: mastectomy, median sternotomy, neck surgery (thoracodorsal, long thoracic, axillary nerve), obturator, pelvic surgery (femoral, ilioinguinal, iliohypogastric sciatic, nerve) Tourniquet paralysis Abdominal weakness Autonomic neuropathy Cranial mononeuropathies Mononeuropathies Muscle infarction Plexopathy (lumbar) Polyneuropathy; several distinct types Thoracic (truncal) radicular lesions Alcohol neuropathy Cocaine: rhabdomyolysis Compartment syndromes Glue sniffing neuropathy Heroin: nerve compression (coma), trauma from injection, brachial and lumbosacral Nerve compression syndromes Plexopathies Phenylcyclidine: rhabdomyolysis

333 Adrenal dysfunction Circulatory disorders

Coma

Complications of medical and surgical treatment

Diabetes mellitus

Drugs and addiction

334 Addison’s disease: Cushing’s disease: steroid myopathy, general muscle weakness Hypercalcemia: muscle weakness Hyperkalemia: potassium retaining diuretics Hyperkalemic paralysis Hypermagnesemia muscle weakness Hypernatremia: muscle weakness Hyperphosphatemia Hypocalcemia: tetany Hypokalemic myopathy Hypokalemic paralysis Hypomagnesemia muscle weakness Hyponatriemia: muscle weakness Churg–Strauss syndrome Eosinophilia myalgia syndromes Eosinophilic fasciitis Eosinophilic polymyositis Parasitic infections Acute abdomen: porphyria, lead poisoning-polyneuropathy Celiac disease: myopathy Chronic diarrhea: malabsorption neuropathies, Whipple’s disease, celiac disease Crohn’s disease: polymyositis Diabetes: autonomic neuropathy Paraneoplastic “intestinal pseudoobstruction” Whipple: macrophagic myofasciitis GBS Myopathy Neuropathy Panarteritis nodosa (hepatitis B) Polyneuropathy (hepatitis B, C) Primary biliary cirrhosis: polymyositis Amyloidosis Anticoagulation Brachial plexus lesions Hematomas in peripheral nerves (femoral nerve, median nerve, obturator nerve, sciatic nerve) Hemophilia:  Median nerve—CTS due to hemorrhage  Nerve compression (femoral nerve, hemorrhage into iliac muscle)  Radial nerve, sciatic nerve, peroneal nerve  Ulnar nerve compression Polyneuropathy:  Castleman’s syndrome  Chemotherapy induced  CIDP  IgM (MAG)  Lymphoma, HIV  Macroglobulinemia  Neuroleukemiosis  Neurolymphomatosis  Paraproteinemia  POEMS syndrome  Waldenstrom’s Thrombocytopenia:  Rarely affects peripheral nerves Median nerve mononeuropathy Polyneuropathy Radiculopathy

General Disease Finder Adrenal dysfunction Electrolyte disorders

Eosinophilic syndromes

Gastrointestinal disorders

Hepatic disease Hepatitis

Hematologic diseases

Hyperuricemia

General Disease Finder Addison’s disease: Cushing’s disease: steroid myopathy, general muscle weakness Polyneuropathies:  Amitryptiline (rare)  Gluthethimide  Imipramine  Li+ carbonate  Metaqualone  Perazine  Phenelzine  Thalidomide and derivatives Influenza Macrophagic microfasciitis (hepatitis A, hepatitis B, tetanus) Mumps: sensorineural deafness Polio (oral): GBS (rare) Rabies Serum sickness Swine flu: GBS Toxoids:  Diphtheria/tetanus: GBS  Haemophilus influenzae: GBS  Plasma-derived hepatitis B: GBS Cachexia Disuse myopathy Mononeuropathies: pressure palsies Muscle atrophy Sarcopenia Antimicrobial therapy:  Emetine-induced myopathy  Ethambutol neuropathy  Isoniazide neuropathy  Metronidazole neuropathy  Nitrofurantoin neuropathy  Streptomycin-ototoxicity  Sulfonamide vasculitis Bacterial meningitis: CN lesions Deafness and vertigo: mumps, measles, varicella, influenza, HSV GBS: CMV, enterovirus, EpsteinBarr, herpes simplex, hepatitis B, HIV, influenza A and B, measles, rabies, rubella, smallpox vaccination Hepatitis:  A: GBS  B: GBS, periarteritis nodosa  C: Polyneuropathy (vasculitis) Herpes zoster:  CN: ophthalmic, trigeminal, Ramsay Hunt syndrome  Postherpetic neuralgia Leprosy:  Leprous neuritis  Lepromatous leprosy  Median: proximal to carpal tunnel  Peroneal nerve  Sensory loss (cool areas)  Skin, superficial nerves  Ulnar: proximal to ulnar groove

335 Adrenal dysfunction Hypnotic drugs

Immunization

Immobilization

Infections

336

General Disease Finder

Addison’s disease: Cushing’s disease: steroid myopathy, general muscle weakness Adrenal dysfunction Lyme disease:  CN: VII (possibly bilateral)  Polyneuropathy (unclear)  Radiculoneuritis (Garin-­Bujadoux-­Bannwarth syndrome)  Root involvement Neurosyphilis:  CN: pupillary abnormality  Posterior nerve root, ataxia, bladder and sexual dysfunction  Tabes dorsalis (“Lightning pain”) Onchocerciasis: blindness Paragonimus: optic atrophy Parasitic infections:  Amebic meningoencephalitis: olfactory nerve, smell  Angiostrongyliasis: radiculomyeloneuritis  Eosinophilic meningitis: cranial neuropathies, paresthesias Poliomyelitis:  Facial diplegia  Laryngeal and pharyngeal  Muscle weakness  “Postpolio syndrome”  Pyomyositis—tropical areas Trichinosis-muscle, respiration, and cardiac and skeletal muscles Tuberculoid leprosy:  Digital, sural nerves  Enlarged superficial cutaneous, radial nerve  Mixed nerve near the tubercle  Ulnar, median, peroneal, facial nerve Tuberculosis:  CN (meningitis): VI, III, IV  Retrobulbar with myelitis  Tuberculomas  Tuberculous arachnoiditis: radiculomyelopathy  Typhoid fever: multifocal neuropathy Viral meningitis:  Cranial nerves: mumps  Mumps: deafness Viral:  Herpes  Myopathy  Rabies Post-viral complications:  Optic neuritis: measles, rubella, mumps, varicella zoster, infectious hepatitis, mononucleosis, rabies vaccine Inflammatory and immune diseases CN: II, VI, VII, VIII, vagus Mononeuropathies: serum sickness, acute mononeuropathies: long thoracic, radial, suprascapular, musculocutaneous, femoral, sciatic, anterior interosseus nerve, intercostal, phrenic nerve Myopathies:  Autonomic autoimmune syndromes  Dermato- and polymyositis  Eosinophilic fasciitis  Lupus  Scleroderma Polyneuropathy:  Chronic idiopathic neuritis  CIDP  Collagen vascular disease  Cryoglobulinemia  GBS  Migratory recurrent polyneuropathy  Multiplex neuropathy-vasculitis  Periarteritis nodosa  Postinfectious and allergic neuropathies  Rheumatoid arthritis

General Disease Finder Addison’s disease: Cushing’s disease: steroid myopathy, general muscle weakness Compartment syndromes Mononeuropathy Polyneuropathy Polyneuropathy:  A-betalipoproteinemia  Alpha 1 lipoprotein deficiency  Hyperlipidemia Statin neuropathy Statin myopathy Asthma Churg–Strauss Syndrome COPD: neuropathy Lung cancer: paraneoplastic disease (anti-Hu) Phrenic neuropathy Sarcoid-polyneuropathy CN: trigeminal Mononeuropathies (median, ulnar) Polyneuropathy (sensorimotor) See also: Rheumatoid disease Focal nerve lymphoma Immune-mediated neuropathies Meningeal spread: CN, meningoradiculopathy Myalgia (Car T cell) Nerve infiltration Neurolymphomatosis See also: Cancer Malnutrition-induced myopathy Polyneuropathy Posterolateral cord degeneration Sarcopenia Strachan’s syndrome Vitamin deficiencies (B) Susceptibility in several diseases:  Central core disease  Duchenne’s dystrophy  HyperCKemia  Myotonia congenita  Myotonic dystrophy Hypomagnesemia Muscle weakness in:  Potassium: hypokalemia, hyperkalemia  Sodium: hyponatriemia  Calcium Tetany, hypocalcemia Acute-chronic Nerve regeneration Plexus lesions—trauma Rehabilitation Surgery Suture Transection Amputation neuroma Ganglia Lipoma Malignant peripheral nerve sheath tumors (MPNST) Nerve metastasis Neurofibroma Schwannoma WHO peripheral nerve tumor classification

337 Adrenal dysfunction Ischemia/peripheral vascular occlusive

Lipid metabolism

Lung disease

Lupus, SLE

Lymphoma

Malnutrition

Malignant hyperpyrexia

Mineral and electrolyte disorders

Nerve injury

Nerve tumors

338 Addison’s disease: Cushing’s disease: steroid myopathy, general muscle weakness “Beaded retinal vasculature”: vasculitis Fabry’s: corneal clouding Myotonic dystrophy Neurofibromatosis: Lisch nodules Optic disk edema: POEMS syndrome, CIDP, GBS Retinal microaneurysms: diabetes mellitus Retinitis pigmentosa: Refsum’s disease, Cockayne syndrome, Bassen-Kornweig Disease Sicca syndrome: Sjögren’s syndrome Xerophthalmia: Sjögren’s syndrome, LEMS Myopathy Neuropathic pain:  CRPS  Erythromelagia  Neuralgia  Phantom pain Muscle pain: generalized, myalgia, ischemia, cramps, drugs Pain classification Therapy of neuropathic pain CN: paraneoplastic retinal degeneration, cancer-associated retinopathy, “Numb chin syndrome” Myopathy:  “Cachectic myopathy”  Dermatomyositis, polymyositis  Necrotizing myopathy  Type 2 fiber atrophy Neuromuscular transmission:  LEMS  MG (thymoma)  Neuromyotonia, Isaacs syndrome Paraproteinemic neuropathies:  Amyloid neuropathy  Anti-MAG IgM  Monoclonal gammopathy of uncertain significance (MGUS)  POEMS syndrome Polyneuropathy:  Distal sensorimotor  Immune mediated  Sensory, subacute sensory neuronopathy  Vasculitic neuropathy  “Terminal” neuropathy See also: Cancer In hypoparathyroidism: tetanic muscular reaction Myopathy, bulbar and respiratory weakness Ocular myopathy Polyneuropathy Thyrotoxic periodic paralysis Acromegaly: entrapment neuropathies: median, ulnar nerve entrapment Proximal myopathy Hypophysitis (ICI) with endocrine deficiency Radiation therapy in children with growth retardation Ascending polyradiculopathy Drug-induced side effects—see specific drugs to be avoided) Polyneuropathy (proximal also respiration can be involved)

General Disease Finder Adrenal dysfunction Ophthalmologic complications

Osteomalacia Pain

Paraneoplastic neuromuscular syndromes

Parathyroid disease

Pituitary disease

Porphyria

General Disease Finder Addison’s disease: Cushing’s disease: steroid myopathy, general muscle weakness Arthrogryposis CN: Bell’s palsy, optic neuritis GBS Immunotherapy and pregnancy Lumbosacral plexus-labor, fetal head, forceps Median neuropathy (CTS) MG (relapse and remission) Mononeuropathies:  Common peroneal nerve  Innervation of sphincter muscle of the pelvic floor  Lateral femoral cutaneous nerve  Obturator nerve  Saphenous nerve  Sciatic nerve Myotonia and myotonic dystrophy, weakness may worsen (uterus contraction, labor) Relapse of CIDP Psoriatic myopathy See: Lung disease Aminoglycoside toxicity Amyloid deposition: nerve and muscle Cachexia, inanition, electrolyte disturbances, rhabdomyolysis Compressive neuropathies: Ischemic myopathy related to shunt Multiplex mononeuropathies Myopathy: (type 2 fiber atrophy) Neuromuscular junction: Polyneuropathy:  Distal symmetric, sensory, motor  Cramps, myokymia  Restless leg syndrome Drug induced Electrolyte disturbances Ethanol intoxication General anesthesia Heroin Metabolic myopathies Multiple organ failure Narcotics Secondary entrapment—compartment syndromes See also: hyperCKemia Bechterew’s disease: cauda equina syndrome, thoracic radiculopathies CN Giant cell arteritis: cranial neuropathies, optic nerve, infarction of tongue, claudication when chewing Muscle:  Dermatomyositis  Eosinophilic myositis/fasciitis  Eosinophilia myalgia syndrome  Polymyositis  RA, scleroderma, penicillamine induced Osteopetrosis: anosmia, optic nerve, atrophy, optomotor, trigeminal nerve, facial nerve, otosclerosis Paget’s disease: anosmia, optic nerve, trigeminal, deafness, caudal and cranial nerves Polyneuropathy:  Eosinophilia myalgia syndrome  Mixed connective tissue disease (“Sharp syndrome”)  Relapsing polychondritis  Rheumatoid arthritis  Scleroderma (rare)  Sjögren’s syndrome with sensory ganglionopathy  Systemic lupus erythematosus Polymyalgia rheumatica: muscle pain, myalgia Raynaud’s syndrome Therapy induced:  Chloroquine: myopathy  Corticosteroid: myopathy  D penicillamine: MG, myositis  Gold therapy: polyneuropathy, myokymia Trigeminal neuropathy Wegener’s disease: cranial neuropathies, neuropathy, vasculitis

339 Adrenal dysfunction Pregnancy

Psoriasis Pulmonary disease Renal disorders

Rhabdomyolysis

Rheumatoid and connective tissue

340 Addison’s disease: Cushing’s disease: steroid myopathy, general muscle weakness CN: facial nerve (bilateral) GBS Hypercalcemia Mononeuropathy Myositis: proximal muscle atrophy Polyneuropathy (distal sensorimotor, small fiber and autonomic) Radiculopathy Rhabdomyolysis Cachexia Critical care myopathy Critical illness neuropathy Malnutrition and avitaminosis Neuromuscular transmission disorders by: anesthetic drugs, aminoglycosides Septic myopathy Therapy induced: steroid myopathy Thick filament myopathy Angiokeratoma: Fabry’s disease Cheilosis/glossitis: vitamin B and folate deficiency Collagenosis, autoimmune disease Dupytren’s contracture: alcoholic liver disease, diabetes mellitus Erythema nodosum: leprosy, sarcoidosis, inflammatory bowel disease Hair loss: thallium, alopecia areata (in autoimmune disease, also in MG), hypothyroidism, thallium, lupus Hyperpigmentation: POEMS syndrome, adrenomyeloneuropathy, adrenoleukodystrophy Hypertrichosis: POEMS syndrome Hypopigmentation: POEMS syndrome, leprosy (patchy) Ichthyosis: Refsum’s disease Macroglossia: amyloidosis, hypothyroid Mechanic’s hands: dermatomyositis Mees’ lines (nails): arsenic, thallium intoxication Neurofibromatosis Photosensitivity: lupus, porphyria Purpura: vasculitis, cryoglobulinemia, amyloidosis Raynaud’s syndrome Skin rash: dermatomyositis Skin thickening: scleroderma, fasciitis Vitiligo: vitamin B deficiency Cachexia Myopathy Sarcopenia Strachan’s syndrome Wernicke’s disease Acute myopathy in status asthmaticus Critical illness myopathy Myopathy Type 2 fiber atrophy Basedow’s disease Entrapment mononeuropathy (CTS) Graves ophthalmopathy Hyperthyroidism Hyperthryroid periodic paralysis (Asian, Chinese) Hypothyroidism Median neuropathy MG and hyperthyrosis Myopathy (pseudomyotonia—Hoffman’s sign) Neuropathy Thyroid myopathy

General Disease Finder Adrenal dysfunction Sarcoidosis

Sepsis

Skin changes

Starvation

Steroid therapy

Thyroid disease

General Disease Finder Addison’s disease: Cushing’s disease: steroid myopathy, general muscle weakness Drugs:  Antimicrobial drugs  Cardiovascular, e.g., amiodarone  Chemotherapy: see Cancer  CNS drugs  Others Focal toxicity: Extravasation IT therapy toxicity Limb perfusion: cancer therapy Gasoline Heavy metals:  Lead: motor neuropathy (UE > LE)  Arsenic: distal axonopathy (GBS-like)  Mercury: Cranial nerves II, VIII, sensory  Thallium: Polyneuropathy, autonomic  Tin: papilledema Insecticides, pesticides Late immunological effects: immune-mediated neuropathies: ICI Myopathies:  Chloroquine  Emtansine  Taxanes  Vincristine Nicotinic effects: inhibition of neuropathy target esterase—distal axonopathy (TOCP) triorthocresyl phosphate Organophosphates:  Acetylcholinesterase inhibition: fasciculations, weakness, respiration Polyneuropathies:  Acrylamide (monomer): sensory  Biological toxins: venoms, ciguatera, tetrodotoxin  Industrial agents  Organic solvents (n-hexane, methyl n-butyl ketone, carbon disulfide) Trichlorethylene: cranial neuropathies Amyloid deposition—autonomic Mononeuropathies Optic neuropathy Polyneuropathy Shunt monomelic neuropathies Color vision changes: anthelmintic drugs, barbiturates, digitalis, methaqualone, nalidixic acid, streptomycin sulfonamides, thiazide diuretics, troxidone Optic neuropathy: chlorambucil, chloramphenicol chlorpropamide, dapsone, ethambutol, ibuprofen, indomethacin, isoniazid, MAO-­inhibitors, morphine, penicillamine streptomycin, sulfas Pyridoxine high overdose: sensory neuropathy Vitamin B1 (Thiamine): polyneuropathy, myopathy Vitamin B6: isoniazid neuropathy, median neuropathy Vitamin B12 deficiency: polyneuropathy, posterior column degeneration Vitamin D: muscle weakness, osteomalacia Vitamin E: myopathy, lordosis

341 Adrenal dysfunction Toxin exposure/working conditions

Uremia

Visual disorders

Vitamin deficiency

Index

A Abdominal walls anterior abdominal wall muscles and innervation, 176 external and internal oblique muscle, 177 fascia, 178 lower cupula, 176 muscular components, 178 muscular innervation of the abdominal cavity, 176 nerves involved, 178 posterior abdominal muscle, 178 posterior wall, 176 rectus abdominis, 177 rostral cupula, 178 transverse abdominal muscle, 178 upper cupula, 176 Abducens nerve disease, 77, 81, 82 Accessory nerve disease, 92–94 Acoustic nerve disease, 88, 89 Acute brachial neuritis, 93, 122, 125 Acute disc herniation surgery, 111, 113 Acute inflammatory demyelinating polyneuropathy (AIDP), 14, 216, 234–236, 244, 247, 254, 255, 258, 260 Acute motor and sensory axonal neuropathy (AMSAN), 216, 235–236 Acute motor axonal neuropathy (AMAN), 216, 234–235 Acute paralytic poliomyelitis (APP), 318 Alcohol polyneuropathy, 243 Allograft, 48 Amputation neuromas, 206 Amyloid neuropathy, 223, 225–226 Amyotrophic lateral sclerosis (ALS), 5, 6, 8, 13, 21, 27, 29, 32, 35, 36, 42, 55, 85, 94–96, 106, 240, 250, 286, 313–316, 318 anatomy and pathophysiology, 313 diagnosis, 314 differential diagnosis, 315 epidemiology, 313 fALS, 313–315 features and prognosis of, 313 signs, 313, 314 symptoms, 313 treatment, 315 Angiosome, 142 Ankylosing spondylitis, 104, 105, 111, 244 Anterior interosseous syndrome, 147 Anterior tarsal tunnel syndrome, 202 Aortic aneurysms, 134 Autoimmune testing, 15–16 Autonomic nervous system (ANS) anatomy autonomic CNS structures, 321 enteric nervous system, 323 parasympathetic nervous system, 323 sympathetic nervous system, 321 autonomic testing, 323, 324, 327, 329

diabetic autonomic neuropathy, 327 orthostatic hypotension, 321, 325 PoTS, 327, 329 reflex syncope, 321, 325, 327–329 sudomotor tests, 325 TLOC, 323 Axillary nerve anatomy, 142 Axillary nerve dysfunction, 125 B Baker’s cyst, 198 Becker muscular dystrophy (BMD), 28, 37, 287, 289, 290 Bell’s palsy, 83–85, 87, 90, 233 Berrettini anastomosis, 147 Big toe drop, 196 Botulism, 74, 84, 91, 98, 99, 234, 267, 271, 318 Brachial plexus anatomy, 120 diagnosis, 125, 126 differential diagnosis, 125, 126, 129 lesion types, 120–126 pathogenesis acute brachial neuritis, 125 Burner syndrome, 126 chronic neuralgic amyotrophy, 123 HNPP, 122, 125 immunotherapy, 124 Lyme disease, 124 multifocal motor neuropathy, 124 neonatal brachial plexopathy, 122 neurofibromas, 125 pancoast tumor, 121, 125, 127 Parsonage-Turner syndrome, 125 radiation fibrosis, 123 rucksack paralysis, 124 prognosis, 122, 124, 125, 128 signs, 121, 122, 125 symptoms, 121–123, 125, 127, 129 therapy, 123, 124, 127 Breast intercostobrachial nerve, 175 latissimus dorsi flap, 175 male gynecomastia, 175 phantom pain, 175 PMS, 175 scar pain and neuroma, 175 Bruns-Garland syndrome, 113 Burner syndrome, 126, 141 C Calcaneal nerves, 203

© Springer Nature Switzerland AG 2021 E. L. Feldman et al., Atlas of Neuromuscular Diseases, https://doi.org/10.1007/978-3-030-63449-0

343

344 Cardiovascular reflex tests deep breathing, 324 tilt table, 325 valsalva maneuver, 324 Carnitine palmitoyl transferase 2 deficiency (CPT2), 304–306 Carotid sinus syncope (CSS), 328, 329 Carpal tunnel syndrome (CTS), 1, 10, 58, 64, 106, 130, 148–151, 226 Cauda equina syndrome anatomy, 114 diagnosis, 115 differential diagnosis, 133 pathogenesis, 114 signs, 114 symptoms, 114 therapy, 111, 113, 115 Central core disease (CCD), 299–301 Centronuclear myopathy (CNM), 251, 277, 299–301 Cervical plexopathy, 119 Cervical plexus anatomy, 119 clinical presentation, 119 diagnosis, 119, 120 differential diagnosis, 120 pathogenesis, 119 symptoms, 119 therapy, 119, 120 Cervical radiculopathy anatomy, 103 C8 radiculopathy, 104 diagnosis, 106 differential diagnosis, 106 meningeal carcinomatosis, 104 pathogenesis, 105 prognosis, 106 signs, 104 symptoms, 103–106 treatment, 106 Cervical spondylosis, 105 Charcot-Marie-tooth disease (CMT) causes, 249 diagnosis, 249 differential diagnosis, 251 epidemiology, 248 pathophysiology, 248 signs, 248 symptoms, 248 therapy, 251 Chemotherapy-induced polyneuropathies (CIPN) chemotherapeutic drugs, 257, 258 clinical presentation, 258–260 pathogenesis, 257 signs, 258 symptoms, 258 Chronic inflammatory demyelinating polyneuropathy (CIDP) clinical presentation, 237, 239 diagnosis, 237 differential diagnosis, 237 pathogenesis, 237 prognosis, 240 signs/symptoms, 237 therapy, 239 Chronic neuralgic amyotrophy, 123 Classic stocking–glove, 217 Clinical picture, 119 Cluneal nerves, 181, 182

Index Cobalamin neuropathy, 241 Colchicine myopathy, 284 Complex regional pain syndrome (CRPS), 128, 202 Congenital fiber-type disproportion (CFD), 299–301 Congenital myasthenic syndrome (CMS), 36, 267, 269, 301 Congenital myopathies clinical presentation, 299, 301 diagnosis, 301 differential diagnosis, 301 pathogenesis, 299 prognosis, 301 therapy, 301 Connective tissue diseases (CTDs), 10, 77, 280–282 clinical presentation, 281 diagnosis, 281 differential diagnosis, 281 pathogenesis, 281 prognosis, 281 therapy, 281 Cranial mononeuropathies, 218, 221–222 Cranial nerves abducens nerve, 72, 80–82 accessory nerve, 85, 89, 90, 92–94 acoustic nerve, 88, 89 anatomy, 69, 70 examination in coma, 97 facial nerve, 77, 79, 82–88, 96 glossopharyngeal nerve, 89–90, 96 hypoglossal nerve, 94–96 lesions site, 69, 71, 72, 99 oculomotor nerve, 70, 72, 74, 77, 99–100 optic nerve, 72, 76, 77, 98, 100 oral cavity, 95, 96 painful conditions, 97 pupil, 72–74, 97–99 trigeminal nerve, 70, 75–80, 82, 83, 96, 98 trochlear nerve, 72, 74–75, 100 vagus nerve, 89–92 vestibular nerve, 86, 88–89 Critical illness myopathy (CIM), 285–286 Critical illness neuropathy, 216, 248 Critical illness polyneuropathy (CIP), 285, 286 Cutaneous forearm nerves lateral antebrachial cutaneous nerve, 162 medial antebrachial cutaneous nerve, 162 posterior antebrachial cutaneous nerve, 162 Cutaneous nerves of the shoulder and upper arm, 144, 145 D Deep peroneal lesions, 196 Demyelinating neuropathy, 8, 11, 89, 216, 224, 227, 244, 249, 255–257, 260 Dermatomyositis (DM) clinical presentation, 277 diagnosis, 277 differential diagnosis, 278 pathogenesis, 277 prognosis, 278 therapy, 278 Diabetic amyotrophy, 133, 286 Diabetic autonomic neuropathy (DAN), 220, 221, 327 Diabetic distal symmetric polyneuropathy (DPN) clinical presentation, 219 diagnosis, 219

Index differential diagnosis, 219 pathogenesis, 219 prognosis, 219 syndrome/signs, 219 therapy, 219 Diabetic truncal neuropathy, 107 Digital nerves of hand, 162, 163 Disc herniation, 105, 110–112, 114 Distal desmin body myofibrillar myopathy (DBM), 298 Distal hereditary motor neuropathies (d-HMN), 216, 251, 254 Distal myopathies, 250, 277, 279, 296, 298, 300 Distal symmetric polyneuropathy, 217–219, 222 Dorsal scapular nerve, 165 Dorsal scapular nerve dysfunction, 120 Drug-induced neuropathy causes, 244 diagnosis, 244 differential diagnosis, 245 epidemiology, 243 pathophysiology, 243 signs/symptoms, 244 therapy, 245 Duchenne muscular dystrophy (DMD) clinical presentation, 287 diagnosis, 287 differential diagnosis, 287 pathogenesis, 287 prognosis, 288 therapy, 287 E Edrophonium test, 266 Enteric nervous system (ENS), 323 F Facial nerve disease anatomy, 82 course of, 84 diagnosis, 85 pathogenesis, 84 prognosis, 85 signs, 83 symptoms, 83, 84 therapy, 84 topographical lesions, 83 Facioscapulohumeral muscular dystrophy (FSHD), 29, 41, 85, 277, 294–296, 298 clinical presentation, 294 diagnosis, 294, 296 differential diagnosis, 296 pathogenesis, 296 prognosis, 296 therapy, 296 Familial amyloid polyneuropathy (FAP), 225, 226 Familial amyotrophic lateral sclerosis (fALS), 313–315 Fasciculations, 95, 125, 218, 240, 247, 258, 272, 286, 313–316, 318 Femoral nerve (L2-L4), 178, 186–188 Femoral neuropathy, 133, 134 Foot drop, 190, 195, 197 Foot nerves, 203 Froment’s sign, 155 Froment–Rauber nerve, 160 Functional ambulation category (FAC), 54

345 G Ganglionopathy, 217, 221, 230, 237, 255, 256, 258, 259 Genitofemoral nerve (L1-L2), 178, 180, 181 Genitofemoral nerve dysfunction, 131, 133 Glossopharyngeal nerve disease, 89–90, 93, 94, 96 Glycogen storage diseases (GSDs) clinical presentation, 303 diagnosis, 303 differential diagnosis, 304 pathogenesis, 303 prognosis, 304 therapy, 304 Guillain-Barré syndrome, 74, 318 Guyon’s canal, 153–155 Gynecomastia, 175, 315, 316 H Hemorrhagic compartment syndromes, 135 Hereditary autonomic and sensory neuropathy (HSAN), 216 Hereditary motor and sensory neuropathy (HMSN) causes, 249, 250 diagnosis, 249 differential diagnosis, 251 epidemiology, 248 pathophysiology, 248 signs, 248 symptoms, 248 therapy, 251 Hereditary neuralgic amyotrophy (HNA), 122, 123, 125, 253–254 Hereditary neuropathy with liability to pressure palsies (HNPP), 122, 251, 254 causes, 32 diagnosis, 252 differential diagnosis, 251 epidemiology, 252 pathophysiology, 252 signs, 252 symptoms, 252 therapy, 252 Hereditary sensory and autonomic neuropathy (HSAN), 218 Herpes zoster, 108 Herpes zoster neuropathy, 216, 231–232 Hip and neuromuscular disease, 185, 186 Hip arthroplasty, 185 Hip arthroscopy, 186 Hip trauma, 185 Horner’s syndrome, 72, 77, 97, 98, 119, 121, 122, 124 Human immunodeficiency virus-1 neuropathy, 230–231 Hyperkalemic periodic paralysis (HyPP), 13, 307–309 Hypoglossal nerve disease, 94–96, 119 Hypokalemic periodic paralysis (HoPP), 309–310 Hypothyroidism, 88, 286 I Ice test, 267 Iliacus hematoma syndrome, 187 Iliacus muscle, 178 Iliohypogastric nerve, 178, 179 Iliohypogastric nerve dysfunction, 133 Ilioinguinal nerve (L1), 178–180 Ilioinguinal nerve dysfunction, 131, 133 Iliopsoas abscess, 133 Immune polyneuropathies, 14

346 Immune-mediated necrotizing myopathy (IMNM), 280–281, 284 Inclusion body myositis (IBM), 16, 56, 240, 278–281, 284, 286, 298, 315 Inferior gluteal nerve, 181 Inflammatory-immune mediated neuralgic amyotrophy, 168 Infrapatellar branch, 188 Intercostal nerve dysfunction, 106–108 Intercostal neuralgia, 107, 221 Intercostobrachial nerve, 175 Intercostobrachial nerve dysfunction, 106, 107, 125 Interdigital neuroma and “neuritis”, 203, 204 International Classification of Functioning, Disability, and Health (ICF), 17 Interosseus anterior nerve, 146 Intraneural perineuroma, 206 Isaacs’ syndrome, 7, 271–272 Ischemic plexopathy, 123, 133, 134 J Joplin’s neuroma or medial plantar proper digital nerve syndrome, 203 K Kearns–Sayre syndrome (KSS), 71, 277, 301, 302 Kennedy syndrome, 315, 316 Kiloh-Nevin syndrome, see Anterior interosseous syndrome Knee, 194 L Laing distal myopathy (LDM), 298 Lambert-Eaton myasthenic syndrome (LEMS) causes, 270 diagnosis, 270 differential diagnosis, 270 electrophysiology, 270 epidemiology, 269 pathophysiology, 269 prognosis, 270 signs, 270 symptoms, 269 therapy, 270 Lateral antebrachial cutaneous nerve, 162 Lateral calcaneal neuropathy, 203 Lateral femoral cutaneous nerve (L2-L3), 178, 188, 189 Lateral femoral cutaneous nerve dysfunction, 10, 131 Latissimus dorsi flap, 175 Leprosy, 77, 84, 85, 216, 233–234 Lesser occipital nerve, 119, 253 Likert scale, 54, 55 Limb-girdle muscular dystrophy (LGMD), 42, 277, 287, 289–293, 296, 304, 316 clinical presentation, 291 diagnosis, 292 differential diagnosis, 293 pathogenesis, 292 prognosis, 293 therapy, 293 Lipomas, 206 Local pain syndromes, 105, 186 Loge de Guyon’s canal, 155 Loge-de-Guyon syndrome, 157 Long thoracic nerve, 168 Lower extremities, mononeuropathies

Index anterior tarsal tunnel syndrome, 202 around the knee, 194 femoral nerve, 186–188 hip and neuromuscular disease, 185, 186 interdigital neuroma and “neuritis”, 203–205 lateral femoral cutaneous nerve, 188–190 nerves of the foot, 203, 204 obturator nerve, 184, 185 peroneal nerve anatomy, 195 causes, 195, 196 diagnosis, 196 differential diagnosis, 196 imaging, 196 lesions, 196 prognosis, 196 signs and symptoms, 195 treatment, 196 posterior cutaneous femoral nerve, 189 posterior tarsal tunnel syndrome, 201, 202 saphenous nerve, 188 sciatic nerve anatomy, 189 causes, 191, 192 diagnosis, 192 differential diagnosis, 194 signs and symptoms, 190, 191 treatment, 194 sural nerve, 202, 203 tibial nerve (posterior tibial nerve) anatomy, 197 causes, 198, 200 signs and symptoms, 197 Lumbar and sacral radiculopathy acute disc herniation surgery, 113 anatomy, 109 conservative treatment, 113 diagnosis, 113 differential diagnosis, 113 myotomal distribution, 111 pathogenesis, 111 prognosis, 113 radicular sensory findings, 111 signs, 110 surgical techniques, 113 symptoms, 109 Lumbar fusion, 113 Lumbar stenosis, 111, 112 Lumbosacral plexus anatomy, 131 diagnosis, 135–136 differential diagnosis, 134, 136 pathogenesis aortic aneurysms, 134 cancer, 134 diabetic amyotrophy, 133 episodic weakness, 133 hemorrhagic compartment syndromes, 135 ischemic plexopathy, 134 malignant psoas syndrome, 134 maternal lumbosacral plexopathy, 134 postoperative lumbosacral plexopathy, 134 radiation plexus lesion, 134 retroperitoneal hematoma, 134 prognosis, 136

Index symptom/sign, 133 therapy, 136 Lumbosacral spinal stenosis syndrome, 111 Lumbosacral spondylosis, 112 Lumbosacral trunk (L4-L5), 178 Lumbricals 1 and 2, Opponens pollicis, Abductor pollicis brevis, and Flexor pollicis brevi (LOAF), 146 Lyme disease brachial plexus, 124 neuroborreliosis, 232–233 M Male gynecomastia, 175 Malignant foot drop, 184 Malignant peripheral nerve sheath tumors (MPNST), 206 Malignant psoas syndrome, 134 Markesbery distal myopathy (MDM), 298 Martin–Gruber anastomosis, 146 Maternal lumbosacral plexopathy, 134 Medial antebrachial cutaneous nerve, 162 Medial epicondyle and cubital tunnel, 155 Medial winging, 172 Median benediction, 147 Median nerve, 145 anatomic variations, 146 anatomy, 145 anterior interosseous syndrome, 148 Carpal tunnel syndrome, 148, 149 clinical syndrome, 147 conservative therapy, 152 diagnosis, 149 differential diagnosis, 149 at elbow, 147 invasive therapy, 152 lesions above elbow, 147 lesions in shoulder, axilla, upper arm, 147 Pronator Teres syndrome, 147 Medical Research Council (MRC) scale, 4, 5, 53, 54 Meralgia paresthetica, 190 Metabolic diseases diabetic distal symmetric polyneuropathy clinical presentation, 219 diagnosis, 219 differential diagnosis, 219 pathogenesis, 219 prognosis, 219 syndrome/signs, 218, 219 therapy, 219 distal symmetric polyneuropathy, renal disease clinical presentation, 222 diagnosis, 222 differential diagnosis, 222 pathogenesis, 222 prognosis, 222 signs/symptoms, 222 therapy, 222 Migrant sensory neuritis, 189 Miller Fisher syndrome, 74, 90, 99, 216, 236–237, 244 Mitochondrial myopathies, 71, 267, 282–284, 294, 296, 301–302, 304, 306 Mixed connective tissue disease (MCTD), 281, 282 Miyoshi distal myopathy (MIDM), 298 Monoclonal gammopathy of undetermined significance (MGUS), 216, 223, 224, 226

347 Mononeuropathies causes of entrapment/injury, 139 lower extremities (see Lower extremities, mononeuropathies) peripheral nerve tumors (see Peripheral nerve tumors) sclerotome and angiosome, 142 sensory cutaneous nerves, 139–141 truncal mononeuropathies (see Truncal mononeuropathies) upper extremities (see Upper extremities, mononeuropathies) Morton’s neuroma, 203, 204, 206 Motor neuron disease syndrome, 85, 267 Motor neuron diseases amyotrophic lateral sclerosis, 313–315 poliomyelitis/post-polio syndrome, 318–319 spinal and bulbar muscular atrophy, 315 spinal muscular atrophies, 315–316 Motricity index, 53, 54 Multi/minicore disease (MCD), 299, 301 Multifocal motor neuropathy (MMN), 14, 106, 124, 161, 216, 228, 237, 240, 314 Multiple acyl-CoA dehydrogenation deficiency (MADD), 304 Multiple myeloma neuropathy, 222 Muscle and myotonic diseases Becker muscular dystrophy, 289–290 congenital myopathies, 298–301 connective tissue diseases, 281–282 critical illness myopathy, 285–286 dermatomyositis, 277–278 distal myopathies, 298 Duchenne muscular dystrophy, 286–289 electrophysiology, 275–276 fatty acid metabolism, 276, 305, 306 gene defects, 276 glycogen storage diseases, 302–304 histology, 276 hypothyroidism, 7 immune-mediated necrotizing myopathy, 280–281 immunohistochemistry, 276 inclusion body myositis, 279–280 limb-girdle muscular dystrophy, 291–293 mitochondrial myopathies, 301–302 myotonia congenita, 306–307 myotonic dystrophy, 290 paramyotonia congenita, 307–308 polymyositis, 277–278 toxic myopathy, 281, 283–285 viral myopathy, 282–283 Muscle cramps, 8, 258, 267, 318 Musculocutaneous nerve, 143, 144 Musculocutaneous nerve dysfunction, 49, 125 Myasthenia gravis causes, 265 diagnosis, 266 differential diagnosis, 267 electrophysiology, 270 epidemiology, 263 medication, 267 myasthenic crisis, 263 pathophysiology, 263 pregnancy, 268 prognosis, 267 signs, 263 symptoms, 263 therapy, 267 Mycobacterium avium intracellular (MAI), 282 Myoedema, 7

348 Myokymia, 7, 75, 133, 134, 272, 279 Myotonia congenita clinical presentation, 306 diagnosis, 306 differential diagnosis, 307 pathogenesis, 306 prognosis, 307 therapy, 307 Myotonic dystrophy (DM), 13, 32, 36, 41, 276, 290, 291, 293, 307, 308 N Neck-Tongue Syndrome, 119 Nemaline myopathy (NM), 282, 299, 300 Nerve and muscle rehabilitation electrotherapy, 57 endurance training, 55 exercise therapy, 55 femoral neuropathy, 59 lymphatic drainage, 57 massage techniques, 58 myopathies, 60 neural plasticity, 56–57 occupational therapy, 56 orthoses, 56 outcome measurements, 53–55 peroneal neuropathy, 59 plexopathies, 59 polyneuropathies, 59–60 primary nerve surgery, 57 strength training, 55 symptoms and treatment goals, 58 thermotherapy, 58 tibial neuropathy, 59 ulnar neuropathy, 58–59 ultrasound, 58 wrist cock-up splint, 58 Nerve biopsy, 133, 222, 227, 229, 240, 241, 244, 251, 252, 257 Nerve entrapment syndrome, 107, 170 Nerve grafting, 94 Nerve sheath ganglia, 206 Nerve sheath tumors, 205 Neuralgic amyotrophy, 142, 143 Neuroborreliosis causes, 232 diagnosis, 232 differential diagnosis, 233 epidemiology, 232 pathophysiology, 232 signs/symptoms, 232 therapy, 233 Neurofibromas, 205 Neuromuscular disease clinical methodology, 1 clinical phenomenology fasciculations, 6 motor function, 4–6 muscle cramps, 8 muscle tone, 8

Index myoedema, 7 myokymia, 7 myotonia, 7 neuromyotonia, 7 neuropathic tremor, 8 painful legs and moving toes, 7 pseudoathetosis, 7 reflex testing, 8 rippling muscle, 7 sensory symptoms, 8–10 EMG techniques, 14 evidence based medicine, 1 genetic testing, 16 laboratory tests, 14–16 motor NCV studies, 11 MRI, 16 muscle biopsy, 16–17 nerve biopsy, 16–17 patient evaluation, 3 peripheral nerve, 12 physical examination, 4 Schwann cell cytoplasm, 2 sensory information, 3 sensory NCV studies, 12 sensory qualities autonomic function, 11 clinical pitfalls, 11 gait, 11 ice cream headache, 10 Kehr’s sign, 10 myalgia, 10 negative symptoms, 8 neuropathic pain, 11 positive symptoms, 8 radicular/peripheral nerve distribution, 10 Raynaud’s phenomenon, 10 small fiber neuropathy, 10 Tinel-Hoffmann sign, 10 ultrasound imaging, 16 Neuromuscular hamartomas, 206 Neuromuscular transmission (NMT) disorder botulism, 271 congenital myasthenic syndromes, 269 Lambert-Eaton myasthenic syndrome, 269–271 myasthenia gravis, 263–269 neuromyotonia, 271–272 Neuromyotonia, 248, 271–272 Neuronopathy, 230, 255, 259 Neuropathic pain anticonvulsants, 258 CRPS, 128 Neuropathic tremor, 8 Neuropathy, 241, 254 demyelinating neuropathy, 260 Neurothekomas, 206 Neutral lipid storage disease and myopathy (NLSDM), 306 Neutral lipid storage disease with ichthyosis (NLSDI), 306 9-hole peg test, 54 NMT–neuromuscular junction transmission, 263 NMT disorders, 263

Index Nonaka distal myopathy (NDM), 298 Notalgia paresthetica, 107, 108 Nutritional neuropathy cobalamin neuropathy, 241 post-gastroplasty neuropathy, 241 pyridoxine neuropathy, 241–242 Strachan’s syndrome, 242 thiamine neuropathy, 242 tocopherol neuropathy, 242–243 O Obturator nerve (L2-L4), 178, 184, 185 Occipital neuralgia, 119 Occupational therapy, 234, 258, 296 Oculomotor nerve disease anatomy, 72 cavernous sinus, 72 clivus and plica petroclinoidea, 72 diagnosis, 74 differential diagnosis, 74 extracranial pathway/orbit, 72 fascicular lesions, 72 intracranial pathway, 72 nuclear lesions, 72 orbital lesion, 72 pathogenesis, 74 prognosis, 74 signs, 73 symptoms, 73 therapy, 74 transtentorial herniation, 72 Oculopharyngeal muscular dystrophy (OPMD), 41, 267, 293–294 Olfactory nerve disease, 69 Optic nerve disease, 70–72 Orator’s hand, 147 Orthostatic hypotension (OH), 11, 53, 54, 221, 231, 236, 243, 244, 255, 269, 270, 321, 325, 327–329 Osteosclerotic myeloma, 224 Overlap myositis (OM), 281–282 P Palisaded encapsulated neuromas, 206 Panplexopathy, 121 Paramyotonia congenita, 277, 307, 308 Paraneoplastic neuropathy clinical presentation, 255 diagnosis, 255 differential diagnosis, 255 pathogenesis, 255 signs, 255 symptoms, 255 therapy, 255 Paraproteinemias critical illness neuropathy, 248 MGUS, 223 multiple myeloma neuropathy, 222 POEMS syndrome, 224–225 vasculitis neuropathy, 226–230

349 Waldenström’s macroglobulinemia, 224 Parasympathetic nervous system (PSNS), 323 Parosmia and anosmia, 69, 70 Parsonage-Turner syndrome (neuralgic amyotrophy), 125, 165, 169 Pectoral nerve, 173, 174 Perineuromas, 205 Peripheral mononeuropathies, 91, 258 Peripheral nerve amyloidosis, 226 Peripheral nerve surgery clinical presentation, 45 end-to-end coaptation, 45–47 end-to-side coaptation, 48–49 nerve grafting, 48 nerve transfer, 49 neurolysis, 49–51 timing, 45 Peripheral nerve tumors amputation neuromas, 206 benign nerve tumors, 206 hybrid tumors, 206 malignant peripheral nerve involvement, 206 malignant peripheral nerve sheath tumors, 206 Morton’s neuromas, 206 nerve sheath tumors, 205 perineuromas, 205 treatment, 207 WHO classification, 205 Peroneal nerve, 195–197 Peroneal neuropathy, 59 Phantom breast syndrome, 175 Phrenic nerve, 163–165 Piriformis syndrome, 191 Plexopathies brachial plexus, 120–128 cervical plexus/cervical spinal nerves anatomy, 119 clinical presentation, 119 diagnosis, 119 differential diagnosis, 120 pathogenesis, 119 symptoms, 119 therapy, 120 lumbosacral plexus, 131–136 thoracic outlet syndromes arterial, 130 disputed neurogenic, 131 traumatic, 131 true neurogenic, 129–130 venous, 128 POEMS syndrome, 216, 224–225, 237, 238 Poliomyelitis, 84, 90, 91, 318 Polymyositis (PM) clinical presentation, 277 diagnosis, 277 differential diagnosis, 278 pathogenesis, 277 prognosis, 278 therapy, 278

350 Polyneuropathies alcohol polyneuropathy, 243 amyloid neuropathy, 225–226 cancer, 256 chemotherapy-induced neuropathies, 255, 257–260 lymphoma/leukemia, 256 motor neuron disease syndrome, 228 neoplastic neuropathy, 257 paraneoplastic neuropathy, 255 terminal neuropathy, 224 classic stocking-glove distribution, 217 clinical presentation, 217–218 drug-induced neuropathy, 257 hereditary motor and sensory neuropathy HNA, 254 HNPP, 252–253 HSAN, 216, 218 porphyria, 254–255 hereditary neuropathy dHMN, 254 HMSN, 253 infectious neuropathy herpes zoster neuropathy, 231–232 human immunodeficiency virus-1 neuropathy, 230–231 leprosy, 233–234 neuroborreliosis, 232–233 inflammatory, 260 inflammatory neuropathy acute motor axonal neuropathy, 234–235 AIDP, 234 AMSAN, 235–236 CIDP, 237–240 demyelinating neuropathy, 224, 237, 249 Miller Fisher syndrome, 236–237 multifocal motor neuropathy, 240 metabolic diseases diabetic autonomic neuropathy, 220–221 distal symmetric polyneuropathy, 222 DPN, 218–219 nutritional neuropathy cobalamin neuropathy, 241 post-gastroplasty neuropathy, 241 pyridoxine neuropathy, 241–242 Strachan’s syndrome, 242 thiamine neuropathy, 242 tocopherol neuropathy, 242–243 paraproteinemias MGUS, 223 multiple myeloma neuropathy, 222 POEMS syndrome, 224–225 vasculitis neuropathy, 226–230 Waldenström’s macroglobulinemia, 224 proximal symmetric polyneuropathy, 217 toxic neuropathy industrial agents, 245–246 metals, 246–247 Porphyria, 85, 90, 216, 234, 254–255 Posterior abdominal wall, 178 Posterior cutaneous femoral nerve, 189 Posterior cutaneous nerve of forearm, 162 Posterior interosseus nerve (PIN), 160 Posterior tarsal tunnel syndrome, 201, 202 Postmastectomy syndrome (PMS), 175

Index Post-polio syndrome (PPS), 55, 315, 318–319 anatomy and pathophysiology, 318 causes, 318 diagnosis, 318 differential diagnosis, 318 epidemiology, 318 signs, 318 symptoms, 318 therapy, 318 Postural orthostatic tachycardia syndrome (POTS), 329 Primary carnitine deficiency (PCD), 304–306 Pronator Teres syndrome, 147 Proximal symmetric polyneuropathy, 217 Pseudoathetosis, 7 “Pseudo”-radial nerve paralysis, 161 Pseudoradicular symptoms, 106, 112 Psoas fascia, 178 Psoas/iliacus syndrome, 135 Psoas major muscle, 178 Pudendal, 133 Pudendal nerve, 183, 184 Pudendal nerve dysfunction, 109, 132, 133 Pyridoxine neuropathy, 241–242, 245 Q Quadratus lumborum fascia, 178 Quadratus lumborum muscle, 178 Quadrilateral space syndrome (QSS), 142, 170, 173 Quantitative sensory testing (QST), 54 Quantitative sudomotor axon reflex test (QSART), 221, 322, 325, 329 R Radial nerve anatomy, 158, 159 axilla, 158 causes, 161 clinical syndrome, 158 differential diagnosis, 161 lesions at elbow, 160 posterior cutaneous nerve of arm and forearm, 161 posterior interosseus nerve, 160 radial tunnel syndrome, 160 tennis elbow, 160 therapy, 161 torsion, 160 upper arm, 158, 160 wrist drop, 160 Radial tunnel syndrome, 160 Radiculomyelitis, 105 Radiculomyeloneuropathy, 105 Radiculopathy cauda equina symptoms anatomy, 114 diagnosis, 115 pathogenesis, 114 signs, 114 symptoms, 114 cervical radiculopathy anatomy, 103 diagnosis, 106 differential diagnosis, 106

Index treatment, 106 lumbar and sacral radiculopathy anatomy, 109 conservative treatment, 113 diagnosis, 113 differential diagnosis, 113 myotomal distribution, 111 pathogenesis, 111 prognosis, 113 radicular sensory findings, 111 signs, 110 surgical techniques, 113 symptoms, 109 thoracic radicular nerves anatomy, 106 diagnosis, 108 differential diagnosis, 109 pathogenesis, 107 prognosis, 109 signs, 107 symptoms, 107 therapy, 109 Ramsey hunt syndrome, 85, 89, 98 Raynaud’s phenomenon, 10, 277, 281 Rectus abdominis, 177 Reflex syncope, 321, 325, 327–329 Retroperitoneal hematoma, 134, 221 Rheumatoid arthritis (RA), 6, 85, 95, 105, 119, 229, 230, 244, 263, 281 Rippling muscle disease, 7, 292 Rostral cupula, 178 Rotator cuff rupture, 171 Rotator cuff tears and nerve injuries, 171 Rucksack paralysis, 124 S Saphenous nerve, 188 Saphenous nerve dysfunction, 48, 49, 113, 133, 136 Schwannomas, 205 Sciatic nerve, 190–194 Sclerotoma, 142 Sclerotome, 139, 142 Sensory neuronopathy (SSN), 230, 241, 255 Shoulder impingement syndrome, 172 6-minute walk test (6MWT), 37, 54, 287, 302 Sjögren’s syndrome, 77, 255, 279 Spermatic and inguinal neuralgia, 180 Spinal and bulbar muscular atrophy (SBMA), 29 anatomy and pathophysiology, 315 caused by, 315 diagnosis, 315 differential diagnosis, 315 epidemiology, 315 signs, 315 symptoms, 315 Spinal and bulbar muscular atrophy (SBMA), 315, 316 Spinal muscular atrophy (SMA), 6, 21, 36–38, 41, 89, 240, 251, 254, 290, 298, 315–318 anatomy and pathophysiology, 316 causes, 316 diagnosis, 316 epidemiology, 315

351 signs, 316 symptoms, 316 Split hand, 158 Spondylolisthesis, 109, 111–113 Sprengel syndrome, 168 Strachan’s syndrome, 71, 216, 242 Subcostal nerve (T12), 178 Subscapular nerve (inferior scapular nerve), 166, 167 Sudomotor tests, 325 Superficial peroneal nerve lesions, 196 Superior and inferior gluteal nerves, 132 Superior gluteal nerve, 181 Suprascapular nerve, 120, 129, 166 Sural nerve, 202, 203 Sural nerve dysfunction, 5, 12, 16, 47, 48, 113, 136, 220, 228, 238, 244, 253, 257, 315 Sympathetic nervous system (SNS), 321 Sympathetic skin response test (SSRT), 322, 325 Symptoms and treatment goals, median neuropathy, 58 Systemic lupus erythematous (SLE), 77, 81, 90, 279, 281 Systemic sclerosis (SSc), 281 T Tennis elbow, 145 Tennis leg, 194 Thenar branch, 146 Thoracic outlet syndromes (TOS), 121, 130 arterial, 130 disputed neurogenic, 131 traumatic, 131 true neurogenic, 129–130 Thoracic outlet syndromes (TOS), 128–131 Thoracic radicular nerve disease abdominal muscle weakness, 107 anatomy, 106 diagnosis, 108 differential diagnosis, 109 herpes zoster, 107–109 pathogenesis, 107 prognosis, 109 signs, 107 symptoms, 107 therapy, 109 Thoracic radicular nerves, 106–109 Thoracic spinal nerves, 107, 174, 175 Thoracodorsal nerve, 120, 169, 170 Thoracolumbar fascia, 178 Tibialis posterior tendon transfer, 197 Tibial lateral plantar nerve, 199 Tibial nerve (posterior tibial nerve), 197, 198, 200 Tibial nerve lesions, 198 Tibial nerve schwannoma, 200 Tilt table test, 325, 327, 329 Timed get up and go test (TUG), 54 Tongue atrophy, 263, 265, 313–315 Toxic myopathies, 276 clinical presentation, 283 diagnosis, 284 differential diagnosis, 284 pathogenesis, 284 prognosis, 285 therapy, 284

352 Toxic neuropathy industrial agents, 245–246 metals, 246–247 Toxic optic neuropathy, 71 Transient loss of consciousness (TLOC), 323 Transverse abdominal muscle, 178 Trigeminal nerve disease anatomy, 75 diagnosis, 77 features, 75 metastasis with lesions, 79 neurologic examination, 77 pathogenesis, 77 signs, 76 symptomatic trigeminal neuralgia, 77 symptoms, 76 therapy, 79 tic douloureux, 77 Trochlear nerve disease, 74, 75, 100 Truncal mononeuropathies abdominal walls and innervation anterior abdominal wall muscles and innervation, 176 external and internal oblique muscle, 177 fascia, 178 lower cupula, 176 muscular components, 178 muscular innervation of the abdominal cavity, 176 nerves involved, 178 posterior abdominal muscle, 178 posterior wall, 176 rectus abdominis, 177 rostral cupula, 178 transverse abdominal muscle, 178 upper cupula, 176 breast intercostobrachial nerve, 175 latissimus dorsi flap, 175 male gynecomastia, 175 phantom pain, 175 PMS, 175 scar pain and neuroma, 175 cluneal nerves, 181, 182 dorsal scapular nerve, 165 genitofemoral nerve, 180, 181 iliohypogastric nerve, 178, 179 ilioinguinal nerve, 179, 180 innervation of shoulder complex structure and function, 170 muscles, 170 nerve entrapment syndrome, 170, 171 neuronal structures passing through the shoulder, 170 quadrilateral space syndrome, 170 rotator cuff tears and nerve injuries, 171 scapular winging, 172, 173 sensory innervation, 170 shoulder impingement syndrome, 172 intercostobrachial nerve, 175 long thoracic nerve, 168, 169 pectoral nerve, 173, 174 phrenic nerves anatomy, 163 causes, 164 diagnosis, 164 differential diagnosis, 164 lesion sites, 164 symptoms, 163

Index therapy, 165 pudendal nerves, 183, 184 subscapular nerve (inferior scapular nerve), 166, 167 superior and inferior gluteal nerve, 181 suprascapular nerve, 165, 166 thoracic spinal nerves, 174, 175 thoracodorsal nerve, 169, 170 U Ulnar nerve anatomy, 153 causes, 155 diagnosis, 155 differential diagnosis, 157 motor disability, 155 prognosis, 157 signs and symptoms, 154 treatment, 157 ulnar tardy palsy, 157 wrist lesion, 155 Ulnar tardy palsy, 157 Ulnar-to-median Riche–Cannieu anastomosis, 147 Upper extremities, mononeuropathies axillary nerve anatomy, 139 causes, 141, 142 diagnosis, 142 differential diagnosis, 142 rotator cuff lesions, 142 signs, 141 symptoms, 141 cutaneous nerves of forearm (see Cutaneous forearm nerves) cutaneous nerves of shoulder and upper arm, 144 digital nerves of hand, 162, 163 median nerves anatomic variations, 146, 147 anatomy, 145–147 anterior interosseous syndrome, 148 carpal tunnel syndrome, 148, 150 clinical syndrome, 147, 148 conservative therapy, 152 diagnosis, 149 differential diagnosis, 149 distal median nerve bifurcation, 147 invasive therapy, 152 lesions above elbow, 147 lesions at elbow, 147 lesions in shoulder, axilla, upper arm, 147, 149 musculocutaneous nerve anatomy, 143 causes, 143 diagnosis, 144 neuralgic amyotrophy, 143 signs and symptoms, 143 nerves around the elbow anatomy, 145 joint innervation, 145 nerve lesions, 145 sensory innervation, 145 radial nerve (see Radial nerve) ulnar nerves anatomy, 153 causes, 155 diagnosis, 155, 157 differential diagnosis, 157

Index

353 motor disability, 155 prognosis, 157 signs and symptoms, 154 treatment, 157 ulnar tardy palsy, 157 wrist lesion, 155

V Vagus nerve disease, 89–93, 96, 242, 323 Vasculitic neuropathy, 227–230, 237–238, 256, 257 Venipuncture, 143, 147

Venous, 130–131 Very-long-chain acyl-CoA dehydrogenase deficiency (VLACD), 304 Vestibular nerve disease, 86, 88–89 Visual analog scale (VAS), 54, 55 W Waldenström’s macroglobulinemia, 77, 89, 260 Wartenberg’s syndrome, 161, 189 Wegener’s granulomatosis, 97 Welander distal myopathy (WDM), 298