Acquired Neuromuscular Disorders: Pathogenesis, Diagnosis and Treatment

Introduction
Acquired Neuromuscular Disorders and Covid-19 Pandemia
Patients with Neuromuscular Disease (NMD) at Higher Risk
Advice for Patients with Acquired NMD to Avoid Covid-19 Infection
Consequences of the Risk of Covid-19 Infection During Treatments Used in NMD Patients
Importance to Assure Ventilatory Services (Home Ventilators, etc.)
Acquired NMD Admission to Hospital for Symptoms of Covid-19 Infection
Effects on Neuromuscular Disease Treatments by Covid-19 Common Drugs
Neuromuscular Specialists Advice for Emergency Medical and Intensive Care Decisions on Admission to Units, and Care in Acquired Neuromuscular Patients
Patient Support by Neuromuscular Centres
Vaccination
Acknowledgements
Contents
Part I: Diagnostic Tools
1: Autoantibodies in Neuromuscular Disorders
1.1 Antibodies in Autoimmune Neuromuscular Disorders
1.1.1 General Principles
1.2 Autoantibodies to Neuromuscular Junction Components
1.2.1 Myasthenia Gravis
1.2.1.1 Autoantibodies to Acetylcholine Receptor
1.2.1.2 Autoantibodies to MuSK
1.2.1.3 Autoantibodies to LRP4
1.2.1.4 Low-Affinity Antibodies to AchR
1.2.1.5 Autoantibodies to Cortactin
1.2.1.6 Striational Antibodies
1.2.2 Lambert-Eaton Myasthenic Syndrome (LEMS)
1.2.3 Autoantibody Testing
1.2.3.1 Diagnosis
1.2.3.2 Correlation with Disease Severity
1.3 Antibodies in Inflammatory Neuropathies
1.3.1 General Considerations
1.3.2 Guillain-Barre Syndrome and Variants
1.3.2.1 Anti-ganglioside Antibodies
1.3.2.2 Other Autoantibodies in GBS
1.3.3 Chronic Inflammatory Neuropathies
1.3.4 Chronic Inflammatory Demyelinating Polyradiculoneuropathy
1.3.4.1 Nodo-Paranodal Autoantibodies
1.3.4.2 Antibodies Against Myelin Proteins
1.3.4.3 Anti-ganglioside Antibodies
1.3.5 Multifocal Motor Neuropathy
1.3.6 Polyneuropathy Associated to Monoclonal Gammopathy of Unknown Significance (MGUS-P)
1.3.7 Other Diseases of the Peripheral Nerve
1.3.7.1 Neuromyotonia
1.4 Myositis-Specific Autoantibodies
1.4.1 General Considerations
1.4.1.1 Anti-synthetase Antibodies
1.4.1.2 Anti-Mi2 Antibodies
1.4.1.3 Anti-TIF-1γ Antibodies
1.4.1.4 Anti-SRP Antibodies
1.4.1.5 Anti-HMGCoAR Antibodies
1.4.1.6 Anti-MDA5 Antibodies
1.4.1.7 Anti-SAE Antibodies
1.4.1.8 Anti-NXP2 Antibodies
1.4.1.9 Anti-cN1A Antibodies
References
2: Electromyography
2.1 Introduction
2.2 Anatomo-Physiological Basis
2.3 Plan of the Electrodiagnostic Examination
2.4 General Findings
2.4.1 Resting Activity
2.4.2 MUP Analysis
2.4.3 MU Recruitment
2.5 Specific Findings
2.5.1 Muscular Dystrophies
2.5.2 Inflammatory Myopathies
2.5.3 Endocrine Myopathies
2.5.4 Metabolic Myopathies
2.5.5 Congenital Myopathies
2.5.6 Myopathies with Myotonic Discharges
2.5.7 Myasthenia Gravis
2.5.8 Congenital Myasthenic Syndromes (CMS)
2.5.9 Lambert-Eaton Myasthenic Syndrome
2.5.10 Botulism
References
3: Imaging of the Muscle in Idiopathic Inflammatory Myopathies
3.1 Introduction
3.2 MRI Imaging of Muscular Diseases
3.2.1 Volume
3.2.2 Fat Replacement
3.2.3 Edema
3.2.4 The Role of Whole-Body MRI (WB-MRI)
3.3 Conventional MRI of Dermatomyositis and Polymyositis
3.4 MRI Advanced Techniques in Inflammatory Idiopathic Myopathies
3.5 Imaging of Inclusion Body Myositis
3.6 Imaging of Other Acquired Neuromuscular Diseases
3.7 Other Imaging Options
References
4: Ultrasound Evaluation of Peripheral Nerves: Evidence, Clinical Application, and Recent Developments
4.1 Basics of Ultrasound
4.2 Literature History of Nerve Ultrasound
4.3 Nerve Ultrasound in Clinical Practice
4.3.1 Fundamentals
4.3.2 Association with Electrophysiology and Magnetic Resonance
4.3.3 Scores
4.4 Main Diseases
4.4.1 Entrapment Neuropathies
4.4.2 Traumatic Nerve Injuries
4.4.3 Immune-Mediated Neuropathies
4.4.4 Charcot-Marie-Tooth Disease
4.5 Other Diseases
4.5.1 Amyotrophic Lateral Sclerosis
4.5.2 Morton’s Neuroma
4.5.3 Neuralgic Amyotrophy
4.5.4 Nerve Tumors
4.5.5 Vasculitic Neuropathies
4.6 Ultrasound-Guided Nerve Intervention
4.7 New Developments and Future Directions
References
5: Magnetic Resonance Imaging of the Peripheral Nerve
5.1 Introduction
5.2 Magnetic Resonance Neurography
5.3 Guillain–Barre Syndrome
5.4 Chronic Immune-Mediated Neuropathies
5.4.1 CIDP
5.4.2 Multifocal Motor Neuropathy
5.5 Diabetic Polyneuropathy
5.6 Amyloid Neuropathy
5.7 Sarcoidosis
References
Part II: Clinical Myology Entities
6: The Spectrum of Inflammatory Myopathies: Dermatomyositis, Polymyositis, Necrotizing Myositis, Anti-synthetase Syndrome-overlap Myositis, and Inclusion-Body Myositis
6.1 Introduction
6.2 General Clinical Features Relevant to All IM
6.3 Dermatomyositis
6.4 Polymyositis
6.5 Necrotizing Autoimmune Myositis (NAM)
6.6 Inclusion-Body Myositis (IBM)
6.7 Diagnosis
6.7.1 Serum Muscle Enzyme Levels
6.7.2 Electromyography
6.7.3 MRI
6.7.4 Muscle Biopsy
6.7.5 Autoantibodies
6.8 Pathogenesis
6.8.1 Dermatomyositis
6.8.2 Polymyositis and IBM
6.9 Treatment of DM, PM, and NAM
6.10 Treatment of IBM
References
7: Necrotizing Autoimmune Myopathy
7.1 Introduction
7.2 Clinical Features and Epidemiology
7.3 Pulmonary and Cardiac Manifestations
7.4 Risk Factors and Etiologies
7.5 Diagnostic Workup and Laboratory Testing
7.5.1 Antibodies in NAM
7.5.2 Serum CK
7.5.3 Electromyography (EMG)
7.5.4 Muscle Imaging
7.5.5 Muscle Biopsy
7.6 Diagnosis and Differential Diagnosis
7.7 Pathophysiology
7.8 Treatment and Prognosis
References
8: Statin Myopathy
8.1 Epidemiological Impact of Statins in Cardiovascular Disease
8.2 Definition of Statin Myotoxicity
8.3 Epidemiology of Statin-Related Myotoxicity
8.4 Pathogenesis of Statin-Induced Myopathy
8.5 Clinical Evaluation of Suspected Statin Myopathy
8.5.1 Clinical Features
8.5.2 Diagnosis and Monitoring
8.5.3 Risk Factors for Statin Myopathy
8.6 Management of Statin-Induced Myopathies
8.6.1 Creatine Kinase <4x ULN
8.6.2 Creatine Kinase >4x ULN and <10x ULN
8.6.3 Creatine Kinase >10x ULN
8.6.4 Complete Statin Intolerance
References
9: Myasthenia Gravis
9.1 Introduction
9.2 Epidemiology
9.3 Pathogenesis
9.3.1 MG with Abs to AChR
9.3.2 MG with Abs to MuSK
9.3.3 MG with Abs to LRP4
9.4 Clinical Features
9.5 Diagnosis
9.5.1 Serum Ab Assay
9.5.2 Electrophysiological Studies
9.5.3 Pharmacological Test (Response to AChE-Is)
9.6 Treatment
9.6.1 Symptomatic Treatment
9.6.2 Thymectomy
9.6.3 Short-Term Immunomodulation
9.6.4 Immunosuppressive Therapy
9.6.4.1 Steroids
9.6.4.2 Immunosuppressants
9.6.4.3 Therapies in Developmental Stage
References
10: Endocrinological Myopathies
10.1 Thyroid-Related Myopathies (Table 10.1)
10.1.1 Thyrotoxic Myopathy
10.1.2 Thyrotoxic Periodic Paralysis (TPP)
10.1.3 Hypothyroidism
10.2 Parathyroid-Related Myopathy
10.2.1 Hyperparathyroidism
10.2.2 Hypoparathyroidism
10.3 Steroid Myopathy
10.4 Myopathy Due to Excess of Adrenocorticotrophic Hormone (ACTH)
10.5 Drug-Related Myopathies (Table 10.2)
10.5.1 Valproate
10.5.2 Opioids and Clofibrate
10.5.3 Chloroquine, Hydroxychroloquine, Emetine, Vincristine, and Colchicine
10.6 Nutritional and Secondary Deficiency States (Table 10.3)
10.6.1 Carnitine
10.6.2 Myopathies Caused by Nutritional Deficiency (Table 10.3)
10.6.3 Vitamin E Deficiency
10.6.4 Iron and Copper Deficiency
References
11: Vitamin D Deficiency in Muscle
11.1 Epidemiology of Vitamin D Deficiency
11.2 Biochemistry of Vitamin D
11.3 Causes of Vitamin D Deficiency
11.4 Effects of Vitamin D on Muscles and Nervous System
11.5 Myopathy and Myalgia
11.6 Myotonic Dystrophy
11.7 Myasthenia Gravis
11.8 Drug-Induced Myopathy
11.9 Painful Peripheral Diabetic Neuropathy
11.10 Treatment and Complications
11.11 Conclusions
References
12: Intensive Care Unit-Acquired Weakness
12.1 Introduction
12.2 Prevalence and Risk Factors
12.3 Clinical Signs
12.4 Diagnosis
12.4.1 Manual Muscle Testing
12.4.2 Electrophysiological Testing
12.4.3 Muscle Ultrasound
12.4.4 Muscle Biopsy
12.4.5 Nerve Biopsy
12.5 Pathophysiology
12.5.1 CIM
12.5.1.1 Muscle Wasting
12.5.1.2 Muscle Contractile Dysfunction
Decreased Excitability of Sarcolemma
Myosin Loss
Inflammation
Uncoupling of Excitation-Contraction
Mitochondrial Dysfunction/Abnormalities
12.5.2 CIP
12.5.2.1 Microvascular Injury and Membrane Depolarization Defect
12.6 Biomarkers
12.7 Prevention and Therapy
12.8 Long-Term Disability After ICU-Acquired Weakness
12.9 Update on Experimental Pharmacological Interventions in Intensive Care Unit-Acquired Weakness
12.9.1 Experimental Rat Model of CIM and Ventilator-Induced Diaphragmatic Dysfunction
12.9.2 Vamorolone
12.9.3 BGP-15
References
13: Acquired Immune-Mediated Rippling Muscles With and Without Myasthenia Gravis
13.1 Introduction
13.2 Inherited Rippling Muscle Disease
13.2.1 Symptoms and Signs
13.2.2 Phenotypic Variability
13.2.3 Caveolin-3 and Caveolae
13.2.4 Caveolin-3 Immunohistochemistry and Western Blots
13.2.5 Electron Microscopy
13.3 Acquired Immune-Mediated Rippling Muscles with Myasthenia Gravis
13.3.1 Symptoms and Signs
13.3.2 Laboratory Findings
13.3.2.1 Muscle Enzymes
13.3.2.2 Autoantibodies to NMJ
13.3.2.3 Anti-skeletal Muscle Antibodies in Acquired Immune-Mediated Rippling Muscles with Myasthenia Gravis
13.3.2.4 Electrophysiological Studies
13.4 Muscle Biopsies in Immune-Mediated RMD
13.4.1 Immunohistochemistry in iRMD
13.4.2 Western Blots in iRMD
13.4.3 Electron Microscopy in iRMD
13.5 Immune-Mediated Rippling Muscles Without Myasthenia Gravis
13.5.1 Isolated Presumably Immune-Mediated Cases of Rippling Muscle Disease
13.6 Comparison of Pathology on Muscle Biopsies of hRMD and iRMD with and without Myasthenia Gravis
13.6.1 Homogeneous Vs. Mosaic Pattern of Caveolin-3 Immunohistochemistry
13.6.2 Caveolin-3 Absent or Markedly Decreased with hRMD and Decreased or Slightly Decreased with iRMD
13.6.3 Caveolae Absent in Sarcolemma of hRMD and Decreased in iRMD
13.7 Other Autoimmune Disorders Reported with iRMD
13.7.1 Other Autoimmune Disorders Reported with iRMD with Myasthenia Gravis
13.7.2 Other Autoimmune Disorders Reported with iRMD Without Myasthenia Gravis
13.8 Treatment of Acquired Immune-Mediated Rippling Muscle Disease with Myasthenia Gravis
13.8.1 Treatment of Immune-Mediated RMD Without Myasthenia Gravis
13.9 Where and What Are the Immunogenic Targets in Immune-Mediated Rippling Muscles?
13.9.1 Post-synaptically Near the Neuromuscular Junction?
13.9.2 On or Near Caveolar Lipid Raft?
13.9.3 In the Triad or T-Tubules or Near Their Openings in the Sarcolemmal Membrane?
13.9.3.1 Caveolin-3 and T-Tubules
13.9.3.2 Caveolin-3 LGMD and T-Tubules
13.9.3.3 Ryanodine and Dihydropyridine Receptors
13.9.4 Skeletal Muscle Autoantibodies
13.9.4.1 Titin
13.10 Why Are Rippling Muscle Diseases with Immune-Mediated and Genetic Etiologies Important?
13.10.1 Rippling Muscle Diseases Are Also Important from a Scientific Viewpoint Because
13.10.1.1 Mechanoprotection in Dystrophic and Non-dystrophic Myopathic Skeletal Muscle
13.10.1.2 Clinical and Electrophysiologic Evidence for Mechanosensitive Stretch-Activated Channels in Neuromuscular Disorders in Humans
13.10.1.3 May Use Both Genetic and Immunological Clues and Tools to Unravel Pathophysiologic Mechanisms in Diseases with Clearly Different Etiologies
13.10.2 Immune-Mediated Rippling Muscle Diseases Are Treatable
13.11 Summary
References
Part III: Neurogenic Disorders
14: Idiopathic Chronic Immune-Mediated Neuropathies: Chronic Inflammatory Demyelinating Polyradiculoneuropathy and Multifocal Motor Neuropathy
14.1 Chronic Inflammatory Demyelinating Polyradiculoneuropathy
14.1.1 Introduction
14.1.2 Clinical Presentation
14.1.3 Variants of CIDP
14.1.4 CIDP with Associated Diseases
14.1.5 Etiology and Pathogenesis
14.1.6 Diagnosis of CIDP
14.1.7 Treatment of CIDP
14.2 Multifocal Motor Neuropathy
14.2.1 Introduction
14.2.2 Clinical Features
14.2.3 Diagnosis of MMN
14.2.4 Etiology and Pathogenesis
14.2.5 Therapy
References
15: Immune Neuropathies
15.1 General Introduction
15.2 Diagnostic Guidelines
15.2.1 Electrodiagnostic Features
15.2.2 Histologic Features
15.3 Immune Neuropathies
15.3.1 Guillain-Barré Syndrome
15.3.1.1 Variants of Guillain-Barré Syndrome
Acute Motor Axonal Neuropathy and Acute Motor and Sensory Axonal Neuropathy
Miller-Fisher Syndrome
Pharyngeal-Cervical-Brachial Variant
Acute Small Fiber Sensory Neuropathy
15.3.2 Chronic Inflammatory Demyelinating Polyradiculopathy
15.3.2.1 Variants of Chronic Inflammatory Demyelinating Polyneuropathy
Chronic Immune Sensory Polyradiculopathy
Chronic Inflammatory Motor Polyradiculopathy
Chronic Inflammatory Sensorimotor Polyradiculopathy
Multifocal Acquired Demyelinating Sensory and Motor Neuropathy or Lewis-Sumner Syndrome
CMAN (Chronic Motor Axonal Neuropathy)
CIDP with Antibodies Against Nodal and Paranodal Proteins
Novel Variant of CIDP
15.3.3 Multifocal Motor Neuropathy
15.3.4 Other Immune-Mediated Neuropathies
15.3.4.1 Monoclonal Gammopathies
IgG/IgA Monoclonal Gammopathy of Undetermined Significance
IgM MGUS (with or Without Anti-MAG Antibodies)
Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Gammopathy, and Skin Abnormalities
15.3.4.2 Paraneoplastic Neuropathies (Anti-ANNA-1 [Anti-Hu] Antibodies)
15.3.4.3 CANOMAD and CANDA
15.3.4.4 Facial-Onset Sensory and Motor Neuropathy Syndrome with Anti-MAG or Anti-sulfatide IgG
15.3.4.5 Sjögren Syndrome with Neuropathy
15.3.4.6 Nodo-Paranodopathy Case Report: Sensory Neuropathy with Anti-GT1a and GQ1b Antibodies Associated with Cold Urticaria
15.3.4.7 Immune-Mediated Polyradiculoneuropathy Among Swine Abattoir Workers
15.4 Available Treatment Options
15.4.1 Intravenous Immunoglobulin
15.4.2 Subcutaneous Immunoglobulin
15.4.3 Corticosteroids
15.4.4 Plasma Exchange
15.4.5 Monoclonal Antibody-Based Treatments
15.4.6 Immunosuppressive Drugs
15.4.7 Treatments for Immune Neuropathy Subtypes
15.5 Discussion and Conclusions
References
16: Amyotrophic Lateral Sclerosis: Neurochemical Biomarkers
16.1 Introduction
16.2 Neurofilaments
16.2.1 Structure of Neurofilaments and Biological Rationale as Biomarkers
16.2.2 CSF Neurofilaments for the Diagnosis of ALS
16.2.3 Blood Neurofilaments for the Diagnosis of ALS
16.2.4 Prognostic Value of Neurofilaments
16.2.5 Relationship of Neurofilaments with Disease Characteristics
16.2.6 Longitudinal Studies of Neurofilaments
16.2.7 Antibodies Against Neurofilaments
16.3 Neuroinflammatory Biomarkers
16.3.1 The Involvement of Neuroinflammation in ALS
16.3.2 Limited Role of Cytokines and Other Mediators as Biomarkers
16.3.3 Chitinases and Chitotriosidase
16.3.4 Chit1
16.3.5 The Other Chitinases
16.3.6 Perspectives for the Use of Chitinases as ALS Biomarkers
References
17: Paraneoplastic Diseases of the Peripheral Nervous System
17.1 Introduction
17.1.1 Subacute Sensory Neuronopathy
17.1.2 Monoclonal Gammopathy and Neuropathy
17.1.3 Paraneoplastic Vasculitic Neuropathy
17.1.4 Paraneoplastic Dysautonomic Neuropathy
17.1.5 Other Paraneoplastic Neuropathies
17.1.6 Motor Neuron Disease
17.2 Syndromes of the Neuromuscular Junction
17.2.1 Presynaptic Disorders
17.2.1.1 Acquired Neuromyotonia
17.2.1.2 Lambert-Eaton Myasthenic Syndrome
17.2.2 Post-synaptic Disorders
17.2.2.1 Myasthenia Gravis
17.3 Differential Diagnosis
17.3.1 Neoplastic Neuropathies
17.3.2 Chemotherapy-Induced Peripheral Neuropathy (CIPN)
17.3.2.1 Acute Effects of Chemotherapy
17.3.2.2 Late Effects
17.3.2.3 Autoimmune Effects
17.3.2.4 Mimics
17.4 Conclusions
References
18: Diabetic Neuropathy
18.1 Definition
18.2 Epidemiology
18.3 Clinical Subtypes
18.4 Complications
18.5 Pathology and Pathophysiology
18.5.1 Multifocal Neuropathies
18.6 Risk Factors and Pathogenesis
18.7 Diagnosis and Laboratory Investigations
18.7.1 Diabetes and Prediabetes
18.7.2 DSP and SFN
18.7.3 DAN
18.7.4 Asymmetrical Focal/Multifocal Neuropathies
18.7.5 Other or Additional Causes of Neuropathy
18.8 Therapy
18.8.1 Disease-State Modifiers
18.8.2 Symptomatic Treatment of Pain
18.8.3 Treatment of DAN
18.8.4 Treatment of LSRP
References
19: Infectious Neuropathies
19.1 Introduction
19.2 Hepatitis C Virus (HCV)-Related Neuropathies
19.3 Human Immunodeficiency Virus (HIV)-Related Neuropathies
19.3.1 Distal Symmetrical Polyneuropathy (DSP)
19.3.2 Demyelinating Neuropathy
19.3.3 Mononeuropathy Multiplex (MM)
19.3.4 Progressive Polyradiculopathy (PLP)
19.3.5 Diffuse Infiltrative Lymphocytosis Syndrome (DILS)
19.3.6 IRIS and Peripheral Nervous System
19.4 Leprosy
19.5 Borrelia burgdorferi-Related Neuropathies
19.6 COVID-19 Pandemic and PNS Involvement
19.6.1 Critical Illness Polyneuropathy
19.6.2 Guillain Barré Syndrome (GBS)
19.6.3 Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
19.6.4 Nerve Injuries
References
20: Toxic Neuropathies
20.1 Introduction
20.2 General Aspects of PNS Neurotoxicity
20.3 Drug-Induced Peripheral Neurotoxicity
20.3.1 Antineoplastic Drugs
20.3.2 Antiarrhythmic Drugs
20.3.3 Antiretroviral Drugs
20.4 Alcohol-Related Peripheral Neuropathy
20.5 Environmental and Industrial Toxics
20.5.1 Organic Solvents
20.5.2 Industrial Chemicals
20.5.3 Heavy Metals
20.6 Toxicity of Local Anesthetic Drugs
References
Index