Amyotrophic Lateral Sclerosis (Neurological Disease and Therapy, 78)

Front cover......Page 1
Foreword......Page 10
Preface......Page 14
Contents......Page 18
Contributors......Page 28
FRANCOIS-AMILCAR ARAN (1817–1861)......Page 34
GUILLAUME BENJAMIN ARMAND DUCHENNE DE BOULOGNE (1806–1875)......Page 35
JEAN-MARTIN CHARCOT (1825–1893)......Page 36
JOSEPH FRANCOIS FELIX BABINSKI (1857–1932)......Page 37
JOSEPH JULES DEJERINE (1849–1917)......Page 39
HIROSHI KAWAHARA (1858–1918)......Page 40
W. RUSSELL BRAIN (1895–1966)......Page 41
HENRY LOUIS GEHRIG (1903–1941)......Page 42
LEONARD T. KURLAND (1921–2001)......Page 43
FORBES H. NORRIS (1928–1993)......Page 44
EDWARD H. LAMBERT (1915–2003)......Page 45
REFERENCES......Page 46
EPIDEMIOLOGIC CLASSIFICATION OF FORMS OF ALS......Page 50
METHODOLOGICAL CONSIDERATIONS IN ALS RESEARCH......Page 51
DESCRIPTIVE STUDIES Incidence and Mortality Data......Page 52
Epidemiology of Western Pacific ALS......Page 54
The Role of Clusters in ALS......Page 55
EPIDEMIOLOGY OF FAMILIAL ALS......Page 56
RISK FACTORS FOR ALS......Page 57
Physical Activity......Page 60
Occupational......Page 61
Lifestyle Risk Factors......Page 64
FUTURE DIRECTIONS......Page 65
CONCLUSION......Page 66
REFERENCES......Page 67
INTRODUCTION......Page 76
PATHOLOGY OF SPORADIC ALS......Page 77
Cytoplasmic Inclusions......Page 78
Chromatolytic Cells and Cell Death......Page 86
Ventral Spinal Roots and Peripheral Nerves......Page 88
Other......Page 89
PROGRESSIVE MUSCULAR ATROPHY AND MULTIFOCAL MOTOR NEUROPATHY......Page 90
PRIMARY LATERAL SCLEROSIS......Page 92
ALS-DEMENTIA......Page 93
FAMILIAL ALS......Page 94
REFERENCES......Page 95
GENETIC SUSCEPTIBILITY TO ALS......Page 114
TRANSMISSIBLE AGENTS IN ALS......Page 115
Viral Diseases......Page 117
AUTOIMMUNITY IN ALS......Page 119
Paraneoplastic ALS......Page 120
ALS and Lymphoma......Page 122
Monoclonal Gammopathy (Plasma Cell Dyscrasia) and ALS/MND......Page 123
ACKNOWLEDGMENTS......Page 124
REFERENCES......Page 125
UPPER MOTOR NEURON FEATURES......Page 132
Initial Symptoms......Page 134
Fasciculations......Page 136
Bulbar Lower Motor Neuron Symptoms and Signs......Page 138
Upper Extremity Lower Motor Neuron Symptoms and Signs......Page 140
Weakness of Axial and Trunk Musculature......Page 142
Respiratory Features......Page 143
Sphincter Involvement......Page 144
CONCLUSION......Page 145
REFERENCES......Page 146
INTRODUCTION AND TERMINOLOGY......Page 150
CLINICAL FEATURES......Page 151
NEUROIMAGING CORRELATES......Page 153
GENETICS OF FTD AND ALS......Page 154
Classical Neuropathology of ALS......Page 156
Neuropathology of Frontotemporal Degeneration in ALS......Page 159
Tau Metabolism......Page 162
FTD Associated with Motor Neuron Degeneration......Page 163
FRONTOTEMPORAL DYSFUNCTION IN ALS: CLINICAL IMPACT AND PROGNOSIS......Page 164
CONCLUSIONS......Page 166
REFERENCES......Page 167
APPROACHES TO MENDELIAN INHERITED ALS......Page 174
Mendelian Inherited ALS......Page 181
Association Studies in SALS......Page 188
FALS......Page 190
REFERENCES......Page 191
INTRODUCTION......Page 200
Nerve Conduction Studies......Page 201
Standard Needle Electromyography......Page 202
Diagnostic Criteria......Page 204
Electrophysiologic Differential Diagnosis......Page 205
Neuromuscular Junction Dysfunction......Page 208
LOWER MOTOR NEURON DISEASE MARKERS: MOTOR UNIT NUMBER ESTIMATION Basic Concepts of Motor Unit Number Estimation......Page 210
Overview of MUNE Methods......Page 211
MUNE and Amyotrophic Lateral Sclerosis......Page 213
Magnetic Resonance Imaging......Page 216
Magnetic Resonance Spectroscopy......Page 217
Functional Imaging Studies......Page 218
UPPER AND LOWER MOTOR NEURON DISEASE MARKERS: TRANSCRANIAL MAGNETIC STIMULATION Introduction: Basic Concepts of Transcranial Magnetic Stimulation......Page 219
TMS Techniques and Measures in ALS......Page 220
SUMMARY......Page 223
REFERENCES......Page 224
CLASSIFICATION OF ALS......Page 234
Acquired ALS......Page 235
Inherited ALS......Page 237
THE DIAGNOSTIC PROCESS......Page 238
Differential Diagnosis of Bulbar-Onset ALS......Page 240
Differential Diagnosis of PMA-Onset ALS......Page 242
Differential Diagnosis of PLS-Onset ALS......Page 246
EMG Studies......Page 248
Clinical Laboratory Studies......Page 249
PRESENTATION OF THE DIAGNOSIS......Page 251
CONCLUSIONS......Page 253
REFERENCES......Page 254
INTRODUCTION......Page 260
PRECLINICAL PHASE......Page 261
CLINICAL SUBTYPES Spinal ALS......Page 262
Clinical Variants......Page 266
FAMILIAL ALS AND GENETIC RISK FACTORS......Page 271
VARIABLES OF PROGNOSTIC SIGNIFICANCE Age......Page 274
Gender......Page 275
El Escorial Criteria......Page 276
The Effect of Sub-Specialist Care......Page 277
CONCLUSION......Page 278
REFERENCES......Page 281
11 Specifying Motor Neuron Identity in the Developing Spinal Cord......Page 290
SPECIFICATION OF GENERIC MOTOR NEURON IDENTITY......Page 291
SPECIFICATION OF MOTOR NEURON COLUMNAR IDENTITY......Page 296
ESTABLISHING THE DIVISIONAL IDENTITY AND AXONAL TRAJECTORY OF LMC NEURONS......Page 299
THE EMERGENCE OF MOTOR NEURON POOL IDENTITY......Page 300
APPLIED INSIGHTS FROM PATHWAYS OF MOTOR NEURON DIFFERENTIATION: TURNING EMBRYONIC STEM CELLS INTO MOTOR NEURONS......Page 303
ACKNOWLEDGMENTS......Page 304
REFERENCES......Page 305
INTRODUCTION......Page 312
ALS OR THE TALE OF THE LUMPERS AND THE SPLITTERS......Page 313
SOD1 Mutations......Page 314
Other Genetic Causes for ALS......Page 315
NATURAL COURSE OF ALS......Page 316
Motor Neuron Pathology......Page 318
Non-Neuronal Pathology......Page 319
NEURONAL DEATH PATHWAYS IN ALS Programmed Cell Death (PCD)—Definition......Page 320
Programmed Cell Death in ALS......Page 321
Excitotoxicity......Page 322
Hypoxia and Motor Neuron Vulnerability......Page 323
COMMON PATHOGENIC THEMES FOR MOTOR NEURON DEGENERATION......Page 324
CONCLUSION......Page 325
REFERENCES......Page 326
GLUTAMATERGIC NEUROTRANSMISSION......Page 332
Classification of Glutamate Receptors......Page 334
EXCITOTOXICITY......Page 341
Acute Excitotoxicity......Page 343
Role of Specific Glutamate Receptor Subtypes in Mediating Excitotoxicity......Page 344
Non-NMDA Receptors......Page 345
Metabotropic Receptors......Page 347
Levels of Glutamate and Glutamate Metabolism in ALS......Page 348
Toxicity of CSF from ALS Patients......Page 349
Alterations in the Expression of Glutamate Receptor Subtypes in ALS......Page 350
Glutamate Transporters and Excitotoxicity in ALS......Page 351
Interaction Between SOD1 Mutations and the Glutamate Neurotransmitter System......Page 353
Effects of Mutant SOD1 on Glutamate Transporters......Page 354
Mitochondrial Involvement and Excitotoxicity in ALS......Page 355
Potentiation of Excitotoxicity by Inflammatory Mediators......Page 356
Vulnerability Factors Predisposing Motor Neurons to Excitotoxicity......Page 357
EXCITOTOXICITY AND OTHER MOTOR SYSTEM DISORDERS......Page 358
REFERENCES......Page 359
INTRODUCTION......Page 372
SUPEROXIDE DISMUTASE......Page 373
SOD MUTATIONS AND ALS......Page 375
The Role of Copper in ALS......Page 376
AGGREGATION......Page 377
Zinc-Deficient SOD......Page 378
ZINC-DEFICIENT DIETS......Page 381
REFERENCES......Page 382
PATHOLOGIC EVIDENCE FOR NON-NEURONAL CELL INVOLVEMENT IN HUMAN ALS......Page 388
NON-NEURONAL INVOLVEMENT IN A MURINE MODEL OF FALS......Page 390
TRANSGENIC, KNOCKOUT, AND CHIMERA MICE: GENETIC EVIDENCE FOR NON-NEURONAL CELL INVOLVEMENT IN ALS......Page 393
MECHANISMS OF NEURONAL AND NON-NEURONAL CELL INTERACTION......Page 398
GROWTH FACTORS: BENEFICIAL NEURONAL–NON-NEURONAL INTERACTIONS......Page 401
NON-PROTEIN MEDIATED CELL–CELL INTERACTIONS IN ALS......Page 404
REFERENCES......Page 406
INTRODUCTION......Page 414
THE GENETICS OF ALS SOD1......Page 415
Caspases......Page 416
IAPs: Inhibitors of Apoptosis......Page 418
Family Feud: Bcl-2 Members in ALS......Page 419
Caspases......Page 420
Contagious Apoptosis: ‘‘The Kindergarten Effect’’......Page 421
REFERENCES......Page 422
INTERMEDIATE FILAMENT METABOLISM Developmental Expression Patterns......Page 428
Molecular Motors......Page 431
Alterations in IF Expression in ALS......Page 432
Transgenic Mouse Models of Altered IF Metabolism......Page 433
Post-Translational Modifications of NF Expression in ALS......Page 439
NON-IF PROTEIN AGGREGATION......Page 440
Tau Protein......Page 441
CONCLUSIONS......Page 442
REFERENCES......Page 443
INTRODUCTION......Page 450
Mitochondrial Degeneration Is an Early Event in Motor Neuron Degeneration Pathway......Page 451
Mitochondrial Vacuolation by Intermembrane Space Expansion (MVISE)......Page 452
How Mutant SOD1 Damages Mitochondria: The Mechanistic Models......Page 453
CONSEQUENCES OF MITOCHONDRIAL DYSFUNCTION AND DEGENERATION Vulnerability of Motor Neuron Mitochondria and the Role of Excitotoxicity......Page 454
Dysfunction of Oxidative Phosphorylation and Elevation of ROS......Page 455
Mitochondrial DNA Mutations and Their Dysfunction......Page 456
Mitochondrial Dysfunction and Cell Death......Page 457
REFERENCES......Page 458
INTRODUCTION......Page 468
ENVIRONMENTAL FACTORS AND ALS CLUSTERS......Page 470
A MURINE MODEL OF ALS-PDC In Vivo Cycad Toxicity: Motor, Cognitive, and Sensory Phenotypes......Page 473
In Vitro Studies of Cycad-Induced Neurotoxicity......Page 477
DISCUSSION......Page 478
REFERENCES......Page 479
BACKGROUND Linkage Analysis......Page 482
Association Analysis......Page 484
ASSOCIATION STUDIES FOR SPORADIC ALS......Page 486
Neurofilament Accumulation......Page 487
Oxidative Stress and Mitochondria......Page 488
Apolipoprotein E......Page 489
Phenotypic Modifiers......Page 490
Gene–Environment Interaction......Page 491
REFERENCES......Page 492
INTRODUCTION......Page 498
WHY DO PROTEINS AGGREGATE?......Page 501
PROTEIN AGGREGATION IN ALS AND OTHER MOTOR NEURON DISORDERS......Page 502
PROTEIN AGGREGATION AND THE MOLECULAR PATHOLOGY OF FAMILIAL ALS......Page 503
THE UBIQUITIN-PROTEASOME SYSTEM AND ALS......Page 505
INADEQUATE CELLULAR DEFENSE......Page 508
PROPOSED MECHANISM OF SOD1 AGGREGATION IN ALS......Page 510
CONCLUDING REMARKS......Page 511
REFERENCES......Page 512
INTRODUCTION......Page 520
In Humans......Page 521
EVIDENCE FOR A ROLE IN INITIATING DISEASE......Page 524
EVIDENCE FOR A ROLE IN AMPLIFYING DISEASE......Page 526
EVIDENCE FOR A ROLE IN REPAIR AND PROTECTION......Page 527
REFERENCES......Page 529
THERAPEUTIC CONTEXT......Page 538
Preclinical Models for ALS Therapy......Page 539
Protein-Based Therapy of ALS......Page 540
Recombinant Viral Vectors as Carriers of Therapeutic Instructions......Page 542
Cellular and Molecular Targets: The Delivery Issue......Page 547
Ex Vivo Gene Therapy......Page 549
CONCLUSION......Page 550
REFERENCES......Page 551
INTRODUCTION......Page 558
Models of Motor Neuron Diseases Due to Spontaneous Mutations......Page 559
Transgenic and Knockout Models of Motor Neuron Diseases......Page 562
Mutations Causing Motor Neuron Disease of Unknown Pathogenic Significance in Human Paralytic Diseases......Page 569
Cycad Seed Products (Cycas Circinals)......Page 571
INFECTION-MEDIATED MODELS OF MOTOR NEURON DISEASES......Page 572
CONCLUSION......Page 573
REFERENCES......Page 574
THE DRUG SCREENING PROCESS TODAY High-throughput Screening: Principles and Practice......Page 584
Chemical Libraries......Page 586
Biological Readouts for Screening......Page 588
Screening on Specific Targets Vs. Phenotypic Screens......Page 590
Molecular and Cellular Screens Focused on Mutant SOD......Page 591
Importance of Screening Using Cell Types Related to the Disease Process......Page 592
Existing Cell Models for Motor Neuron Screening......Page 593
Techniques for Screening Using Motor Neurons......Page 596
Need for New Cell Models Directly Related to ALS......Page 597
A Screening Platform Based on Primary Neurons......Page 599
From Hit Compound to Drug Candidate......Page 601
Review of Recent Clinical Trials......Page 602
New Drugs for ALS......Page 606
REFERENCES......Page 610
DRUG DEVELOPMENT AND TRANSLATIONAL RESEARCH......Page 616
CHOOSING TRIAL CANDIDATES: PATIENT INCLUSION AND EXCLUSION CRITERIA......Page 618
ASSESSMENTS AND OUTCOME MEASURES......Page 619
Primary and Secondary Outcomes......Page 620
The Open-Label Study......Page 625
The Randomized, Double-Blind, Placebo-Controlled, Parallel Study......Page 626
BIOSTATISTICAL SUPPORT......Page 627
Statistical Analyses......Page 628
The Institutional Review Board, Informed Consent and Protection of Human Subjects......Page 629
ETHICAL ISSUES The Ethics of Clinical Research......Page 630
Patient Obligations......Page 631
REFERENCES......Page 632
INTRODUCTION......Page 638
THE MULTIDISCIPLINARY CARE CLINIC......Page 640
The MDC Clinic Members......Page 641
Consultants......Page 644
The ALS Care System......Page 645
Difficulties Facing MDC Clinics......Page 646
Germany and the ALS/MND Clinic in Munich......Page 647
Canada and the ALS Clinic at Montreal Neurological Hospital, McGill University......Page 648
Ireland and the MDC Clinic in Dublin......Page 650
The United Kingdom and the King’s MND Care Center......Page 652
France and the ALS Center at Salpe´trie` re and Regional ALS Centers......Page 656
Belgium and the NMRC of the University Hospital Gasthuisberg in Leuven......Page 657
Japan and the Kitasato University Higashi Hospital......Page 659
Switzerland and the MND Clinic in St. Gallen......Page 661
REFERENCES......Page 663
28 The ALS Patient CARE Program—North American Patient CARE Database......Page 666
METHODS Background......Page 667
Data Collection......Page 668
Study Coordinating Center......Page 669
RESULTS Overview......Page 670
Symptomatic Treatment......Page 673
Non-Invasive Positive Pressure Ventilation......Page 674
Palliative Care......Page 675
Caregivers......Page 676
Epidemiologic Studies......Page 677
Limitations of the Database......Page 678
REFERENCES......Page 679
SYMPTOMS RELATED TO BULBAR WEAKNESS Sialorrhea......Page 682
Thick Phlegm......Page 685
SYMPTOMS RELATED TO UPPER MOTOR NEURON DEGENERATION Emotional Lability......Page 686
Spasticity......Page 687
Bladder Urgency......Page 688
SYMPTOMS RELATED TO IMMOBILITY Edema......Page 689
Sleep Disruption......Page 690
Fatigue......Page 691
Constipation......Page 692
Pain......Page 693
SYMPTOMS RELATED TO ANXIETY AND DEPRESSION......Page 694
SUMMARY......Page 695
REFERENCES......Page 696
INTRODUCTION......Page 698
Randomized, Controlled Clinical Trials of Riluzole......Page 699
Safety......Page 700
Impact on ALS Care......Page 701
Targeting Oxidative Stress......Page 702
Antiglutamate Strategies......Page 708
Neuronal Rescue by Growth Factors......Page 709
Antiviral Strategies......Page 710
Other Neuroprotective Strategies......Page 711
ISSUES THAT MAY HAVE NEGATIVELY AFFECTED RECENT ALS CLINICAL TRIALS Validity of Animal Models for Drug Testing in ALS......Page 712
Outcome Measures......Page 713
Clinical Trial Design and Implementation......Page 715
REFERENCES......Page 716
INTRODUCTION......Page 724
EXERCISE......Page 725
MUSCLE WEAKNESS......Page 727
Assistive Devices—Mobility Aids......Page 728
Orthoses......Page 730
Wheelchairs......Page 734
Adaptive Devices and Equipment......Page 737
Adhesive Capsulitis......Page 741
Pharmacological Management of Pain......Page 742
SPASTICITY......Page 743
Diagnosis of Dysarthria and Communication Impairments......Page 744
Management of Dysarthria and Communication Impairments......Page 745
Diagnosis of Dysphagia......Page 747
Management of Dysphagia......Page 749
REFERENCES......Page 750
INTRODUCTION......Page 754
THEORETICAL ISSUES Nutritional Complexities in ALS and the Risk for Nutritional Insufficiency......Page 755
The Concept of Energy Intake and Energy Expenditure......Page 756
Identifying ALS Patients with Impending Nutritional Insufficiency......Page 758
Synergism Between Nutritional and Respiratory Support......Page 759
PRACTICAL ISSUES Monitoring of the Nutritional State and Swallowing......Page 760
Early Nutritional Intervention......Page 761
PEG as an Alternative Route for Nutrition......Page 762
Vitamins and Supplements......Page 763
GLOSSARY......Page 766
REFERENCES......Page 767
PULMONARY PHYSIOLOGY AND PATHOPHYSIOLOGY Physiology of Respiration......Page 770
Respiratory Muscle Weakness......Page 771
Pattern of Restrictive Lung Impairment in ALS......Page 772
Pathophysiology of Sleep Disturbances in ALS......Page 773
CLINICAL EVALUATION Symptoms of Respiratory Muscle Fatigue......Page 774
Physical Examination......Page 775
Pulmonary Function Testing......Page 776
Arterial Blood Gases, Nocturnal Oximetry, Sleep Studies, and Serum Chloride......Page 779
General Care......Page 780
Treatment of Respiratory Failure......Page 782
SUMMARY......Page 787
REFERENCES......Page 788
INTRODUCTION......Page 794
Caregiver Burden and Distress......Page 795
Special Issues Regarding Spousal and Adult Child Caregivers......Page 798
Respite Service for Family Caregivers......Page 799
SEXUALITY AND INTIMACY......Page 800
ADDRESSING THE NEEDS OF CHILDREN......Page 801
SPIRITUALITY......Page 802
Assessing the Patient’s Spiritual Needs......Page 803
Issues and Types of Grief in ALS......Page 805
Resources for the Patient and Family......Page 806
END-OF-LIFE CHOICES AND EXPECTATIONS......Page 808
BEING ‘‘PRESENT’’ WITH THE DYING PATIENT......Page 809
PSYCHOLOGICAL ASPECTS OF WITHDRAWAL OF VENTILATION......Page 810
REFERENCES......Page 811
RECOGNIZING THE TERMINAL PHASE......Page 816
ETHICAL ISSUES......Page 817
SUPPORTING THE PATIENT......Page 820
SUPPORTING SIGNIFICANT OTHERS......Page 823
SUPPORTING THE PROFESSIONALS......Page 824
Opioids......Page 825
Sedatives......Page 827
SUMMARY......Page 828
REFERENCES......Page 829
INTRODUCTION......Page 832
PALLIATIVE CARE AND HOSPICE USE IN THE TERMINAL PERIOD......Page 833
FAMILY AS CAREGIVERS......Page 834
DAILY CAREGIVING CHALLENGES IN END-OF-LIFE CARE......Page 835
CAREGIVER BURDEN, DISTRESS, AND DEPRESSION......Page 836
CAREGIVER RECOGNITION OF DYING AND THE END OF LIFE......Page 837
MEDICAL PROFESSIONALS IN THE HOME......Page 838
CONCLUSION......Page 839
REFERENCES......Page 840
End-of-Life Decisions: ALS Compared to Other Terminal Conditions......Page 844
Ethical Principles in End-of-Life Care......Page 845
Determination of Decision-Making Capacity......Page 846
ALS Specialists’ Views, Understanding, and Experiences in End-of-Life Care......Page 848
Decisions About Life-Sustaining Treatments......Page 849
Sedation and Pain Relief for Terminally Ill Patients......Page 851
Physician-Assisted Suicide and Euthanasia......Page 852
The Approach to the Patient Who Wishes to Hasten Death......Page 854
REFERENCES......Page 855
Index......Page 858
About the Editors......Page 864
Back cover......Page 873