Motor Neuron Disease

1 Motor Neuron Disease: The Clinical Syndrome.- Classification of Motor Neuron Diseases.- Spinal Muscular Atrophies.- Motor Neuron Disease (Amyotrophic Lateral Sclerosis).- Clinical Features.- Other Clinical Syndromes of MND.- Outcome of MND.- Possible Associations of MND with Other Diseases.- Poliomyelitis.- Hexosaminidase Deficiency (GM2 Gangliosidosis).- MND and Plasma Cell Dyscrasia.- Hyperparathyroidism and Thyrotoxicosis.- AIDS.- Creutzfeldt-Jakob Disease.- Other Disorders.- Diagnosis and Investigation.- Differential Diagnosis.- 2 Epidemiology of Motor Neuron Disease.- Some Important Clinical Patterns of Motor Neuron Disease/Amyotrophic Lateral Sclerosis (MND/ALS).- Frequency of MND/ALS and its Determinants.- Prevalence Rate.- Incidence Rate.- Mortality Rate.- High-Risk Foci.- Risk Factors.- Case-Control Studies.- Ecological Studies.- Definite Risk Factors for MND/ALS.- Familial Aggregation of MND/ALS and Separation of Genetic Entities.- Aetiological Hypotheses.- 3 Familial Motor Neuron Disease.- The Case for Studying Familial Motor Neuron Disease: Rapid Development of Techniques of Molecular Genetics and their Successful Application.- The Problems: Few Families, Clinical and Pathological Heterogeneity and Incomplete Penetrance.- Profile of Familial Motor Neuron Disease.- Phenotypic Variation in FMND.- Neuropathology.- Linkage Analysis in Familial Motor Neuron Disease.- What is Involved in Locating a Defective Gene?.- Linkage to Chromosome 21 Markers.- Identification of Mutations in FMND.- Mutations of Human Cu,Zn SOD in FMND.- The Significance of Mutations of Cu,Zn SOD.- The Next Steps: Identification of other MND genes.- Improvements in DNA Markers.- Choice of Families — Informative Families.- Statistical Analysis.- Candidate Genes.- Other Motor Neuron Disorders: the Spinal Muscular Atrophies.- Androgen Receptors and Typical Motor Neuron Disease (ALS).- Summary and Future Prospects.- 4 Pathology of Motor System Disorder.- Physiological Anatomy of the Motor System.- Axonal Transport in the Motor System.- Macroscopic Pathology of ALS.- Microscopic Pathology of ALS.- Motoneuron Loss.- “Senescent Changes” in ALS.- Cytoplasmic Inclusions in ALS.- Proximal and Distal Axonopathy in ALS.- Tract Degeneration.- Conclusions.- 5 The Pathology of Motor Neuron Disease.- General Autopsy and Neuropathological Findings.- Motor Cortex.- Subcortical White Matter and Cortical Pyramidal Tracts.- Central Grey Matter and Basal Ganglia.- Brainstem and Cranial Nerve Nuclei.- Lower Motor Neurons and Corticospinal Tracts.- Spinocerebellar Pathways.- Sensory Systems.- Autonomic Nervous System.- Peripheral Nerve.- Muscle.- Intellect, the Frontal Lobe and Parkinsonism.- Relation to Other Neuronal Degenerations.- 6 Alternative Approaches to the Pathology of Motor Neuron Disease.- Animal Models in the Study of MND.- Naturally Occurring Animal Models of MND.- Neurotoxic Substances.- Neurotropic Viruses.- Axonal Sprouting and the Motor End Plate.- Axonal Transport.- Slow Axonal Transport.- Fast Axonal Transport.- Axonal Transport in MND.- Selective Neuronal Vulnerability in MND: Onuf’s Nucleus and Other Nuclei.- Conclusion.- 7 The Molecular Pathology of Motor Neuron Disease.- The Cytoskeleton and Cytoskeletal Pathology in Neurodegenerative Disorders.- Neurofilaments and Neurofilamentous Pathology in MND.- Ubiquitin, the Stress Response and Neuronal Damage in MND.- The Ubiquitin Conjugation Pathway.- Selection of Substrates for Conjugation and Degradation.- Ubiquitin-Protein Ligase.- Protein Degradation and Regeneration of Free Ubiquitin.- Ubiquitin and MND.- Morphological Features of Ubiquitin-Immunoreactive Inclusions in MND.- Clinicopathological Correlations.- Pathogenic Significance of Ub-IR Inclusions in MND.- Conclusions.- 8 Neurochemistry of Motor Neuron Disease.- Excitatory Amino Acids in Plasma and CSF in MND.- Glutamate, Glutamate Dehydrogenase (GDH) and Excitotoxicity.- N-Acetyl-Aspartyl-Glutamate (NAAG) and MND.- Plasma Cysteine and Metabolism of Sulphur-Containing Compounds.- Glycine and GABA.- Spinal Cholinergic Systems.- Monoamines.- Neuropeptides.- Thyrotropin-Releasing Hormone (TRH).- Substance P.- Calcitonin Gene-Related Peptide (CGRP).- Neurotrophic Factors and Motoneuronal Death.- Summary and Conclusions.- 9 Calcium and Aluminium in the Chamorro Diet: Unlikely Causes of Alzheimer-Type Neurofibrillary Degeneration on Guam.- Geology, Villages and Water Sources of Guam and Rota.- Implications of These Findings.- Conclusions.- 10 Toxicology of Motor Systems.- Mechanistic Basis of Neuronotoxicity.- General Considerations.- Neuroexcitatory Amino Acid Receptors in the Central Nervous System.- The Excitotoxic Hypothesis of Neuronal Death.- Glutamate as an Endogenous and Exogenous Factor in Neurological Disease.- General Considerations.- Neurotoxicity of Exogenous Glutamate.- Glutamate Metabolism and Neurological Disease.- Glutamate Metabolism in Motor Neuron Disease.- Other Endogenous Factors: Sulphur-Containing Amino Acids.- Amino Acids Containing Oxidised Sulphur Atoms.- Cysteine and Cystine.- Cystine and Glutamate Transport.- Cysteine, Sulphate and Motor Neuron Disease.- Exogenous Factors.- General Considerations.- Lathyrus sativus Seed.- Cycas circinalis Seed.- Nitschia pungens.- Non-NMDA Receptors on Glia.- Summary.- 11 Theories of Causation.- Toxins.- Ageing.- Trophic Factors.- Viruses.- Metabolic Abnormalities.- Autoimmunity.- 12 Neurotrophic Factors and Neurodegeneration.- The Neurotrophins.- Nerve Growth Factor.- Brain-Derived Neurotrophic Factor.- Neurotrophins -3, -4, and -5.- Ciliary Neurotrophic Factor and Related Cytokines.- Platelet-Derived Growth Factor.- The Fibroblast Growth Factors.- Insulin-like Growth Factors.- Epidermal Growth factor.- Growth Factor Receptors and Signal Transduction Pathways.- Neurotrophic Factors and Neurodegeneration.- NGF and Alzheimer’s Disease.- Motor Neuron Disease and Neurotrophic Factors.- CNTF and Motor Neuron Disease.- BDNF, Motor Neurons and Parkinson’s Disease.- 13 Somatic Motoneurons and Descending Motor Pathways. Limbic and Non-limbic Components.- Somatic Motoneurons in Spinal Cord and Brainstem.- Somatic Motoneurons in the Spinal Cord.- Somatic Motoneurons in the Brainstem.- Local Projections to Motoneurons.- Recurrent Motoneuronal Axon Collateral Projections to Motoneurons.- Muscle Spindle Afferent Projections to Motoneurons in Spinal Cord and Brainstem.- Propriospinal Pathways.- Bulbospinal Interneurons Projecting to Motoneurons.- Pathways Controlling Respiration and Abdominal Pressure.- Pathways Involved in Micturition Control.- Descending Pathways of Somatic Motor Control Systems.- The Medial Descending System.- The Lateral Descending System.- Descending Pathways Involved in Limbic Motor Control Systems.- Pathways Projecting Diffusely to the Spinal Gray Matter.- Projections from the Mesencephalon to Caudal Brainstem and Spinal Cord.- Projections from the Hypothalamus to Caudal Brainstem and Spinal Cord.- Projections from Amygdala and Bed Nucleus of the Stria Terminalis to Caudal Brainstem and Spinal Cord.- Projections from the Prefrontal Cortex to Caudal Brainstem and Spinal Cord.- Conclusions.- The First Motor System.- The Second Motor System.- The Third Motor System.- 14 Neurophysiological Changes in Motor Neuron Disease.- Electromyography (EMG).- Fasciculations in MND.- Fibrillation Potentials and Positive Sharp Waves.- Other Spontaneous Discharges in MND.- Motor Unit Potentials in MND.- Fatigue, Decrement and Neuromuscular Jitter.- Motor Conduction in MND.- Late Responses in Motor Conduction Studies.- Sensory Conduction in MND.- Central Motor Conduction in MND.- Stages of the Disease: EMG Criteria.- Electrophysiological Assessment in Treatment Trials.- Differential Diagnosis of MND by its Electrophysiological Features.- 15 Clinical Pharmacology of Motor Neurons.- Trophic Factors and Motor Neurons.- Neurotransmitters, Neuropeptides and Receptors in the Ventral Horn.- Excitotoxins and Motor Neurons.- Assessment Tools for Drug Effects on Human Motor Neurons.- Clinical Measurements.- Electrophysiology.- TRH and TRH Analogues.- Trophic and Protective Effects of TRH on Motor Neurons.- Neurophysiological Data.- Spasticity.- Drugs Used in Spasticity.- Conclusion.- 16 The Management of Motor Neuron Disease.- Background.- Epidemiology.- Who Looks After MND Patients?.- The Organisation of Services.- The Hospital.- Keyworker.- Phase I: The Stage of Diagnosis.- The Diagnosis.- “Treatment”.- Prognosis.- Telling the Diagnosis.- Phase II: The Stage of Deterioration Without Major Disability.- Phase III: The Phase of Major Disability With Multiple Problems.- Bulbar Problems in Motor Neuron Disease.- Salivary Dribbling (Drooling).- Dysphagia.- Choking.- Dysarthria and Communication Problems.- Respiratory Failure.- Weight and Nutrition.- Constipation.- Management of Constipation.- Pain.- Control of Pain.- Decreasing Mobility.- Wheelchairs.- Leg Swelling.- Weakness of Muscles.- Sleeping Problems.- Emotional Problems.- Equipment.- Phase IV: The Terminal Stage.- Use of Narcotics.- Audit.- Appendix I. MND Table of Responsibilities.- 17 Clinical Trial Methodology.- Measurement Techniques.- Natural History.- Sample Size Determination.- The Problem of Drop-outs.- Controls.- Statistical Analysis.- Regulatory Processes.- 18 New Therapeutic Approaches: Rationale and Results.- Rationale and Results.- The Use of Thyrotropin-Releasing Hormone (TRH).- Approaches to Counteract Excitatory Amino Acids.- Treatment of Immunological Abnormalities.- Approaches to Trace Metal Intoxication.- Antiviral Agents.- Enhancing Axonal Sprouting and Regeneration.- Neurotrophic Factors.- Other Approaches.- Conclusion.- 19 Living with Motor Neuron Disease.