Amyotrophic Lateral Sclerosis (Clinical)

Overview

Definition

• Neurodegenerative disease involving both upper motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology neurons Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. Nervous System: Histology (UMNs) and lower motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology neurons Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. Nervous System: Histology (LMNs)
• Also known as Lou Gehrig’s disease Lou Gehrig’s disease Amyotrophic lateral sclerosis (ALSs), also known as Lou Gehrig’s disease, is a sporadic or inherited neurodegenerative disease of upper motor neurons (UMNs) and lower motor neurons (LMNs). Als is the most common progressive motor neuron disease in North America, primarily affecting men and individuals of caucasian ethnicity. Amyotrophic Lateral Sclerosis
• Progressive disease leading eventually to paralysis and subsequently death
• There is no cure.

Classification^[8]

• Sporadic Sporadic Selective IgA Deficiency (aka acquired): no other known occurrences of the disease within a family
• Familial ALS ALS Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a sporadic or inherited neurodegenerative disease of upper motor neurons (UMNs) and lower motor neurons (LMNs). ALS is the most common progressive motor neuron disease in North America, primarily affecting men and individuals of Caucasian ethnicity. Amyotrophic Lateral Sclerosis: multiple occurrences of the disease within a family

Epidemiology^[8,16,22]

• Most common progressive motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology neuron disease
• 90%–95% of cases are sporadic Sporadic Selective IgA Deficiency
• 10% of cases are inherited as an autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance trait.
• Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency: 5.2 per 100,000 in the United States
• Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: 1.6 per 100,000 in the United States
• Age at onset: 40 years
• Men > Women: 1.3–1.5
• Caucasians more commonly affected

Risk factors^[8]

• Age
• Family history Family History Adult Health Maintenance
• Cigarette smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases 

Etiology^[3,8]

The cause of sporadic Sporadic Selective IgA Deficiency ALS ALS Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a sporadic or inherited neurodegenerative disease of upper motor neurons (UMNs) and lower motor neurons (LMNs). ALS is the most common progressive motor neuron disease in North America, primarily affecting men and individuals of Caucasian ethnicity. Amyotrophic Lateral Sclerosis is unknown. However, there are multiple contributing factors:

• Inherent instability of the mutant protein superoxide dismutase Superoxide dismutase An oxidoreductase that catalyzes the reaction between superoxides and hydrogen to yield molecular oxygen and hydrogen peroxide. The enzyme protects the cell against dangerous levels of superoxide. Myeloperoxidase Deficiency type 1 Type 1 Spinal Muscular Atrophy ( SOD1 SOD1 A superoxide dismutase (sod1) that requires copper and zinc ions for its activity to destroy superoxide free radicals within the cytoplasm. Mutations in the sod1 gene are associated with amyotrophic lateral sclerosis-1. Amyotrophic Lateral Sclerosis), leading to free radical Free Radical Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. Nitroimidazoles toxicity Toxicity Dosage Calculation
• Gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics mutations perturb RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure processing, transport, and metabolism:
  • C9orf73 C9orf73 A widely-expressed protein of approximately 400 to 500 amino acids. Its n-terminal region (denn domain) interacts with rab GTP-binding proteins and may regulate autophagy, as well as protein transport to endosomes. Expansion of the ggggcc hexanucleotide repeat in the first intron of the c9orf72 gene is associated with frontotemporal dementia with amyotrophic lateral sclerosis (ftdals1). Amyotrophic Lateral Sclerosis
  • TDP-43
  • Fused in sarcoma (FUS)
• Cascading inflammatory responses
• Accelerated cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death
• Excessive concentrations of glutamate Glutamate Derivatives of glutamic acid. Included under this heading are a broad variety of acid forms, salts, esters, and amides that contain the 2-aminopentanedioic acid structure. Synthesis of Nonessential Amino Acids
• Familial ALS ALS Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a sporadic or inherited neurodegenerative disease of upper motor neurons (UMNs) and lower motor neurons (LMNs). ALS is the most common progressive motor neuron disease in North America, primarily affecting men and individuals of Caucasian ethnicity. Amyotrophic Lateral Sclerosis associated with:
  • C9orf72 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics expansion
  • SOD1 SOD1 A superoxide dismutase (sod1) that requires copper and zinc ions for its activity to destroy superoxide free radicals within the cytoplasm. Mutations in the sod1 gene are associated with amyotrophic lateral sclerosis-1. Amyotrophic Lateral Sclerosis gene mutation Gene Mutation Myotonic Dystrophies

Pathophysiology

The exact pathogenic mechanism of ALS ALS Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a sporadic or inherited neurodegenerative disease of upper motor neurons (UMNs) and lower motor neurons (LMNs). ALS is the most common progressive motor neuron disease in North America, primarily affecting men and individuals of Caucasian ethnicity. Amyotrophic Lateral Sclerosis is unknown. There appear to be both molecular and genetic pathways that combine to cause UMN and LMN apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage.^[3,8,16]

• Molecular pathways:
  • Reduced uptake of glutamate Glutamate Derivatives of glutamic acid. Included under this heading are a broad variety of acid forms, salts, esters, and amides that contain the 2-aminopentanedioic acid structure. Synthesis of Nonessential Amino Acids from the synaptic cleft Synaptic cleft Synapses and Neurotransmission causes glutamate Glutamate Derivatives of glutamic acid. Included under this heading are a broad variety of acid forms, salts, esters, and amides that contain the 2-aminopentanedioic acid structure. Synthesis of Nonessential Amino Acids excitotoxicity
  • Mediated by poorly functioning excitatory amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids transporter 2 (EAAT2) on astrocyte Astrocyte A class of large neuroglial (macroglial) cells in the central nervous system – the largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from ‘star’ cells) are irregularly shaped with many long processes, including those with ‘end feet’ which form the glial (limiting) membrane and directly and indirectly contribute to the blood-brain barrier. They regulate the extracellular ionic and chemical environment, and ‘reactive astrocytes’ (along with microglia) respond to injury. Astrocytoma cell membranes
  • Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)²⁺-dependent enzymatic pathways are activated, inducing neurodegeneration 
• Genetic pathways:
  • Mutations in the following genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure are pathogenic:
    • C9orf72
    • TDP-43
    • FUS
  • These mutations cause dysregulation in RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure metabolism:
    • Abnormal translation Translation Translation is the process of synthesizing a protein from a messenger RNA (mRNA) transcript. This process is divided into three primary stages: initiation, elongation, and termination. Translation is catalyzed by structures known as ribosomes, which are large complexes of proteins and ribosomal RNA (rRNA). Stages and Regulation of Translation ensues
    • Intracellular neuronal aggregates form
  • Mutations in the SOD1 SOD1 A superoxide dismutase (sod1) that requires copper and zinc ions for its activity to destroy superoxide free radicals within the cytoplasm. Mutations in the sod1 gene are associated with amyotrophic lateral sclerosis-1. Amyotrophic Lateral Sclerosis gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics is pathogenic:
    • Causes dysfunction of the mitochondria Mitochondria Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive ribosomes, transfer RNAs; amino Acyl tRNA synthetases; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs. Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. The Cell: Organelles
    • Increases free radical Free Radical Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. Nitroimidazoles → cellular oxidative stress Oxidative stress A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products. Cell Injury and Death
    • Further accumulation of intracellular aggregates
    • Axonal transport becomes defective
• Microglial activation:
  • Abnormal secretion Secretion Coagulation Studies of proinflammatory cytokines Proinflammatory Cytokines Metabolic Syndrome
  • Cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response further contribute to neurotoxicity

Clinical Presentation

History^[2,5,8,9,19]

• Affected individuals report:
  • Limb weakness
  • Cramping in the early morning
  • Gait instability Gait Instability Lateral Medullary Syndrome (Wallenberg Syndrome)
  • Falling
  • Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia when walking
  • Stiffness of the affected limb(s)
  • Incoordination of the affected limb(s)
• Pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways:
  • Commonly due to muscle spasticity Spasticity Spinal Disk Herniation or decreased mobility
  • Traumatic injury from falls is also a common source of pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways. 
• Average time between onset of symptoms and diagnosis is roughly 1 year. 

Physical examination^[8,9]

During the usual natural course of the disease, more muscle groups are affected with time, starting with an asymmetrical distribution of weakness, later becoming symmetrical Symmetrical Dermatologic Examination. 

Neurologic examination^[8,9,19]

• Coexistence of UMN and LMN signs

• In bulbar-onset ALS Bulbar-onset ALS Amyotrophic Lateral Sclerosis:^[20]
  • Speech difficulties (e.g., dysarthria Dysarthria Disorders of speech articulation caused by imperfect coordination of pharynx, larynx, tongue, or face muscles. This may result from cranial nerve diseases; neuromuscular diseases; cerebellar diseases; basal ganglia diseases; brain stem diseases; or diseases of the corticobulbar tracts. The cortical language centers are intact in this condition. Wilson Disease)
  • Dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming “stuck.” Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia and sialorrhea due to progressive weakening of the muscles of mastication Mastication The act and process of chewing and grinding food in the mouth. Jaw and Temporomandibular Joint: Anatomy and swallowing Swallowing The act of taking solids and liquids into the gastrointestinal tract through the mouth and throat. Gastrointestinal Motility
  • Exaggeration of the motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology expressions of emotion
  • Excessive forced yawning
  • Pseudobulbar affect (e.g., episodes of uncontrollable laughter or crying)
• Frontotemporal dementia Dementia Major neurocognitive disorders (NCD), also known as dementia, are a group of diseases characterized by decline in a person’s memory and executive function. These disorders are progressive and persistent diseases that are the leading cause of disability among elderly people worldwide. Major Neurocognitive Disorders ( frontal lobe dysfunction Frontal lobe dysfunction Heterogeneous group of neurodegenerative disorders characterized by frontal and temporal lobe atrophy associated with neuronal loss, gliosis, and dementia. Patients exhibit progressive changes in social, behavioral, and/or language function. Multiple subtypes or forms are recognized based on presence or absence of tau protein inclusions. Ftld includes three clinical syndromes: frontotemporal dementia, semantic dementia, and primary progressive nonfluent aphasia. Amyotrophic Lateral Sclerosis):
  • Early behavioral abnormalities and personality changes 
  • Weight loss Weight loss Decrease in existing body weight. Bariatric Surgery (predictor of poor outcome)
  • Poor executive functioning
• Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation due to immobility 
• Extrapyramidal symptoms Extrapyramidal Symptoms Ataxia-telangiectasia and parkinsonism Parkinsonism West Nile Virus before or after motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology neuron manifestations
• Pearl: Weakness is followed by muscle atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation as the disease progresses.

Diagnosis

Diagnosis is made with clinical presentation alone, but laboratory tests and imaging are typically performed to rule out other illnesses. 

Diagnostic criteria

Diagnostic criteria have been revised and updated since the 1990s and include electromyographic (EMG) information to improve diagnostic sensitivity.^[8]  The complexity and reliability Reliability Reliability refers to the reproducibility of a test or research finding. Causality, Validity, and Reliability of previous criteria have been criticized, as the categories of “definite ALS ALS Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a sporadic or inherited neurodegenerative disease of upper motor neurons (UMNs) and lower motor neurons (LMNs). ALS is the most common progressive motor neuron disease in North America, primarily affecting men and individuals of Caucasian ethnicity. Amyotrophic Lateral Sclerosis,” “probable ALS ALS Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a sporadic or inherited neurodegenerative disease of upper motor neurons (UMNs) and lower motor neurons (LMNs). ALS is the most common progressive motor neuron disease in North America, primarily affecting men and individuals of Caucasian ethnicity. Amyotrophic Lateral Sclerosis,” or “possible ALS ALS Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a sporadic or inherited neurodegenerative disease of upper motor neurons (UMNs) and lower motor neurons (LMNs). ALS is the most common progressive motor neuron disease in North America, primarily affecting men and individuals of Caucasian ethnicity. Amyotrophic Lateral Sclerosis” do not predict disease progression.^[5]

Simplified diagnostic criteria include:^[9]

• Progressive motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology impairment based on history or repeat clinical assessment (with previously normal motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology function)
• Plus either:
  • UMN and LMN dysfunction in ≥ 1 body region 
  • LMN dysfunction in ≥ 2 body regions
• No evidence of other disease processes that explain the signs of motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology neuron degeneration

Definitions:

• UMN dysfunction requires ≥ 1 of the following:
  • ↑ Deep tendon reflexes Deep Tendon Reflexes Neurological Examination
  • Pathologic reflexes (e.g., Hoffman, Babinski)
  • ↑ Velocity-dependent tone ( spasticity Spasticity Spinal Disk Herniation)
  • Slowed, uncoordinated movement that cannot be attributed to LMN causes or parkinsonian features
• LMN dysfunction requires either:
  • Muscle weakness and muscle wasting Muscle Wasting Duchenne Muscular Dystrophy, OR
  • EMG evidence of chronic neurogenic change and ongoing denervation

Laboratory evaluation^[7,8,22]

Laboratory studies are used to rule out other disorders and should be guided by the clinical picture. These studies may include (but are not limited to):

• Blood tests:
  • CBC
  • CK
  • Glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance
  • Electrolytes Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. Electrolytes:
    • Calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes
    • Phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes
    • Magnesium Magnesium A metallic element that has the atomic symbol mg, atomic number 12, and atomic weight 24. 31. It is important for the activity of many enzymes, especially those involved in oxidative phosphorylation. Electrolytes
  • Liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests
  • ESR ESR Soft Tissue Abscess and CRP
  • VDRL VDRL Treponema test 
  • HIV HIV Anti-HIV Drugs screening Screening Preoperative Care
  • HbA_1c
  • Thyroid Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy function studies
  • Parathyroid Parathyroid The parathyroid glands are 2 pairs of small endocrine glands found in close proximity to the thyroid gland. The superior parathyroid glands are lodged within the parenchyma of the upper poles of the right and left thyroid lobes; the inferior parathyroid glands are close to the inferior tips or poles of the lobes. Parathyroid Glands: Anatomy hormone
  • Vitamin B₁₂ level
• CSF analysis CSF analysis Meningitis (from a lumbar puncture Lumbar Puncture Febrile Infant) if there is clinical suspicion of:
  • Lyme disease Lyme disease Lyme disease is a tick-borne infection caused by the gram-negative spirochete Borrelia burgdorferi. Lyme disease is transmitted by the black-legged Ixodes tick (known as a deer tick), which is only found in specific geographic regions. Patient presentation can vary depending on the stage of the disease and may include a characteristic erythema migrans rash. Lyme Disease
  • HIV HIV Anti-HIV Drugs infection
  • Chronic inflammatory demyelinating polyneuropathy Chronic inflammatory demyelinating polyneuropathy A slowly progressive autoimmune demyelinating disease of peripheral nerves and nerve roots. Clinical manifestations include weakness and sensory loss in the extremities and enlargement of peripheral nerves. The course may be relapsing-remitting or demonstrate a step-wise progression. Protein is usually elevated in the spinal fluid and cranial nerves are typically spared. Guillain-barre syndrome features a relatively rapid progression of disease which distinguishes it from this condition. Polyneuropathy ( CIDP CIDP A slowly progressive autoimmune demyelinating disease of peripheral nerves and nerve roots. Clinical manifestations include weakness and sensory loss in the extremities and enlargement of peripheral nerves. The course may be relapsing-remitting or demonstrate a step-wise progression. Protein is usually elevated in the spinal fluid and cranial nerves are typically spared. Guillain-barre syndrome features a relatively rapid progression of disease which distinguishes it from this condition. Polyneuropathy)

Electromyography Electromyography Recording of the changes in electric potential of muscle by means of surface or needle electrodes. Becker Muscular Dystrophy (EMG)^[7–9,22]

Evidence of acute denervation, chronic denervation, and chronic reinnervation supports ALS ALS Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a sporadic or inherited neurodegenerative disease of upper motor neurons (UMNs) and lower motor neurons (LMNs). ALS is the most common progressive motor neuron disease in North America, primarily affecting men and individuals of Caucasian ethnicity. Amyotrophic Lateral Sclerosis diagnosis.

• Nerve conduction velocity (NCV) studies are usually normal in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with ALS ALS Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a sporadic or inherited neurodegenerative disease of upper motor neurons (UMNs) and lower motor neurons (LMNs). ALS is the most common progressive motor neuron disease in North America, primarily affecting men and individuals of Caucasian ethnicity. Amyotrophic Lateral Sclerosis.
• Compound muscle action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential (CMAP) amplitudes may be reduced in severely atrophic and denervated muscles.

Neuroimaging Neuroimaging Non-invasive methods of visualizing the central nervous system, especially the brain, by various imaging modalities. Febrile Infant (MRI)^[7,8,21,22]

• Mainly used to rule out other illnesses
• Findings associated with ALS ALS Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a sporadic or inherited neurodegenerative disease of upper motor neurons (UMNs) and lower motor neurons (LMNs). ALS is the most common progressive motor neuron disease in North America, primarily affecting men and individuals of Caucasian ethnicity. Amyotrophic Lateral Sclerosis (T2-weighted):
  • Decreased intensity of the motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology cortex, known as the “ motor band sign Motor Band Sign Amyotrophic Lateral Sclerosis”
  • Hyperintense Hyperintense Magnetic Resonance Imaging (MRI) lesions of the corticospinal tracts Corticospinal Tracts Central Cord Syndrome 
• Brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification MRI: if bulbar disease is noted
• Cervical and lumbosacral spine Spine The human spine, or vertebral column, is the most important anatomical and functional axis of the human body. It consists of 7 cervical vertebrae, 12 thoracic vertebrae, and 5 lumbar vertebrae and is limited cranially by the skull and caudally by the sacrum. Vertebral Column: Anatomy MRI: to evaluate LMN findings in the extremities

Genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies^[8,22,23]

• Reserved as screening Screening Preoperative Care tool for patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with family history Family History Adult Health Maintenance, as only a small proportion of cases of ALS ALS Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a sporadic or inherited neurodegenerative disease of upper motor neurons (UMNs) and lower motor neurons (LMNs). ALS is the most common progressive motor neuron disease in North America, primarily affecting men and individuals of Caucasian ethnicity. Amyotrophic Lateral Sclerosis is familial
• Available gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics testing covers only a small fraction of causative genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure for ALS ALS Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a sporadic or inherited neurodegenerative disease of upper motor neurons (UMNs) and lower motor neurons (LMNs). ALS is the most common progressive motor neuron disease in North America, primarily affecting men and individuals of Caucasian ethnicity. Amyotrophic Lateral Sclerosis. 
• C9orf72 genotype Genotype The genetic constitution of the individual, comprising the alleles present at each genetic locus. Basic Terms of Genetics, in particular, occurs in a high percentage of those with sporadic Sporadic Selective IgA Deficiency ALS ALS Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a sporadic or inherited neurodegenerative disease of upper motor neurons (UMNs) and lower motor neurons (LMNs). ALS is the most common progressive motor neuron disease in North America, primarily affecting men and individuals of Caucasian ethnicity. Amyotrophic Lateral Sclerosis.

Pulmonary tests^[17,19]

The following measurements can be used to detect respiratory insufficiency:

• Nocturnal oximetry
• Maximal inspiratory pressure
• Forced vital capacity Vital capacity The volume of air that is exhaled by a maximal expiration following a maximal inspiration. Ventilation: Mechanics of Breathing (FVC): Supine measurements may be more sensitive than erect measurements for detecting diaphragm Diaphragm The diaphragm is a large, dome-shaped muscle that separates the thoracic cavity from the abdominal cavity. The diaphragm consists of muscle fibers and a large central tendon, which is divided into right and left parts. As the primary muscle of inspiration, the diaphragm contributes 75% of the total inspiratory muscle force. Diaphragm: Anatomy weakness.

Management

Management may vary depending on practice location. The following information is based on US, European, and UK literature and guidelines.

There is no definitive treatment for ALS ALS Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a sporadic or inherited neurodegenerative disease of upper motor neurons (UMNs) and lower motor neurons (LMNs). ALS is the most common progressive motor neuron disease in North America, primarily affecting men and individuals of Caucasian ethnicity. Amyotrophic Lateral Sclerosis. Current management is symptomatic and supportive. Disease-modifying drugs that slow ALS ALS Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a sporadic or inherited neurodegenerative disease of upper motor neurons (UMNs) and lower motor neurons (LMNs). ALS is the most common progressive motor neuron disease in North America, primarily affecting men and individuals of Caucasian ethnicity. Amyotrophic Lateral Sclerosis progression have recently become available.

Patient discussion^{[11,18,19,22]}

Communicating a diagnosis of ALS ALS Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a sporadic or inherited neurodegenerative disease of upper motor neurons (UMNs) and lower motor neurons (LMNs). ALS is the most common progressive motor neuron disease in North America, primarily affecting men and individuals of Caucasian ethnicity. Amyotrophic Lateral Sclerosis to the patient can be difficult.

• Have the patient bring a family member or other support person.
• Allow adequate time for questions.
• Provide support and hope; emphasize non-abandonment.
• Schedule a short-term follow-up visit for more questions or so that support persons may attend.

Consultations^[18,19,22]

Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with ALS ALS Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a sporadic or inherited neurodegenerative disease of upper motor neurons (UMNs) and lower motor neurons (LMNs). ALS is the most common progressive motor neuron disease in North America, primarily affecting men and individuals of Caucasian ethnicity. Amyotrophic Lateral Sclerosis benefit from care delivered by a multidisciplinary team. This team may include (but is not limited to):

• Primary care physician
• Neurologist
• Physical therapist
• Occupational therapist
• Speech pathologist
• Dietitian
• Social worker
• Respiratory therapist
• Palliative caregiver

Disease-modifying therapies

• Clinical benefit is seen more in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with early disease (symptoms < 5 years); all patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with ALS ALS Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a sporadic or inherited neurodegenerative disease of upper motor neurons (UMNs) and lower motor neurons (LMNs). ALS is the most common progressive motor neuron disease in North America, primarily affecting men and individuals of Caucasian ethnicity. Amyotrophic Lateral Sclerosis may benefit.
• Riluzole Riluzole A glutamate antagonist used as an anticonvulsant (anticonvulsants) and to prolong the survival of patients with amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis:^{[8,12,14,17,22]}
  • Improved survival by 6–19 months
  • Available in tablet, suspension, or orally disintegrating film
  • Monitor liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests monthly for the 1st 3 months, then every 3 months thereafter.
  • Benefit is uncertain in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship requiring tracheostomy Tracheostomy Surgical formation of an opening into the trachea through the neck, or the opening so created. Laryngomalacia and Tracheomalacia for ventilation Ventilation The total volume of gas inspired or expired per unit of time, usually measured in liters per minute. Ventilation: Mechanics of Breathing.
  • Common side effects:
    • Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics
    • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
    • Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia
    • Dizziness Dizziness An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. Lateral Medullary Syndrome (Wallenberg Syndrome)
    • Elevated liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
• Edaravone:^[8]
  • Slows disease progression
  • Start in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship who cannot take riluzole Riluzole A glutamate antagonist used as an anticonvulsant (anticonvulsants) and to prolong the survival of patients with amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis, or add a few weeks after starting riluzole Riluzole A glutamate antagonist used as an anticonvulsant (anticonvulsants) and to prolong the survival of patients with amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis
  • Specific forms contain sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia bisulfite and can cause allergic asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma reactions in up to 5% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma.
• PB-TURSO ( sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia phenylbutyrate–taurursodiol):^[13,15]
  • Reduces neuronal cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death
  • Extends survival by 10 months, reduces risk of tracheostomy Tracheostomy Surgical formation of an opening into the trachea through the neck, or the opening so created. Laryngomalacia and Tracheomalacia/permanent assisted ventilation Ventilation The total volume of gas inspired or expired per unit of time, usually measured in liters per minute. Ventilation: Mechanics of Breathing and first hospitalization Hospitalization The confinement of a patient in a hospital. Delirium
  • Recommended for all patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with ALS ALS Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a sporadic or inherited neurodegenerative disease of upper motor neurons (UMNs) and lower motor neurons (LMNs). ALS is the most common progressive motor neuron disease in North America, primarily affecting men and individuals of Caucasian ethnicity. Amyotrophic Lateral Sclerosis, in addition to other medications
  • Comes in sachets of powder, which contain 3 g sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia phenylbutyrate/1 g taurursodiol to be dissolved in 250 mL water
  • May cause fluid retention in individuals with hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR), and kidney disease
• Novel agents being studied:^[8]
  • Antisense oligonucleotide therapy for genetic forms of ALS ALS Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a sporadic or inherited neurodegenerative disease of upper motor neurons (UMNs) and lower motor neurons (LMNs). ALS is the most common progressive motor neuron disease in North America, primarily affecting men and individuals of Caucasian ethnicity. Amyotrophic Lateral Sclerosis
  • Skeletal muscle activators
  • Masitinib: a selective oral tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids kinase inhibitor that may slow microglial-related disease progression; in phase 3 Phase 3 Skin: Structure and Functions trials
  • Mesenchymal stromal cells and other stem cell treatments

Respiratory management^[17,19,22]

Respiratory insufficiency can result in death for patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with ALS ALS Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a sporadic or inherited neurodegenerative disease of upper motor neurons (UMNs) and lower motor neurons (LMNs). ALS is the most common progressive motor neuron disease in North America, primarily affecting men and individuals of Caucasian ethnicity. Amyotrophic Lateral Sclerosis. The following respiratory support measures are often required as the disease progresses.

• Noninvasive positive pressure ventilation Noninvasive Positive Pressure Ventilation Noninvasive Ventilation (NPPV) is considered in the following scenarios:
  • Onset of dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea
  • Orthopnea Orthopnea Pulmonary Edema
  • Nocturnal hypoxia Hypoxia Sub-optimal oxygen levels in the ambient air of living organisms. Ischemic Cell Damage
  • Forced vital capacity Vital capacity The volume of air that is exhaled by a maximal expiration following a maximal inspiration. Ventilation: Mechanics of Breathing (FVC) < 50%
  • Oxygen therapy is not recommended for dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with ALS ALS Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a sporadic or inherited neurodegenerative disease of upper motor neurons (UMNs) and lower motor neurons (LMNs). ALS is the most common progressive motor neuron disease in North America, primarily affecting men and individuals of Caucasian ethnicity. Amyotrophic Lateral Sclerosis except during the active dying process.
• Invasive ventilation Ventilation The total volume of gas inspired or expired per unit of time, usually measured in liters per minute. Ventilation: Mechanics of Breathing is considered when noninvasive measures are not tolerated:
  • Secure airway Airway ABCDE Assessment: tracheostomy Tracheostomy Surgical formation of an opening into the trachea through the neck, or the opening so created. Laryngomalacia and Tracheomalacia
  • Chronic ventilatory support

Symptom management^[17–19,22]

Medical therapy for other associated symptoms is based on underlying conditions and clinical presentation. There is insufficient evidence to suggest specific therapies for most symptoms, but the following options may be considered:

• Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia:
  • Reported in approximately 90% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
  • May improve with NPPV
  • May be an adverse effect of riluzole Riluzole A glutamate antagonist used as an anticonvulsant (anticonvulsants) and to prolong the survival of patients with amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis; consider temporary withdrawal of medication
  • Consider:
    • Glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids 
    • Modafinil Modafinil Stimulants
    • Megestrol acetate Megestrol acetate Megestrol acetate is a progestogen with actions and uses similar to those of the progestogens in general. It also has anti-androgenic properties. It is given by mouth in the palliative treatment or as an adjunct to other therapy in endometrial carcinoma and in breast cancer. Noncontraceptive Estrogen and Progestins
• Muscle spasm:
  • Mexiletine Mexiletine Antiarrhythmic agent pharmacologically similar to lidocaine. It may have some anticonvulsant properties. Class 1 Antiarrhythmic Drugs (Sodium Channel Blockers) is an oral Na⁺ channel blocker used to treat muscle spasms Spasms An involuntary contraction of a muscle or group of muscles. Spasms may involve skeletal muscle or smooth muscle. Ion Channel Myopathy.
  • Baclofen Baclofen A gamma-aminobutyric acid derivative that is a specific agonist of gaba-b receptors. It is used in the treatment of muscle spasticity, especially that due to spinal cord injuries. Its therapeutic effects result from actions at spinal and supraspinal sites, generally the reduction of excitatory transmission. Spasmolytics is an oral GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNS agonist used to treat muscle spasms Spasms An involuntary contraction of a muscle or group of muscles. Spasms may involve skeletal muscle or smooth muscle. Ion Channel Myopathy. 
  • Botulinum toxin Botulinum toxin Toxic proteins produced from the species Clostridium botulinum. The toxins are synthesized as a single peptide chain which is processed into a mature protein consisting of a heavy chain and light chain joined via a disulfide bond. The botulinum toxin light chain is a zinc-dependent protease which is released from the heavy chain upon endocytosis into presynaptic nerve endings. Once inside the cell the botulinum toxin light chain cleaves specific snare proteins which are essential for secretion of acetylcholine by synaptic vesicles. This inhibition of acetylcholine release results in muscular paralysis. Botulism causes neuromuscular junction Neuromuscular junction The synapse between a neuron and a muscle. Skeletal Muscle Contraction blockade; IM injections may be used to treat muscle spasms Spasms An involuntary contraction of a muscle or group of muscles. Spasms may involve skeletal muscle or smooth muscle. Ion Channel Myopathy when oral intake is no longer possible. 
  • Other options:
    • Gabapentin Gabapentin A cyclohexane-gamma-aminobutyric acid derivative that is used for the treatment of partial seizures; neuralgia; and restless legs syndrome. Second-Generation Anticonvulsant Drugs
    • Tizanidine Tizanidine Spasmolytics
    • Dantrolene Dantrolene Skeletal muscle relaxant that acts by interfering with excitation-contraction coupling in the muscle fiber. It is used in spasticity and other neuromuscular abnormalities. Although the mechanism of action is probably not central, dantrolene is usually grouped with the central muscle relaxants. Spasmolytics
• Sialorrhea:
  • Atropine Atropine An alkaloid, originally from atropa belladonna, but found in other plants, mainly solanaceae. Hyoscyamine is the 3(s)-endo isomer of atropine. Anticholinergic Drugs is an anticholinergic Anticholinergic Anticholinergic drugs block the effect of the neurotransmitter acetylcholine at the muscarinic receptors in the central and peripheral nervous systems. Anticholinergic agents inhibit the parasympathetic nervous system, resulting in effects on the smooth muscle in the respiratory tract, vascular system, urinary tract, GI tract, and pupils of the eyes. Anticholinergic Drugs; drops are given sublingually to treat sialorrhea. 
  • Amitriptyline Amitriptyline Tricyclic antidepressant with anticholinergic and sedative properties. It appears to prevent the reuptake of norepinephrine and serotonin at nerve terminals, thus potentiating the action of these neurotransmitters. Amitriptyline also appears to antagonize cholinergic and alpha-1 adrenergic responses to bioactive amines. Tricyclic Antidepressants is an oral tricyclic antidepressant Antidepressant Antidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and psychiatric conditions, as well as those with chronic pain and symptoms of menopause. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own. Serotonin Reuptake Inhibitors and Similar Antidepressants with anticholinergic Anticholinergic Anticholinergic drugs block the effect of the neurotransmitter acetylcholine at the muscarinic receptors in the central and peripheral nervous systems. Anticholinergic agents inhibit the parasympathetic nervous system, resulting in effects on the smooth muscle in the respiratory tract, vascular system, urinary tract, GI tract, and pupils of the eyes. Anticholinergic Drugs properties used to treat sialorrhea.
  • Botulinum toxin Botulinum toxin Toxic proteins produced from the species Clostridium botulinum. The toxins are synthesized as a single peptide chain which is processed into a mature protein consisting of a heavy chain and light chain joined via a disulfide bond. The botulinum toxin light chain is a zinc-dependent protease which is released from the heavy chain upon endocytosis into presynaptic nerve endings. Once inside the cell the botulinum toxin light chain cleaves specific snare proteins which are essential for secretion of acetylcholine by synaptic vesicles. This inhibition of acetylcholine release results in muscular paralysis. Botulism injections (into parotid and submandibular glands Submandibular glands One of two salivary glands in the neck, located in the space bound by the two bellies of the digastric muscle and the angle of the mandible. It discharges through the submandibular duct. The secretory units are predominantly serous although a few mucous alveoli, some with serous demilunes, occur. Gastrointestinal Secretions) can be used for refractory symptoms.
• Thick bronchial/mucous secretions:
  • Guaifenesin is an oral mucolytic used to manage thick mucous secretions. 
  • N-acetylcysteine is a nebulized mucolytic used to manage thick bronchial secretions, especially when respiratory support equipment is in use. 
  • Other options:
    • Beta-blockers Beta-blockers Drugs that bind to but do not activate beta-adrenergic receptors thereby blocking the actions of beta-adrenergic agonists. Adrenergic beta-antagonists are used for treatment of hypertension, cardiac arrhythmias, angina pectoris, glaucoma, migraine headaches, and anxiety. Class 2 Antiarrhythmic Drugs (Beta Blockers) (e.g., metoprolol Metoprolol A selective adrenergic beta-1 blocking agent that is commonly used to treat angina pectoris; hypertension; and cardiac arrhythmias. Antiadrenergic Drugs, propranolol Propranolol A widely used non-cardioselective beta-adrenergic antagonist. Propranolol has been used for myocardial infarction; arrhythmia; angina pectoris; hypertension; hyperthyroidism; migraine; pheochromocytoma; and anxiety but adverse effects instigate replacement by newer drugs. Antiadrenergic Drugs)
    • Nebulized saline
    • Anticholinergic Anticholinergic Anticholinergic drugs block the effect of the neurotransmitter acetylcholine at the muscarinic receptors in the central and peripheral nervous systems. Anticholinergic agents inhibit the parasympathetic nervous system, resulting in effects on the smooth muscle in the respiratory tract, vascular system, urinary tract, GI tract, and pupils of the eyes. Anticholinergic Drugs bronchodilators Bronchodilators Asthma Drugs (e.g., ipratropium Ipratropium A muscarinic antagonist structurally related to atropine but often considered safer and more effective for inhalation use. It is used for various bronchial disorders, in rhinitis, and as an antiarrhythmic. Anticholinergic Drugs)
• Pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways management:
  • 1st line: antiinflammatory agents (e.g., NSAIDs NSAIDS Primary vs Secondary Headaches)
  • 2nd line: opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation analgesics
  • Special mattresses, pillows, and wheelchairs may prevent onset of pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways.
• Depression:
  • Amitriptyline Amitriptyline Tricyclic antidepressant with anticholinergic and sedative properties. It appears to prevent the reuptake of norepinephrine and serotonin at nerve terminals, thus potentiating the action of these neurotransmitters. Amitriptyline also appears to antagonize cholinergic and alpha-1 adrenergic responses to bioactive amines. Tricyclic Antidepressants is a tricyclic antidepressant Antidepressant Antidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and psychiatric conditions, as well as those with chronic pain and symptoms of menopause. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own. Serotonin Reuptake Inhibitors and Similar Antidepressants shown to improve quality Quality Activities and programs intended to assure or improve the quality of care in either a defined medical setting or a program. The concept includes the assessment or evaluation of the quality of care; identification of problems or shortcomings in the delivery of care; designing activities to overcome these deficiencies; and follow-up monitoring to ensure effectiveness of corrective steps. Quality Measurement and Improvement of life in ALS ALS Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a sporadic or inherited neurodegenerative disease of upper motor neurons (UMNs) and lower motor neurons (LMNs). ALS is the most common progressive motor neuron disease in North America, primarily affecting men and individuals of Caucasian ethnicity. Amyotrophic Lateral Sclerosis.
  • Can simultaneously treat insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia, sialorrhea, and pseudobulbar affect

Nonmedical therapy^[17,19,22]

Nutrition:

• Refer to speech-language pathology for clinical swallow evaluation early in the disease course.
• Changes to diet may include:
  • Supplementation with calorie-dense foods
  • High-dose vitamins and minerals Minerals Electrolytes
  • Altering food consistency Consistency Dermatologic Examination
• Percutaneous gastrostomy should be considered to decrease effects of dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming “stuck.” Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia (e.g., weight loss Weight loss Decrease in existing body weight. Bariatric Surgery and aspiration)

Physical therapy Physical Therapy Becker Muscular Dystrophy, occupational therapy Occupational Therapy Skilled treatment that helps individuals achieve independence in all facets of their lives. It assists in the development of skills needed for independent living. Fetal Alcohol Spectrum Disorder, and communication Communication The exchange or transmission of ideas, attitudes, or beliefs between individuals or groups. Decision-making Capacity and Legal Competence therapy:

• Overall goal: improve the ability to carry out activities of daily living for as long as possible
• Different tools are used to accomplish this. 

End-of-life Care^[18,19,22]

• Advance directives Advance Directives The term advance directive (AD) refers to treatment preferences and/or the designation of a surrogate decision-maker in the event that a person becomes unable to make medical decisions on their own behalf. Advance directives represent the ethical principle of autonomy and may take the form of a living will, health care proxy, durable power of attorney for health care (DPAHC), and/or a physician’s order for life-sustaining treatment (POLST). Advance Directives on care and death should be obtained as soon as the diagnosis is made (e.g., when to withdraw ventilator support when to discontinue gastrostomy feedings). 
• Opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics (e.g., morphine Morphine The principal alkaloid in opium and the prototype opiate analgesic and narcotic. Morphine has widespread effects in the central nervous system and on smooth muscle. Opioid Analgesics) and benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines (e.g., diazepam Diazepam A benzodiazepine with anticonvulsant, anxiolytic, sedative, muscle relaxant, and amnesic properties and a long duration of action. Its actions are mediated by enhancement of gamma-aminobutyric acid activity. Benzodiazepines) are used to treat dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea and anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder. 
• Care at home increases the likelihood of a peaceful death.

Complications and Prognosis

Complications^[17–19]

• Need for mechanical ventilatory support
• Malnutrition Malnutrition Malnutrition is a clinical state caused by an imbalance or deficiency of calories and/or micronutrients and macronutrients. The 2 main manifestations of acute severe malnutrition are marasmus (total caloric insufficiency) and kwashiorkor (protein malnutrition with characteristic edema). Malnutrition in children in resource-limited countries
• Functional decline 

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas^[8,12,19]

• Relentlessly progressive
• Median survival: 3–5 years, but 10%–20% survive > 10 years
• Weight gain, younger age, and limb symptoms (as opposed to bulbar symptoms Bulbar Symptoms Botulism) have been associated with improved survival. 
• At least 30% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship develop cognitive impairment.
• Affected individuals ultimately die from respiratory paralysis.

Differential Diagnosis

• Spinal muscular atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation (SMA): spectrum of autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance syndromes characterized by progressive proximal muscle weakness Proximal Muscle Weakness Lambert-Eaton Myasthenic Syndrome and atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation due to degeneration of the anterior horn Anterior horn One of three central columns of the spinal cord. It is composed of gray matter spinal laminae VIII and ix. Brown-Séquard Syndrome cells in the spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord: Anatomy and motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology nuclei in the lower brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification stem. There are 5 clinical types of SMA, each with their distinctive clinical presentation. Initial diagnosis is made clinically and then definitively with genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies. Management is mostly supportive, and prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas depends on the clinical type. 
• Myasthenia gravis Myasthenia Gravis Myasthenia gravis (MG) is an autoimmune neuromuscular disorder characterized by weakness and fatigability of skeletal muscles caused by dysfunction/destruction of acetylcholine receptors at the neuromuscular junction. MG presents with fatigue, ptosis, diplopia, dysphagia, respiratory difficulties, and progressive weakness in the limbs, leading to difficulty in movement. Myasthenia Gravis: autoimmune neuromuscular disorder characterized by weakness and fatigability of skeletal muscles Skeletal muscles A subtype of striated muscle, attached by tendons to the skeleton. Skeletal muscles are innervated and their movement can be consciously controlled. They are also called voluntary muscles. Muscle Tissue: Histology caused by dysfunction/destruction of acetylcholine Acetylcholine A neurotransmitter found at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. Receptors and Neurotransmitters of the CNS receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors at the neuromuscular junction Neuromuscular junction The synapse between a neuron and a muscle. Skeletal Muscle Contraction. Myasthenia gravis Myasthenia Gravis Myasthenia gravis (MG) is an autoimmune neuromuscular disorder characterized by weakness and fatigability of skeletal muscles caused by dysfunction/destruction of acetylcholine receptors at the neuromuscular junction. MG presents with fatigue, ptosis, diplopia, dysphagia, respiratory difficulties, and progressive weakness in the limbs, leading to difficulty in movement. Myasthenia Gravis presents with fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia, ptosis Ptosis Cranial Nerve Palsies, diplopia Diplopia A visual symptom in which a single object is perceived by the visual cortex as two objects rather than one. Disorders associated with this condition include refractive errors; strabismus; oculomotor nerve diseases; trochlear nerve diseases; abducens nerve diseases; and diseases of the brain stem and occipital lobe. Myasthenia Gravis, dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming “stuck.” Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia, respiratory difficulties, and progressive weakness in the limbs, leading to difficulty in movement. Diagnosis is clinical but confirmed with electrodiagnostic studies. Treatment is with acetylcholinesterase inhibitors and immune therapies. 
• Lambert-Eaton myasthenic syndrome Lambert-Eaton Myasthenic Syndrome Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder affecting the neuromuscular junction and has a strong association with small cell lung carcinoma. Lambert-Eaton myasthenic syndrome affects the voltage-gated calcium channels at the presynaptic membrane. Lambert-Eaton Myasthenic Syndrome: autoimmune disorder Autoimmune Disorder Septic Arthritis affecting the neuromuscular junction Neuromuscular junction The synapse between a neuron and a muscle. Skeletal Muscle Contraction with strong association to small cell lung carcinoma. This syndrome affects the voltage-gated calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes channels Channels The Cell: Cell Membrane at the presynaptic membrane Presynaptic membrane Synapses and Neurotransmission and presents with proximal muscle weakness Proximal Muscle Weakness Lambert-Eaton Myasthenic Syndrome and symptoms of autonomic dysfunction Autonomic Dysfunction Anterior Cord Syndrome such as dry mouth and sluggish pupillary reflexes. Diagnosis includes electrodiagnostics and detection of antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions. Management is symptomatic, using potassium Potassium An element in the alkali group of metals with an atomic symbol k, atomic number 19, and atomic weight 39. 10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. Hyperkalemia channel blockers and immunosuppressants Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. Immunosuppressants. 
• Poliomyelitis Poliomyelitis Poliomyelitis is an infectious disease caused by the poliovirus. Transmission occurs through the fecal-oral route and through respiratory aerosols. The majority of patients will be asymptomatic or have a mild, abortive presentation with flu-like symptoms. Those who develop nonparalytic poliomyelitis will develop signs and symptoms of aseptic meningitis. A very minor proportion of patients will progress to paralytic poliomyelitis. Poliovirus/Poliomyelitis: infectious disease caused by the poliovirus Poliovirus Poliomyelitis is an infectious disease caused by the poliovirus. This virus is a member of the Picornaviridae family. It is a small, single-stranded, positive-sense RNA virus without a lipid envelope. Transmission occurs through the fecal-oral route and, occasionally, through respiratory aerosols. Poliovirus/Poliomyelitis. The majority of individuals with poliomyelitis Poliomyelitis Poliomyelitis is an infectious disease caused by the poliovirus. Transmission occurs through the fecal-oral route and through respiratory aerosols. The majority of patients will be asymptomatic or have a mild, abortive presentation with flu-like symptoms. Those who develop nonparalytic poliomyelitis will develop signs and symptoms of aseptic meningitis. A very minor proportion of patients will progress to paralytic poliomyelitis. Poliovirus/Poliomyelitis will be asymptomatic or have a mild, abortive presentation with flu-like symptoms Flu-Like Symptoms Babesia/Babesiosis. A very minor proportion of individuals will progress to paralytic poliomyelitis Paralytic poliomyelitis Poliovirus/Poliomyelitis, with neurologic progression (including asymmetric flaccid paralysis). The diagnosis is determined by the clinical presentation and can be supported by viral culture Viral culture West Nile Virus, PCR PCR Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (PCR), and serology Serology The study of serum, especially of antigen-antibody reactions in vitro. Yellow Fever Virus. Current antivirals are ineffective, and management is supportive. The 2 available vaccines have almost eradicated this disease worldwide. 
• Thyrotoxicosis Thyrotoxicosis A hypermetabolic syndrome caused by excess thyroid hormones which may come from endogenous or exogenous sources. The endogenous source of hormone may be thyroid hyperplasia; thyroid neoplasms; or hormone-producing extrathyroidal tissue. Thyrotoxicosis is characterized by nervousness; tachycardia; fatigue; weight loss; heat intolerance; and excessive sweating. Thyrotoxicosis and Hyperthyroidism: classic physiologic manifestations of excess thyroid Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview and Types. Thyrotoxicosis Thyrotoxicosis A hypermetabolic syndrome caused by excess thyroid hormones which may come from endogenous or exogenous sources. The endogenous source of hormone may be thyroid hyperplasia; thyroid neoplasms; or hormone-producing extrathyroidal tissue. Thyrotoxicosis is characterized by nervousness; tachycardia; fatigue; weight loss; heat intolerance; and excessive sweating. Thyrotoxicosis and Hyperthyroidism is not synonymous with hyperthyroidism Hyperthyroidism Hypersecretion of thyroid hormones from the thyroid gland. Elevated levels of thyroid hormones increase basal metabolic rate. Thyrotoxicosis and Hyperthyroidism, which is caused by sustained overproduction and release of the thyroid Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview and Types triiodothyronine Triiodothyronine A T3 thyroid hormone normally synthesized and secreted by the thyroid gland in much smaller quantities than thyroxine (T4). Most T3 is derived from peripheral monodeiodination of T4 at the 5′ position of the outer ring of the iodothyronine nucleus. The hormone finally delivered and used by the tissues is mainly t3. Thyroid Hormones (T₃) and thyroxine Thyroxine The major hormone derived from the thyroid gland. Thyroxine is synthesized via the iodination of tyrosines (monoiodotyrosine) and the coupling of iodotyrosines (diiodotyrosine) in the thyroglobulin. Thyroxine is released from thyroglobulin by proteolysis and secreted into the blood. Thyroid Hormones (T₄). Clinical features of thyrotoxicosis Thyrotoxicosis A hypermetabolic syndrome caused by excess thyroid hormones which may come from endogenous or exogenous sources. The endogenous source of hormone may be thyroid hyperplasia; thyroid neoplasms; or hormone-producing extrathyroidal tissue. Thyrotoxicosis is characterized by nervousness; tachycardia; fatigue; weight loss; heat intolerance; and excessive sweating. Thyrotoxicosis and Hyperthyroidism are mostly due to an increase in the metabolic rate and overactivity of the sympathetic nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. Nervous System: Anatomy, Structure, and Classification (i.e., an increase in the β-adrenergic “tone”). Treatment consists of beta blockade for symptomatic management while the underlying endocrine dysfunction is addressed.