Amyotrophic Lateral Sclerosis

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
• Progressive disease leading eventually to paralysis and subsequently death
• There is no cure.

Classification

• Sporadic Sporadic Selective IgA Deficiency (aka acquired): no other known occurrences of the disease within a family
• Familial ALS: multiple occurrences of the disease within a family

Epidemiology

• 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

• 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

The cause of sporadic Sporadic Selective IgA Deficiency ALS 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), 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
  • 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 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 gene mutation Gene Mutation Myotonic Dystrophies

Pathophysiology

The exact pathogenic mechanism of ALS 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. 

• 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 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

• 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

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

• Coexistence of UMN and LMN signs

• In bulbar-onset ALS:
  • 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 Frontal lobe The part of the cerebral hemisphere anterior to the central sulcus, and anterior and superior to the lateral sulcus. Cerebral Cortex: Anatomy dysfunction):
  • 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

The specific criteria for the diagnosis of ALS are also known as the El Escorial World Federation of Neurology criteria.

Inclusion criteria:

• Clinical, electrophysical, or neuropathologic evidence of LMN degeneration
• Clinical, electrophysical, or neuropathologic evidence of UMN degeneration
• Evidence of progressive spread of symptoms or signs within a region or to other regions

Exclusion criteria:

• Electrophysiologic or pathologic evidence of other disease processes that might explain the patient’s motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology neuron degeneration
• Neuroimaging Neuroimaging Non-invasive methods of visualizing the central nervous system, especially the brain, by various imaging modalities. Febrile Infant evidence of other diseases that might explain the observed clinical and electrophysiologic signs

Laboratory evaluation

Used to rule out other disorders and include:

• CBC
• Serum CK concentration
• 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
• VDRL VDRL Treponema test 
• HIV HIV Anti-HIV Drugs screening Screening Preoperative Care
• ACE
• 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
• Serum 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

Electromyography Electromyography Recording of the changes in electric potential of muscle by means of surface or needle electrodes. Becker Muscular Dystrophy (EMG)

Evidence of acute denervation, chronic denervation, and chronic reinnervation supports ALS diagnosis.

Neuroimaging Neuroimaging Non-invasive methods of visualizing the central nervous system, especially the brain, by various imaging modalities. Febrile Infant (MRI)

• Mainly used to rule out other illnesses
• Findings associated with ALS (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 Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology band sign”
  • Hyperintense Hyperintense Magnetic Resonance Imaging (MRI) lesions of the corticospinal tracts Corticospinal Tracts Central Cord Syndrome 

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

• 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 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. 
• 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.

Management

No definitive treatment. Current management is symptomatic and supportive.

Respiratory management

• Noninvasive ventilation Ventilation The total volume of gas inspired or expired per unit of time, usually measured in liters per minute. Ventilation: Mechanics of Breathing ( NIV NIV Noninvasive ventilation (NIV) is an advanced respiratory support that does not require an artificial, invasive airway. This technique is commonly used during acute respiratory failure. The most common forms of NIV are noninvasive positive pressure ventilation (NIPPV) and high-flow nasal cannula (HFNC). Noninvasive Ventilation) 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%
• 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

Medical therapy

Medical therapy is based on underlying conditions and clinical presentation.

• Disease-specific:
  • Riluzole:
    • Associated with improved survival (2–3 months)
    • Has several sites of action:
      • Blockade of presynaptic release 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
      • Partial blockade of postsynaptic N-methyl-D-aspartate (NMDA) 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
      • Blockade of Na channels Channels The Cell: Cell Membrane 
  • Edaravone:
    • 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 scavenger
    • Slows disease progression
  • 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 (PB-TURSO):
    • 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
    • Recommended for all individuals with ALS, in addition to other medications
• 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. 
• 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.
• 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. 
• 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.
  • 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

Nutrition:

• Adequate supplementation with calorie-dense foods
• 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:

The overall goal of these therapies is to improve the ability to carry out activities of daily living for as long as possible. Different tools are used to do so.

End-of-life Care

• 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 

• 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

• Relentlessly progressive
• Median survival: 3–5 years 
• Weight gain, younger age, and limb symptoms 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.