Polyneuropathy

Overview

Definition and terminology

Polyneuropathy is part of a spectrum of neurologic disorders affecting the integrity and function of the peripheral nerves Peripheral Nerves The nerves outside of the brain and spinal cord, including the autonomic, cranial, and spinal nerves. Peripheral nerves contain non-neuronal cells and connective tissue as well as axons. The connective tissue layers include, from the outside to the inside, the epineurium, the perineurium, and the endoneurium. Nervous System: Histology. The nomenclature corresponds with the number of nerves involved:

• Neuropathy Neuropathy Leprosy: This is the general term; it may refer to any disorder of a nerve or nerves affecting the CNS or the peripheral nervous system Peripheral nervous system The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. Nervous System: Anatomy, Structure, and Classification (PNS).
• Mononeuropathy Mononeuropathy Disease or trauma involving a single peripheral nerve in isolation, or out of proportion to evidence of diffuse peripheral nerve dysfunction. Mononeuropathy multiplex refers to a condition characterized by multiple isolated nerve injuries. Mononeuropathies may result from a wide variety of causes, including ischemia; traumatic injury; compression; connective tissue diseases; cumulative trauma disorders; and other conditions. Mononeuropathy and Plexopathy: single nerve affected
  • Often due to a focal process:
    • Trauma
    • Entrapment
    • Compression Compression Blunt Chest Trauma
  • Examples include:
    • Carpal tunnel Carpal Tunnel The carpal tunnel is formed by the transverse carpal ligament (flexor retinaculum) superiorly and the carpal bones inferiorly. Carpal Tunnel Syndrome syndrome
    • Radiculopathy Radiculopathy Disease involving a spinal nerve root which may result from compression related to intervertebral disk displacement; spinal cord injuries; spinal diseases; and other conditions. Clinical manifestations include radicular pain, weakness, and sensory loss referable to structures innervated by the involved nerve root. Rheumatoid Arthritis
• Mononeuropathy Mononeuropathy Disease or trauma involving a single peripheral nerve in isolation, or out of proportion to evidence of diffuse peripheral nerve dysfunction. Mononeuropathy multiplex refers to a condition characterized by multiple isolated nerve injuries. Mononeuropathies may result from a wide variety of causes, including ischemia; traumatic injury; compression; connective tissue diseases; cumulative trauma disorders; and other conditions. Mononeuropathy and Plexopathy multiplex (also known as multifocal Multifocal Retinoblastoma neuropathy Neuropathy Leprosy): several nerves (or nerve trunks) are affected by a common etiology, usually in an asymmetric fashion.
  • Often due to a more expansive focal process (may or may not be systemic):
    • Compression Compression Blunt Chest Trauma
    • Ischemia Ischemia A hypoperfusion of the blood through an organ or tissue caused by a pathologic constriction or obstruction of its blood vessels, or an absence of blood circulation. Ischemic Cell Damage
    • Inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation
  • Examples include:
    • Vasculitis Vasculitis Inflammation of any one of the blood vessels, including the arteries; veins; and rest of the vasculature system in the body. Systemic Lupus Erythematosus
    • Tumor Tumor Inflammation invasion
• Polyneuropathy: numerous nerves are affected, generally in a symmetrical Symmetrical Dermatologic Examination, distal-to-proximal fashion (glove-and-stocking distribution).
  • Due to a systemic process:
    • Autoimmune processes
    • Toxic/metabolic processes
  • Examples:
    • Diabetic neuropathy Neuropathy Leprosy
    • Alcoholic Alcoholic Persons who have a history of physical or psychological dependence on ethanol. Mallory-Weiss Syndrome (Mallory-Weiss Tear) neuropathy Neuropathy Leprosy
• Peripheral neuropathy Neuropathy Leprosy: a more general term that may refer to a mononeuropathy Mononeuropathy Disease or trauma involving a single peripheral nerve in isolation, or out of proportion to evidence of diffuse peripheral nerve dysfunction. Mononeuropathy multiplex refers to a condition characterized by multiple isolated nerve injuries. Mononeuropathies may result from a wide variety of causes, including ischemia; traumatic injury; compression; connective tissue diseases; cumulative trauma disorders; and other conditions. Mononeuropathy and Plexopathy, mononeuropathy Mononeuropathy Disease or trauma involving a single peripheral nerve in isolation, or out of proportion to evidence of diffuse peripheral nerve dysfunction. Mononeuropathy multiplex refers to a condition characterized by multiple isolated nerve injuries. Mononeuropathies may result from a wide variety of causes, including ischemia; traumatic injury; compression; connective tissue diseases; cumulative trauma disorders; and other conditions. Mononeuropathy and Plexopathy multiplex, polyneuropathy, or radiculopathy Radiculopathy Disease involving a spinal nerve root which may result from compression related to intervertebral disk displacement; spinal cord injuries; spinal diseases; and other conditions. Clinical manifestations include radicular pain, weakness, and sensory loss referable to structures innervated by the involved nerve root. Rheumatoid Arthritis.

Epidemiology

• The overall 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 of polyneuropathies Polyneuropathies Diseases of multiple peripheral nerves simultaneously. Polyneuropathies usually are characterized by symmetrical, bilateral distal motor and sensory impairment with a graded increase in severity distally. The pathological processes affecting peripheral nerves include degeneration of the axon, myelin or both. The various forms of polyneuropathy are categorized by the type of nerve affected (e.g., sensory, motor, or autonomic), by the distribution of nerve injury (e.g., distal vs. Proximal), by nerve component primarily affected (e.g., demyelinating vs. axonal), by etiology, or by pattern of inheritance. Mononeuropathy and Plexopathy is 2.5%–5% in the general population; 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 increases with advancing age.
• The number of causes of polyneuropathies Polyneuropathies Diseases of multiple peripheral nerves simultaneously. Polyneuropathies usually are characterized by symmetrical, bilateral distal motor and sensory impairment with a graded increase in severity distally. The pathological processes affecting peripheral nerves include degeneration of the axon, myelin or both. The various forms of polyneuropathy are categorized by the type of nerve affected (e.g., sensory, motor, or autonomic), by the distribution of nerve injury (e.g., distal vs. Proximal), by nerve component primarily affected (e.g., demyelinating vs. axonal), by etiology, or by pattern of inheritance. Mononeuropathy and Plexopathy is estimated at approximately 100.
• Diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus is the most common identifiable cause of polyneuropathy.
• In approximately 20%–30% of individuals, the cause is undetermined (also known as idiopathic Idiopathic Dermatomyositis polyneuropathy).
• Women > men (1.5–2 to 1)
• More common in Western civilizations than in developing countries

Classification

Polyneuropathies Polyneuropathies Diseases of multiple peripheral nerves simultaneously. Polyneuropathies usually are characterized by symmetrical, bilateral distal motor and sensory impairment with a graded increase in severity distally. The pathological processes affecting peripheral nerves include degeneration of the axon, myelin or both. The various forms of polyneuropathy are categorized by the type of nerve affected (e.g., sensory, motor, or autonomic), by the distribution of nerve injury (e.g., distal vs. Proximal), by nerve component primarily affected (e.g., demyelinating vs. axonal), by etiology, or by pattern of inheritance. Mononeuropathy and Plexopathy may be classified on the basis of:

• Anatomy: location of lesion 
• Etiology:
  • Axonopathies 
  • Demyelinating diseases 
  • Mixed lesions 
• Types of impairment:
  • Sensory Sensory Neurons which conduct nerve impulses to the central nervous system. Nervous System: Histology
  • Motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology
  • Sensorimotor
  • Autonomic 
• Clinical progression:
  • Acute
  • Subacute
  • Chronic
  • Relapsing

Etiology and Pathophysiology

Etiology

There are numerous causes of polyneuropathy; however, diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus mellitus (diabetic neuropathy Neuropathy Leprosy) and chronic alcohol use ( alcoholic Alcoholic Persons who have a history of physical or psychological dependence on ethanol. Mallory-Weiss Syndrome (Mallory-Weiss Tear) neuropathy Neuropathy Leprosy) are responsible for almost 50% of all polyneuropathies Polyneuropathies Diseases of multiple peripheral nerves simultaneously. Polyneuropathies usually are characterized by symmetrical, bilateral distal motor and sensory impairment with a graded increase in severity distally. The pathological processes affecting peripheral nerves include degeneration of the axon, myelin or both. The various forms of polyneuropathy are categorized by the type of nerve affected (e.g., sensory, motor, or autonomic), by the distribution of nerve injury (e.g., distal vs. Proximal), by nerve component primarily affected (e.g., demyelinating vs. axonal), by etiology, or by pattern of inheritance. Mononeuropathy and Plexopathy. Most cases are likely multifactorial. Therefore, the various etiologic entities will be presented as both risk factors and distinct etiologic causes.

• Diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus:
  • Occurs in approximately 50% of individuals with types 1 and 2 diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus
  • Primarily axonal in nature
  • Metabolic syndrome Metabolic syndrome Metabolic syndrome is a cluster of conditions that significantly increases the risk for several secondary diseases, notably cardiovascular disease, type 2 diabetes, and nonalcoholic fatty liver. In general, it is agreed that hypertension, insulin resistance/hyperglycemia, and hyperlipidemia, along with central obesity, are components of the metabolic syndrome. Metabolic Syndrome likely poses some degree of risk.
  • Sensory Sensory Neurons which conduct nerve impulses to the central nervous system. Nervous System: Histology symptoms more common than motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology symptoms:
    • Begins in lower extremities
    • Upper-extremity involvement presents later.
  • Neuropathic pain Neuropathic pain Caused by lesion or disease affecting the nervous system (PNS or CNS). Pain: Types and Pathways may be disabling.
  • Sensory Sensory Neurons which conduct nerve impulses to the central nervous system. Nervous System: Histology loss compounds risk of fall and progression of diabetic wounds.
  • Autonomic neuropathy Neuropathy Leprosy is often present.
• Alcohol use disorder Alcohol use disorder Alcohol is one of the most commonly used addictive substances in the world. Alcohol use disorder (AUD) is defined as pathologic consumption of alcohol leading to impaired daily functioning. Acute alcohol intoxication presents with impairment in speech and motor functions and can be managed in most cases with supportive care. Alcohol Use Disorder:
  • Occurs in approximately 40% of individuals with chronic alcoholism Alcoholism A primary, chronic disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. The disease is often progressive and fatal. It is characterized by impaired control over drinking, preoccupation with the drug alcohol, use of alcohol despite adverse consequences, and distortions in thinking, most notably denial. Each of these symptoms may be continuous or periodic. Wernicke Encephalopathy and Korsakoff Syndrome
  • Primarily axonal in nature
  • Sensory Sensory Neurons which conduct nerve impulses to the central nervous system. Nervous System: Histology symptoms and motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology weakness:
    • Begins in lower extremities
    • Upper-extremity involvement presents later.
  •  Autonomic neuropathy Neuropathy Leprosy is often present.
  • Contributing factors:
    • Direct/indirect toxic effects of alcohol
    • Thiamine Thiamine Also known as thiamine or thiamin, it is a vitamin C12H17N4OSCl of the vitamin B complex that is essential to normal metabolism and nerve function and is widespread in plants and animals Water-soluble Vitamins and their Deficiencies deficiency
    • Inability to metabolize thiamine Thiamine Also known as thiamine or thiamin, it is a vitamin C12H17N4OSCl of the vitamin B complex that is essential to normal metabolism and nerve function and is widespread in plants and animals Water-soluble Vitamins and their Deficiencies in the presence of alcohol
• Family history Family History Adult Health Maintenance:
  • Charcot-Marie-Tooth (CMT) disease is the most common inherited polyneuropathy:
    • Presents with polyneuropathy, high arches, hammer toes, and wasting of intrinsic muscles of the feet.
    • Due to mutations in the CMT 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(s), which may lead to axonal, demyelinating, or mixed polyneuropathy.
  • Friedreich ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia is an inherited condition that causes progressive weakness and neurologic changes; it usually presents in late childhood.
• Chronic inflammation Chronic Inflammation Inflammation:
  • Autoimmune disease:
    • Guillain-Barré syndrome Guillain-Barré syndrome Guillain-Barré syndrome (GBS), once thought to be a single disease process, is a family of immune-mediated polyneuropathies that occur after infections (e.g., with Campylobacter jejuni). Guillain-Barré Syndrome (GBS) is a rapid-onset progressive sensorimotor polyneuropathy that peaks in intensity in as few as 2–4 weeks, often following bacterial or viral infection that may resolve or persist.
    • Chronic inflammatory demyelinating polyneuropathy (CIDP) is a more gradual-onset version of GBS that is more likely to persist.
  • Vasculitis Vasculitis Inflammation of any one of the blood vessels, including the arteries; veins; and rest of the vasculature system in the body. Systemic Lupus Erythematosus
• Toxic exposure:
  • Chemotherapy Chemotherapy Osteosarcoma:
    • Multiple neurotoxic chemotherapeutic agents
    • Most common are taxanes Taxanes A group of diterpenoid cyclodecanes named for the taxanes that were discovered in the taxus tree. The action on microtubules has made some of them useful as antineoplastic agents. Microtubule and Topoisomerase Inhibitors, platinums, and vinca alkaloids Vinca Alkaloids A group of indole-indoline dimers which are alkaloids obtained from the vinca genus of plants. They inhibit polymerization of tubulin into microtubules thus blocking spindle formation and arresting cells in metaphase. They are some of the most useful antineoplastic agents. Microtubule and Topoisomerase Inhibitors.
  • Drugs:
    • Fluoroquinolones Fluoroquinolones Fluoroquinolones are a group of broad-spectrum, bactericidal antibiotics inhibiting bacterial DNA replication. Fluoroquinolones cover gram-negative, anaerobic, and atypical organisms, as well as some gram-positive and multidrug-resistant (MDR) organisms. Fluoroquinolones
    • Statins Statins Statins are competitive inhibitors of HMG-CoA reductase in the liver. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides. Statins
    • Amiodarone Amiodarone An antianginal and class III antiarrhythmic drug. It increases the duration of ventricular and atrial muscle action by inhibiting potassium channels and voltage-gated sodium channels. There is a resulting decrease in heart rate and in vascular resistance. Pulmonary Fibrosis
• Vitamin deficiencies:
  • B₁₂
  • Folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12
  • Thiamine Thiamine Also known as thiamine or thiamin, it is a vitamin C12H17N4OSCl of the vitamin B complex that is essential to normal metabolism and nerve function and is widespread in plants and animals Water-soluble Vitamins and their Deficiencies
• Malignancy Malignancy Hemothorax
• Renal disease/failure
• 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 disease/failure
• Deposition disease:
  • Cryoglobulinemia Cryoglobulinemia A condition characterized by the presence of abnormal quantities of cryoglobulins in the blood. Upon cold exposure, these abnormal proteins precipitate into the microvasculature leading to restricted blood flow in the exposed areas. Rapidly Progressive Glomerulonephritis
  • Amyloidosis Amyloidosis Amyloidosis is a disease caused by abnormal extracellular tissue deposition of fibrils composed of various misfolded low-molecular-weight protein subunits. These proteins are frequently byproducts of other pathological processes (e.g., multiple myeloma). Amyloidosis
• Hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto’s disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism
• Critical illness
• Infection:
  • HIV HIV Anti-HIV Drugs
  • 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

Pathophysiology

The following description is of the pathophysiology of diabetic polyneuropathy, as its pathogenesis is the most studied and most well understood. Many of the pathologic processes are common to other forms of polyneuropathy. Key distinguishing characteristics of other entities will be pointed out in the discussions of those entities.

• Presents most commonly as a distal, symmetrical Symmetrical Dermatologic Examination, sensorimotor polyneuropathy:
  • Sensory Sensory Neurons which conduct nerve impulses to the central nervous system. Nervous System: Histology manifestations more common than motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology manifestations
  • A “dying back” phenomenon is often observed, progressing more proximally with time.
• Primarily due to axonal degeneration with varying degrees of demyelination Demyelination Multiple Sclerosis
• May affect peripheral (primarily sensory Sensory Neurons which conduct nerve impulses to the central nervous system. Nervous System: Histology) and autonomic nerves:
  • Distal portions of sensory Sensory Neurons which conduct nerve impulses to the central nervous system. Nervous System: Histology and autonomic nerves are unmyelinated
  • Lack of myelination creates susceptibility to damage
• Underlying mechanisms include:
  • Chronic inflammation Chronic Inflammation Inflammation:
    • Chronic hyperglycemia Hyperglycemia Abnormally high blood glucose level. Diabetes Mellitus and hyperlipidemia overwhelm metabolic machinery and lead to increased circulating reactive oxygen species Reactive oxygen species Molecules or ions formed by the incomplete one-electron reduction of oxygen. These reactive oxygen intermediates include singlet oxygen; superoxides; peroxides; hydroxyl radical; and hypochlorous acid. They contribute to the microbicidal activity of phagocytes, regulation of signal transduction and gene expression, and the oxidative damage to nucleic acids; proteins; and lipids. Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD).
    • Damaged intracellular machinery may lead to impaired protein synthesis Synthesis Polymerase Chain Reaction (PCR), cellular regeneration Regeneration The physiological renewal, repair, or replacement of tissue. Wound Healing and repair, axonal transport of intracellular products, etc ETC The electron transport chain (ETC) sends electrons through a series of proteins, which generate an electrochemical proton gradient that produces energy in the form of adenosine triphosphate (ATP). Electron Transport Chain (ETC).
  • Exposure to circulating toxins:
    • Hyperglycemia Hyperglycemia Abnormally high blood glucose level. Diabetes Mellitus
    • Glycosylated Glycosylated Glycopeptides end products
    • Reactive oxygen species Reactive oxygen species Molecules or ions formed by the incomplete one-electron reduction of oxygen. These reactive oxygen intermediates include singlet oxygen; superoxides; peroxides; hydroxyl radical; and hypochlorous acid. They contribute to the microbicidal activity of phagocytes, regulation of signal transduction and gene expression, and the oxidative damage to nucleic acids; proteins; and lipids. Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD)
  • Microvascular ischemia Ischemia A hypoperfusion of the blood through an organ or tissue caused by a pathologic constriction or obstruction of its blood vessels, or an absence of blood circulation. Ischemic Cell Damage:
    • Morphologic abnormalities are observed in the vasa nervorum.
    • Endothelial dysfunction tips the balance of vascular autoregulation Autoregulation Systemic and Special Circulations toward vasoconstriction Vasoconstriction The physiological narrowing of blood vessels by contraction of the vascular smooth muscle. Vascular Resistance, Flow, and Mean Arterial Pressure.
    • Endothelial dysfunction is associated with increased local levels of 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 and interleukins Interleukins Interleukins are a type of cytokines (signaling proteins) that communicate messages between different parts of the immune system. The majority of interleukins are synthesized by helper CD4 T lymphocytes along with other cells such as monocytes, macrophages, and endothelial cells. Interleukins.
    • Impairs delivery of oxygen and nutrients to the distal nerves
  • Impaired mitochondrial transport:
    • 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 generate the metabolic energy for the cell.
    • 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 must traverse the entire length from cell body to the end of the axon.
    • More distal sections of axon most likely to be deficient in 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
    • Decreased availability of cellular energy to these vulnerable sections

Clinical Presentation

History

• Onset of presentation is usually insidious and progressive.
• Glove-and-stocking sensorimotor disturbances in the extremities:
  • Usually lower extremities (feet) are affected first.
  • Longest nerve fibers Nerve Fibers Slender processes of neurons, including the axons and their glial envelopes (myelin sheath). Nerve fibers conduct nerve impulses to and from the central nervous system. Nervous System: Histology are primarily affected.
  • Proximal progression and involvement of the upper limbs occurs over time.
• Description of pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways with neuropathic features:
  • Radiating
  • Lancinating
  • Shooting
  • Burning
  • Stinging 
• Hypoesthesia (loss of sensation):
  • Often described as numbness
  • Predisposes to:
    • Development of lower-extremity wounds (unnoticed by the individual)
    • Falls (combination of loss of sensation, position sense, and weakness)
  • Loss of vibratory sensation
  • Loss of position sense and proprioception Proprioception Sensory functions that transduce stimuli received by proprioceptive receptors in joints, tendons, muscles, and the inner ear into neural impulses to be transmitted to the central nervous system. Proprioception provides sense of stationary positions and movements of one’s body parts, and is important in maintaining kinesthesia and postural balance. Neurological Examination
• Paresthesia:
  • Tingling Tingling Posterior Cord Syndrome
  • Crawling sensation
  • Foreign-body sensation (“feels like I am wearing socks”)
  • Heaviness
• Weakness:
  • Perceived loss of strength in the affected limb(s):
    • May or may not manifest as a loss of gradable strength on exam 
    • May manifest with symptoms of gait Gait Manner or style of walking. Neurological Examination abnormality
  • Progressive inability to control limb movements (combination of sensory Sensory Neurons which conduct nerve impulses to the central nervous system. Nervous System: Histology loss, proprioceptive loss, and motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology weakness)

Signs of damaged motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology nerve fibers Nerve Fibers Slender processes of neurons, including the axons and their glial envelopes (myelin sheath). Nerve fibers conduct nerve impulses to and from the central nervous system. Nervous System: Histology

• Gait Gait Manner or style of walking. Neurological Examination abnormalities
• Distal flaccid paresis Paresis A general term referring to a mild to moderate degree of muscular weakness, occasionally used as a synonym for paralysis (severe or complete loss of motor function). In the older literature, paresis often referred specifically to paretic neurosyphilis. ‘general paresis’ and ‘general paralysis’ may still carry that connotation. Bilateral lower extremity paresis is referred to as paraparesis. Spinal Disk Herniation ( foot Foot The foot is the terminal portion of the lower limb, whose primary function is to bear weight and facilitate locomotion. The foot comprises 26 bones, including the tarsal bones, metatarsal bones, and phalanges. The bones of the foot form longitudinal and transverse arches and are supported by various muscles, ligaments, and tendons. Foot: Anatomy flexor paresis Paresis A general term referring to a mild to moderate degree of muscular weakness, occasionally used as a synonym for paralysis (severe or complete loss of motor function). In the older literature, paresis often referred specifically to paretic neurosyphilis. ‘general paresis’ and ‘general paralysis’ may still carry that connotation. Bilateral lower extremity paresis is referred to as paraparesis. Spinal Disk Herniation)
• Loss of distal reflexes (Achilles tendon reflex)
• Fasciculations
• Muscle cramps Cramps Ion Channel Myopathy
• 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
• Varying degrees of foot drop Foot Drop Leprosy (peroneal neuropathy Neuropathy Leprosy) is common in the lower limbs with or without a compressive component.
• Restless legs

Signs of damage to the autonomic nervous system Autonomic nervous system The ANS is a component of the peripheral nervous system that uses both afferent (sensory) and efferent (effector) neurons, which control the functioning of the internal organs and involuntary processes via connections with the CNS. The ANS consists of the sympathetic and parasympathetic nervous systems. Autonomic Nervous System: Anatomy

• Vascular dysregulation with distal cyanosis Cyanosis A bluish or purplish discoloration of the skin and mucous membranes due to an increase in the amount of deoxygenated hemoglobin in the blood or a structural defect in the hemoglobin molecule. Pulmonary Examination 
• Dry mouth
• Orthostatic hypotension Orthostatic hypotension A significant drop in blood pressure after assuming a standing position. Orthostatic hypotension is a finding, and defined as a 20-mm hg decrease in systolic pressure or a 10-mm hg decrease in diastolic pressure 3 minutes after the person has risen from supine to standing. Symptoms generally include dizziness, blurred vision, and syncope. Hypotension
• Hyperhidrosis Hyperhidrosis Excessive sweating. In the localized type, the most frequent sites are the palms, soles, axillae, inguinal folds, and the perineal area. Its chief cause is thought to be emotional. Generalized hyperhidrosis may be induced by a hot, humid environment, by fever, or by vigorous exercise. Malassezia Fungi, anhidrosis
• Trophic changes in the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions and nails

Diagnosis

History

Take a complete history, including:

• Past medical history Past Medical History Adult Health Maintenance
• Family history Family History Adult Health Maintenance
• Exposure to drugs and toxins
• Substance use history

Physical exam

Full neurologic exam to discover any focal neurologic deficits Neurologic Deficits High-Risk Headaches:

• Sensory Sensory Neurons which conduct nerve impulses to the central nervous system. Nervous System: Histology exam:
  • Light touch Light touch Neurological Examination (performed with a standard Semmes-Weinstein monofilament):
    • Inability to feel the monofilament in the affected limbs is correlated with “loss of protective sensation.”
    • Loss of protective sensation is correlated with increased risk of wounds and/or ulcerations that may go unnoticed → increased risk of limb amputation Amputation An amputation is the separation of a portion of the limb or the entire limb from the body, along with the bone. Amputations are generally indicated for conditions that compromise the viability of the limb or promote the spread of a local process that could manifest systemically. Amputation
  • Pressure 
  • Vibration Vibration A continuing periodic change in displacement with respect to a fixed reference. Neurological Examination
  • 2-point discrimination
  • Position sense
• Motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology exam:
  • Grade strengths I–V
  • Screen for gait Gait Manner or style of walking. Neurological Examination abnormalities.
  • Note 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 muscle tone Muscle tone The state of activity or tension of a muscle beyond that related to its physical properties, that is, its active resistance to stretch. In skeletal muscle, tonus is dependent upon efferent innervation. Skeletal Muscle Contraction and bulk.
  • Note presence of fasciculations and spasm.
  • Check deep tendon reflexes Deep Tendon Reflexes Neurological Examination (DTRs).

Laboratory studies

• Metabolic labs (screen for diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus mellitus and 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):
  • Fasting 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
  • HbA_1c to screen for diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus mellitus
  • CMP:
    • Includes renal function (creatinine, GFR GFR The volume of water filtered out of plasma through glomerular capillary walls into Bowman’s capsules per unit of time. It is considered to be equivalent to inulin clearance. Kidney Function Tests, BUN)
    • Includes 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 function ( AST AST Enzymes of the transferase class that catalyze the conversion of l-aspartate and 2-ketoglutarate to oxaloacetate and l-glutamate. Liver Function Tests, ALT ALT An enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate. Liver Function Tests)
  • Vitamin B₁₂, folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12, thiamine Thiamine Also known as thiamine or thiamin, it is a vitamin C12H17N4OSCl of the vitamin B complex that is essential to normal metabolism and nerve function and is widespread in plants and animals Water-soluble Vitamins and their Deficiencies levels for vitamin deficiency
  • Methylmalonic acid in the urine is an indirect marker of vitamin B₁₂ deficiency.
• Inflammatory markers:
  • Erythrocyte sedimentation rate Erythrocyte Sedimentation Rate Soft Tissue Abscess
  • CRP
  • Antinuclear antibody test 
• Infectious disease markers:
  • HIV HIV Anti-HIV Drugs
  • Hepatitis C Hepatitis C Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C virus can cause both acute and chronic hepatitis, ranging from a mild to a serious, lifelong illness including liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis C Virus
  • 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 
  • EBV EBV Epstein-barr virus (EBV) is a linear, double-stranded DNA virus belonging to the herpesviridae family. This highly prevalent virus is mostly transmitted through contact with oropharyngeal secretions from an infected individual. The virus can infect epithelial cells and B lymphocytes, where it can undergo lytic replication or latency. Epstein-Barr Virus
  • Rapid plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products reagin
• CBC
• Immunoelectrophoresis for amyloidosis Amyloidosis Amyloidosis is a disease caused by abnormal extracellular tissue deposition of fibrils composed of various misfolded low-molecular-weight protein subunits. These proteins are frequently byproducts of other pathological processes (e.g., multiple myeloma). Amyloidosis and other protein-related disorders
• Testing for heavy metal toxicities:
  • Heavy metals
  • Lead
  • Arsenic Arsenic A shiny gray element with atomic symbol as, atomic number 33, and atomic weight 75. It occurs throughout the universe, mostly in the form of metallic arsenides. Most forms are toxic. According to the fourth annual report on carcinogens, arsenic and certain arsenic compounds have been listed as known carcinogens. Metal Poisoning (Lead, Arsenic, Iron)
  • Pesticides
• 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 test for hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto’s disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism
• Molecular genetic tests to evaluate for inherited disorders

Imaging

• Magnetic resonance neurography:
  • Allows direct imaging of the nerves
  • More useful for proximal than for distal lesions
• Magnetic resonance imaging if compression Compression Blunt Chest Trauma of nerve is suspected.

Other procedures

• Electrodiagnostic studies:
  • Includes electromyography Electromyography Recording of the changes in electric potential of muscle by means of surface or needle electrodes. Becker Muscular Dystrophy (EMG) and nerve conduction velocity testing 
  • Tool to distinguish between axonal, demyelinating, and axonal–demyelinating diseases:
    • In demyelinating diseases, the nerve conduction velocity is reduced.
    • In axonal diseases, the overall 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 is reduced.
• Nerve/ muscle biopsy Muscle Biopsy Trichinella/Trichinellosis:
  • Reserved for if the cause is unknown after extensive workup.
  • Usually used for inflammatory processes or storage diseases 

Management

General concepts

• After confirming the etiology, manage the underlying cause of disease:
  • Glycemic control
  • Weight loss Weight loss Decrease in existing body weight. Bariatric Surgery
  • Alcohol cessation
  • Stop/modify offending toxic agents
• Next steps include:
  • Prevention of further damage
  • Pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways management
  • Restoration of nerve and muscular function
  • Weight loss Weight loss Decrease in existing body weight. Bariatric Surgery is often useful, along with exercise
  • Assistive devices:
    • Walker
    • Cane
    • Ankle– foot Foot The foot is the terminal portion of the lower limb, whose primary function is to bear weight and facilitate locomotion. The foot comprises 26 bones, including the tarsal bones, metatarsal bones, and phalanges. The bones of the foot form longitudinal and transverse arches and are supported by various muscles, ligaments, and tendons. Foot: Anatomy orthotic(s) for foot drop Foot Drop Leprosy
  • Working with a physical therapist or occupational therapist is useful for many people.

Pharmacotherapy

Pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways management:

• Anticonvulsants are 1st-line agents:
  • Gabapentinoids are most commonly used:
    • 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 (multiple formulations available)
    • Pregabalin Pregabalin A gamma-aminobutyric acid (gaba) derivative that functions as a calcium channel blocker and is used as an anticonvulsant as well as an anti-anxiety agent. It is also used as an analgesic in the treatment of neuropathic pain and fibromyalgia. Second-Generation Anticonvulsant Drugs
  • Other anticonvulsants may be used (e.g., valproic acid Valproic acid A fatty acid with anticonvulsant and anti-manic properties that is used in the treatment of epilepsy and bipolar disorder. The mechanisms of its therapeutic actions are not well understood. It may act by increasing gamma-aminobutyric acid levels in the brain or by altering the properties of voltage-gated sodium channels. First-Generation Anticonvulsant Drugs, carbamazepine Carbamazepine A dibenzazepine that acts as a sodium channel blocker. It is used as an anticonvulsant for the treatment of grand mal and psychomotor or focal seizures. It may also be used in the management of bipolar disorder, and has analgesic properties. First-Generation Anticonvulsant Drugs).
• Antidepressants may also be 1st- or 2nd-line agents:
  • Serotonin Serotonin A biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Receptors and Neurotransmitters of the CNS– norepinephrine Norepinephrine Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus. Receptors and Neurotransmitters of the CNS reuptake inhibitors ( SNRIs SNRIs Serotonin Reuptake Inhibitors and Similar Antidepressants):
    • Venlafaxine Venlafaxine A cyclohexanol and phenylethylamine derivative that functions as a serotonin and noradrenaline reuptake inhibitor (SNRI) and is used as an antidepressant agent. Serotonin Reuptake Inhibitors and Similar Antidepressants
    • Duloxetine Duloxetine A thiophene derivative and selective neurotransmitter uptake inhibitor for serotonin and noradrenaline (SNRI). It is an antidepressant agent and anxiolytic, and is also used for the treatment of pain in patients with diabetes mellitus and fibromyalgia. Serotonin Reuptake Inhibitors and Similar Antidepressants
  • Tricyclic antidepressants Tricyclic antidepressants Tricyclic antidepressants (TCAs) are a class of medications used in the management of mood disorders, primarily depression. These agents, named after their 3-ring chemical structure, act via reuptake inhibition of neurotransmitters (particularly norepinephrine and serotonin) in the brain. Tricyclic Antidepressants:
    • 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
    • Clomipramine Clomipramine A tricyclic antidepressant similar to imipramine that selectively inhibits the uptake of serotonin in the brain. It is readily absorbed from the gastrointestinal tract and demethylated in the liver to form its primary active metabolite, desmethylclomipramine. Tricyclic Antidepressants
• Topical agents may be useful in cases with limited areas of pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways or as an adjuvant Adjuvant Substances that augment, stimulate, activate, potentiate, or modulate the immune response at either the cellular or humoral level. The classical agents (freund’s adjuvant, bcg, corynebacterium parvum, et al.) contain bacterial antigens. Some are endogenous (e.g., histamine, interferon, transfer factor, tuftsin, interleukin-1). Their mode of action is either non-specific, resulting in increased immune responsiveness to a wide variety of antigens, or antigen-specific, i.e., affecting a restricted type of immune response to a narrow group of antigens. The therapeutic efficacy of many biological response modifiers is related to their antigen-specific immunoadjuvanticity. Vaccination:
  • Capsaicin
  • Compounded topical preparations 
• Muscle relaxants for cramps Cramps Ion Channel Myopathy/ 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
  • Cyclobenzaprine Cyclobenzaprine Spasmolytics
  • Quinine Quinine An alkaloid derived from the bark of the cinchona tree. It is used as an antimalarial drug, and is the active ingredient in extracts of the cinchona that have been used for that purpose since before 1633. Quinine is also a mild antipyretic and analgesic and has been used in common cold preparations for that purpose. It was used commonly and as a bitter and flavoring agent, and is still useful for the treatment of babesiosis. Quinine is also useful in some muscular disorders, especially nocturnal leg cramps and myotonia congenita, because of its direct effects on muscle membrane and sodium channels. The mechanisms of its antimalarial effects are not well understood. Antimalarial Drugs sulfate products

Disease-modifying therapies:

• IV immune globulin:
  • May be useful for inflammatory/autoimmune neuropathies Neuropathies Chédiak-Higashi Syndrome
  • Infusion therapies are administered in a monitored setting (i.e., certified infusion center).
• There are no approved disease-modifying therapies for diabetic polyneuropathy.

Management of selected types of polyneuropathy

• Diabetic polyneuropathy:
  • Normalize metabolism with tight 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 control
  • Compliance Compliance Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. Veins: Histology with strict diet and exercise 
  • Pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways management with 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
  • Physical rehabilitation for restoration of motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology function
• Alcoholic Alcoholic Persons who have a history of physical or psychological dependence on ethanol. Mallory-Weiss Syndrome (Mallory-Weiss Tear) polyneuropathy:
  • Abstinence from alcohol 
  • Supplementation of vitamin B complex
• Critical illness polyneuropathy (CIP):
  • Creates difficulty in individuals weaning Weaning Techniques for effecting the transition of the respiratory-failure patient from mechanical ventilation to spontaneous ventilation, while meeting the criteria that tidal volume be above a given threshold (greater than 5 ml/kg), respiratory frequency be below a given count (less than 30 breaths/min), and oxygen partial pressure be above a given threshold (pao2 greater than 50mm hg). Weaning studies focus on finding methods to monitor and predict the outcome of mechanical ventilator weaning as well as finding ventilatory support techniques which will facilitate successful weaning. Present methods include intermittent mandatory ventilation, intermittent positive pressure ventilation, and mandatory minute volume ventilation. Invasive Mechanical Ventilation off mechanical ventilation Ventilation The total volume of gas inspired or expired per unit of time, usually measured in liters per minute. Ventilation: Mechanics of Breathing
  • Management is supportive.
  • Once individuals recover from the severe underlying disease, complete remission Remission A spontaneous diminution or abatement of a disease over time, without formal treatment. Cluster Headaches from CIP is possible and common. 

Clinical Relevance

• Type 2 Type 2 Spinal Muscular Atrophy diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus mellitus: metabolic disease characterized by hyperglycemia Hyperglycemia Abnormally high blood glucose level. Diabetes Mellitus due to dysfunction of regulation of 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 metabolism by insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin secondary to insulin resistance Insulin resistance Diminished effectiveness of insulin in lowering blood sugar levels: requiring the use of 200 units or more of insulin per day to prevent hyperglycemia or ketosis. Diabetes Mellitus. Type 2 Type 2 Spinal Muscular Atrophy diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus mellitus is associated with obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity. Because there is no definitive cure, management centers around close monitoring and maintenance of blood 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 levels. Complications of type 2 Type 2 Spinal Muscular Atrophy diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus mellitus include retinopathy Retinopathy Degenerative changes to the retina due to hypertension. Alport Syndrome, nephropathy, and neuropathy Neuropathy Leprosy. Neuropathy Neuropathy Leprosy typically presents many years into the disease course.
• Guillain-Barré syndrome Guillain-Barré syndrome Guillain-Barré syndrome (GBS), once thought to be a single disease process, is a family of immune-mediated polyneuropathies that occur after infections (e.g., with Campylobacter jejuni). Guillain-Barré Syndrome (GBS): immune-mediated polyneuropathy Immune-Mediated Polyneuropathy Guillain-Barré Syndrome that may occur after Campylobacter jejuni Campylobacter jejuni A species of bacteria that resemble small tightly coiled spirals. Its organisms are known to cause abortion in sheep and fever and enteritis in man and may be associated with enteric diseases of calves, lambs, and other animals. Campylobacter infection. Classically, this disease is associated with a recent outdoor vacation or trip. The extracellular lipooligosaccharide of the bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology is similar to that of the peripheral nerves Peripheral Nerves The nerves outside of the brain and spinal cord, including the autonomic, cranial, and spinal nerves. Peripheral nerves contain non-neuronal cells and connective tissue as well as axons. The connective tissue layers include, from the outside to the inside, the epineurium, the perineurium, and the endoneurium. Nervous System: Histology, which are targeted by 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. This syndrome is characterized by acute neuromuscular paralysis that is symmetric and ascending in nature. Guillain-Barré syndrome Guillain-Barré syndrome Guillain-Barré syndrome (GBS), once thought to be a single disease process, is a family of immune-mediated polyneuropathies that occur after infections (e.g., with Campylobacter jejuni). Guillain-Barré Syndrome can progress into respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure, requiring prolonged hospitalization Prolonged Hospitalization Surgical Infections. Management is mostly supportive and may require either plasma exchange Plasma exchange Removal of plasma and replacement with various fluids, e.g., fresh frozen plasma, plasma protein fractions (ppf), albumin preparations, dextran solutions, saline. Used in treatment of autoimmune diseases, immune complex diseases, diseases of excess plasma factors, and other conditions. Thrombotic Thrombocytopenic Purpura or IV immunoglobulin Iv Immunoglobulin Dermatomyositis. 
• Alcohol use disorder Alcohol use disorder Alcohol is one of the most commonly used addictive substances in the world. Alcohol use disorder (AUD) is defined as pathologic consumption of alcohol leading to impaired daily functioning. Acute alcohol intoxication presents with impairment in speech and motor functions and can be managed in most cases with supportive care. Alcohol Use Disorder ( AUD AUD Alcohol is one of the most commonly used addictive substances in the world. Alcohol use disorder (AUD) is defined as pathologic consumption of alcohol leading to impaired daily functioning. Acute alcohol intoxication presents with impairment in speech and motor functions and can be managed in most cases with supportive care. Alcohol Use Disorder): excessive consumption of alcohol leading to impaired daily functioning. Alcohol use disorder Alcohol use disorder Alcohol is one of the most commonly used addictive substances in the world. Alcohol use disorder (AUD) is defined as pathologic consumption of alcohol leading to impaired daily functioning. Acute alcohol intoxication presents with impairment in speech and motor functions and can be managed in most cases with supportive care. Alcohol Use Disorder affects almost every part of the human body and has serious impacts on a person’s mental and physical health. Some complications of chronic AUD AUD Alcohol is one of the most commonly used addictive substances in the world. Alcohol use disorder (AUD) is defined as pathologic consumption of alcohol leading to impaired daily functioning. Acute alcohol intoxication presents with impairment in speech and motor functions and can be managed in most cases with supportive care. Alcohol Use Disorder include hepatitis, pancreatitis Pancreatitis Inflammation of the pancreas. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of chronic pancreatitis. The two most common forms of acute pancreatitis are alcoholic pancreatitis and gallstone pancreatitis. Acute Pancreatitis, and neuropathy Neuropathy Leprosy. Alcohol use disorder Alcohol use disorder Alcohol is one of the most commonly used addictive substances in the world. Alcohol use disorder (AUD) is defined as pathologic consumption of alcohol leading to impaired daily functioning. Acute alcohol intoxication presents with impairment in speech and motor functions and can be managed in most cases with supportive care. Alcohol Use Disorder can be managed with psychotherapy Psychotherapy Psychotherapy is interpersonal treatment based on the understanding of psychological principles and mechanisms of mental disease. The treatment approach is often individualized, depending on the psychiatric condition(s) or circumstance. Psychotherapy as well as medications; however, 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 is usually poor, with high rates of relapse Relapse Relapsing Fever and complications. 
• Critical illness polyneuropathy and myopathy Myopathy Dermatomyositis: syndromes that occur in roughly 70% of critically ill individuals with sepsis Sepsis Systemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by hypotension despite adequate fluid infusion, it is called septic shock. Sepsis and Septic Shock and multiorgan failure. This illness is characterized by diffuse, flaccid muscle weakness. Respiratory muscles and limbs are usually affected. Diagnosis requires EMG as well as nerve conduction studies. Management is 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 is positive if individuals recover from the severe underlying illness.