Peripheral neuropathy pathophysiology: Difference between revisions
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==Overview== | ==Overview== | ||
==Pathophysiology== | ==Pathophysiology== | ||
The pathophysiologic processes that can adversely affect peripheral nerves is very extensive. | |||
The | |||
Processes which can damage the peripheral nerves at multiple levels via many molecular pathways include: | |||
* Immunologic | |||
* Metabolic | |||
* Genetic | |||
* Infectious | |||
* Toxic | |||
* Traumatic processes | |||
The origin of the peripheral nerve lies in the neuronal cell bodies located in the dorsal root ganglion (DRG) for sensory nerves, and in the ventral horn of the spinal cord for motor nerves. Any pathologic process affecting the cell body will result in downstream degeneration of the cell's axon. Primary motor neuron diseases, such as ALS or SMA, demonstrate axonal pathology peripherally when central neurons degenerate. Similarly, metabolic conditions, such as diabetes, the metabolic syndrome, nutritional deficiencies, or chronic renal failure, affect DRG cell bodies by mechanisms involving insulin resistance, oxidative stress, and apoptosis. Pathologic damage may also be considered to take place directly at the axon, independent of the cell body. For example, processes that affect the cytoskeletal components of axons may give rise to neuropathy. Thus, chemotherapeutics, particularly those that affect microtubules, have a propensity to produce neuropathic side effects by disrupting axonal structure. Other toxic exposures may disrupt metabolic homeostasis, myelin composition, and mitochondrial function, producing demyelinating and axonopathic disease to varying degrees. Schwann cells and the myelin sheath are often selectively targeted in immune-mediated processes such as GBS, CIDP, paraproteinemias, and their variants. It is theorized that a phenomenon of molecular mimicry occurs in these diseases, wherein glycoprotein epitopes found in myelin bear structural similarity to those found in other infectious agents (''Campylobacter jejuni'', CMV, Epstein-Barr virus, etc.). Immune recognition of these pathogens then spreads to include normal epitopes on the myelin sheath. Pathologic studies reveal both humoral and cellular immune activation and lymphocytic infiltration with patchy demyelination and remyelination (the classic “onion bulb” formation). Interestingly, a number of GBS variants which are more prevalent in Asia and Central/South America also damage axons along with myelin, and are commonly associated with ''Campylobacter jejuni'' infection. Anti-MAG negative IgM gammopathies, as well as less common gammopathies, can also present with a mixed demyelinating/axonopathic picture. Hereditary neuropathies can also affect both axons and/or their myelin sheaths. The most common type, hereditary motor sensory neuropathy (HMSN or Charcot-Marie-Tooth disease), is classified into many clinical subtypes. Type 1 encompasses demyelinating processes and results from mutations in proteins integral to myelin formation. Type 2 chiefly results in axonal pathologies and involves mutations that affect cellular structure or metabolism. A characteristic of inherited neuropathies is that the entire length of the nerve is affected more or less uniformly given the genetic underpinnings of the disease. Many other genetic syndromes also produce varying disruption of Schwann cell, axon and/or neuronal function. Both the Schwann cells and axons of the peripheral nerve depend upon delicate vasa nervorum for perfusion and metabolic support. Many metabolic and inflammatory processes, while directly affecting peripheral nerves and neuronal cell bodies, can also result in damage to nerve vasculature and indirectly produce ischemic damage, particularly to axons. Primary vasculitides as well as other rheumatologic disorders (systemic lupus erythematosus, Sjögren's syndrome, nonsystemic vasculitis of the peripheral nerves, etc.) may compromise vascular supply to nerves.<sup>31,32</sup> Thus, ischemic changes represent a common neuropathologic mechanism by which peripheral nerves may be damaged. | |||
==References== | ==References== | ||
Revision as of 14:55, 17 August 2018
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamadmostafa Jahansouz M.D.[2]
Overview
Pathophysiology
The pathophysiologic processes that can adversely affect peripheral nerves is very extensive.
Processes which can damage the peripheral nerves at multiple levels via many molecular pathways include:
- Immunologic
- Metabolic
- Genetic
- Infectious
- Toxic
- Traumatic processes
The origin of the peripheral nerve lies in the neuronal cell bodies located in the dorsal root ganglion (DRG) for sensory nerves, and in the ventral horn of the spinal cord for motor nerves. Any pathologic process affecting the cell body will result in downstream degeneration of the cell's axon. Primary motor neuron diseases, such as ALS or SMA, demonstrate axonal pathology peripherally when central neurons degenerate. Similarly, metabolic conditions, such as diabetes, the metabolic syndrome, nutritional deficiencies, or chronic renal failure, affect DRG cell bodies by mechanisms involving insulin resistance, oxidative stress, and apoptosis. Pathologic damage may also be considered to take place directly at the axon, independent of the cell body. For example, processes that affect the cytoskeletal components of axons may give rise to neuropathy. Thus, chemotherapeutics, particularly those that affect microtubules, have a propensity to produce neuropathic side effects by disrupting axonal structure. Other toxic exposures may disrupt metabolic homeostasis, myelin composition, and mitochondrial function, producing demyelinating and axonopathic disease to varying degrees. Schwann cells and the myelin sheath are often selectively targeted in immune-mediated processes such as GBS, CIDP, paraproteinemias, and their variants. It is theorized that a phenomenon of molecular mimicry occurs in these diseases, wherein glycoprotein epitopes found in myelin bear structural similarity to those found in other infectious agents (Campylobacter jejuni, CMV, Epstein-Barr virus, etc.). Immune recognition of these pathogens then spreads to include normal epitopes on the myelin sheath. Pathologic studies reveal both humoral and cellular immune activation and lymphocytic infiltration with patchy demyelination and remyelination (the classic “onion bulb” formation). Interestingly, a number of GBS variants which are more prevalent in Asia and Central/South America also damage axons along with myelin, and are commonly associated with Campylobacter jejuni infection. Anti-MAG negative IgM gammopathies, as well as less common gammopathies, can also present with a mixed demyelinating/axonopathic picture. Hereditary neuropathies can also affect both axons and/or their myelin sheaths. The most common type, hereditary motor sensory neuropathy (HMSN or Charcot-Marie-Tooth disease), is classified into many clinical subtypes. Type 1 encompasses demyelinating processes and results from mutations in proteins integral to myelin formation. Type 2 chiefly results in axonal pathologies and involves mutations that affect cellular structure or metabolism. A characteristic of inherited neuropathies is that the entire length of the nerve is affected more or less uniformly given the genetic underpinnings of the disease. Many other genetic syndromes also produce varying disruption of Schwann cell, axon and/or neuronal function. Both the Schwann cells and axons of the peripheral nerve depend upon delicate vasa nervorum for perfusion and metabolic support. Many metabolic and inflammatory processes, while directly affecting peripheral nerves and neuronal cell bodies, can also result in damage to nerve vasculature and indirectly produce ischemic damage, particularly to axons. Primary vasculitides as well as other rheumatologic disorders (systemic lupus erythematosus, Sjögren's syndrome, nonsystemic vasculitis of the peripheral nerves, etc.) may compromise vascular supply to nerves.31,32 Thus, ischemic changes represent a common neuropathologic mechanism by which peripheral nerves may be damaged.