Pathogenesis of Peripheral Neuropathies

Basic responses of peripheral nerve fibers to injury :

DISTAL AXONAL DEGENERATION

DEGENERATION OF CELL BODY AND AXON

SEGMENTAL DEMYELINATION REMYELINATION REGENERATING AXON REGENERATED NERVE FIBER

Axonal Degeneration
Degeneration (necrosis) of the axon occurs in many neuropathies and reflects significant injury of the neuronal cell body or its axon. Axonal degeneration is quickly followed by breakdown of the myelin sheath and Schwann cell proliferation.

Axonal Degeneration
Myelin degradation is initiated by Schwann cells and completed by macrophages, which infiltrate the nerve within 3 days after axonal degeneration.

Axonal Degeneration
If the degeneration is restricted to the distal axon, regenerating axons may sprout within 1 week from the intact, proximal axonal stump. There are several types of axonal degeneration.

Axonal Degeneration
DISTAL AXONOPATHY: In many neuropathies, axonal degeneration is initially restricted to the distal ends of the larger, longer fibers . Peripheral neuropathies characterized by the selective degeneration of distal axons are known as dying-back neuropathies (distal axonopathies)

Axonal Degeneration
DISTAL AXONOPATHY: The neuronal cell body and proximal axon remain intact. Therefore, axonal regeneration and return of nerve function may be possible if the cause can be identified and removed.

Axonal Degeneration
NEURONOPATHY: Axonal degeneration may also be the result of degeneration of the neuronal cell body, as occurs in poliomyelitis. Neuropathies showing selective degeneration of the neuronal cell body are referred to as neuronopathies and are much less common than distal axonopathies.

Axonal Degeneration
WALLERIAN DEGENERATION: This term refers to the axonal degeneration that occurs in a nerve distal to a transection or crush of the nerve, lead to the accumulation of supernumerary Schwann cells around axons (onion-bulbs) and clinically apparent nerve enlargement (hypertroplzic neuropathy).

Segmental Demyelination
The loss of myelin from one or more internodes (segments) along a myelinated fiber is common in many neuropathies and reflects Schwann cell dysfunction. This dysfunction may be caused by direct injury of the Schwann cell-myelin sheath (primary demyelination), or it may be the result of underlying axonal abnormalities (secondary demyelination).

Segmental Demyelination
Degeneration of the internodal myelin sheath is followed sequentially by : (1) Schwann cell proliferation (2) remyelination of the demyelinated segments (3) recovery of function

PERIPHERAL NEUROPATHIES
Peripheral neuropathy is a process that affects the function of one or more peripheral nerves. The disease may be restricted to the peripheral nervous system, involve both the peripheral and central nervous systems, or affect multiple organ systems. Peripheral neuropathies are encountered in all age groups and may be hereditary or acquired.

PERIPHERAL NEUROPATHIES
The causes of peripheral neuropathy are diverse. Charcot-Marie-Tooth disease (CMT) is the most common hereditary peripheral neuropathy. Diabetic neuropathy is the most common acquired neuropathy in the United States.

PERIPHERAL NEUROPATHIES
Pathologically, the involved nerves may show mainly axonal degeneration (axonal neuropathy), segmental demvelination (lencuelinating neuropathy), or a mixture of both. Most neuropathies are axonal.

PERIPHERAL NEUROPATHIES
Clinical Features : The major clinical manifestations of peripheral neuropathy are muscle weakness, muscle atrophy, alterations of sensation, and autonomic dysfunction. Motor, sensory, and autonomic functions may be equally or preferentially affected.

PERIPHERAL NEUROPATHIES
Clinical Features : Sensory abnormalities may reflect predominant involvement of largediameter fibers (position and vibration sense) or smalldiameter fibers (pain and temperature).

PERIPHERAL NEUROPATHIES
Inflammatory Demyelinating Neuropathy
is an acquired neuropathy that (1) may be sporadic; (2) may follow immunization, surgery, or viral (include HIV) and mycoplasmal infections; (3) or may complicate cancer.

PERIPHERAL NEUROPATHIES
Inflammatory Demyelinating Neuropathy
Pathogenesis is unknown but current evidence suggests that it may be immunologically mediated. Pathology : may involve all levels of the peripheral nervous system, including spinal roots, ganglia, craniospinal nerves, and autonomic nerves.

PERIPHERAL NEUROPATHIES
Inflammatory Demyelinating Neuropathy
Pathology : The involved regions show endoneurial infiltrates of lymphocytes and macrophages, segmental demyelination, and relative sparing of axons. The lymphoid infiltrates are often perivascular, but there is no true vasculitis.

PERIPHERAL NEUROPATHIES
Inflammatory Demyelinating Neuropathy
Pathology : Macrophages are frequently found adjacent to degenerating myelin sheaths and have been observed to strip off and phagocytose the superficial myelin lamellae.

PERIPHERAL NEUROPATHIES
Dorsal Root Ganglionitis (Sensory Ganglionitis)
Dorsal root ganglionitis is a sensory neuronopathy that may occur independently, as a remote effect of cancer (paraneoplastic neuropathy), or in association with Sjogren syndrome.

PERIPHERAL NEUROPATHIES
Dorsal Root Ganglionitis (Sensory Ganglionitis)
The neuronopathy typically is seen as a subacute or chronic sensory polyneuropathy with sensory ataxia. The pathogenesis of the ganglionitis is unknown, but an immune mechanism is likely.

PERIPHERAL NEUROPATHIES
Diabetic Neuropathy
The neuropathy may manifest as a distal sensory or sensorimotor polyneuropathy, autonomic neuropathy, mononeuropathy, or mononeuropathy multiplex. DistaL predominantly sensory, polyneuropathy is the most common form of diabetic neuropathy.

PERIPHERAL NEUROPATHIES
Diabetic Neuropathy
The pathogenesis of the nerve fiber injury in diabetes is unknown. It has long been held that the metabolic alterations of diabetes are responsible for the distal symmetric polyneuropathy and that nerve ischemia caused by the small-vessel disease is responsible for the mononeuropathies.

PERIPHERAL NEUROPATHIES
Diabetic Neuropathy
The distal symmetric polyneuropathy of diabetes is characterized pathologically by a mixture of axonal degeneration and segmental demyelination, with axonal degeneration predominating.

PERIPHERAL NEUROPATHIES
Uremic Neuropathy
Uremic neuropathy is a distal sensorimotor axonal polyneuropathy that may complicate chronic renal failure. The pathogenesis of the nerve fiber damage is not known, but the disease usually stabilizes or improves with chronic dialysis.

PERIPHERAL NEUROPATHIES
Uremic Neuropathy
Characterized pathologically by both distal axonal degeneration and segmental demyelination, with axonal degeneration predominating and preferentially involving large-diameter fibers. The neuropathy resolves after renal transplantation

PERIPHERAL NEUROPATHIES
Alcoholic Neuropathy
Alcoholic neuropathy is a distal sensorimotor axonal polyneuropathy that is generally attributed to nutritional deficiencies, rather than to a direct toxic effect of ethanol on the peripheral nervous system

PERIPHERAL NEUROPATHIES
Alcoholic Neuropathy
Peripheral nerves show loss of nerve fibers from axonal degeneration of the dyingback type. Axonal neuropathy is also associated with a lack of vitamins B1, B6, B12, or E, but is much less common than alcoholic neuropathy.

PERIPHERAL NEUROPATHIES
Vasculitic Neuropathy
Vasculitis may involve the nutrient arteries of nerves and produce ischemic nerve injury (ischemic neuropathy). Vasculitis-induced ischemic neuropathy may complicate polyarteritis nodosa and other systemic vasculitidies, rheumatoid arthritis, other collagen-vascular diseases, cryoglobulinemia, and HIV infection.

PERIPHERAL NEUROPATHIES
Vasculitic Neuropathy
Vasculitic neuropathy is characterized pathologically by axonal degeneration and typically is seen as a mononeuropathy or mononeuropathy multiplex.

PERIPHERAL NEUROPATHIES
Toxic Neuropathy
A wide variety of drugs, environmental agents, and industrial compounds cause peripheral neuropathy. The majority of toxic neuropathies are iatrogenic (i.e., they are caused by drugs). Most toxic neuropathies are characterized by axonal degeneration, usually of the dying-back type.

PERIPHERAL NEUROPATHIES
Paraneoplastic Neuropathy
Paraneoplastic neuropathy is a disease of peripheral nerves that occurs as a remote effect of cancer. Other paraneoplastic diseases of the nervous system include chronic encephalomyelitis, necrotizing myelopathy, cerebellar degeneration, and the Eaton-Lambert syndrome.

PERIPHERAL NEUROPATHIES
Paraneoplastic Neuropathy
Several clinicopathological types : * Chronic axonal polyneuropathy * Dorsal root ganglionitis (subacute sensory polyneuropathy, sensory ganglionitis) * Subacute motor polyneuropathy * Inflammatory demyelinating neuropathy

PERIPHERAL NEUROPATHIES
Hereditary Neuropathy
Hereditary neuropathy is the most common form of chronic neuropathy in children and an often unrecognized cause in adults. CHARCOT-MARIE-TOOTH DISEASE: CMT is a slowly progressive form of hereditary motor and sensory neuropathy (HMSN), which is seen in late childhood or adolescence as a distal sensorimotor polyneuropathy.

PERIPHERAL NEUROPATHIES
Cryptogenic Neuropathy
In at least 10% of patients who have peripheral neuropathy, no etiology is apparent, despite careful and extensive investigations. These cryptogenic neuropathies are usually axonal and are seen as a chronic, distal, sensorimotor polyneuropathy.

PERIPHERAL NEUROPATHIES
NERVE TRAUMA Traumatic Neuroma
Traumatic neuroma is a mass of regenerating axons and scar tissue that forms at the end of the proximal stump of a nerve that has been disrupted physically. After the transection of a peripheral nerve, regenerating axonal sprouts arise within 1 week from the distal ends of the intact axons in the proximal nerve stump.