Peripheral Neuropathy

Mark A. Thomas

Maya Therattil

INCIDENCE, PREVALENCE, DISABILITY, AND COST

The overall incidence, prevalence, disability rates, and cost of peripheral neuropathy in the United States are unknown. There are studies, however, that hint at the scope of the problem. For diabetic peripheral neuropathy alone the estimated prevalence is more than 20 million, with an annual cost of 10.9 billion dollars (1). The annual cost of patient care and disability payments for acute idiopathic demyelinating polyneuropathy (Guillain-Barre syndrome) is approximately $1.7 billion. An estimated 11% of patients have permanent disability (2). Of patients with vasculitic disease, approximately 60% to 70% suffer from peripheral neuropathy, and of these, 65% have mild to moderate disability, 13% moderately severe disability, and 4% severe disability (3).

PERIPHERAL NEUROANATOMY AND NEUROPHYSIOLOGY

The peripheral nerve is vulnerable to a wide variety of insults but has a great capacity for repair and regeneration. The peripheral nerve includes the cell body, axons and dendrites, the cell membrane (neurolemma), the endoneurium, perineurium, mesoneurium, epineurium, and the Schwann cell. The specifics of these structures help understand the classification, pathophysiology, and treatment of peripheral neuropathy.

The cell body of motor nerve fibers is the anterior horn cell. The cell body of sensory nerves is located in the dorsal root ganglion. The autonomic nerve fibers in contrast to the somatic fibers have both preganglionic and postganglionic neurons, with the cell body of the postganglionic neuron lying in the periphery and extending through unmyelinated C fibers.

The axon is contained by the cell membrane, the axolemma. It contains the axoplasm which has tracts for both antegrade and retrograde flow, with the tracts maintained by electrical polarity. Axoplasmic flow occurs at 1 to 3 mm per day and is one rate-limiting aspect of nerve regeneration, although the flow can occur more rapidly in response to injury.

The axolemma of myelinated nerve fibers is enclosed by the Schwann cell, which elaborates the lipoprotein myelin. This is why lipid lowering medications are a risk factor for peripheral neuropathy (4).

The Schwann cell internode space, or node of Ranvier, is the site of membrane depolarization, saltatory conduction, and any axonal branching. In unmyelinated nerve fibers, the relationship of nerve fibers is less complex, and several fibers may be contained in the Schwann cell trough. These fibers propagate signal conduction by continuous depolarization along the axolemma (eddy depolarization).

Axon fascicles divide and fuse with others in the epineurium. Communication between fascicles occurs every 0.5 to 15 mm, more frequently in the proximal peripheral nerve. They branch between 20 and 100 times before reaching the motor endplate.

The mesoneurium supports the capillary network that supplies the nerve fibers. The mesoneurium is easily compromised and this accounts for the peripheral nerve’s susceptibility to ischemia. The endoneurium contains the axon and Schwann cell in a grouped arrangement. These fascicles are in turn contained by the perineurium which maintains a positive intrafascicular pressure. This structure presents a barrier to diffusion, the blood-nerve barrier. When the perineurium is compromised, diffusion produces axonal swelling which impairs signal conduction (Table 29-1). The epineurium is a loose collection of collagen and elastin fibers that support the fascicles of a peripheral nerve. This arrangement is elaborate in the proximal nerve and becomes progressively less complicated in more distal nerve segments. The external epineurium surrounds the peripheral nerve and is largely responsible for its resistance to mechanical disruption. Its elastic properties allow a degree of deformation beyond which rupture occurs. This is why a stretched nerve is more readily injured than when at its resting length.

A number of age-related physiologic changes occur in the peripheral nervous system (5). There is a decrease in the number of anterior horn cells, a decreased capacity for neuronal sprouting, biosynthesis, transport and proliferation, and decreased Schwann cell synthesis of trophic factors. This results in slowed protective reflexes and decreased proprioception, vibratory sense, and stretch reflexes. The pain and temperature recognition thresholds increase.

CLASSIFICATION OF PERIPHERAL NEUROPATHY

Peripheral neuropathy can be classified by etiology, pathology (including genetic error), location of the lesion, time since insult,
or clinical presentation. It may be generalized, proximal, or distal in location. Possible etiologies include trauma, metabolic disease, malnutrition, response to infection, other autoimmune disease, collagen-vascular disease, genetic error, toxin (including medication) exposure, thermal injury, or ischemia (Table 29-2).

TABLE 29.1 Correlation of Peripheral Nerve Anatomy and Pathology

Structure	Function	Pathologic Consequence of Impaired Function
Axon	1-3 mm axonal flow	Rate limit to healing
Schwann cell	Myelin synthesis	Susceptibility to lipid lowering medication
Mesoneurium	Capillary support	Ischemia
Perineurium	Blood-nerve barrier	Axonal swelling
Epineurium	Resistance to stretch	Vulnerability to compression injury

The neuropathy can affect the axon and/or the myelin sheath. The neuropathy can result in neurapraxia, axonotmesis, or neurotmesis. The disease may be confined to a single nerve (mononeuropathy), involve multiple nerves (polyneuropathy), and be symmetric or asymmetric. The neuropathy can be acute or chronic although this may be unclear when there is an insidious onset and delayed diagnosis. Depending upon the nerve involved, the clinical presentation includes weakness, paresthesia, hypesthesia, anesthesia, or changes in autonomic function such as changes in circulation or hidrosis.

The Seddon classification of peripheral nerve pathology is clinically relevant. It can be used to predict functional outcome and suggest appropriate care (Table 29-3). There are three degrees of nerve pathology: neurapraxia, axonotmesis, and neurotmesis.

Neurapraxia is a local conduction block due to transient demyelination and rarely affects sensory or autonomic fibers. Thick myelinated nerves are most affected. Neurapraxia commonly results from compression of the peripheral nerve. These lesions heal by Schwann cell repair, and normal conduction is generally resumed in 1 to 2 months (6, 7).

Axonotmesis is a more significant injury and results in Wallerian degeneration. With an axonotmetic lesion, the endoneurial tube remains intact. This lesion follows a traction injury or a severe nerve compression. The prognosis for regeneration is good, particularly for shorter injured or distal nerve segments. The distance of regeneration is the primary limiting factor, so recovery is less certain with proximal injury.

TABLE 29.3 Correlations of the Seddon Classification of Peripheral Nerve Pathology

Class	Cause	Consequence	Usual Site Affected	Prognosis
Neurapraxia	Compression	Conduction block	Thick myelinated motor nerves	Healing in 1-2 months
Axonotmesis	Traction Severe compression	Wallerian degeneration	Myelinated motor and sensory nerves	Good for healing if short or distal motor or sensory segments are affected
Neurotmesis	Trauma Transection	Complete disruption of nerve continuity	Any	Poor, even with surgery

TABLE 29.2 Classification of Peripheral Neuropathy Related to Site of Pathology

Classification		Structure Most Commonly Affected
Distribution	Proximal	One nerve
	Distal	Multiple nerves
	Generalized
Pathology	Neurapraxia	Myelin
	Axonotmesis	Axon
	Neurotmesis	Axon, myelin
Etiology	Traumatic	Myelin or axon, myelin
	Hereditary/genetic	Axon, myelin
	Toxic/metabolic	Axon, possibly myelin
	Endocrine	Axon
	Nutritional	Myelin
	Postinfectious/autoimmune disease	Myelin
	Vasculitic	Axon
	Thermal	Axon, myelin
	Ischemic	Axon

Neurotmesis is complete severance of the peripheral nerve trunk and is the most severe lesion. Recovery is unlikely unless neurorrhaphy is performed (6). Healing of a neurotmetic lesion often results in the misconnection of nerve fibers and incomplete reinnervation.

TRAUMATIC PERIPHERAL NERVE INJURY AND SUBSEQUENT DEGENERATION AND REGENERATION

Traumatic peripheral nerve injury can result from compression, crush injury, laceration, stretch/traction, ischemia, thermal injury, or high-velocity trauma (Table 29-4). Further injury of the peripheral nerve may result from associated infection, scar tissue formation, fracture callus, or vasculopathy.

TABLE 29.4 Traumatic Causes of Peripheral Neuropathy

Compression

Crush injury

Laceration

Stretch/traction

Thermal injury

High-velocity trauma

The most common mechanism of traumatic nerve injury is transection due to blunt or penetrating trauma. In such instances, there may be a delay in diagnosis due to adjacent tissue injury.

Fracture and fracture/dislocation carry a high risk of associated nerve damage. Nerve injury after shoulder dislocation occurs in 48% of cases. The incidence of radial nerve damage following humeral fracture is 11% (8). Ulnar neurapraxia is the most commonly identified nerve lesion associated with fracture dislocation at the elbow. Dislocation of the hip is associated with a nerve injury rate of 3% and the rate associated with knee dislocation is 18% (8).

Iatrogenic injury can also occur. Plating of forearm fractures results in a reported nerve injury in 1% to 10% of cases. Damage has also been reported during elbow and shoulder arthroscopy (9, 10).

Compression injury of a peripheral nerve generally results in focal demyelination. This causes a conduction block. Recovery depends upon remyelination. With all peripheral nerve lesions that leave the axon intact, there is axonal transport of tumor necrosis factor alpha (TNF α) to the lesion and a concomitant reorganization of peripheral nerve TNF receptors (11).

A crush injury provokes segmental demyelination but the Schwann cell tube is commonly preserved and recovery can occur. A laceration injury due to blunt or penetrating trauma produces a well-localized lesion, usually millimeters in size. A stretch of the peripheral nerve beyond 10% to 20% of its resting length increases the risk of axonotmesis (9). This is the common mechanism of injury during joint dislocations. Stretch alone may provoke a mild conduction block which recovers in hours. A more severe stretch will interrupt axons and connective tissue, cause hemorrhage and might require surgical repair.

Cold injury can cause necrosis of all tissues. Large myelinated fibers are most susceptible to cold injury. Damage to the blood-nerve barrier results in endoneurial edema and increased intraneurial pressure, with a resulting focal conduction block. If the pathology is progressive, axonal transport ceases and the axon degenerates within a few days.

Peripheral nerves vary in their vulnerability to compressive, thermal, or traumatic injury. Fiber-type composition, size of the nerve, number of nerve fascicles, amount of soft-tissue protective cushioning, course of the nerve (on bone, through fascia or muscle), and tethering all affect the nerves’ ability to sustain and spontaneously recover from injury. For example, the peroneal division of the sciatic nerve is tethered at the fibular neck and at the sciatic notch and is more vulnerable than the tibial division, which is tethered at the sciatic notch alone. Scar formation, heterotopic ossification, and fracture callus can tether the peripheral nerve.

Degeneration

Primary, or retrograde, degeneration is a consequence of trauma and is less common than secondary (Wallerian) degeneration. The degenerative process proceeds from the site of injury to the next proximal node of Ranvier (6).

Secondary or Wallerian degeneration is antegrade, progressing distally from the point of injury (7). Wallerian degeneration begins on the second or third day after injury, with retraction of myelin. Nerve fragmentation on day 2 to 3 precedes neurofibrillar degeneration. The nerve body swells. Neuron edema continues for 10 to 20 days. These changes are more pronounced and longer lasting with proximal nerve lesions. The Schwann cells at the site of injury activate and, by the end of the first week after injury, participate in the removal of myelin debris.

Regeneration

Axonal regeneration and remyelination progress in a sequence that follows degeneration of the injured nerve segment beginning with the activation of Schwann cells in the empty endoneurial tube. Axonal sprouts appear and progress down the endoneurial tube. These regenerating axons are guided along the perineurium by neutropins. They are directed toward the largest surviving distal fascicles (9).

The peripheral nerve can form a neuroma during the repair process. This may be a nerve stump neuroma (neuroma in continuity) which is usually located lateral to the nerve trunk. It forms as axonal/fascicular continuity is reestablished. A laterally located neuroma indicates partial neurotmesis with preserved ability to conduct signals. When the neuroma is imbedded in scar tissue, the prognosis for recovery is worse. A fusiform-shaped neuroma is likely to be in continuity, while a bulbous or dumbbell-shaped neuroma is indicative of widespread neurotmesis. This should be treated by excision and neurorrhaphy. (Surgery following trauma is discussed in the treatment section of this chapter.) Similarly, if more than 50% of the nerve trunk is involved, function will be impaired and the neuroma should be resected (6).

Initially, unmyelinated axonal sprouts unite with the distal peripheral nerve remnant, then remyelination begins. Both sheath and axon increase in diameter. If the gap in continuity is greater than 2 mm, reconnection is much less likely. In such instances, the immature neurite (sprout) dies back or forms a neuroma.

Later, a shrinking area of sensory loss with an enlarging area of partial sensation occurs as anastomotic branches with other nerves form (12). Involvement of autonomic fibers causes anhidrosis and impaired pilomotor and vasomotor activity.
If the skin wrinkles on immersion in water, or if sweating is present, the peripheral nerve damage is incomplete.

As recovery progresses, there is a return of pain and temperature sensation, a return of sudomotor function, and later a return of light touch, vibratory sensation, and stereognosis. Perhaps the best predictor of outcome is two-point discrimination which positively correlates with a return of function (6).

A nerve percussion sign is indicative of demyelination/remyelination. When the nerve percussion sign progresses from a proximal location in the nerve to more distal segments, healing is taking place by regenerating sprouts and incomplete myelination (13).

NONTRAUMATIC PERIPHERAL NEUROPATHIES

The peripheral nerve axon is particularly vulnerable to toxic, metabolic, endocrine, and genetic insults. The myelin sheath is most commonly affected by autoimmune, nutritional, or genetic disorders and toxic or metabolic disease. In the United States, diabetes and alcohol abuse are the most frequent agents of peripheral nerve injury. Fifteen to twenty percent of nontraumatic peripheral nerve injuries are idiopathic (14).

Injury results in an increase in the neuropeptides galanin and pituitary adenylate cyclase-activating peptide with a net neurite outgrowth that can result in excessive branching during repair (15).

HEREDITARY PERIPHERAL NEUROPATHIES

The hereditary peripheral neuropathies include the hereditary sensory motor neuropathies (HSMNs) types I and II (Charcot-Marie-Tooth [CMT] disease), type III (Dejerine-Sottas disease), type IV (Refsum’s disease), and HSMN types V-VII (Table 29-5). Other inherited peripheral neuropathies include Friedreich’s ataxia, pressure-sensitive hereditary neuropathy, and various diseases that include altered structure or function of the peripheral nerve such as acute intermittent porphyria, Roussy-Levy syndrome, Riley-Day syndrome, Fabry disease, and Pelizaeus-Merzbacher disease. These neuropathies demonstrate segmental demyelination and remyelination of the peripheral nerve, resulting in a slowing of signal conduction (16). Large myelinated motor fibers are the most severely affected (17). The distribution of weakness and atrophy includes the peroneal and distal leg muscles, and the peak strength loss is between 60% and 80% (18). Sensory loss and areflexia are notable. Atrophy and weakness in the upper extremities are less prominent.

TABLE 29.5 Hereditary Sensory Motor Neuropathies

Type	Name
I	Charcot-Marie-Tooth (CMT) disease
II	CMT
III	Dejerine-Sottas disease
IV	Refsum’s disease
V	With spastic paraplegia
VI	With optic atrophy
VII
Other inherited diseases associated with peripheral neuropathy	Friedreich’s ataxia, pressure-sensitive hereditary neuropathy, porphyria, Roussy-Levy syndrome, Riley-Day syndrome, Fabry disease, Pelizaeus-Merzbacher disease

Inheritance of a HSMN is usually autosomal dominant with variable penetration. Autosomal recessive and X-linked diseases occur less frequently and generally have a poorer prognosis.

The mutations in HSMN affect the genes that encode myelin proteins. Several abnormalities have been identified. These include duplication of chromosome 17p11.2, resulting in abnormalities of peripheral myelin protein 22 (19, 20). The mutation produces abnormal endoplasmic proteins that lead to Schwann cell apoptosis (21). The specifics of myelin gene mutation determine disease severity. Deletion of myelin protein zero results in the most severe disease. Deletion of the 17p11.2 chromosome results in a hereditary neuropathy with susceptibility to pressure palsies. Point mutation of the PO gene and defects of the connexin 32 gene (which encodes a gap junction protein) occur in X-linked forms of HSMN (22). In 30% of CMT type II disease, there is a defect in mitofusin 2 genes with a decoupling of mitochondria in the axon, leading to decreased oxidative phosphorylation (23).

CMT type I can also be defined by the genetic error. Type Ia CMT disease results from a defect in chromosome 17. In type Ib CMT disease, the defect is located in chromosome 1.

The prevalence of the most common neuropathy, HMSN type I and II CMT disease, ranges from 1 per 50,000 to 1 per 250,000 (24, 25, 26, 27). The clinical manifestations are variable. The slowly progressive weakness is symmetric and more pronounced in distal musculature. In type I disease, the myelin is affected and onset is within the first decade of life. In type II disease, the axon is most affected and onset is usually within the second decade. For both type I and type II, the onset is often insidious and the patient asymptomatic until much later. The distribution of sensory deficit parallels that of the motor deficit. Loss of balance and tripping due to foot drop are often noted, as are deformities such as equinovarus, calcaneovalgus, and pes cavus. Pain is uncommon.

CMT type II inheritance is more heterogeneous than in type I, with wider phenotypic variation. The resulting disability ranges from very mild to severe. Type II disease is characterized by less hypertrophic change in myelin and more neuronal or axonal involvement than is seen in CMT type I (19, 20, 28, 29, 30, 31).

HSMN type III, Dejerine-Sottas disease, is another inherited hypertrophic peripheral neuropathy with prominent demyelination and remyelination. Neurapraxia is typical of this disease (29). Patients present with delay in motor
development, difficulty running and jumping, and weakness affecting the arms as well as legs.

Refsum’s disease (HSMN type IV) is characterized by altered mitochondria within the Schwann cell, and a similar abnormality is likely in other HSMN types (24). HSMN type V is associated with prominent spinocerebellar degeneration, type VI with optic atrophy, and type VII occurs with retinitis pigmentosa.

In the HSMNs, ambulation is frequently impaired and falls are common. Rehabilitation interventions focus on maintaining a safe and effective gait. Bracing, particularly ankle-foot orthoses (AFOs), usually provide adequate support. If contractures require surgical release, postoperative bracing or splinting is essential. Attention to footwear is important, particularly as equinus/cavus deformities typically occur. A comfortable, protective shoe with adequate depth and reinforced medial counter helps avoid pain, skin breakdown, and progressive deformity. Exercise is most effective for strengthening the proximal muscles of the lower extremities (32).

IMMUNE-MEDIATED PERIPHERAL NEUROPATHIES

In the peripheral nerve, immune-mediated demyelinating protein attacks myelin and produces vasculitis and ischemia (33). The inflammatory mechanism is both cellular and humeral (34). TNF α modulates the immune response, particularly in T-cell-mediated tissue injury.

The acute demyelination characteristic of AIDP results from postinfection antibodies that recognize glycolipids and gangliosides GM1, GD12, and GD16. Lymphocytic infiltration of the spinal roots and peripheral nerves aids macrophages in myelin stripping.

Acute inflammatory demyelinating polyneuropathy (AIDP, Guillain-Barre syndrome) is most typically a postinfection demyelination of the peripheral nerve with both perineurial and axonal damage. There is a breakdown of the blood-nerve barrier and segmental, macrophage-mediated damage to the myelin sheath. Inflammation and demyelination result in varying degrees of axonal degeneration, and neurapraxia is prominent.

Sixty-seven percent of patients with AIDP have a history of preceding viral infection, immunization, surgery, or a disease affecting the immune system. AIDP presents with acute onset of weakness, hypotonia, and areflexia (35). The weakness is progressive and involves the extremities. Bulbar and facial muscles can be affected. Autonomic dysfunction and sensory symptoms are usually mild (34). Respiratory failure occurs in up to 30% of cases within 1 to 2 weeks after disease onset (36). Recovery generally takes 3 to 18 months. Residual weakness is common and usually mild.

The Miller Fisher syndrome is a relatively benign variant, occurring in about 5% of AIDP cases. It is characterized by ophthalmoplegia, areflexia, and ataxia (34). Antibodies to GQ1b are common.

Acute motor axonal neuropathy (AMAN) is an axonal variant that follows C. jejuni infection. Wallerian degeneration occurs. The clinical presentation is similar to that of AIDP but myelin is not affected. The antibody mediators include GM1, GD1a, and GD16 (34).

Acute motor sensory axonal neuropathy (AMSAN) is another clinical syndrome characterized by axonopathy. There is also a sensory variant of AIDP and, most rare, an acute pandysautonomia.

The medical management of AIDP includes the administration of high-dose immunoglobulins, plasmapheresis, or plasma exchange (37, 38, 39). Treatment reduces the duration of paralysis and intubation, particularly in the most severe cases (39). Cerebrospinal fluid filtration of antibody complexes can be useful. Corticosteroid therapy has no proven efficacy.

The rehabilitation management of AIDP focuses on the prevention of contractures, skin breakdown, pneumonia, and depression. During the acute phase, communication devices, a trapeze, pressure relief bed surfaces, and bed rails are helpful. Because AIDP presents with evolving weakness, strengthening, bracing, adaptive equipment, and vocational retraining are not appropriate until the clinical findings have stabilized. Retraining for activities of daily living (ADLs), wheelchair and ambulation training, and bracing may be necessary if there is significant residual impairment and disability.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a T-cell-mediated autoimmune peripheral neuropathy. It involves motor and sensory fibers. Disability results from weakness of both proximal and distal muscles (40). Cramps and fasciculations are common in the upper extremities (41).

The differential diagnosis of CIDP includes HSMN and amyotrophic lateral sclerosis. Histologic changes characteristic of CIDP include mononuclear cell infiltrates, prominent endoneurial edema, and wide interfascicle variability. CIDP can be associated with malignancy, particularly melanoma, due to shared immunoreactivity with common surface antigens present in both the myelin and the tumor (42).

The medical management of CIDP includes high-dose intravenous immunoglobulins, immunosuppressive drugs, or immune adsorption (43). Treatment with steroids is probably not effective (44). There is evidence that CIDP responds well to stem cell therapy (45).

Other immune neuropathies include multifocal acquired demyelinating sensory and motor neuropathy (Lewis Sumner syndrome, MADSAM), distal acquired demyelinating symmetric neuropathy, and multifocal motor neuropathy (Table 29-6) (46, 47, 48). Other forms of the disease are the subacute inflammatory demyelinating polyneuropathy (SIDP) and monoclonal gammopathy of undetermined significance (MGUS) (49, 50).

Critical illness polyneuropathy (CIP) can present as failure to wean from mechanical ventilation (50, 51). In septic multisystem organ failure, the systemic inflammatory response syndrome or high fever leads to a polyneuropathy of mixed or
motor nerves (50

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