CHAPTER 53

Peripheral Neuropathy

Henry Cohen, MS, PharmD, FCCM, BCPP, CGP • Benjamin C. Wee, PharmD, BS

Peripheral neuropathy (PN) is a serious complication that occurs in a myriad of clinical conditions treated by the primary care provider. PN is defined as deranged function and structure of peripheral motor, sensory, and autonomic neurons, involving either the entire neuron or selected levels. The disorders of the peripheral nervous system are clinically diverse and depend on the severity of the pathological process, the rate of progression, the population of neurons or Schwann cells affecting the level within the neurons affected, and the subcellular pathological events involved (Albright, Soldan, & González-Scarano, 2003; Boulton, 2005).

PN may manifest a wide variety of signs and symptoms, including burning sensations, paresthesias, and dysesthesias and a “pins and needles” sensation. Underlying disease states that may cause PN include diabetes mellitus (DM; Boulton, 2005; Lindsay, Rodgers, Savath, & Hettinger, 2010), HIV infection, uremia, neoplasms, and chronic alcohol abuse. Nutritional deficits in thiamine, pyridoxine, or cyanocobalamin may cause PN (Chaudhry, 2008). Drugs have also been implicated in causing PN and are listed in Table 53.1. Environmental toxins, including heavy metals such as lead and mercury, have also been implicated.

ANATOMY, PHYSIOLOGY, AND PATHOLOGY

Each peripheral nerve has a well-defined anatomic course, supplies a dermatome (although there is some overlap), and innervates specific muscles. The proximity of some nerves to bony structures makes them particularly vulnerable to compression or entrapment injury. Although there are several etiologies for PN, the pathologic processes can generally be divided into four categories: Wallerian degeneration, axonal degeneration, neuropathy, and segmental demyelination (Jacewicz & Timmons, 2011).

An injury that causes interruption of the axon and myelin, as in a transection of a nerve, results in Wallerian degeneration distal to the injury site. In this distal segment, the myelin and axon degenerate, resulting in a loss of electrical conduction. Proximal to the transection, regrowth may occur, but it is slow and often incomplete, and the recovery of the nerve is limited. Axonal degeneration refers to distal axonal breakdown resembling Wallerian degeneration, but it is the result of metabolic derangement within neurons (e.g., DM, toxins). This results in denervation of the muscle and muscle atrophy.

Neuropathy refers to primary loss or destruction of nerve cell bodies, along with degeneration of their entire peripheral and central processes. Inherited conditions such as spinal muscular atrophies (lower motor neurons) and hereditary sensory neuropathies (primary sensory neurons) may be affected. Toxins and organic compounds such as mercury and pyridoxine overdose can result in primary neuronal degeneration (Jacewicz & Timmons, 2011). Segmental demyelination (e.g., Guillain–Barré syndrome [GBS]) is an injury of the myelin sheath or the myelin-producing Schwann cells, resulting in breakdown of myelin with relative sparing of axons so that no atrophy occurs unless nerve fibers are affected, as can occur in severe cases.

There are two broad classes of peripheral nerve injury. Mononeuropathies are focal lesions of peripheral nerves (e.g., traumatic or ischemic). Polyneuropathies are bilateral symmetric disturbances of function (e.g., toxic, hereditary, inflammatory, or metabolic). Multifocal isolated lesions are termed “mononeuropathy multiplex” and most commonly affect peroneal median, and ulnar nerves.

Most PNs are associated with a loss of function, either sensory, motor, or both, and are typically not painful. Pain is characteristic of diabetic, alcoholic, and nutritional deficiency neuropathies.

Diabetic PN

The exact etiology and pathogenesis of diabetic PN has not been well elucidated and may be multifactorial. Chronic hyperglycemia has been associated with diminished nerve-conduction velocity and the clinical presentation of PN. Glucose is usually metabolized by hexokinase to glucose-6-phosphate. In the presence of constant hyperglycemia, saturation of the hexokinase enzymatic pathway occurs, and excess glucose is converted to sorbitol by the polyol pathway.

A likely mechanism for the pathogenesis of human diabetic neuropathy is increased polyol pathway activity secondary to diabetic hyperglycemia. During hyperglycemia, however, the cellular level of glucose increases in tissues such as the peripheral nerve, where glucose entry is independent of insulin.

TABLE 53.1

Categories and Etiologies of Peripheral Neuropathies

Metabolic/nutritional	DM, hypothyroidism, acromegaly, uremia, liver disease, and vitamin B₁₂ deficiency
Drug induced	Antineoplastics: Cisplatin, oxaliplatin, thalidomide, vincristine Antimicrobials: Chloramphenicol, chloroquine, dapsone, ethambutol, isoniazid, metronidazole, nitrofurantoin Cardiovascular: Amiodarone, hydralazine Central nervous system: Alcohol, lithium, phenytoin Other: Cimetidine, colchicine, disulfiram, gold, pyridoxine
Industrial/environmental toxins	Organic and industrial compounds: Acrylamide, carbon disulfide, dimethylamino-propionitrile, ethylene oxide, hexacarbons, organophosphates, thallium, trichlorethylene, vacor Heavy metals: Arsenic, lead, mercury, gold, platinum
Connective tissue processes/vasculitis	Polyarteritis nodosa, RA, systemic lupus erythematosus, scleroderma, ischemic neuropathies, systemic necrotizing vasculitis, giant cell arteritis, Wegener’s granulomatosis
Infections/infectious processes	Leprosy, HIV; diphtheria, Epstein—Barr virus, rabies, sarcoidosis, cytomegalovirus
Inflammatory processes	Acute idiopathic polyneuropathy (Guillain—Barré syndrome), chronic inflammatory demyelinating polyneuropathy
Neoplasms	Compression and infiltration by tumor, multiple myeloma, nonhereditary amyloidosis
Trauma/compression	Severance contusion, stretching, compression, crushing, ischemia, electrical, thermal, and radiation injuries and drug injection, stretch injuries from orthopedic traction, compression from prolonged pressure, herniated discs, osteophytes, or fractures
Entrapment syndromes	Lower extremities: Sciatic and peroneal entrapment syndromes Upper extremities: Carpal tunnel syndrome, ulnar entrapment syndrome, radial nerve entrapment, thoracic outlet syndrome
Hereditary	Hereditary motor and sensory neuropathies, hereditary sensory and autonomic neuropathies Types I–IV, Friedreich’s ataxia, porphyria, hereditary amyloidosis

DM, diabetes mellitus; RA, rheumatoid arthritis.

In peripheral nerve tissues, the excess glucose is metabolized predominantly by aldose reductase. Increased flux of glucose through the polyol pathway may be associated with myo-inositol depletion, decreased sodium–potassium ATPase activity, decreased nitric oxide synthase, tissue hypoxia, and subsequent structural lesions.

Aldose reductase inhibitors block the flux of glucose through the pathway and prevent these abnormalities. Aldose reductase inhibitors are under clinical investigation for the treatment and prophylaxis of diabetic PN.

HIV Peripheral Neuropathy

PNs are a common complication of HIV disease, occurring at all stages of infection. Acute PN in HIV disease may be an early feature of the infection, especially around the time of seroconversion (Albright et al., 2003). HIV-related PN may manifest in a variety of forms: a predominantly sensory neuropathy, an autonomic neuropathy, a mononeuritis multiplex, or an inflammatory demyelinating polyneuropathy. One of the distinguishing features of the neuropathies that occur in HIV patients is the relative specificity of the individual neuropathic syndromes with the stages of infection.

Neuropathies may be the result of immunopathogenic events, such as the inflammatory demyelinating polyneuropathies. During the early stages of infection, the immune system is relatively competent but is stimulated and has altered responsiveness. A vasculitic syndrome occurs mainly during the early symptomatic phase of infection and has been postulated to be the result of circulating immune complexes of HIV-1 antibody and antigen that are deposited in vessel walls.

Distal symmetric polyneuropathy occurs mainly in the late phase of HIV infection (AIDS), when there is severe immunosuppression. At this stage, the mechanisms that have been proposed include productive infection of neural tissue with HIV-1 or cytomegalovirus or toxic or metabolic abnormalities as a result of advanced systemic disease.

Another possible mechanism for HIV PN is a dysregulation of macrophages within the peripheral nerve, resulting in excessive production of tumor necrosis factor and other interleukins. Additional factors that may damage the peripheral nerves in HIV patients include gp-120 (the coat protein of HIV virus) or a nutritional deficiency (e.g., vitamin B₁₂).

The most common neuropathy is a predominantly sensory neuropathy presenting distally and symmetrically with little functional weakness. Predominantly sensory neuropathies are a common feature of advanced HIV disease, with an estimated prevalence of 45% in AIDS patients.

Toxin-Induced PN

Exposure to environmental, biological, and experimental toxins, metals, and drugs can produce neurologic manifestations resulting from impaired function of the central and peripheral nervous systems. Metals that are associated with PN include mercury, lithium, gold, and platinum. Sources of human exposure to neurotoxins include occupational exposure, environmental contamination, drug therapy, and food poisoning. Botulinum toxin, a potent neurotoxin, causes paralysis when ingested in contaminated foods.

Neoplasm PN

Neoplasm PN is most common in carcinoma of the lung, but it is also associated with carcinoma of the stomach, colon, rectum, and other organs. It is difficult to ascertain the prevalence of PN in malignancy, because it depends on the pathologic type and site of the tumor, the stage and duration of the illness, the techniques for diagnosis used, and the criteria for diagnosis. Pathogenic mechanisms for neoplasm-associated PN include direct infiltration of roots and nerves by tumor cells, toxic factors released by the tumor, alterations in protein, and fat metabolism as a result of the tumor, nutritional deficiencies, vascular causes, viral infections, and immunologic disturbances.

Alcoholic PN

Despite the observation that chronic excessive alcohol ingestion is associated with peripheral nerve disease, there is still controversy about whether the neuropathy is the result of a direct toxic effect of alcohol, malnutrition, or both. Human studies have not been able to differentiate a direct toxic action of alcohol on the peripheral nervous system from the effects of poor nutrition. The neuropathy observed may be the result of a deficiency in vitamin B₁, niacin, vitamin B₆, vitamin B₁₂, or vitamin E.

Neuropathy Associated With Renal Failure

PN became clearly established as a complication of chronic renal failure in the early 1960s. In progressive chronic renal failure, slowing of nerve conduction tends to occur when creatinine clearance is approximately 10% of normal. Nerve conduction continues to worsen as renal function deteriorates. The diminished nerve conduction occurs proximally and distally to the same degree. Uniform generalized slowing of conduction tends to occur subclinically and does not predict the appearance or clinical signs and symptoms of neuropathy.

The subclinical diminished nerve conduction in chronic renal failure is functional and is not accompanied by evident renal morphologic change; thus, it is readily reversible by restoration of normal renal function. Chronic dialysis may prevent, stabilize, or improve uremic neuropathy, but dialysis has relatively little effect on nerve-conduction velocity. Other observations suggest widespread axonal dysfunction in chronic renal failure (Jacewicz & Timmons, 2011).

EPIDEMIOLOGY

An accurate accounting of the epidemiology of PN is unknown because, in most instances, the neuropathy is part of a clinical presentation or a complication associated with a long-term, chronic condition (e.g., DM, alcoholism, or exposure to toxins). DM is the most common human metabolic disease (5 million cases in the United States), and diabetic neuropathy is the most common complication of DM.

Forty percent of patients with insulin-dependent DM for >20 years and 5% to 10% of patients with noninsulin-dependent DM develop neuropathies. The incidence is declining, perhaps as a result of improved glycemic control (Diabetes Control and Complications Trial [DCCT], 1993).

Neuropathies associated with toxic substances used in industries such as farming or the oil industry are seen in such workers (Table 53.2). The incidence of toxin-related neuropathies is not known, partly because of the long delay (often more than 20 years) between exposure and development of symptoms.

Thirty percent of all cases of PN are attributed to alcoholic neuropathy. A close association between alcoholic neuropathy and nutritional deficiency has also been noted (Jacewicz & Timmons, 2011).

TABLE 53.2

Sensory, Motor, Reflex, or Autonomic/Trophic Disturbances

Sensory: Decreased or loss of light touch and pinprick sensation along the involved dermatome; tingling, numbness, and dyesthesias are common. Loss of appreciating vibration and position are also seen. Pain is a feature of some neuropathies, especially if small fibers within the nerves are affected. Polyneuropathies with pain include those related to diabetes alcoholism, porphyria, RA, and AIDS. Pain is also common with many entrapment syndromes.

Motor: Involvement of the motor fibers of a purely motor nerve or a mixed nerve results in lower motor neuron weakness, paresis, or paralysis of the muscles innervated by the involved peripheral nerve. Atrophy of the specific muscle groups and related deformities may follow. Fasciculations may also be noted.

Reflexes: Deep tendon reflexes of the involved muscle or muscle groups are decreased or absent.

Autonomic/trophic: Skin in the affected area may become dry, thin, scaly, inelastic, and cold and may cease to sweat. The nails may become curved and brittle; nail and hair growth becomes stunted. Orthostatic hypotension is a less common symptom.

RA, rheumatoid arthritis.

Entrapment syndromes are more common in persons who use their hands in repetitive motions, such as musicians, hairdressers, and computer users. The risk of developing carpal tunnel syndrome is more than doubled in persons with DM.

Although a few conditions produce mononeuropathy and mononeuropathy multiplex, there are many etiologies of polyneuropathy. Diagnosis often depends on obtaining a thorough history (e.g., alcohol abuse or occupational exposures and risk factors), identifying systemic conditions associated with neuropathies (e.g., DM, systemic lupus erythematosus), and conducting a careful physical and neurological examination.

DIAGNOSTIC CRITERIA

Disorders of one or more peripheral nerves cause various signs and symptoms that correspond to the anatomic distribution and normal function of the peripheral nerve. Some peripheral nerves are purely motor, some are purely sensory, and others are mixed. Diagnostic accuracy depends on a thorough knowledge of specific sensory dermatomes, muscle innervations, reflexes, and autonomic function related to a particular nerve. The signs and symptoms of a peripheral nerve disorder may include sensory, motor, reflex, or autonomic/trophic disturbances (Table 53.2; Jacewicz & Timmons, 2011).

Classification of Neuropathies

PNs are classified based on the number of peripheral nerves involved and the pattern of involvement (e.g., symptoms may be confined to one side or both). The classification includes the following: Mononeuropathy simplex involves a single peripheral nerve (e.g., the median nerve in carpal tunnel syndrome).

Mononeuropathy multiplex involves several isolated, unilateral nerves, often widely separated in location. Mononeuropathy multiplex is usually the result of disseminated vasculitis, as in DM or polyarteritis.

Polyneuropathy describes impairment of multiple peripheral nerves simultaneously, resulting in a symmetric, bilateral pattern of functional loss, usually distal. Polyneuropathy is seen with many systemic processes. The presentation may be mainly sensory (e.g., amyloidosis, leprosy), mainly motor (Guillaine–Barré, porphyria), or both.

Distribution of Involvement

DISTAL SYMMETRIC POLYNEUROPATHY

A distal distribution of motor and sensory deficit is the most common pattern observed in generalized symmetric polyneuropathies. Distal symmetric polyneuropathy can be mixed (sensory-motor autonomic) or predominantly sensory. With motor involvement, weakness and wasting begin distally in the limbs and spread proximally. The lower limbs are affected before the upper limbs. Distal symmetric polyneuropathy that is predominantly motor is less common than mixed or sensory polyneuropathy. For sensory involvement, the distal distribution produces glove-and-stocking sensory loss in the limbs.

With advanced neuropathy, sensory loss appears in the midline of the anterior abdominal wall and spreads laterally. Later the vertex of the head and central face are affected. In severe sensory neuropathy, there may be virtually universal sensory loss, with the exception of the midline area over the posterior trunk and neck and peripheral aspects of the face.

Sensory polyneuropathies are usually symmetric, involving both sides of the body, and involve distal rather than proximal sensory nerves. Sensory neuropathy may involve large (myelinated) or small (nonmyelinated) fibers, or both. When sensory polyneuropathy involves small fibers, pain and paresthesias in the legs and feet most commonly occur. The pain is described as dull, burning, lancinating, crushing, aching, or cramp-like. Paresthesia is also observed. In addition, temperature and pain perception may be decreased or lost, especially in the legs and feet.

Large-fiber neuropathies produce deficits in proprioception. Abnormalities in gait and Chareot joints occasionally occur with the involvement of proprioceptive fibers. Sensory polyneuropathies are often more intense in the evening. Extremely painful periods are often limited to a few months or years.

Distal polyneuropathy may present with a predominantly autonomic involvement, affecting gastrointestinal motility, bladder and anal sphincter control, sexual function, perspiration, and pupillary accommodation reactions. Cardiovascular autonomic dysfunction can lead to tachycardia at rest, orthostatic hypotension, and painless myocardial infarction.

PROXIMAL SYMMETRIC POLYNEUROPATHY

In symmetric polyneuropathies, a proximal distribution of motor involvement is occasionally observed. This is encountered in GBS and in rare cases of chronic progressive inflammatory demyelinating polyneuropathy. Proximal symmetric motor neuropathy may result in bilateral or unilateral weakness and wasting of pelvifemoral muscles. A proximal distribution of sensory loss is less frequent.

Proximal motor neuropathies may possess asymmetric or symmetric patterns, and are subdivided clinically into acute, subacute, and chronically evolving. Sudden onset of asymmetric weakness of the hip and thigh muscles with or without pain characterizes acute and subacute presentations. The reason for selective proximal involvement is unknown. A possible cause may be that the proximal portions of the limbs are supplied by nerve fibers of larger diameter than those in the more distal regions and the trunk. These fibers may have differing susceptibility to metabolic aberrations or immunologic insult.

CRANIAL MOTOR NEUROPATHY

Focal and multifocal cranial nerve lesions can occur alone or in combination with a generalized polyneuropathy. In progressive polyneuropathies, the cranial nerves tend to be involved late in the evolution of the disease, being preceded by symptoms distally in the legs and arms. Cranial motor neuropathy results from occlusion of the vascular supply. This neuropathy is usually asymmetric and involves mononeuropathy of cranial nerves III (oculomotor), IV (trochlear), and VI (abducens), which are responsible for ocular movement and pupillary accommodation and constriction, resulting in extraocular muscle palsies. Cranial neuropathies involving cranial nerves III and VI are common.

ENTRAPMENT SYNDROMES

Entrapment syndromes occur in the limbs and are mononeuropathies involving the median, ulnar, common peroneal, and femoral nerves. Entrapment syndromes are characterized by sudden wrist or foot drop. The carpal tunnel syndrome (media nerve) is prevalent and commonly affects the hands. Carpal tunnel syndrome characteristically presents with pain and paresthesia that worsens at night. Etiologies include occupational trauma, DM, amyloidosis, rheumatoid arthritis (RA), and hypothyroidism.

DIABETIC PN

The classification of PN in the diabetic patient has been categorized based on the characteristics of the pain. These categories include muscular pain, superficial pain, and deep pain. Muscular pain, described as muscle cramping and spasm, is believed to be caused by damage to the reflex loop or to the motor neurons. Superficial pain is described as burning or allodynia (ordinarily nonpainful stimuli evoke pain) and is believed to be caused by an increased firing of damaged or abnormally excitable nociceptive fibers. Deep pain, described as pins and needles, is believed to be caused by spontaneous activity or increased sensitivity of damaged afferent fibers in the dorsal root ganglion and loss of inhibition of large-myelinated and small-nonmyelinated fibers.

HISTORY AND PHYSICAL EXAMINATION