DEFINITION AND ETIOLOGY

Peripheral neuropathy, in the broadest sense, refers to a range of clinical syndromes affecting a variety of peripheral nerve cells and fibers, including motor, sensory, and autonomic fibers (Box 1). Most peripheral neuropathies affect all fiber types to some extent. However, a single fiber type may be predominantly or exclusively affected in some disorders. For example, in small-fiber neuropathy (SFN) (Table 1), small-caliber, unmyelinated, or only thinly myelinated autonomic fibers and somatic sensory fibers that subserve pain and thermal receptors are predominantly involved.¹ Thus, patients with SFN present primarily with pain and autonomic dysfunction. Peripheral neuropathies are also defined by the pattern of nerve-fiber involvement. For example, some disorders involve single individual peripheral nerves—mononeuropathies—and some involve numerous individual peripheral nerves, the mononeuritis multiplex syndrome. In addition, peripheral nerve disorders can involve the brachial plexus, lumbosacral plexus, or a single root, resulting in signs and symptoms in one limb.

Table 1 Drugs that Can Induce Polyneuropathies

Most generalized disorders conform to a polyneuropathy syndrome, which usually implies both sensory and motor fiber involvement in a relatively symmetrical fashion and typically with a distal-to-proximal gradient of involvement. These disorders are termed generalized sensorimotor polyneuropathies, and they represent the most common form of peripheral neuropathy. This review focuses primarily on this form of peripheral neuropathy.

The peripheral nervous system can be involved in a wide range of medical disorders with various pathophysiologies (see Box 1). It may be affected by numerous toxins, drugs (Table 2), and industrial agents (Table 3) and by a variety of chronic infections, including human immunodeficiency virus (HIV). A number of apparently immune-mediated disorders result in peripheral neuropathies, including Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and multifocal motor neuropathy with conduction block syndrome (MMNCB). A host of hereditary polyneuropathies can cause a wide range of peripheral neuropathy syndromes (Box 2).

Table 2 Environmental and Industrial Toxins That Cause Polyneuropathy

Table 3 Heredofamilial Polyneuropathies

This diverse array of possible etiologies can make the diagnosis of peripheral neuropathies challenging. Nevertheless, the diagnosis can be facilitated with a systematic approach that classifies the peripheral neuropathy on the basis of clinical features, taking into account the type of peripheral nerve fiber that may be involved (i.e., sensory, motor, or autonomic), the distribution or pattern of peripheral nerve fiber involvement (generalized and symmetrical versus asymmetrical and multifocal), and the mode of evolution (acute, subacute, or chronic).

PREVALENCE AND RISK FACTORS

Peripheral nerve disorders are relatively common conditions that affect 2.4% of the population.² However, the prevalence increases to 8.0% with advancing age.

The most common generalized polyneuropathy is diabetic sensorimotor polyneuropathy, which may be present in as many as 66% of type 1 diabetes patients and in nearly 59% of type 2 diabetes patients.³ Even higher prevalence rates have been reported depending on the criteria used to diagnose polyneuropathy. Considering that the prevalence rate of diabetes is approximately 1.3%, this common complication of diabetes could affect nearly 1% of the general population.

The most common genetic sensorimotor polyneuropathy is Charcot-Marie-Tooth disease type 1a, which has a prevalence of approximately 30 per 100,000 population. Carpal tunnel syndrome, caused by chronic entrapment of the median nerve in the carpal tunnel, is the most common mononeuropathy, with a prevalence estimated to be between 3% and 5% of adults.

PATHOPHYSIOLOGY AND NATURAL HISTORY

Despite the diverse array of medical disorders that cause peripheral neuropathies, peripheral nerves exhibit only a few distinct pathologic reactions to an insult or disease: wallerian degeneration, axonal degeneration, and segmental demyelination. The specific mechanisms by which the various disorders affecting peripheral nerves induce these pathologic changes are largely unknown.

In wallerian degeneration, the axon degenerates distal to a focal lesion that interrupts the continuity of the axon. This reaction often occurs in focal mononeuropathies that result from trauma or nerve infarction.

Axonal degeneration, sometimes referred to as the dying-back phenomenon, results in axonal degeneration at the most distal extent of the axon. Axonal degenerative polyneuropathies are usually symmetrical, and as the disorder progresses, the axons typically degenerate in a distal-to-proximal gradient. Axonal degeneration is the most common type of pathologic reaction in generalized polyneuropathies, and it is often attributed to a metabolic cause.

Segmental demyelination refers to focal degeneration of the myelin sheath with sparing of the axon. This reaction can be seen in focal mononeuropathies and in generalized sensorimotor or predominantly motor neuropathies. Acquired segmental demyelinating polyneuropathies are often immune-mediated or inflammatory in origin. However, segmental demyelination can also occur in some hereditary polyneuropathies.

In peripheral nerve disorders that are characterized by either wallerian degeneration or axonal degeneration, prognosis is less favorable because the axon must regenerate and reinnervate muscle, the sensory organ, blood vessels, and other structures before clinical recovery is noted. Recovery may be more rapid with segmental demyelination because remyelination is accomplished more quickly, thereby re-establishing normal conductivity of the axon and return of function.