The peripheral nervous system can be involved in a wide range of medical disorders with various pathophysiologies (Table 1).¹ It may be affected by numerous toxins, both drugs (Table 2) and industrial agents (Table 3), and by a variety of chronic infections, including human immunodeficiency virus (HIV). Furthermore, 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).² Finally, a host of hereditary polyneuropathies may cause a wide range of peripheral neuropathy syndromes (Table 4).

This diverse array of possible etiologies can make the diagnosis of peripheral neuropathies quite challenging. Nevertheless, 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 ( ie, sensory, motor, or autonomic), the distribution or pattern of peripheral nerve-fiber involvement (ie, generalized and symmetric versus asymmetric and multifocal), and lastly, the mode of evolution (ie, acute, subacute, or chronic).

DEFINITION

Peripheral neuropathy, in the broadest sense, refers to a scope of clinical syndromes (Table 1) affecting a variety of peripheral nerve cells and fibers, including motor, sensory, and autonomic fibers. 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 5), small-caliber, unmyelinated, or only thinly myelinated autonomic fibers and somatic sensory fibers that subserve pain and thermal receptors are predominantly involved.³ 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 individual, single peripheral nerves, ie, mononeuropathies, or numerous individual peripheral nerves, the so-called mononeuritis multiplex syndrome. In addition, peripheral nerve disorders may involve the brachial plexus, lumbosacral plexus, or a single root, resulting in signs and symptoms in one limb.

Most generalized disorders conform to a polyneuropathy syndrome, which usually implies both sensory- and motor-fiber involvement in a relatively symmetric 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 will focus primarily on this form of peripheral neuropathy.

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 nerve 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 symmetric, 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" etiology.

Segmental demyelination refers to focal degeneration of the myelin sheath with sparing of the axon. This reaction can be seen in focal mononeuropathies but also 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 those peripheral nerve disorders that are characterized by either wallerian degeneration or axonal degeneration, prognosis is less favorable due to the fact that 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, in turn reestablishing normal conductivity of the axon and return of function.

A host of symptoms and signs that reflect sensory, motor, and autonomic nerve fiber dysfunction are typical of peripheral neuropathies, and some combinations of symptoms and signs may be recognized as specific syndromes of peripheral nerve disease. Sensory symptoms include sensory loss, often described by patients as a sense of numbness or a "Novocain-like" feeling. In most generalized polyneuropathies, these symptoms begin in the most distal extent of the longest sensory fibers, ie, those that subserve sensation in the toes and feet. The pathologic changes in most of these polyneuropathies are those of a distal-to-proximal axonal degeneration, which have been referred to as distal axonopathies or dying-back neuropathies. Similar symptoms may be seen in hereditary or acquired demyelinating polyneuropathies. Typically, all sensory modalities are affected to some extent, including light touch, pain, thermal sensation, vibratory sense, and joint position sense. As the disease progresses, sensory loss ascends the lower extremities, typically in a symmetric fashion. When the sensory loss is at or above the level of the knee, the axons supplying the distal fingertips begin to be involved, and the length-dependent process then begins in the upper extremities. In addition to sensory loss, patients frequently complain of paresthesias and dysesthesias, often characterized by a sense of numbness, tingling, prickling, and pins-and-needles sensations. They may also complain of intense bandlike sensations and feelings of pressure.

The sensory examination will often disclose a distal-to-proximal loss of the various sensory modalities. In certain polyneuropathies, pain predominates in the clinical picture, and the sensory examination tends to disclose deficits predominantly of pain and thermal sensation, conforming to a SFN. On occasion, when significant proprioceptive deafferentation occurs, patients are found to have altered joint position sense that may manifest as an ataxia or tremor of the affected limbs and an imbalance of gait and station.

Pain is a serious symptom for many patients. It may be described as a dull aching sensation, an intense burning sensation or, occasionally, as intermittent lancinating pulses of pain. On occasion, patients notice that their skin is hypersensitive to tactile stimulation such as from the touch of bed sheets or clothing, or standing on their feet. Some patients note an exaggerated painful sensation resulting from any stimulus to the affected area, a form of pain termed allodynia.

Impairment of motor function typically produces weakness in a distal-to-proximal gradient consistent with a length-dependent axonal degeneration. As with sensory loss, weakness begins in the toes, and as the polyneuropathy progresses, ascends up the distal lower extremities to the level of the knees, at which time motor involvement in the hands may be observed. Similar patterns of weakness may be seen in demyelinating polyneuropathies. However, in the acquired segmental demyelinating polyneuropathies such as CIDP and related disorders, proximal muscle weakness resulting from root involvement may be observed outside the proximal-to-distal gradient of the dying-back mechanism. This pattern of involvement is termed a polyradiculoneuropathy. Axonal degenerative polyneuropathies tend to produce weakness along with muscle atrophy, but atrophy is much less conspicuous in segmental demyelinating polyneuropathies because in these disorders the axon remains in continuity with the muscle, preventing denervation atrophy. The most common symptom in polyneuropathy is weakness in dorsiflexion of the feet at the ankles. This may result in a partial or complete foot drop that typically causes the feet to slap while walking and predisposes the patient to stumble and fall when the toes catch on an uneven surface. Tendon reflexes are usually depressed or absent in a distal-to-proximal pattern of involvement, with the lower extremities affected more than the upper extremities. An exception to this is in SFN, in which the large-caliber sensory afferent fibers from muscle spindles are relatively preserved and the tendon reflexes may thus remain intact.

In some polyneuropathies, typically in SFN, autonomic fibers are also affected. In these disorders, a variety of autonomic symptoms may be present, although certainly the most dramatic and incapacitating is orthostatic hypotension, which causes postural light-headedness and/or syncope. However, orthostatic hypotension typically occurs only with advanced autonomic involvement. Earlier in the course of autonomic neuropathy, patients may notice reduced or absent sweating, ie, anhidrosis, often in a distal-to-proximal gradient. Some patients complain of excessive sweating confined to the head and neck region. This is most often secondary to anhidrosis in the limbs and thorax, and reflects compensatory hyperhidrosis in the restricted areas that maintain normal sweating. Other autonomic symptoms include dryness of the eyes and mouth and gastrointestinal dysmotility, often manifested by alternating constipation and diarrhea or by early satiety from gastroparesis. In addition, patients may have urinary bladder dysfunction caused by an atonic bladder, which results in overflow incontinence. In men, erectile dysfunction may represent a very early autonomic symptom, reflecting parasympathetic autonomic nervous system involvement.

Various limb deformities and trophic changes may be observed in chronic polyneuropathies. Pes cavus, characterized by high arches and hammer toes and the clawfoot deformity, are typical foot deformities in hereditary polyneuropathies with childhood onset. These deformities are due to progressive weakness and atrophy of intrinsic foot muscles. A similar clawlike deformity may be observed in the hand. Autonomic involvement of a limb may at times cause the affected area to appear warm, red, and swollen, and at other times, pale and cold, owing to abnormal regulation of small vessels due to autonomic denervation. In addition, various trophic changes may occur including a tight, shiny skin. In patients who have had severe sensory loss in the limbs, the affected areas may be subject to incidental traumas, including burns, pressure sores, and other injuries that are not perceived by the patient. In these patients, repeated injuries and traumas may result in chronic infections, sometimes leading to osteomyelitis.
In those peripheral nerve disorders that are focal and asymmetric, sensory and motor and occasionally autonomic symptoms and signs may conform to a specific peripheral nerve distribution. For example, in carpal tunnel syndrome, patients may complain of intermittent numbness and tingling in the median nerve distribution in the hand or, as the entrapment progresses, atrophy and weakness of the thenar muscle group. In the mononeuritis multiplex syndrome, multiple individual peripheral nerves may be affected, and thus the sensory, motor, and/or autonomic symptoms and signs will be distributed in a multifocal pattern conforming to numerous individual peripheral nerve lesions. On occasion, some peripheral nerve disorders cause generalized sensory and motor fiber involvement with asymmetric and focal features (Table 1).

Diagnosis begins by the recognition of typical symptoms of peripheral nerve disease and the identification of the pattern of peripheral nerve involvement. For example, if the symptoms are highly restricted and focal they may conform to the distribution of an individual peripheral nerve or, possibly, to an individual root. More diffuse involvement of an entire limb might be caused by involvement of the brachial or lumbosacral plexus. Alternatively, if generalized symptoms are distributed in an asymmetric and focal fashion, they may be consistent with a mononeuritis multiplex picture or possibly a polyradiculoneuropathy or polyradiculopathy syndrome. Most often, peripheral neuropathies produce symptoms that are generalized and relatively symmetric, conforming to a distal-to-proximal gradient typical of a distal axonopathy.

Once their distribution is recognized, the symptoms should be analyzed to determine which fiber types appear to be involved, ie, sensory, motor, and/or autonomic. In addition, the temporal profile of the disorder, ie, chronic, subacute, or acute, is noted. The neurologic examination is then helpful in confirming signs of sensory, motor, and/or autonomic dysfunction and in documenting the pattern and fiber type involved. These clinical features, which can be derived solely from the history and physical examination, are valuable for characterizing the nature of the peripheral nerve syndrome, which is essential in constructing a differential diagnosis (Tables 1 and 5).

Another important component to the evaluation of peripheral nerve disease are electrodiagnostic (Edx) studies, primarily nerve conduction studies and the needle electrode examination. Edx testing can document the presence of peripheral nerve disease, define the distribution and pattern of various sensory and motor fibers, and characterize the underlying pathologic processes, ie, wallerian degeneration, axon degeneration, segmental demyelination, or some mixture of these pathologic reactions. Characterizing the Edx features, particularly whether the process is axonal or demyelinating, adds additional information.⁵

Other special studies include lumbar puncture for cerebrospinal fluid analysis, which may be useful in the diagnosis of inflammatory or infectious causes of polyneuropathy, in the evaluation of acquired demyelinating polyneuropathies such as those in GBS, in CIDP, and in a variety of immune-mediated polyneuropathies. Nerve biopsy, typically sural nerve biopsy, is most often recommended in patients with asymmetric or focal polyneuropathies in whom a diagnosis of vasculitis is being considered. In addition, biopsies may be used to assist in the diagnosis of some inflammatory, infectious, and metabolic polyneuropathies. Lastly, nerve biopsy may help to establish the pathologic basis of the polyneuropathy when Edx studies cannot conclusively distinguish an axonal from an acquired segmental demyelinating disorder. Special autonomic studies, particularly those that measure cardiovascular autonomic reflexes-including heart rate response to deep breathing, heart rate and blood pressure responses to the Valsalva maneuver, and heart rate and blood pressure responses to head-up-tilt may also be valuable in documenting autonomic cardiovascular involvement. In addition, various tests of sudomotor function including the sympathetic skin response, quantitative sudomotor axon reflex test, and thermoregulatory sweat testing may provide valuable information regarding the extent and distribution of sudomotor impairment in polyneuropathy. Quantitative sensory testing is a technique that allows precise measurement of sensory perception thresholds of various fiber types, which can also be helpful in assessing peripheral neuropathy, especially SFN, in which the Edx studies are often normal.

By recognizing the peripheral nerve syndrome and appreciating the potential differential diagnosis, one may systematically perform appropriate medical tests to explore the various possible causes. The most common peripheral nerve syndrome is the generalized sensorimotor polyneuropathy with Edx features of a distal axonopathy. For this disorder, it is usually appropriate to pursue a history of toxin exposure (Tables 2 and 3) and alcoholism with nutritional deficiency. It is also reasonable to perform routine laboratory screening studies including a complete blood cell count; erythrocyte sedimentation rate; a blood chemistry panel encompassing hepatic function, renal function, and electrolytes; thyroid function studies; and vitamin B₁₂ level. In addition, it is important to screen patients for diabetes mellitus. In the past, a fasting blood sugar and/or hemoglobin A_1c test was often performed, but recent reports suggest that impaired glucose tolerance detected on a glucose tolerance test may provide more meaningful information regarding diabetes as a potential cause for polyneuropathy.⁶ Screening the serum and urine with protein electrophoresis with immunofixation is also important in assessing patients with generalized polyneuropathy. In one series, the only laboratory tests that were helpful in establishing a precise etiology for the polyneuropathy were vitamin B₁₂, serum protein electrophoresis with immunofixation, and serum glucose.⁷ Additional laboratory studies may be considered pending the specific clinical features, and may include chest radiograph, skeletal bone survey, antinuclear antibodies, rheumatoid factor, and angiotensin-converting enzyme level. In patients with an aggressive, evolving polyneuropathy or a specific paraneoplastic syndrome, additional testing for an occult malignancy is often performed, usually in conjunction with autoantibodies, especially anti-Hu. A variety of autoantibodies have been associated with different polyneuropathy syndromes.⁸ The most useful of these include anti-GM₁ antibodies in the setting of MMNCB, anti-Hu antibodies in the context of a sensory neuronopathy, and anti-myelin-associated glycoprotein antibodies in acquired demyelinating polyneuropathy with predominately sensory features and with a distal pattern of involvement.^2,8 Most of the other antibodies are much less specific, and their roles in the mechanism of the polyneuropathies are less certain.⁸ Thus, the precise value of performing panels of antibody tests is unclear at this time.⁹ Lumbar puncture is often reserved for patients with possible immune-mediated polyneuropathies, particularly those with demyelinating features on Edx testing. However, CSF studies are also frequently assessed in cryptogenic axonal degeneration polyneuropathies and in patients with possible infectious or inflammatory disorders.

In patients with Edx features suggesting acquired segmental demyelination, a variety of tests are indicated to assess for CIDP and related disorders (Table 6), including serum and urine for protein electrophoresis with immunofixation, skeletal bone survey for myeloma or osteosclerotic myeloma, and HIV testing in patients at risk. In patients with SFN, various hereditary diseases must also be considered if the more common acquired disorders are not present (Table 5). In the asymmetric polyneuropathies, particularly those of acute or subacute evolution, the differential diagnosis includes various connective tissue disorders associated with vasculitis. Thus, appropriate laboratory studies must be obtained to investigate these disorders.

The acute polyneuropathies are a special category that includes GBS, although variants and other less common causes must also be considered. The inherited polyneuropathies are of course identified by a typical chronic course, often with onset in childhood and a family history of similar illness. Some of the hereditary polyneuropathies, in particular Charcot-Marie-Tooth disease, may be confirmed with genetic tests performed on blood.

Despite comprehensive testing and assessments, an etiologic diagnosis may not be determined in nearly 25% of patients with polyneuropathy.¹⁰ In this group, particularly those with chronic sensorimotor polyneuropathies, careful assessment of first-degree relatives may be helpful in identifying an unrecognized familial disorder. In addition, in patients with "idiopathic" polyneuropathy, judicious reassessment of their laboratory investigations should be performed periodically, particularly if symptoms and signs progress.

Specific therapies for polyneuropathy are based upon the precise etiologic diagnosis. In those disorders attributed to underlying medical conditions, management is focused on the medical disorder. For example, optimizing glycemic control in diabetic polyneuropathy will often stabilize or improve the polyneuropathy. In patients with idiopathic immune-mediated polyneuropathies, including GBS, CIDP, and MMNCB (multifocal motor neuropathy with conduction block), specific immune-modulating therapies are often recommended.^2,11 For GBS, intravenous gamma globulin (IVIg), typically administered at a dosage of 400 mg/kg daily for 5 consecutive days, is initiated early in the patient's course. Alternatively, plasmapheresis may also be instituted as initial therapy. Treatment of CIDP may begin with corticosteroid therapy; however, chronic IVIg and/or plasmapheresis are usually very effective and obviate the need for long-term steroid therapy. Toxic polyneuropathies are managed by discontinuing the offending drug or removing the industrial toxin from the patient's environment. Management of hereditary polyneuropathies includes education of the affected family members regarding the nature and genetic features of the disorder and judicious screening of family members at risk.

For all patients. but particularly for those without a specific or treatable etiology, therapy focuses on supportive measures. This may include the use of various physical therapy and occupational therapy modalities including bracing and aids to ambulation. The use of an ankle-foot orthosis may be very effective in improving ambulation in a patient with foot drop. In those patients with severe sensory loss in the feet and lower extremities, careful daily foot inspection for signs of trauma and infection are essential to prevent serious infections and other complications.

In those patients who have associated pain, particularly patients with SFN, specific neuropathic pain management is instituted. Neuropathic pain typically does not respond to simple analgesics, and its potential chronicity precludes narcotic therapy as a first choice. Typically, patients with SFN and other painful polyneuropathies respond to drugs known to be effective for neuropathic pain, including tricyclic antidepressants and a variety of antiepileptic drugs and membrane stabilizers (Table 7).^3,7,12 The choice for each patient must be individualized, taking into account potential side effects and drug interactions, among other factors. For patients requiring sedation due to disturbed sleep from the pain, a sedating tricyclic drug taken at bedtime, such as amitriptyline, is a good choice. However, the anticholinergic side effects of the tricyclic antidepressants make them a poor choice in those patients with prominent dysautonomia, as they are likely to worsen gastrointestinal dysmotility and bladder dysfunction. Because most of these drugs can potentially cause sedation, it is customary to begin therapy with small doses and gradually escalate as needed and tolerated. However, it is important to increase a drug to a reasonable dosage before determining its clinical efficacy. Drugs with little efficacy despite high doses should be tapered and discontinued before starting an alternative drug. On the other hand, drugs that provide some relief but are not controlling the pain adequately may be maintained in some circumstances, and another drug may be added to the regimen.

Peripheral neuropathies are common disorders associated with a wide range of medical conditions and immune-mediated mechanisms. With a systematic approach to the evaluation of these disorders, approximately 75% of patients will have a specific etiologic diagnosis. Nevertheless, despite comprehensive evaluations, the peripheral nerve disorder must be regarded as cryptogenic or idiopathic in nearly 25% of patients. In most patients with a peripheral neuropathy related to a medical disorder or immune-mediated mechanism, specific therapies directed at the underlying mechanism are usually effective in controlling the peripheral neuropathy. However, despite these therapies, the symptoms and signs of the peripheral neuropathy remain a chronic problem in most patients. Nevertheless, even in the absence of a specific treatable etiology, the symptoms of polyneuropathy can be treated with a variety of supportive measures including medications for neuropathic pain, physical therapy modalities, and orthotic devices. Fortunately, for most of these patients, the peripheral nerve disorder does not result in serious disability.

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