Peripheral neuropathy is dysfunction of one or more peripheral nerves (the part of a nerve distal to the root and plexus). It includes numerous syndromes characterized by varying degrees of sensory disturbances, pain, muscle weakness and atrophy, diminished deep tendon reflexes, and vasomotor symptoms, alone or in any combination. Initial classification is based on history and physical examination. Electromyography and nerve conduction studies (electrodiagnostic testing) help localize the lesion and determine whether the pathophysiology is primarily axonal (often metabolic) or demyelinating (often autoimmune). Treatment is aimed mainly at the cause.

Peripheral neuropathy may affect a single nerve (mononeuropathy), ≥ 2 discrete nerves in separate areas (multiple mononeuropathy), or many nerves simultaneously suggesting a diffuse process (polyneuropathy).

Mononeuropathies

Single mononeuropathies are characterized by sensory disturbances and weakness in the distribution of the affected nerve. Diagnosis is clinical but may require confirmation with electrodiagnostic tests. Treatment is directed at the cause, sometimes with splinting, NSAIDs, corticosteroid injections, and, for severe cases of nerve entrapment, surgery.

Trauma is the most common cause of acute mononeuropathy and may occur as follows:

• Violent muscular activity or forcible overextension of a joint may cause focal neuropathy, as may repeated small traumas (eg, tight gripping of small tools, excessive vibration from air hammers).
• Prolonged, uninterrupted pressure at bony prominences can cause pressure neuropathy, usually affecting superficial nerves (ulnar, radial, peroneal), particularly in thin people; such pressure may occur during sound sleep, intoxication, bicycle riding, or anesthesia.
• Compression of nerves in narrow passageways causes entrapment neuropathy (eg, in carpal tunnel syndrome).
• Nerve compression by a tumor, hyperostosis, a cast, crutches, or prolonged cramped postures (eg, during gardening) may cause compression paralysis.

Hemorrhage that compresses a nerve, exposure to cold or radiation, or direct tumor invasion may also cause neuropathy. Compression of a nerve may be transient (eg, caused by an activity) or fixed (eg, caused by a mass or anatomic abnormality).

Symptoms and Signs

Single mononeuropathies are characterized by pain, weakness, and paresthesias in the distribution of the affected nerve or nerves. Pure motor nerve involvement begins with painless weakness; pure sensory nerve involvement begins with sensory disturbances and no weakness.

Ulnar nerve palsy at the elbow is often caused by trauma to the nerve in the ulnar groove of the elbow by repeated leaning on the elbow or by asymmetric bone growth after a childhood fracture (tardy ulnar palsy). The ulnar nerve can also be compressed at the cubital tunnel. Compression at the level of the elbow can cause paresthesias and a sensory deficit in the 5th digit and medial half of the 4th digit; the thumb adductor, 5th digit abductor, and interosseus muscles are weak and may be atrophied. Severe chronic ulnar palsy causes a clawhand deformity. Sensory symptoms due to this syndrome are similar to those due to C8 root dysfunction secondary to cervical radiculopathy; however, radiculopathy normally affects the more proximal aspects of the C8 dermatome.

Carpal tunnel syndrome (see also Hand Disorders: Carpal Tunnel Syndrome) may be unilateral or bilateral. It results from compression of the median nerve in the volar aspect of the wrist between the transverse superficial carpal ligament and the flexor tendons of the forearm muscles. The compression causes paresthesias in the radial-palmar aspect of the hand and pain in the wrist and palm. Pain may be referred to the forearm and shoulder. Pain may be more severe at night. A sensory deficit in the palmar aspect of the first 3 fingers may follow, and the muscles that control thumb abduction and opposition may become weak and atrophied. Sensory symptoms due to this syndrome are similar to those due to C6 root dysfunction secondary to cervical radiculopathy.

Peroneal nerve palsy is usually caused by compression of the nerve against the lateral aspect of the fibular neck. It is most common among emaciated bedbound patients and thin people who habitually cross their legs. It causes footdrop (weakened dorsiflexion and eversion of the foot) and, occasionally, a sensory deficit in the anterolateral aspect of the lower leg and the dorsum of the foot or in the web space between the 1st and 2nd metatarsals. L5 radiculopathy can cause similar deficits but, unlike peroneal nerve palsy, tends to weaken hip abduction by the gluteus medius.

Radial nerve palsy (Saturday night palsy) is caused by compression of the nerve against the humerus, as when the arm is draped over the back of a chair for a long time (eg, during intoxication or deep sleep). Typical symptoms include wristdrop (weakness of the wrist and finger extensors) and sensory loss in the dorsal aspect of the first dorsal interosseous muscle. C7 radiculopathy can cause similar motor deficits.

Diagnosis

• Clinical evaluation
• Electrodiagnostic testing if clinical diagnosis is inconclusive

Symptoms and examination findings may be nearly pathognomonic.

Electrodiagnostic tests are usually done to clarify the diagnosis, particularly when clinical findings are inconclusive—for example,

• To distinguish sensory symptoms due to ulnar nerve palsy from C8 root dysfunction due to cervical radiculopathy
• To distinguish sensory symptoms due to carpal tunnel syndrome from C6 root dysfunction due to cervical radiculopathy

Electrodiagnostic tests also help localize the lesion, assess severity, and estimate prognosis.

Treatment

Underlying disorders are treated. Treatment of compression neuropathy depends on cause:

• Fixed compression (eg, by tumor) often must be relieved surgically.
• For transient compression, rest, heat, limited courses of NSAIDs in doses that reduce inflammation (eg, ibuprofen 800 mg tid), and avoidance or modification of the causative activity usually relieve symptoms.
• For carpal tunnel syndrome, conservative therapy includes splinting the wrist, oral or injected corticosteroids, and ultrasound. For refractory cases, surgical release is usually effective.

Braces or splints are often used pending resolution to prevent contractures. Surgery should be considered when progression occurs despite conservative treatment.

Key Points

• If findings indicate that a single nerve is affected, trauma is the most likely cause.
• Do electrodiagnostic tests if necessary to distinguish mononeuropathies from radiculopathies and other disorders that cause similar symptoms.
• For transient nerve compression, advising patients to avoid the causative activity may be all that is needed.

Multiple Mononeuropathy

(Mononeuritis Multiplex)

Multiple mononeuropathies are characterized by sensory disturbances and weakness in the distribution of the affected nerve or nerves.

Multiple mononeuropathy is usually secondary to connective tissue disorders (eg, polyarteritis nodosa, SLE, other types of vasculitis, Sjögren's syndrome, RA), sarcoidosis, metabolic disorders (eg, diabetes, amyloidosis), or infectious disorders (eg, Lyme disease, HIV infection, leprosy). However, diabetes usually causes sensorimotor distal polyneuropathy.

Multiple mononeuropathies are characterized by pain, weakness, and paresthesias in the distribution of the affected nerve or nerves. Pure motor nerve involvement begins with painless weakness; pure sensory nerve involvement begins with sensory disturbances and no weakness. Multiple mononeuropathy is often asymmetric at first; nerves may be involved all at once or progressively. Extensive involvement of many nerves may simulate polyneuropathy.

Symptoms and examination findings may be nearly pathognomonic. When they are not, electrodiagnostic testing is done to establish the diagnosis, localize the lesion, assess severity, and estimate prognosis.

Underlying disorders are treated.

Polyneuropathy

A polyneuropathy is a diffuse peripheral nerve disorder that is bilaterally symmetrical and thus not confined to the distribution of a single nerve or a single limb. Electrodiagnostic tests should always be done to classify the nerve structures involved, distribution, and severity of the disorder and thus help identify the cause. Treatment is directed toward correcting the cause.

Some polyneuropathies (eg, due to lead toxicity, dapsone use, tick bite, porphyria, or Guillain-Barré syndrome) affect primarily motor fibers; others (eg, due to dorsal root ganglionitis of cancer, leprosy, AIDS, diabetes mellitus, or chronic pyridoxine intoxication) affect primarily sensory fibers. Some disorders (eg, Guillain-Barré syndrome, Lyme disease, diabetes, diphtheria) can also affect cranial nerves. Certain drugs and toxins can affect sensory or motor fibers or both (see Table 6: Peripheral Nervous System and Motor Unit Disorders: Toxic Causes of Polyneuropathies).

Table 6
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Toxic Causes of Polyneuropathies Type of Neuropathy Causes Axonal motor Gangliosides, tetanus, tick paralysis With prolonged exposure, lead, mercury Axonal sensorimotor Acrylamide, alcohol (ethanol), allyl chloride, arsenic, cadmium, carbon disulfide, chlorphenoxy compounds, ciguatoxin, colchicine, cyanide, dapsone, disulfiram, DMAPN, ethylene oxide, lithium, methyl bromide, nitrofurantoin, organophosphates, PCBs, PNU, podophyllin, saxitoxin, Spanish toxic oil, taxol, tetrodotoxin, thallium, trichloroethylene, TOCP, vinca alkaloids Axonal sensory Almitrine, bortezomib, chloramphenicol, dioxin, doxorubicin, ethambutol, ethionamide, etoposide, gemcitabine, glutethimide, hydralazine, ifosfamide, interferon alfa, isoniazid, lead, metronidazole, misonidazole, nitrous oxide, nucleosides (didanosine [ddI], stavudine [d4T], zalcitabine [ddC]), phenytoin, platinum analogs, propafenone, pyridoxine, statins, thalidomide Demyelinating Buckthorn, chloroquine, diphtheria, hexachlorophene, muzolimine, perhexiline, procainamide, tacrolimus tellurium, zimeldine Mixed Amiodarone, ethylene glycol, gold, hexacarbons, n-hexane, Na cyanate, suramin DMAPN = dimethylaminopropionitrile; PCBs = polychlorinated biphenyls; PNU = N-3 pyridylmethyl-N´-p-nitrophenyl urea; TOCP = triorthocresyl phosphate.

Symptoms and Signs

Symptoms may appear suddenly or develop slowly and become chronic depending on the cause. Because pathophysiology and symptoms are related, polyneuropathies are often classified by area of dysfunction: myelin, vasa nervorum, or axon. They may be acquired or inherited (see Peripheral Nervous System and Motor Unit Disorders: Hereditary Neuropathies).

Myelin dysfunction

Myelin dysfunction (demyelinating) polyneuropathies most often result from a parainfectious immune response triggered by encapsulated bacteria (eg, Campylobacter sp), viruses (eg, enteric or influenza viruses, HIV), or vaccines (eg, influenza vaccine). Presumably, antigens in these agents cross-react with antigens in the peripheral nervous system, causing an immune response (cellular, humoral, or both) that culminates in varying degrees of myelin dysfunction. In acute cases (eg, in Guillain-Barré syndrome—see Peripheral Nervous System and Motor Unit Disorders: Guillain-Barré Syndrome (GBS)), rapidly progressive weakness and respiratory failure may develop. In chronic inflammatory demyelinating polyneuropathy (CIDP), symptoms may recur or progress over months and years.

Myelin dysfunction usually results in large-fiber sensory disturbances (paresthesias), significant muscle weakness greater than expected for degree of atrophy, and greatly diminished reflexes. Trunk musculature and cranial nerves may be involved. Demyelination typically occurs along the entire length of a nerve, causing proximal and distal symptoms. There may be side-to-side asymmetries, and the upper body may be affected before the lower body, or vice versa. Muscle bulk and tone are relatively preserved.

Vasa nervorum compromise

Chronic arteriosclerotic ischemia, vasculitis, infections, and hypercoagulable states can compromise the vascular supply to nerves, causing nerve infarction.

Usually, small-fiber sensory and motor dysfunction occurs first. Patients typically have painful, often burning sensory disturbances. Pain and temperature sensation are deficient. Vasa nervorum involvement (eg, caused by vasculitis or infections) can begin as multiple mononeuropathies, which, when many nerves are affected bilaterally, can look like polyneuropathy. Abnormalities tend to be asymmetric early in the disorder and rarely affect the proximal one third of the limb or trunk muscles. Cranial nerve involvement is rare, except in diabetes, which commonly affects the 3rd cranial (oculomotor) nerve. Later, if nerve lesions coalesce, symptoms and signs may appear symmetric. Dysautonomia and skin changes (eg, atrophic, shiny skin) sometimes occur. Muscle weakness tends to be proportional to atrophy, and reflexes are rarely lost completely.

Axonopathy

Axonopathies tend to be distal; they may be symmetric or asymmetric.

Symmetric axonopathies result most often from toxic-metabolic disorders. Common causes include the following:

• Diabetes mellitus
• Chronic renal insufficiency
• Adverse effects of chemotherapy drugs (eg, vinca alkaloids)

Axonopathy may result from nutritional deficiencies (most commonly, of thiamin or vitamin B₆, B₁₂, or E) or from excess intake of vitamin B₆ or alcohol. Less common metabolic causes include hypothyroidism, porphyria, sarcoidosis, and amyloidosis. Other causes include certain infections (eg, Lyme disease), drugs (eg, nitrous oxide), and exposure to certain chemicals (eg, Agent Orange, n-hexane) or heavy metals (eg, lead, arsenic, mercury). In a paraneoplastic syndrome associated with small-cell lung cancer, loss of dorsal root ganglia and their sensory axons results in subacute sensory neuropathy.

Primary axon dysfunction may begin with symptoms of large- or small-fiber dysfunction or both. Usually, the resulting neuropathy has a distal symmetric, stocking-glove distribution; it evenly affects the lower extremities before the upper extremities and progresses symmetrically from distal to proximal areas.

Asymmetric axonopathy can result from parainfectious or vascular disorders.

Diagnosis

• Electrodiagnostic tests
• Laboratory tests, determined by suspected type of neuropathy

Polyneuropathy is suspected in patients with diffuse or multifocal sensory deficits, weakness without hyperreflexia, or both. However, if findings are relatively diffuse but began asymmetrically, the cause may be multiple mononeuropathy.

Pearls & Pitfalls If findings are consistent with polyneuropathy, try to determine whether symptoms began asymmetrically (possibly suggesting multiple mononeuropathy).

Clinical findings, particularly tempo of onset, help clinicians diagnose and identify the cause of polyneuropathy, as in the following:

• Asymmetric neuropathies suggest a disorder affecting the myelin sheath or vasa nervorum.
• Symmetric, distal neuropathies suggest toxic or metabolic causes.
• Slowly progressive, chronic neuropathies tend to be inherited or due to long-term toxic exposure or metabolic disorders.
• Acute neuropathies suggest an autoimmune cause, vasculitis, a toxin, an infection, or a postinfectious cause or possibly a drug or cancer.
• Rash, skin ulcers, and Raynaud's syndrome in patients with an asymmetric axonal neuropathy suggest a hypercoagulable state or parainfectious or autoimmune vasculitis.
• Weight loss, fever, lymphadenopathy, and mass lesions suggest a tumor or paraneoplastic syndrome.

Electrodiagnostic tests

Regardless of clinical findings, electromyography (EMG) and nerve conduction studies are necessary to classify the type of neuropathy. At a minimum, EMG of both lower extremities should be done to assess for asymmetry and full extent of axon loss. Because EMG and nerve conduction studies assess primarily large myelinated fibers in distal limb segments, EMG may be normal in patients with proximal myelin dysfunction (eg, early in Guillain-Barré syndrome) and in patients with primarily small-fiber dysfunction. In such cases, quantitative sensory or autonomic testing or skin punch biopsy may be done depending on the presenting symptoms.

Laboratory tests

Baseline laboratory tests for all patients include CBC, electrolytes, renal function tests, rapid plasma reagin test, a 2-h glucose tolerance test, and measurement of fasting plasma glucose, HbA_1C, vitamin B₁₂, folate, and thyroid-stimulating hormone. Some clinicians include serum protein electrophoresis. The need for other tests is determined by polyneuropathy subtype. When EMG and clinical differentiation are inconclusive, tests for all subtypes may be necessary.

For acute myelin dysfunction neuropathies, the approach is the same as that for Guillain-Barré syndrome (see Peripheral Nervous System and Motor Unit Disorders: Guillain-Barré Syndrome (GBS)); forced vital capacity is measured to check for incipient respiratory failure. In acute or chronic myelin dysfunction, tests for infectious disorders and immune dysfunction, including tests for hepatitis and HIV and serum protein electrophoresis, are done. A lumbar puncture should also be done; myelin dysfunction due to an autoimmune response often causes albuminocytologic dissociation: increased CSF protein (> 45 mg%) but normal WBC count (≤ 5/μL).

For vasa nervorum compromise or asymmetric axonal polyneuropathies, tests for hypercoagulable states and parainfectious or autoimmune vasculitis, particularly if suggested by clinical findings, should be done; the minimum is ESR, serum protein electrophoresis, and measurement of rheumatoid factor, antinuclear antibodies, and serum CK. CK may be elevated when rapid onset of disease results in muscle injury. Coagulation studies (eg, protein C, protein S, antithrombin III, anticardiolipin antibody, and homocysteine levels) should be done only if personal or family history suggests a hypercoagulable state. Tests for sarcoidosis, hepatitis C, or Wegener's granulomatosis should be done only if symptoms and signs suggest one of these disorders. If no cause is identified, nerve and muscle biopsy should be done. An affected sural nerve is usually biopsied. A muscle adjacent to the biopsied sural nerve or a quadriceps, biceps brachii, or deltoid muscle may be biopsied. The muscle should be one with moderate weakness that has not been tested by needle EMG (to avoid misinterpretation of needle artifacts). An abnormality is more often detected when the contralateral muscle has EMG abnormalities, particularly when the neuropathy is somewhat symmetric. Nerve biopsies are useful in symmetric and asymmetric polyneuropathies but are particularly useful in asymmetric axonopathies.

If initial tests do not identify the cause of distal symmetric axonopathies, a 24-h urine collection is tested for heavy metals, and urine protein electrophoresis is done. If chronic heavy metal poisoning is suspected, testing of hairs from the pubis or axillary region may help.

Whether tests for other causes are needed depends on history and physical examination findings.

Treatment

• Treatment directed at the cause
• Supportive care

Treatment focuses on correcting the causes when possible; a causative drug or toxin can be eliminated, or a dietary deficiency corrected. Although these actions may halt progression and lessen symptoms, recovery is slow and may be incomplete. If the cause cannot be corrected, treatment focuses on minimizing disability and pain. Physical and occupational therapists can recommend useful assistive devices. Tricyclic antidepressants such as amitriptyline or anticonvulsants such as gabapentin, are useful for relief of neuropathic pain (eg, diabetic burning feet).

For myelin dysfunction polyneuropathies, immune system–modifying treatments are usually used:

• Plasma exchange or IV immune globulin for acute myelin dysfunction
• Corticosteroids or antimetabolite drugs for chronic myelin dysfunction

Key Points

• Suspect polyneuropathy if patients have diffuse sensory deficits, weakness without hyperreflexia, or both.
• Consider a hereditary cause, long-term toxic exposure, or a metabolic disorder if patients have a slowly progressive chronic polyneuropathy.
• Consider toxic or metabolic causes if patients have a symmetric distal neuropathy.
• Consider disorders that affect the myelin sheath or vasa nervorum if patients have an asymmetric polyneuropathy.
• Consider a demyelinating disorder if patients have polyneuropathy with profound motor weakness, minimal atrophy, and hyporeflexia.
• Consider vasa nervorum compromise if patients have polyneuropathy, pain and temperature sensation abnormalities, atrophy in proportion to weakness, and sometimes disproportionate preservation of reflexes.
• Consider axonopathies in all patients with polyneuropathy.

Last full review/revision August 2012 by Michael Rubin, MDCM