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Peripheral neuropathy is dysfunction of one or more peripheral nerves (the part of a spinal 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 velocity studies 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 and often suggesting a diffuse process (polyneuropathy).

Mononeuropathies

Single and multiple mononeuropathies are characterized by sensory disturbances and weakness in the distribution of the affected nerve or nerves. Diagnosis is clinical but should be confirmed 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 result 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, bony 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).

Multiple mononeuropathy (mononeuritis multiplex) 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 (see Peripheral Nervous System and Motor Unit Disorders: Polyneuropathy).

Symptoms and Signs

Single and 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 its onset; nerves may be involved all at once or progressively. Extensive involvement of many nerves may simulate polyneuropathy.

Ulnar nerve palsy of 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.

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.

Diagnosis

Symptoms and examination findings may be nearly pathognomonic. Palpating muscles while they are contracting may detect weakness better than testing movement because during movement, other muscles may compensate for the weak one.

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.

Treament

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 Some Trade Names
  ADVIL
  MOTRIN
  NUPRIN
  Click for Drug Monograph
  800 mg tid), and avoidance or modification of the causative activity usually relieve symptoms.
• For carpal tunnel syndrome, corticosteroid injections are sometimes helpful.

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

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 Some Trade Names
ACZONE
Click for Drug Monograph
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 Neuropathies).

Table 6
Toxic Causes of Neuropathies Type 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, dapsone Some Trade Names ACZONE Click for Drug Monograph , colchicine Some Trade Names No US trade name Click for Drug Monograph , cyanide, DMAPN, disulfiram Some Trade Names ANTABUSE Click for Drug Monograph , ethylene oxide, lithium Some Trade Names ESKALITH LITHOBID LITHONATE Click for Drug Monograph , methyl bromide, nitrofurantoin Some Trade Names FURADANTIN MACROBID MACRODANTIN Click for Drug Monograph , organophosphates, PCBs, podophyllin, saxitoxin, Spanish toxic oil, taxol, tetrodotoxin, thallium, trichloroethylene, TOCP, PNU, vinca alkaloids Axonal sensory Almitrine, bortezomib Some Trade Names VELCADE Click for Drug Monograph , chloramphenicol Some Trade Names CHLOROMYCETIN Click for Drug Monograph , dioxin, doxorubicin Some Trade Names ADRIAMYCIN Click for Drug Monograph , ethambutol Some Trade Names MYAMBUTOL Click for Drug Monograph , ethionamide Some Trade Names TRECATOR Click for Drug Monograph , etoposide Some Trade Names ETOPOPHOS VEPESID Click for Drug Monograph , gemcitabine Some Trade Names GEMZAR Click for Drug Monograph , glutethimide, hydralazine Some Trade Names APRESOLINE Click for Drug Monograph , ifosfamide Some Trade Names IFEX MITOXANA Click for Drug Monograph , interferon-α, isoniazid Some Trade Names INH NYDRAZID Click for Drug Monograph , lead, metronidazole Some Trade Names FLAGYL Click for Drug Monograph , misonidazole, nitrous oxide, nucleosides ( didanosine Some Trade Names VIDEX Click for Drug Monograph [ddI], stavudine Some Trade Names ZERIT Click for Drug Monograph [d4T], zalcitabine Some Trade Names HIVID Click for Drug Monograph [ddC]), phenytoin Some Trade Names DILANTIN Click for Drug Monograph , platinum analogs, propafenone Some Trade Names RYTHMOL Click for Drug Monograph , pyridoxine, statins, thalidomide Some Trade Names THALOMID Click for Drug Monograph Demyelinating Buckthorn, chloroquine Some Trade Names ARALEN Click for Drug Monograph , diphtheria, hexachlorophene Some Trade Names PHISOHEX Click for Drug Monograph , muzolimine, perhexiline, procainamide Some Trade Names PROCAN SR PRONESTYL Click for Drug Monograph , tacrolimus Some Trade Names PROGRAF Click for Drug Monograph tellurium, zimeldine Mixed Amiodarone Some Trade Names CORDARONE Click for Drug Monograph , ethylene glycol, gold, hexacarbons, n-hexane, Na cyanate, suramin Some Trade Names No US trade name Click for Drug Monograph DMAPN = dimethylaminopropionitrile; PCBs = polychlorinated biphenyls; PNU = N-3 pyridilmethyl-N´-nitrophenyl urea; TOCP = triorthocresyl phosphate.

Symptoms and Signs

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 polyneuropathies most often result from a parainfectious immune response triggered by an encapsulated bacterium (eg, Campylobacter sp), virus (eg, enteric or influenza viruses, HIV), or vaccine (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, and hypercoagulable states can compromise the vascular supply to nerves.

Usually, small-fiber sensory and motor dysfunction occurs first. Patients typically have painful, often burning sensory disturbances. Abnormalities tend to be asymmetric early in the disorder and rarely affect the proximal ¹⁄₃ 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 testing
• Laboratory tests, determined by suspected type of neuropathy

Polyneuropathy is suspected in patients with diffuse or multifocal sensory deficits, weakness without hyperreflexia, or both. Clinical findings, particularly tempo of onset, aid in diagnosis and identification of the cause, 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 response, vasculitis, or a postinfectious cause.
• 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 may suggest a tumor or paraneoplastic syndrome.

Electrodiagnostic tests: Regardless of clinical findings, electromyography (EMG) and nerve conduction velocity studies are necessary to classify 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 both 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, and measurement of fasting plasma glucose, hemoglobin A1C, 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 CPK. CPK 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 EMG using a needle. 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 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. Amitriptyline Some Trade Names
ELAVIL
ENDEP
Click for Drug Monograph
, gabapentin Some Trade Names
NEURONTIN
Click for Drug Monograph
, mexiletine Some Trade Names
MEXITIL
Click for Drug Monograph
, and topical lidocaine Some Trade Names
XYLOCAINE
Click for Drug Monograph
may relieve neuropathic pain (eg, diabetic burning feet).

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

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

Last full review/revision February 2008 by Michael Rubin, MD

Content last modified February 2008