Merck Manual

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Michael Rubin

, MDCM, New York Presbyterian Hospital-Cornell Medical Center

Reviewed/Revised Apr 2022
Topic Resources

A polyneuropathy is a diffuse peripheral nerve disorder Overview of Peripheral Nervous System Disorders The peripheral nervous system refers to parts of the nervous system outside the brain and spinal cord. It includes the cranial nerves and spinal nerves from their origin to their end. The anterior... read more that is not confined to the distribution of a single nerve or a single limb and typically is relatively symmetrical bilaterally. 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 affect primarily motor fibers. They include

Others affect primarily sensory fibers. They include

Some disorders can also affect cranial nerves. They include

Certain drugs and toxins can affect sensory or motor fibers or both (see table Toxic Causes of Neuropathies Toxic Causes of Polyneuropathies Toxic Causes of Polyneuropathies ).


Symptoms and Signs of Polyneuropathy

Symptoms of polyneuropathy 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

  • Axon

Myelin dysfunction

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 and, slightly less commonly, the 6th cranial (abducens) 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.


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:

Axonopathy may result from nutritional deficiencies (most commonly, of thiamin Thiamin Deficiency Thiamin deficiency (causing beriberi) is most common among people subsisting on white rice or highly refined carbohydrates in countries with high rates of food insecurity and among people with... read more , vitamin B6 Vitamin B6 Deficiency and Dependency Because vitamin B6 is present in most foods, dietary deficiency is rare. Secondary deficiency may result from various conditions. Symptoms can include peripheral neuropathy, a pellagra-like... read more , vitamin B12 Vitamin B12 Deficiency Dietary vitamin B12 deficiency usually results from inadequate absorption, but deficiency can develop in vegans who do not take vitamin supplements. Deficiency causes megaloblastic anemia, damage... read more , or vitamin E Vitamin E Deficiency Dietary vitamin E deficiency is common in countries with high rates of food insecurity; deficiency among adults in other countries is uncommon and usually due to fat malabsorption. The main... read more ) or from excess intake of vitamin B6 Vitamin B6 Toxicity The ingestion of megadoses (> 500 mg/day) of pyridoxine may cause peripheral neuropathy. Vitamin B6 includes a group of closely related compounds: pyridoxine, pyridoxal, and pyridoxamine... read more or alcohol Alcohol Toxicity and Withdrawal Alcohol (ethanol) is a central nervous system depressant. Large amounts consumed rapidly can cause respiratory depression, coma, and death. Large amounts chronically consumed damage the liver... read more . Less common metabolic causes include hypothyroidism Hypothyroidism Hypothyroidism is thyroid hormone deficiency. Symptoms include cold intolerance, fatigue, and weight gain. Signs may include a typical facial appearance, hoarse slow speech, and dry skin. Diagnosis... read more Hypothyroidism , porphyria Acute Porphyrias Acute porphyrias result from deficiency of certain enzymes in the heme biosynthetic pathway, resulting in accumulation of heme precursors that cause intermittent attacks of abdominal pain and... read more , sarcoidosis Sarcoidosis Sarcoidosis is an inflammatory disorder resulting in noncaseating granulomas in one or more organs and tissues; etiology is unknown. The lungs and lymphatic system are most often affected, but... read more Sarcoidosis , and amyloidosis Amyloidosis Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally... read more Amyloidosis . Other causes include certain infections (eg, Lyme disease Lyme Disease Lyme disease is a tick-transmitted infection caused by the spirochete Borrelia species. Early symptoms include an erythema migrans rash, which may be followed weeks to months later by... read more Lyme Disease ), drugs (eg, nitrous oxide), and exposure to certain chemicals (eg, Agent Orange, n-hexane) or heavy metals (eg, lead Lead Poisoning Lead poisoning often causes minimal symptoms at first but can cause acute encephalopathy or irreversible organ damage, commonly resulting in cognitive deficits in children. Diagnosis is by whole... read more , arsenic, mercury).

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 of Polyneuropathy

  • 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. Clinicians must ask patients for a thorough description of symptom onset to determine whether symptoms began symmetrically or asymmetrically. For example, patients should be asked whether symptoms appeared in both feet at about the same time (symmetrically) or appeared in one foot, then one hand, then the other foot (asymmetrically).

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 vasculitis.

  • 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 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.

Axonopathies should be considered in all patients with polyneuropathy.

Electrodiagnostic tests

Regardless of clinical findings, electromyography (EMG) and nerve conduction studies are necessary to classify the type of neuropathy and help clinicians tailor laboratory tests based on possible causes. At a minimum, EMG of both lower extremities should be done to assess for asymmetry and full extent of axon loss.

Because nerve conduction studies assess primarily large myelinated fibers in distal limb segments, they may be normal, except for prolonged F wave responses,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, done at specialized testing centers, or skin punch biopsy may be done depending on the presenting symptoms.

Laboratory tests

Baseline laboratory tests for all patients include

  • Complete blood count

  • Electrolytes

  • Renal function tests

  • Rapid plasma reagin test

  • Measurement of fasting plasma glucose, glycosylated hemoglobin (HbA1C), and sometimes a 2-hour glucose tolerance test

  • Vitamin B12 and folate levels

  • Thyroid-stimulating hormone (TSH) level

Some clinicians include serum protein electrophoresis, especially if patients have a painful sensory neuropathy not explained by diabetes. The need for other tests is determined by polyneuropathy subtype (large- or small-fiber). When electrodiagnostic tests 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 Diagnosis Guillain-Barré syndrome is an acute, usually rapidly progressive but self-limited inflammatory polyneuropathy characterized by muscular weakness and mild distal sensory loss. Cause is thought... read more ; 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 Lumbar Puncture (Spinal Tap) Lumbar puncture is used to do the following: Evaluate intracranial pressure and cerebrospinal fluid (CSF) composition (see table ) Therapeutically reduce intracranial pressure (eg, idiopathic... read more should also be done; myelin dysfunction due to an autoimmune response often causes albuminocytologic dissociation: increased cerebrospinal fluid protein (> 45 mg%) but normal white blood cell count ( 5/mcL).

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

  • Erythrocyte sedimentation rate

  • Serum protein electrophoresis

  • Measurement of rheumatoid factor, antinuclear antibodies, and serum creatine kinase (CK)

CK may be elevated when rapid onset of disease results in muscle injury.

Other tests depend on the suspected cause:

  • 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 granulomatosis with polyangiitis (formerly known as Wegener 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, blood levels may be measured or a 24-hour urine collection may be done to check for heavy metals. Hairs or nails may be tested and may confirm heavy metals as the cause.

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

Treatment of Polyneuropathy

  • Treatment directed at the cause

  • Supportive care

Treatment of polyneuropathy focuses on correcting the causes when possible; a causative drug or toxin can be eliminated, or a dietary deficiency can be 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 antiseizure drugs such as gabapentin are useful for relief of neuropathic pain Neuropathic Pain Neuropathic pain results from damage to or dysfunction of the peripheral or central nervous system, rather than stimulation of pain receptors. Diagnosis is suggested by pain out of proportion... read more (eg, diabetic burning feet).

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

Key Points

  • Suspect polyneuropathy if patients have diffuse sensory deficits, weakness without hyperreflexia, or both.

  • Use clinical findings, particularly time course and progression and distribution of sensory and/or motor deficits, to classify polyneuropathies and identify possible causes.

  • Do electromyography and nerve conduction studies in all patients with polyneuropathy and tailor laboratory evaluation to possible causes.

  • Treat the cause of polyneuropathy.

  • Give immune–system modifying treatments (IVIG, plasma exchange, corticosteroids, antimetabolites) to treat myelin dysfunction polyneuropathies.

  • Treat neuropathic pain with tricyclic antidepressants or antiseizure drugs; minimize disability by providing physical and occupational therapy.

Drugs Mentioned In This Article

Drug Name Select Trade
B-Natal, Neuro-K-500
Alph-E-Mixed , AQUA-E, Aquasol E , Aquavite-E
ATryn, Thrombate III
Elavil, Tryptanol, Vanatrip
Active-PAC with Gabapentin, Gabarone , Gralise, Horizant, Neurontin
NOTE: This is the Professional Version. CONSUMERS: View Consumer Version
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