* This is the Professional Version. *
A polyneuropathy is a diffuse peripheral nerve disorder 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.
(See also Overview of Peripheral Nervous System Disorders.)
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: Toxic Causes of Polyneuropathies).
Toxic Causes of Polyneuropathies
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:
Polyneuropathies may be acquired or inherited.
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), 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.
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.
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 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.
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.
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 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.
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.
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, HbA1C, 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; 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
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, 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 of polyneuropathy 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
Plasma exchange or IV immune globulin, corticosteroids, and/or antimetabolite drugs for chronic myelin dysfunction
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.
* This is the Professional Version. *