Polyneuropathy

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 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:

• Diabetes mellitus

• Chronic kidney disease

• Adverse effects of chemotherapy medications (eg, vinca alkaloids)

Axonopathy may result from nutritional deficiencies (most commonly, of thiamin, vitamin B6, vitamin B12, or ) 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.

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.

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; 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 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.