Polyneuropathy

Myelin dysfunction

Myelin dysfunction (demyelinating) polyneuropathies can 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.

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 diminished.

Vasa nervorum involvement caused by vasculitis or infections can present as multiple mononeuropathies; when many nerves are affected bilaterally, this can resemble 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 third cranial (oculomotor) nerve and, slightly less commonly, the sixth 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.

Axonopathy

Axonopathies tend to be distal and 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 vitamin 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).

A paraneoplastic syndrome associated with small-cell lung cancer can cause a subacute sensory neuropathy due to loss of dorsal root ganglia and their sensory axons.

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.

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 include the following (1– 3):

• Measurement of fasting plasma glucose, glycosylated hemoglobin (HbA1C)

• Vitamin B12 (with methylmalonic acid) and folate

• Serum protein electrophoresis with immunofixation

• Complete blood count

• Complete metabolic panel (electrolytes, renal function, liver function)

• Thyroid-stimulating hormone (TSH) level

• Infections workup (HIV, Lyme, RPR)

• Autoimmune testing (ANA, antineutrophil cytoplasmic antibodies)

• Heavy metals

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.

Diagnosis references

1. 1. Mauermann ML, Staff NP. Peripheral Neuropathy: A Review. JAMA. 2026;335(3):255-266. doi:10.1001/jama.2025.19400

2. 2. England JD, Gronseth GS, Franklin G, et al. Practice Parameter: evaluation of distal symmetric polyneuropathy: role of laboratory and genetic testing (an evidence-based review). Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation. Neurology. 2009;72(2):185-192. doi:10.1212/01.wnl.0000336370.51010.a1

3. 3. Castelli G, Desai KM, Cantone RE. Peripheral Neuropathy: Evaluation and Differential Diagnosis. Am Fam Physician. 2020;102(12):732-739.

Treatment reference

1. 1. Feldman A, Weaver J. Pharmacologic and Nonpharmacologic Management of Neuropathic Pain. Semin Neurol. 2025;45(1):145-156. doi:10.1055/s-0044-1791770