Introduction

Peripheral neuropathy usually presents with weakness and sensory loss or pain in the arms and legs. An estimated that 10% to 22% of people in the United States suffer from neuropathy, the incidence of which increases with age. Neuropathies are classified according to cause (endocrine, metabolic, nutritional, toxic, etc) or clinical presentation (sensory, motor, autonomic, mixed sensory and motor, mononeuritis, mononeuritis multiplex, etc). Owing to the diverse causes of neuropathy, laboratory testing is invariably required for diagnosis or etiologic identification. The following is a brief review of the known causes of acquired peripheral neuropathies and the laboratory tests available for evaluation and diagnosis (see also Table).

Endocrine and metabolic causes

Endocrine causes of neuropathy include diabetes mellitus and hypothyroidism. The most common cause of neuropathy is diabetes mellitus, which accounts for approximately 30% of cases. Approximately 50% of individuals with diabetes will develop neuropathy, and in some cases, neuropathy is the presenting complaint. The most frequent presentation is distal sensory polyneuropathy, but patients may also present with small fiber neuropathy (commonly caused by glucose intolerance), sensorimotor neuropathy, amyotrophy, mononeuritis, or mononeuritis multiplex. Diagnostic tests for diabetes mellitus include glycated hemoglobin (ie, hemoglobin A1c), blood glucose, and glucose tolerance assays. Hemoglobin A1c is also useful for monitoring diabetic control. Hypothyroidism presents predominantly as a sensory neuropathy and can be diagnosed with thyroid function tests including TSH and T4.

Metabolic causes of neuropathy include renal failure and porphyria. Renal failure, indicated by elevated serum creatinine and BUN, is associated with a predominantly sensory axonal neuropathy. Porphyria is associated with an acute, predominantly motor, neuropathy and is detected by urine porphyrin analysis.

Nutritional and toxic causes

Vitamin deficiency (B1, B6, B12, and E) and folate deficiency, as well as excessive intake of vitamin B6, can cause peripheral neuropathy. B12 deficiency is associated with achlorhydria or pernicious anemia and sometimes with parietal cell or intrinsic factor antibodies. Vitamin E deficiency is often associated with ataxia. Measurement of serum vitamin levels is useful in making the diagnosis.

Peripheral neuropathy may also be caused by several heavy metals. Lead toxicity is associated with motor neuropathy, whereas arsenic and mercury cause sensory neuropathy. The 24-hour urine heavy metal test is the most useful test for diagnosis of heavy metal toxicity.

Immune-mediated peripheral neuropathies

The immune system mediates peripheral neuropathies in autoimmune diseases, in systemic diseases such as vasculitis and primary amyloidosis, and in paraneoplastic syndromes. Autoimmune neuropathies are usually divided into Guillain-Barré syndrome (GBS), variants that are of acute onset and self-limiting, and variants that are chronic and follow a progressive or relapsing course. Glycoconjugate antigens, both glycoproteins and glycolipids, have been identified as putative targets for many of these autoimmune polyneuropathies. In general, IgG glycoconjugate autoantibodies have been associated with acute neuropathies, whereas IgM autoantibodies are associated with the chronic neuropathic syndromes.

Acute immune-mediated neuropathies include GBS (acute inflammatory demyelinating polyneuropathy), acute motor axonal polyneuropathy, acute sensory polyneuropathy, acute autonomic polyneuropathy, and Miller-Fisher syndrome in which the extra-ocular muscles are affected. Increased titers of IgG GM1 or GD1a ganglioside antibodies have been associated with GBS and acute motor axonal neuropathy, whereas increased IgG GQ1b ganglioside antibodies are closely associated with the Miller-Fisher syndrome. Tests for these autoantibodies can help evaluate patients suspected of having these syndromes.

Chronic immune-mediated polyneuropathies in which the peripheral nerves are selectively affected include chronic inflammatory demyelinating polyneuropathy (CIDP), demyelinating polyneuropathy associated with IgM MAG (myelin-associated glycoprotein) antibodies or SGPG (sulfoglucuronyl paragloboside) antibodies, multifocal motor neuropathy associated with IgM GM1 or GD1a antibodies, and sensory polyneuropathy associated with IgM sulfatide antibodies or GD1b or disialosyl ganglioside antibodies. Other neuropathies may be associated with GM2 antibodies. The presence of increased titers of these autoantibodies helps diagnose an immune-mediated polyneuropathy that may respond to specific immunotherapy. Some of these autoantibodies also occur as IgM monoclonal gammopathies in patients with non-malignant monoclonal gammopathies or in association with B-cell lymphoproliferative disorders (see paraneoplastic syndromes below).

Peripheral neuropathy can also occur in patients with rheumatologic diseases or systemic vasculitis, including systemic lupus erythematosus, Sjögren syndrome, rheumatoid arthritis, and granulomatosis with polyangiitis (GPA; Wegener). SLE can be diagnosed with the aid of tests for anti-nuclear antibodies (ANA). SS-A/Ro and SS-B/La antibodies are consistent with Sjögren syndrome, and rheumatoid factor and cyclic citrullinated peptide antibody are consistent with rheumatoid arthritis.

Anti-neutrophil cytoplasmic antibodies (ANCA), myeloperoxidase (MPO) antibody, and proteinase 3 (PR3) antibody are helpful for diagnosing GPA. Polyarteritis nodosa is another disease that is associated with vasculitis of the peripheral nerves, sometimes associated with hepatitis B. Chronic hepatitis C virus infection is associated with cryoglobulinemia, in which deposition of cryoglobulin-containing immune complexes causes small- and medium-size vessel disease. Vasculitis can also result from viral infections such as parvovirus. In viral infections, circulating immune complexes, cryoglobulins, or decreased complement levels (CH50) may be present. Vasculitic neuropathies typically present as mononeuritis, mononeuritis multiplex, or polyneuritis. However, Sjögren syndrome sometimes presents with sensory neuropathy or ganglioneuritis. Ribosomal P antibody may be present in these individuals.

Celiac disease, an inflammatory disease of the gut that results from gluten intolerance, may be associated with a sensory neuropathy, sometimes with ganglioside antibodies. It can be recognized by the presence of gliadin, transglutaminase, or endomysial antibodies. Endomysial antibodies commonly, but not always, react with transglutaminase.

Other neuropathies that are, in part, mediated by the immune system are those associated with neoplasia, monoclonal gammopathies, and primary amyloidosis (see below).

Autoimmune encephalitis

Symptoms of autoimmune encephalitis include seizures, psychosis, and changes in memory, behavior, and cognition. These encephalopathies may be caused by antibodies to neurotransmitter receptors such as N-methyl-D-aspartate receptor 1 (NMDAR1), glutamate receptors AMPAR1 and AMPAR2, and GABAB receptors. Encephalitis may also be caused by antibodies to proteins within the voltage-gated potassium channel (VGKC) complex such as leucine-rich glioma inactivated 1 (LGI1) and contactin-associated protein 2 (CASPR2). Some cases of autoimmune encephalitis have been associated with neoplasms such as teratomas.

Paraneoplastic neuropathies, monoclonal gammopathies, and primary amyloidosis

Paraneoplastic syndromes are thought to be caused by indirect effects of tumors, usually via immune or metabolic mechanisms. Several paraneoplastic neuropathic syndromes have been recognized. One of these is a predominantly sensory neuropathy that occurs in patients with carcinoma of the lung in association with Hu antibodies, which serve as a marker for the disease. Neuropathy is also associated with IgM monoclonal gammopathies in patients with Waldenstrom macroglobulinemia or B-cell leukemia or lymphoma and with IgG or IgA monoclonal gammopathies in myeloma. The monoclonal IgMs in patients with neuropathy frequently exhibit reactivity to one of the glycoconjugate antigens in peripheral nerves (see above). In myeloma, the monoclonal IgG or IgA antibodies do not have demonstrable autoantibody activity. Monoclonal gammopathy of any isotype, or light chain disease, can also be associated with primary amyloidosis in which the amyloid deposits contain fragments of the monoclonal light chains. The same neuropathic syndromes can also be associated with non-malignant IgM, IgG, or IgA monoclonal gammopathies, or monoclonal gammopathies of unknown significance (MGUS). Laboratory tests that are useful for detecting monoclonal gammopathies include an immunoglobulin profile (IgA, IgG, IgM) and immunofixation electrophoresis of serum and urine. Measurement of free kappa and free lambda light chain is useful for detecting light chain disease.

Polyneuropathies caused by infections or inflammatory diseases

Several infectious diseases also cause peripheral neuropathy. Human immunodeficiency virus-1 (HIV-1) infection is typically associated with a distal sensory neuropathy. Lyme disease can cause mononeuritis multiplex or diffuse polyneuropathy. Cytomegalovirus (CMV) infection of nerves causes an ascending polyradiculopathy. Herpes zoster infection can cause radiculopathy (shingles). Hepatitis B or C infections, or parvovirus infection in immunocompromised patients, can be associated with polyarteritis nodosa and vasculitic neuropathy. Bacterial (eg, Campylobacter jejuni) and viral (Epstein-Barr, Zika, Haemophilus influenzae) infections can trigger GBS. Reports of an association of GBS with SARS-CoV-2 are less clear, however. Based on ganglioside antibody positivity rate, mitigation strategies (social distancing, hand hygiene, and masking) reduced the frequency of certain GBS forms during the pandemic, especially those associated with GQ1b ganglioside antibodies (Miller-Fisher syndrome). Sarcoidosis can also cause a multifocal or diffuse neuropathy. Serologic testing for suspected infections or for angiotensin-converting enzyme (ACE) levels in sarcoidosis is helpful in the evaluation and diagnosis of patients with neuropathy.

The following Table is provided for informational purposes only and is not intended as medical advice. Test selection and interpretation, diagnosis, and patient management decisions should be based on the physician’s education, clinical expertise, and assessment of the patient.