Autoimmune Neuropathies

Indications for Autoantibody Testing

Antibody testing should be considered in individuals presenting with severe or rapidly progressive muscle weakness and/or sensory symptoms and with no known underlying etiology.

Diagnosis

The diagnosis of autoimmune neuropathy is dependent on clinical history, neurologic examination, and paraclinical data, including imaging and electrodiagnostic studies and laboratory tests. Antibody testing may be supportive of a diagnosis but should not preclude a careful clinical assessment. In addition, empiric treatment of suspected autoimmune neuropathy should not be withheld while awaiting the results of antibody testing if the clinical assessment is consistent with autoimmunity and other etiologies have been adequately excluded. 

Clinical history is important when investigating for possible underlying autoimmune neuropathy. Infection with Campylobacter jejuni, Mycoplasma pneumoniae, or cytomegalovirus often precedes the onset of GBS. The tempo of symptom onset (acute vs. subacute/chronic) and the characteristics of symptoms (e.g., motor, sensory, or mixed symptoms and their distribution) provide information that narrows the differential diagnosis and may suggest what additional testing is indicated.

The antibody testing approach depends on the antibody to be tested, laboratory availability, and interpretive expertise. Repeat testing using a second assay is recommended to confirm results, with special attention given to the test’s sensitivity and specificity as well as its positive predictive value.  Given the rarity of these disorders, it is important to consider the clinical phenotype; false-positive results are possible and can result in inappropriate or even harmful treatment strategies.  Each of the known paraneoplastic antibodies can be associated with various neurologic syndromes, but they are also highly specific for cancer presence, as well as cancer type. 

Laboratory Testing

Antibody testing for autoimmune neuropathies has evolved over the years. Neurologist and laboratory specialist guidance can help with the selection of appropriate antibody tests and interpretation of results.

Initial Laboratory Workup

Initial laboratory evaluation of neuropathy includes a CBC, comprehensive metabolic panel, and hemoglobin A1c, thyroid-stimulating hormone, vitamin B₁₂, and serum protein electrophoresis with immunofixation testing. Additional initial testing based on clinical suspicion may include ethanol, folate, thiamine, phosphorus, HIV antibody, hepatitis panel, Lyme antibodies, rapid plasma reagin, urine protein electrophoresis and immunofixation, antinuclear antibody, and antineutrophil cytoplasmic antibodies. Testing for uncommon causes of neuropathy may include autoantibody testing, cryoglobulin testing, CSF analysis, genetic testing, uric acid levels, heavy metal testing, testing for West Nile virus, herpes simplex virus, Epstein-Barr virus, and Zika virus, and skin and nerve fiber biopsy.

Autoantibody Test Selection

Clinicians need to familiarize themselves with the laboratory performing their autoantibody testing, the methods used, and how to interpret the results. Negative antibody results do not rule out autoimmune neuropathy. Positive antibody results in the absence of clinical criteria associated with that antibody are not sufficient for diagnosis. When in doubt about ordering or interpreting testing, consult your laboratory.

Test Selection Based on Patient Phenotype

Many antibodies involved in autoimmune neuropathy have low positivity rates. Some antibodies may be detected in the general population or may be associated with other systemic disorders,  which can make it difficult to interpret positive results. Ordering comprehensive panels that are not consistent with a patient’s clinical phenotype reduces the positive predictive value of positive results, complicating the clinical picture. Overinterpretation of false-positive and low-positive results can delay accurate diagnosis, increase healthcare costs, and potentially lead to harm with inappropriate use of immunotherapy.

Targeted panels focus on antibodies relevant for specific clinical phenotypes (e.g., based on presentation and anatomic distribution; motor, sensory, or mixed symptoms; acute, subacute, or chronic onset), improving the positive predictive value of these tests. A variety of targeted, phenotype-specific panels are available from clinical reference laboratories. Clinicians should choose the panel that represents the predominant clinical phenotype in a given patient.

In some cases, testing for a specific antibody (e.g., anti-GQ1b immunoglobulin G [IgG] when Miller Fisher syndrome is suspected) may be appropriate. When the clinical picture is less clear, panel testing may provide a more efficient way to assess for associated antibodies. In rare cases, monitoring a previously positive autoantibody over time may help inform clinical decision-making; testing for that single antibody is often more cost-effective and results in faster turnaround times.

Specimens for Antibody Testing

Serum is the sample type of choice for laboratory testing for autoimmune neuropathies. In rare cases, such as in the workup for some paraneoplastic diseases, testing both serum and CSF may maximize diagnostic yield. Ideally, samples will be collected before initiation of empiric immunotherapy with plasma exchange or intravenous immunoglobulin (IVIg), which may confound interpretation of results.