Clinical background [return to contents]

Peripheral neuropathy usually presents with weakness and sensory loss or pain in the arms and/or legs. An estimated 1% to 7% of people in the United States have peripheral neuropathy, with incidence increasing with age (>50 years).¹ Peripheral neuropathies can be classified according to cause (immune-mediated, endocrine, metabolic, nutritional, toxic, etc) or clinical presentation (sensory, motor, autonomic, mixed sensory and motor, mononeuritis, mononeuritis multiplex, etc).

Immune-mediated peripheral neuropathy may be caused by antibodies that directly target peripheral nerve antigens or secondary to systemic disease (eg, rheumatic disease, vasculitis, celiac disease), cancer (paraneoplastic syndromes), and infection (eg, HBV, HCV, HIV). This Clinical Focus provides information on laboratory testing that supports evaluation and diagnosis of immune-mediated causes of primary peripheral neuropathy, including Guillain-Barré syndrome (GBS) or acute inflammatory demyelinating polyradiculoneuropathy (AIDP), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and autoimmune nodopathy. Apart from differential diagnoses of autoimmune causes, information on autoimmune neuropathies secondary to other diseases is not covered, but other resources are available (eg, Paraneoplastic Neurological Syndromes: Laboratory Support of Diagnosis | Clinical Focus | Quest Diagnostics).This information 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.

Autoimmune peripheral neuropathies

Autoimmune peripheral neuropathies (or polyneuropathies when affecting multiple nerves) can be characterized by their onset and disease progression. Acute-onset immune-mediated neuropathies are usually self-limiting, and chronic immune-mediated neuropathies follow a progressive or relapsing course.

Acute immune-mediated peripheral neuropathies

The most common acute immune-mediated peripheral neuropathy is GBS. GBS is a peripheral nervous system demyelinating autoimmune syndrome that appears 1 to 2 weeks after routine infection, progresses over several weeks and can have a prolonged recovery phase of months to years.² Bacterial (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.³ An autoimmune response leads to the production of IgG and IgM antibodies that target neuronal membranes, specifically gangliosides, which participate in cell signaling and cell-to-cell communication.⁴ Patients experience symmetric limb weakness starting from the lower extremities and ascending to the upper extremities, which may progress to symmetrical paralysis.⁴

GBS includes other acute-onset clinical variants, which can be characterized as syndromes that are sensory, sensory-ataxic (ie, sensory neuropathy with profound ataxia), pharyngeal-cervical-brachial, or associated with motor and/or sensory neurons (Table 1).^4-6 Miller-Fisher syndrome (MFS) is another variant of GBS and is characterized by ophthalmoplegia, ataxia, and lower limb areflexia; some patients present with pupillary abnormalities (mydriasis), facial and bulbar palsy, sensory disturbances, weakness, or autonomic symptoms.⁴

CIDP is a relatively common form of chronic peripheral neuropathy that can follow a progressive disease course or occur aggressively at onset. It is a sensory-motor symmetric syndrome in which patients have chronic, symmetrical, and proximal and distal limb weakness associated with sensory-motor dysfunction. Evidence from nerve biopsies and responsiveness to intravenous immunoglobulin (IVIg) therapies, plasma exchange, and efgartigimod (a neonatal Fc receptor inhibitor) suggest a role of autoantibodies in the pathogenesis of CIDP although specific antibodies have not been identified.^4,9 Testing for antibodies against myelin-associated glycoproteins (MAG), however, may be beneficial in a diagnostic evaluation to help distinguish suspected CIDP from demyelinating polyneuropathies associated with MGUS polyneuropathies (MGUSP), which mimic CIDP; anti-MAG antibodies are diagnostic of MGUSP but are rarely found in patients with CIDP.⁴

MGUSP is characterized by a slowly progressing disease course, with mostly sensory disturbances, ataxia, and tremor. Patients with MGUSP may also present with distal weakness in the lower limbs. More than 50% of patients with MGUSP have IgM antibodies against MAG. A smaller percentage (5%) have anti-sulfatide antibodies, which may help inform treatment; in a small study, sulfatide antibodies indicated a favorable response to immunotherapy in 89% of patients.¹⁰ Patients with predominantly sensory or sensorimotor demyelinating neuropathy have elevated antibodies to cross-reactive glycolipid sulfoglucuronyl paragloboside (SGPG) in addition to anti-MAG antibodies.¹¹ Testing for anti-MAG antibodies is important to identify patients who may be candidates for immunomodulatory treatment.⁴

Autoimmune nodopathy (CIDP-like) is a syndrome that was previously considered a type of CIDP but differs both clinically (due to the additional presence of ataxia and tremor) and in terms of pathogenesis. In contrast to CIDP, the absence of significant inflammatory infiltrate suggests that autoantibodies directly target and disrupt the interaction of cell-adhesion molecules (CAMs) at myelinated paranodes or at the nodes of Ranvier.¹² The most common autoantibody is directed against CAM neurofascin 155 (NF155), which is found on myelin surfaces and binds to a complex of 2 proteins (ie, contactin 1 [CNTN1] and contactin associated protein 1 [CASPR1]) at the paranode. Patients with pan-NF-autoimmune nodopathy have autoantibodies to NF186 or both NF186 and NF155, although this is less common than NF155 alone. Testing for these autoantibodies can help distinguish autoimmune nodopathy from CIDP; unlike CIDP, autoimmune nodopathy is unlikely to respond to IVIg therapies and may need alternative therapies, such as rituximab.¹³

Chronic ataxic neuropathy with anti-disialosyl antibodies (CANDA) is an IgM-mediated neuropathy that presents in some patients as a syndrome characterized by chronic ataxic neuropathy, ophthalmoplegia, M-protein, agglutinins, and disialosyl antibodies (CANOMAD syndrome). A positive GD1b test is important in the diagnosis of CANDA/CANOMAD, given the broad differential diagnosis for chronic sensory ataxic neuropathies that includes toxic, metabolic, or mitochondrial disorders or vitamin deficiencies.⁴

Multifocal motor neuropathy (MMN) is the most common chronic pure motor autoimmune neuropathy. Patients with MMN present with asymmetric and distal weakness of the limbs that usually begins with the arms. Patients with MMN respond well to IVIg therapy. Confirmatory testing for GM1 IgM antibodies, which are detected in about 50% of patients, is important to help distinguish MMN from other untreatable lower motor neuron syndromes such as amyotrophic lateral sclerosis.⁴

Guidelines for testing

Laboratory testing plays an important role in identifying the underlying etiologies of acute and chronic peripheral neuropathies, which is essential for guiding some forms of treatment. The European Academy of Neurology/Peripheral Nerve Society guideline task force recommends antibody testing for peripheral neuropathies including MFS and CIDP.^13,14 While testing is not advised for most patients with sensory-motor GBS or for the purpose of diagnosing specific variants (eg, AIDP, AMAN, AMSAN), antibody testing can be helpful if there is diagnostic uncertainty or in the evaluation of idiopathic peripheral neuropathy, which occurs in 25% to 46% of cases.^1,14

The selection of appropriate laboratory tests depends on the clinical presentation and suspected etiology. For patients presenting with "garden variety" distal symmetric polyneuropathy, a tiered approach starting with high-yield sensory (test code 15977), motor (test code 90137), or sensory-motor screening (test code 90136) panels potentially provide a faster diagnosis than individual tests; these panels include detection of autoantibodies associated with systemic autoimmune disease for differential diagnosis of primary peripheral neuropathy vs peripheral neuropathy secondary to disease (Table 3). Testing for peripheral neuropathy secondary to paraneoplastic neurological syndromes (test code 94604) can also be used to monitor response to therapy.

Panels for primary peripheral neuropathy can be used in the diagnosis of motor neuropathies (test code 90131), or when patients present with sensory (test code 90124) or sensory-motor (test code 90129) neuropathies that may overlap with suspected MFS. Testing for MFS is available through panel (test 90128) and individual confirmatory antibody testing (test code 34144).

For other atypical clinical phenotypes (eg, rapid progression, motor-predominant symptoms, or asymmetry), more extensive testing may be required.¹⁵ Such testing may identify specific antibodies associated with autoimmune neuropathies (eg, anti-MAG [test codes 37438, 37078], anti-GM1 [test codes 37093, 18951], or nodal/paranodal antibodies [test code 18702]).

Glycoconjugate antigens have been identified as putative targets. IgG glycoconjugate autoantibodies are generally associated with acute onset, and IgM autoantibodies are associated with chronic disease.⁴ Testing may identify these antibodies, which target both glycoproteins (ie, MAG) and glycolipids (asialo-GM-1 [test codes 39462, 38836], GD1a [test codes 38916, 38964], GD1b [test codes 39461, 37439], GM-1 [test codes 37093, 18951], and GQ1b [test code 34144]).