Autoimmune Neuropathies - Neuropathic Disease

Autoimmune neuropathies present with a broad range of symptoms, including subacute progression, asymmetric or multifocal deficits, and selective involvement of motor, sensory, or autonomic nerves.  The overlap of symptoms among syndromes often makes diagnosis difficult. Presumptive diagnosis is based on patient history and clinical presentation. Initial laboratory testing aims to rule out underlying etiologies, including potential infection, metabolic disturbances, and brain tumors; if nothing is uncovered, further evaluation, including imaging, nerve conduction studies, and cerebrospinal fluid (CSF) analysis may be required.  Autoimmune neuropathies can also arise as paraneoplastic disorders in the setting of cancer; refer to the Paraneoplastic Neurological Syndromes and Associated Disorders ARUP Consult topic for more information. The detection of an autoantibody in the right clinical setting provides some evidence that the peripheral nerve disturbance is immune mediated and may direct treatment, but antibody testing cannot be used as the sole diagnostic tool. 

Quick Answers for Clinicians

What is the role of antibody testing in suspected autoimmune neuropathies?

Antibody testing is not part of accepted diagnostic criteria or management strategies for autoimmune neuropathies. In most cases, such as in Guillain-Barre syndrome (GBS), the initial diagnosis is based on clinical presentation and is established if cerebrospinal fluid (CSF) and electrodiagnostic studies (eg, nerve conduction studies) show abnormalities.  Antibody testing may help to clarify the diagnosis, but cannot be used as the sole diagnostic tool.

Are certain biomarkers associated with specific neuropathies?

Some antibodies show statistically significant associations with specific neuropathic syndromes. For example, antimyelin-associated glycoprotein (anti-MAG) antibodies are often present in patients with predominant sensory symptoms, and anti-GM1 antibodies are present in patients with predominant motor symptoms. Refer to the Nonparaneoplastic Markers and Paraneoplastic Markers tables for more examples.

Do antibody titers correlate with the level of disease activity?

Most antibody titers do not correlate with the level of disease activity in autoimmune neuropathies.

Should all patients with monoclonal gammopathy of undetermined significance be tested for autoimmune neuropathy?

Monoclonal gammopathy of undetermined significance (MGUS) has a prevalence of 3-4% among those older than 50 years, and the presence of an M protein does not automatically indicate a causal relationship to the neuropathy.  Additional investigation is required to differentiate monoclonal gammopathy-associated peripheral neuropathy from specific plasma cell disorders (eg, immunoglobulin light chain amyloidosis, POEMS [polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes] syndrome) that are known to have a definite causal relationship. 

Which differential diagnoses should be considered when investigating autoimmune neuropathies?

Frequent differential diagnoses include infections (eg, West Nile virus, enterovirus, and poliovirus), myasthenia gravis, and other autoimmune diseases (eg, rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, and mixed connective tissue disease).

Indications for Testing

Autoantibody testing can be considered in individuals presenting with severe or rapidly progressive muscle weakness and sensory symptoms and no known underlying infection or etiology.

Classification

Autoimmune neuropathies are categorized as acute or chronic. Acute neuropathies include Guillain-Barre syndrome (GBS) and its variants. Chronic autoimmune neuropathies are described in relation to classic chronic inflammatory demyelinating polyneuropathy (CIDP). Neuropathies are further distinguished by their dominant presentation: motor, sensory, or a combination of both. Test choice depends on both the clinical manifestation and the risk of malignancy.

Nonparaneoplastic Markers
Autoantibody Examples of Associated Neuropathic Syndromes

GM1

MMN, ALS/MND, GBS, AMAN

GM2

GBS variants

GD1a

Axonal GBS

GD1b

Sensory peripheral neuropathy, MND, GBS

GQ1b

MFS, acute ophthalmoplegia, cerebellar ataxia

MAG/SGPG

Inflammatory (often demyelinating) neuropathy with IgM gammopathy, gait ataxia, hand tremor

Sulfatide

Chronic sensory peripheral neuropathy, GALOP syndrome

ALS, amyotrophic lateral sclerosis; AMAN, acute motor axonal neuropathy; GALOP syndrome, gait disorder, antibody, late-age onset polyneuropathy; IgM, immunoglobulin M; MAG, myelin-associated glycoprotein; MFS, Miller-Fisher syndrome; MMN, multifocal motor neuropathy; MND, motor neuron disease; SGPG, sulfate-3-glucuronyl paragloboside

Source: Vernino, 2007 

Paraneoplastic Markersa
Autoantibody Examples of Associated Neuropathic Syndromes Associated Malignancies

Hu (ANNA-1)

PN, limbic encephalitis, ataxia, sensory neuronopathy, autonomic and sensorimotor neuropathies, GI dysmotility

SCLC

CV2 (CRMP5)

PN, limbic encephalitis, ataxia, chorea, optic neuritis

SCLC, thymoma

Amphiphysin

Encephalomyelitis, neuropathy, stiff-person syndrome

Lung, breast

Ri (ANNA-2)

Ataxia, opsoclonus-myoclonus, neuropathy

Lung, breast

ANNA-3

Ataxia, limbic encephalitis, neuropathy

Lung, breast

N-type calcium channel antibodies

PN, other syndromes

Lung, breast

aRefer to the Paraneoplastic Neurological Syndromes topic for more information.

GI, gastrointestinal; PN, peripheral neuropathy; SCLC, small cell lung cancer

Source: Vernino, 2007 

ARUP Laboratory Tests

Panels for Suspected Malignancy

Evaluate for sensory neuropathy when malignancy other than plasma cell dyscrasia (PCD) is suspected

Components: Purkinje cell/neuronal nuclear IgG and titer; neuronal nuclear (Hu, Ri, Yo, Tr/DNER) IgG; neuronal nuclear antibody (ANNA) IgG titer; MAG IgM; and SGPG IgM

Evaluate combined motor/sensory neuropathy when malignancy other than PCD is suspected

Components: Purkinje cell/neuronal nuclear IgG and titer; neuronal nuclear (Hu, Ri, Yo, Tr/DNER) IgG; neuronal nuclear antibody (ANNA) IgG titer; MAG IgM; SGPG IgM; asialo-GM1, GM1, GD1a, GD1b IgG and IgM; GQ1b abs

Evaluate motor neuropathy when PCD or other malignancy is suspected

Method

Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Quantitative Nephelometry/Quantitative Capillary Electrophoresis/Qualitative Immunofixation Electrophoresis/Quantitative Spectrophotometry

Components: MAG IgM; SGPG IgM; asialo-GM1, GM1, GD1a, GD1b IgG and IgM; GQ1b abs; serum protein electrophoresis (SPEP); albumin, alpha-1 and 2 globulins; beta globulins; gamma globulins; immunoglobulins A, G, and M

Evaluate combined motor/sensory neuropathy when PCD or other malignancy is suspected

Components: Purkinje cell/neuronal nuclear IgG and titer; neuronal nuclear (Hu, Ri, Yo, Tr/DNER) IgG; neuronal nuclear antibody (ANNA) IgG titer; MAG IgM; SGPG IgM; asialo-GM1, GM1, GD1a, GD1b IgG and IgM; GQ1b abs; SPEP; albumin, alpha-1 and 2 globulins; beta globulins; gamma globulins; immunoglobulins A, G, and M

Aids in the diagnosis of paraneoplastic syndromes associated with ANNA-1 (Hu), ANNA-2 (Ri), PCCA-1 (Yo), amphiphysin, SOX1 antibody, and CV2.1 antibodies

Components: Purkinje cell/neuronal nuclear IgG and titer; neuronal nuclear (Hu, Ri, Yo, Tr/DNER) IgG; neuronal nuclear antibody (ANNA) IgG titer; CV2.1 antibody and titers; amphiphysin antibody; SOX1 antibody, IgG

Other Tests (Single and Combined Antibodies)

Medical Experts

Contributor

Klonoski

 

Joshua M. Klonoski, MD, PhD
Former Resident Physician, Department of Pathology, University of Utah
Former Assistant Medical Director of Informatics and Content Editor at ARUP Laboratories
Contributor