Autoimmune Neuropathies - Neuropathic Disease

Diagnosis

Indications for Testing

  • Progressive extremity weakness, sensory symptoms

Laboratory Testing

  • Initial testing to rule out more common disease
    • CBC
    • Sedimentation rate (ESR) and C-reactive protein (CRP)
    • Electrolytes to rule out obvious infectious cause or metabolic derangement
  • Cerebrospinal fluid testing – glucose, protein, cell count and culture
    • Protein – elevated in ~80%
    • WBC is usually normal
      • Typically <10 cells/mm3 – usually monocytes  
      • Presence of >50 cells/mm3 with polymorphonuclear leukocyte predominance should prompt investigation of infectious etiologies
  • Other testing (based on individual presentation)
  • Neuronal markers – consider if above testing is normal
    • Test choice depends on whether the presentation is
      • Sensory only – most common
      • Sensorimotor
      • Motor predominant
    • Test choice also depends on risk of underlying malignancy

Histology

  • Nerve biopsy

Imaging Studies

  • Perform MRI/CT if any question of structural lesion

Other Testing

  • Nerve conduction study – confirmatory of motor or sensory pattern
    • Conduction block, prolonged distal latencies, delayed F-waves, reduction in maximum motor conduction velocity

Differential Diagnosis

Monitoring

  • Antibody titers do not correlate with disease level activity in paraneoplastic syndromes
    • Do not use titers for monitoring treatment

Clinical Background

Autoimmune neuropathies can be acute or chronic and can involve axonal degeneration and demyelination.

Autoimmune neuropathy classifications

  • Monoclonal gammopathy-associated neuropathy
  • Polyclonal inflammatory polyneuropathy
  • Guillain-Barré syndrome (GBS)
  • Chronic inflammatory demyelinating polyneuropathy
  • Multifocal motor neuropathy (MMN)
  • Paraneoplastic neuropathy

Classification

  • Neuronal Markers (Nonparaneoplastic)

    Nonparaneoplastic Markers

    Autoantibody test

    Associated neuropathic syndromes

    GM1

    Motor – GBS, MMN, multiple sclerosis (MS)

    GM2

    Motor – GBS-variants, MMN, MS

    Sensory – demyelinating sensory neuropathy

    GD1a

    Motor – GBS-like syndrome (acute motor and axonal), MMN, demyelinating motor neuropathy (with IgM M-protein)

    Combined – demyelinating sensory-motor neuropathy

    GD1b

    Motor – cranial nerve neuropathy

    Combined – sensory-motor neuropathy (ataxic)

    GQ1b

    Motor – Miller-Fisher syndrome, GBS with ataxia or ophthalmoplegia

    Combined – sensory-motor neuropathy (ataxic)

    Myelin-associated glycoprotein (MAG) and sulfate-3-glucuronyl paragloboside (SGPG)

    Motor – multifocal motor neuropathy with conduction block (SGPG only); IgM-related neuropathy

    Combined – chronic demyelinating sensory-motor polyneuropathy (MAG and SGPG); axonal sensory-motor neuropathy (SGPG only)

    Sulfatide

    Sensory – axonal, demyelinating

    Combined – GALOP syndrome (gait disorder, antibody, late-age onset polyneuropathy)

    Vernino S 2007; Willison HJ 2011)

    Neuronal Markers (Paraneoplastic)

    Paraneoplastic Markers

    Neuronal Marker

    Associated Neuropathic Syndromes

    Associated Tumors

    Hu (ANNA-1)

    Sensory neuronopathy, encephalomyelitis, limbic encephalitis, opsoclonus-myoclonus, subacute cerebellar degeneration, autonomic neuropathy, enteric neuropathy (GI dysmotility)

    Small-cell lung carcinoma (SCLC), neuroblastoma

    Ri (ANNA-2)

    Opsoclonus-myoclonus, brainstem encephalitis, cerebellar degeneration

    SCLC, breast, ovary

    Yo (PCA-1)

    Subacute cerebellar degeneration, occasional GI dysmotility, chorea

    Ovary, breast

Pathophysiology

  • Antibodies against specific glycolipids or glycoproteins, such as anti-GM1 and anti-myelin associated glycoprotein, are associated with inflammatory and often demyelinating neuropathies
  • Multiple antibodies are associated with neuropathic disease
    • These antibodies interfere with processes of myelination, myelin maintenance or axon-Schwann cell interaction
  • Paraneoplastic antibodies are directed against intracellular antigens in the nucleus or cytoplasm of neurons
    • Main effect is cell-mediated damage to neurons and axons
    • No specific antibody has been shown to be sensitive enough for use as a diagnostic tool
    • Paraneoplastic neuronal markers frequently precede a diagnosis of cancer

Clinical Presentation

  • Non-paraneoplastic neuropathies
    • Most common presentation is GBS
    • Subtypes
      • Acute inflammatory demyelinating polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN), acute motor sensory axonal neuropathy (AMSAN), acute sensory neuropathy, Fisher syndrome
        • AIDP is the most frequent subtype of GBS in North America and Europe (associated with GM1, GM2, GD1a antibodies)
          • May cause acute sensory ataxia or acute pandysautonomia
        • AMAN and AMSAN are associated with the ganglioside antibodies (GM1, GM1b, GD1a)
        • Fisher variant of GBS is associated with GQ1b antibodies
          • Characterized by extraocular symptoms, ataxia, hyporeflexia and ophthalmoplegia
        • AMAN and Fisher variants are uncommon in children
    • Other GBS variants
      • Bickerstaff brainstem encephalitis
        • Usually a post-viral inflammatory illness with progressive ophthalmoplegia, ataxia and disturbance of consciousness (or hyperreflexia)
        • May overlap with Fisher syndrome and GBS
      • Chronic form of Guillain-Barré inflammatory demyelinating polyneuropathy
        • Shares features with GBS but has a much poorer prognosis for full recovery
    • Symptoms
      • Infection (eg, upper respiratory infection, gastroenteritis) during the 6 weeks prior to presentation in ~33% of patients
      • Acute limb paralysis, weakness (ascending and often asymmetric), numbness and other motor disturbances
      • Sensory symptoms are a minor feature
      • Axonal form – more rapid onset and more severe respiratory symptoms
      • AMAN – purely motor form
      • Fisher syndrome – includes ophthalmoplegia, optic neuritis, ptosis or lid retraction, ataxia, areflexia
  • Paraneoplastic polyneuropathies
  • Other autoimmune neuropathies – frequently present with slow-onset muscle weakness

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Sensory Neuropathy Antibody Panel with Reflex to Titer and Neuronal Immunoblot 2007965
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody/Qualitative Immunoblot

Aid in diagnosis for sensory neuropathy with no suspicion for plasma cell dyscrasia, but suspicion present for other malignancy

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

PCCA/ANNA antibodies are screened by IFA; if IFA screen is positive at 1:10, then a specific titer (PCCA or ANNA) and immunoblot will be added

Some antibodies may be associated with more than one disease and/or cancer

 
Motor and Sensory Neuropathy Evaluation with Reflex to Titer and Neuronal Immunoblot 2007966
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody/Qualitative Immunoblot

Aid in diagnosis for combined motor/sensory neuropathy with no suspicion for plasma cell dyscrasia, but suspicion present for other malignancy

Components include Purkinje cell/neuronal nuclear IgG; Purkinje cell antibody titer; neuronal nuclear (Hu, Ri, and Yo) IgG; neuronal nuclear antibody (ANNA) IgG titer; MAG IgM; SGPG IgM; asialo-GM1 IgG and IgM; IgG and IgM for GM1, GD1a, and GD1b; GQ1b antibodies

PCCA/ANNA antibodies are screened by IFA; if IFA screen is positive at ≥1:10, then a titer (PCCA or ANNA) and immunoblot will be added

Some antibodies may be associated with more than one disease and/or cancer

 
Motor and Sensory Neuropathy Evaluation with Immunofixation Electrophoresis and Reflex to Titer and Neuronal Immunoblot 2007967
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody/Qualitative Immunoblot/Quantitative Nephelometry/Quantitative Capillary Electrophoresis/Qualitative Immunofixation Electrophoresis

Aid in diagnosis for combined motor/sensory neuropathy with suspicion for plasma cell dyscrasia or suspicion for other malignancy

Components include Purkinje cell/neuronal nuclear IgG; Purkinje cell antibody titer; neuronal nuclear (Hu, Ri, and Yo) IgG; neuronal nuclear antibody (ANNA) IgG titer; MAG IgM; SGPG IgM; asialo-GM1 IgG and IgM; IgG and IgM for GM1, GD1a, GD1b; GQ1b antibodies; total protein electrophoresis, serum; albumin; alpha-1 and alpha-2 globulins; beta globulins; gamma globulins; immunoglobulins A, G, and M

PCCA/ANNA antibodies are screened by IFA; if IFA screen is positive at ≥1:10, then a titer (PCCA or ANNA) and immunoblot will be added

Some antibodies may be associated with more than one disease and/or cancer

 
Motor Neuropathy Panel 0051225
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Quantitative Nephelometry/Quantitative Capillary Electrophoresis/Qualitative Immunofixation Electrophoresis

Aid in diagnosis for motor neuropathy with suspicion for plasma cell dyscrasia

Components include MAG IgM; SGPG IgM; asialo-GM1 IgG and IgM; IgG and IgM for GM1, GD1a, GD1b; GQ1b antibodies; total protein electrophoresis, serum; albumin; alpha-1 and alpha-2 globulins; beta globulins; gamma globulins; immunoglobulins A, G, and M

Some antibodies may be associated with more than one disease and/or cancer

 
Myelin Associated Glycoprotein (MAG) Antibodies, IgM and Sulfate-3-Glucuronyl Paragloboside (SGPG) Antibodies, IgM 2004412
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Non-panel testing for autoimmune neuropathies

   
Ganglioside (Asialo-GM1, GM1, GM2, GD1a, GD1b, and GQ1b) Antibodies 0051033
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Non-panel testing for autoimmune neuropathies

Role of isolated anti-GM2 antibodies unknown

Test by itself not diagnostic; should be used in conjunction with other clinical parameters to confirm disease

 
Amphiphysin Antibody, IgG 2008893
Method: Qualitative Immunoblot

Consider ordering in individuals with stiff-person syndrome, paraneoplastic encephalomyelitis (PEM), and sensory neuronopathy (SN)

May aid in diagnosis of occult tumor, recurrence of tumor, or second tumor

   
Sulfate-3-Glucuronyl Paragloboside (SGPG) Antibody, IgM 0051284
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Non-panel testing for autoimmune neuropathies    
Myelin Associated Glycoprotein (MAG) Antibody, IgM 0051285
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Non-panel testing for autoimmune neuropathies    
Ganglioside (GM1) Antibodies, IgG and IgM 0050591
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Non-panel testing for autoimmune neuropathies

   
Ganglioside (GM1, GD1b, and GQ1b) Antibodies, IgG and IgM 2004998
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Non-panel testing for autoimmune neuropathies

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Use to rule out obvious infectious cause or metabolic derangement 

Sedimentation Rate, Westergren (ESR) 0040325
Method: Visual Identification

Use to rule out obvious infectious cause or metabolic derangement

Electrolyte Panel 0020410
Method: Quantitative Ion-Selective Electrode/Enzymatic

Use to rule out obvious infectious cause or metabolic derangement

Glucose, CSF 0020515
Method: Enzymatic

Use to rule out meningitis

Protein, Total, CSF 0020514
Method: Reflectance Spectrophotometry

Use to rule out meningitis

Cell Count, CSF 0095018
Method: Cell Count/Differential

Use to rule out meningitis

Cerebrospinal Fluid (CSF) Culture and Gram Stain 0060106
Method: Stain/Culture/Identification

Use to rule out meningitis

Anti-Neutrophil Cytoplasmic Antibody with Reflex to Titer and MPO/PR-3 Antibodies 2002068
Method: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay

Differentially diagnose systemic vasculitic syndromes such as

  • Granulomatosis with polyangiitis (GPA)
  • Microscopic polyangiitis (MPA)
  • Eosinophilic granulomatosis with polyangiitis (EGPA)
  • Necrotizing and crescentic glomerulonephritis
  • Autoimmune hepatitis
  • Primary sclerosing cholangitis

If screen is positive, titer and MPO/PR-3 antibodies testing will be added to aid in antibody determination

Campylobacter jejuni Antibody, IgG 0098841
Method: Semi-Quantitative Indirect Fluorescent Antibody

Use if patient presents with diarrheal illness

Neuronal Cell Antibodies, CSF 0098726
Method: Enzyme-Linked Immunosorbent Assay
Neuronal Cell Antibodies Quantitative, Serum 0099465
Method: Quantitative Enzyme Immunoassay
Mycoplasma pneumoniae by PCR 0060256
Method: Qualitative Polymerase Chain Reaction

Order if patient presents with recent upper respiratory infection

Distinguish M. pneumoniae from other viruses and atypical pathogens (Chlamydophila pneumoniae, Bordetella pertussis and Legionella)

Heterophile Antibody (Infectious Mononucleosis) by Latex Agglutination, Qualitative 0050385
Method: Qualitative Latex Agglutination

Order if patient presents with recent upper respiratory infection

Initial serologic test to detect acute Epstein-Barr virus infectious mononucleosis

Cytomegalovirus Rapid Culture 0065004
Method: Cell Culture/Immunofluorescence

Order if patient presents with recent upper respiratory infection

Gold standard test for tissue

High sensitivity and specificity

Human Immunodeficiency Virus Types 1 and 2 (HIV-1, HIV-2) Antibodies by CIA with Reflex to HIV-1 Antibody Confirmation by Western Blot 2005377
Method: Qualitative Chemiluminescent Immunoassay/Qualitative Western Blot

Screen for presence of HIV infection

Screen for antibodies against HIV-1 and HIV-2

Hepatitis Panel, Acute with Reflex to HBsAg Confirmation 0020457
Method: Qualitative Chemiluminescent Immunoassay

Order when patient has had clinical acute hepatitis of unknown origin for less than 6 months

Panel includes HAV IgM, HBV core antibody IgM, HBV surface antigen, HCV antibody

Positive HAV IgM shows current or recent infection with 98% sensitivity and specificity

Acetylcholine Receptor Blocking Antibody 0099580
Method: Semi-Quantitative Flow Cytometry

Use to rule out myasthenia gravis if ocular symptoms consistent with MG are present