Neuropathic Disease

Diagnosis

Indications for Testing

• Progressive weakness in both arms and legs and areflexia (may initially start in legs)

Laboratory Testing

• Initial testing – CBC, sedimentation rate (ESR), and electrolytes to rule out obvious infectious cause or metabolic derangement
  • Elevated ESR and systemic symptoms – consider vasculitis/connective tissue disease evaluation (anti-nuclear antibodies, antineutrophil cytoplasmic antibodies)
• Cerebrospinal fluid testing – glucose, protein, cell count and culture
  • Elevated protein in ~80% – typically <10 cells/mm³ (usually monocytes)
    • Normal WBC in this process is called cytoalbuminemic dissociation
  • Presence of >50 cells/mm³ with polymorphonuclear leukocyte predominance should prompt investigation of infectious etiologies
• Other testing
  • If patient presents with diarrheal illness – C. jejuni testing should be ordered
  • If patient presents with recent upper respiratory infection – consider mycoplasma, EBV, CMV
  • Other tests to consider – HIV, hepatitis A (HAV) and B (HBV)
  • If ocular symptoms consistent with myasthenia gravis – acetylcholine receptor testing
• Neuronal markers – based on clinical presentation
  • Titers do not correlate with disease activity in paraneoplastic syndromes
  • Most useful antibodies are GQ1b, GM1, GD1a, GD1b

Histology

• Nerve biopsy

Imaging Studies

• Perform MRI/CT if any question of structural lesion

Other Testing

• Nerve conduction study – confirmatory in most patients
  • Conduction block, prolonged distal latencies, delayed F-waves, reduction in maximum motor conduction velocity

Differential Diagnosis

• Disorders of the central nervous system
  • Brainstem stroke
  • Brainstem encephalitis
  • Acute polio-like syndrome
    • Viral illness – enterovirus (polio), rabies, West Nile virus
  • Acute myelopathy
    • Acute transverse myelitis
    • Space-occupying lesions
    • Cord compression
  • Brain tumor
  • Multiple sclerosis
• Peripheral neuropathy (axonal)
  • Metabolic 
    • Diabetes mellitus
    • Uremia
    • Toxin ingestion
      • Snake/spider venoms
      • Metals – arsenic, lead, gold (soluble), thallium
      • Alcohol
    • Acute intermittent porphyria
    • Vitamin deficiency
      • B₁₂
      • B₁
    • Hypothyroidism
  • Autoimmune diseases   
    • Rheumatoid arthritis
    • Systemic lupus erythematosus 
    • Sjögren syndrome
    • Mixed connective tissue disease
  • Vasculitis
    • Nonsystemic vasculitic neuropathy
    • Microscopic polyangiitis
    • Polyarteritis nodosa
    • Churg-Strauss syndrome
    • Wegener granulomatosis
  • Critical illness neuropathy
  • Malignancy
    • Lymphoma (B-cell, T/NK-cell)
    • Plasma cell dyscrasias (paraproteinemias)
    • Chronic lymphocytic leukemia
    • Amyloidosis
    • Cold agglutinin disease
    • Paraneoplastic syndrome
  • Chronic inflammatory demyelinating polyneuropathy
  • Granulomatous disease – sarcoidosis, M. tuberculosis
  • Infectious neuropathy
    • M. leprae (leprosy)
    • Hepatitis C (HCV)
    • HIV
    • Tick-borne disease
      • Borrelia burgdorferi
      • Babesia microti
      • Rickettsia rickettsii
      • Rickettsia typhi
    • C. diphtheria
    • Brucella spp
    • T. pallidum
    • Trypanosoma cruzi
  • Multiple sclerosis
  • Post-vaccination neuropathy
  • Amyotrophic lateral sclerosis
• Hereditary
  • Charcot Marie tooth disease
  • Hereditary sensory neuropathy
• Disorders of neuromuscular transmission
  • Industrial toxicity
  • Myasthenia gravis
  • Eaton-Lambert syndrome
  • Neuromuscular-blocking drugs
• Disorders of muscle
  • Electrolyte abnormalities
    • Severe hypocalcemia
    • Hypophosphatemia
    • Hypokalemia
    • Hypermagnesemia/hypomagnesemia
  • Inflammatory myopathy
    • Polymyositis
    • Dermatomyositis
  • Acute rhabdomyolysis
  • Infection – Trichinella spiralis
  • Periodic paralyses
  • Acid maltase deficiency
  • Drugs – steroids
  • Eosinophilic muscle diseases

Monitoring

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 (Non-paraneoplastic)

  Neuronal Markers (Non-paraneoplastic)
  Neuronal Marker*	Associated Clinical Syndrome(s)
  GM1	Motor neuropathy – GBS, MMN, multiple sclerosis (MS)
  GM2	Motor neuropathy – GBS variants, MMN, MS Demyelinating sensory neuropathy
  GD1a	Motor neuropathy – GBS-like syndrome (motor & axonal), MMN Demyelinating motor neuropathy (with IgM M-protein) Demyelinating sensory-motor neuropathy
  GD1b	Sensory-motor neuropathy (ataxic) Cranial nerve neuropathy
  GQ1b	Sensory-motor neuropathy (ataxic), brainstem or cranial nerve Miller-Fisher syndrome, ophthalmoplegia
  Myelin-associated glycoprotein (MAG) & Sulfate-3-glucuronyl paragloboside (SGPG)	Chronic demyelinating sensory-motor polyneuropathy (both MAG and SGPG) Axonal sensory-motor neuropathy (SGPG only) Multifocal motor neuropathy with conduction block (SGPG only) IgM-related neuropathy
  Sulfatide	Sensory neuropathy (axonal, demyelinating) Gait disorder, autoantibody, late-age onset polyneuropathy
  * In the presence of appropriate clinical symptoms, these markers may suggest a diagnosis and may be helpful when used in conjunction with a clinician's diagnostic impression

• Neuronal Markers (Paraneoplastic)

  Neuronal Markers (Paraneoplastic)
  Neuronal Marker*	Associated Clinical Syndrome(s)
  Hu (ANNA-1)	Paraneoplastic neurological disorders Sensory neuropathy associated with small-cell lung carcinoma Paraneoplastic encephalomyelitis, cerebellar disorders, gastrointestinal dysfunction
  Ri (ANNA-2)	Paraneoplastic neurological disorders Sensory neuropathy associated with neuroblastoma (children) and fallopian or breast cancer (adults) Paraneoplastic opsoclonus myoclonus ataxia
  Yo (PCA-1)	Paraneoplastic neurological disorders Sensory neuropathy associated with ovarian and breast carcinomas Paraneoplastic cerebellar degeneration
  Amphiphysin	Paraneoplastic neurological disorders Sensory neuropathy associated with breast carcinomas, stiff person syndrome (stiff man syndrome)
  * In the presence of appropriate clinical symptoms, these markers may suggest a diagnosis and may be helpful when used in conjunction with a clinician's diagnostic impression

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
    • Epidemiology
      • Incidence – 0.6-4.0/100,000 worldwide
        • Fisher syndrome – 0.1/100,000
        • Pediatric (<18 years) – 0.5-1.5/100,000
      • Age – peaks in 20s
        • Incidence increases with age
      • Sex – M>F, 1.5:1
      • Infections linked to GBS  
        • Campylobacter jejuni
        • Epstein-Barr virus (EBV)
        • Cytomegalovirus (CMV)
        • Mycoplasma pneumoniae
        • Human immunodeficiency virus (HIV)
  • 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
  • Associated with malignancies – refer to paraneoplastic neurological syndromes
    • Syndromes present in a variety of ways
• 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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Motor Neuropathy Panel 0051225 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Quantitative Nephelometry/Quantitative Capillary Electrophoresis/Qualitative Immunofixation Electrophoresis
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	PCCA/ANNA antibodies screened by IFA; if IFA screen is positive at 1:10, then a titer (PCCA or ANNA) and immunoblot will be added
Neuronal Cell Antibodies, CSF 0098726 Method: Enzyme-Linked Immunosorbent Assay
Neuronal Cell Antibodies, Serum 0099465 Method: Enzyme Immunoassay
Sulfate-3-Glucuronyl Paragloboside (SGPG) Antibody, IgM 0051284 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay	Use as general screen for patients with neuropathy Aid in monitoring changes in antibody levels before, during, and after treatment May be clinically helpful in conjunction with other tests and clinical symptoms for evaluating treatment in patients with certain neurological disorders (eg, lower motor neuron syndrome, ALS, MS, other multifocal neuropathies, SLE with central nervous system involvement)
Myelin Associated Glycoprotein (MAG) Antibody, IgM 0051285 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay	Aid in the diagnosis of neuropathy involving nerve demyelination Aid in evaluating patient for neurological disorders (eg, lower motor neuron syndrome, ALS, MS, other multifocal neuropathies, SLE with central nervous system involvement) Aid in monitoring changes in antibody levels before, during and after treatment
Ganglioside (GM1) Antibodies, IgG and IgM 0050591 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay	Use as general screen for patients with neuropathy Aid in monitoring changes in antibody levels before, during and after treatment  Aid in evaluating patient for neurological disorders (eg, lower motor neuron syndrome, ALS, MS, other multifocal neuropathies, SLE with central nervous system involvement)
Ganglioside (GM1, GD1b, and GQ1b) Antibodies, IgG and IgM 2004998 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay	Use as general screen for patients with neuropathy Aid in monitoring changes in antibody levels before, during and after treatment Aid in evaluating patient for neurological disorders (eg, lower motor neuron syndrome, ALS, MS, other multifocal neuropathies, SLE with central nervous system involvement)
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	Use as general screen for neuropathy Components include Purkinje cell/neuronal nuclear IgG screen; neuronal nuclear antibody (ANNA) IFA titer, IgG; Purkinje cell antibody, titer; neuronal nuclear (Hu, Ri, Yo, and amphiphysin) antibodies IgG by immunoblot; myelin associated glycoprotein (MAG) antibody, IgM; sulfate-3-glucuronyl paragloboside (SGPG) antibody, IgM; Asialo-GM1 antibodies, IgG/IgM; GM1 antibodies, IgG/IgM; GD1a antibodies, IgG/IgM; GD1b antibodies, IgG/IgM; GQ1b antibodies, IgG/IgM PCCA/ANNA antibodies are screened by IFA; if IFA screen is positive at 1:10 or greater, then a titer (PCCA or ANNA) and immunoblot will be added