Classification of Polyneuropathy
Polyneuropathy is primarily classified based on pathophysiology (demyelinating vs axonal), inheritance pattern, and etiology, with electrodiagnostic studies and genetic testing being essential for accurate classification. 1
Primary Classification Methods
Pathophysiological Classification
- Demyelinating polyneuropathies: Characterized by damage to the myelin sheath surrounding nerve fibers, resulting in slowed nerve conduction velocities on electrodiagnostic testing 1
- Axonal polyneuropathies: Characterized by damage to the nerve axon itself, with relatively preserved conduction velocities but reduced amplitude on nerve conduction studies 1
Inheritance Pattern Classification
- Autosomal dominant: Most common pattern in hereditary neuropathies 1
- Autosomal recessive: Less common inheritance pattern 1
- X-linked: Seen in conditions like CMTX (Cx32/GJB1 mutations) 1
Etiological Classification
- Hereditary polyneuropathies: Genetically determined, most commonly variants of Charcot-Marie-Tooth disease with a prevalence of approximately 1:2,500 people 1, 2
- Acquired polyneuropathies: Further classified as 3, 4:
- Inflammatory (e.g., Guillain-Barré syndrome, CIDP)
- Vascular (e.g., vasculitic neuropathies)
- Exotoxic (e.g., alcohol, chemotherapy-induced)
- Endotoxic-metabolic (e.g., diabetic neuropathy, uremic neuropathy)
Clinical Manifestation Classification
Based on Distribution
- Distal symmetric polyneuropathy (DSP): Most common presentation, with "glove and stocking" distribution 1, 2
- Asymmetric/multifocal neuropathies: Seen in vasculitic neuropathies and some inflammatory conditions 3
Based on Fiber Type Involvement
- Sensory predominant: Common in toxic, metabolic neuropathies 3, 5
- Motor predominant: Seen in some immune-mediated neuropathies 3
- Sensorimotor: Combined sensory and motor involvement 6
- Autonomic: Involving autonomic nerve fibers 3, 6
Diagnostic Approach to Classification
Electrodiagnostic Studies
- Essential for distinguishing between demyelinating and axonal polyneuropathies 1, 2
- Provides critical information to guide subsequent genetic testing in suspected hereditary cases 1
Genetic Testing
- Established as useful for accurate diagnosis and classification of hereditary polyneuropathies (Level A evidence) 1
- Should follow a tiered approach based on clinical phenotype, inheritance pattern, and electrodiagnostic features 1
- First-tier genetic testing should focus on the most common abnormalities 1:
- CMT1A duplication/HNPP deletion (70% of demyelinating CMT)
- Cx32 (GJB1) mutations (12% of all CMT)
- MFN2 mutations (33% of axonal CMT)
Laboratory Testing
- Helps classify acquired polyneuropathies by identifying underlying causes 1
- High-yield tests include blood glucose, serum B12 with metabolites, and serum protein immunofixation electrophoresis 1
Common Pitfalls in Classification
- Failure to perform electrodiagnostic studies: These are essential for proper classification and subsequent management 1, 2
- Overlooking hereditary causes in sporadic cases: Up to 30% of hereditary neuropathy mutations are de novo 1
- Premature attribution to common causes: Always consider alternative diagnoses even when common risk factors (e.g., diabetes) are present 4
- Incomplete genetic testing: Following the tiered approach to genetic testing is crucial for cost-effective diagnosis 1
Clinical Algorithm for Classification
- Determine if polyneuropathy is primarily demyelinating or axonal through electrodiagnostic studies 1
- Assess for family history and inheritance pattern (autosomal dominant, autosomal recessive, X-linked) 1
- For suspected hereditary neuropathies, follow the tiered genetic testing approach based on electrodiagnostic findings and inheritance pattern 1
- For suspected acquired neuropathies, perform targeted laboratory testing based on clinical presentation 1
- If no clear cause is identified after initial evaluation, consider referral to a specialized center for comprehensive assessment 4