What are the causes and classifications of polyneuropathy?

Causes and Classification of Polyneuropathy

Polyneuropathy is a diffuse, symmetrical disorder of peripheral nerves characterized by distal, symmetric sensory or sensorimotor deficits that typically begin in the toes and feet, progressing proximally in a length-dependent pattern. 1

Clinical Presentation

• Symptoms typically begin symmetrically in the toes and feet, later progressing to fingertips as the condition advances 2
• Physical examination reveals distal sensory loss, reduced or absent reflexes, and sometimes distal muscle weakness 2
• Gait may be wide-based and unsteady due to proprioceptive sensory loss 2
• Autonomic symptoms may include orthostatic hypotension, alternating diarrhea and constipation, urinary retention, and sexual dysfunction 2

Classification by Etiology

1. Metabolic/Endocrine Causes

• Diabetes mellitus - most common cause of polyneuropathy in Europe and North America 3
• Pre-diabetes (impaired glucose tolerance) 2
• Uremic neuropathy 4
• Vitamin deficiencies (particularly B12 with abnormal methylmalonic acid levels) 2

2. Inflammatory/Immune-Mediated

• Guillain-Barré syndrome - acute inflammatory demyelinating polyneuropathy 5, 4
• Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) 5
• Vasculitic neuropathies 4
• Neuroborreliosis 4

3. Toxic/Drug-Induced

• Alcohol-associated polyneuropathy (prevalence 22-66% among persons with chronic alcoholism) 3
• Chemotherapy-induced neuropathies (CIN) - prevalence often 30-40% 3
• Other toxic exposures 3

4. Hereditary

• Charcot-Marie-Tooth disease (CMT) - prevalence approximately 1:2,500 people 2
• CMT1A (PMP22 gene duplication) accounts for about 70% of demyelinating CMT cases 2
• Other genetic neuropathies 2

5. Amyloid-Related

• AL amyloidosis (17-35% develop polyneuropathy) 2
• ATTRv amyloidosis (variant-dependent, up to 80% with Val30Met variant) 2
• ATTRwt (approximately 30% may have polyneuropathy) 2

6. Idiopathic

• About 20-25% of chronic polyneuropathies have no identifiable cause 5, 6

Classification by Pathophysiology

1. Axonal Polyneuropathies

• Most common pattern (36.1% in one study) 6
• Greater etiological heterogeneity 6
• Predominance of idiopathic and multifactorial causes 6
• Characterized by marginal slowing of nerve conduction, small compound muscle or sensory action potential, and denervation on EMG 7

2. Demyelinating Polyneuropathies

• Characterized by prolonged terminal latency, slowing of nerve conduction velocity, dispersion and conduction block 7
• Uniform demyelinating features suggest hereditary causes 7
• Differences between nerves and segments of the same nerve favor acquired demyelination 7

3. Mixed "Demyelinating and Axonal" Polyneuropathies

• Second most common pattern (27.9% in one study) 6
• Predominantly hereditary and inflammatory causes 6

Classification by Fiber Type Involvement

1. Large Fiber Polyneuropathy

• Manifests with loss of joint position and vibration sense, sensory ataxia 7
• Detectable on conventional nerve conduction studies 1, 8

2. Small Fiber Polyneuropathy

• Presents with prominent pain and autonomic symptoms, minimal motor findings 1
• Burning pain affecting the feet 1
• Normal conventional nerve conduction studies 8
• Requires skin biopsy showing decreased epidermal nerve fiber density for diagnosis 8

3. Autonomic Neuropathy

• Can occur as component of generalized polyneuropathy or as distinct entity 1
• Cardiovascular manifestations (orthostatic hypotension) 1
• Gastrointestinal manifestations (early satiety, nausea, vomiting, gastroparesis) 1
• Sudomotor dysfunction (abnormal sweating patterns) 1

Classification by Distribution Pattern

1. Distal Symmetric Polyneuropathy

• Most common pattern 1, 7
• Length-dependent, "stocking-glove" distribution 1

2. Asymmetric/Multifocal Neuropathies

• Asymmetric sensory/motor deficits affecting multiple individual nerves 1
• Includes mononeuritis multiplex, radiculopathies, and plexopathies 1
• Pain is often a prominent feature 1

Diagnostic Approach

• Nerve conduction studies and electromyography are essential to document large fiber involvement and distinguish between axonal and demyelinating patterns 2, 7
• Skin biopsy with intraepidermal nerve fiber density assessment for small fiber neuropathy 8
• Laboratory screening should include blood glucose, serum B12 with metabolites, and serum protein immunofixation electrophoresis 2
• Genetic testing for hereditary neuropathies when family history or clinical features suggest genetic cause 2

Clinical Implications

• Early diagnosis and treatment is crucial, particularly for treatable causes 8, 3
• Approximately 20% of patients with polyneuropathy remain undiagnosed despite thorough evaluation 7
• Patients with severe neuropathy of unidentified cause should be referred to specialized centers 3