What are the causes of axonal sensory neuropathy?

Causes of Axonal Sensory Neuropathy

Axonal sensory neuropathy results from a broad spectrum of etiologies, with chemotherapy agents, metabolic disorders (particularly diabetes and nutritional deficiencies), toxic exposures, hereditary conditions, and immune-mediated diseases being the most common culprits, while approximately 20-25% remain idiopathic despite thorough evaluation. 1

Chemotherapy-Induced Causes

Neurotoxic chemotherapy agents are among the most frequent causes of acquired axonal sensory neuropathy, presenting as a symmetric, distal, length-dependent "glove and stocking" distribution with predominantly sensory rather than motor symptoms. 2

• Platinum compounds, taxanes, vinca alkaloids, bortezomib, and thalidomide cause dose-dependent sensory axonal damage by targeting dorsal root ganglion cell bodies, leading to sensory neuronopathy (ganglionopathy) that may be irreversible. 2
• The incidence varies considerably by agent, with approximately 38% of patients treated with multiple neurotoxic agents developing chemotherapy-induced peripheral neuropathy (CIPN). 2
• Risk increases with cumulative dose, duration of exposure, and combination therapies. 2

Metabolic and Nutritional Causes

Vitamin B12 deficiency affects 2.2-8% of polyneuropathy patients and represents a critical reversible cause. 1 Even patients with low-normal B12 levels (5-10%) may have true deficiency when metabolites are elevated. 1

• Thiamine (B1), pyridoxine (B6), folate, and vitamin E deficiencies cause axonal sensory neuropathy, particularly in the setting of alcoholism, bariatric surgery, or anorexia. 1, 3
• Diabetes mellitus causes distal symmetric polyneuropathy affecting both sensory and motor fibers, though sensory involvement predominates. 1
• Hypothyroidism, chronic kidney disease, and mitochondrial disorders (including mitochondrial trifunctional protein deficiency) are established metabolic causes. 1, 4

Toxic and Drug-Induced Causes

Beyond chemotherapy, multiple toxins and medications cause axonal sensory neuropathy:

• Heavy metals: Lead and arsenic toxicity produce characteristic axonal damage. 1
• Alcohol abuse directly causes toxic neuropathy and predisposes to nutritional deficiencies. 2
• Concurrent neurotoxic medications should be identified and discontinued when possible. 2

Immune-Mediated and Inflammatory Causes

Chronic inflammatory demyelinating polyneuropathy (CIDP) commonly presents with predominant sensory axonal neuropathy, though it classically causes demyelination. 5

• Guillain-Barré syndrome, vasculitic neuropathies, and sarcoidosis can manifest with axonal sensory features. 1
• Monoclonal gammopathies occur in approximately 10% of patients with polyneuropathy of unknown etiology, with IgG monoclonal proteins causing sensory and proprioceptive symptoms including paresthesias and neuropathic pain. 1

Hereditary Causes

Charcot-Marie-Tooth disease type 1A should be ruled out, particularly when patients develop severe neurotoxicity with chemotherapy exposure (especially vincristine), as these patients present with predominant motor involvement and distinct deformities. 2

• Refsum's syndrome and adrenoleukodystrophy are additional hereditary causes requiring genetic testing for accurate diagnosis. 1

Malignancy-Related Causes

Paraneoplastic syndromes cause axonal sensory neuropathy and should be considered in patients with unexplained neuropathy, particularly with asymmetric presentation and predominant proprioception involvement. 1

• Polycythemia rubra vera is an established hematologic cause. 1

Infectious Causes

HIV, syphilis, Lyme disease, and leprosy are established infectious etiologies that must be screened in appropriate clinical contexts. 1

Acute Hepatic Porphyrias

Acute porphyria attacks can be complicated by axonal motor neuropathy and paresis, with nerve conduction studies detecting chronic neuropathy as the cause of ongoing pain, sensory loss, or muscle weakness. 2

Diagnostic Approach Priorities

The highest-yield screening tests are blood glucose, serum B12 with metabolites (methylmalonic acid and homocysteine), and serum protein immunofixation electrophoresis (more sensitive than standard electrophoresis for detecting monoclonal gammopathies). 1

• Electrodiagnostic studies confirm axonal patterns, showing reduced sensory nerve action potential amplitudes with preserved motor nerve function in pure sensory neuropathy. 2
• Screen for renal insufficiency, thyroid dysfunction, and vitamin deficiencies (B1, B6, folate, E) based on clinical context. 2, 1
• Consider genetic testing when hereditary neuropathy is suspected or when severe neurotoxicity occurs with standard chemotherapy doses. 1

Critical Risk Factors

Pre-existing neuropathy, concurrent neurotoxic agent exposure, diabetes mellitus, and age ≥75 years are strong independent risk factors for developing or worsening axonal sensory neuropathy. 2

• Alcohol abuse, renal insufficiency, hypothyroidism, vitamin deficiency, HIV infection, and autoimmune rheumatologic conditions predispose to neuropathy development. 2

Idiopathic Cases

Despite comprehensive evaluation, 20-25% of chronic axonal sensory polyneuropathies remain idiopathic, with recent evidence suggesting metabolic syndrome may be associated with unexplained axonal sensorimotor neuropathy. 1, 6