What is the pathophysiology of small fiber neuropathy?

Pathophysiology of Small Fiber Neuropathy

Small fiber neuropathy (SFN) is characterized by damage to small-diameter peripheral nerve fibers, specifically the thinly myelinated Aδ-fibers and unmyelinated C-fibers, which constitute 70-90% of peripheral nerve fibers. 1

Affected Nerve Fibers

• Small Fiber Types:

  • Thinly myelinated Aδ-fibers
  • Unmyelinated C-fibers 1, 2

• Functional Role:

  • These fibers are responsible for:
    • Pain sensation
    • Temperature perception
    • Autonomic functions (including sudomotor function)
    • Pressure-induced vasodilation 3

Pathological Process

Small fiber damage in SFN involves:

1. Reduction in Intraepidermal Nerve Fiber (IENF) Density:

   • Quantifiable through skin biopsy
   • Correlates with disease severity
   • Shows inverse relationship with neuropathic symptoms 3

2. Sudomotor Dysfunction:

   • Affects sweat gland innervation
   • Correlates with neuropathic symptoms and neurological deficits 3

3. Early Manifestation:

   • Small fiber damage often precedes large fiber damage in diabetic neuropathy
   • Can occur with normal nerve conduction studies 3, 1

Clinical Manifestations Related to Pathophysiology

The pathophysiological changes result in:

• Sensory Symptoms:

  • Burning pain
  • Prickling sensations
  • Aching
  • Sharp stabbing electric shock-like pains
  • Dysesthesias
  • Allodynia 3

• Autonomic Dysfunction:

  • Sudomotor dysfunction (affecting sweating)
  • Vascular dysregulation
  • Impaired pressure-induced vasodilation 3

Disease Progression

The pathophysiological course typically follows:

1. Early Phase:

   • Small fiber damage occurs first
   • May have normal nerve conduction studies
   • Reduced IENF density even with normal electrophysiology 3

2. Progressive Phase:

   • Increasing loss of IENF density correlates with neuropathic severity
   • Potential progression to large fiber involvement (occurs in approximately 13% of patients over 2 years) 2

3. Differential Impact:

   • More severe IENF loss in painful neuropathy compared to painless neuropathy 3

Diagnostic Implications

The pathophysiology explains why:

• Standard nerve conduction studies may be normal (they primarily assess large fiber function)
• Skin biopsy with IENF quantification has high diagnostic efficiency (88.4%)
• Quantitative sensory testing shows abnormalities in temperature thresholds
• Clinical examination may reveal pinprick and thermal hypoesthesia 3, 2

Common Pitfalls in Understanding SFN Pathophysiology

• Misdiagnosis: Relying solely on electrophysiology will miss SFN as it primarily assesses large fiber function 3, 1
• Incomplete Assessment: Failing to recognize the autonomic component of SFN pathophysiology
• Progression Misconception: Assuming all cases will progress to large fiber involvement (only about 13% do within 2 years) 2

The pathophysiological understanding of SFN continues to evolve, with increasing recognition of its importance in conditions like diabetic neuropathy, where it may serve as an early marker of neural damage and a potential target for intervention.