Quartz 4

Small Fiber Neuropathy

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Small Fiber Neuropathy

Small Fiber Neuropathy (SFN) is damage to the small-diameter nerve fibers — the thin, unmyelinated C-fibers and thinly myelinated Aδ-fibers that carry pain, temperature, and autonomic signals. It connects to MCAS, POTS, and EDS through multiple pathways.

What Small Fibers Do

Small nerve fibers serve two main functions:

Sensory (somatic): Pain perception, temperature sensing, and light touch. When damaged, patients experience burning pain, tingling, numbness, or hypersensitivity — often in a “stocking-glove” distribution (feet and hands) but sometimes patchy or widespread.

Autonomic: These fibers run the autonomic nervous system at the tissue level — controlling blood vessel tone, sweating, gut motility, heart rate modulation, and bladder function. When damaged, autonomic dysfunction results → directly relevant to POTS and GI dysmotility.

The Mast Cell Connection

Chronic exposure to Mast Cell Mediators may damage small nerve fibers over time:

  • Tryptase and other proteases can directly damage nerve endings
  • Chronic neuroinflammation from Cytokines (TNF-α, IL-1β, IL-6) injures nerve fibers
  • Histamine and substance P create a nerve-mast cell activation loop that, when chronic, may lead to nerve fiber degeneration
  • Local tissue inflammation from ongoing mast cell activation creates an environment hostile to nerve fiber maintenance

Additionally, mast cells and small nerve fibers are physically adjacent in tissues. They form functional contacts. Chronic mast cell activation in the immediate vicinity of nerve fibers subjects them to sustained mediator exposure.

The POTS Connection

Damage to autonomic small fibers impairs the sympathetic vasoconstriction needed to maintain blood pressure on standing → neuropathic POTS. This is testable — quantitative sudomotor axon reflex testing (QSART) and skin biopsy with intraepidermal nerve fiber density (IENFD) measurement can document small fiber loss.

The EDS Connection

EDS patients have elevated rates of SFN. Proposed mechanisms include mechanical nerve damage from hypermobile joints, abnormal connective tissue support for nerve fibers, and the co-occurring mast cell activation contributing to nerve fiber injury.

Diagnosis

  • Skin punch biopsy with IENFD measurement — the gold standard. A 3mm punch biopsy (typically from the distal leg) is stained for nerve fibers. Reduced density compared to age-matched norms confirms SFN.
  • QSART — tests autonomic small fiber function by measuring sweat output
  • Standard nerve conduction studies (EMG/NCS) are typically normal in SFN because they test large fibers. A normal EMG does NOT rule out SFN.

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