Small Fiber Neuropathy Overview


This testing is used to help diagnose or confirm the diagnosis of distal symmetrical polyneuropathy, in particular, small fiber neuropathy.

Small fiber neuropathy affects the small, unmyelinated nerve fibers in the skin that convey pain and temperature sensations as well as mediate autonomic functions such as sweating. This type of neuropathy typically presents as bilateral painful sensations, numbness, or hypersensitivity in the feet, legs, hands and arms, depending on the severity of the condition. It typically progresses in an ascending pattern up the legs and arms (stocking/glove paresthesias). Because these small unmyelinated cutaneous sensory fibers are primarily involved, the patient may show little or no changes in the physical exam, i.e., no signs of decreased sensation to light touch or pin prick and normal ankle reflexes, yet have significant subjective comints of burning, painful feet or numbness. Also, because these small sensory fibers are unmyelinated, sensory nerve conduction studies which only measure the larger myelinated sensory fibers tend to be normal.

Common causes for small fiber neuropathy include diabetes mellitus, Sjogren’s syndrome, connective tissue disorders such as lupus, vasculitis, sarcoid, amyloidosis, alcohol abuse, toxins nutritional deficiencies, HIV infections, and aging. While this testing can diagnose the presence of a small fiber neuropathy, it cannot determine a particular underlying cause or predict a response to therapy.

The test can be useful in the following circumstances:

This testing procedure and related articles to date was carefully reviewed by a panel of physicians representing the American Academy of Neurology, American Association of Neruomuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation and their findings were reported in the journal Neurology as part of the AAN practice guidelines. “Practice Parameter: Evaluation of distal symmetric polyneuropathy: Role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review).” Neurology 2009; 72:177-184.

This article in regards to skin biopsy procedure states the following:

Conclusions. ENF density assessment using PGP 9.5 immunohistochemistry is a validated, reproducible marker of small fiber sensory pathology. Skin biopsy with ENF density assessment is possibly useful to identify distal symmetrical polyneuropathy which includes small fiber sensory neuropathy in symptomatic patients with suspected polyneuropathy.

Recommendations. For symptomatic patients with suspected polyneuropathy, skin biopsy may be considered to diagnose the presence of a polyneuropathy, particularly small fiber sensory neuropathy.


NOTE: Only three sites have established normative values for comparison purposes for this biopsy procedure: 1) the foot over the EDB muscle; 2) the calf at 10cm above the ankle; and 3) the thigh at the level of the pubis (although any site so long as specified can be sampled). Usually for comparison purposes, a biopsy is done at two locations. Since small fiber neuropathy first presents with symptoms distally, the biopsy sites can be from the right and left foot or from the foot and unilateral calf. However, if for any reason the clinician is concerned about the adequacy of blood flow to the foot which could interfere with proper healing of the biopsy site , then it is recommended that bilateral calf biopsies be performed.



The above information was prepared by Jo Marie Lyons, MD, who is board certified in Pathology and Neurology. Please address any questions you may have about this procedure directly to her at 404-917-1770 or e-mail

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