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The majority of patients with peripheral neuropathy exhibit evidence of large fiber involvement, characterized by numbness, tingling, loss of deep tendon reflexes, and abnormal electrophysiologic studies. In contrast, damage to small fibers is not detected by routine nerve conduction studies. Patients with small fiber neuropathy, involving myelinated A delta and unmyelinated C fibers, may complain of severe pain and exhibit diminished thermal and pain perception. The pain, which is frequently reported in the feet, is described as burning, prickling, stabbing, jabbing, or tight band-like pressure. Small fiber neuropathy occurs most often in patients with diabetic neuropathy, but may also be found in patients with impaired glucose tolerance, severe hypertriglyceridemia, the metabolic syndrome, HIV infection, and toxic neuropathy from antiretroviral drugs. For many patients, no specific etiology is identified.

Small fiber neuropathy is diagnosed clinically, but has traditionally been a diagnosis of exclusion based on clinical findings and the absence of large fiber involvement as determined by electrophysiologic studies. The disparity between subjective complaints and objective signs increases the difficulty of diagnosis. In addition, conditions other than nerve fiber damage, including venous insufficiency, spinal stenosis, myelopathy and psychosomatic disturbances may mimic small fiber neuropathy. There is no treatment to cure small fiber peripheral neuropathy. Medications may be provided for pain management, and for some etiologies treatment of the underlying condition (e.g., glucose control, intravenous immunoglobulin or plasma exchange) may be given to reduce progression of the disease and its symptoms.

In the last decade, a specific test to assess intraepidermal nerve fiber (IENF) density using skin biopsy and immunostaining of the tissue has been developed that allows the identification and counting of intraepidermal nerve fibers. Assessment of IENF density typically involves a 3 mm punch biopsy of skin from the calf (and sometimes foot or thigh). After sectioning by microtome the tissue is immunostained with anti-protein-gene-product 9.5 (PGP 9.5) antibodies and examined with immunohistochemical or immunofluorescent methods. This technique has improved research and contributed greatly to the understanding of small fiber neuropathy. Skin biopsy with measurement of IENF density has also been investigated as an objective measure for the diagnosis of small fiber neuropathy. Assessment of epidermal nerve fiber density with PGP 9.5 is commercially available from Therapath (New York) with a biopsy kit, although IENF density measurement (i.e., tissue preparation, immunostaining with PGP 9.5 and counting) may also be done by local research pathology labs.

Indications for Quantitative Sensory Testing are discussed in a separate policy.

1. Individual presents with symptoms of painful sensory neuropathy; AND
2. There is no history of a disorder known to predispose to painful neuropathy (e.g., diabetic neuropathy, toxic neuropathy, HIV neuropathy, celiac neuropathy, inherited neuropathy); AND
3. Physical examination shows no evidence of findings consistent with large-fiber neuropathy, such as reduced or absent muscle-stretch reflexes or reduced proprioception and vibration sensation; AND
4. Electromyography and nerve-conduction studies are normal and show no evidence of large-fiber neuropathy.

Skin biopsy with epidermal nerve fiber density measurement is considered investigational for all other conditions, including, but not limited to, the monitoring of disease progression or response to treatment.

Measurement of sweat gland nerve fiber density is investigational.

None

11/19/2009: Approved by MPAC

12/30/2010: Policy reviewed; no changes.

01/17/2012: Added a policy statement to indicate that skin biopsy with epidermal nerve fiber density measurement for the diagnosis of small-fiber neuropathy may be considered medically necessary when certain conditions are met.

01/09/2013: Policy title changed from "Intraepidermal Nerve Fiber Density" to "Nerve Fiber Density Testing." Added the following investigational policy statement: Measurement of sweat gland nerve fiber density is investigational.

All codes billed for this procedure are considered investigational and not eligible for coverage. 

Covered Codes        

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