DESCRIPTION
Skin biopsy with immunostaining is used to assess the density of epidermal (intraepidermal) nerve fibers. This procedure is being investigated as an objective measure to diagnose small fiber neuropathy.
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 electrophysiological 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.
POLICY
Intraepidermal nerve fiber density testing for the diagnosis of small-fiber neuropathy is considered investigational.
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ADDITIONAL INFORMATION
No literature was identified to evaluate the diagnostic accuracy of intraepidermal nerve fiber (IENF) density testing density in an appropriate patient population. Unknown at this time is whether this test can be used to identify individual patients with small fiber neuropathy and rule out other disorders with similar symptoms. Scientific data on the technical performance, reproducibility and interpretation of IENF density testing are inconclusive at this time. There are no randomized controlled trials establishing the accuracy and reproducibility of intraepidermal nerve fiber density testing density testing. The few studies on sensitivity, specificity and positive and negative predictive value consist of small nonrandomized studies with mixed results. Treatment of small fiber neuropathy consists of treating the underlying systemic condition and reducing symptoms.
SOURCES
BlueCross BlueShield Association. Medical Policy Reference Manual. (9:2009). Intraepidermal nerve fiber density (2.04.58). Retrieved September 13, 2010 from BlueWeb. (13 articles and / or guidelines reviewed)
Devigili, G., Tugnoli, V., Penza, P., Camozzi, F., Lombardi, R., Melli, G., et al. (2008). The diagnostic criteria for small fiber neuropathy: from symptoms to neuropathology. Brain, 131 (Pt 7), 1912 - 1925. (Level 4 Evidence)
England, J. D., Gronseth, G. S., Franklin, G., Carter, G. T., Kinsella, J. J., Cohen, J. A., et al. (2009). Practice Parameter: Evaluation of distal symmetric polyneuropathy: Role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation. Neurology, 72 (2), 177-184.
England, J. D., Gronseth, G. S., Franklin, G., Miller, R. G., Asbury, A. K., Carter, G. T., et al. (2005). Distal symmetric polyneuropathy: A definition for clinical research. Report of the American Academy of Neurology, the American Association of Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology, 64 (2), 199-207.
Goransson, L., Brun, J., Harboe, E., Mellgren, S., & Omdal, R. (2006). Intraepidermal nerve fiber densities in chronic inflammatory autoimmune diseases. Arch Neurology, 63 (10),1410 - 1413. (Level 4 Evidence)
Holland, N., Stocks, A., Hauer, P., Cornblath, D., Griffin, J., & McArthur, J. (1997). Intraepidermal nerve fiber density in patients with painful sensory neuropathy. Neurology, 48 (3), 708 - 711. (Level 4 Evidence)
Loseth, S., Stalberg, E., Jorde, R., Mellgren,S. (2008). Early diabetic neuropathy: Thermal thresholds and intraepidermal nerve fiber density in patients with normal nerve conduction studies. J Neurology, 255 (8), 1197 - 1202. (Level 4 Evidence)
Skopelitis, E., Aroni, K., Kontos, A., Konstantinou, K., Kokotis, P., Karandreas, N., et al. (2007). Early detection of subclinical HIV sensory polyneuropathy using intraepidermal nerve fibre density quantification: Association with HIV stage and surrogate markers. International Journal of STD & Aids, 18 (12), 856 - 860. (Level 4 Evidence)
ORIGINAL EFFECTIVE DATE: 5/9/2009
MOST RECENT REVIEW DATE: 10/14/2010
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