Epidermal Nerve Fiber Density (ENFD) Testing 


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About Small Fiber Neuropathy

Small-fiber neuropathy, also known as small-fiber sensory/peripheral neuropathy, is a peripheral nerve disease that selectively affects small diameter nerve fibers. These fibers innervate the skin, and aid in temperature perception, nociception (pain), and autonomic regulation. Common symptoms with peripheral neuropathy include:

  • pain
  • numbness
  • pins and needles
  • burning
  • electric shock
  • restless leg syndrome
  • tingling
  • reduced pain/
    temperature perception
  • autonomic dysfunction

Symptoms of small fiber neuropathy (SFN) correlate with a decrease in the number, density and length of small nerve fibers in the epidermis of skin biopsy specimens1. Standard electrophysiological tests for nerve injury such as nerve conduction tests and electromyograms (NCS and EMG, respectively) are gross measures of large nerves and cannot give information about the health of small sensory nerve fibers2. Current consensus is that small fiber neuropathy is extremely under-recognized3. An early diagnosis is important since detection of reduced small nerve fiber density can predict the progression to a larger-spread neuropathy.2 Small fiber neuropathy can result from many underlying disorders, including:

  • auto-immune disease
  • drugs and toxins
  • vasculitis
  • amyloidosis
  • genetic disorders
  • HIV
  • diabetes
  • alcohol abuse
  • Lyme disease

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Skin Biopsy to Diagnose Small Fiber Neuropathy

Performing a skin biopsy to analyze and quantify nerve fibers in the epidermis is a relatively simple and convenient way to identify and monitor small fiber neuropathies. Studies support the high sensitivity and specificity of skin biopsy in detecting small nerve fiber loss and it has been used not only in diagnosis, but also to evaluate disease progression and treatment success4,5. ENFD studies have been found to have 88.4% sensitivity in detection, compared with 54.6% for clinical exam alone2. Moreover, the test can detect early nerve fiber damage even in asymptomatic patients6.

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Ideal Biopsy Sites and Why

Different areas of the body have different densities of intra-epidermal nerve fibers (IENF); generally, the average IENF density decreases the further one moves from the dorsal root ganglia. For example, IENF density is higher at the trunk that at the thigh and a lower density is found at the calf as compared to the thigh. IENF loss is more marked at distal anatomic locations (length-dependent), which is why the calf (10cm above the lateral malleolus) is the most common biopsy site for testing for small fiber neuropathy4. There are two to three standard biopsy sites for length-dependent sensory neuropathy. The sites are located on the lateral leg and have well-established, given normative values. The advantage to performing two or three biopsies on the same leg (for example, one distal leg and one proximal thigh) is the results can paint a clear picture of the progression of small fiber neuropathy.

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How is the test performed?

The ENFD test is a simple 3mm punch biopsy of skin from the leg, performed under local anesthetic. Once the sample is received at the lab, small sensory nerve fibers are stained and easily visualized under a microscope. A video on how the procedure is performed and post-biopsy care instructions can be found at www.advanced-lab.com. Biopsy kits include everything needed for the procedure except gloves, 1% or 2% lidocaine with epinephrine and a syringe. The requisition form, fixative, sterile punch biopsy tool kit, instructions and pre-paid express shipping materials are all provided.

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Results include assessment of IENF density through a pathological review by neurological experts. Reports are mailed to the ordering physician, but can also be viewed more rapidly via Advanced Laboratory Services web portal.

Example of normal intra-epidermal nerve fiber density
Normal Fiber

Example of reduced intra-epidermal small nerve fiber density, consistent with small fiber neuropathy
Reduced Density Fiber
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Why Choose Advanced Laboratory Services?

Personalized service—speak directly with a qualified lab technician every time you call

Quality result images.

Pathological review of specimens by highly trained neurological experts.

Insurance plan billing (PPO)

Biopsy kits with tools and return shipping provided at no charge

Online access to results

Fast turnaround time for results

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Order a Skin Biopsy Kit:

Contact the lab or your local Advanced Laboratory Services, Inc representative, or Click here to Order Kits.

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Our focus at Advanced Laboratory Services is to bring the highest quality testing and results to health care providers and their patients. To contact Laboratory Management about patient safety concerns and quality of care, please call 855-238-4949 or email questions@advanced-lab.com.

Advanced Laboratory Services is accredited by The Joint Commission. To contact the Joint Commission to report concerns about patient safety and quality of care, please call 1-800-994-6610 or email complaint@jointcommission.org.


  1. Walk D, Wendelshcafer-Crabb G, Davey C, Kennedy WR. (2007). Concordance between epidermal nerve fiber density and sensory examination in patients with symptoms of idiopathic small fiber neuropathy. J Neurol Sci 255 (1-2), 23-26.
  2. Devigili G, Tugnoli V, Penza P, Camozzi F, Lombardi R, Melli G, Broglio L, Granieri E, and Lauria G (2008). The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain. 2008 July; 131(7): 1912–1925.
  3. Mendell JR, Sahenk Z (2003). Painful Sensory Neuopathy. New Engl J Med 348 (13):1243-1255
  4. McArthur JC, Stocks EH, Hauer P, Cornblath DR & Griffen JW (1998). Epidermal Nerve Fiber Density: Normative reference range and diagnostic efficiency. Arch Neurol 55: 1513-1520.
  5. Sommer C. (2008). Skin biopsy as a diagnostic tool. Curr Opin Neurol 21 (5): 563-568.
  6. Loseth S, Stalberg E, Jorde R, Melgren SI (2008). Early diabetic neuropathy: Thermal thresholds and intraepidermal nerve fibre density in patients with normal nerve conduction studies. J Neurol 255 (8): 1197-1202

This test was developed and its performance characteristics determined by Advanced Laboratory Services. It has not been cleared or approved by the U.S. Food and Drug Administration.