The assessment of nerve fibers is a component of evaluating peripheral nerve disease. Most nerve disease targets the small nerve fibers (as opposed to large nerve fibers). This document addresses the pathological analysis from skin biopsy specimens of intraepidermal nerve fiber (IENF) density for the diagnosis of small-fiber neuropathy (SFN). This document also addresses the pathological analysis of sweat gland nerve fiber density for the diagnosis of SFN.

Medically Necessary:

Pathological analysis of intraepidermal nerve fiber density for the diagnosis of small-fiber neuropathy is considered medically necessary when all of the following conditions are met:

1. Individual presents with painful sensory neuropathy; AND
2. 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
3. Electromyography and nerve-conduction studies are normal and show no evidence of large-fiber neuropathy.

Investigational and Not Medically Necessary:

Pathological analysis of intraepidermal nerve fiber density for the diagnosis of small-fiber neuropathy is considered investigational and not medically necessary in all other cases.

Pathological analysis of sweat gland nerve fiber density testing for the diagnosis of small-fiber neuropathy is considered investigational and not medically necessary for all indications.

Since the 1990's, clinical pathological techniques have been gradually refined to enable accurate quantitative assessment of epidermal small nerve fiber density from skin biopsy specimens that have been specially prepared and stained. This occurred concomitantly with the recognition of a syndrome, small-fiber neuropathy (SFN), characterized by painful (and rarely disabling) symptoms that appear to correlate reasonably well with a decrease in the amount and density of small nerve fibers within the epidermis of skin biopsy specimens. SFN is the most common type of painful sensory neuropathy in individuals over age 50. In most cases, no cause can be found. Current consensus is that SFN is extremely under-recognized (Mendell, 2003).

A variety of IENF density tests have been developed and validated as being reasonably sensitive for the diagnosis of SNF, including thermoregulatory sweat testing, quantitative sudomotor axon reflex testing, quantitative thermal threshold testing, and cardiovascular autonomic reflex testing.

In a 2005 study of 30 individuals with neuropathy including SFN and diabetic neuropathy, and 22 healthy controls, the number of small nerve fibers per epidermal area and per epidermal length was significantly reduced in individuals with SFN or diabetic neuropathy versus individuals in the control group (Koskinen, 2005). There was excellent correlation between area and length measurements, and between 2 different pathologists who counted the specimens. Overall, this study showed a sensitivity of 90% and specificity of 95% for the diagnosis of SFN or diabetic neuropathy. In a population with a similar distribution of individuals with and without neuropathy, the positive predictive value was therefore estimated to be 95% and the negative predictive value 91%. In addition, diagnosis in this study would obviate the need for the more traditional sural nerve biopsy, which is often painful and can produce permanent residual paresthesias (Koskinen, 2005). In another study of individuals with and without diabetic neuropathy, IENF density was not reduced until after the first 5 years after diagnosis of diabetes (Pittenger, 2004). These and other researchers raised some doubt as to the ability of the stain, protein-gene-product (PGP) 9.5, to completely stain all epidermal nerve fibers, especially under conditions of neuropathy.

There is a paucity of evidence in the peer-reviewed literature that diagnosis by skin biopsy significantly alters treatment outcome. SFN is indeed a clinically valid entity, and techniques for assessing IENF density by skin biopsy (as well as other methods) are reasonably advanced. Treatment is generally symptomatic, and the long-term course of this disease, with or without treatment, is still poorly understood (Mendell, 2003).

However, consensus opinion from neurologists and pain specialists, both in the literature and from direct discussion, suggests that many individuals with chronic pain syndromes often travel from specialist to specialist in search of both relief and answers. The pain management literature is replete with examples of the importance of establishing a diagnosis whenever possible. Individuals with chronic pain often seek out and utilize multiple healthcare services and therapies, while remaining frustrated and concerned as their chronic pain persists. In one study of 62 adults under chronic pain management, regression analysis revealed that the strongest unique predictors of treatment satisfaction involved the individual feeling that his or her evaluation was complete, that he or she had received an explanation for clinic procedures, and that treatment helped improve his or her daily activity (McCracken, 2002). In another study, assessment of individuals attending a pain clinic revealed that the explanation of the etiology of their pain problem is as important as the cure or relief of their pain (Petrie, 2005).

Consequently, in view of the under-recognized prevalence of SFN, it is plausible to consider that attaching a specific diagnosis to individuals with this condition may promote both increased satisfaction as well as lead to greater adherence to continuity of care with a specific provider and pain control protocol, leading to enhanced clinical outcomes. Until additional studies prove otherwise, it appears reasonable to offer pathological analysis of IENF for the diagnosis of SNF to selected individuals meeting medically necessary criteria.

Gibbons and colleagues (2009) reported on a new test to quantify the sweat gland nerve fiber density using the same tissue which was prepared for IENF density testing. Ninety-four subjects (30 diabetic and 64 healthy controls) had punch skin biopsies in the distal leg, distal thigh and proximal thigh. Participants were assessed using three systems; the Neuropathy Impairment Score in the Lower Limb system, the Michigan Diabetic Neuropathy Score and the Toronto Clinical Scoring System. For the diabetic participants, the sweat gland nerve fiber density at the distal leg was 20.8, 28.2 at the distal thigh and 42.5 at the proximal thigh. In the control group, distal leg showed 40.8, distal thigh was 28.2 and proximal thigh was 51.3. Density of the sweat gland nerve fibers at the distal leg of diabetic participants decreased as the Neuropathy Impairment Score in the Lower Limbs worsened. While the results showed that sweat gland nerve density fibers can be quantified by skin punch biopsies, there is no overall standard way of doing so and further studies are required with larger participant groups.

Neuropathy is an abnormal and usually degenerative state of the nervous system or nerves. Typically it affects the lower extremities. It can affect one nerve or many nerves. The form of neuropathy can be broken down by the size of the fiber involvement (i.e., small-fiber or large-fiber neuropathy). Small nerve fibers are those near the surface of the skin and the symptoms deal with sensation. The small nerve fibers within the epidermis generally assist with perception of hot and cold sensation, as well as pain. In addition, small autonomic fibers assist with control of sweating and blood vessel tone. SFN is among the least understood of all neuropathies, primarily because standard diagnostic tests for neuropathy such as electromyography (EMG) and nerve conduction studies (NCS) are usually normal in this group of individuals. The test involves a 3-mm punch biopsy of skin from the leg performed under local anesthesia. The tissue is stained with PGP 9.5 antibodies and examined. The staining allows the IENF to be identified and counted. A deeper biopsy (6-8mm) may be required for the sweat glands. Small-fiber neuropathy is identified when there is a reduction of the IENF density.

SFN generally presents as a painful neuropathy that may rarely become disabling. Symptoms suggestive of this condition may include pain (burning, tingling, shooting, or prickling in character), paresthesia, sheet intolerance, or restless legs syndrome. Symptoms of autonomic dysfunction may include altered sweating, diarrhea or constipation, urinary incontinence or retention, gastroparesis, sicca syndrome, blurry vision, facial flushes, orthostatic hypotension, or sexual dysfunction. Leading causes of SFN include diabetes, alcohol abuse, human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS), certain neurotoxins, various genetic diseases, as well as an idiopathic form.

Comprehensive information about the natural history of SFN is scarce. Some individuals may evolve to a large-fiber sensory neuropathy, while spontaneous remission also may occur. One review suggested that about 1/3 of individuals experienced continuous symptoms, another 1/3 had intermittent symptoms, and the remaining 1/3 had a monophasic course with symptom resolution after months or years (Hoitsma, 2004).

If SFN is secondary to another condition, then treatment appropriate for that condition should be administered. In addition, treatment of SFN itself is usually based on symptoms, and may include tricyclic antidepressants, anticonvulsants, opioid medications, or local anesthetics applied to the painful areas (Mendell, 2003). Nonpharmacologic treatment may include cool soaks, heat, massage, skin moisturizers, elevation or lowering of the limbs, exercise, spinal cord stimulation, intrathecal morphine, or transcutaneous electrical nerve stimulation (Hoitsma, 2004).

There are challenges with being able to quantify sweat gland nerve fibers due to the complex 3-D structure of individual sweat glands, the variable number and size of sweat glands in each tissue section and the lack of a "gold standard" technique.

In the 2006 conference, the National Institute of Neurological Disorders and Stroke supported the ongoing research to improve and standardize the diagnostic criteria and treatment outcomes for small-fiber neuropathy.

Small-fiber neuropathy (SFN): A disease characterized by diminished nerve fiber density in the epidermis (outer layer) of the skin, resulting in painful symptoms, usually in the extremities, that may rarely become disabling. It may occur either independently or as the result of another disease, such as diabetes or alcohol abuse.

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

When services are Investigational and Not Medically Necessary:
For the procedure described above when criteria are not met; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

When services are also Investigational and Not Medically Necessary:

Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding

Peer Reviewed Publications:

1. Al-Shekhlee A, Chelimsky TC, Preston DC. Review: small-fiber neuropathy. The Neurologist. 2002; 8(4):237-253.
2. Devigili G, Tugnoli V, Penza P, et al. The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain. 2008; 131(Pt 7):1912-1925.
3. Gibbons CH, Illigens BM, Wang N, Freeman R. Quantification of sweat gland innervation: a clinical-pathologic correlation. Neurology. 2009; 72(17):1479-1486.
4. Hoitsma E, Reulen JP, de Baets M, et al. Small fiber neuropathy: a common and important clinical disorder. J Neurol Sci. 2004; 227(1):119-130.
5. Koskinen M, Hietaharju A, Kylaniemi M, et al. A quantitative method for the assessment of intraepidermal nerve fibers in small-fiber neuropathy. J Neurol. 2005; 252(7):789-794.
6. Lacomis D. Small-fiber neuropathy. Muscle & Nerve. 2002; 26(2):173-188.
7. McCracken LM, Evon D, Karapas ET, et al. Satisfaction with treatment for chronic pain in a specialty service: preliminary prospective results. Eur J Pain. 2002; 6(5):387-393.
8. Mendell JR, Sahenk Z. Painful sensory neuropathy. New Engl J Med. 2003; 348(13):1243-1255.
9. Petrie KJ, Frampton T, Large RG, et al. What do patients expect from their first visit to a pain clinic? Clin J Pain. 2005; 21(4):297-301.
10. Pittenger G, Ray M, Burcus NI, et al. Intraepidermal nerve fibers are indicators of small-fiber neuropathy in both diabetic and non-diabetic patients. Diabetes Care. 2004; 27(8): 1974-1979.
11. Schuller T, Hermann K, Baron R. Quantitative assessment and correlation of sympathetic, parasympathetic, and afferent small fiber function in peripheral neuropathy. J Neurol. 2000; 247(4):267-272.
12. Singer W, Spies JM, McArthur J, et al. Prospective evaluation of somatic and autonomic small fibers in selected autonomic neuropathies. Neurology. 2004; 62(4):612-618.
13. Smith AG, Russell J, Feldman EL, et al. Lifestyle intervention for pre-diabetic neuropathy. Diabetes Care. 2006; 29(6):1294-1299.
14. Sumner C, Sheth S, Griffin JW, et al. The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology. 2003; 60(1):108-111.
15. Tobin K, Giuliani MJ, Lacomis D. Comparison of different modalities for detection of small fiber neuropathy. Clin Neurophysiol. 1999; 110(11):1909-1912.
16. Vinik A, Erbas T, Stansberry KB, Pittenger GL. Small fiber neuropathy and neurovascular disturbances in diabetes mellitus. Exp Clin Endocrinol Diabetes. 2001; 109Suppl2:S451-4573.

Government Agency, Medical Society, and Other Authoritative Publications: 

1. England JD, Gronseth GS, Franklin G, et al. 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. 2009; 72(2):177-184.
2. Lauria G, Hsieh ST, Johansson O, et al. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. Eur J Neurol. 2010; 17(7):903-912.

1. National Institute of Neurological Disorders and Stroke. Available at: http://www.ninds.nih.gov/. Accessed on February 8, 2011.

Autonomic Neuropathy
Diabetes Mellitus
Intraepidermal Nerve Fiber Density
Peripheral Neuropathy
Sensory Neuropathy
Skin Biopsy
Small-Fiber Neuropathy
Sweat Gland Nerve Fiber Density