Clinical UM Guideline

This document addresses the pathological analysis from skin biopsy specimens of intra-epidermal 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. 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).

Medically Necessary:

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

1. Individual presents with painful sensory neuropathy; and
2. No evidence of large-fiber neuropathy is present on the following:
   1. Physical examination (for example, reduced or absent muscle-stretch reflexes or reduced proprioception and vibration sensation); and
   2. Electromyography and nerve-conduction studies.

Not Medically Necessary:

Pathological analysis of intra-epidermal nerve fiber density for the diagnosis of small-fiber neuropathy is considered 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 not medically necessary for all indications.

The following codes for treatments and procedures applicable to this guideline 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 Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met, or when the code describes a procedure, such as analysis of sweat gland nerve fiber density, designated in the Clinical Indications section as not medically necessary.

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 (that is, 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 (6-8 mm) may be required for the sweat glands. SFN 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.

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. 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.

There are challenges involved in quantifying sweat gland nerve fibers, including the complex 3-D structure of individual sweat glands, the variable number and size of sweat glands in different tissue segments and the lack of a “Gold standard” technique.

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 one-third of individuals experienced continuous symptoms, another one-third had intermittent symptoms, and the remaining one-third had a monophasic course with symptom resolution after months or years (Hoitsma, 2004).

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 good correlation between area and length measurements, and between two 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 following the 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.

In 2013, Boruchow and colleagues reported on a retrospective chart review in which they looked at the role of skin biopsy in the evaluation and management of individuals with suspected SFN. A total of 69 individuals underwent skin biopsy. Twenty-five of those individuals had pathological evidence of an SFN and 9 individuals had evidence of borderline SFN. A change in treatment plan or diagnosis occurred in 14 out of 25 individuals with SFN. Of the 9 individuals with borderline SFN, 6 had a change in treatment plan or diagnosis.

There is a paucity of evidence in the peer-reviewed literature that diagnosis of SFN by skin biopsy significantly alters treatment outcomes. Treatment of SFN is generally symptomatic, and the long-term course of this disease, with or without treatment, is still poorly understood (Mendell, 2003).

The consensus opinion from neurologists and pain specialists 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 greater adherence to continuity of care with a specific provider and pain control protocol. This, in turn, may lead to enhanced clinical outcomes. Until additional, larger, well-designed studies are available, pathological analysis of IENF is limited to the diagnosis of SFN for selected individuals when medically necessary criteria are met.

In 2010, the European Federation of Neurological Societies updated their guidelines for neuropathic pain assessment. Their recommendations are that skin biopsy should be performed in those individuals with painful or burning feet of unknown origin and a clinical impression of small fiber dysfunction.

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. A total of 94 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 currently no standardized methodology, and further studies are required with larger participant groups and outcomes data.

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, which may rarely become disabling. It may occur either independently or as the result of another disease, such as diabetes or alcohol abuse.

Peer Reviewed Publications:

1. Al-Shekhlee A, Chelimsky TC, Preston DC. Review: small-fiber neuropathy. The Neurologist. 2002; 8(4):237-253.
2. Boruchow SA, Gibbons CH. Utility of skin biopsy in management of small fiber neuropathy. Muscle Nerve. 2013; 48(6):877-882.
3. Devigili G, Tugnoli V, Penza P, et al. The diagnostic criteria for small fiber neuropathy: from symptoms to neuropathology. Brain. 2008; 131(Pt 7):1912-1925.
4. Gibbons CH, Illigens BM, Wang N, Freeman R. Quantification of sweat gland innervation: a clinical-pathologic correlation. Neurology. 2009; 72(17):1479-1486.
5. Haensch CA, Tosch M, Katona I, et al. Small-fiber neuropathy with cardiac denervation in postural tachycardia syndrome. Muscle Nerve. 2014; 50(6):956-961.
6. Haroutounian S, Todorovic MS, Leinders M, et al. Diagnostic criteria for idiopathic small fiber neuropathy: A systematic review. Muscle Nerve. 2021; 63(2):170-177.
7. 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.
8. 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.
9. Liutkeviciene R, Mecejus G, Zilovic D, Bumbuliene Z. Endometrial biopsy and density of nerve fibers in eutopic endometrium. Looking for easier ways to diagnose endometriosis. Gynecol Endocrinol. 2019; 35(12):1107-1110.
10. 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.
11. Mendell JR, Sahenk Z. Painful sensory neuropathy. New Engl J Med. 2003; 348(13):1243-1255.
12. 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.
13. 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.
14. Saperstein DS, Levine TD, Levine M, Hank N. Usefulness of skin biopsies in the evaluation and management of patients with suspected small fiber neuropathy. Int J Neurosci. 2013; 123(1):38-41.
15. Smith AG, Russell J, Feldman EL, et al. Lifestyle intervention for pre-diabetic neuropathy. Diabetes Care. 2006; 29(6):1294-1299.
16. Sumner C, Sheth S, Griffin JW, et al. The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology. 2003; 60(1):108-111.
17. Saperstein DS. Small fiber neuropathy. Neurol Clin. 2020; 38(3):607-618.
18. Vinik A, Erbas T, Stansberry KB, Pittenger GL. Small fiber neuropathy and neurovascular disturbances in diabetes mellitus. Exp Clin Endocrinol Diabetes. 2001; 109Suppl2:S451-S473.

Government Agency, Medical Society, and Other Authoritative Publications:

1. Cruccu G, Sommer C, Anand P, et al. EFNS guidelines on neuropathic pain assessment: revised 2009. Eur J Neurol. 2010; 17(8):1010-1018.
2. England JD, Gronseth GS, Franklin Get al.; American Academy of Neurology; American Association of Neuromuscular and Electrodiagnostic Medicine; American Academy of Physical Medicine and Rehabilitation. Practice parameter: the evaluation of distal symmetric polyneuropathy: the role of laboratory and genetic testing (an evidence-based review). Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. PM R. 2009; 1(1):5-13.
3. European Federation of Neurological Societies/Peripheral Nerve Society Joint Task Force of the EFNS and the PNS. 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. J Peripher Nerv Syst. 2010; 15(2):79-92.
4. Handelsman Y, Mechanick JI, Blonde L, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract. 2011; 17 Suppl 2(Suppl 2):1-53.
5. 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. Peripheral neuropathy Fact Sheet. Last reviewed March 13, 2023. Available at: https://www.ninds.nih.gov/health-information/disorders/peripheral-neuropathy. Accessed on October 9, 2023.

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

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