Latest Review Date: December 2023

Category: Medicine                                                               

POLICY:

Skin biopsy with epidermal nerve fiber density measurement for the diagnosis of small-fiber neuropathy may be considered medically necessary when all of the following conditions are met:

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 considered investigational.

DESCRIPTION OF PROCEDURE OR SERVICE:

Skin biopsy is used to assess the density of epidermal (intraepidermal) and sweat gland (sudomotor) nerve fibers using antibodies to a marker found in peripheral nerves. This procedure is proposed as an objective measure of small fiber neuropathy by identifying a reduction in the density of nerve fibers.

Peripheral Neuropathy

Most patients with peripheral neuropathy exhibit evidence of large fiber involvement, characterized by numbness, tingling, loss of deep tendon reflexes, and abnormal electrophysiological 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. If there is involvement of autonomic C fibers, symptoms such as coldness, discoloration, and hyper- or hypohidrosis may be present. Small fiber neuropathy occurs most often in patients with diabetic neuropathy but may also be found in patients with impaired glucose tolerance, severe hypertriglyceridemia, metabolic syndrome, human immunodeficiency virus (HIV) infection, and toxic neuropathy from antiretroviral drugs. For many patients, no specific etiology is identified.

Diagnosis

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.

Skin Biopsy

Skin biopsy is used to assess the density of epidermal (intraepidermal) and sweat gland (sudomotor) nerve fibers using antibodies to a marker found in peripheral nerves. A specific test to assess intraepidermal nerve fiber (IENF) density and sweat gland nerve fiber (SGNF) density using skin biopsy and immunostaining of the tissue have been developed that allow the identification and counting of intraepidermal and sudomotor nerve fibers. Assessment of nerve fiber 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. SGNF density can be assessed from the same tissue that has been prepared for IENF density testing, provided that the biopsy sample is of sufficient depth. Tissue samples may also be counterstained to better identify the boundaries of the sweat glands.

Treatment

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.

KEY POINTS:

Literature searches using the PubMed database have been performed through November 20, 2023.

Summary of Evidence

For individuals with suspected idiopathic small fiber neuropathy who receive intraepidermal nerve fiber (IENF) density testing, the evidence includes reports on technical reliability, diagnostic accuracy, and the effect on health outcomes. Relevant outcomes are test accuracy, change in disease status, symptoms, and quality of life. Techniques to measure IENF density have led to an improved understanding of the relation between the loss of small nerve fibers and symptoms of peripheral neuropathy. The literature also indicates that low IENF density may provide supportive evidence of a lesion in the peripheral somatosensory system. For example, there is a significant decrease in average IENF density in patients diagnosed with small fiber neuropathy compared with controls, and an IENF density of 4 to 8 per mm in the calf is near the fifth percentile of normal values, suggesting an increased probability of small fiber neuropathy below these cutoffs. For individuals who have symptoms suggestive of neuropathy but no evidence of large nerve neuropathy and no disease associated with neuropathy (e.g., diabetic neuropathy, toxic neuropathy, HIV neuropathy, celiac neuropathy, inherited neuropathy), establishing a cause for the symptoms is problematic. Thus, IENF density measurement may be helpful for the diagnosis of idiopathic small fiber neuropathy in those who have no evidence of large fiber neuropathy and no known cause of neuropathy. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have established small fiber neuropathy who receive repeated IENF density testing, the evidence is limited. Relevant outcomes are test accuracy, change in disease status, symptoms, and quality of life. A number of trials are ongoing or have recently been completed that assess the efficacy of activity and medications on small fiber neuropathy. If successful, there might be a potential role for repeated IENF density measurements to result in a change in management such as changing dose or class of medication. However, current treatments for small fiber neuropathy only palliate symptoms and do not modify the underlying changes in nerve fiber density in patients with symptomatic neuropathy. There is no evidence that monitoring progression of neuropathy has clinical utility. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have suspected small fiber neuropathy who receive sweat gland nerve fiber (SGNF) density testing, the evidence includes comparisons with control values. Relevant outcomes are test accuracy, change in disease status, symptoms, and quality of life. Measurement of SGNF density may lead to an improved understanding of the relation between the loss of sudomotor nerve fibers and symptoms of peripheral neuropathy. However, no studies were identified that evaluated the diagnostic accuracy of SGNF density measurement. The evidence is insufficient to determine the effects of the technology on health outcomes.

Practice Guidelines and Position Statements

American Association of Clinical Endocrinologists

The American Association of Clinical Endocrinologists (AACE) published 2015 guidelines for clinical practice for developing a diabetes mellitus comprehensive care plan.

The guidelines state: “Painful neuropathies may have no physical signs, and diagnosis may require skin biopsy or other surrogate measures of small-fiber neuropathy (SFN) (Grade D, not evidence-based; BEL 4, no evidence).” The AACE references the (2010) European Federation of Neurological Societies’ guidelines on the use of IENF quantification to confirm the clinical diagnosis of small fiber neuropathy (consensus).

In 2022, the AACE published updated clinical practice guidelines on developing a diabetes mellitus comprehensive care plan.The guidelines state that "skin biopsy and/or standardized quantitative sensory testing are sensitive tests for small-fiber neuropathy and should be considered if the clinical features are atypical and a different etiology is suspected."

American Academy of Neurology et al

The 2009 practice parameters from the American Academy of Neurology (AAN), American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM), and the American Academy of Physical Medicine and Rehabilitation (AAPMR) concluded that IENF density assessment using PGP 9.5 immunohistochemistry is a validated, reproducible marker of small fiber sensory pathology and provided a Level C (possibly useful) recommendation to consider use of skin biopsy to diagnose the presence of a polyneuropathy, particularly small fiber neuropathy. This guideline was reaffirmed by the AAN in 2013.

In 2009, AANEM, in conjunction with AAN and AAPMR, published an ordered set of case definitions of “distal symmetrical polyneuropathy” for clinical research ranked by the likelihood of disease. The recommendations for case definitions that include symptoms, signs, and nerve conduction studies were for clinical research studies and based on a systematic analysis of peer-reviewed literature supplemented by consensus from an expert panel. IENF density was not included in the case definitions.

U.S. Preventive Services Task Force Recommendations

Nerve fiber density testing is not a preventive service.

KEY WORDS:

Epidermal nerve fiber density, intraepidermal nerve fiber density, IENF, painful small fiber neuropathy, small fiber neuropathy, TheraPath, Nerve Fiber Density, Sweat Gland, sudomotor nerve fibers, sweat gland nerve fiber, SGNF, sweat gland nerve fiber density

APPROVED BY GOVERNING BODIES:

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). These tests are available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

Assessment of IENF and sweat gland nerve fiber density with anti-protein-gene-product 9.5 is commercially available using a biopsy kit, although local research pathology labs may also do IENF density measurement (i.e., tissue preparation, immunostaining with anti-protein-gene-product 9.5, and counting). Some laboratories that offer IENF density testing include Therapath Neuropathology, Advanced Laboratory Services, Mayo Medical Laboratories, Corinthian Reference Lab, and Bako Integrated Physician Solutions.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits.  Group-specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP: Special benefit consideration may apply. Refer to member’s benefit plan. 

CURRENT CODING: 

There is not a specific code for this analysis. Claims should be billed with the following code:

CPT Codes:                           

REFERENCES:

1. Alport AR, Sander HW. Clinical approach to peripheral neuropathy: anatomic localization and diagnostic testing. Continuum (Minneap Minn) Feb 2012; 18(1):13-38.
2. American Academy of Neurology. Evaluation of distal symmetric polyneuropathy: role of autonomic testing, nerve biopsy, and skin biopsy (guideline detail). 2019; www.aan.com/Guidelines/home/GuidelineDetail/316. 
3. Blonde L, Umpierrez GE, Reddy SS, et al. American Association of Clinical Endocrinology Clinical Practice Guideline:Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. Endocr Pract. Oct 2022; 28(10): 923-1049.
4. Boruchow SA, Gibbons CH. Utility of skin biopsy in management of small fiber neuropathy. Muscle Nerve. Dec 2013; 48(6):877-882.
5. Devigili G, Tugnoli V, Penza P, et al. The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain Jul 2008; 131(Pt 7):1912-25.
6. England JD, Gronseth GS, Franklin G, et al. Evaluation of distal symmetric polyneuropathy: the role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Muscle Nerve. Jan 2009; 39(1):106-115.
7. 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 Jan 13 2009; 72(2):177-84.
8. Fabry V, Gerdelat A, Acket B, et al. Which Method for Diagnosing Small Fiber Neuropathy?. Front Neurol. 2020; 11: 342.
9. Gibbons CH, Illigens BM, Wang N et al. Quantification of sudomotor innervation: a comparison of three methods. Muscle Nerve Jul 2010; 42(1):112-9.
10. Gibbons CH, Illigens BM, Wang N et al. Quantification of sweat gland innervation: a clinical-pathologic correlation. Neurology Apr 28 2009; 72(17):1479-86.
11. Handelsman Y, Mechanick JI, Blonde L et al. AACE task force for developing diabetes care plan. American Association of Clinical Endocrinologists Medical Guidelines for clinical practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract 2011; 17 Suppl 2:1-53. 
12. Holland NR, Stocks A, Hauer P, et al. Intraepidermal nerve fiber density in patients with painful sensory neuropathy. Neurology Mar 1997; 48(3):708-11.
13. Hovaguimian A, Gibbons CH. Diagnosis and treatment of pain in small-fiber neuropathy. Curr Pain Headache Rep Jun 2011; 15(3):193-200.
14. Lauria G, Hsieh ST, Johansson O, et al. European Federation of Neurological Societies/Peripheral Nerve SocietyGuideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the EuropeanFederation of Neurological Societies and the Peripheral Nerve Society. J Peripher Nerv Syst. Jun 2010; 15(2): 79-92.
15. Lauria G, Bakkers M, Schmitz C et al. Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study. J Peripher Nerv Syst 2010 Sep; 15(3):202-7.
16. Luo KR, Chao CC, Chen YT et al. Quantitation of sudomotor innervation in skin biopsies of patients with diabetic neuropathy. J Neuropathol Exp Neurol Oct 2011; 70(10):930-8.
17. McArthur JC, Stocks EA, Hauer P, et al. Epidermal nerve fiber density: Normative reference range and diagnostic efficiency. Arch Neurol Dec 1998; 55(12):1513-20.
18. Nebuchennykh M, Loseth S, Lindal S et al. The value of skin biopsy with recording of intraepidermal nerve fiber density and quantitative sensory testing in the assessment of small fiber involvement in patients with different causes of polyneuropathy. J Neurol Jul 2009; 256(7):1067-75.
19. Oaklander AL, Herzog ZD, Downs HM, et al. Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia. Pain. Nov 2013; 154(11):2310-2316.
20. Periquet MI, Novak V, Collins MP, et al. Painful sensory neuropathy: prospective evaluation using skin biopsy. Neurology Nov 10 1999; 53(8):1641-7.
21. Walk D, Wendelschafer-Crabb G, Davey C, et al. Concordance between epidermal nerve fiber density and sensory examination in patients with symptoms of idiopathic small fiber neuropathy. J Neurol Sci Apr 15 2007; 255(1-2):23-6.
22. Walk D. Role of skin biopsy in the diagnosis of peripheral neuropathic pain. Curr Pain Headache Rep Jun 2009; 13(3):191-6.

POLICY HISTORY:

Medical Policy Group, September 2009 (3)

Medical Policy Administration Committee, September 2009

Available for comment September 18-November 2, 2009

Medical Policy Group, September 2010 (3)

Medical Policy Group, October 2011 (3); Updated Policy Section, Key Points Section, References

Medical Policy Administration Committee, November 2011

Medical Policy Group, October 2012 (3): 2012 Update to Description, Policy, Key Points, Governing Bodies, and References

Medical Policy Administration Committee, October 2012

Available for comment October 24 through December 10, 2012

Medical Policy Panel, October 2013

Medical Policy Group, December 2013 (2): No change to policy statement. Removed “Intraepidermal” from title. Description, Key Points, References updated to reflect findings of literature search through September 2013.

Medical Policy Panel, October 2014

Medical Policy Group, October 2014 (5): No change to policy statement. Updated Key Points and References with literature review through August 20, 2014.

Medical Policy Panel, December 2015

Medical Policy Group, December 2015 (6): Updates to Description, Key Points and Approved by Governing Bodies; no change to policy statement.

Medical Policy Panel, December 2016

Medical Policy Group, December 2016 (6): Updates to Key Points and Summary; removed old policy statement from 2011. No change to current policy statement.

Medical Policy Panel, December 2017

Medical Policy Group, December 2017 (6): Updates to Description, Key Points and Practice Guidelines.

Medical Policy Panel, December 2018

Medical Policy Group, January 2019 (3): Updates to Description, Key Points, Practice Guidelines and Position Statements, References, and Key Words: added IENF, sudomotor nerve fibers, sweat gland nerve fiber density, and SGNF. No changes to policy statement or intent.

Medical Policy Panel, December 2019

Medical Policy Group, January 2020 (3): 2020 Updates to Key Points and Approved by Governing Bodies. No changes to policy statement or intent.

Medical Policy Panel, December 2020

Medical Policy Group, January 2021 (3): 2021 Updates to Key Points, Practice Guidelines and Position Statements, and References. No changes to policy statement or intent.

Medical Policy Panel, December 2021

Medical Policy Group, December 2021 (3): 2021 Updates to Key Points. Policy statement updated to remove “not medically necessary.” No other changes to policy statement or intent.

Medical Policy Panel, December 2022

Medical Policy Group, December 2022 (3): 2022 Updates to Key Points and References. No other changes to policy statement or intent.

Medical Policy Panel, December 2023

Medical Policy Group, December 2023 (11): Updates to Key Points, Approved by Governing Bodies, Benefit Application and References. No changes to policy statement or intent.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.