mp-392 - mp-392 - Medical Policies
Nerve Fiber Density Measurement
Policy Number: MP-392
Latest Review Date: January 2021
Policy Grade: C
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:
Individual presents with symptoms of painful sensory neuropathy; AND
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
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
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 not medically necessary and 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 not medically necessary and 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.
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.
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 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.
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.
Literature searches using the MEDLINE database have been performed through November 3, 2020.
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 5th 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).
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.
European Federation of Neurological Societies
The European Federation of Neurological Societies (EFNS) jointly updated its guidelines with Peripheral Nerve Society on the use of skin biopsy in the diagnosis of small fiber neuropathy in 2010.The guidelines stated that IENF density is a reliable and efficient technique to assess the diagnosis of small fiber neuropathy (recommendation level A). Normative reference values are available for bright-field immunohistochemistry (recommendation level A) but not for confocal immunofluorescence. The guidelines recommended that newly established laboratories should provide their own values stratified for age and sex normative values, intra- and interobserver reliability, and interlaboratory agreement.
U.S. Preventive Services Task Force
Nerve fiber density testing is not a preventive service.
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 Act (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 IENF density measurement (i.e., tissue preparation, immunostaining with anti-protein-gene-product 9.5, and counting) may also be done by local research pathology labs. Some laboratories that offer IENF density testing include Therapath Neuropathology, Advanced Laboratory Services, Mayo Medical Laboratories, Corinthian Reference Lab, and Bako Integrated Physician Solutions.
Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.
ITS: Home Policy provisions apply
FEP: FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.
There is not a specific code for this test. Claims should be billed with the following code:
Unlisted surgical pathology procedure
Alport AR, Sander HW. Clinical approach to peripheral neuropathy: anatomic localization and diagnostic testing. Continuum (Minneap Minn) 2012; 18(1):13-38.
American Academy of Neurology. Evaluation of distal symmetric polyneuropathy: role of autonomic testing, nerve biopsy, and skin biopsy (guideline detail). 2019; https://www.aan.com/Guidelines/home/GuidelineDetail/316. Accessed November 3, 2020.
Bakkers M, Merkies IS, Lauria G et al. Intraepidermal nerve fiber density and its application in sarcoidosis. Neurology 2009; 73(14):1142-8.
Boruchow SA, Gibbons CH. Utility of skin biopsy in management of small fiber neuropathy. Muscle Nerve. Dec 2013;48(6):877-882.
Bril V, England JD, Franklin GM et al. Evidence-based guideline: treatment of painful diabetic neuropathy—report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine & Rehabilitation. Neurology 2011; 76(20):1758-1765. Available online at: www.neurology.org/content/76/20/1758.full.pdf+html?sid=d4664917-c2c7-4b5e-a8ba-8813fa5501fa.
Devigili G, Tugnoli V, Penza P, et al. The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain 2008; 131(Pt 7):1912-25.
Dworkin RH, O'Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 2007; 132(3):237-51.
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.
England JD, Gronseth GS, Franklin G, et al. 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 2005; 64(2):199-207.
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):177-84.
Fabry V, Gerdelat A, Acket B, et al. Which Method for Diagnosing Small Fiber Neuropathy?. Front Neurol. 2020; 11: 342.
Gibbons CH, Illigens BM, Wang N et al. Quantification of sudomotor innervation: a comparison of three methods. Muscle Nerve 2010; 42(1):112-9.
Gibbons CH, Illigens BM, Wang N et al. Quantification of sweat gland innervation: a clinical-pathologic correlation. Neurology 2009; 72(17):1479-86.
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. Available online at www.aace.com/sites/default/files/DMGuidelinesCCP.pdf. Last accessed December 2013.
Holland NR, Stocks A, Hauer P, et al. Intraepidermal nerve fiber density in patients with painful sensory neuropathy. Neurology 1997; 48(3):708-11.
Hovaguimian A, Gibbons CH. Diagnosis and treatment of pain in small-fiber neuropathy. Curr Pain Headache Rep 2011; 15(3):193-200.
Jacobs AM, Cheng D. Management of diabetic small-fiber neuropathy with combination L-methylfolate, methylcobalamin, and pyridoxal 5’-phosphate. Rev Neurol Dis 2011; 8(1-2):39-47.
Joint Task Force of the EFNS and the PNS. 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. J Peripher Nerv Syst 2010; 15(2): 79-92.
Kles KA and Bril V. Diagnostic tools for diabetic sensorimotor polyneuropathy. Curr Diabetes Rev 2006; 2(3):353-61.
Krishnan ST, Quattrini C, Jeziorska M, et al. Abnormal LDIflare but normal quantitative sensory testing and dermal nerve fiber density in patients with painful diabetic neuropathy. Diabetes Care 2009; 32(3):451-5.
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; 15(3):202-7.
Lauria G, Cornblath DR, Johansson O, et al. European Federation of Neurological Societies. EFNS guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathy. Eur J Neurol 2005; 12(10):747-58.
Luo KR, Chao CC, Chen YT et al. Quantitation of sudomotor innervation in skin biopsies of patients with diabetic neuropathy. J Neuropathol Exp Neurol 2011; 70(10):930-8.
McArthur JC, Stocks EA, Hauer P, et al. Epidermal nerve fiber density: Normative reference range and diagnostic efficiency. Arch Neurol 1998; 55(12):1513-20.
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 2009; 256(7):1067-75.
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.
Periquet MI, Novak V, Collins MP, et al. Painful sensory neuropathy: prospective evaluation using skin biopsy. Neurology 1999; 53(8):1641-7.
Scherens A, Maier C, Haussleiter IS, et al. Painful or painless lower limb dysesthesias are highly predictive of peripheral neuropathy: Comparison of different diagnostic modalities. Eur J Pain 2009; 13(7):711-8.
Sommer C, Lauria G. Skin biopsy in the management of peripheral neuropathy. Lancet Neurol 2007; 6(7):632-42.
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 2007; 255(1-2):23-6.
Walk D. Role of skin biopsy in the diagnosis of peripheral neuropathic pain. Curr Pain Headache Rep 2009; 13(3):191-6.
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.
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