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Nerve Fiber Density Measurement

Policy Number: MP-392

Latest Review Date: January 2019

Category: Medicine                                                               

Policy Grade: C

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.

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 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.

Key Points:

Literature searches using the MEDLINE database have been performed through October 30, 2018.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. The balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose.

Nerve Fiber Density Measurement

Clinical Context and Test Purpose

The purpose of intraepidermal nerve fiber density measurement is to provide a diagnostic option that is an alternative to or an improvement on existing testing in patients with suspected idiopathic small fiber neuropathy.

The question addressed in this evidence review is: does the evidence on intraepidermal nerve fiber density and sweat gland density measurements effect the diagnosis and monitoring of small fiber neuropathy?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest are individuals with suspected idiopathic small fiber neuropathy.

Interventions

The test being considered is intraepidermal nerve fiber density measurement.

Comparators

Comparators of interest include standard clinical workup.

Outcomes

The general outcomes of interest are test accuracy, change in disease status, symptoms, and quality of life.

Timing

Though not completely standardized, follow-up for suspected idiopathic small fiber neuropathy symptoms would typically occur in the weeks to months after starting treatment.

Setting

Patients with suspected idiopathic small fiber neuropathy are actively managed by neurologists and primary care providers in an outpatient clinical setting.

Study Selection Criteria

Below are selection criteria for studies to assess whether a test is clinically valid.

1. The study population represents the population of interest. Eligibility and selection are   

    described.

2. The test is compared with a credible reference standard.

3. If the test is intended to replace or be an adjunct to an existing test; it should also be  

    compared with that test.

4. Studies should report sensitivity, specificity, and predictive values. Studies that  completely   

    report true- and false-positive results are ideal. Studies reporting other measures (e.g., ROC,

    AUROC, c-statistic, likelihood ratios) may be included but are  less informative.

5. Studies should also report reclassification of diagnostic or risk category.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

The American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation performed a literature review (2009) to evaluate the diagnostic accuracy of IENF density in the detection of small fiber neuropathy.

They adopted a clinical diagnosis of small fiber neuropathy as the independent reference standard for calculation of sensitivity and specificity. Eight studies were reviewed that employed a case-control design with patients with established polyneuropathy and normal controls. Significant differences were found between the two groups. For example, McArthur et al (1998) studied 98 normal controls and 20 patients with sensory neuropathies.

The density of epidermal nerve fibers in the controls was 13.8 per mm in the calf (5th percentile of controls: 3.8 per mm), with a significant mean reduction in the patient population (value not reported) and a diagnostic efficiency of 88% (compared to healthy controls). An earlier report by this group showed a mean IENF density of 4.9 in 20 patients with sensory neuropathy and a mean IENF density of 16.3 in 20 age-matched controls.

However, none of the studies reviewed included an appropriate group of patients, i.e., those with conditions causing lower extremity pain or sensory complaints that might be confused with polyneuropathy. In addition, the sensitivity of IENF density ranged from 45% to 90% compared to healthy controls, indicating that the absence of reduced IENF density would not rule out polyneuropathy.

The American Association of Clinical Endocrinologists (AACE) conducted an evidence review on diabetic neuropathy for their 2011 guidelines for clinical practice for developing a diabetes mellitus comprehensive care plan.

The evidence review found that there is Level 3 evidence (cross-sectional studies) to show that intraepidermal nerve fiber density correlates inversely with both cold and heat detection thresholds and is significantly reduced in symptomatic patients with normal findings from nerve conduction studies and those with metabolic syndrome, impaired glucose tolerance, and impaired fasting glucose, suggesting early damage to small nerve fibers. Level 3 evidence (surveillance studies) indicates that intraepidermal nerve fiber density is reduced in painful neuropathy compared with that observed in painless neuropathy. Level-2 evidence (prospective cohort studies) indicates that diet and exercise intervention in impaired glucose tolerance lead to increased intraepidermal nerve fiber density. The review concludes that these data suggest that intraepidermal nerve fiber loss is an early feature of metabolic syndrome, prediabetes, and established diabetes mellitus and that the loss progresses with increasing neuropathic severity. In addition, there may be nerve regeneration with treatment (diet and exercise).

The single prospective study (1999) that was identified in the 2009 AAN, AANEM, and AAPMR literature review included a cohort of 117 patients presenting with bilateral painful feet.  In this report, skin biopsy was done only in the subset of 32 patients who had normal nerve conduction studies, and the study did not compare the results of the IENF density to an independent reference standard to confirm the presence of small fiber neuropathy. The AAN, AANEM, and AAPMR concluded that IENF density assessment is “possibly useful” to identify distal symmetric polyneuropathy, including small fiber neuropathy, in symptomatic patients with suspected polyneuropathy (Level C recommendation). Future research recommendations included the need for studies to characterize the diagnostic accuracy of skin biopsy in distinguishing patients with suspected polyneuropathy (particularly small fiber neuropathy) from appropriate patients with sensory complaints or pain unrelated to peripheral neuropathy, using a predetermined reference standard.

Diagnostic accuracy of skin biopsy was assessed in a 2009 study with 210 patients who had signs of small fiber neuropathy from various conditions. The diagnosis of pure small fiber neuropathy (n=45) was established if patients had clinical symptoms and sensory deficits but preserved vibration and joint sense. Using the 5th percentile as the threshold (6.7 fibers per millimeter), IENF density had a sensitivity of 35% and a specificity of 95%.

Additional studies include large retrospective series. Devigili et al (2008) retrospectively reviewed 486 patients referred for suspected sensory neuropathy. This study lacked an independent reference standard, because the IENF results determined whether patients were included in the study group. Walk et al (2007) examined the concordance between foot IENF density and clinical findings in 106 patients with possible idiopathic small fiber neuropathy. An IENF density of 8 per millimeter was found to have the highest sensitivity (88%) and specificity (81%), using the sensory deficit to pinprick as the standard. In a 2009 review, Walk concluded that a reduction in IENF density provides supportive evidence of a loss of cutaneous efferent, but “clinical features remain paramount in the diagnostic process and the possibility of small fiber dysfunction is not excluded by an IENF density in the normal range.”

Section Summary: Clinical Validity

IENF density decreases across age and sex in healthy controls and, therefore, density measurements in patients suspected of small fiber neuropathy are compared with age- and sex-adjusted normative values. Few studies have prospectively compared the clinical validity of IENF density measurements in a population of patients suspected of small fiber neuropathy with an established reference standard. The available studies have shown low sensitivity and high specificity, suggesting that an IENF density below the 5th percentile of healthy controls may support a diagnosis of small fiber neuropathy, but IENF density above the 5th percentile cannot be used to rule it out.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

An issue to consider for this diagnostic test is whether objective confirmation in patients with a clinical diagnosis of small fiber neuropathy will alter treatment decisions and lead to improved health outcomes. Oaklander et al (2013) conducted a prospective study to evaluate whether small fiber neuropathy may have been the cause of symptoms in patients who had a prior diagnosis of fibromyalgia by an independent physician.

Of 27 patients, skin biopsies were consistent with small fiber neuropathy (<5 percentile of the norm) in 41% compared with 3% of matched control subjects, leading to investigation of other potential causes. A 2013 retrospective analysis by Boruchow and Gibbons found a change in diagnosis or management in 36 of 69 patients (52%) who had a skin biopsy at their institution for evaluation of possible small fiber neuropathy.

Determination of low or borderline IENF density led to newly identified diseases in eight patients, more aggressive management of diabetes mellitus in eight patients, and further laboratory testing in four patients. Of the 35 patients who had normal skin biopsies, 14 had new treatments and/or diagnoses, including musculoskeletal pain, plantar fasciitis, Morton’s neuroma, restless legs syndrome, lumbar spinal stenosis, Raynaud’s syndrome, peripheral nerve hyperexcitability, autoimmune autonomic ganglionopathy, and depression. The authors reported that examination findings were not effective at distinguishing patients with or without pathologic determination of small fiber neuropathy, and that some physicians at their institution appeared to use skin biopsies as a way to rule out, rather than rule in, a diagnosis of small fiber neuropathy. The authors did not report if the changes in diagnosis or management led to an improvement in health outcomes.

A 2011 review of the diagnosis and treatment of pain in small-fiber neuropathy indicate that the history and physical exam are still considered the gold standard and that further testing may be unnecessary, particularly in the context of an associated disease.

However, the authors suggest that IENF-density testing may provide diagnostic confirmation or additional guidance if the diagnosis is less clear. Thus, facilitating a diagnosis in patients with idiopathic small fiber neuropathy can potentially change management.

Section Summary: Clinical Utility

There would be little benefit on health outcomes in patients who can be diagnosed clinically or who have a condition such as diabetes that is associated with neuropathy. However, 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, potentially changing management.

Repeated Intraepidermal Nerve Fiber Density Measurement

Clinical Context and Test Purpose

The purpose of repeated intraepidermal nerve fiber density measurement is to provide a diagnostic option that is an alternative to or an improvement on existing testing in patients with an established diagnosis of small fiber neuropathy.

The question addressed in this evidence review is: does the evidence on repeated intraepidermal nerve fiber density effect the diagnosis and monitoring of small fiber neuropathy?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest are individuals with an established diagnosis of small fiber neuropathy.

Interventions

The test being considered is repeated intraepidermal nerve fiber density measurement.

Comparators

Comparators of interest include continued clinical monitoring.

Outcomes

The general outcomes of interest are test accuracy, change in disease status, symptoms, and quality of life.

Timing

Though not completely standardized, follow-up for an established diagnosis of small fiber neuropathy would typically occur in the weeks to months after starting treatment.

Setting

Patients with an established diagnosis of small fiber neuropathy are actively managed by neurologists and primary care providers in an outpatient clinical setting.

Study Selection Criteria

Below are selection criteria for studies to assess whether a test is clinically valid.

1. The study population represents the population of interest. Eligibility and selection are described.

2. The test is compared with a credible reference standard.

3. If the test is intended to replace or be an adjunct to an existing test; it should also be  

    compared with that test.

4. Studies should report sensitivity, specificity, and predictive values. Studies that  completely report true- and false-positive results are ideal. Studies reporting other measures (e.g., ROC, AUROC, c-statistic, likelihood ratios) may be included but are less        informative.

5. Studies should also report reclassification of diagnostic or risk category.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse). Further studies are needed to establish the sensitivity, specificity, and predictive values of repeated intraepidermal nerve fiber density testing in patients with small fiber neuropathy.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials. No such studies have been identified.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Section Summary: Clinical Utility

There are no RCTs that have directly evaluated the use of repeat testing of nerve fiber density to improve health outcomes for patients with small fiber neuropathy. The available evidence does not demonstrate that the addition of repeat nerve fiber density testing to standard clinical assessment would influence treatment or define a treatment pathway.

Sweat Gland Nerve Fiber Density Measurement

Clinical Context and Test Purpose

The purpose of sweat gland nerve fiber density measurement is to provide a diagnostic option that is an alternative to or an improvement on existing testing in patients with suspected small fiber neuropathy.

The question addressed in this evidence review is: does the evidence on intraepidermal nerve fiber density and sweat gland density measurements effect the diagnosis and monitoring of small fiber neuropathy?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest are individuals with suspected small fiber neuropathy.

Interventions

The test being considered is sweat gland nerve fiber density measurement.

Comparators

Comparators of interest include standard clinical workup.

Outcomes

The general outcomes of interest are test accuracy, change in disease status, symptoms, and quality of life.

Timing

Though not completely standardized, follow-up for suspected small fiber neuropathy would typically occur in the weeks to months after starting treatment.

Setting

Patients with suspected small fiber neuropathy are actively managed by neurologists and primary care providers in an outpatient clinical setting.

Study Selection Criteria

Below are selection criteria for studies to assess whether a test is clinically valid.

1. The study population represents the population of interest. Eligibility and selection are described.

2. The test is compared with a credible reference standard.

3. If the test is intended to replace or be an adjunct to an existing test; it should also be compared with that test.

4. Studies should report sensitivity, specificity, and predictive values. Studies that completely report true- and false-positive results are ideal. Studies reporting other measures (e.g., ROC, AUROC, c-statistic, likelihood ratios) may be included but are less          informative.

5. Studies should also report reclassification of diagnostic or risk category.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility

Clinically Valid

In their report, Gibbons et al (2009) found a significant decrease in the mean SGNF density of diabetic subjects compared to controls, although there was considerable overlap in the ranges.

There was also a significant association between the SGNF density and neuropathy scores measured by the Neuropathy Impairment Score in the Lower Limb, the Michigan Diabetic Neuropathy Score Part 1, and the Toronto Clinical Scoring System, but not the Michigan Neuropathy Screening Instrument. There was a moderate correlation (r=0.66) between SGNF density and IENF density.

Luo et al (2011) evaluated SGNF density in 35 patients with Type 2 diabetes and sensory neuropathy (stocking distribution and reduced IENF density).

Normative values were established in 107 control subjects, and sudomotor denervation was defined as a SGNF density less that the 5th percentile cutoff value for the sex (1.58% for men and 2.63% for women). There was no effect of age on the SGNF density. Sudomotor denervation was present in 42.86% of patients with diabetic neuropathy. The SGNF was lower in patients with anhidrosis of the feet compared with patients with normal sweating (0.89% vs. 3.10%) and was not associated with autonomic symptoms in the cardiovascular, gastrointestinal, or genitourinary systems.

No studies were identified that evaluated the sensitivity or specificity of SGNF density measurement.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials.

Analysis of SGNF density could potentially be considered complementary to IENF density, since they assess autonomic and somatic nerves, respectively. However, no studies were identified to support an improvement in health outcomes.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Section Summary: Sweat Gland Nerve Fiber Density Measurement

There is considerable overlap in the ranges of SGNF-density in patients with diabetic neuropathy and controls. No studies were identified that evaluated the diagnostic accuracy of SGNF density measurement. No studies were identified that showed an improvement in health outcomes with SGNF-density measurements.

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) published a 2005 guideline on the use of skin biopsy in peripheral neuropathy.

The EFNS concluded that skin biopsy is a safe, validated, and reliable technique for the determination of IENF density. The EFNS published updated guidelines 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 stratified for age and gender normative values, intra- and interobserver reliability, and interlaboratory agreement.

U.S. Preventive Services Task Force

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 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 PGP 9.5 is commercially available using a biopsy kit, although IENF density measurement (i.e., tissue preparation, immunostaining with PGP 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.

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:  FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

Current Coding: 

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

CPT Codes:                 88399              Unlisted surgical pathology procedure

References:

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  3. Boruchow SA, Gibbons CH. Utility of skin biopsy in management of small fiber neuropathy. Muscle Nerve. Dec 2013;48(6):877-882.

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  22. 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.

  23. 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.

  24. 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.

  25. Periquet MI, Novak V, Collins MP, et al. Painful sensory neuropathy: prospective evaluation using skin biopsy. Neurology 1999; 53(8):1641-7.

  26. 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.

  27. Sommer C, Lauria G. Skin biopsy in the management of peripheral neuropathy. Lancet Neurol 2007; 6(7):632-42.

  28. 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.

  29. Walk D. Role of skin biopsy in the diagnosis of peripheral neuropathic pain. Curr Pain Headache Rep 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.

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.