Most patients with peripheral neuropathy exhibit evidence of large fiber involvement, characterized by numbness, tingling, loss of deep tendon reflexes, and abnormal electrophysiologic 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, 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 electrophysiologic studies. The disparity between subjective complaints and objective signs increases the difficulty of diagnosis. Also, 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 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 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. Sweat gland nerve fiber density can be assessed from the same tissue prepared for IENF density testing provided that the biopsy sample is of sufficient depth. Tissue samples may also be counterstained to identify the boundaries of the sweat glands better.

Treatment

There is no curative treatment for 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 the progression of the disease and its symptoms.

Regulatory Status

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. These tests are available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments 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.

Related Policies

• Quantitative Sensory Testing (Policy #031 in the Medicine Section)

A. Individual presents with symptoms of painful sensory neuropathy; AND
B. 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
C. 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
D. Electromyography and nerve conduction studies are normal and show no evidence of large-fiber neuropathy.

For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.

FIDE SNP:

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

[RATIONALE: This policy was created in 2010 and has been updated regularly with searches of the MEDLINE database. The most recent literature update was performed through October 14, 2019.

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. That is, 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

Intraepidermal Nerve Fiber Density Measurement

Clinical Context and Test Purpose

The purpose of IENF 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 policy is: Does the evidence on IENF density and sweat gland density measurements affect the diagnosis and monitoring of small fiber neuropathy?

The following PICOs were used to select literature to inform this policy.

Patients

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

Interventions

The test being considered is IENF density measurement.

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

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 (QOL).

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

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., receiver operating characteristic , area under receiver operating characteristic , c-statistic, likelihood ratios) may be included but are less informative.
5. Studies should also report reclassification of the diagnostic or risk category.

Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy and alternative sources exist. This policy 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 (2009)performed a literature review to evaluate the diagnostic accuracy of IENF density in the detection of small fiber neuropathy.^1, They adopted a clinical diagnosis of small fiber neuropathy as the independent reference standard for the 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 who have sensory neuropathies.⁴ 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 study population (p-value not reported) and diagnostic efficiency of 88% (vs healthy controls). An earlier report (1997) by this group showed a mean IENF density of 4.9 per mm in 20 patients with sensory neuropathy and a mean IENF density of 16.3 per mm in 20 age-matched controls.^2, 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 with healthy controls, indicating that the absence of reduced IENF density would not rule out polyneuropathy.

The American Association of Clinical Endocrinologists (2011) conducted an evidence review on diabetic neuropathy for its guidelines used to develop a comprehensive diabetes care plan.^3, The evidence review found level 3 evidence (cross-sectional studies) that IENF density correlated inversely with 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) indicated that IENF density is reduced in painful neuropathy compared with that observed in painless neuropathy. Level 2 evidence (prospective cohort studies) indicated that diet and exercise interventions in impaired glucose tolerance lead to increased IENF density. Reviewers concluded these data suggested that IENF loss is an early feature of metabolic syndrome, prediabetes, and established diabetes and that the loss progresses with increasing neuropathic severity. Also, there may be nerve regeneration with treatment (diet and exercise).

The single prospective study (1999) identified in the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine and American Academy of Physical Medicine and Rehabilitation (2009) literature review included a series of 117 patients presenting with painful bilateral feet.^4, In this report, a 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 with an independent reference standard to confirm the presence of small fiber neuropathy. American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation 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.

The diagnostic accuracy of skin biopsy was assessed in a 2009 study of 210 patients who had signs of small fiber neuropathy from various conditions.^5, 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 a threshold (6.7 fibers per mm), the sensitivity of IENF density was 35%, and specificity was 95%.

Additional studies include large retrospective series. Devigili et al (2008) retrospectively reviewed 486 patients referred for suspected sensory neuropathy.^6, 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.^7, An IENF density of 8 per mm was found to have the highest sensitivity (88%) and specificity (81%), using the sensory deficit to a pinprick as the standard. In a review, Walk (2009) concluded that a reduction in IENF density provides supportive evidence of a loss of cutaneous efferents, 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.”^8,

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 fifth percentile of healthy controls may support a diagnosis of small fiber neuropathy, but IENF density above the fifth 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 (RCTs).

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) prospectively evaluated whether small fiber neuropathy may have been the cause of symptoms in patients who had a prior diagnosis of fibromyalgia by an independent physician.^9, Of 27 patients, skin biopsies were consistent with small fiber neuropathy (<5th percentile of the norm) in 41% compared with 3% of matched control subjects, leading to an investigation of other potential causes. A retrospective analysis by Boruchow and Gibbons (2013) found a change in diagnosis or management in 36 (52%) of 69 patients who had a skin biopsy at their institution for evaluation of possible small fiber neuropathy.^10, Determination of low or borderline IENF density led to newly identified diseases in eight patients, more aggressive diabetes management 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 neuroma, restless legs syndrome, lumbar spinal stenosis, Raynaud 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 to rule in, a diagnosis of small fiber neuropathy. The authors did not report whether the changes in diagnosis or management led to improved health outcomes.

A 2011 review of the diagnosis and treatment of pain in small fiber neuropathy indicated that the history and physical exam are still considered the criterion standard and that further testing may be unnecessary, particularly in the context of associated disease.^11, However, the authors suggested that IENF density measurement 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 to health outcomes in patients who can be diagnosed clinically or who have a condition (e.g., diabetes) 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 help diagnose idiopathic small fiber neuropathy, potentially changing management.

Repeated IENF Density Measurement

Clinical Context and Test Purpose

The purpose of repeated IENF 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 policy is: Does the evidence on repeated IENF density affect the diagnosis and monitoring of small fiber neuropathy?

The following PICOs were used to select literature to inform this policy.

Patients

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

Interventions

The test being considered is repeated IENF density measurement.

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

Comparators

Comparators of interest include continued clinical monitoring.

Outcomes

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

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.

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., receiver operating characteristic , area under receiver operating characteristic , c-statistic, likelihood ratios) may be included but are less informative.
5. Studies should also report reclassification of the diagnostic or risk category.

Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy and alternative sources exist. This policy 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 IENF 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 RCTs. 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 SGNF 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 policy is: Does the evidence on IENF density and sweat gland density measurements affect the diagnosis and monitoring of small fiber neuropathy?

The following PICOs were used to select literature to inform this policy.

Patients

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

Interventions

The test being considered is SGNF density measurement.

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

Comparators

Comparators of interest include standard clinical workup.

Outcomes

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

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

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., receiver operating characteristic , area under receiver operating characteristic , c-statistic, likelihood ratios) may be included but are less informative.
5. Studies should also report reclassification of the diagnostic or risk category.

Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy and alternative sources exist. This policy 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 with controls, although there was considerable overlap in the ranges.^12, There was also a significant association between SGNF density and neuropathy scores as 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 by 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).^13, Normative values were established in 107 control subjects, and sudomotor denervation was defined as an SGNF density less than the 5th percentile cutoff value for the sex (1.58% for men, 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 density was lower in patients with anhidrosis of the feet (0.89%) compared with patients with normal sweating (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 RCTs.

Analysis of SGNF density could be considered complementary to IENF density, because they assess autonomic and somatic nerves, respectively.^14, However, no studies were identified to support 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: SGNF 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 clinical validity of SGNF density measurement. No studies were identified that showed improvements 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 measurement, the evidence includes reports assessing whether IENF density measurement is technically reliable, clinically valid, and clinically useful. The 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 has also indicated 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 help to diagnose 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 an established diagnosis of small fiber neuropathy who receive repeated IENF density measurement, the evidence is limited. The 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; they assess the efficacy of activity and medications on small fiber neuropathy. If successful, there might be a role for repeated IENF density measurements to result in a change in management (e.g., 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 the 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 density measurement, the evidence includes comparisons with control values. The relevant outcomes are test accuracy, change in disease status, symptoms, and quality of life. Measurement of sweat gland nerve fiber 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 sweat gland nerve fiber density measurement. The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION

Clinical Input From Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from 4 physician specialty societies and 2 academic medical centers while this policy was under review in 2011. References were provided and reviewed. The input was mixed. Some respondents indicated that the criteria standard for diagnosis of small fiber neuropathy is the history and clinical examination combined with nerve conduction studies and that the skin biopsy only supports a clinical impression of a small fiber polyneuropathy and cannot exclude the diagnosis. One reviewer commented that patients who benefit from this test are those who suffer from the symptoms of small fiber neuropathy but have no predisposing condition (idiopathic). Other reviewers, who generally supported the medical necessity of intraepidermal nerve fiber (IENF)density management for diagnosis, acknowledged that the test has limited utility when disease is clinically advanced and that evidence to demonstrate that the use of skin biopsy with intraepidermal nerve fiber density measurement improves clinical outcomes is only now emerging.

Practice Guidelines and Position Statements

American Association of Clinical Endocrinologists

The American Association of Clinical Endocrinologists published guidelines in 2015 on developing a comprehensive diabetes care plan.^3, 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 Association referenced the 2010 European Federation of Neurological Societies (EFNS) and Peripheral Nerve Society guidelines on the use of IENF quantification to confirm the clinical diagnosis of small fiber neuropathy (consensus).^15,

American Academy of Neurology et al

The practice parameters from the AAN, American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation (2009) concluded that IENF density assessment using protein gene product 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.^1,These guidelines were reaffirmed by AAN in 2013.

The American Association of Neuromuscular Electrodiagnostic Medicine, in conjunction with AAN and American Academy of Physical Medicine and Rehabilitation (2009), published an ordered set of case definitions of “distal symmetrical polyneuropathy” for clinical research ranked by the likelihood of disease.^16, The recommendations for case definitions that included 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 EFNS (2005) published guidelines on the use of skin biopsy in peripheral neuropathy.^17, The EFNS concluded that skin biopsy was a safe, validated, and reliable technique for the determination of IENF density. The EFNS jointly updated its guidelines with Peripheral Nerve Society on the use of skin biopsy in the diagnosis of small fiber neuropathy in 2010.^15, 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 sex normative values, intra- and interobserver reliability, and interlaboratory agreement.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this policy are listed in Table 1.

Table 1. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT00780559	Improving Neuropathy and Mobility in Subjects With Early Diabetes	72	Feb 2018
NCT02341261	Activity for Diabetic Polyneuropathy: the ADAPT Study	140	Apr 2020
Unpublished
NCT01503892a	Metanx Effects on Nerve Fiber Density in Neuropathic Diabetics	100	Oct 2013 (unknown)
NCT01079325a	A Phase 2b Repeat Dosing Clinical Trial of SB-509 in Subjects With Moderately Severe Diabetic Neuropathy	170	Apr 2016 (completed)

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.]
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Nerve Fiber Density Measurement
Nerve Fiber Density Testing
Nerve Fiber Density, Epidermal
Nerve Fiber Density, Intraepidermal
Nerve Fiber Density, Sweat Gland
Intraepidermal Nerve Fiber Density
Epidermal Nerve Fiber Density
Small Fiber Neuropathy Testing
Neuropathy Testing, Small Fiber
Sweat Gland Nerve Fiber Density
Therapath Skin Biopsy

References:
1. England JD, Gronseth GS, Franklin G, et al. Practice Parameter: evaluation of distal symmetric polyneuropathy: role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation. Neurology. Jan 13 2009;72(2):177-184. PMID 19056667

2. Holland NR, Stocks A, Hauer P, et al. Intraepidermal nerve fiber density in patients with painful sensory neuropathy. Neurology. Mar 1997;48(3):708-711. PMID 9065552

3. 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. Mar- Apr 2011;17(Suppl 2):1-53. PMID 21474420

4. Periquet MI, Novak V, Collins MP, et al. Painful sensory neuropathy: prospective evaluation using skin biopsy. Neurology. Nov 10 1999;53(8):1641-1647. PMID 10563606

5. 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):1067-1075. PMID 19252773

6. 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):1912-1925. PMID 18524793

7. 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):23-26. PMID 17337273

8. Walk D. Role of skin biopsy in the diagnosis of peripheral neuropathic pain. Curr Pain Headache Rep. Jun 2009;13(3):191-196. PMID 19457279

9. 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. PMID 23748113

10. Boruchow SA, Gibbons CH. Utility of skin biopsy in management of small fiber neuropathy. Muscle Nerve. Dec 2013;48(6):877-882. PMID 23553795

11. Hovaguimian A, Gibbons CH. Diagnosis and treatment of pain in small-fiber neuropathy. Curr Pain Headache Rep. Jun 2011;15(3):193-200. PMID 21286866

12. Gibbons CH, Illigens BM, Wang N, et al. Quantification of sweat gland innervation: a clinical-pathologic correlation. Neurology. Apr 28 2009;72(17):1479-1486. PMID 19398703

13. 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):930-938. PMID 21937916

14. Alport AR, Sander HW. Clinical approach to peripheral neuropathy: anatomic localization and diagnostic testing. Continuum (Minneap Minn). Feb 2012;18(1):13-38. PMID 22810068

15. 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. Jun 2010;15(2):79-92. PMID 20626771

16. 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. PMID 19086069

17. 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. Sep 2010;15(3):202-207. PMID 21040142

18. Centers for Medicare & Medicaid. National Coverage Determination (NCD) for Services Provided for the Diagnosis and Treatment of Diabetic Sensory Neuropathy with Loss of Protective Sensation (aka Diabetic Peripheral Neuropathy) (70.2.1). 2002; https://www.cms.gov/medicare-coverage-database/details/ncd- details.aspx?NCDId=171&ncdver=1&DocID=70.2.1&SearchType=Advanced&bc=IAAAABAAAAAAAA%3d%3d&. Accessed October 14, 2019.

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

11102
11103
11104
11105
11106
11107
88356