Nerve Fiber Density Testing
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Reviewed with literature search/10:2014
|Original Policy Date
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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 being investigated as an objective measure of small fiber neuropathy by identifying a reduction in the density of nerve fibers.
The majority of 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, the 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 electrophysiologic 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. 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.
In the last decade, 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.
Assessment of IENF and SGNF density with PGP 9.5 is commercially available from Therapath (New York) with 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.
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 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 investigational.
There are no specific codes for this analysis. Multiple CPT pathology codes would be used such as:
88305 - Level IV - Surgical pathology, gross and microscopic examination;
88314 - Special stains (List separately in addition to code for primary service); histochemical staining with frozen section(s)
88342 - Immunohistochemistry (including tissue immunoperoxidase), each antibody; and
88356 - Morphometric analysis; nerve.
There is a CPT code for skin biopsy:
11100 - Biopsy of skin, subcutaneous tissue and/or mucous membrane (including simple closure), unless otherwise listed; single lesion.
BlueCard/National Account Issues
No applicable information.
This policy was created in 2009 and updated periodically using the MEDLINE database. The most recent literature update was performed through August 20, 2014. In addition to recent studies, the searches identified a systematic review by the European Federation of Neurological Societies (EFNS) from 2005, updated guidelines from EFNS in 2010, and a jointly published evidence review and practice parameter for the American Academy of Neurology (AAN), American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM), and American Academy of Physical Medicine and Rehabilitation (AAPM&R) from 2009.(1-3) Assessment of a diagnostic technology typically focuses on the following 3 categories of evidence: (1) technical performance, (2) clinical validity in an appropriate patient population (diagnostic accuracy including sensitivity, specificity, and positive and negative predictive value), and (3) demonstration that the diagnostic information can be used to improve patient outcomes. Intraepidermal Nerve Fiber Density
This policy was created in 2009 and updated periodically using the MEDLINE database. The most recent literature update was performed through August 20, 2014. In addition to recent studies, the searches identified a systematic review by the European Federation of Neurological Societies (EFNS) from 2005, updated guidelines from EFNS in 2010, and a jointly published evidence review and practice parameter for the American Academy of Neurology (AAN), American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM), and American Academy of Physical Medicine and Rehabilitation (AAPM&R) from 2009.(1-3)
Assessment of a diagnostic technology typically focuses on the following 3 categories of evidence: (1) technical performance, (2) clinical validity in an appropriate patient population (diagnostic accuracy including sensitivity, specificity, and positive and negative predictive value), and (3) demonstration that the diagnostic information can be used to improve patient outcomes.
Intraepidermal Nerve Fiber Density
The EFNS systematic review determined that skin biopsy from the distal leg or foot with immunostaining with anti-protein-gene-product 9.5 (PGP 9.5) is a safe, validated, and reliable technique for the determination of intraepidermal nerve fiber (IENF) density, indicating adequate technical performance of this test. (1) The EFNS also concluded that IENF density is diagnostically efficient at distinguishing polyneuropathy patients (including small fiber neuropathy) from normal controls.
Assessment of clinical validity necessitates that studies include a representative patient population with an appropriate spectrum of patients and that the test be compared with an independently assessed gold standard. As discussed in the jointly published 2009 practice parameters of the AAN, AANEM, and AAPMR, (3) the EFNS systematic review did not assess the more clinically relevant question, which is: what is the diagnostic accuracy of skin biopsy in distinguishing symptomatic patients with polyneuropathy from symptomatic patients without polyneuropathy? For example, in patients with painful feet, would skin biopsy accurately distinguish patients with polyneuropathy from other conditions causing painful feet?
To address these questions, a committee of the AAN, AANEM, and AAPMR performed a literature review 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 2 groups. For example, McArthur et al. studied 98 normal controls and 20 patients with sensory neuropathies. (5) 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. (5) 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 conducted an evidence review on diabetic neuropathy for their 2011 guidelines for clinical practice for developing a diabetes mellitus comprehensive care plan.(6) 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 that was identified in the 2009 AAN, AANEM, and AAPM&R literature review included a cohort of 117 patients presenting with bilateral painful feet.(7) 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 AAPM&R 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.
Additional studies identified in the MEDLINE search for this policy included a 2007 retrospective evaluation by Walk et al of the concordance between foot IENF density and clinical findings in patients with possible idiopathic small fiber neuropathy who underwent skin biopsy for IENF density determination.(8)
Of 178 patients referred for evaluation, 106 met the inclusion criteria of idiopathic symmetric burning, paresthesias, hyperalgesia, or allodynia in a length-dependent distribution, with normal strength, reflexes, and nerve conduction studies. Sensory examination included assessment of pinprick sensitivity and a qualitative determination of vibration perception using a 128 Hz tuning fork at the great toe. An IENF density of 8 per mm was found to have the highest sensitivity (88%) and specificity (81%), using sensory deficit to pinprick as the standard. The mean foot IENF density for patients with normal sensation was 13.9±7.7 per mm, with a range of 0 to 36 per mm. The mean IENF density in the foot in the patient population was reduced to approximately 3 per mm (SD=4.9, 8.0, and 5.7 for the 3 patient groups, respectively; range, 0-29.5 per mm), depending on the severity of sensory deficit. Thus,there was considerable overlap in the range of IENF density between patients who showed a sensory deficit and those who did not. In a 2009 review, Walk 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.”(9)
In 2008, Devigili et al published a retrospective review of 486 patients referred for suspected sensory neuropathy.(10) A total of 150 patients met the entry criteria for the study, which were symptoms suggesting sensory neuropathy and availability of (1) clinical examination, including spontaneous and stimulusevoked pain, (2) a sensory and motor nerve conduction study, (3) warm and cooling thresholds assessed by quantitative sensory testing (QST), and (4) skin biopsy with distal IENF density. Based on the combined assessments, neuropathy was ruled out in 26 patients; 124 patients were diagnosed with
sensory neuropathy, 67 of whom were diagnosed with small fiber neuropathy. Using a cutoff of 7.63 IENF/mm at the distal leg (based on the 5th percentile of controls), 59 patients (88%) were considered to have abnormal nerve density. Only 7.5% of patients had abnormal results for all 3 examinations (clinical,
QST, skin biopsy), 43% had both abnormal skin biopsy and clinical findings, and 37% of patients had both abnormal skin biopsy and QST results. The combination of abnormal clinical and QST results was observed in only 12% of patients. These results indicate that most of the patients evaluated showed IENF
of less than 7.63 together with either abnormal spontaneous or evoked pain (clinical examination) or abnormal thermal thresholds (QST). The authors of this study recommended a new diagnostic “gold standard” based on the presence of at least 2 of 3 abnormal results (clinical, QST, and IENF density).
This study is limited by the lack of an independent reference standard, particularly since the IENF results affected whether patients were included in the study group. Prospective studies are needed to evaluate whether the addition of skin biopsy to clinical diagnoses improves detection of small fiber neuropathy in
an appropriately mixed patient population.
Scherens et al conducted a prospective study to assess the percentage of patients with lower limb dysesthesias (painful or painless) who had evidence of small fiber neuropathy.(11) Forty-two patients who presented to clinic with dysesthesias underwent standard neurophysiology, quantitative sensory testing
and measurement of IENF density. Thirty-seven of the patients (88%) were found to have abnormal IENF density, defined as a reduction of 1 SD below the mean of healthy controls (mean IENF density, 12 per mm) from a prior study. Four patients (9.5%) were categorized with pure large fiber neuropathy, 15
(35.7%) with pure small fiber neuropathy, and 22 (52.4%) with mixed large and small fiber neuropathy. Given that nearly 90% of patients with dysesthesias showed abnormal IENF density, this study raises questions about the value added from skin biopsy in a clinical setting. In another study, Krishnan et al
compared dermal nerve density, quantitative sensory testing (vibration, cold, warmth, and heat pain), and a new functional test of dermal vasodilation, called the laser Doppler imager flare in 2 groups of patients with type 2 diabetes (10 with painful neuropathy, 12 with more advanced painless neuropathy), and 15 healthy controls.(12) This study measured dermal (instead of intraepidermal) nerve density as a direct measure of the structural integrity of the innervation of dermal blood vessels as a reference for the noninvasive functional test. These and other authors have noted that deficits in nerve function may
precede anatomic changes. Studies are needed to evaluate when in the course of disease (ie, severity of clinical symptoms) decreases in IENF density become apparent.
In 2009, Bakkers et al reported a multicenter assessment of IENF density in 188 healthy volunteers and 72 patients with sarcoidosis to assess the discriminative ability of IENF density.(13) Of the 72 patients with sarcoidosis, 58 had symptoms of small fiber neuropathy, and 14 were without symptoms. Normative
values were stratified for age and sex, showing age-dependent decreases in IENF density and lower densities in men compared with women. Two of the 14 patients (14%) with sarcoidosis without symptoms of small fiber neuropathy had reduced IENF density. Nineteen of the 58 patients (33%) with sarcoidosis
and symptoms of small fiber neuropathy had reduced IENF density (less than 5th percentile of age- and sex-stratified normative values). Thus, a reduction in IENF density was able to identify one-third of sarcoidosis patients with symptoms of small fiber neuropathy.
Nebuchennykh et al assessed the diagnostic characteristics of skin biopsy in 210 patients with signs of small fiber neuropathy from various conditions.(14) The diagnosis of pure small fiber neuropathy (n=45) was established if patients had clinical symptoms and sensory deficits but with preserved vibration and joint
sense. Mixed fiber neuropathy (n=165) was diagnosed if there were more extensive sensory findings with a proximo-distal gradient, muscle weakness, or abnormal nerve conduction studies. The z scores were calculated from a reference set of 134 healthy individuals, with gender and age associated with a
decrease in IENF density. Using a z score less than 2 as the threshold, IENF density had a sensitivity of 31% and a specificity of 98%. Using the 5th percentile as a threshold (6.7 fibers/mm), the sensitivity of IENF density was 35% and specificity was 95%. When sensitivity was maximized from receiver operating
characteristic analysis (78% sensitivity, at a threshold of 10.3 fibers/mm), specificity decreased to 64%.
In 2010, Lauria et al published a multicenter study (8 sites) of normative reference values for IENF density at the distal leg.(15) Groups that previously reported normative IENF density values using brightfield immunohistochemistry provided available data to a coordinating center. Density data from a total of 550 healthy subjects (age range, 18-84 years) in the United States, Europe, and Asia were included in the analysis. There was a significant decrease in IENF density in both men and women with age. For women, the 5th percentile ranged from 8.4 fibers per mm at 20 to 29 years of age to 1.6 fibers per mm at
80 years or older. For men, the 5th percentile ranged from 6.1 fibers per mm at 20 to 29 years of age to 1.7 at 80 years or older. IENF density was lower in men than women between 20 and 69 years of age, but not for subjects 70 years or older. This finding may be limited by the smaller sample size in the older
age groups. There was no significant influence of height, weight, or body mass index for the IENF density normative scores (5th percentile).
Another 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 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.(16) 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 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.(17) Determination of low or borderline IENF density led to
newly identified diseases in 8 patients, more aggressive management of diabetes mellitus in 8 patients, and further laboratory testing in 4 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 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 2006 review of diagnostic tools for diabetic sensorimotor polyneuropathy by Kles and Bril (Eli Lilly Research Institute, Washington, DC) indicates that although many therapies are in clinical trials, current treatment options only palliate pain symptoms and do not target the underlying disease etiology.(18)
Kles and Bril concluded that although biopsy of skin and nerve may be beneficial for identifying the underlying pathology of the damaged nerve and extending our knowledge concerning the pathophysiology of diabetic sensory polyneuropathy when used in carefully controlled clinical trials, “initial testing in the
primary care and diabetes clinic settings can be done with simple tests for signs of neuropathy such as tuning fork, monofilament, and pinprick insensitivity.” A 2011 review of the diagnosis and treatment of pain in small-fiber neuropathy indicates 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.(19) However, the authors suggest that IENF-density testing may provide diagnostic confirmation or additional guidance if the diagnosis is less clear.
Sweat Gland Nerve Fiber Density
In a 2009 report, Gibbons et al evaluated sweat gland nerve fiber (SGNF) density measurements in punch skin biopsies from 30 diabetic subjects and 64 controls that were sectioned and stained with PGP 9.5 and compared with confocal microscopy with stereology.(20) Measurements of SGNF density were
normalized by area due to the large variability in sweat gland size, and specific methods were used to reduce the high inter- and intrareviewer variability in manual outlining of sweat gland area. The authors noted nonspecific background staining of the sweat glands with PGP 9.5 that made it difficult to measure
individual nerve fibers and sweat gland margins. There was an average of 1.6 sweat glands per biopsy. Blinded evaluation found a correlation of r equal to 0.93 between SGNF density and the stereologic estimate of sweat gland nerve fiber length. The intrareviewer intraclass correlation coefficient (ICC) was
0.886 and the interreviewer ICC was 0.892. A 2010 publication by the same authors found good reliability for either automated or manual quantification of SGNF density, but poor inter- and intrareviewer reliability when using a semiquantitative approach (5-point scale).(21)
In their 2009 report, Gibbons et al found a significant decrease in the mean SGNF density of diabetic subjects compared to controls, although there was considerable overlap in the ranges.(20) 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 evaluated SGNF density in 35 patients with type 2 diabetes and sensory neuropathy (stocking distribution and reduced IENF density).(22) 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, 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.
Analysis of SGNF density could potentially be considered complementary to IENF density, since they assess autonomic and somatic nerves, respectively.(23) However, no studies were identified to support an improvement in health outcomes.
Ongoing and Unpublished Clinical Trials
An online search of ClinicalTrials.gov in September 2014 identified a number of relevant trials on small fiber neuropathy.
- NCT01288937 is a randomized, double-blind trial of milnacipran for the treatment of idiopathic neuropathy pain. Included in the study will be 52 patients with signs and symptoms of a peripheral neuropathy, with either abnormal nerve conductions or abnormal epidermal nerve fiber density with neuropathic pain. Exclusion criteria include other causes of neuropathy (eg, diabetic neuropathy, toxic neuropathy, HIV neuropathy, celiac neuropathy, inherited neuropathy). The estimated study completion date is October 2014.
- NCT01503892 is a randomized, double-blind, placebo-controlled trial of Metanx for improving and reversing nerve damage in type 2 diabetic patients with peripheral neuropathy. IENF density will be measured at baseline and at the end of 12 months of treatment. The study had an expected enrollment of 100 patients with completion anticipated in October 2013. The status of this study is unknown.
- NCT01498211 will establish normative IENF density in 300 subjects without pain or neurologic impairment. The estimated study completion date is June 2013. The status of this study is unknown.
- NCT01079325 is a phase 2 study of the investigational drug SB-509 in patients with diabetic neuropathy. The study has an estimated enrollment of 150 patients with completion expected December 2014.
- The Department of Veteran Affairs is conducting a study (NCT00780559) to determine if an individually tailored diet and physical enhancement program can improve mobility, physical activity, and neuropathy in people with early diabetes. The primary outcome measure is the 6-minute walk test. Secondary outcome measures are physical activity and IENF density. There is an estimated enrollment of 142 patients; the estimated study completion date is January 2016.
Identified through clinical input was a 2011 pilot study of 11 patients with confirmed type 2 diabetes mellitus and symptoms consistent with small fiber neuropathy of the feet who were treated with a combination of the B vitamins L-methylfolate, methylcobalamin, and pyridoxal 5'-phosphate.(24) After 6
months of treatment, there was an increase in IENF density from 1.56 fibers/mm to 3.07 fibers/mm. Eight of the 11 patients (73%) had an increase in IENF density; 82% of study patients reported reduced frequency and intensity of paresthesias and dysesthesias. Limitations of this study included its small size,
method of participant selection, possible volunteer bias, lack of a placebo-treated group for comparison, lack of blinding, and the subjective nature of the visual analog scale. Randomized, double-blinded, controlled trials are needed to evaluate this potentially disease-modifying treatment.
Clinical Input Received 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, which were subsequently reviewed. The input was mixed. Some respondents indicated that the gold 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. Among those who supported the medical necessity of IENF-density testing, several
commented that this is the only test to allow an objective diagnosis and that small fiber neuropathy may be effectively managed with products such as L-methylfolate, methylcobalamin, and/or pyridoxal 5'-phosphate (study discussed above). Another 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 were generally in support of the medical necessity of 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 IENF density measurement improves clinical outcomes is only now emerging.
Summary of Evidence
Techniques to measure intraepidermal nerve fiber (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 the average IENF in groups of patients diagnosed with small fiber neuropathy in comparison with groups of 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.
However, there is limited evidence to indicate that measurement of IENF density in a patient clinically diagnosed with probable small fiber neuropathy improves health outcomes. Clinical input on the medical necessity of IENF density measurements was mixed but suggests acceptance of the procedure as an
objective measure for diagnosis among some providers. One population that may particularly benefit from IENF density measurement is individuals who have no known causes of neuropathy.
Overall, a number of questions remain about whether a quantitative assessment of IENF density results in improved health outcomes. Additional prospective studies are needed to evaluate the effect of this procedure in comparison with clinical diagnosis alone in patients with known causes of neuropathy. IENF density measurement may be considered medically necessary in patients with suspected idiopathic small fiber neuropathy when the individual presents with symptoms of painful sensory neuropathy, and there is no history of a disorder known to predispose to painful neuropathy (eg, diabetic neuropathy, toxic
neuropathy, human immunodeficiency virus 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. Assessment of IENF density in all other conditions is considered investigational.
Measurement of sweat gland nerve fiber (SGNF) density may lead to an improved understanding of the relation between the loss of sudomotor nerve fibers and symptoms of peripheral neuropathy. However, evidence is insufficient to permit conclusions regarding the impact of measurement of SGNF density on
health outcomes. Measurement of SGNF density is considered investigational.
Practice Guidelines and Position Statements
The American Association of Clinical Endocrinologists (AACE) published 2011 guidelines for clinical practice for developing a diabetes mellitus comprehensive care plan.(6) The guidelines state, based on consensus opinion, that diabetic painful neuropathy is diagnosed clinically and must be differentiated from other painful conditions. AACE references the European Federation of Neurological Societies’ guidelines on the use of IENF quantification to confirm the clinical diagnosis of small fiber neuropathy (consensus).(2)
The 2008 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 (AAPM&R) 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.(3)
In 2005, AANEM, in conjunction with AAN and AAPM&R, published an ordered set of case definitions of “distal symmetrical polyneuropathy” for clinical research ranked by the likelihood of disease.(25) 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.
The European Federation of Neurological Societies (EFNS) published a 2005 guideline on the use of skin biopsy in peripheral neuropathy.(1) EFNS concluded that skin biopsy is a safe, validated, and reliable technique for the determination of IENF density. EFNS published updated guidelines on the use of skin
biopsy in the diagnosis of small fiber neuropathy in 2010.2 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. Proposals for new studies included:
- A clinimetric approach to assess the correlation between skin innervation and the clinical symptoms and signs of small fiber neuropathy. Such studies should include patients whose clinical picture mimics that of small fiber neuropathy, to definitely assess specificity and sensitivity of skin biopsy in the diagnosis of this type of neuropathy.
- A consensus definition of small fiber neuropathy is needed to plan new studies that will determine the sensitivity and specificity of skin biopsy and other potential diagnostic strategies.
- Further studies should focus on the ability of skin biopsy to detect early changes of nerve fibers that predict the progression of neuropathy and that assist in assessing nerve degeneration and regeneration rates over time, to confirm the potential usefulness of the technique as an outcome measure in clinical practice and research.
U.S. Preventive Services Task Force Recommendations
Nerve fiber density testing is not a preventive service.
Medicare National Coverage
There is no national coverage decision (NCD) specifically regarding IENF density testing. The NCD for services provided for the diagnosis and treatment of diabetic sensory neuropathy with loss of protective sensation (also known as diabetic peripheral neuropathy) (70.2.1) provides the following information26 :
Effective for services furnished on or after July 1, 2002, Medicare covers, as a physician service, an evaluation (examination and treatment) of the feet no more often than every six months for individuals with a documented diagnosis of diabetic sensory neuropathy and loss of protective sensation, as long
as the beneficiary has not seen a foot care specialist for some other reason in the interim. Loss of protective sensation shall be diagnosed through sensory testing with the 5.07 monofilament using established guidelines, such as those developed by the National Institute of Diabetes and Digestive
and Kidney Diseases guidelines. Five sites should be tested on the plantar surface of each foot, according to the National Institute of Diabetes and Digestive and Kidney Diseases guidelines. The areas must be tested randomly since the loss of protective sensation may be patchy in distribution, and the patient may get clues if the test is done rhythmically. Heavily callused areas should be avoided. As suggested by the American Podiatric Medicine Association, an absence of sensation at two or more sites out of 5 tested on either foot when tested with the 5.07 Semmes-Weinstein monofilament must be present and documented to diagnose peripheral neuropathy with loss of protective sensation.
- Lauria G, Cornblath DR, Johansson O et al. EFNS guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathy. Eur J Neurol 2005; 12(10):747-58.
- 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.
- 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.
- 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.
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|CPT||No specific code for this analysis. See Policy Guidelines section.|
|ICD-9 Diagnosis||356.9||Unspecified peripheral neuropathy|
|729.2||Neuralgia, neuritis, and radiculitis, unspecified|
|ICD-10-CM (effective 10/1/15)||G56.90-G56.92||Unspecified mononeuropathy of upper limb, code range|
|G57.90-G57.92||Unspecified mononeuropathy of lower limb, code range|
|M79.2||Neuralgia and neuritis, unspecified|
|ICD-10-PCS (effective 10/1/15)||Not applicable. No ICD procedure codes for laboratory tests. ICD-10-PCS codes are used for inpatient services only|
Epidermal nerve fiber density
Intraepidermal nerve fiber density
Small fiber neuropathy
|09/10/09||New policy; add to Medicine section||Policy created with literature search through July 2009;
|09/16/10||Replace policy||Policy updated with literature search through July 2010; references added and reordered; policy statement unchanged|
|10/04/11||Replace policy||Policy updated with literature search through May 2011; references added and reordered; 2 references removed; clinical input reviewed; policy statement changed; may be medically necessary under specified conditions.|
|10/09/14||Replace policy||Policy updated with literature review through August 20, 2014; reference 16 added; policy statements unchanged|