National Medical Policy

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1 National Medical Policy Subject: Policy Number: Intraepidermal Nerve Fiber Density Testing in the Diagnosis of Small Fiber Neuropathy NMP453 Effective Date*: April 2009 Updated: April 2016 This National Medical Policy is subject to the terms in the IMPORTANT NOTICE at the end of this document For Medicaid Plans: Please refer to the appropriate State s Medicaid manual(s), publication(s), citation(s), and documented guidance for coverage criteria and benefit guidelines prior to applying Health Net Medical Policies The Centers for Medicare & Medicaid Services (CMS) For Medicare Advantage members please refer to the following for coverage guidelines first: Use Source Reference/Website Link X National Coverage Determination (NCD) Sensory Nerve Conduction Threshold Tests (sncts) (160.23): National Coverage Manual Citation Local Coverage Determination (LCD)* Article (Local)* X Other Decision Memo for Electrodiagnostic Sensory Nerve Conduction Threshold: &NcaName=Electrodiagnostic+Sensory+Nerve+ Conduction+Threshold&IsPopup=y&bc=AAAAAA AACAAAAA%3D%3D& None Use Health Net Policy Instructions Medicare NCDs and National Coverage Manuals apply to ALL Medicare members in ALL regions. Medicare LCDs and Articles apply to members in specific regions. To access your specific region, select the link provided under Reference/Website and follow the search instructions. Enter the topic and your specific state to find the coverage 1

2 determinations for your region. *Note: Health Net must follow local coverage determinations (LCDs) of Medicare Administration Contractors (MACs) located outside their service area when those MACs have exclusive coverage of an item or service. (CMS Manual Chapter 4 Section 90.2) If more than one source is checked, you need to access all sources as, on occasion, an LCD or article contains additional coverage information than contained in the NCD or National Coverage Manual. If there is no NCD, National Coverage Manual or region specific LCD/Article, follow the Health Net Hierarchy of Medical Resources for guidance. Current Policy Statement Health Net, Inc. considers intraepidermal nerve fiber density testing by skin biopsy medically necessary for the diagnosis of small-fiber neuropathy when all of the following criteria 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. Definitions IENF Intraepidermal nerve fiber ENFD Epidermal nerve fiber density PGP Protein gene product SFN Small fiber neuropathy SFSN Small fiber sensory neuropathy EMG Electromyography NCV Nerve conduction velocity NCS Nerve conduction studies INMED Improving Neuropathy and Mobility in People With Early Diabetes AAN American Academy of Neurology HIV Human immunodeficiency virus QRST Quantitative sudomotor axon test QST TST DSP IGT LEP CKD LFI SN PN LFN MFN SENPD SNAP QSART Quantitative sensory testing Thermoregulatory sweat testing Distal symmetric polyneuropathy Impaired glucose tolerance Laser evoked potentials Chronic kidney disease Large fiber involvement Sensory neuropathy Peripheral neuropathy Large fiber neuropathy Mixed fiber neuropathy Subepidermal nerve plexus density Sensory nerve action potential Quantitative sudomotor axon reflex test 2

3 CMAP CASS MPNAP MPSNAP Compound muscle action potential Composite autonomic scoring scale Medial plantar nerve action potential Medial Plantar sensory nerve action potential Codes Related To This Policy NOTE: The codes listed in this policy are for reference purposes only. Listing of a code in this policy does not imply that the service described by this code is a covered or noncovered health service. Coverage is determined by the benefit documents and medical necessity criteria. This list of codes may not be all inclusive. On October 1, 2015, the ICD-9 code sets used to report medical diagnoses and inpatient procedures have been replaced by ICD-10 code sets. ICD-9 Codes 337- Idiopathic peripheral autonomic neuropathy Reflex sympathetic dystrophy Unspecified disorder of autonomic neuropathy Mononeuritis of upper limb Mononeuritis of lower limb Hereditary peripheral neuropathy Hereditary sensory neuropathy Other specified, unspecified idiopathic peripheral neuropathy (no specific diagnosis code for small fiber neuropathy) Polyneuropathy in diabetes Alcoholic polyneuropathy ICD-10 Codes EØ8.42 Diabetes mellitus due to underlying condition with diabetic polyneuropathy EØ9.42 Drug or chemical induced diabetes mellitus with neurological complications with diabetic polyneuropathy E1Ø.42 Type 1 diabetes mellitus with diabetic polyneuropathy E11.42 Type 2 diabetes mellitus with diabetic polyneuropathy E13.42 Other specified diabetes mellitus with diabetic polyneuropathy G Causalgia of upper limb G56.42 G Other specified mononeuropathies of upper limb G56.82 G Unspecified mononeuropathy of upper limb G56.92 G Causalgia of lower limb G57.72 G Other specified mononeuropathies of lower limb G57.82 G58.9 Mononeuropathy, unspecified G60.0 Hereditary motor and sensory neuropathy G60.8 Other hereditary and idiopathic neuropathies G60.9 Hereditary and idiopathic neuropathy, unspecified 3

4 G62.1 Alcoholic polyneuropathy G Complex regional pain syndrome I (CRPS II) G90.59 G Idiopathic peripheral autonomic neuropathy G90.09 G Complex regional pain syndrome I (reflex sympathetic dystrophy) G90.59 G90.8 Other disorders of autonomic nervous system G90.9 Disorder of the autonomic nervous system, unspecified CPT Codes N/A There are no specific codes for Intra-Epidermal Nerve Fiber Density Measurement Level IV - Surgical pathology, gross and microscopic examination Special Stain including interpretation and report; Group II, histochemical stain on frozen tissue block Immunohistochemistry or immunocytochemistry, per specimen; initial single antibody stain procedure (description revised in 2015) Morphometric analysis; nerve Unlisted surgical pathology procedure HCPCS Codes NA Scientific Rationale Update April 2016 Per Smith et al. (2016, UpToDate) Traditional measures of neuropathy severity are insensitive to small fiber injury. Skin biopsy provides a unique and powerful tool to visualize and assess small nociceptive fibers in a reproducible and validated manner. Thus, the most frequent clinical indication for skin biopsy in neuromuscular disease is for the diagnosis of patients with suspected small fiber sensory neuropathy. Skin biopsy may also be useful for the evaluation of patients with suspected non-length dependent painful gangliopathy, postherpetic neuralgia, or anhidrosis, to document the status of sweat gland innervation. Scientific Rationale Update April 2014 Truini et al (2014) reported that although the reference standard technique for diagnosing painful small-fiber neuropathies is nerve fiber density assessment by skin biopsy, however, the relationship between the epidermal nerve fiber (ENF) density and neuropathic pain is still unclear. In a clinical and skin biopsy study designed to investigate whether changes in ENF density are directly related to pain, the investigators enrolled 139 consecutive patients with distal symmetric peripheral neuropathy. All patients underwent clinical examination. The Neuropathic Pain Symptom Inventory was used to distinguish the different neuropathic pain types. A skin biopsy was conducted, and ENFs were immunostained with the antiprotein gene product 9.5, and their linear density was quantified with bright-field microscopy. No difference was found in ENF density between patients with and without neuropathic pain, nor between patients with and without ongoing burning pain. Conversely, ENF density was higher in patients with provoked pains (including mechanical dynamic allodynia) than in those without. The variable association between ENF density and symptoms of neuropathic pain supports the idea that neuropathic pain symptoms arise through distinct underlying mechanisms. The lack of relationship between ongoing burning pain and ENF density suggests that this type of pain reflects factors other than loss of nociceptive afferents. The association between ENF density and provoked pain (including mechanical dynamic allodynia) suggests that this type of pain might be mediated by spared and sensitised nociceptive afferents. 4

5 Giannoccaro et al (2013) evaluated patients for small fiber neuropathy (SFN) who were referred for fibromyalgia (FM). Investigators studied 20 consecutive subjects with primary FM. Patients underwent neurological examination, nerve conduction studies, and skin biopsies from distal leg and thigh. Electrdiagnostic studies were normal in all patients. SFN was diagnosed in 6 patients by reduced epidermal nerve fiber density. These patients also showed abnormalities of both adrenergic and cholinergic fibers. Investigators concluded a subset of FM subjects have SFN which may contribute to their sensory and autonomic symptoms. Skin biopsy should be considered in the diagnostic workup of FM. Gibbons et al (2013) sought to define the neuropathology, clinical phenotype, autonomic physiology and differentiating features in individuals with neuropathic and non-neuropathic postural tachycardia syndrome (POTS). Twenty-four subjects with POTS and 10 healthy control subjects had skin biopsy analysis of intra-epidermal nerve fiber density (IENFD), quantitative sensory testing (QST) and autonomic testing. Subjects completed quality of life, fatigue and disability questionnaires. Subjects were divided into neuropathic and non-neuropathic POTS, defined by abnormal IENFD and abnormal small fiber and sudomotor function. Nine of 24 subjects had neuropathic POTS and had significantly lower resting and tilted heart rates; reduced parasympathetic function; and lower phase 4 valsalva maneuver overshoot compared with those with non-neuropathic POTS (P<0.05). Neuropathic POTS subjects also had less anxiety and depression and greater overall selfperceived health-related quality of life scores than non-neuropathic POTS subjects. A sub-group of POTS patients (cholinergic POTS) had abnormal proximal sudomotor function and symptoms that suggest gastrointestinal and genitourinary parasympathetic nervous system dysfunction. Investigators concluded POTS subtypes may be distinguished using small fiber and autonomic structural and functional criteria. Patients with non-neuropathic POTS have greater anxiety, greater depression and lower health-related quality of life scores compared to those with neuropathic POTS. These findings suggest different pathophysiological processes underlie the postural tachycardia in neuropathic and non-neuropathic POTS patients. The findings have implications for the therapeutic interventions to treat this disorder. Scientific Rationale - Update April 2013 Sensory neuropathic symptoms are predominately caused by impairment of small nerve fibers. The purpose of confirming a diagnosis of sensory neuropathy is to narrow the range of possible etiologies and thereby identify appropriate treatment strategies. In addition to history and clinical exam, ancillary testing (e.g., nerve conduction studies and quantitative sensory testing) may be necessary to confirm the diagnosis of small nerve fiber neuropathy (SFN). There currently is no clinically established reference standard for diagnosing SFN and no reference standard for verification. Epidermal nerve fiber density testing (ENFD) may be performed in individuals who have sensory symptoms, signs, or ancillary test results that suggest SFN. ENFD is assessed in skin biopsy samples by means of immunohistochemical techniques and microscopic examination. A practice parameter from the American Academy of Neurology, Evaluation of Distal Symmetric Polyneuropathy: Role of Autonomic Testing, Nerve Biopsy, and Skin Biopsy has not been updated since its 2009 publication. Per the guideline, Skin biopsy is being increasingly used to evaluate patients with polyneuropathy. Skin biopsy is a validated technique for determining intraepidermal nerve fiber density and may be considered for the diagnosis of distal symmetric polyneuropathy (DSP), 5

6 particularly sensory polyneuropathy (SFSN) (Level C). There is a need for additional prospective studies to define more exact guidelines for the evaluation of polyneuropathy. Donadio et al (2012) reported skin biopsy has gained widespread use for the diagnosis of somatic small-fiber neuropathy, but it also provides information on sympathetic fiber morphology. They sought to ascertain the diagnostic accuracy of skin biopsy in disclosing sympathetic nerve abnormalities in patients with autonomic neuropathy. Peripheral nerve fiber autonomic involvement was confirmed by routine autonomic laboratory test abnormalities. Punch skin biopsies were taken from the thigh and lower leg of 28 patients with various types of autonomic neuropathy for quantitative evaluation of skin autonomic innervation. Results were compared with scores obtained from 32 age-matched healthy controls and 25 patients with somatic neuropathy. The autonomic cutoff score was calculated using the receiver operating characteristic curve analysis. Skin biopsy disclosed a significant autonomic innervation decrease in autonomic neuropathy patients versus controls and somatic neuropathy patients. Autonomic innervation density was abnormal in 96% of patients in the lower leg and in 79% of patients in the thigh. The abnormal findings disclosed by routine autonomic tests ranged from 48% to 82%. The authors concluded data indicate the high sensitivity and specificity of skin biopsy in detecting sympathetic abnormalities; this method should be useful for the diagnosis of autonomic neuropathy, together with currently available routine autonomic testing. Schley et al (2012) aimed to link reduced skin nerve fiber density in different levels to layer-specific functional impairment in neuropathic pain patients and tried to identify pain-specific functional and structural markers. Clinical characteristics, thermal thresholds (quantitative sensory testing) and electrically induced pain and axon reflex erythema were assessed in 12 healthy controls and 36 patients with neuropathic pain. At the most painful sites and at intra-individual control sites, skin biopsies were taken and innervation densities in the different skin layers were assessed. Moreover, neuronal calcitonin gene-related peptide staining was quantified. Perception of warm, cold and heat pain and nerve fiber density were reduced in the painful areas compared with the control sites and with healthy controls. Warm and cold detection thresholds correlated best with epidermal innervation density, whereas heat and cold pain thresholds and axon reflex flare correlated best with dermal innervation density. Clinical pain ratings correlated only with epidermal nerve fiber density (r = 0.38, p < 0.05) and better preserved cold detection thresholds (r = 0.39, p < 0.05), but not with other assessed functional and structural parameters. Investigators concluded thermal thresholds, axon reflex measurements and assessment of skin innervation density are valuable tools to characterize and quantify peripheral neuropathy and link neuronal function to different layers of the skin. The severity of small fiber neuropathy, however, did not correspond to clinical pain intensity and a specific parameter or pattern that would predict pain intensity in peripheral neuropathy could not be identified. Scientific Rationale Update April 2012 Koskinen et al. (2011) completed a prospective pilot study on skin biopsies in newly diagnosed cancer patients receiving neurotoxic chemotherapeutic agents as adjuvant treatment in order to study the occurrence of small-fibre pathology and its relationship to clinical symptoms. Skin biopsies from distal leg were performed in 12 patients before, during and after chemotherapy. Using light microscopy, the intraepidermal nerve fibre (IENF) density was determined from the skin biopsies by counting morphometrically the immunopositive nerves per epidermal area. Reduced IENF density was observed in eight patients at baseline. During the follow-up, the IENF density increased significantly in six patients and remained unchanged in two. 6

7 In four patients, the IENF density was normal both at baseline and at the end of the follow-up period. Neuropathic symptoms were manifested in nine patients, but no association with the IENF count was found. During chemotherapy, results from patients revealed different evolutionary patterns of IENF density, but symptoms and IENF density were not related. Ragé et al. (2011) completed a study aimed at evaluating the performance of a battery of morphological and functional tests for the assessment of small nerve fiber loss in asymptomatic diabetic neuropathy (DNP). Patients diagnosed for 10 years with type 1 (n = 10) or type 2 (n = 13) diabetes mellitus (DM) without conventional symptoms or signs of DNP were recruited and compared with healthy controls (n = 18) and patients with overt DNP (n = 5). Intraepidermal nerve fiber density (IENFd) was measured with PGP9.5 immunostaining on punch skin biopsies performed at the distal leg. Functional tests consisted of quantitative sensory testing (QST) for lighttouch, cool, warm and heat pain detection thresholds and brain-evoked potentials with electrical (SEPs) and CO(2) laser stimulation [laser-evoked potentials (LEPs)] of hand dorsum and distal leg using small (0.8 mm(2)) and large (20 mm(2)) beam sizes. Results confirmed a state of asymptomatic DNP in DM, but only at the distal leg. Defining a critical small fiber loss as a reduction of IENFd -2 z scores of healthy controls, this state prevailed in type 2 (30%) over type 1 DM (10%) patients despite similar disease duration and current glycemic control. LEPs with the small laser beam performed best in terms of sensitivity (91%), specificity (83%) and area-under-the ROC curve (0.924). Although this performance was not statistically different from that of warm and cold detection threshold, LEPs offer an advantage over QST given that they bypass the subjective report and are therefore unbiased by perceptual factors. However, this was a very small study of 23 patients. Larger, peer-reviewed, comparative studies are necessary to determine the effectiveness of laser-evoked potentials (LEPs) over the quantitative sensory testing (QST) to evaluate intraepidermal nerve fiber density in asymptomatic diabetic neuropathy. Luo et al. (2011) developed a quantitative system of sudomotor innervation in skin biopsies of the distal leg by immunostaining of nerve fibers with anti-protein gene product 9.5 (PGP9.5) and by counterstaining with Congo red. A computerized areabased morphometric analysis was used to quantify the sweat gland innervation index (SGII), defined as the area of nerve fibers normalized to the area of sweat glands. This approach reduced the variations in measurements of sweat gland areas compared to the commonly used method by 5.6-fold (2.47% ± 2.54% vs 13.97% ± 14.24%, p < 0.001); hence, variations in SGII were also reduced. We examined 35 Type 2 diabetic patients (24 men and 11 women; mean age, 56.5 ± 12.8 years), with symmetrical length-dependent neuropathy and reduced intraepidermal nerve fiber density (0.76 ± 0.95 fibers/mm). By light and electron microscopy, PGP9.5- positive nerve terminals surrounded Congo red-positive sweat gland secretory coils in controls; these periglandular nerve terminals were either absent or markedly reduced in diabetic patients. Diabetic patients had lower SGII values than age- and sex-matched controls (2.60% ± 1.96% vs 4.84% ± 1.51%, p < ). The SGII values were lower in patients with anhidrosis of the feet versus those with normal sweating of the feet (0.89% ± 0.71% vs 3.10% ± 1.94%, p < 0.01). Thus, skin biopsy offers combined assessment of sudomotor innervation. However, although the results were positive, this study was very small with only 35 individuals. Larger, peer-reviewed studies are needed to determine the efficacy of this quantitative system of sudomotor innervation in skin biopsies in those with Type 2 diabetes with reduced intraepidermal nerve fiber density. Schuhknecht et al. (2011) biopsies taken from lesional and nonlesional skin of 53 patients (37 women and 16 men; mean ± SD age 60 6 ± 14 9 years) with peripheral neuropathy (PN) of diverse origin were immunostained for protein gene product

8 According to the guideline of the European Federation of Neurological Societies, the IENF density per millimetre was determined and compared with that in 20 healthy volunteers. Lesional and uninvolved PN skin biopsies showed significantly decreased IENF density (P < 0 001) regardless of patient age, origin of PN, intensity or quality of pruritus. Hypoplasia of epidermal sensory nerves independently of clinical parameters is a new finding in PN and suggests involvement of epidermal nerves in PN pathophysiology. To date, it cannot be ruled out that reduced IENF density is due to repeated scratching. However, the presence of hypoplasia in nonlesional PN skin suggests the presence of a subclinical small fibre neuropathy. Loseth et al. (2010) evaluated possible differences in distal polyneuropathy (PN) characteristics and degree of abnormalities for various small and large fiber parameters in diabetes type 1 (DM1) and type 2 (DM2). Sixty-six DM1 and 57 DM2 patients with or without PN symptoms were included. Nerve conduction studies (NCS), quantitative sensory testing (QST) and quantification of intraepidermal nerve fibres (IENFs) were performed. Z-scores were calculated from reference materials. In both groups, 42% had abnormal NCS classification, 42% (DM1) and 39% (DM2) abnormal QST, as well as 40% (DM1) and 32% (DM2) abnormal IENF density. In multivariate analysis, some NCS and QST Z-scores were more abnormal in DM2. Symptom scoring correlated better with NCS and QST parameters in DM1. The investigators concluded that the differences could be referred to disease duration, glycaemic control and possibly patient age. The various parameters from NCS, QST and IENF analysis contribute differently in the assessment of polyneuropathy. These findings have not been translated into clinical practice demonstrating improved outcomes. Scientific Rational - Update April 2010 In the United States, peripheral neuropathy affects approximately 15 to 20 million people over the age of 40 years and approximately 8% of people over the age of 55 years. Peripheral neuropathy, also classified as polyneuropathy or mononeuropathy, is the most prevalent form of diabetic neuropathy, occurring in 26% to 47% of diabetic adults. Clinicians consider the possibility of peripheral neuropathy when patients report pain, suggesting a neuropathic origin. The patient s history, combined with a clinical examination, sometimes makes the cause of neuropathy obvious, as in the case of diabetes, alcoholism, or drug toxicity. There are more than 100 variations of peripheral neuropathy, which can be characterized as sensory, motor, sensorymotor, or autonomic. Sensory neuropathic symptoms are predominately caused by impairment of small nerve fibers. Symptoms common in sensory peripheral neuropathy include pain, often consisting of burning sensations, paresthesias, and numbness, or inability to sense vibration and touch. Difficulty walking and lack of coordination can result from the partial numbness. The purpose of confirming a diagnosis of sensory neuropathy and characterizing the type of sensory neuropathy is to narrow the range of possible etiologies and thereby identify appropriate treatment strategies. Etiologies associated with small nerve fiber neuropathy (SFN) include diabetes, impaired glucose tolerance (IGT), several hereditary disorders, certain autoimmune disorders, HIV infection, medication toxicity, and alcoholism. Motor peripheral neuropathy typically results in muscle weakness, muscle wasting, and diminished reflexes, but sensory neuropathy can also produce these symptoms. Autonomic peripheral neuropathy can result in malfunction of the sweat glands, gastrointestinal difficulties, sexual dysfunction, dysphagia, or organ failure. Small fiber pathology can also cause autonomic neuropathy. 8

9 Pure SFN sometimes progresses to include involvement of large fibers. If neither small fiber nor large fiber impairment can be confirmed in patients with sensory symptoms, several alternatives to sensory neuropathy are suspected including venous insufficiency, spinal stenosis, myelopathy, plantar fasciitis, stroke, or a psychosomatic disorder. Although clinicians use various forms of ancillary testing to identify a mechanism of dysfunction in the peripheral nerves, several of the following factors may still prevent a complete diagnosis based on history and examination: 1. 20% to 50% of small fiber neuropathies are idiopathic; 2. Clinical examinations can be normal in patients with neuropathic symptoms; 3. Patients with abnormal clinical findings can be asymptomatic, and 4. Other pathologies can produce symptoms similar to those associated with peripheral neuropathy. Most electrophysiological studies, (i.e. electromyography, and nerve conduction studies), reveal only large nerve fiber pathology, and are thus not diagnostic in patients who have pure small fiber neuropathy (SFN). Laser evoked potentials (LEP) represent an electrophysiological means of detecting small fiber pathology, but these tests entail stimulation of nociceptive (pain-receptive) nerves and the discomfort to the patient makes them impractical for nonresearch purposes. Patients with symptoms or clinical findings suggesting sensory neuropathy and who have normal NCS therefore require additional testing. Since small fibers are also involved in autonomic as well as sensory function, autonomic testing can help in confirming a diagnosis of SFN. The key approach to clinical testing for SFN, called quantitative sensory testing (QST), has two important disadvantages: 1. QST consists of psychophysiological tests that require normal cognition on the part of the patient and even then entail a subjective element, and 2. QST provides no information on whether sensory dysfunction is due to peripheral or central pathology. For these reasons, a combination of clinical and ancillary testing often fails to settle the issue. There currently is no clinically established reference standard for diagnosing SFN, or a reference standard for verification, and no consensus on the definition of mixed fiber neuropathy. Pathological evaluation of nerve tissue may be warranted to add morphological information to the functional information provided by clinical, electrophysiological, and autonomic testing. Common Tests for Peripheral Neuropathy Type of Pathology Small Fiber Clinical Sensory: Pinprick (sensation to touch) Autonomic: Quantitative sensory testing [QST] (use of simple tools or Electrophysiological Skin Biopsy Sensory: laserevoked potentials [LEPs] (not usually available in clinical practices) Autonomic: Quantitative sudomotor axon reflex test [QSART], sympathetic skin ENFD subepidermal nerve plexus density [SENPD] 9

10 Large Fiber specialized equipment to test thermal and thermal-pain thresholds) Sensory: Pinprick (sensation to touch), tests for sensation to vibration, tests for prioproception Motor: Reflex tests response, heart rate variability and other cardiovascular reflexes, thermoregulatory sweat testing [TST], Composite autonomic scoring scale [CASS] Sensory: Sensory nerve action potential (SNAP) [most commonly applied to the sural nerve]; a type of NCS Motor: EMG, compound muscle action potential [CMAP] N/A Skin Biopsy and Quantification of Epidermal Nerve Fiber Density (ENFD) Intraepidermal nerve fiber density (IENF) testing is proposed to identify the density or number of small nerve fibers from skin biopsy specimens for the diagnosis of small-fiber neuropathy (SFN). IENF or epidermal nerve fiber density (ENFD) is often referred to as a skin biopsy test. A skin biopsy is considered when neurological examination is inconclusive and electrophysiological testing rules out large fiber neuropathy. Skin biopsy allows quantification of the nerve fibers in the epidermis and thus enables objective confirmation of small nerve fiber pathology. Several studies have shown ENFD to be lower in patients with symptoms of sensory neuropathy compared with healthy controls. When skin biopsies are taken from multiple locations in the same patient, typically at the distal leg and proximal thigh, ENFD loss is often greater at the distal site, which is consistent with the observation that symptoms often progress in a proximal direction. ENFD does not require normal cognitive function and cannot be affected by other types of dysfunction outside the peripheral nervous system, unlike the QST. Nerve biopsy can help identify the nature of peripheral neuropathy, but nerve biopsy is more invasive than skin biopsy and more difficult to perform. Diminished ENFD has been found to be associated with disorders characterized by loss of sensation, such as anhidrosis, and thus might be promising for detecting painless SFN. In addition, ENFD loss often precedes painful symptoms in diabetic neuropathy. ENFD confirmed SFN raises the suspicion of diabetes, impaired glucose tolerance (IGT), certain autoimmune diseases, and other disorders known to cause SFN. Additional investigation through laboratory tests, genetic testing, or evaluation by another specialist must be done to find the etiology of the SFN and allow a definitive diagnosis. Treatment of sarcoidosis, autoimmune diseases, celiac disease, and IGT has been shown to improve associated SFN symptoms. ENFD also may identify presymptomatic SFN in patients with such diseases and modify disease management to arrest or reverse neuropathy before irreversible damage occurs. However, it is estimated that up to 50% of peripheral neuropathies are idiopathic. 10

11 Treatment of Peripheral Neuropathy Early detection of the underlying cause of peripheral neuropathy will assist in improving neuropathic symptoms or slowing their progression. Epidermal nerve fiber density (ENFD) is assessed in skin biopsy samples by means of immunohistochemical techniques and microscopic examination. ENFD testing is proposed in individuals who have sensory symptoms, signs, or ancillary test results that suggest small fiber neuropathy (SFN). ENFD below a normal reference range is considered confirmation of peripheral neuropathy. ENFD within the normal range suggests the need for testing for etiologies other than those known to produce peripheral neuropathy. There continues to be a paucity of evidenced based scientific literature to determine conclusions regarding the impact of ENFD testing on identification of etiology, changes in clinical management, or improvement in neuropathic symptoms. Scientific Rationale - Initial The small nerve fibers within the epidermis generally assist with perception of hot and cold sensation, as well as pain. In addition, small autonomic fibers assist with the control of sweating and blood vessel tone. Small fiber neuropathy (SFN) is among the least understood of all neuropathies, primarily because standard diagnostic tests for neuropathy such as electromyography (EMG) and nerve conduction studies (NCS) are usually normal in this group of patients. Small fiber neuropathy generally presents as a painful neuropathy that may rarely become disabling. Symptoms suggestive of this condition may include pain (burning, tingling, shooting, or prickling in character), paresthesia, sheet intolerance, or restless legs syndrome. Symptoms of autonomic dysfunction may include altered sweating, diarrhea or constipation, urinary incontinence or retention, gastroparesis, sicca syndrome, blurry vision, facial flushes, orthostatic hypotension, or sexual dysfunction. Leading causes of SFN include diabetes, alcohol abuse, HIV or AIDS, certain neurotoxins, various genetic diseases, as well as an idiopathic form. Intraepidermal nerve fiber (IENF) density testing consists of examination of the small nerve fiber endings, obtained in a skin punch biopsy specimen. This is done by immunocytochemistry staining of the tissue specimen using Mouse monoclonal Anti- Human Protein Gene Product (PGP) 9.5, antibodies. This staining allows for the identification and counting of intraepidermal nerve fibers. Protein gene product (PGP) 9.5 is a neuron specific protein, that has been demonstrated in neurons and nerve fibers at all levels of the central and peripheral nervous system. The test is used to diagnose small fiber neuropathy (SFN) in which there may be a reduction in the number and structural integrity of small fibers in the outer layer of the skin. The IENF density test may offer some unique advantages over nerve conduction velocity (NCV) tests and nerve biopsy. The use of the epidermal nerve fiber density test to diagnose neuropathy has been examined for a variety of conditions, including small-diameter nerve fiber neuropathies, diabetic neuropathy, and neuropathy associated with human immunodeficiency virus (HIV). Other diagnostic studies currently used in the diagnosis of small fiber neuropathy may include thermoregulatory sweat testing, quantitative sudomotor axon reflex testing, quantitative thermal threshold testing, sural nerve biopsy and cardiovascular autonomic reflex testing. 11

12 Therapath (New York, NY) is currently the only laboratory in the United States that offers this test. IENF density testing has been used to objectively document neuropathy in clinical trials. However, no clinical trials focus on how the test results may be used to direct treatment decisions. There is currently an ongoing Clinical Trial on " Improving Neuropathy and Mobility in People With Early Diabetes (INMED)" that is now recruiting members. The secondary outcome measure of this study involves 'Physical activity and intraepidermal nerve fiber density.' For the past decade the histological study of unmyelinated nerve fibers in the skin has grown in importance in the diagnosis of peripheral nerve disorders, both generalized and focal, including those associated with neuropathic pain. Epidermal nerve fiber density and morphology, (eg, tortuosity, complex ramifications, clustering, and axon swellings), can be quantified and compared with control values. Distal symmetric polyneuropathy (DSP) is the most common variety of neuropathy. A reduced density of epidermal nerve fibers is seen in small-fiber neuropathies, diabetic neuropathy, and impaired glucose tolerance neuropathy, each of which is associated with neuropathic pain. Recommendations and Studies The American Academy of Neurology (AAN) practice parameter Evaluation of Distal Symmetric Polyneuropathy (England et al. 2009) recommends that autonomic testing should be considered in the evaluation of patients with polyneuropathy to document autonomic nervous system dysfunction. [Level B Recommendation] Such testing should be considered especially for the evaluation of suspected autonomic neuropathy [Level B Recommendation] and distal small fiber sensory polyneuropathy [Level C Recommendation]. In addition, it states that for symptomatic patients with suspected polyneuropathy, skin biopsy is a validated technique for determining IENFD and may be considered for the diagnosis of distal symmetric polyneuropathy, especially small fiber sensory polyneuropathy [Level C Recommendation]. There is a need for additional prospective studies to define more exact guidelines for the evaluation of polyneuropathy. (E.g. the rating scheme for the strength of the AAN recommendations is noted as follows: The Level B rating requires at least one convincing Class II study or overwhelming Class III evidence. Class II: Prospective matched group cohort study in a representative population with masked outcome assessment that meets a d noted below or a randomized, controlled trial in a representative population that lacks one criterion a d. a. Primary outcome(s) is/are clearly defined. b. Exclusion/inclusion criteria are clearly defined. c. Adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias d. Relevant baseline characteristics are presented and substantially equivalent among treatment groups, or there is appropriate statistical adjustment for differences. Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome assessment is independent of patient treatment. Level C rating requires at least two convincing Class III studies. Regarding the 2009 practice parameter noted above, the AAN states: 12

13 Nine studies met inclusion criteria. One was a prospective cohort survey of patients presenting with bilateral painful feet and normal strength, but skin biopsy was done only in those with normal NCS. Patients with reduced IENF density and normal NCS were assumed to have painful small fiber neuropathies. However, the study did not compare the results of the IENF density to an independent reference standard to confirm the presence of small fiber neuropathy. Thus, for the purposes of determining the diagnostic accuracy of skin biopsy for polyneuropathy, this study was graded Class IV. The remaining studies employed a case-control design. In these studies, the investigators performed skin biopsies on patients with established polyneuropathy and normal controls. No study included patients with conditions causing lower extremity pain or sensory complaints that might be confused with polyneuropathy. Thus, all studies had potential spectrum bias. Following the evidence classification scheme for studies of diagnostic accuracy, all of these studies were graded Class III. The AAN also notes: The following comprehensive review of the 2009 practice parameter reveals several weaknesses in the current approach to the evaluation of polyneuropathy and highlights opportunities for research: Autonomic testing can with a high degree of accuracy document autonomic system dysfunction in polyneuropathy. This is particularly relevant to small fiber polyneuropathy and the autonomic neuropathies. Research is necessary to determine whether the documentation of autonomic abnormalities is important in modifying the evaluation and treatment of polyneuropathy. Specific tests such as a quantitative sudomotor axon test (QSART) can document small fiber (i.e., sudomotor axon) loss with a high degree of sensitivity, making the test useful to confirm the diagnosis of small fiber polyneuropathy. Since skin biopsy with determination of IENF density can also document small fiber loss, there is a need for studies that compare and correlate the two techniques. There are no studies of nerve biopsy in the evaluation of distal symmetric polyneuropathy (DSP). Although it would be useful to know the outcome of welldesigned prospective studies in this area, it is unlikely that such studies will be done. Skin biopsy with determination of IENF density is a technique that has come of age for the objective documentation of small fiber loss. This technique provides a unique opportunity for research in different varieties of neuropathy. Further studies are needed to characterize the diagnostic accuracy of skin biopsy in distinguishing patients with suspected polyneuropathy, particularly SFSN, from patients with sensory complaints or pain unrelated to peripheral neuropathy. Prospective studies with appropriate "other disease" controls should be done to assess the sensitivity, specificity, and predictive values of IENF density measurement to identify SFSN in patients with lower extremity pain or sensory complaints. A predetermined independent reference standard for the diagnosis of SFSN should be specifically stated in such studies. Serial IENF density measurements and IENF regenerative capacity are being studied and used as outcome measures in therapeutic trials. Further studies are needed to validate and determine the value of skin biopsy for this purpose. Sorenson et al. (2006) completed a small case control study on The Relationship Among Pain, Sensory Loss and Small Nerve Fibers in Diabetes. This small study included patients with Type 2 Diabetes, 25 patients with neuropathic pain and 13 without. There was significantly lower IENF density and lower intraepithelial fibers in subjects with pain compared to those without. 13

14 The majority of studies on intraepidermal nerve fiber density testing include small, nonrandomized case series by various authors including Quattrini [2007], Dabby [2007], Zhou [2007], DeSousa [2006], Hermann [2004], and Lauria [2003]. Additional small studies include a case control study by Gibbons [2006], a review by Lauria [2005], a cohort study by Koskinen [2005] Smith et al. (2005) completed one, small, nonrandomized, unblinded case series on intraepidermal nerve fiber (IENF) density testing that focused on inter-evaluator variability of test interpretation. This study tested only two evaluators. In summary, it does seem that intraepidermal nerve fiber (IENF) density testing may offer advantages in the diagnosis of peripheral nerve disorders, both generalized and focal, including those associated with neuropathic pain. However, peer-reviewed medical literature on the technical performance, reproducibility and interpretation of intraepidermal nerve fiber (IENF) density testing, are inconclusive at this time. Treatment of small fiber neuropathy consists of treating the underlying systemic condition and reducing symptoms. Useful diagnostic testing would assist in determining the etiology of the symptoms, the degree to which symptoms impact the patient s daily functioning and the patient s response to treatment. Intraepidermal nerve fiber (IENF) density testing has not been determined to improve patient clinical management and health outcomes. IENFD is invasive and involves a 3 mm punch skin biopsy. The complications associated with peripheral neuropathy secondary to diabetes, are mainly ulcers and infections. The risk of routinely inflicting wounds on diabetic patients by doing biopsies on those with peripheral neuropathies far outweighs the benefits that they would get from the results. Additional data from large, long-term, randomized, controlled clinical trials are needed to determine standard selection criteria to note which individuals may benefit from IENF density testing, the clinical benefit of basing treatment decisions on these findings, and whether this technique may replace current diagnostic tests, such as the sural nerve biopsy. No evidence-based clinical practice guidelines were found that recommend the use of intraepidermal nerve fiber density testing in the diagnosis, treatment and monitoring of neuropathy. Review History April 2009 Medical Advisory Council Committee initial approval April 2010 Update. No revisions. Codes reviewed. April 2011 Update. Added Medicare Table. No revisions April 2012 Update. No revisions. April 2013 Update - revised policy to consider intraepidermal nerve fiber density testing by skin biopsy medically necessary for the diagnosis of small-fiber neuropathy when specified criteria is met. Code updates April 2014 Update no revisions April 2015 Update no revisions. Code updates April 2016 Update no revisions. Code updates This policy is based on the following evidence-based guidelines: 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 14

15 Medicine, and American Academy of Physical Medicine and Rehabilitation. Neurology. 2009;72 (1). Available at: 2. Hayes. Search and Summary. Epidermal Nerve Fiber Density Test for Diagnosing Neuropathy. August 24, Hayes Medical Technology Directory. Epidermal Nerve Fiber Density Test for Diagnosing Neuropathy. February 22, Update Feb Archived March 22, Lauria G, Hsieh ST, Johansson O, et al. 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. Eur J Neurol. 2010; 17(7): Hayes. Medical Technology Directory. Quantitative Sensory Testing for the Diagnosis of Lower Extremity Peripheral Neuropathy. June 19, Updated June 18, References Update April Goldenberg DL. Clinical manifestations and diagnosis of fibromyalgia in adults. UpToDate. July Li XM, Yang Y, Hou Y, et al. Diagnostic accuracy of three sensory tests for diagnosis of sensory disturbances. Journal of reconstructive microsurgery Jan;31(1): Liu Y, Billiet J, Ebenezer GJ, et al. Factors influencing sweat gland innervation in diabetes. Neurology. 2015;84(16): Smith AG, Gibson S. Skin biopsy for the evaluation of peripheral nerve disease. UpToDate. September 5, References Update April Lai S, Ahmed U, Bollineni A, et al. Diagnostic accuracy of qualitative versus quantitative tuning forks: outcome measure for neuropathy. J Clin Neuromuscul Dis. 2014;15 (3): National Institute of Neurological Disorders and Stroke (NINDS). Peripheral Neuropathy Information Page. Updated April 16, Available at: htm 3. Pourhamidi K, Dahlin LB, Englund E, et al. Evaluation of clinical tools and their diagnostic use in distal symmetric polyneuropathy. Prim Care Diabetes. 2014;8(1): References Update April Buonocore M. Unilateral peripheral neuropathic pain: The role of neurodiagnostic skin biopsy. World J Clin Cases Feb 16;2(2): Giannoccaro MP, Donadio V, Incensi A, et al. Small nerve fiber involvement in patients referred for fibromyalgia. Muscle Nerve Dec Gibbons CH, Bonyhay I, Benson A, et al. Structural and functional small fiber abnormalities in the neuropathic postural tachycardia syndrome. PLoS One Dec 27;8(12):e Karlsson P, Møller AT, Jensen TS, Nyengaard JR. Epidermal nerve fiber length density estimation using global spatial sampling in healthy subjects and neuropathy patients. J Neuropathol Exp Neurol Mar;72(3): Truini A, Biasiotta A, Di Stefano G, et al. Does the epidermal nerve fibre density measured by skin biopsy in patients with peripheral neuropathies correlate with neuropathic pain? Pain Apr;155(4):

16 References Update April Alport AR, Sander HW. Clinical approach to peripheral neuropathy: anatomic localization and diagnostic testing. Continuum (Minneap Minn) Feb;18(1): Donadio V, Incensi A, Giannoccaro MP, et al. Peripheral autonomic neuropathy: diagnostic contribution of skin biopsy. J Neuropathol Exp Neurol Nov;71(11): Kharkar S, Venkatesh YS, Grothusen JR, et al. Skin biopsy in complex regional pain syndrome: case series and literature review. Pain Physician May- Jun;15(3): McArthur JC. Painful small fiber neuropathies. Continuum (Minneap Minn) Feb;18(1): Saperstein DS, Levine TD, Levine M, Hank N. Usefulness of skin biopsies in the evaluation and management of patients with suspected small fiber neuropathy. Int J Neurosci Jan;123(1): Schley M, Bayram A, Rukwied R, et al. Skin innervation at different depths correlates with small fibre function but not with pain in neuropathic pain patients. Eur J Pain Nov;16(10): References Update April Burakgazi AZ, Messersmith W, Vaidya D, et al. Longitudinal assessment of oxaliplatin-induced neuropathy. Neurology Sep 6;77(10): Epub 2011 Aug Koskinen MJ, Kautio AL, Haanpää ML, et al. Intraepidermal nerve fibre density in cancer patients receiving adjuvant chemotherapy. Anticancer Res Dec;31(12): Loseth S, Mellgren SI, Jorde R, et al.. Polyneuropathy in type 1 and type 2 diabetes: comparison of nerve conduction studies, thermal perception thresholds and intraepidermal nerve fibre densities. Diabetes Metab Res Rev Feb;26(2): 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;70(10): Ragé M, Van Acker N, Knaapen MW, et al. Asymptomatic small fiber neuropathy in diabetes mellitus: investigations with intraepidermal nerve fiber density, quantitative sensory testing and laser-evoked potentials. J Neurol Oct;258(10): Epub 2011 Apr Schuhknecht B, Marziniak M, Wissel A, et al. Reduced intraepidermal nerve fibre density in lesional and nonlesional prurigo nodularis skin as a potential sign of subclinical cutaneous neuropathy. Br J Dermatol Jul;165(1): References Update - April Nebuchennykh M, Løseth S, Mellgren SI. Aspects of peripheral nerve involvement in patients with treated hypothyroidism. Eur J Neurol. 2010;17(1): 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): Magri F, Buonocore M, Oliviero A, et al. Intraepidermal nerve fiber density reduction as a marker of preclinical asymptomatic small-fiber sensory neuropathy in hypothyroid patients. Eur J Endocrinol. 2010;163(2):