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DESCRIPTIONSkin 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.
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.
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 has 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. Some laboratories who offer IENF density testing include Therapath, Advanced Laboratory Services, Mayo Medical Laboratories, Corinthian Reference Lab, and Bako Integrated Physician Solutions.
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). These tests are available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.
Indications for Quantitative Sensory Testing are discussed in a separate policy.
POLICYSkin 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:
Skin biopsy with epidermal nerve fiber density measurement is considered 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.
Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Nervous/Mental Conditions, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:
A. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and
B. appropriate with regard to standards of good medical practice; and
C. not solely for the convenience of the Member, his or her Provider; and
D. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.
For the definition of Medically Necessary, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member’s specific benefit plan language.
POLICY HISTORY10/13/2009: Policy added.
11/19/2009: Approved by MPAC
12/30/2010: Policy reviewed; no changes.
01/17/2012: Added a policy statement to indicate that skin biopsy with epidermal nerve fiber density measurement for the diagnosis of small-fiber neuropathy may be considered medically necessary when certain conditions are met.
01/09/2013: Policy title changed from "Intraepidermal Nerve Fiber Density" to "Nerve Fiber Density Testing." Added the following investigational policy statement: Measurement of sweat gland nerve fiber density is investigational.
12/13/2013: Policy reviewed; no changes.
11/17/2014: Policy reviewed; description updated regarding sweat gland nerve fibers. Policy statements unchanged.
07/31/2015: Code Reference section updated for ICD-10.
01/13/2016: Policy description updated regarding laboratory-developed tests. Policy statements unchanged. Policy guidelines updated to add medically necessary and investigative definitions.
06/06/2016: Policy number added.
SOURCESBlue Cross Blue Shield Association # 2.04.58
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.