Test Catalog

Test ID: SPBX    
Epidermal Nerve Fiber Density Consultation, Varies

Useful For Suggests clinical disorders or settings where the test may be helpful

Investigation of polyneuropathies

Testing Algorithm Delineates situations when tests are added to the initial order. This includes reflex and additional tests.

A battery of enzyme histochemical stains or immunostains are performed; other tests can be performed as indicated at an additional charge.


Wet tissue for consultation: When adequately prepared tissue is provided, routine testing will include: PGP 9.5 immunostain, morphometric analysis, Congo red stain, and hematoxylin and eosin stain. PGP 9.5 reactions cannot be done on previously embedded tissue eg, paraffin blocks, epoxy blocks etc.


Slides and blocks sent for consultation must include PGP 9.5-reacted sections:

Special stains and studies performed on the case should be sent with the case for review. In order to determine an accurate diagnosis, some of these stains or studies may be deemed to warrant repeat testing at an additional charge at the discretion of the reviewing Mayo Clinic neuromuscular pathologist. In addition, testing requested by the referring physician (immunostains, molecular studies, etc) may not be performed if deemed unnecessary by the reviewing Mayo Clinic neuromuscular pathologist. For all consultations, ancillary testing necessary to determine a diagnosis is ordered at the discretion of the Mayo Clinic neuromuscular pathologist. An interpretation, which includes an evaluation of the specimen and determination of a diagnosis, will be provided within a formal pathology report.


See Pathology Consultation Ordering Algorithm in Special Instructions.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Small fiber peripheral neuropathy is a common neurological complaint and a frequent source of morbidity in many patient populations. Direct investigation of small fiber involvement has been limited as most classical techniques such as electromyography (EMG), nerve conduction studies (NCS), and nerve biopsy, focus on large diameter nerve fibers and may be normal in patients with small fiber neuropathies.


The advent of epidermal skin biopsies and PGP 9.5 immunohistochemistry allows the direct visualization and morphologic assessment of small sensory fibers innervating the skin.(1) Assessment of intraepidermal nerve fiber density has been used to reliably demonstrate pathologic abnormalities in small fiber neuropathy of various etiologies including diabetes, HIV, systemic lupus erythematosus, and neurosarcoidosis. Further, the technique has been validated, shown to have acceptable sensitivity and specificity, and is minimally invasive. The publication of normative data for commonly tested sites such as the distal and proximal legs and arms permits direct comparison of patients to age- and sex-matched controls facilitating localization and diagnosis.(2-4)


Based on class 1 evidence and American Medical Association CPT code review process acceptance, intraepidermal nerve fiber density (IENFD) measurements are now an accepted investigational method in the workup of polyneuropathy, including the characterization and diagnosis of varieties of length-dependent small fiber polyneuropathies. IEFND measurements have been incorporated in recent practice guidelines published by the American Academy of Neurology and the European Federation of Neurological Science.(5,6)

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

A consultative report will be provided.

Interpretation Provides information to assist in interpretation of the test results

The number of intraepidermally originating nerve fibers that cross the basement membrane between the dermis and epidermis are counted in several sections.(2,5) The total linear length of the epidermis is measured using standard morphometric techniques and a density of epidermal nerve fibers (number of fibers/mm) is reported. This value is compared to previously published normative data.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Poor fixation, orientation, and improper handling of the tissue may hinder the neuromuscular pathologist's interpretation of the biopsy. See Epidermal Nerve Fiber Density Instructions in Special Instructions.

Supportive Data

Investigators at Mayo Clinic (Bolton, Winkelmann, Dyck) did previous work on cutaneous receptors preceding the recent work on intraepidermal nerve fiber densities. With recent findings, PJ Dyck and colleagues have developed the technique to national standards.(7)

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Lauria G, Lombardi R, Camozzi F, Devigili G: Skin biopsy for the diagnosis of peripheral neuropathy. Histopathology. 2009;54(3):273-285

2. McArthur JC, Stocks EA, Hauer P, et al: Epidermal nerve fiber density: normative reference range and diagnostic efficiency. Arch Neurol. 1998;55(12):1513-1520

3. Goransson LG, Mellgren SI, Lindal S, Omdal R: The effect of age and gender on epidermal nerve fiber density. Neurology. 2004;62(5):774-777

4. Umapathi T, Tan WL, Tan NC, Chan YH: Determinants of epidermal nerve fiber density in normal individuals. Muscle Nerve. 2006;33(6):742-746

5. 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):747-758

6. 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):177-184

7. Engelstad JK, Taylor SW, Witt LV, et al: Epidermal nerve fibers. Confidence intervals and continuous measures with nerve conduction. Neurology. 2012;79:2187-2193

8. England JD, Gronseth GS, Franklin G, et al: Evaluation of distal symmetric polyneuropathy: the role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Muscle Nerve. 2009 Jan;39(1):106-115

Special Instructions Library of PDFs including pertinent information and forms related to the test