Epidermal Nerve Fiber Density Consult
Investigation of polyneuropathies
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 (IENFD) 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, 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.
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.
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.(8)
Clinical Reference Provides recommendations for further 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. 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
8. Engelstad JK, Taylor SW, Witt LV, et al: Epidermal nerve fibers. Confidence intervals and continuous measures with nerve conduction. Neurology 2012;79:2187-2193