Therapath Neuropathology

Epidermal Nerve Fiber Density

Demonstration of a reduction in the Epidermal Nerve Fiber Density (ENFD) on punch skin biopsy is a highly sensitive and specific test for Small Fiber Neuropathy (SFN).

Diagnosis Of Small Fiber Neuropathy (SFN); Technical Performance And Diagnostic Accuracy

ENFD Abnormal

Skin biopsy with abnormal Epidermal Nerve Fiber Density

Demonstration of a reduction in the Epidermal Nerve Fiber Density (ENFD) on punch skin biopsy is a highly sensitive and specific test for Small Fiber Neuropathy (SFN).1–4 Skin specimens are routinely obtained using a 3 mm punch biopsy at standard sites, including the proximal arm, distal arm, proximal thigh, distal calf, and dorsum of the foot. The small nerve fibers are visualized by immunohistochemistry, using an antibody to an axonal protein, PGP-9.5, and the number and structural integrity of the small fibers is evaluated by a pathologist. Patients with small fiber neuropathy exhibit a reduction in the ENFD, or structural abnormalities such as axonal swellings, that are indicative of neuropathy.5 Procedures are done according to international standards and guidelines.

Biopsy procedure guide

The sensitivity of skin biopsy in diagnosing small fiber neuropathy has been reported to be 88.4%, in comparison to 54% for the clinical examination, and 49% for quantitative sensory testing (QST). The specificity of the test is 95 to 97%,6,7 and the test is normal in non-peripheral neuropathic causes for pain such as multiple sclerosis.8,9 The ENFD is also reduced in patients with both small and large fiber neuropathy, but not in those with purely large fiber neuropathy.

ENFD Normal

Skin biopsy with normal Epidermal Nerve Fiber Density

In length dependent neuropathies, such as toxic neuropathies, the ENFD is more severely reduced distally at the foot or calf, but in sensory neuronopathies or multifocal neuropathies, it may be preferentially reduced proximally at the thigh.10–12 The ENFD would also be normal in patients with lumbar radiculopathy resulting from compression of the sensory nerve root proximally to the dorsal root ganglia, but reduced in those with more distal lesions in the lumbosacral plexus or sciatic nerve. In mononeuropathy, a reduction in the ENFD may be seen in the distribution of the affected nerve in comparison to the normal side.13 The ENFD has been reported to be increased in atopic dermatitis.14

In addition to the Epidermal Nerve Fiber Density that measures the sensory nerve fibers, the Sweat Gland Nerve Fiber Density (SGNFD) provides a measure of the autonomic nerve fibers in that innervate the sweat glands in the skin. Both types of fibers can be affected in small fiber neuropathy, although to different extents, depending on the type of neuropathy.15–17


Periquet M, Novak V, Collins M, et al. Painful sensory neuropathy: prospective evaluation using skin biopsy. Neurology. 1999;53(8):1641-1647. [PubMed]
Ebenezer G, McArthur J, Thomas D, et al. Denervation of skin in neuropathies: the sequence of axonal and Schwann cell changes in skin biopsies. Brain. 2007;130(Pt 10):2703-2714. [PubMed]
Lauria G, Hsieh S, 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):903-912, e44-9. [PubMed]
Hays A. Utility of skin biopsy to evaluate peripheral neuropathy. Curr Neurol Neurosci Rep. 2010;10(2):101-107. [PubMed]
Lauria G, Morbin M, Lombardi R, et al. Axonal swellings predict the degeneration of epidermal nerve fibers in painful neuropathies. Neurology. 2003;61(5):631-636. [PubMed]
Lauria G, Devigili G. Skin biopsy as a diagnostic tool in peripheral neuropathy. Nat Clin Pract Neurol. 2007;3(10):546-557. [PubMed]
Devigili G, Tugnoli V, Penza P, et al. The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain. 2008;131(Pt 7):1912-1925. [PubMed]
Herrmann D, O’Connor A, Schwid S, et al. Broadening the spectrum of controls for skin biopsy in painful neuropathies. Muscle Nerve. 2010;42(3):436-438. [PubMed]
Hlubocky A, Wellik K, Ross M, et al. Skin biopsy for diagnosis of small fiber neuropathy: a critically appraised topic. Neurologist. 2010;16(1):61-63. [PubMed]
Sghirlanzoni A, Pareyson D, Lauria G. Sensory neuron diseases. Lancet Neurol. 2005;4(6):349-361. [PubMed]
Gorson K, Herrmann D, Thiagarajan R, et al. Non-length dependent small fibre neuropathy/ganglionopathy. J Neurol Neurosurg Psychiatry. 2008;79(2):163-169. [PubMed]
Gemignani F, Giovanelli M, Vitetta F, et al. Non-length dependent small fiber neuropathy. a prospective case series. J Peripher Nerv Syst. 2010;15(1):57-62. [PubMed]
Schüning J, Scherens A, Haussleiter I, et al. Sensory changes and loss of intraepidermal nerve fibers in painful unilateral nerve injury. Clin J Pain. 2009;25(8):683-690. [PubMed]
Urashima R, Mihara M. Cutaneous nerves in atopic dermatitis. A histological, immunohistochemical and electron microscopic study. Virchows Arch. 1998;432(4):363-370. [PubMed]
Sommer C, Lindenlaub T, Zillikens D, Toyka K, Naumann M. Selective loss of cholinergic sudomotor fibers causes anhidrosis in Ross syndrome. Ann Neurol. 2002;52(2):247-250. [PubMed]
Hilz M, Axelrod F, Bickel A, et al. Assessing function and pathology in familial dysautonomia: assessment of temperature perception, sweating and cutaneous innervation. Brain. 2004;127(Pt 9):2090-2098. [PubMed]
Gibbons C, Illigens B, Wang N, Freeman R. Quantification of sweat gland innervation: A clinical–pathologic correlation. Neurology. 2009;72(17):1479-1486. [PMC]