Epidermal Nerve Fiber Density (ENFD)

Intraepidermal nerve fibers in skin biopsy Full width view of a 3 mm punch biopsy from the thigh with intraepidermal nerve fibers (arrow) visualized by immunohistochemical labeling for PGP9.5 (above).

Normal IENFD

A higher magnification of small nerve fibers (arrow) in the epidermal layer of a skin biopsy with normal intraepidermal nerve fiber density (IENFD). Arrow head points to the basement membrane that separates the epidermis from the dermis.

Abnormal IENFD

Skin with abnormally low intraepidermal nerve fiber density, consistent wtih small fiber neuropathy.

Axonal Bulbing

This image demonstrates skin with significantly reduced epidermal nerve fiber density, consistent with small fiber neuropathy. The small arrowhead points to the epidermal nerve fiber and just below is an axonal swelling.

Diagnosis of Small Fiber Neuropathy (SFN); Technical Performance and Diagnostic Accuracy

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). (Periquet et al, 1999; Ebenezer et al, 2007; Lauria et al, 2010; Hays et al, 2010). Skin specimens are routinely obtained using a 3 mm punch biopsy at standard sites, including the distal calf or dorsum of the foot and the proximal thigh. The small nerve fibers are visualized by immunocytochemistry, 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 (Lauria et al, 2003). Procedures are done according to international standards and guidelines.

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% (Lauria and Devigli, 2007; Devigli et al, 2008), and the test is normal in non-peripheral neuropathic causes for pain such as multiple sclerosis (Hermann et al, 2010; Hlubocky et al, 2010). The ENFD is also reduced in patients with both small and large fiber neuropathy, but not in those with purely large fiber neuropathy.

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 (Sghirlanzoni et al, 2005; Gorson et al, 2008; Gemignani et al, 2010). 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 (Schuning et al, 2009).

In addition to the ENFD 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 (Sommer et al, 2002; Hilz et al, 2004; Gibbons et al, 2009).

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