DIAGNOSIS: A. SKIN, RIGHT CALF, PUNCH BIOPSY: - INTRA-EPIDERMAL NERVE FIBER DENSITY IS MILDLY DECREASED (4.10 FIBERS/MM ). - PAPILLARY DERMAL NERVE FIBERS ATRETIC AND SLIGHTLY DIMINISHED. - SEE COMMENT. COMMENT: Immunohistochemical studies and morphometric analysis disclose a mildly diminished number of all small myelinated (A-delta) and unmyelinated (C) nerve fibers within the epidermis. In addition, fibers within the papillary dermis are atretic and are slightly decreased in number. The depressed number of fibers following immunohistochemical analysis using anti-PGP 9.5 antibodies is indicative of early-evolving small fiber neuropathy**. The published specificity below the fifth percentile, (less than 3.8 fibers/mm), is 97% (in the context of an appropriately fixated post-biopsy specimen). Reference: Ebenezer GJ, P Hauer, C Gibbons, et al. J Neuropathol Exp Neurol 66(12):1059-1073, 2007. **If this analysis appears discordant with this patient's clinical exam, verification of appropriate fixation (complete submersion in Zamboni's fixative, duration >10 hours but <36 hours, maintained refrigeration (without freezing), and appropriate anesthetic technique (infiltration around biopsy site, but not within it), would be indicated. Based on the epidermal nerve fiber density analysis in this case, one potential clinical course for this patient could include a dietary supplement containing Alpha-Lipoic Acid (≥600mg daily) and Benfotiamine (600mg daily). When clinically indicated, such products may be helpful to both diminish the symptoms of neuropathy, and to improve overall epidermal nerve health. Additionally, investigators have shown benefit to using combination therapy that includes L-methylfolate, methylcobalamin (B12) and pyridoxal 5’-phosphate (B6). References: Ziegler D. Effect of 4-year antioxidant treatment with alpha-lipoic acid in diabetic polyneuropathy: the NATHAN 1 trial. Diabetes 2007; 56(Suppl.1):A2. Luong KV, et al.. The impact of thiamine treatment in diabetes mellitus. J Clin Med Res 2012; 4(3):153-160. Walker M, et al.. Improvement of cutaneous sensitivity in diabetic peripheral neuropathy. Rev Neurol Dis 2010; 7(4):132-139.

B. SKIN, LEFT CALF, PUNCH BIOPSY: - INTRA-EPIDERMAL NERVE FIBER DENSITY IS MODERATELY DECREASED (3.56 FIBERS/MM ). - PAPILLARY DERMAL NERVE FIBERS ATRETIC AND DIMINISHED. - SEE COMMENT. COMMENT: Immunohistochemical studies and morphometric analysis disclose a moderate decreased in the number of small myelinated (A-delta) and unmyelinated (C) nerve fibers within the epidermis. In addition, fibers within the papillary dermis are atretic and diminished in number. The depressed number of fibers following immunohistochemical analysis using anti-PGP 9.5 antibodies is indicative of established small fiber neuropathy**. The published specificity below the fifth percentile, (less than 3.8 fibers/mm), is 97% (in the context of an appropriately fixated post-biopsy specimen). Reference: Ebenezer GJ, P Hauer, C Gibbons, et al. J Neuropathol Exp Neurol 66(12):1059-1073, 2007.




Based on the epidermal nerve fiber density analysis in this case, one potential clinical course for this patient could include a dietary supplement containing Alpha-Lipoic Acid (≥600mg daily) and Benfotiamine (600mg daily). When clinically indicated, such products may be helpful to both diminish the symptoms of neuropathy, and to improve overall epidermal nerve health. Additionally, investigators have shown benefit to using combination therapy that includes L-methylfolate, methylcobalamin (B12) and pyridoxal 5’-phosphate (B6). References: Ziegler D. Effect of 4-year antioxidant treatment with alpha-lipoic acid in diabetic polyneuropathy: the NATHAN 1 trial. Diabetes 2007; 56(Suppl.1):A2. Luong KV, et al.. The impact of thiamine treatment in diabetes mellitus. J Clin Med Res 2012; 4(3):153-160. Walker M, et al.. Improvement of cutaneous sensitivity in diabetic peripheral neuropathy. Rev Neurol Dis 2010; 7(4):132-139.







CLINICAL INFORMATION: A. Rule out neuropathy; right calf. B. Rule out neuropathy; left calf. GROSS DESCRIPTION: A. Received in Cryoprotectant is a 3-mm punch biopsy for further processing. B. Received in Cryoprotectant is a 3-mm punch biopsy for further processing. MICROSCOPIC DESCRIPTION: A. Representative fifty micron-thick frozen-tissue sections were taken for immunohistochemical analysis. Antibodies directed against PGP 9.5 demonstrate reactivity within surface epithelium to the degree listed above (a mild decrease in the number of intra-epidermal fibers). Scattered varicosities and axonal swellings are noted. Intra-dermal nerves appear slightly faint and diminished in number. Routine stains fail to demonstrate evidence of associated vasculitis or amyloid deposition. B. Representative fifty micron-thick frozen-tissue sections were taken for immunohistochemical analysis. Antibodies directed against PGP 9.5 demonstrate reactivity within surface epithelium to the degree listed above (moderate decrease in intra-epidermal fibers). Scattered varicosities and axonal swellings are noted. Intra-dermal nerves appear slightly faint and diminished in number. Routine stains fail to demonstrate evidence of associated vasculitis or amyloid deposition.