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Grand Rounds | Clinician's Corner

New Insights Into Diabetic Polyneuropathy

Michael Polydefkis, MD; John W. Griffin, MD; Justin McArthur, MBBS, MPH
JAMA. 2003;290(10):1371-1376. doi:10.1001/jama.290.10.1371.
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Patients with complaints of numbness, tingling, and dysesthesias in the toes and feet are frequently referred to neurologists. Often, the only objective evidence for peripheral nerve dysfunction in these patients is limited to small-caliber sensory nerve fibers. On examination these patients may have reduced distal pinprick sensation, and distal leg skin biopsies show loss of small-caliber nerve fibers. Studies focusing on small-caliber nerve fibers have led to a growing impression that neuropathy can be associated with early diabetes or impaired glucose tolerance (IGT). Often, neuropathy can be the presenting symptom of either diabetes or IGT. Furthermore, the oral glucose tolerance test appears to be a more sensitive measure of glucose dysmetabolism in these patients than levels of fasting blood glucose or glycated hemoglobin. Patients with IGT-associated neuropathy may represent an attractive target population for future regenerative studies given that their neuropathy is less severe and presumably more easily reversed than neuropathy occurring in patients with diabetes.

Historically, small-caliber fibers have not been extensively evaluated due to a lack of objective measures. Several measures to evaluate these fibers are emerging, including skin biopsy with visualization of epidermal nerve fibers. The accessibility of epidermal nerve fibers makes them an attractive target for nerve injury models, which have potential for development as novel outcome measures. Such approaches may address some of the challenges of past diabetic polyneuropathy trials.

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Figure 1. Representative Regions of Skin Biopsy Samples From a Healthy Patient and Patient 1
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Epidermal nerve fiber (ENF) density at all biopsy sites from the healthy control patient is normal. In patient 1, ENF density at proximal and distal thigh sites is normal, but there is complete denervation of the epidermis and subepidermal dermis at the distal leg site. Ubiquitin hydrolase expression in ENFs is indicated by blue staining and was immunolocalized using protein gene product polyclonal antibody and an avidin-biotin peroxidase complex method with Vector SG as the chromogen. The sections were counterstained with eosin Y (original magnification ×40).
Figure 2. Duration of Symptoms by Neuropathy Type (N = 41)
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Neuropathy type was classified using nerve conduction and skin biopsy results. Patients were classified as having predominantly small-fiber sensory neuropathy25 if the only abnormality was their distal leg skin biopsy. Patients were classified as having large-fiber sensory neuropathy if they had abnormal sural responses and normal deep peroneal responses. Sensorimotor neuropathy was defined as abnormal sural and deep peroneal responses. Based on this classification, there appears to be a stepwise progression of involvement by fiber type, from small-caliber sensory axons to large myelinated sensory axons to motor-fiber involvement. Curves were generated from raw data. Adapted with permission.31
Figure 3. Representative Skin Biopsy Sections at Baseline, After Capsaicin Denervation, and at 2 Reinnervation Time Points
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The baseline skin biopsy shows normal innervation of the epidermis. Following capsaicin treatment (day 0), there is complete denervation of the epidermis and subepidermal dermis. Biopsy samples at 28 and 56 days demonstrate reinnervation of the epidermis. Recovery of epidermal nerve fiber density was correlated with heat pain thresholds (data not shown). See Figure 1 legend for details of staining method (original magnification ×20).

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