Correlation Between Epidermal Nerve And Sural Nerve

Twenty six patients with neuropathic complaints had sural nerve morphometry and determination of epidermal nerve fiber density at the distal part of the leg (20). The intraepidermal nerve fiber (IENF) density correlated with the densities of total myelinated fibers within the sural nerve (r = 0.57, p = 0.0011), small myelinated (r = 0.53, p = 0.029), and large myelinated fibers (r = 0.49, p = 0.0054). There was a trend toward an association between intraepidermal nerve fiber density and sural nerve unmyelinated nerve fiber densities (r = 0.32, p = 0.054). Sensory nerve action potential amplitudes and large myelinated nerve fiber densities were highly correlated (r = 0.87, p < 0.0001). Intraepidermal nerve fiber density and sural nerve small fiber measures were concordant in 73% of patients. In 23% of cases, reduced intraepidermal nerve fiber density was the only indicator of small fiber depletion. An editorial in Neurology suggested that determination of distal leg intraepidermal nerve fiber density may be more sensitive than sural nerve biopsy in identifying small fiber sensory neuropathies (21).

Measurement of cutaneous innervation has proven to be particularly useful in the study of diabetic neuropathy. Abnormalities in epidermal innervation have been demonstrated to be more sensitive for the diagnosis of diabetic neuropathy than clinical or electrophysio-logical methods. Several investigators have demonstrated that dermal PGP immunoreac-tivity was reduced in subjects with diabetes testing normal on clinical examination, electrophysiology, and quantitative sensory testing (QST) when compared with healthy control subjects (22). This likely reflects the observation that small unmyelinated nerve fibers are vulnerable early in diabetes (23). Evaluation of epidermal nerve fibers (ENFs) appear to be even more sensitive, perhaps because of their further distance from the cell body, absence of a Schwann cell or collagen covering sheath, and the avascular nature of the epidermis that increase their susceptibility to disease. Kennedy demonstrated that subjects with diabetes had reduced innervation densities and nerve fiber lengths with many

Diabetes Cutaneous Nerve Fibers

Fig. 4. Example of neuropathy diagnosis by skin biopsy. Representative skin biopsy sections from a diabetic individual with small fiber sensory neuropathy (panels A-C) and comparable biopsy sections from a normal control subject (panels D-F). Panels A and D are skin sections from the proximal thigh; B and E from the distal thigh; C and F from the distal leg. The epidermal nerve fiber densities from both proximal thigh sites are within a normal range, although the section from the diabetic patient (panel A) contains several small swellings. At the distal thigh site (panels B and E), the ENF densities are again within a normal range, though the morphological abnormalities such as nerve fiber swellings are more prominent in the panel B. In panel C, the epidermis is completely denervated, while the skin section form the normal control subject (panel F) has a normal ENF density. The bottom of panel C contains an arrector pili muscle fragment that is well innervated which may suggest a relative sparing of large fiber function. From ref. 43.

Fig. 4. Example of neuropathy diagnosis by skin biopsy. Representative skin biopsy sections from a diabetic individual with small fiber sensory neuropathy (panels A-C) and comparable biopsy sections from a normal control subject (panels D-F). Panels A and D are skin sections from the proximal thigh; B and E from the distal thigh; C and F from the distal leg. The epidermal nerve fiber densities from both proximal thigh sites are within a normal range, although the section from the diabetic patient (panel A) contains several small swellings. At the distal thigh site (panels B and E), the ENF densities are again within a normal range, though the morphological abnormalities such as nerve fiber swellings are more prominent in the panel B. In panel C, the epidermis is completely denervated, while the skin section form the normal control subject (panel F) has a normal ENF density. The bottom of panel C contains an arrector pili muscle fragment that is well innervated which may suggest a relative sparing of large fiber function. From ref. 43.

subjects being completely denervated (12). Changes in fiber morphology such as increased branching patterns or the presence of swellings are also noted to be present in subjects with diabetes and may represent degenerative changes (24,25). Increased numbers of large axonal swellings predict the degeneration of epidermal nerve fibers and progression of neuropathy in diabetes as well as other forms of neuropathy (26). Nerve fiber swellings stained positively for PGP and tubulin and less prominently for neurofilament markers, suggesting that tubules are the main component of epidermal nerve fiber (ENF) cytoskeleton and that they accumulate with ubiquitin-associated proteins within swellings (26). IENF density has been shown to be inversely related to diabetes duration in people with type 2 diabetes, but not to HbA1C levels (27). The latter might represent an effect of historical glycemic control or "metabolic memory" as has been demonstrated for other diabetes end organ complications (28).

Many patients with idiopathic small fiber predominant neuropathy symptoms have been found to have either occult diabetes or impaired glucose tolerance after rigorous assessment with an oral glucose tolerance test (29,30). The diagnosis of diabetes was missed in these patients because of the inappropriate use of glycated hemoglobin as a screening test for diabetes. Using fasting 75 g oral glucose tolerance testing (OGTT), nearly 60% of patients were found to have diabetes or impaired glucose tolerance (IGT) (31). It is possible, but unlikely that the association between neuropathy and abnormalities on OGTT represents a spurious overlap of two common conditions, as the prevalence of IGT in the neuropathy populations was two- to threefold more than what would have been predicted by the National Health and Nutrition Examination Study (NHANES) study. Furthermore, there was a dose response relationship between the pathological and electrophysiological severity of neuropathy and the degree of hyperglycemia (31). In this study, the IENF density was the most sensitive measure of neuropathy and was abnormally low compared with control subjects in both subjects with diabetes and IGT. This observation is consistent with the clinical impression that patients with idiopathic small fiber neuropathy are indistinguishable to those with early diabetic neuropathy. Longitudinal follow-up of subjects with IGT-associated or de-novo diabetes associated neuropathy suggest that the rate of neuropathy progression is slower in those with IGT-associated neuropathy compared with de novo diabetes (Mammen, Polydefkis, unpublished).

A subsequent study that investigated factors associated with neuropathy among 50 idiopathic neuropathy patients and controls concluded that triglyceride levels and not hyperglycemia was the strongest predictor of neuropathy irrespective of pain (32). Together, these results suggest that it may be a combination of diabetic risk factors, perhaps even the metabolic syndrome that are responsible for neuropathy in these patients (33). Impaired glucose tolerance is a potentially reversible entity with diet and exercise having been demonstrated to slow or prevent progression to diabetes (34). Based on these studies, patients with IGT-associated neuropathy are routinely advised to adopt a diet and exercise regimen. Many patients who have succeeded in doing so have also reported improvements in their neuropathic pain. Weight loss and exercise can have dramatic effects on an individual's sense of well-being and pain perception. It remains unclear whether these patients' reductions in neuropathic pain are related to improvements in nerve function or the constitutional effects of exercise and weight loss.

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Supplements For Diabetics

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