Which Test for Diagnosing Early Human Diabetic Neuropathy?

Abstract

Epidemiological studies show that diabetic neuropathy can affect 50-90% of patients with diabetes. Diabetes increases the risk of foot ulceration and amputation more than 23-fold (1), and neuropathy is the major contributory factor to this increased risk. Neuropathy presents as painful neuropathy in ;20% of patients (2), and it independently predicts all-cause and diabetes-related mortality (3).Several longitudinal studies have shown that glycemic control and vascular risk factors are important in the development of diabetic neuropathy in patients with both type 1 (4) and type 2 (5) diabetes. However, the time of onset and exact deficits associated with early diabetic neuropathy have not been established using a comprehensive neuropathy assessment. In an early study of 132 newly diagnosed patients with type 2 diabetes, symptoms and clinical signs of neuropathy had a low prevalence (1.5 and 2.3%, respectively), while polyneuropathy assessed by electrophysiology was identified in 15.2% of patients and autonomic neuropathy based on an abnormal expirationto-inspiration ratio was increased threefold compared with healthy control subjects (6). In a 5-year follow-up of this cohort, there was only a minimal deterioration in electrophysiology (7).The latest recommendations continue to advocate a multimodal approach to assessing diabetic neuropathy. This should include symptoms and signs, quantitative sensory testing, and electrophysiology (8). There is no doubt that symptoms and neurological deficits matter most to patients. However, the excessive variability and poor reproducibility (9) of these measures limit their utility in observational studies as well as in clinical trials. Although neurophysiology has been considered to be the most objective measure of diabetic neuropathy, it assesses only large myelinated fibers, which constitute about 10% of peripheral nerves. Further, the reproducibility of this approach has been questioned (10).Small fibers constitute the majority of peripheral nerve fibers, are the earliest to be damaged, and have direct pathophysiological relevance to generation of nociceptive signals, leading to both neuropathic pain (11) and impaired pressure-induced vasodilation (12) predisposing to foot ulceration. Despite these factors, small nerve fibers receive considerably less attention than large ones. Perhaps not surprisingly, a reduction in intraepidermal nerve fiber density (IENFD) has been demonstrated in subjects with impaired glucose tolerance, which improved after lifestyle intervention (13). In contrast, Dyck et al. (14) found no evidence of neuropathy in subjects with impaired glycemia. However, their diagnosis of neuropathy was based on composite abnormality in nerve conduction. Although small fibers can be assessed objectively by quantifying IENFD in skin biopsies, this is an invasive procedure requiring expert laboratory assessment (15).We have pioneered corneal confocal microscopy (CCM), a rapid and noninvasive ophthalmic technique. The technique has been shown to be reproducible and h...

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