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The LDIflare

A novel test of C-fiber function demonstrates early neuropathy in type 2 diabetes

From The Ipswich Diabetic Foot Unit and Diabetes Centre, Ipswich Hospital NHS Trust, Ipswich, U.K

Address correspondence and reprint requests to G. Rayman, MD, FRCP, The Ipswich Diabetes Centre, Ipswich Hospital NHS Trust, Heath Road, Ipswich, U.K. E-mail: gerry.rayman{at}ipswichhospital.nhs.uk

OBJECTIVE—The aim of this study was to evaluate a novel method for assessing the axon reflex and to determine its value in detecting neuropathy in type 2 diabetes.

RESEARCH DESIGN AND METHODS—The neurogenic flare response to nociceptive stimuli is mediated by an axon reflex involving small unmyelinated C-fibers. We developed a method to assess this reflex involving skin heating to 44°C to evoke the flare followed by scanning the site using a laser Doppler imager (LDI) to measure the area; we termed this method LDIflare. To confirm its neurogenic nature, we examined the LDIflare in eight healthy subjects before and after topical administration of anesthesia. We used this technique to detect C-fiber neuropathy in people with type 2 diabetes. A total of 36 subjects were studied: 12 subjects with neuropathy (group DN), 12 subjects without neuropathy (group DC), and 12 age- and sex-matched control subjects (group NC). For comparison, small-fiber function was also assessed using the Computer Aided Sensory Evaluator–IV (CASE IV) (WR Medical Electronics, Stillwater, MN).

RESULTS—In the eight healthy control subjects, LDIflare was markedly reduced after topical administration of anesthesia (1.62 [1.45–1.72] vs. 5.2 cm² [3.9–5.9], P < 0.0001), confirming its neurogenic nature. Similarly, in neuropathic subjects, LDIflare was significantly smaller compared with normal and diabetic control subjects (LDIflare area: DN 1.3 cm² [0.9–1.8], NC 5.5 cm² [3.9–5.8], and DC 2.8 cm² [2.5–3.8]; P < 0.0001 and P = 0.01, respectively). The group without neuropathy (DC) also demonstrated a reduced flare compared with the NC group (P = 0.01). In contrast, C-fiber function assessed by evaluating the quantitative thermal thresholds (CASE IV) did not detect a difference between the latter two groups.

CONCLUSIONS—This study confirms the neurogenic nature of the LDIflare and clearly demonstrates loss of C-fiber function in neuropathic subjects with type 2 diabetes. Moreover, it demonstrates C-fiber dysfunction before its detection by other currently available methods, including CASE IV. The LDIflare seems to be a simple objective method to detect early neuropathy and may be of value in assessing therapeutic interventions aimed at preventing or reversing C-fiber dysfunction.

Abbreviations: CASE IV, Computer Aided Sensory Evaluator–IV • CDT, cold detection threshold • IGT, impaired glucose tolerance • JND, just-noticeable difference • LDI, laser Doppler imager • VPT, vibration perception threshold • WDT, warm detection threshold

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