The LDIflare

Abstract

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.

Small fibre dysfunction, microvascular complications and glycaemic control in type 1 diabetes: a case–control study

“…Furthermore, in idiopathic painful peripheral neuropathy, a condition primarily affecting small nerve fibres, metabolic dysregulation has been implicated [7,8]. In support of these observations, we have recently demonstrated impaired C-fibre function in individuals with type 2 diabetes free from clinical neuropathy and in individuals with IGT using a relatively new method, the laser Doppler imager flare (LDIflare) technique [3,9,10]. This involves heating the skin on the dorsum of the foot to 44°C and measuring the size of the axon-reflex-mediated flare using a laser Doppler imager (LDI).…”

“…This involves heating the skin on the dorsum of the foot to 44°C and measuring the size of the axon-reflex-mediated flare using a laser Doppler imager (LDI). The neurogenic nature of the LDIflare has been confirmed by demonstrating that the LDIflare is abolished by prior application of eutectic mixture of local anaesthetics (EMLA) cream over the area to be heated [3,11]. The LDIflare also correlates well with dermal nerve fibre density (r00.57, p<0.0001) and intra-epidermal nerve fibre density (r00.57, p<0.0001) and is more sensitive than quantitative sensory testing [9,10].…”

“…Additionally, the LDImax in the skin immediately beneath the heater was also measured using the imager. Unlike the flare, LDImax is mediated by non-neurogenic means and reflects endothelial function [3,11]. The size of the LDIflare depends on C-fibre function and the underlying skin small fibre neural network and extent of interconnections.…”

“…Assessment of the LDIflare The exact method used for the LDIflare technique is published in detail elsewhere [3]. It involves skin heating to 44°C for 20 min.…”

“…There is increasing evidence that small unmyelinated nerve fibres that mediate pain and temperature (C-fibres) are involved early in the development of neuropathy in type 2 diabetes [2][3][4][5]. Indeed, Smith et al showed that the neuropathy associated with impaired glucose tolerance (IGT) primarily affects small fibres and is similar to early diabetes-associated neuropathy [6].…”