Abnormal LDIflare but Normal Quantitative Sensory Testing and Dermal Nerve Fiber Density in Patients with Painful Diabetic Neuropathy

Abstract

OBJECTIVE -Abnormal small nerve fiber function may be an early feature of diabetic neuropathy and may also underlie painful symptoms. Methods for assessing small-fiber damage include quantitative sensory testing (QST) and determining intraepidermal nerve fiber density. We recently described a reproducible physiological technique, the LDIflare, which assesses small-fiber function and thus may reflect early dysfunction before structural damage. The value of this technique in painful neuropathy was assessed by comparing it with QST and dermal nerve fiber density (NFD).RESEARCH DESIGN AND METHODS -Fifteen healthy control subjects, 10 subjects with type 2 diabetes and painful neuropathy (PFN), and 12 subjects with type 2 diabetes and painless neuropathy (PLN) were studied. LDIflare and QST were performed on the dorsum of the foot, and dermal NFD was determined.RESULTS -Results of both large-and small-fiber quantitative sensory tests were abnormal in patients with PLN but not those with PFN compared with control subjects. Dermal NFD was also significantly reduced in the PLN group compared with control subjects (205.8 Ϯ 165.3 vs. 424.9 Ϯ 176.3 [mean Ϯ SD]; P ϭ 0.003) but not in the PFN group (307.6 Ϯ 164.5). In contrast, the LDIflare (square centimeters) was reduced in both PFN (1.59 Ϯ 0.41) and PLN (1.51 Ϯ 0.56) groups compared with control subjects (4.38 Ϯ 1.4) (P Ͻ 0.001 for both). NFD correlated significantly with the LDIflare (r ϭ 0.57, P Ͻ 0.0001).CONCLUSIONS -The LDIflare demonstrated impaired small-fiber function in patients with PFN when other assessments revealed no abnormality. We believe that this method has potential diagnostic value, particularly because it is noninvasive, has excellent reproducibility, and correlates with NFD. Furthermore, it may have an important role in assessing preventative therapies in early neuropathy. Diabetes Care 32:451-455, 2009

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

“…Furthermore, although LDImax was similarly reduced in the MV− and MV+ groups, the LDIflare in the MV− group was greater and not significantly different from that in the control group; this would not expected if LDIflare was related to LDImax. Finally, as with our previous studies, there was no correlation between LDImax and LDIflare, confirming that they measure different physiological variables and are not influenced by each other within the range of microvascular blood flow studied [3,9,10]. LDImax represents the maximum vasodilatory capacity.…”

“…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).…”

“…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].…”

Role of Small-Fiber Afferents in Pain Mechanisms With Implications on Diagnosis and Treatment

“…QST, microneurography, and autonomic testing such as laser Doppler-induced flare reactions have been utilized to detect SFN, and advances in human in vivo imaging have demonstrated corneal innervation to be another potential site of monitoring SFN [15,47,52,57]. However, because QST is dependent upon subjective feedback, autonomic dysregulation may have origins in sensory neuropathy, and microneurography and corneal imaging are still largely experimental, cutaneous skin biopsy with direct measures of small-caliber axons provides a definitive diagnosis of SFN [45, 46, 48, 58•].…”

Distal Sensorimotor Neuropathy: Improvements in Diagnosis

“…As with IENFD and CCM, LDIflare has been validated against large and small fiber markers and bears a strong correlation to IENFD (r = 0.77, p < 0.001) [62]. It can detect abnormal small fiber function in increasing severity of diabetic neuropathy [64][65], impaired glucose tolerance with normal thermal thresholds [26], and as reported recently, in non-diabetic nonneuropathic individuals with hypertriglyceridemia [66]. Studies have shown that glycemic control and HbA1c have a strong relationship with LDIflare results [67][68].…”