Electrically Stimulated Axon Reflexes Are Diminished in Diabetic Small Fiber Neuropathies

Abstract

Axon reflex mediated flare depends on the density and the function of cutaneous C-fibers and may be impaired in diabetic neuropathy. We induced neurogenic axon reflex flare by intracutaneous electrical stimulation and analyzed size and intensity of the flare on the dorsum of the foot and ventral thigh with laser Doppler imaging (LDI). We investigated 12 diabetic subjects with small fiber neuropathies (SFNs), 5 diabetic subjects without neuropathy (NO-Ns), and 14 healthy control subjects. Five of the normal subjects were reassessed after 12 months. In comparing patients with SFN to control subjects, we found that SFN flare size but not the intensity of vasodilation (flux) was reduced on the feet (P < 0.001) and thighs (P < 0.007). Furthermore, electrical thresholds for flare induction were increased (thighs P < 0.001 and feet P < 0.03). In NO-Ns, flare size at the feet (P < 0.02) and flux at both sites (thighs P < 0.001 and feet P < 0.002) were even increased. Test/ retest evaluation of our method revealed a good correlation (r ‫؍‬ 0.83, P < 0.004). Intracutaneous electrical stimulation of C-fibers and scanning the flare with LDI is a sensitive tool to reliably detect small fiber impairment in diabetic SFN subjects and even increased neuropeptide release in NO-Ns. Diabetes 53:769 -774, 2004 S mall fiber neuropathy (SFN) is a common complication in diabetes and other disorders. Clinical features of this disease often include pain and dysesthesia such as burning feet and neurovascular abnormalities (1). Despite its high incidence and clinical importance, there are only a few methods to quantify peripheral small fiber dysfunction. These include quantitative sensory testing (2), analysis of heart rate variability, assessment of sudomotor axon reflexes (3), or skin biopsies (4). However, availability of these procedures in clinical routine is limited and sensitivity of the psychophysical methods may be questioned.Analysis of axon reflexes is a simple and specific test for peripheral C-fiber function. Activation of nociceptive Cfibers in the skin by mechanical (5) or chemical stimuli (6,7) induces a spreading vasodilation, which is visible as a "flare response" surrounding the injured site (8). The flare depends on both the density and function of C-fiber nociceptors in the skin, in particular the subgroup of mechanoinsensitive "silent" nociceptors (9). The neuronal pathway of neurogenic vasodilation is organized as an axon reflex. Activation of peripheral C-nociceptors provokes nerve impulses, which are conducted centrally. At some branching points of the axonal tree these action potentials may invade peripheral branches (10), causing the release of vasodilatory neuropeptides from skin nerve terminals, e.g., calcitonin gene-related peptide and substance P (11,12).In previous studies, quantitative analysis of vasodilation in axon reflex flares (flare intensity) employing single channel laser Doppler flowmetry (5,13) was not sensitive enough to reliably distinguish between control subjects and patients with mild to mode...

Abnormal Function of C-Fibers in Patients with Diabetic Neuropathy

“…If the CMi fibers are less affected than CM fibers, this may explain hyperalgesia observed in early stages of diabetic neuropathy on the background of elevated thresholds for painful stimuli. However, the efferent function of the CMi fibers, which has been found to be impaired in diabetic neuropathy (Kramer et al, 2004b), was not tested in this study.…”

Prevalence of somatic small fiber neuropathy in obesity

“…15,33 The difference in the flare and pain response to a heat-ramp stimulus among the normal and obese subjects may be indicative of such a dissociation and, in fact, would favor a concept that the organism attempts to elicit an early protective reaction (neurogenic vasodilatation) at a temperature (441C) just below that which will become injurious to tissue. 14 Flare can be suppressed or abolished by denervation, 21,42 local anesthetics, 12,21 capsaicin-desensitization, 22,34 disease (diabetes, post-herpetic neuralgia), 21,43 and aging. 32 Under circumstances of prolonged depression of small fiber function, tissue integrity can be substantially impaired.…”

Comparison of electrically induced flare response patterns in human and pig skin

“…Noteworthy, the flare response does not reach a plateau under the given experimental settings. Similarly, previous human studies also demonstrated a linear increase of flare development, which does not saturate at current intensities of 30 mA [14,15]. If current intensities are further increased, the flare area gains a maximum after 50 min of continuous stimulation at about 50-80 mA [16].…”