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Electrically Stimulated Axon Reflexes Are Diminished in Diabetic Small

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Electrically Stimulated Axon Reflexes Are Diminished in Diabetic Small Electrically Stimulated Axon Reflexes Are Diminished in Diabetic Small Fiber Neuropathies Heidrun H. Kra¨mer,1 Martin Schmelz,2 Frank Birklein,1 and Andreas Bickel3 Axon reflex mediated flare depends on the density and (6,7) induces a spreading vasodilation, which is visible as the function of cutaneous C-fibers and may be impaired a “flare response” surrounding the injured site (8). The in diabetic neuropathy. We induced neurogenic axon flare depends on both the density and function of C-fiber reflex flare by intracutaneous electrical stimulation and nociceptors in the skin, in particular the subgroup of analyzed size and intensity of the flare on the dorsum of mechanoinsensitive “silent” nociceptors (9). The neuronal the foot and ventral thigh with laser Doppler imaging pathway of neurogenic vasodilation is organized as an (LDI). We investigated 12 diabetic subjects with small axon reflex. Activation of peripheral C-nociceptors pro- fiber neuropathies (SFNs), 5 diabetic subjects without vokes nerve impulses, which are conducted centrally. At neuropathy (NO-Ns), and 14 healthy control subjects. some branching points of the axonal tree these action Five of the normal subjects were reassessed after 12 months. In comparing patients with SFN to control potentials may invade peripheral branches (10), causing subjects, we found that SFN flare size but not the the release of vasodilatory neuropeptides from skin nerve intensity of vasodilation (flux) was reduced on the feet terminals, e.g., calcitonin gene-related peptide and sub- (P < 0.001) and thighs (P < 0.007). Furthermore, elec- stance P (11,12). trical thresholds for flare induction were increased In previous studies, quantitative analysis of vasodilation (thighs P < 0.001 and feet P < 0.03). In NO-Ns, flare size in axon reflex flares (flare intensity) employing single at the feet (P < 0.02) and flux at both sites (thighs P < channel laser Doppler flowmetry (5,13) was not sensitive 0.001 and feet P < 0.002) were even increased. Test/ enough to reliably distinguish between control subjects retest evaluation of our method revealed a good corre- and patients with mild to moderate SFN. In contrast, in a ؍ lation (r 0.83, P < 0.004). Intracutaneous electrical pilot study we have been able to demonstrate that the stimulation of C-fibers and scanning the flare with LDI is a sensitive tool to reliably detect small fiber impair- extension, and not the intensity, of histamine-induced flare ment in diabetic SFN subjects and even increased neu- was significantly reduced in SFN patients (14). However, ropeptide release in NO-Ns. Diabetes 53:769–774, 2004 there are some drawbacks of histamine stimulation; epi- dermal thickness varies seasonally. This could have an impact on the amount of histamine reaching histamine- sensitive nerve endings (15). Furthermore, only a minor mall fiber neuropathy (SFN) is a common com- population of C-fibers are activated by histamine (16), and plication in diabetes and other disorders. Clinical the number of action potentials induced by a chemical features of this disease often include pain and stimulus in C-fibers varies. This makes standardization Sdysesthesia such as burning feet and neurovascu- impossible. Therefore, the neurogenic flare reaction fol- lar abnormalities (1). Despite its high incidence and clin- lowing chemical stimulation appears to be too variable to ical importance, there are only a few methods to quantify be considered a diagnostic tool for SFN. peripheral small fiber dysfunction. These include quanti- In contrast, previous experiments have shown that tative sensory testing (2), analysis of heart rate variability, neurogenic flare in human skin can be reliably induced assessment of sudomotor axon reflexes (3), or skin biop- with low variation by electrical current (17). In this study sies (4). However, availability of these procedures in we employed standardized electrical stimulation at a high clinical routine is limited and sensitivity of the psycho- current density. Microdialysis fibers equipped with inter- physical methods may be questioned. nal stainless steel electrodes were inserted in the dorsum Analysis of axon reflexes is a simple and specific test for of the foot and the ventral thighs for intradermal electrical peripheral C-fiber function. Activation of nociceptive C- stimulation. The flare response was recorded by laser fibers in the skin by mechanical (5) or chemical stimuli Doppler imaging (LDI). The aim was to assess stimulus- response curves of the axon reflex flare for increasing From the 1Department of Neurology, Johannes Gutenberg University, Mainz, current intensity. These stimulus-response curves were Germany; the 2Department of Anesthesiology, University of Heidelberg, compared between diabetic subjects with SFN or without Mannheim, Germany; and the 3Department of Neurology, Friedrich-Alexander neuropathy (NO-Ns) and healthy control subjects. University, Erlangen, Germany. Address correspondence and reprint requests to Dr. Heidrun H. Kra¨mer, Department of Neurology, Johannes Gutenberg-University, Langenbeckstr. 1, 55101 Mainz, Germany. E-mail: [email protected]. RESEARCH DESIGN AND METHODS Received for publication 23 April 2003 and accepted in revised form Twelve patients (5 women and 7 men, mean age 46 Ϯ 3.3 years) suffering from 15 December 2003. LDI, laser Doppler imaging; LFN, large fiber neuropathy; NGF, nerve growth diabetic neuropathy were included in this study. The inclusion criterion was factor; NO-N, diabetic subject without neuropathy; PU, perfusion units; SFN, a clinically suspected small fiber impairment (SFN) because all patients small fiber neuropathy. suffered from neuropathic pain symptoms, such as burning sensation, lanci- © 2004 by the American Diabetes Association. nating, or spontaneous pain in the feet but not in the thighs. Among these DIABETES, VOL. 53, MARCH 2004 769 AXON REFLEX IN DIABETIC NEUROPATHY TABLE 1 Biographical and clinical data of included patients SFN 1 SFN 2 SFN 3 SFN 4 SFN 5 SFN 6 Sex (M/F)/age (years) M/50 M/40 F/38 M/47 M/55 F/34 Diabetes type 2 1 1 2 2 1 Duration of diabetes (years) 6 12 22 4 10 14 Neuropathy impairment score 12 24 31 28 60 22 Type of pain BF BF BF, L, and P L and P BF and P L Sensory disturbances Feet Feet Feet Toes Feet and lower leg Toes Plantar reflex ϩϩ Ϫ ϩ — ϩ Nerve conduction velocity, peroneal nerve (m/s) 40 40 36 36 34 42 Amplitude of compound muscle action potential, peroneal nerve 2.4 2.8 2.8 1.0 1.2 1.6 Nerve conduction velocity, sural nerve (m/s) 42 44 42 48 Absent 40 Amplitude of sensory nerve action potential, sural nerve (␮V) 3.2 3.7 2.2 4.8 Absent 2.0 Plantar reflexes: ϩ, normal; Ϫ, reduced; —, absent. BF, burning feet; L, lancinating pain; P, spontaneous prickling sensations. patients were five patients with type 1 diabetes (two men and three women) backscattered laser light (arbitrary perfusion units [PUs]). Thereby, a two- and seven patients with type 2 diabetes (five men and two women). The type dimensional map of the superficial blood flow is generated. Area and intensity of neuropathic pain resulting from SFN was assessed by the medical history of the neurogenic flare reaction were analyzed offline by dedicated software and neuropathy impairment score (18) and was recorded as burning, lanci- (MLDI 3.0; Moor, London, U.K.). Flare area was determined by total number nating, or spontaneous pain. of pixels (0.22 mm2/pixel) in which flux values exceeded the mean flux by two Moreover, we recruited five diabetic subjects (four women and one man, SDs from the baseline picture. Total flare areas Ͼ0.5 cm2 on the feet and Ͼ1 mean age 43.6 Ϯ 10.8 years; three patients with type 1 and two patients with cm2 on the thighs were regarded as significant. The minimum current needed type 2 diabetes) without clinical and electrophysiological evidence of neurop- to induce a flare reaction according to this definition was noted as electrical athy (NO-N). All patients underwent standard electrophysiological studies, threshold. such as the measurement of nerve conduction velocity of the peroneal and Pain rating. Patients and subjects were asked to quantify pain sensation sural nerve (Table 1). during electrical stimulation by a numeric rating scale from 0 to 10, in which As a control group, 14 healthy subjects (8 women and 6 men, mean age the value of 0 indicated “no pain” and 10 “maximum pain.” Pain ratings were 36.5 Ϯ 2.3 years) without any neurological or dermatological disorders were obtained every minute during stimulation. included. In five subjects (two women and three men, mean age 41.4 Ϯ 6 Statistics. Statistics were calculated using an SPSS (SPSS 10.1 for Windows, years) of this control group, reproducibility of the investigation was evaluated Chicago, IL) software package. To identify significant differences between by retests performed with an interval of 12 months. All healthy volunteers patient groups and control subjects, ANCOVA for repeated measures was were drawn from staff and relatives of the Department of Physiology, performed. The ANCOVA incorporated seven consecutive measurements University of Erlangen-Nuremberg. All investigations were carried out in a (during stimulation), one main factor (SFN subject or NO-N and control temperature (23°C) and humidity (50% relative humidity) controlled labora- subjects), and age and sex as covariates. Since sphericity could not be tory. The time for acclimatization for all subjects was at least 1 h before assumed in all datasets, Greenhouse-Geisser correction was employed. Post starting the experiment. hoc analysis was performed in order to allocate differences at the different Informed consent according to the Declaration of Helsinki was obtained stimulus intensities between SFNs or NO-Ns and control subjects. We used from all participants and the study was approved by the local ethics planned comparisons with t tests using Bonferroni’s correction.
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