Abnormal LDIflare but normal quantitative sensory testing and dermal nerve fiber density in patients with painful diabetic neuropathy.

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 +/- 165.3 vs. 424.9 +/- 176.3 [mean +/- SD]; P = 0.003) but not in the PFN group (307.6 +/- 164.5). In contrast, the LDIflare (square centimeters) was reduced in both PFN (1.59 +/- 0.41) and PLN (1.51 +/- 0.56) groups compared with control subjects (4.38 +/- 1.4) (P < 0.001 for both). NFD correlated significantly with the LDIflare (r = 0.57, P < 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.

Neurovascular factors in wound healing in the foot skin of type 2 diabetic subjects.

OBJECTIVE: Delayed wound healing in diabetic patients without large-vessel disease has been attributed to microvascular dysfunction, neuropathy, and abnormal cellular and inflammatory responses. The role of these abnormalities has mainly been examined in animal models. Few studies have been undertaken in diabetic patients, and those that have are limited due to analysis in wounds from chronic ulcers. In this study, we quantified the rate of wound healing in relation to skin neurovascular function and structure following a dorsal foot skin biopsy in type 2 diabetes. RESEARCH DESIGN AND METHODS: Twelve healthy control subjects and 12 type 2 diabetic subjects with neuropathy but without macrovascular disease were studied. We quantified rate of wound healing and related it to skin microvascular function (laser Doppler imager [LDI](max)), blood vessel density, small nerve fiber function (LDI(flare)) and nerve fiber density, vascular endothelial growth factor (VEGF) and its receptor (FLK1), and hypoxia-inducible factor (HIF)-1alpha expression. RESULTS: The rate of wound closure was identical between control subjects and diabetic patients despite a significant reduction in maximum hyperemia (LDI(max)), epidermal and dermal VEGF-A, and epidermal and dermal blood vessel VEGFR-2 expression as well as the neurogenic flare response (LDI(flare)) and dermal nerve fiber density. There was no significant difference in HIF-1alpha and dermal blood vessel density between control subjects and diabetic patients. CONCLUSIONS: In conclusion, the results of this study suggest that wound closure in subjects with type 2 diabetes is not delayed despite significant alterations in neurovascular function and structure.

The LDIflare: a novel test of C-fiber function demonstrates early neuropathy in type 2 diabetes.

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 degrees 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.

Are we underestimating diabetes-related lower-extremity amputation rates? Results and benefits of the first prospective study.

OBJECTIVE: The objective of this study was to accurately determine the incidence of lower-extremity amputation using prospective data collection and to compare the results with those obtained by retrospective methods. RESEARCH DESIGN AND METHODS: The study was carried out over a 3-year period in a large district general hospital covering a clearly defined and relatively static population. All diabetic inpatients with foot problems were identified and followed-up until discharge or death. The demographic and admission details, medical history, investigations, procedures, and history and etiology of the foot lesion were collected twice weekly by a specialist nurse and podiatrist from all relevant wards. Thus, all subjects who underwent amputation could be identified. For comparison, retrospective data were collected from the hospital coding activities database, operating theater log books, anesthetic database, and limb-fitting records. RESULTS: The total population of the region in 2000 was 337,859, of which 9,183 were known to have diabetes. The total number of amputations during the 3-year survey period was 79, of which 45 were major and 34 minor. In our local population, the mean incidence during the survey period (1997-2000) equates to 7.8/100,000 general population and 2.85/1,000 diabetic population for all amputations, 4.5/100,000 general population and 1.62/1,000 diabetic population for major amputations, and 3.3/100,000 general population and 1.23/1,000 diabetic population for minor amputations. The prospective survey detected all lower-extremity amputations identified by the various retrospective methods; however, for the reverse, this was not the case. All of the retrospective methods, including the most commonly used (ICD-9 and OPCS-4 coding), failed to detect all of the cases revealed by the prospective survey (error rate ranging from 4.2 to 90.6%), and between 4.5 and 17.4% of amputations were misclassified. CONCLUSIONS: This study demonstrates the advantages of prospective data collection as a means of determining the incidence of lower-extremity amputations and highlights the limitations of retrospective data collection methods, which underestimate the incidence. In particular, the operating theater records, which have been the gold standard for many surveys, were found to be unreliable. Moreover, we have shown a 47% reduction in the major amputations during the survey period. Thus, we recommend that a prospective audit be incorporated into the activities of the specialist foot care team as a means of assessing and improving clinical care.

Comparative roles of microvascular and nerve function in foot ulceration in type 2 diabetes.

OBJECTIVE: To determine the relative roles of different modalities of sensory nerve function (large and small fiber) and the role of microvascular dysfunction in foot ulceration in type 2 diabetic subjects. RESEARCH DESIGN AND METHODS: A total of 20 control subjects and 18 type 2 diabetic subjects with foot ulceration and 20 without were studied. None of the subjects had clinical features of peripheral vascular disease. The Computer-Aided Sensory Evaluator IV (CASE IV) was used to determine vibration detection threshold (VDT), cold detection threshold (CDT), warm detection threshold (WDT), and heat pain onset threshold (HPO). Vibration perception threshold (VPT) was also assessed by a neurothesiometer. Microvascular function (maximum hyperemia to skin heating to 44 degrees C) was assessed using laser Doppler flowmetry (mean maximum hyperemia using laser Doppler flowmeter [LDF(max)]), laser Doppler imaging (mean maximum hyperemia using laser Doppler imager [LDI(max)]), and skin oxygenation with transcutaneous oxygen tension (TcpO(2)). RESULTS: VPT, VDT, CDT, and HPO were all significantly higher in individuals with ulceration than in those without (VPT and VDT: P < 0.0001) (CDT and HPO: P = 0.01). LDF(max), LDI(max), and TcpO(2) were significantly lower in the two diabetic groups than in the control subjects, but there was no difference between individuals with and without ulceration. Univariate logistic regression analysis revealed similar odds ratios for foot ulceration for VDT, CDT, HPO, and VPT (OR 1.97 [95% CI 1.30-2.98], 1.58 [1.20-2.08], 2.30 [1.21-4.37], and 1.24 [1.08-1.42], respectively). None of the microvascular parameters yielded significant odds ratios for ulceration. CONCLUSIONS: This study found that there was no additional value in measuring small-fiber function with the CASE IV over measuring vibration by either CASE IV or the inexpensive neurothesiometer in discriminating between individuals with and without ulceration. Furthermore, none of the tests of microvascular function including the TcpO(2) were able to discriminate between individuals with and without ulceration, suggesting that such tests may not be of benefit in identifying subjects at greater risk of foot ulceration.

New treatments for diabetic neuropathy: symptomatic treatments.

Painful diabetic neuropathy is a common distressing and challenging condition. The mechanism or mechanisms involved in its pathogenesis continue to elude clinical scientists. As with other conditions of painful distal symmetrical neuropathic conditions, pain relief involves the use of a variety of analgesic and neuroleptic drugs, aimed at reducing either central responses to painful stimuli or at dampening spontaneous irritability of affected neurons. More recently, several therapies directed at putative pathologic mechanisms specific to painful diabetic neuropathy have evolved. These include vasodilators, protein kinase C beta inhibition, antioxidants, and novel aldose reductase inhibitors. Preliminary clinical studies of these therapies have at present involved small numbers of patients; however, the results have been encouraging. This article considers the clinical aspects of diagnosis and management of chronic painful diabetic neuropathy, focusing on existing and newer therapies.