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.Peripheral neuropathy affects between 40 and 60% of individuals with diabetes and is commonly diagnosed by assessing large-fiber sensory modalities. However, detection of small-fiber neuropathy may be of equal or more importance for several reasons. Structural and functional changes in small fibers precede large-fiber pathological changes and have been implicated in foot ulceration and delayed wound healing (1–3). Furthermore, C-fiber dysfunction may be involved in the genesis of neuropathic pain (4).Until recently, few objective methods have been available to quantify small-fiber function. Quantitative sensory tests to define thermal and pain thresholds using the Computer Aided Sensory Evaluator–IV (CASE IV; WR Medical Electronics, Stillwater, MN) or the TSA-II NeuroSensory Analyzer (Medoc Advanced Medical Systems, Ramat Ysihai, Israel) have been used primarily in clinical research (5,6). However, they are dependent on subjective responses and therefore have a high interobserver variability and poor reproducibility (7,8). We recently described a novel and reproducible (coefficient of variation <15%) technique to assess small-fiber dysfunction, the “LDIflare,” which measures axon reflex–mediated vasodilatation in response to skin heating (9). We have also demonstrated that LDIflare detects early C-fiber dysfunction in type 2 diabetes before small-fiber neuropathy can be detected by other currently available noninvasive methods (10). However, the structural basis for an abnormal LDIflare response has not been established.Although intraepidermal nerve fiber density (IENFD), with good intraobserver reproducibility, has been increasingly used to diagnose small-fiber neuropathies, it is an invasive procedure (11,12). In the present study we assessed small-fiber function using quantitative sensory testing (QST) and the LDIflare and compared these results with the results of dermal NFD in foot skin biopsy specimens from the same area. Dermal NFD as opposed to IENFD was quantified to define the underlying structural basis of the LDIflare, as this depends on an abnormality in dermal blood flow. In addition, as there is no current consensus as to whether an abnormality in small-fiber dysfunction and damage underlie painful diabetic neuropathy, we compared diabetic patients with painful neuropathy (PFN) and painless neuropathy (PLN).