Epidermal Nerve Fiber Density

McArthur, Justin C.; Stocks, E. A.; Hauer, Peter; Cornblath, David R.; Griffin, John W.

doi:10.1001/archneur.55.12.1513

Cited by 501 publications

(131 citation statements)

References 37 publications

(43 reference statements)

Supporting

Mentioning

119

Contrasting

Order By: Relevance

“…However, we have identified a specific trend of IENF in painful diabetic neuropathy that was previously unreported. As a group, our diabetic subjects also have greatly reduced IENF compared with the normative mean values of 36 fibers/3 mm reported by McArthur et al (17) and significantly different from those obtained by neurological colleagues at our hospital measured with the identical method (42 fibers/3 mm) (P. Spring, personal communication). Similar to previous descriptions, the fibers in our cohort often terminated abruptly at the dermalepidermal junction and showed more nodularity (8,21).…”

Section: Research Design Andcontrasting

confidence: 67%

See 1 more Smart Citation

The Relationship Among Pain, Sensory Loss, and Small Nerve Fibers in Diabetes

2006

View full text Add to dashboard Cite

OBJECTIVE -Many individuals with diabetes experience neuropathic pain, often without objective signs of large-fiber neuropathy. We examined intraepidermal nerve fibers (IENFs) to evaluate the role of small nerve fibers in the genesis of neuropathic pain.RESEARCH DESIGN AND METHODS -Twenty-five diabetic subjects with neuropathic pain and 13 without were studied. The pain was present for at least 6 months for which no other cause could be found. Punch skin biopsies were obtained from the distal leg. IENFs were stained using antibody to protein gene product 9.5 and counted with confocal microscopy. Neuropathy was graded by vibration perception and cold detection thresholds and the Michigan Neuropathy Screening Instrument.RESULTS -In the total cohort, IENF density was significantly lower in those with pain compared with those without (3 [1-6] vs. 10 [3-19], respectively, P ϭ 0.02). There were significant inverse correlations between IENF and severity of neuropathy, with the pain group having a flatter gradient than their pain-free counterparts (P Ͻ 0.02). The difference in IENF density was greatest in subjects with less objective evidence of neuropathy (P Յ 0.01).CONCLUSIONS -More severe loss of IENF is associated with the presence of neuropathic pain only in those with little or no objective sign of neuropathy. Thus, loss of IENF cannot explain pain in all cases, suggesting that different mechanisms underpin the genesis of pain at various stages of neuropathy. Diabetes Care 29:883-887, 2006P eripheral neuropathy is a common complication of both type 1 and type 2 diabetes (1). Most commonly, it manifests as sensory loss, which predisposes subjects to foot abnormalities and high risk of ulceration. However, it has been reported that between 4 and 33% of subjects with diabetes suffer from the painful type of neuropathy, which can become chronic and produce unremitting pain for which there is little satisfactory treatment (2-4).It is known that pain transmission in peripheral nerves occurs along the small A␦ and C-type fibers (5,6). However, conventional clinical investigation of individuals with painful diabetic neuropathy is usually limited to nerve conduction studies that measure large-nerve fiber function. The results of these tests are often normal and unable to provide an explanation for the presence of pain (7,8). This conundrum reflects a common clinical observation that pain is often present in the absence of objective signs of neuropathy. Even in the presence of abnormal nerve conduction studies, some individuals may experience pain while others with the same degree of electrophysiological abnormalities are completely asymptomatic. It is commonly assumed that more specific testing of small-fiber function may better discriminate those with or without pain, but several studies, including our own, have shown this not to be the case (9 -11). However, in view of the pivotal role played by small nerve fibers in the transmission of pain sensation, further studies are obviously of importance.Direct examination of int...

show abstract

Section: Research Design Andcontrasting

confidence: 67%

“…Skin biopsies were obtained and analyzed according to the protocol developed by McArthur et al (17). Skin specimens were obtained using a 3-mm punch biopsy from the leg 10 cm above the lateral malleolus.…”

Section: Research Design Andmentioning

confidence: 99%

The Relationship Among Pain, Sensory Loss, and Small Nerve Fibers in Diabetes

2006

View full text Add to dashboard Cite

show abstract

“…1b). Cut-off values Hypothyroidism 3 (7) 16 (10) Sjøgren's syndrome 1 (2) 8 (5) Chronic idiopathic axonal polyneuropathy 17 (38) 53 (32) Other causes 4 (9) 28 (17) for each group were chosen on the basis of the optimal combination of sensitivity and specificity. The cut-off point established for patients with SFN was 10.3 fibers/mm, with a sensitivity 0.78 and specificity 0.64; that estimated for all patients was 9.8 fibers/mm, with a sensitivity 0.73 and a specificity 0.69.…”

Section: Resultsmentioning

confidence: 99%

The value of skin biopsy with recording of intraepidermal nerve fiber density and quantitative sensory testing in the assessment of small fiber involvement in patients with different causes of polyneuropathy

et al. 2009

View full text Add to dashboard Cite

The primary aim of our study was to demonstrate how the diagnostic characteristics of skin biopsy used to evaluate small fiber involvement in patients with different causes of polyneuropathy are intrinsically related to the method used to establish the reference values (cut-off values). We also investigated intraepidermal nerve fiber (IENF) density and abnormalities in quantitative sensory testing (QST) in patients with different causes of polyneuropathy and signs of small fiber involvement. A total of 210 patients with symptoms and signs of polyneuropathy were entered into the study. All patients underwent neurological examination, nerve conduction studies, QST on the thigh and distal part of the calf with detection of warm and cold perception thresholds, and skin biopsy with assessment of IENF density. Cut-off values for IENF density were established from our reference material using Z-scores (calculated from multiple regression analysis), fifth percentile, and receiver operating characteristic (ROC) analysis. Of the patients participating in the study, 65 had an established diagnosis of diabetes mellitus, 70 were classified with idiopathic polyneuropathy, and 75 had other possible causes of polyneuropathy. Forty-five patients met the criteria for small fiber polyneuropathy (SFN), and the remaining 165 had also involvement of large nerve fibers. Of the total patient cohort, 84 (40%) had reduced IENF density based on the Z-score, and 106 patients (50%) had at least one abnormality based on QST. In the SFN group, skin biopsy showed a sensitivity of 31% and a specificity of 98% when reference values were presented with Z-scores. When the fifth percentile was used as the cut-off value (6.7 fibers/mm), sensitivity was 35% and specificity 95%. Applying the ROC analysis with a chosen sensitivity of 78% and specificity of 64%, we had a cut-off point of 10.3 fibers/mm. We conclude that skin biopsy with assessment of IENF is a useful method for investigating patients with SFN. The diagnostic value of the test, however, depends upon on the approach used to estimate the reference values.

show abstract

“…In healthy subjects, IENF is substantially higher at the thigh level than at the ankle level. In DPN, IENF is reduced at both the distal and proximal levels, but again, this decrease is most obvious distally 15, 16…”

Section: Discussionmentioning

confidence: 96%

Magnetic resonance neurography detects diabetic neuropathy early and with Proximal Predominance

Pham

Oikonomou

Hornung

et al. 2015

Annals of Neurology

102

View full text Add to dashboard Cite

ObjectiveThe aim of this work was to localize and quantify alterations of nerve microstructure in diabetic polyneuropathy (DPN) by magnetic resonance (MR) neurography with large anatomical coverage.MethodsPatients (N = 25) with mild‐to‐moderate (Neuropathy‐Symptom‐Score [NSS]/Neuropathy Deficit Score [NDS] 3.8 ± 0.3/2.6 ± 0.5) and patients (n = 10) with severe DPN (6.2 ± 0.6/7.4 ± 0.5) were compared to patients (n = 15) with diabetes but no DPN and to age‐/sex‐matched nondiabetic controls (n = 25). All subjects underwent MR neurography with large spatial coverage and high resolution from spinal nerve to ankle level: four slabs per leg, each with 35 axial slices (T2‐ and proton‐density–weighted two dimensional turbo‐spin‐echo sequences; voxel size: 0.4 × 0.3 × 3.5 mm3) and a three‐dimensional T2‐weighted sequence to cover spinal nerves and plexus. Nerve segmentation was performed on a total of 280 slices per subject. Nerve lesion voxels were determined independently from operator input by statistical classification against the nondiabetic cohort. At the site with highest lesion‐voxel burden, signal quantification was performed by calculating nerve proton spin density and T2 relaxation time.ResultsTotal burden of nerve lesion voxels was significantly increased in DPN (p = 0.003) with strong spatial predominance at thigh level, where average lesion voxel load was significantly higher in severe (57 ± 18.4; p = 0.0022) and in mild‐to‐moderate DPN (35 ± 4.0; p < 0.001) than in controls (18 ± 3.6). Signal quantification at the site of predominant lesion burden (thigh) revealed a significant increase of nerve proton spin density in severe (360 ± 22.9; p = 0.043) and in mild‐to‐moderate DPN (365 ± 15.2; p = 0.001) versus controls (288 ± 13.4), but not of T2 relaxation time (p = 0.49). Nerve proton spin density predicted severity of DPN with an odds ratio of 2.9 (95% confidence interval: 2.4–3.5; p < 0.001) per 100 proton spins.InterpretationIn DPN, the predominant site of microstructural nerve alteration is at the thigh level with a strong proximal‐to‐distal gradient. Nerve proton spin density at the thigh level is a novel quantitative imaging biomarker of early DPN and increases with neuropathy severity. Ann Neurol 2015;78:939–948

show abstract

Epidermal Nerve Fiber Density

Cited by 501 publications

References 37 publications

The Relationship Among Pain, Sensory Loss, and Small Nerve Fibers in Diabetes

The Relationship Among Pain, Sensory Loss, and Small Nerve Fibers in Diabetes

The value of skin biopsy with recording of intraepidermal nerve fiber density and quantitative sensory testing in the assessment of small fiber involvement in patients with different causes of polyneuropathy

Magnetic resonance neurography detects diabetic neuropathy early and with Proximal Predominance

Contact Info

Product

Resources

About