Early diabetic neuropathy: thermal thresholds and intraepidermal nerve fibre density in patients with normal nerve conduction studies

J Neurol. 2008 Aug;255(8):1197-202. doi: 10.1007/s00415-008-0872-0. Epub 2008 Jun 27.


Objectives: To determine whether neuropathy in diabetic patients with normal nerve conduction studies could be detected by measurements of thermal thresholds and quantification of intraepidermal nerve fibre (IENF) density, and to evaluate differences in parameters between patients with and without neuropathic symptoms.

Methods: A total of 22 patients with and 37 patients without sensory symptoms suggesting distal neuropathy were included. Measurements of warm and cold perception thresholds and skin biopsy for quantification of IENFs were performed distally on the leg. Reference data were used to normalize test results for age and height or gender of individual patients by calculating the Z-scores.

Results: IENF density was significantly reduced in both symptomatic and asymptomatic patients compared to controls (p < 0.001), and in patients with symptoms compared to those without (p = 0.01). Thermal thresholds were significantly elevated (more abnormal) in patients with symptoms compared to controls (p < 0.01), but only for cold perception threshold (CPT) (p < 0.001) in the asymptomatic group. When comparing symptomatic and asymptomatic patients, there was no statistically significant difference in thermal thresholds. Depletion of IENFs in skin biopsy was the most frequent abnormal finding in the subgroup of patients with neuropathic symptoms (36 %) followed by abnormal CPT (27 %).

Conclusion: Patients with diabetes and normal nerve conduction studies had significantly lower IENF density and higher CPT than controls, whether they had symptoms of polyneuropathy or not. In patients with neuropathic symptoms, abnormal IENF density predominated and seemed thus to be the most sensitive tool of detecting small diameter nerve fibre involvement.

MeSH terms

  • Adult
  • Aged
  • Biophysical Phenomena
  • Diabetic Neuropathies / pathology*
  • Diabetic Neuropathies / physiopathology*
  • Electric Stimulation / methods
  • Female
  • Humans
  • Male
  • Middle Aged
  • Neural Conduction / physiology*
  • Norway
  • Peripheral Nerves / physiopathology*
  • Sensory Thresholds / physiology*
  • Skin / innervation
  • Young Adult