Journal of Neurology

, Volume 258, Issue 10, pp 1852–1864 | Cite as

Asymptomatic small fiber neuropathy in diabetes mellitus: investigations with intraepidermal nerve fiber density, quantitative sensory testing and laser-evoked potentials

  • Michael RagéEmail author
  • Nathalie Van Acker
  • Michiel W. M. Knaapen
  • Maarten Timmers
  • Johannes Streffer
  • Michel P. Hermans
  • Christian Sindic
  • Theo Meert
  • Léon Plaghki
Original Communication


This study aimed at evaluating the performance of a battery of morphological and functional tests for the assessment of small nerve fiber loss in asymptomatic diabetic neuropathy (DNP). Patients diagnosed for ≥10 years with type 1 (n = 10) or type 2 (n = 13) diabetes mellitus (DM) without conventional symptoms or signs of DNP were recruited and compared with healthy controls (n = 18) and patients with overt DNP (n = 5). Intraepidermal nerve fiber density (IENFd) was measured with PGP9.5 immunostaining on punch skin biopsies performed at the distal leg. Functional tests consisted of quantitative sensory testing (QST) for light-touch, cool, warm and heat pain detection thresholds and brain-evoked potentials with electrical (SEPs) and CO2 laser stimulation [laser-evoked potentials (LEPs)] of hand dorsum and distal leg using small (0.8 mm2) and large (20 mm2) beam sizes. Results confirmed a state of asymptomatic DNP in DM, but only at the distal leg. Defining a critical small fiber loss as a reduction of IENFd ≤−2 z scores of healthy controls, this state prevailed in type 2 (30%) over type 1 DM (10%) patients despite similar disease duration and current glycemic control. LEPs with the small laser beam performed best in terms of sensitivity (91%), specificity (83%) and area-under-the ROC curve (0.924). Although this performance was not statically different from that of warm and cold detection threshold, LEPs offer an advantage over QST given that they bypass the subjective report and are therefore unbiased by perceptual factors.


Diabetic neuropathy Skin punch biopsy Intraepidermal nerve fiber density Laser-evoked potentials Quantitative sensory testing 



M. Ragé was supported by a grant from Janssen Research and Development, Janssen Pharmaceutica N.V.

Conflict of interest

The authors declare that they have no competing interests, but MT, JS and TM are employees of Janssen Pharmaceutica N.V.


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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Michael Ragé
    • 1
    Email author
  • Nathalie Van Acker
    • 2
  • Michiel W. M. Knaapen
    • 2
  • Maarten Timmers
    • 3
  • Johannes Streffer
    • 3
  • Michel P. Hermans
    • 4
  • Christian Sindic
    • 5
  • Theo Meert
    • 3
  • Léon Plaghki
    • 1
  1. 1.Faculty of Medicine, Institute of NeuroscienceUniversité catholique de LouvainBrusselsBelgium
  2. 2.HistogenexAntwerpBelgium
  3. 3.Experimental Medicine and External InnovationJanssen Research and Development, Janssen Pharmaceutica N.V.BeerseBelgium
  4. 4.Service d’Endocrinologie et NutritionCliniques universitaires St LucBrusselsBelgium
  5. 5.Service de NeurologieCliniques universitaires St LucBrusselsBelgium

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