Abstract
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.
Similar content being viewed by others
References
Zochodne DW (2007) Diabetes mellitus and the peripheral nervous system: manifestations and mechanisms. Muscle Nerve 36:144–166
Boulton AJ (1998) Lowering the risk of neuropathy, foot ulcers and amputations. Diabet Med 15(Suppl 4):S57–S59
Veves A, Backonja M, Malik RA (2008) Painful diabetic neuropathy: epidemiology, natural history, early diagnosis, and treatment options. Pain Med 9:660–674
Perkins BA, Bril V (2003) Diabetic neuropathy: a review emphasizing diagnostic methods. Clin Neurophysiol 114:1167–1175
Boulton AJ, Vinik AI, Arezzo JC, Bril V, Feldman EL, Freeman R, Malik RA, Maser RE, Sosenko JM, Ziegler D, American Diabetes Association (2005) Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care 28:956–962
Quattrini C, Tavakoli M, Jeziorska M, Kallinikos P, Tesfaye S, Finnigan J, Marshall A, Boulton AJ, Efron N, Malik RA (2007) Surrogate markers of small fiber damage in human diabetic neuropathy. Diabetes 56:2148–2154
Umapathi T, Tan WL, Loke SC, Soon PC, Tavintharan S, Chan YH (2007) Intraepidermal nerve fiber density as a marker of early diabetic neuropathy. Muscle Nerve 35:591–598
Løseth S, Stålberg E, Jorde R, Mellgren SI (2008) Early diabetic neuropathy: thermal thresholds and intraepidermal nerve fibre density in patients with normal nerve conduction studies. J Neurol 255:1197–1202
Malik RA (2008) Early detection of nerve damage and repair in diabetic neuropathy. Nat Clin Pract Neurol 4:646–647
Cruccu G, Sommer C, Anand P, Attal N, Baron R, Garcia-Larrea L, Haanpaa M, Jensen TS, Serra J, Treede RD (2010) EFNS guidelines on neuropathic pain assessment: revised 2009. Eur J Neurol 17:1010–1018
Rossi P, Morano S, Serrao M, Gabriele A, Di Mario U, Morocutti C, Pozzessere G (2002) Pre-perceptual pain sensory responses (N1 component) in type 1 diabetes mellitus. Neuroreport 13:1009–1012
Pozzessere G, Rossi P, Gabriele A, Cipriani R, Morocutti A, Di Mario U, Morano S (2002) Early detection of small-fiber neuropathy in diabetes: a laser-induced pain somatosensory-evoked potentials and pupillometric study. Diabetes Care 25:2355–2358
Agostino R, Cruccu G, Romaniello A, Innocenti P, Inghilleri M, Manfredi M (2000) Dysfunction of small myelinated afferents in diabetic polyneuropathy, as assessed by laser evoked potentials. Clin Neurophysiol 111:270–276
Agostino R, Cruccu G, Iannetti GD, Innocenti P, Romaniello A, Truini A, Manfredi M (2000) Trigeminal small-fibre dysfunction in patients with diabetes mellitus: a study with laser evoked potentials and corneal reflex. Clin Neurophysiol 111:2264–2267
Ragé M, Van Acker N, Facer P, Shenoy R, Knaapen MW, Timmers M, Streffer J, Anand P, Meert T, Plaghki L (2010) The time course of CO(2) laser-evoked responses and of skin nerve fibre markers after topical capsaicin in human volunteers. Clin Neurophysiol 121:1256–1266
Bril V, Perkins BA (2002) Validation of the Toronto Clinical Scoring System for Diabetic Polyneuropathy. Diabetes Care 25:2048–2052
Berquin AD, Lijesevic V, Blond S, Plaghki L (2010) An adaptive procedure for routine measurement of light-touch sensitivity threshold. Muscle Nerve 42:328–338
Dyck PJ, O’Brien PC, Kosanke JL, Gillen DA, Karnes JL (1993) A 4, 2, and 1 stepping algorithm for quick and accurate estimation of cutaneous sensation threshold. Neurology 43:1508–1512
Fruhstorfer H, Lindblom U, Schmidt WC (1976) Method for quantitative estimation of thermal thresholds in patients. J Neurol Neurosurg Psychiatry 39:1071–1075
Mouraux A, Plaghki L (2004) Single-trial detection of human brain responses evoked by laser activation of Adelta-nociceptors using the wavelet transform of EEG epochs. Neurosci Lett 361:241–244
Lauria G, Hsieh ST, Johansson O, Kennedy WR, Leger JM, Mellgren SI, Nolano M, Merkies IS, Polydefkis M, Smith AG, Sommer C, Valls-Solé J (2010) European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. Eur J Neurol 17(903–912):e44–e49
Facer P, Mathur R, Pandya SS, Ladiwala U, Singhal BS, Anand P (1998) Correlation of quantitative tests of nerve and target organ dysfunction with skin immunohistology in leprosy. Brain 121:2239–2247
Facer P, Casula MA, Smith GD, Benham CD, Chessell IP, Bountra C, Sinisi M, Birch R, Anand P (2007) Differential expression of the capsaicin receptor TRPV1 and related novel receptors TRPV3, TRPV4 and TRPM8 in normal human tissues and changes in traumatic and diabetic neuropathy. BMC Neurol 23:7–11
Atherton DD, Facer P, Roberts KM, Misra VP, Chizh BA, Bountra C, Anand P (2007) Use of the novel contact heat evoked potential stimulator (CHEPS) for the assessment of small fibre neuropathy: correlations with skin flare responses and intra-epidermal nerve fibre counts. BMC Neurol 7:21
Rolke R, Baron R, Maier C, Tölle TR, Treede RD, Beyer A, Binder A, Birbaumer N, Birklein F, Bötefür IC, Braune S, Flor H, Huge V, Klug R, Landwehrmeyer GB, Magerl W, Maihöfner C, Rolko C, Schaub C, Scherens A, Sprenger T, Valet M, Wasserka B (2006) Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain 123:231–243
Plaghki L, Mouraux A (2003) How do we selectively activate skin nociceptors with a high power infrared laser? Physiology and biophysics of laser stimulation. Neurophysiol Clin 33:269–277
Said G (2007) Diabetic neuropathy-a review. Nat Clin Pract Neurol 3:331–340
Gøransson LG, Mellgren SI, Lindal S, Omdal R (2004) The effect of age and gender on epidermal nerve fiber density. Neurology 62:774–777
McArthur JC, Stocks EA, Hauer P, Cornblath DR, Griffin JW (1998) Epidermal nerve fiber density: normative reference range and diagnostic efficiency. Arch Neurol 55:1513–1520
Umapathi T, Tan WL, Tan NC, Chan YH (2006) Determinants of epidermal nerve fiber density in normal individuals. Muscle Nerve 33:742–746
Lin YH, Hsieh SC, Chao CC, Chang YC, Hsieh ST (2005) Influence of aging on thermal and vibratory thresholds of quantitative sensory testing. J Peripher Nerv Syst 10:269–281
Gibson SJ, Gorman MM, Helme RD (1991) Assessment of pain in the elderly using event-related cerebral potentials. In: Bond MR, Charlton JE, Woolf CJ (eds) Proc. VIth world congress on pain. Elsevier, Amsterdam, pp 527–533
Truini A, Galeotti F, Romaniello A, Virtuoso M, Iannetti GD, Cruccu G (2005) Laser-evoked potentials: normative values. Clin Neurophysiol 116:821–826
Periquet MI, Novak V, Collins MP, Nagaraja HN, Erdem S, Nash SM, Freimer ML, Sahenk Z, Kissel JT, Mendell JR (1999) Painful sensory neuropathy: prospective evaluation using skin biopsy. Neurology 53:1641–1647
Singleton JR, Smith AG, Bromberg MB (2001) Painful sensory polyneuropathy associated with impaired glucose tolerance. Muscle Nerve 24:1225–1228
Smith AG, Ramachandran P, Tripp S, Singleton JR (2001) Epidermal nerve innervation in impaired glucose tolerance and diabetes-associated neuropathy. Neurology 57:1701–1704
Sumner CJ, Sheth S, Griffin JW, Cornblath DR, Polydefkis M (2003) The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology 60:108–111
The Diabetes Control, Complications Trial Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986
Dyck PJ, Davies JL, Wilson DM, Service FJ, Melton LJ 3rd, O’Brien PC (1999) Risk factors for severity of diabetic polyneuropathy: intensive longitudinal assessment of the Rochester Diabetic Neuropathy Study cohort. Diabetes Care 22:1479–1486
Shun CT, Chang YC, Wu HP, Hsieh SC, Lin WM, Lin YH, Tai TY, Hsieh ST (2004) Skin denervation in type 2 diabetes: correlations with diabetic duration and functional impairments. Brain 127(Pt 7):1593–1605
Polydefkis M, Hauer P, Sheth S, Sirdofsky M, Griffin JW, McArthur JC (2004) The time course of epidermal nerve fibre regeneration: studies in normal controls and in people with diabetes, with and without neuropathy. Brain 127(Pt 7):1606–1615
Beiswenger KK, Calcutt NA, Mizisin AP (2008) Dissociation of thermal hypoalgesia and epidermal denervation in streptozotocin-diabetic mice. Neurosci Lett 442:267–272
Khalili N, Wendelschafer-Crabb G, Kennedy WR, Simone DA (2001) Influence of thermode size for detecting heat pain dysfunction in a capsaicin model of epidermal nerve fiber loss. Pain 91:241–250
Acknowledgments
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ragé, M., Van Acker, N., Knaapen, M.W.M. et al. Asymptomatic small fiber neuropathy in diabetes mellitus: investigations with intraepidermal nerve fiber density, quantitative sensory testing and laser-evoked potentials. J Neurol 258, 1852–1864 (2011). https://doi.org/10.1007/s00415-011-6031-z
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00415-011-6031-z