•• Tesfaye S, Boulton AJ, Dyck PJ, et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care 2010;33:2285–2293. This consensus paper revised definition and grading of diabetic neuropathy, and provides the first definition of small fiber neuropathy for clinical practice and research.
Sumner CJ, Sheth S, Griffin JW, Cornblath DR, Polydefkis M. The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology. 2003;60:108–11.PubMedCrossRefGoogle Scholar
• Devigili G, Tugnoli V, Penza P, et al. The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain 2008;131:1912–1925. A work focused on small fiber neuropathy, providing comparison between clinical examination, quantitative sensory testing, nerve conduction study, laser evoked potentials, and skin biopsy findings. It showed that skin biopsy has higher sensitivity an specificity for the diagnosis and is useful for the assessment of the natural course of neuropathy.
Vlckova-Moravcova E, Bednarik J, Belobradkova J, Sommer C. Small-fibre involvement in diabetic patients with neuropathic foot pain. Diabet Med. 2008;25:692–9.PubMedCrossRefGoogle Scholar
Hughes RA, Umapathi T, Gray IA, et al. A controlled investigation of the cause of chronic idiopathic axonal polyneuropathy. Brain. 2004;127:1723–30.PubMedCrossRefGoogle Scholar
Nebuchennykh M, Loseth S, Jorde R, Mellgren SI. Idiopathic polyneuropathy and impaired glucose metabolism in a Norwegian patient series. Eur J Neurol. 2008;15:810–6.PubMedCrossRefGoogle Scholar
Martina IS, van Koningsveld R, Schmitz PI, van der Meche FG, van Doorn PA. Measuring vibration threshold with a graduated tuning fork in normal aging and in patients with polyneuropathy. European Inflammatory Neuropathy Cause and Treatment (INCAT) group. J Neurol Neurosurg Psychiatry. 1998;65:743–7.PubMedCrossRefGoogle Scholar
Novak V, Freimer ML, Kissel JT, et al. Autonomic impairment in painful neuropathy. Neurology. 2001;56:861–8.PubMedCrossRefGoogle Scholar
Bakkers M, Merkies ISJ, Lauria G, et al. Intraepidermal nerve fiber density and its application in sarcoidosis. Neurology. 2009;73:1142–8.PubMedCrossRefGoogle Scholar
•• Faber CG, Hoeijmakers JG, Ahn HS, et al. Gain of function Na(V) 1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol 2012;71:26–39. This paper demonstrated for the first time that gain-of-function mutations in SCN9A encoding for Nav1.7 subunit of sodium channel cause small fiber neuropathy. These findings contributed to identify the new syndrome of channellopathy-associated small fiber neuropathy.
Feldman EL, Stevens MJ, Thomas PK, Brown MB, Canal N, Greene DA. A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care. 1994;17:1281–9.PubMedCrossRefGoogle Scholar
Kennedy WR, Nolano M, Wendelschafer-Crabb G, Johnson TL, Tamura E. A skin blister method to study epidermal nerves in peripheral nerve disease. Muscle Nerve. 1999;22:360–71.PubMedCrossRefGoogle Scholar
•• Lauria G, Hsieh ST, Johansson O, et al. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the Use of Skin Biopsy in the Diagnosis of Small Fiber Neuropathy. J Periph Nerv Syst 2010;15:79–92. This paper reports the revised guidelines for the diagnostic use of skin biopsy in the diagnosis of small fiber neuropathy. Information on safety, diagnostic yield, and correlation with clinical picture, quantitative sensory testing and non-convetional neurophysiological studies are provided.
Nolano M, Provitera V, Crisci C, et al. Quantification of myelinated endings and mechanoreceptors in human digital skin. Ann Neurol. 2003;54:197–205.PubMedCrossRefGoogle Scholar
Lauria G, Borgna M, Morbin M, et al. Tubule and neurofilament immunoreactivity in human hairy skin: markers for intraepidermal nerve fibers. Muscle Nerve. 2004;30:310–6.PubMedCrossRefGoogle Scholar
Lauria G, Morbin M, Lombardi R, et al. Expression of capsaicin receptor immunoreactivity in human peripheral nervous system and in painful neuropathies. J Peripher Nerv Syst. 2006;11:262–71.PubMedCrossRefGoogle Scholar
Li Y, Hsieh ST, Chien HF, Zhang X, McArthur JC, Griffin JW. Sensory and motor denervation influence epidermal thickness in rat foot glabrous skin. Exp Neurol. 1997;147:452–62.PubMedCrossRefGoogle Scholar
Peier AM, Reeve AJ, Andersson DA, et al. A heat-sensitive TRP channel expressed in keratinocytes. Science. 2002;296:2046–9.PubMedCrossRefGoogle Scholar
Fernandes ES, Fernandes MA, Keeble JE. The functions of TRPA1 and TRPV1: moving away from sensory nerves. Br J Pharmacol 2012.
Denda M, Tsutsumi M. Roles of transient receptor potential proteins (TRPs) in epidermal keratinocytes. Adv Exp Med Biol. 2011;704:847–60.PubMedCrossRefGoogle Scholar
•• Lumpkin EA, Caterina MJ. Mechanisms of sensory transduction in the skin. Nature 2007;445:858–865. A comprehensive overview on the relationship between small nerve fibers and resident cells of the skin in the mechanisms of thermal and nociceptive sensation transduction to the brain. This complex nerve-cell network demonstrates that non-neuronal structures play a critical role in sensory perception and possible neuropathic pain.
Vlckova-Moravcova E, Bednarik J, Dusek L, Toyka KV, Sommer C. Diagnostic validity of epidermal nerve fiber densities in painful sensory neuropathies. Muscle Nerve. 2008;37:50–60.PubMedCrossRefGoogle Scholar
Lauria G, Cazzato D, Porretta-Serapiglia C, et al. Morphometry of dermal nerve fibers in human skin. Neurology. 2011;77:242–9.PubMedCrossRefGoogle Scholar
Nolano M, Provitera V, Perretti A, et al. Ross syndrome: a rare or a misknown disorder of thermoregulation? A skin innervation study on 12 subjects. Brain. 2006;129:2119–31.PubMedCrossRefGoogle Scholar
• Gibbons CH, Illigens BM, Wang N, Freeman R. Quantification of sudomotor innervation: a comparison of three methods. Muscle Nerve 2010;42:112–119. This paper provided evidence for reliable quantification of sweat gland innervation density and correlation with diabetic neuropathy clinical scores.
• Nolano M, Provitera V, Caporaso G, Stancanelli A, Vitale DF, L. S. Quantification of pilomotor nerves. A new tool to evaluate autonomic involvement in diabetes. Neurology 2010;75:1089–1097. This paper provides the first-ever reliable quantification of pilomotor muscle innervation, showing its decrease in diabetic neuropathy patients and correlation with sweating impairment.
• Lauria G, Bakkers M, Schmitz C, et al. Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study. J Peripher Nerv Syst 2010;15:202–207. A collaborative work among nine skin biopsy laboratory from Europe, USA, and Asia in 550 healthy subjects that provided age and gender-adjusted normative reference values for IENF density at the distal leg for clinical use.
Lauria G, Holland N, Hauer PE, Cornblath DR, Griffin JW, McArthur JC. Epidermal innervation: changes with aging, topographic location, and in sensory neuropathy. J Neurol Sci. 1999;164:172–8.PubMedCrossRefGoogle Scholar
Kennedy WR, Wendelschafer-Crabb G, Johnson T. Quantitation of epidermal nerves in diabetic neuropathy. Neurology. 1996;47:1042–8.PubMedCrossRefGoogle Scholar
Holland NR, Crawford TO, Hauer P, Cornblath DR, Griffin JW, McArthur JC. Small-fiber sensory neuropathies: clinical course and neuropathology of idiopathic cases. Ann Neurol 1998;44.
Smith AG, Ramachandran P, Tripp S, Singleton JR. Epidermal nerve innervation in impaired glucose tolerance and diabetes-associated neuropathy. Neurology. 2001;57:1701–4.PubMedCrossRefGoogle Scholar
Smith AG, Russell J, Feldman EL, et al. Lifestyle intervention for pre-diabetic neuropathy. Diabetes Care. 2006;29:1294–9.PubMedCrossRefGoogle Scholar
Umapathi T, Tan WL, Loke SC, Soon PC, Tavintharan S, Chan YH. Intraepidermal nerve fiber density as a marker of early diabetic neuropathy. Muscle Nerve. 2007;35:591–8.PubMedCrossRefGoogle Scholar
Pittenger GL, Mehrabyan A, Simmons K, et al. Small fiber neuropathy is associated with the metabolic syndrome. Metab Syndr Relat Disord. 2005;3:113–21.PubMedCrossRefGoogle Scholar
Loseth S, Stalberg E, Jorde R, Mellgren SI. Early diabetic neuropathy: thermal thresholds and intraepidermal nerve fibre density in patients with normal nerve conduction studies. J Neurol. 2008;255:1197–202.PubMedCrossRefGoogle Scholar
Pittenger GL, Ray M, Burcus NI, McNulty P, Basta B, Vinik AI. Intraepidermal nerve fibers are indicators of small-fiber neuropathy in both diabetic and nondiabetic patients. Diabetes Care. 2004;27:1974–9.PubMedCrossRefGoogle Scholar
Quattrini C, Tavakoli M, Jeziorska M, et al. Surrogate markers of small fiber damage in human diabetic neuropathy. Diabetes. 2007;56:2148–54.PubMedCrossRefGoogle Scholar
Zhou L, Li J, Ontaneda D, Sperling J. Metabolic syndrome in small fiber sensory neuropathy. J Clin Neuromuscul Dis. 2012;12:235–43.CrossRefGoogle Scholar
Smith AG, Howard JR, Kroll R, et al. The reliability of skin biopsy with measurement of intraepidermal nerve fiber density. J Neurol Sci. 2005;228:65–9.PubMedCrossRefGoogle Scholar
Koskinen M, Hietaharju A, Kylaniemi M, et al. A quantitative method for the assessment of intraepidermal nerve fibers in small-fiber neuropathy. J Neurol. 2005;252:789–94.PubMedCrossRefGoogle Scholar
Shun CT, Chang YC, Wu HP, et al. Skin denervation in type 2 diabetes: correlations with diabetic duration and functional impairments. Brain. 2004;127:1593–605.PubMedCrossRefGoogle Scholar
Lauria G, Morbin M, Lombardi R, et al. Axonal swellings predict the degeneration of epidermal nerve fibers in painful neuropathies. Neurology. 2003;61:631–6.PubMedCrossRefGoogle Scholar
Herrmann DN, McDermott MP, Henderson D, Chen L, Akowuah K, Schifitto G. Epidermal nerve fiber density, axonal swellings and QST as predictors of HIV distal sensory neuropathy. Muscle Nerve. 2004;29:420–7.PubMedCrossRefGoogle Scholar
Singleton JR, Smith AG, Bromberg MB. Increased prevalence of impaired glucose tolerance in patients with painful sensory neuropathy. Diabetes Care. 2001;24:1448–53.PubMedCrossRefGoogle Scholar
Luo KR, Chao CC, Chen YT, et al. Quantitation of sudomotor innervation in skin biopsies of patients with diabetic neuropathy. J Neuropathol Exp Neurol. 2012;70:930–8.CrossRefGoogle Scholar
Luo KR, Chao CC, Hsieh PC, Lue JH, Hsieh ST. Effect of glycemic control on sudomotor denervation in type 2 diabetes. Diabetes Care. 2012;35:612–6.PubMedCrossRefGoogle Scholar
Shy ME, Frohman EM, So YT, et al. Quantitative sensory testing: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2003;60:898–904.PubMedCrossRefGoogle Scholar
Freeman R, Chase KP, Risk MR. Quantitative sensory testing cannot differentiate simulated sensory loss from sensory neuropathy. Neurology. 2003;60:465–70.PubMedCrossRefGoogle Scholar
• Hansson P, Backonja M, Bouhassira D. Usefulness and limitations of quantitative sensory testing: clinical and research application in neuropathic pain states. Pain 2007;129:256–259. A recent and comprehensive review on methods and application of quantitative sensory testing in clinical practice and research.
Maier C, Baron R, Tolle TR, et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes. Pain. 2010;150:439–50.PubMedCrossRefGoogle Scholar
Sorensen L, Molyneaux L, Yue DK. The relationship among pain, sensory loss, and small nerve fibers in diabetes. Diabetes Care. 2006;29:883–7.PubMedCrossRefGoogle Scholar
Nebuchennykh M, Loseth S, Lindal S, Mellgren SI. 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. J Neurol. 2009;256:1067–75.PubMedCrossRefGoogle Scholar
Sahin O, Yildiz S, Yildiz N. Cutaneous silent period in fibromyalgia. Neurol Res. 2011;33:339–43.PubMedCrossRefGoogle Scholar
Torebjork E. Human microneurography and intraneural microstimulation in the study of neuropathic pain. Muscle Nerve. 1993;16:1063–5.PubMedCrossRefGoogle Scholar
Campero M, Baumann TK, Bostock H, Ochoa JL. Human cutaneous C fibres activated by cooling, heating and menthol. J Physiol. 2009;587:5633–52.PubMedCrossRefGoogle Scholar
Campero M, Serra J, Bostock H, Ochoa JL. Slowly conducting afferents activated by innocuous low temperature in human skin. J Physiol. 2001;535:855–65.PubMedCrossRefGoogle Scholar
Campero M, Serra J, Ochoa JL. C-polymodal nociceptors activated by noxious low temperature in human skin. J Physiol. 1996;497(Pt 2):565–72.PubMedGoogle Scholar
Campero M, Serra J, Ochoa JL. Peripheral projections of sensory fascicles in the human superficial radial nerve. Brain. 2005;128:892–5.PubMedCrossRefGoogle Scholar
Ochoa JL, Campero M, Serra J, Bostock H. Hyperexcitable polymodal and insensitive nociceptors in painful human neuropathy. Muscle Nerve. 2005;32:459–72.PubMedCrossRefGoogle Scholar
Treede RD, Lorenz J, Baumgartner U. Clinical usefulness of laser-evoked potentials. Neurophysiol Clin. 2003;33:303–14.PubMedCrossRefGoogle Scholar
Creac’h C, Convers P, Robert F, Antoine JC, Camdessanche JP. Small fiber sensory neuropathies: contribution of laser evoked potentials. Rev Neurol (Paris). 2011;167:40–5.CrossRefGoogle Scholar
Chiang HY, Chen CT, Chien HF, Hsieh ST. Skin denervation, neuropathology, and neuropathic pain in a laser-induced focal neuropathy. Neurobiol Dis. 2005;18:40–53.PubMedCrossRefGoogle Scholar
• Casanova-Molla J, Grau-Junyent JM, Morales M, Valls-Sole J. On the relationship between nociceptive evoked potentials and intraepidermal nerve fiber density in painful sensory polyneuropathies. Pain 2011;152:410–418. This study investigated the correlation between skin biopsy and both laser and contact heat-evoked potentials in painful neuropathy, including 52 patients with small fiber neuropathy. Results showed a correlation between low IENF density and impaired latency and amplitude of evoked potentials.
Granovsky Y, Matre D, Sokolik A, Lorenz J, Casey KL. Thermoreceptive innervation of human glabrous and hairy skin: a contact heat evoked potential analysis. Pain. 2005;115:238–47.PubMedCrossRefGoogle Scholar
Wong MC, Chung JW. Feasibility of contact heat evoked potentials for detection of diabetic neuropathy. Muscle Nerve. 2011;44:902–6.PubMedCrossRefGoogle Scholar
Chao CC, Hsieh SC, Tseng MT, Chang YC, Hsieh ST. Patterns of contact heat evoked potentials (CHEP) in neuropathy with skin denervation: correlation of CHEP amplitude with intraepidermal nerve fiber density. Clin Neurophysiol. 2008;119:653–61.PubMedCrossRefGoogle Scholar
Chao CC, Tseng MT, Lin YJ, et al. Pathophysiology of neuropathic pain in type 2 diabetes: skin denervation and contact heat-evoked potentials. Diabetes Care. 2010;33:2654–9.PubMedCrossRefGoogle Scholar
Atherton DD, Facer P, Roberts KM, et al. 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. 2007;7:21.PubMedCrossRefGoogle Scholar
Lauria G, Devigili G. Skin biopsy as a diagnostic tool in peripheral neuropathy. Nat Clin Pract Neurol. 2007;3:546–57.PubMedCrossRefGoogle Scholar
Lauria G, McArthur JC, Hauer PE, Griffin JW, Cornblath DR. Neuropathological alterations in diabetic truncal neuropathy: evaluation by skin biopsy. J Neurol Neurosurg Psychiatry. 1998;65:762–6.PubMedCrossRefGoogle Scholar
Nolano M, Simone DA, Wendelschafer-Crabb G, Johnson T, Hazen E, Kennedy WR. Topical capsaicin in humans: parallel loss of epidermal nerve fibers and pain sensation. Pain. 1999;81:135–45.PubMedCrossRefGoogle Scholar
Polydefkis M, Hauer P, Sheth S, Sirdofsky M, Griffin JW, McArthur JC. The time course of epidermal nerve fibre regeneration: studies in normal controls and in people with diabetes, with and without neuropathy. Brain. 2004;127:1606–15.PubMedCrossRefGoogle Scholar
Kennedy JM, Zochodne DW. Experimental diabetic neuropathy with spontaneous recovery: is there irreparable damage? Diabetes. 2005;54:830–7.PubMedCrossRefGoogle Scholar
Dyck PJ, Dyck PJ, Klein CJ, Weigand SD. Does impaired glucose metabolism cause polyneuropathy? Review of previous studies and design of a prospective controlled population-based study. Muscle Nerve. 2007;36:536–41.PubMedCrossRefGoogle Scholar
Toth C, Brussee V, Zochodne DW. Remote neurotrophic support of epidermal nerve fibres in experimental diabetes. Diabetologia. 2006;49:1081–8.PubMedCrossRefGoogle Scholar
Bianchi R, Buyukakilli B, Brines M, et al. Erythropoietin both protects from and reverses experimental diabetic neuropathy. Proc Natl Acad Sci U S A. 2004;101:823–8.PubMedCrossRefGoogle Scholar
Rajan B, Polydefkis M, Hauer P, Griffin JW, McArthur JC. Epidermal reinnervation after intracutaneous axotomy in man. J Comp Neurol. 2003;457:24–36.PubMedCrossRefGoogle Scholar
•• Ebenezer GJ, O'Donnell R, Hauer P, Cimino NP, McArthur JC, Polydefkis M. Impaired neurovascular repair in subjects with diabetes following experimental intracutaneous axotomy. Brain 2011;134:1853–1863. An elegant work in patients with diabetic neuropathy that investigated the ability of nerves, Schwann cells, and vessels to repair after chemical denervation and excision of the skin. Results demonstrated that diabetes affected the neurovascular regeneration, suggesting a role in the development of diabetic neuropathy.