Abstract
Small fibers constitute the majority of peripheral nerve fibers and are responsible for the symptoms of painful diabetic neuropathy and are also key to the genesis of foot ulceration via reduced heat and pain perception, sudomotor dysfunction, and blunted pressure-induced vasodilation. Small fiber damage may also precede large fiber damage in subjects with impaired glucose tolerance (IGT) and early diabetic neuropathy. A number of functional tests such as thermal thresholds, quantitative sudomotor axon reflex testing (QSART), and the sympathetic skin response as well as the neuropad and the nerve axon reflex can be used to assess small fiber dysfunction. More recently skin biopsy has been advocated to provide a sensitive means to identify early small fiber damage, although the technique is invasive, requiring a skin biopsy. As an alternative corneal confocal microscopy, an ophthalmic technique represents a noninvasive means to quantify small fiber damage and is increasingly being deployed for the assessment of diabetic and other peripheral neuropathies.
Keywords
- Diabetic Neuropathy
- Fabry Disease
- Quantitative Sensory Testing
- Painful Diabetic Neuropathy
- Sympathetic Skin Response
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
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Tesfaye S, Boulton AJ, Dyck PJ et al (2010) Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care 33:2285–2293
Dyck PJ, Overland CJ, Low PA et al (2010) Signs and symptoms versus nerve conduction studies to diagnose diabetic sensorimotor polyneuropathy: Cl vs. NPhys trial. Muscle Nerve 42:157–164
Dyck PJ, Norell JE, Tritschler H et al (2007) Challenges in design of multicenter trials: end points assessed longitudinally for change and monotonicity. Diabetes Care 30:2619–2625
Perkins BA, Dholasania A, Buchanan RA, Bril V (2010) Short-term metabolic change is associated with improvement in measures of diabetic neuropathy: a 1-year placebo cohort analysis. Diabet Med 27:1271–1279
Gibbons CH, Freeman R, Veves A (2010) Diabetic neuropathy: a cross-sectional study of the relationships among tests of neurophysiology. Diabetes Care 33:2629–2634
Said G, Baudoin D, Toyooka K (2008) Sensory loss, pains, motor deficit and axonal regeneration in length-dependent diabetic polyneuropathy. J Neurol 255:1693–1702
Malik RA, Tesfaye S, Newrick PG et al (2005) Sural nerve pathology in diabetic patients with minimal but progressive neuropathy. Diabetologia 48:578–585
Gibbons CH, Illigens BM, Wang N, Freeman R (2010) Quantification of sudomotor innervation: a comparison of three methods. Muscle Nerve 42:112–119
Koitka A, Abraham P, Bouhanick B, Sigaudo-Roussel D, Demiot C, Saumet JL (2004) Impaired pressure-induced vasodilation at the foot in young adults with type 1 diabetes. Diabetes 53:721–725
Fromy B, Sigaudo-Roussel D, Gaubert-Dahan ML et al (2010) Aging-associated sensory neuropathy alters pressure-induced vasodilation in humans. J Invest Dermatol 130:849–855
Kuhtz-Buschbeck JP, Andresen W, Gobel S, Gilster R, Stick C (2010) Thermoreception and nociception of the skin: a classic paper of Bessou and Perl and analyses of thermal sensitivity during a student laboratory exercise. Adv Physiol Educ 34:25–34
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
Quattrini C, Tavakoli M, Jeziorska M et al (2007) Surrogate markers of small fiber damage in human diabetic neuropathy. Diabetes 56:2148–2154
Loseth S, Stalberg 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
Chao CC, Hsieh SC, Yang WS et al (2007) Glycemic control is related to the severity of impaired thermal sensations in type 2 diabetes. Diabetes Metab Res Rev 23:612–620
Sorensen L, Molyneaux L, Yue DK (2006) The level of small nerve fiber dysfunction does not predict pain in diabetic neuropathy: a study using quantitative sensory testing. Clin J Pain 22:261–265
Mueller D, Obermann M, Koeppen S et al (2010) Electrically evoked nociceptive potentials for early detection of diabetic small-fiber neuropathy. Eur J Neurol 17:834–841
Veves A, Akbari CM, Primavera J et al (1998) Endothelial dysfunction and the expression of endothelial nitric oxide synthetase in diabetic neuropathy, vascular disease, and foot ulceration. Diabetes 47:457–463
Caselli A, Spallone V, Marfia GA et al (2006) Validation of the nerve axon reflex for the assessment of small nerve fibre dysfunction. J Neurol Neurosurg Psychiatry 77:927–932
Green AQ, Krishnan ST, Rayman G (2009) C-fiber function assessed by the laser doppler imager flare technique and acetylcholine iontophoresis. Muscle Nerve 40:985–991
Green AQ, Krishnan S, Finucane FM, Rayman G (2010) Altered C-fiber function as an indicator of early peripheral neuropathy in individuals with impaired glucose tolerance. Diabetes Care 33:174–176
Krishnan ST, Rayman G (2004) The LDIflare: a novel test of C-fiber function demonstrates early neuropathy in type 2 diabetes. Diabetes Care 27:2930–2935
Krishnan ST, Quattrini C, Jeziorska M, Malik RA, Rayman G (2009) Abnormal LDIflare but normal quantitative sensory testing and dermal nerve fiber density in patients with painful diabetic neuropathy. Diabetes Care 32:451–455
Lauria G, Devigili G (2007) Skin biopsy as a diagnostic tool in peripheral neuropathy. Nat Clin Pract Neurol 3:546–557
Lauria G, Lombardi R, Camozzi F, Devigili G (2009) Skin biopsy for the diagnosis of peripheral neuropathy. Histopathology 54:273–285
Smith AG, Howard JR, Kroll R et al (2005) The reliability of skin biopsy with measurement of intraepidermal nerve fiber density. J Neurol Sci 228:65–69
Bakkers M, Merkies IS, Lauria G et al (2009) Intraepidermal nerve fiber density and its application in sarcoidosis. Neurology 73:1142–1148
Lauria G, Bakkers M, Schmitz C et al (2010) Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study. J Peripher Nerv Syst 15:202–207
Panoutsopoulou IG, Wendelschafer-Crabb G, Hodges JS, Kennedy WR (2009) Skin blister and skin biopsy to quantify epidermal nerves: a comparative study. Neurology 72:1205–1210
Vlckova-Moravcova E, Bednarik J, Dusek L, Toyka KV, Sommer C (2008) Diagnostic validity of epidermal nerve fiber densities in painful sensory neuropathies. Muscle Nerve 37:50–60
Devigili G, Tugnoli V, Penza P et al (2008) The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain 131:1912–1925
Nebuchennykh M, Loseth S, Lindal S, Mellgren SI (2009) 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 256:1067–1075
Pittenger GL, Mehrabyan A, Simmons K et al (2005) Small fiber neuropathy is associated with the metabolic syndrome. Metab Syndr Relat Disord 3:113–121
Vlckova-Moravcova E, Bednarik J, Belobradkova J, Sommer C (2008) Small-fibre involvement in diabetic patients with neuropathic foot pain. Diabet Med 25:692–699
Shun CT, Chang YC, Wu HP et al (2004) Skin denervation in type 2 diabetes: correlations with diabetic duration and functional impairments. Brain 127:1593–1605
Holland NR, Stocks A, Hauer P, Cornblath DR, Griffin JW, McArthur JC (1997) Intraepidermal nerve fiber density in patients with painful sensory neuropathy. Neurology 48:708–711
Periquet MI, Novak V, Collins MP et al (1999) Painful sensory neuropathy: prospective evaluation using skin biopsy. Neurology 53:1641–1647
Zhou L, Kitch DW, Evans SR et al (2007) Correlates of epidermal nerve fiber densities in HIV-associated distal sensory polyneuropathy. Neurology 68:2113–2119
Loseth S, Mellgren SI, Jorde R, Lindal S, Stalberg E (2010) Polyneuropathy in type 1 and type 2 diabetes: comparison of nerve conduction studies, thermal perception thresholds and intraepidermal nerve fibre densities. Diabetes Metab Res Rev 26:100–106
England JD, Gronseth GS, Franklin G et al (2009) Practice parameter: evaluation of distal symmetric polyneuropathy: role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation. Neurology 72:177–184
Lauria G, Hsieh ST, Johansson O et al (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, e944–909
Pittenger GL, Ray M, Burcus NI, McNulty P, Basta B, Vinik AI (2004) Intraepidermal nerve fibers are indicators of small-fiber neuropathy in both diabetic and nondiabetic patients. Diabetes Care 27:1974–1979
Gibbons CH, Griffin JW, Polydefkis M et al (2006) The utility of skin biopsy for prediction of progression in suspected small fiber neuropathy. Neurology 66:256–258
Ebenezer GJ, Hauer P, Gibbons C, McArthur JC, Polydefkis M (2007) Assessment of epidermal nerve fibers: a new diagnostic and predictive tool for peripheral neuropathies. J Neuropathol Exp Neurol 66:1059–1073
Lauria G, Morbin M, Lombardi R et al (2003) Axonal swellings predict the degeneration of epidermal nerve fibers in painful neuropathies. Neurology 61:631–636
Wendelschafer-Crabb G, Kennedy WR, Walk D (2006) Morphological features of nerves in skin biopsies. J Neurol Sci 242:15–21
Brannagan TH 3rd, Hays AP, Chin SS et al (2005) Small-fiber neuropathy/neuronopathy associated with celiac disease: skin biopsy findings. Arch Neurol 62:1574–1578
Chai J, Herrmann DN, Stanton M, Barbano RL, Logigian EL (2005) Painful small-fiber neuropathy in Sjogren syndrome. Neurology 65:925–927
De Sousa EA, Hays AP, Chin RL, Sander HW, Brannagan TH 3rd (2006) Characteristics of patients with sensory neuropathy diagnosed with abnormal small nerve fibres on skin biopsy. J Neurol Neurosurg Psychiatry 77:983–985
Herrmann DN, McDermott MP, Henderson D, Chen L, Akowuah K, Schifitto G (2004) Epidermal nerve fiber density, axonal swellings and QST as predictors of HIV distal sensory neuropathy. Muscle Nerve 29:420–427
Quattrini C, Jeziorska M, Boulton AJ, Malik RA (2008) Reduced vascular endothelial growth factor expression and intra-epidermal nerve fiber loss in human diabetic neuropathy. Diabetes Care 31:140–145
Sorensen L, Molyneaux L, Yue DK (2006) The relationship among pain, sensory loss, and small nerve fibers in diabetes. Diabetes Care 29:883–887
Smith AG, Russell J, Feldman EL et al (2006) Lifestyle intervention for pre-diabetic neuropathy. Diabetes Care 29:1294–1299
Boucek P, Havrdova T, Voska L et al (2008) Epidermal innervation in type 1 diabetic patients: a 2.5-year prospective study after simultaneous pancreas/kidney transplantation. Diabetes Care 31:1611–1612
Boucek P, Havrdova T, Voska L et al (2005) Severe depletion of intraepidermal nerve fibers in skin biopsies of pancreas transplant recipients. Transplant Proc 37:3574–3575
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 127:1606–1615
Beiswenger KK, Calcutt NA, Mizisin AP (2008) Epidermal nerve fiber quantification in the assessment of diabetic neuropathy. Acta Histochem 110:351–362
Rao MS, Jaszczak E, Landis SC (1994) Innervation of footpads of normal and mutant mice lacking sweat glands. J Comp Neurol 346:613–625
Navarro X, Verdu E, Wendelscafer-Crabb G, Kennedy WR (1995) Innervation of cutaneous structures in the mouse hind paw: a confocal microscopy immunohistochemical study. J Neurosci Res 41:111–120
Hsieh ST, Chiang HY, Lin WM (2000) Pathology of nerve terminal degeneration in the skin. J Neuropathol Exp Neurol 59:297–307
Christianson JA, Riekhof JT, Wright DE (2003) Restorative effects of neurotrophin treatment on diabetes-induced cutaneous axon loss in mice. Exp Neurol 179:188–199
Lauria G, Lombardi R, Borgna M et al (2005) Intraepidermal nerve fiber density in rat foot pad: neuropathologic-neurophysiologic correlation. J Peripher Nerv Syst 10:202–208
Pare M, Albrecht PJ, Noto CJ et al (2007) Differential hypertrophy and atrophy among all types of cutaneous innervation in the glabrous skin of the monkey hand during aging and naturally occurring type 2 diabetes. J Comp Neurol 501:543–567
Johnson MS, Ryals JM, Wright DE (2008) Early loss of peptidergic intraepidermal nerve fibers in an STZ-induced mouse model of insensate diabetic neuropathy. Pain 140:35–47
Wright DE, Johnson MS, Arnett MG, Smittkamp SE, Ryals JM (2007) Selective changes in nocifensive behavior despite normal cutaneous axon innervation in leptin receptor-null mutant (db/db) mice. J Peripher Nerv Syst 12:250–261
Russell JW, Karnes JL, Dyck PJ (1996) Sural nerve myelinated fiber density differences associated with meaningful changes in clinical and electrophysiologic measurements. J Neurol Sci 135:114–117
Bril V, Perkins BA (2002) Validation of the Toronto clinical scoring system for diabetic polyneuropathy. Diabetes Care 25:2048–2052
Thrainsdottir S, Malik RA, Rosen I et al (2009) Sural nerve biopsy may predict future nerve dysfunction. Acta Neurol Scand 120:38–46
Bevilacqua NJ, Rogers LC, Malik RA, Armstrong DG (2007) Technique of the sural nerve biopsy. J Foot Ankle Surg 46:139–142
Hossain P, Sachdev A, Malik RA (2005) Early detection of diabetic peripheral neuropathy with corneal confocal microscopy. Lancet 366:1340–1343
Tavakoli M, Marshall A, Pitceathly R et al (2009) Corneal confocal microscopy: A novel means to detect nerve fibre damage in idiopathic small fibre neuropathy. Exp Neurol 223(1):245–250
Tavakoli M, Marshall A, Thompson L et al (2009) Corneal confocal microscopy: a novel noninvasive means to diagnose neuropathy in patients with Fabry disease. Muscle Nerve 40:976–984
Kim HC, Cho YJ, Ahn CW et al (2009) Nerve growth factor and expression of its receptors in patients with diabetic neuropathy. Diabet Med 26:1228–1234
Messmer EM, Schmid-Tannwald C, Zapp D, Kampik A (2010) In vivo confocal microscopy of corneal small fiber damage in diabetes mellitus. Graefes Arch Clin Exp Ophthalmol 248:1307–1312
Mehra S, Tavakoli M, Kallinikos PA et al (2007) Corneal confocal microscopy detects early nerve regeneration after pancreas transplantation in patients with type 1 diabetes. Diabetes Care 30:2608–2612
Efron N, Edwards K, Roper N et al (2010) Repeatability of measuring corneal subbasal nerve fiber length in individuals with type 2 diabetes. Eye Contact Lens 36:245–248
Tavakoli M, Quattrini C, Abbott C et al (2010) Corneal confocal microscopy: a novel noninvasive test to diagnose and stratify the severity of human diabetic neuropathy. Diabetes Care 33:1792–1797
Dabbah MA, Graham J, Petropoulos I, Tavakoli M, Malik RA (2010) Dual-model automatic detection of nerve-fibres in corneal confocal microscopy images. Med Image Comput Comput Assist Interv 13:300–307
Pritchard N, Edwards K, Vagenas D et al (2010) Corneal sensitivity as an ophthalmic marker of diabetic neuropathy. Optom Vis Sci 87:1003–1008
Rosenberg ME, Tervo TM, Immonen IJ, Muller LJ, Gronhagen-Riska C, Vesaluoma MH (2000) Corneal structure and sensitivity in type 1 diabetes mellitus. Invest Ophthalmol Vis Sci 41:2915–2921
Tavakoli M, Kallinikos PA, Efron N, Boulton AJ, Malik RA (2007) Corneal sensitivity is reduced and relates to the severity of neuropathy in patients with diabetes. Diabetes Care 30:1895–1897
Bril V, Nyunt M, Ngo M (2000) Limits of the sympathetic skin response in patients with diabetic polyneuropathy. Muscle Nerve 23:1427–1430
Tentolouris N, Marinou K, Kokotis P, Karanti A, Diakoumopoulou E, Katsilambros N (2009) Sudomotor dysfunction is associated with foot ulceration in diabetes. Diabet Med 26:302–305
Al-Moallem MA, Zaidan RM, Alkali NH (2008) The sympathetic skin response in diabetic neuropathy and its relationship to autonomic symptoms. Saudi Med J 29:568–572
Sletten DM, Kimpinski K, Weigand SD, Low PA (2010) Comparison of a gel versus solution-based vehicle for the delivery of acetylcholine in QSART. Auton Neurosci 158:123–126
Low VA, Sandroni P, Fealey RD, Low PA (2006) Detection of small-fiber neuropathy by sudomotor testing. Muscle Nerve 34:57–61
Shimada H, Kihara M, Kosaka S et al (2001) Comparison of SSR and QSART in early diabetic neuropathy–the value of length-dependent pattern in QSART. Auton Neurosci 92:72–75
Quattrini C, Jeziorska M, Tavakoli M, Begum P, Boulton AJ, Malik RA (2008) The Neuropad test: a visual indicator test for human diabetic neuropathy. Diabetologia 51:1046–1050
Spallone V, Morganti R, Siampli M et al (2009) Neuropad as a diagnostic tool for diabetic autonomic and sensorimotor neuropathy. Diabet Med 26:686–692
Papanas N, Papatheodorou K, Papazoglou D, Kotsiou S, Maltezos EA (2010) Prospective study on the use of the indicator test neuropad® for the early diagnosis of peripheral neuropathy in type 2 diabetes. Exp Clin Endocrinol Diabetes 119(2):122–125
Gibbons CH, Illigens BM, Wang N, Freeman R (2009) Quantification of sweat gland innervation: a clinical-pathologic correlation. Neurology 72:1479–1486
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Tavakoli, M., Fadavi, H., Malik, R.A. (2014). Optimal Measures of Small Fiber Neuropathy in Diabetic Polyneuropathy. In: Obrosova, I., Stevens, M., Yorek, M. (eds) Studies in Diabetes. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4899-8035-9_6
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