A Comparative Study on the Diagnostic Utility of Corneal Confocal Microscopy and Tear Neuromediator Levels in Diabetic Peripheral Neuropathy

References

• Tesfaye S, Boulton AJM, Dyck PJ, Freeman R, Horowitz M, Kempler P, Lauria G, Malik RA, Spallone V, Vinik A, et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010;33(10):2285–93. doi:10.2337/dc10-1303.
   PubMed Web of Science ®Google Scholar
• Perkins BA, Bril V. Diabetic neuropathy: a review emphasizing diagnostic methods. Clin Neurophysiol. 2003;114(7):1167–75. doi:10.1016/S1388-2457(03)00025-7.
   PubMed Web of Science ®Google Scholar
• Malik RA. Which test for diagnosing early human diabetic neuropathy? Diabetes. 2014;63(7):2206–08. doi:10.2337/db14-0492.
   PubMed Web of Science ®Google Scholar
• Fromy B, Lingueglia E, Sigaudo-Roussel D, Saumet JL, Lazdunski M. Asic3 is a neuronal mechanosensor for pressure-induced vasodilation that protects against pressure ulcers. Nat Med. 2012;18(8):1205–07. doi:10.1038/nm.2844.
   PubMed Web of Science ®Google Scholar
• Malik RA, Veves A, Tesfaye S, Smith G, Cameron N, Zochodne D, Lauria G. Small fibre neuropathy: role in the diagnosis of diabetic sensorimotor polyneuropathy. Diabetes Metab Res Rev. 2011;27(7):678–84. doi:10.1002/dmrr.1222.
   PubMed Web of Science ®Google Scholar
• Chammas NK, Hill RLR, Edmonds ME. Increased mortality in diabetic foot ulcer patients: the significance of ulcer type. J Diabetes Res. 2016;2016:1–7. doi:10.1155/2016/2879809.
   Web of Science ®Google Scholar
• Løseth S, Stålberg 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(8):1197–202. doi:10.1007/s00415-008-0872-0.
   PubMed Web of Science ®Google Scholar
• Jende JME, Groener JB, Rother C, Kender Z, Hahn A, Hilgenfeld T, Juerchott A, Preisner F, Heiland S, Kopf S, et al. Association of serum cholesterol levels with peripheral nerve damage in patients with type 2 diabetes. JAMA Netw Open. 2019;2(5):e194798. doi:10.1001/jamanetworkopen.2019.4798.
   PubMed Web of Science ®Google Scholar
• Dyck PJ, Argyros B, Russell JW, Gahnstrom LE, Nalepa S, Albers JW, Lodermeier KA, Zafft AJ, Dyck PJB, Klein CJ, et al. Multicenter trial of the proficiency of smart quantitative sensation tests. Muscle and Nerve. 2014;49(5):645–53. doi:10.1002/mus.23982.
   PubMed Web of Science ®Google Scholar
• Freeman R, Chase KP, Risk MR. Quantitative sensory testing cannot differentiate simulated sensory loss from sensory neuropathy. Neurology. 2003;60(3):465–70. doi:10.1212/WNL.60.3.465.
   PubMed Web of Science ®Google Scholar
• Edwards K, Pritchard N, Vagenas D, Russell A, Malik RA, Efron N. Utility of corneal confocal microscopy for assessing mild diabetic neuropathy: baseline findings of the LANDMark study. Clin Exp Optom. 2012;95(3):348–54. doi:10.1111/j.1444-0938.2012.00740.x.
   PubMed Web of Science ®Google Scholar
• Krishnan AV, Lin CSY, Park SB, Kiernan MC. Axonal ion channels from bench to bedside: A translational neuroscience perspective. Prog Neurobiol. 2009;89(3):288–313. doi:10.1016/j.pneurobio.2009.08.002.
   PubMed Web of Science ®Google Scholar
• Krishnan AV, Kiernan MC. Altered nerve excitability properties in established diabetic neuropathy. Brain. 2005;128(5):1178–87. doi:10.1093/brain/awh476.
   PubMedGoogle Scholar
• Krishnan AV, Lin CSY, Kiernan MC. Activity-dependent excitability changes suggest Na+/K + pump dysfunction in diabetic neuropathy. Brain. 2008;131(5):1209–16. doi:10.1093/brain/awn052.
   PubMedGoogle Scholar
• Kwai NCG, Arnold R, Poynten AM, Howells J, Kiernan MC, Lin CSY, Krishnan AV. In vivo evidence of reduced nodal and paranodal conductances in type 1 diabetes. Clin Neurophysiol. 2016;127(2):1700–06. doi:10.1016/j.clinph.2015.11.047.
   PubMed Web of Science ®Google Scholar
• Kwai NCG, Arnold R, Wickremaarachchi C, Lin CSY, Poynten AM, Kiernan MC, Krishnan AV. Effects of axonal ion channel dysfunction on quality of life in type 2 diabetes. Diabetes Care. 2013;36(5):1272–77. doi:10.2337/dc12-1310.
   PubMed Web of Science ®Google Scholar
• Tavakoli M, Begum P, Mclaughlin J, Malik RA. Corneal confocal microscopy for the diagnosis of diabetic autonomic neuropathy. Muscle and Nerve. 2015;52(3):363–70. doi:10.1002/mus.24553.
   PubMed Web of Science ®Google Scholar
• Malik RA, Kallinikos P, Abbott CA, Van Schie CHM, Morgan P, Efron N, Boulton AJM. Corneal confocal microscopy: A non-invasive surrogate of nerve fibre damage and repair in diabetic patients. Diabetologia. 2003;46(5):683–88. doi:10.1007/s00125-003-1086-8.
   PubMed Web of Science ®Google Scholar
• Quattrini C, Tavakoli M, Jeziorska M, Kallinikos P, Tesfaye S, Finnigan J, Marshall A, Boulton AJM, Efron N, Malik RA. Surrogate markers of small fiber damage in human diabetic neuropathy. Diabetes. 2007;56(8):2148–54. doi:10.2337/db07-0285.
   PubMed Web of Science ®Google Scholar
• Misra SL, Craig JP, Patel DV, McGhee CNJ, Pradhan M, Ellyett K, Kilfoyle D, Braatvedt GD. In vivo confocal microscopy of corneal nerves: an ocular biomarker for peripheral and cardiac autonomic neuropathy in type 1 diabetes mellitus. Invest Ophthalmol Vis Sci. 2015 Aug 05;56(9):5060–65. doi:10.1167/iovs.15-16711.
   PubMed Web of Science ®Google Scholar
• Alam U, Jeziorska M, Petropoulos IN, Asghar O, Fadavi H, Ponirakis G, Marshall A, Tavakoli M, Boulton AJM, Efron N, et al. Diagnostic utility of corneal confocal microscopy and intra-epidermal nerve fibre density in diabetic neuropathy. PLoS One. 2017;12(7):e0180175. doi:10.1371/journal.pone.0180175.
   PubMed Web of Science ®Google Scholar
• Ahmed A, Bril V, Orszag A, Paulson J, Yeung E, Ngo M, Orlov S, Perkins BA. Detection of diabetic sensorimotor polyneuropathy by corneal confocal microscopy in type 1 diabetes: A concurrent validity study. Diabetes Care. 2012;35(4):821–28. doi:10.2337/dc11-1396.
   PubMed Web of Science ®Google Scholar
• Chen X, Graham J, Dabbah MA, Petropoulos IN, Ponirakis G, Asghar O, Alam U, Marshall A, Fadavi H, Ferdousi M, et al. Small nerve fiber quantification in the diagnosis of diabetic sensorimotor polyneuropathy: comparing corneal confocal microscopy with intraepidermal nerve fiber density. Diabetes Care. 2015;38(6):1138–44. doi:10.2337/dc14-2422.
   PubMed Web of Science ®Google Scholar
• Müller LJ, Marfurt CF, Kruse F, Tervo TMT. Corneal nerves: structure, contents and function. Exp Eye Res. 2003;76(5):521–42. doi:10.1016/S0014-4835(03)00050-2.
   PubMed Web of Science ®Google Scholar
• Garcia-Hirschfeld J, Lopez-Briones LG, Belmonte C. Neurotrophic influences on corneal epithelial cells. Exp Eye Res. 1994;59(5):597–605. doi:10.1006/exer.1994.1145.
   PubMed Web of Science ®Google Scholar
• De Felipe C, Gonzalez GG, Gallar J, Belmonte C. Quantification and immunocytochemical characteristics of trigeminal ganglion neurons projecting to the cornea: effect of corneal wounding. Eur J Pain. 1999;3(1):31–39. doi:10.1016/S1090-3801(99)90186-6.
   PubMed Web of Science ®Google Scholar
• Reid TW, Murphy CJ, Iwahashi CK, Foster BA, Mannis MJ. Stimulation of epithelial cell growth by the neuropeptide substance P. J Cell Biochem. 1993;52(4):476–85. doi:10.1002/jcb.240520411.
   PubMed Web of Science ®Google Scholar
• Markoulli M, You J, Kim J, Duong CL, Tolentino JB, Karras J, Lum E. Corneal nerve morphology and tear film substance Pin diabetes. Optom Vis Sci. 2017;94(7):726–31. doi:10.1097/OPX.0000000000001096.
   PubMed Web of Science ®Google Scholar
• Tummanapalli SS, Willcox MDP, Issar T, Yan A, Pisarcikova J, Kwai N, Poynten AM, Krishnan AV, Markoulli M. Tear film substance P: A potential biomarker for diabetic peripheral neuropathy. Ocul Surf. 2019;17:690–98. doi:10.1016/J.JTOS.2019.08.010.
   PubMed Web of Science ®Google Scholar
• Cornblath DR, Chaudhry V, Carter K, Lee D, Seysedadr M, Miernicki M, Joh T. Total neuropathy score: validation and reliability study. Neurology. 1999;53(8):1660–64. doi:10.1212/WNL.53.8.1660.
   PubMed Web of Science ®Google Scholar
• Sung JY, Park SB, Liu YT, Kwai N, Arnold R, Krishnan AV, Lin CSY. Progressive axonal dysfunction precedes development of neuropathy in type 2 diabetes. Diabetes. 2012;61(6):1592–98. doi:10.2337/db11-1509.
   PubMed Web of Science ®Google Scholar
• Issar T, Arnold R, Kwai NCG, Pussell BA, Endre ZH, Poynten AM, Kiernan MC, Krishnan AV. The utility of the Total Neuropathy Score as an instrument to assess neuropathy severity in chronic kidney disease: A validation study. Clin Neurophysiol. 2018;129(5):889–94. doi:10.1016/j.clinph.2018.02.120.
   PubMed Web of Science ®Google Scholar
• Borire AA, Issar T, Kwai NC, Visser LH, Simon NG, Poynten AM, Kiernan MC, Krishnan AV. Correlation between markers of peripheral nerve function and structure in type 1 diabetes. Diabetes Metab Res Rev. 2018;34(7):e3028. doi:10.1002/dmrr.3028.
   PubMed Web of Science ®Google Scholar
• Kiernan MC, Burke D, Andersen KV, Bostock H. Multiple measures of axonal excitability: A new approach in clinical testing. Muscle Nerve. 2000;23(3):399–409. doi:10.1002/(SICI)1097-4598(200003)23:3<399::AID-MUS12>3.0.CO;2-G.
   PubMed Web of Science ®Google Scholar
• Kiernan MC, Cikurel K, Bostock H. Effects of temperature on the excitability properties of human motor axons. Brain. 2001;124(4):816–25. doi:10.1093/brain/124.4.816.
   PubMedGoogle Scholar
• Barrett EF, Barrett JN. Intracellular recording from vertebrate myelinated axons: mechanism of the depolarizing afterpotential. J Physiol. 1982;323:117–44. doi:10.1113/jphysiol.1982.sp014064.
   PubMed Web of Science ®Google Scholar
• Markoulli M, Gokhale M, You J. Substance p in flush tears and schirmer strips of healthy participants. Optom Vis Sci. 2017;94(4):527–33. doi:10.1097/OPX.0000000000001040.
   PubMed Web of Science ®Google Scholar
• Sack RA, Tan KO, Tan A. Diurnal tear cycle: evidence for a nocturnal inflammatory constitutive tear fluid. Invest Ophthalmol Vis Sci. 1992;33(3):626–40. doi:10.1083/jcb.34.1.327.
   PubMed Web of Science ®Google Scholar
• Petropoulos IN, Ferdousi M, Marshall A, Alam U, Ponirakis G, Azmi S, Fadavi H, Efron N, Tavakoli M, Malik RA. The inferior whorl for detecting diabetic peripheral neuropathy using corneal confocal microscopy. Invest Ophthalmol Vis Sci. 2015;56(4):2498–504. doi:10.1167/iovs.14-15919.
   PubMed Web of Science ®Google Scholar
• Petropoulos IN, Alam U, Fadavi H, Asghar O, Green P, Ponirakis G, Marshall A, Boulton AJMM, Tavakoli M, Malik RA. Corneal nerve loss detected with corneal confocal microscopy is symmetrical and related to the severity of diabetic polyneuropathy. Diabetes Care. 2013;36:3646–51. 10.2337/dc13-0193.
   PubMed Web of Science ®Google Scholar
• Vagenas D, Pritchard N, Edwards K, Shahidi AM, Sampson GP, Russell AW, Malik RA, Efron N. Optimal image sample size for corneal nerve morphometry. Optom Vis Sci. 2012;89(5):812–17. doi:10.1097/OPX.0b013e31824ee8c9.
   PubMed Web of Science ®Google Scholar
• Dabbah MA, Graham J, Petropoulos IN, Tavakoli M, Malik RA. Automatic analysis of diabetic peripheral neuropathy using multi-scale quantitative morphology of nerve fibres in corneal confocal microscopy imaging. Med Image Anal. 2011;15(5):738–47. doi:10.1016/j.media.2011.05.016.
   PubMed Web of Science ®Google Scholar
• Chen X, Graham J, Dabbah MA, Petropoulos IN, Tavakoli M, Malik RA. An automatic tool for quantification of nerve fibers in corneal confocal microscopy images. IEEE Trans Biomed Eng. 2017;64(4):786–94. doi:10.1109/TBME.2016.2573642.
   PubMed Web of Science ®Google Scholar
• Petropoulos IN, Manzoor T, Morgan P, Fadavi H, Asghar O, Alam U, Ponirakis G, Dabbah MA, Chen X, Graham J, et al. Repeatability of in vivo corneal confocal microscopy to quantify corneal nerve morphology. Cornea. 2013;32(5):1–7. doi:10.1097/ICO.0b013e3182749419.
   PubMed Web of Science ®Google Scholar
• Petropoulos IN, Alam U, Fadavi H, Marshall A, Asghar O, Dabbah MA, Chen X, Graham J, Ponirakis G, Boulton AJM, et al. Rapid automated diagnosis of diabetic peripheral neuropathy with in vivo corneal confocal microscopy. Invest Ophthalmol Vis Sci. 2014;55(4):2062–70. doi:10.1167/iovs.13-13787.
   PubMed Web of Science ®Google Scholar
• Chen X, Graham J, Petropoulos IN, Ponirakis G, Asghar O, Alam U, Marshall A, Ferdousi M, Azmi S, Efron N, et al. Corneal nerve fractal dimension: A novel corneal nerve metric for the diagnosis of diabetic sensorimotor polyneuropathy. Invest Ophthalmol Vis Sci. 2018;59(2):1113–18. doi:10.1167/iovs.17-23342.
   PubMed Web of Science ®Google Scholar
• Kalteniece A, Ferdousi M, Petropoulos I, Azmi S, Adam S, Fadavi H, Marshall A, Boulton AJM, Efron N, Faber CG, et al. Greater corneal nerve loss at the inferior whorl is related to the presence of diabetic neuropathy and painful diabetic neuropathy. Sci Rep. 2018;8(1):3283. doi:10.1038/s41598-018-21643-z.
   PubMed Web of Science ®Google Scholar
• Hanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology. 1982;143(1):29–36. doi:10.1148/radiology.143.1.7063747.
   PubMed Web of Science ®Google Scholar
• Hosmer DW, Lemeshow S. Assessing the fit of the model. In: Shewhart WA, Wilks SS, editors. Applied logistic regression. Hoboken (NJ): John Wiley & Sons, Inc.; 2005. p. 143–202. doi:10.1002/0471722146.ch5.
   Google Scholar
• Yamada M, Ogata M, Kawai M, Mashima Y. Decreased substance Pconcentrations in tears from patients with corneal hypesthesia. Am J Ophthalmol. 2000;129(5):671–72. doi:10.1016/S0002-9394(00)00415-3.
   PubMed Web of Science ®Google Scholar
• Pritchard N, Dehghani C, Edwards K, Burgin E, Cheang N, Kim H, Mikhaiel M, Stanton G, Russell AW, Malik RA, et al. Utility of assessing nerve morphology in central cornea versus whorl area for diagnosing diabetic peripheral neuropathy. Cornea. 2015;34(7):756–61. doi:10.1097/ICO.0000000000000447.
   PubMed Web of Science ®Google Scholar
• Marfurt CF, Cox J, Deek S, Dvorscak L. Anatomy of the human corneal innervation. Exp Eye Res. 2010;90(4):478–92. doi:10.1016/j.exer.2009.12.010.
   PubMed Web of Science ®Google Scholar
• Dyck PJ, Giannini C. Pathologic alterations in the diabetic neuropathies of humans: A review. J Neuropathol Exp Neurol. 1996;55(12):1181–93. doi:10.1097/00005072-199612000-00001.
   PubMed Web of Science ®Google Scholar
• Edwards JL, Vincent AM, Cheng HT, Feldman EL. Diabetic neuropathy: mechanisms to management. Pharmacol Ther. 2008;120(1):1–34. doi:10.1016/j.pharmthera.2008.05.005.
   PubMed Web of Science ®Google Scholar
• Yan A, Issar T, Tummanapalli SS, Markoulli M, Kwai NCG, Poynten AM, Krishnan AV. Relationship between corneal confocal microscopy and markers of peripheral nerve structure and function in Type 2 diabetes. Diabet Med. 2019. dme.13952. doi:10.1111/dme.13952.
   Web of Science ®Google Scholar
• Perkins BA, Lovblom LE, Bril V, Scarr D, Ostrovski I, Orszag A, Edwards K, Pritchard N, Russell A, Dehghani C, et al. Corneal confocal microscopy for identification of diabetic sensorimotor polyneuropathy: a pooled multinational consortium study. Diabetologia. 2018;61(8):1856–61. doi:10.1007/s00125-018-4653-8.
   PubMed Web of Science ®Google Scholar
• Pritchard N, Edwards K, Russell AW, Perkins BA, Malik RA, Efron N. Corneal confocal microscopy predicts 4-Year incident peripheral neuropathy in type 1 diabetes. Diabetes Care. 2015;38(4):671–75. doi:10.2337/dc14-2114.
   PubMed Web of Science ®Google Scholar
• Lovblom LE, Halpern EM, Wu T, Kelly D, Ahmed A, Boulet G, Orszag A, Ng E, Ngo M, Bril V, et al. In vivo corneal confocal microscopy and prediction of future-incident neuropathy in type 1 diabetes: a preliminary longitudinal analysis. Can J Diabetes. 2015;39(5):390–97. doi:10.1016/j.jcjd.2015.02.006.
   PubMed Web of Science ®Google Scholar
• Breiner A, Lovblom LE, Perkins BA, Bril V. Does the prevailing hypothesis that small-fiber dysfunction precedes large-fiber dysfunction apply to type 1 diabetic patients? Diabetes Care. 2014;37(5):1418–24. doi:10.2337/dc13-2005.
   PubMed Web of Science ®Google 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 and Nerve. 2007;35(5):591–98. doi:10.1002/mus.20732.
   PubMed Web of Science ®Google Scholar
• Sima AAF. Diabetic neuropathy in type 1 and type 2 diabetes and the effects of C-peptide. J Neurol Sci. 2004;220(1–2):133–36. doi:10.1016/j.jns.2004.03.014.
   PubMed Web of Science ®Google Scholar
• Sima AAF, Kamiya H. Diabetic neuropathy differs in type 1 and type 2 diabetes. Ann N Y Acad Sci. 2006;1084(1):235–49. doi:10.1196/annals.1372.004.
   PubMedGoogle Scholar
• Grunberger G, Qiang X, Li Z, Mathews ST, Sbrissa D, Shisheva A, Sima AAF. Molecular basis for the insulinomimetic effects of C-peptide. Diabetologia. 2001;44(10):1247–57. doi:10.1007/s001250100632.
   PubMed Web of Science ®Google Scholar
• Kamiya H, Murakawa Y, Zhang W, Sima AAF. Unmyelinated fiber sensory neuropathy differs in type 1 and type 2 diabetes. Diabetes Metab Res Rev. 2005;21(5):448–58. doi:10.1002/dmrr.541.
   PubMed Web of Science ®Google Scholar
• Jende JME, Groener JB, Oikonomou D, Heiland S, Kopf S, Pham M, Nawroth P, Bendszus M, Kurz FT. Diabetic neuropathy differs between type 1 and type 2 diabetes: insights from magnetic resonance neurography. Ann Neurol. 2018;83(3):588–98. doi:10.1002/ana.25182.
   PubMed Web of Science ®Google Scholar
• Hanewinckel R, Ikram MA, Franco OH, Hofman A, Drenthen J, van Doorn PA. High body mass and kidney dysfunction relate to worse nerve function, even in adults without neuropathy. J Peripher Nerv Syst. 2017;22(2):112–20. doi:10.1111/jns.12211.
   PubMed Web of Science ®Google Scholar
• Hanewinckel R, Drenthen J, Ligthart S, Dehghan A, Franco OH, Hofman A, Ikram A, Van Doorn PA. Metabolic syndrome is related to polyneuropathy and impaired peripheral nerve function: a prospective population-based cohort study. J Neurol Neurosurg Psychiatry. 2016;87:1336–42. doi:10.1136/jnnp-2016-314171.
   PubMed Web of Science ®Google Scholar
• Arnold R, Issar T, Krishnan AV, Pussell BA. Neurological complications in chronic kidney disease. JRSM Cardiovasc Dis. 2016;5:2048004016677687. doi:10.1177/2048004016677687.
   Web of Science ®Google Scholar