Diabetic Retinopathy and Changes in Corneal Nerve Fibers Assessed by Confocal Microscopy

Česká verzia

Authors: M. Česká Burdová ¹; T. Lainová Vrabcová ¹; D. Dotřelová ¹; G. Mahelková ^1,2
Authors place of work: Oční klinika dětí a dospělých 2. LF UK a FN Motol, Praha ¹; Ústav fyziologie, 2. LF UK v Praze ²
Published in the journal: Cesk Slov Neurol N 2017; 80/113(1): 59-65
Category: Original Paper

Summary

Aim:
The aim of the study was to test possible correlation between corneal sub-basal nerve plexus changes and the grade of diabetic retinopathy (DR).

Methods:
A total of 38 patients with type 1 diabetes, divided into three groups according to the grade of diabetic retinopathy, and 12 age-matched healthy subjects underwent corneal confocal microscopy. Corneal main nerve fiber density (CNFD), total corneal nerve fiber density (t-CNFD), nerve fiber length (CNFL) and nerve tortuosity (CNFT) were evaluated.

Results:
CNFD was lower in patients without DR, with mild grade DR, and with advanced grade DR than in healthy subjects (p < 0.0001, p = 0.004 and p < 0.0001, respectively). There was also lower CNFD in patients with advanced grade DR than with mild grade DR (p = 0.036). T-CNFD was lower in patients without DR and advanced grade DR than in healthy subjects (p = 0.024 and p < 0.0001, respectively). CNFL was lower in patients without DR and advanced grade DR than in healthy subjects (p = 0.028). CNFT was higher in patients with advanced grade DR than in healthy subjects and patients without DR (p < 0.0001; p = 0.001).

Conclusion:
We demonstrated changes in corneal sub-basal nerve fiber count in all diabetic patient groups, with or without DR. The changes were more pronounced in patients without DR than with mild grade DR. The study suggests no direct correlation between progression of corneal nerve fiber changes and changes in DR.

Key words:
confocal microscopy – cornea – small fiber neuropathy – diabetes mellitus type 1 – diabetic retinopathy

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.

Chinese summary - 摘要

糖尿病性视网膜病和神经纤维的改变

额定角膜共聚焦显微镜

摘要

目标：

研究I型糖尿病患视网膜病患患者角膜神经丛变化与糖尿病程度的相关性。

方法：

根据角膜共聚焦显微镜检查，根据糖尿病性视网膜病的程度（DR）将38例患者分为三组，以及12名健康志愿者。评价神经纤维和芯毛（CNFD，CNFD）的数量，总长度（CNFL）和扭曲（CNFT）。

结果：

轻度和重度DR患者的CNFD比健康人降低（P <0.0001，P = 0.004，P <0.0001）。 CNFD在较低组比DR轻微程度（P = 0.036），重度。 T-CNFD在较低没有DR和DR严重组较健康者（P = 0.024，P <0.0001）。 CNFL较健康无DR和DR组中重度低受试者（P = 0.007，P <0.0001），重症患者有轻步比较DR（p值= 0.028）。 CNFT是比较健康有严重的DR组高个人和无DR组（p <0.0001; P = 0.001）。

结论：

我们证明角膜受损神经纤维的DM患者所有组

1.变化更为明显在患者无DR比DR的程度轻微。这表明角膜神经纤维受损程度和DR的程度不平行。

关键词：

共聚焦显微镜 - 角膜 - 糖尿病第一类型 - 糖尿病视网膜病变

Zdroje

1. Threatt J, Williamson JF, Huynh K, et al. Ocular disease, knowledge and technology applications in patients with diabetes. Am J Med Sci 2013;345(4):266– 70. doi: 10.1097/ MAJ.0b013e31828aa6fb.

2. LeCaire TJ, Palta M, Klein R, Klein BE, et al. Assessing progress in retinopathy outcomes in type 1 diabetes: comparing findings from the Wisconsin Diabetes Registry Study and the Wisconsin Epidemiologic Study of Diabetic Retinopathy. Diabetes Care 2013;36(3):631– 7. doi: 10.2337/ dc12-0863.

3. Lorenzi GM, Braffett BH, Arends VL, et al. Quality Control Measures over 30 Years in a Multicenter Clinical Study: Results from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions andComplications (DCCT/ EDIC) Study. PLoS One 2015;10(11): e0141286. doi: 10.1371/ journal.pone.0141286.

4. Lutty GA. Effects of diabetes on the eye. Invest Ophthalmol Vis Sci 2013;54:ORSF81– 7. doi: 10.1167/ iovs.13-12979.

5. Muller LJ, Vrensen GF, Pels L, et al. Architecture of human corneal nerves. Invest Ophthalmol Vis Sci 1997;38(5):985– 94.

6. Guthoff RF, Wienss H, Hahnel C, et al. Epithelial innervation of human cornea: a three-dimensional study using confocal laser scanning fluorescence microscopy. Cornea 2005;24(5):608– 13.

7. Stachs O, Zhivov A, Kraak R, et al. In vivo three-dimensional confocal laser scanning microscopy of the epithelial nerve structure in the human cornea. Graefes Arch Clin Exp Ophthalmol 2007;245(4):569– 75.

8. Oliveira-Soto L, Efron N. Morphology of corneal nerves using confocal microscopy. Cornea 2001;20(4):374– 84.

9. Chiou AG, Kaufman SC, Kaufman HE, et al. Clinical corneal confocal microscopy. Sury Ophthalmol 2006;51(5):482– 500.

10. Jalbert I, Stapleton F, Papas E, et al. In vivo confocal microscopy of the human cornea. Br J Ophthalmol 2003;87(2):225– 36.

11. Erie JC, McLaren JW, Patel SV. Confocal microscopy in ophthalmology. Am J Ophthalmol 2009;148(5):639– 46. doi: 10.1016/ j.ajo.2009.06.022.

12. Zochodne DW. Diabetes mellitus and the peripheral nervous system: manifestations and mechanisms. Muscle Nerve 2007;36(2):144– 66.

13. Jiang MS, Yuan Y, Gu ZX, et al. Corneal confocal microscopy for assessment of diabetic peripheral neuropathy: a meta-analysis. Br J Ophthalmol 2015;100(1):9– 14. doi: 10.1136/ bjophthalmol-2014-306038.

14. Dyck PJ, Kratz KM, Karnes JL, et al. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study. Neurology 1993;43(4):817– 24.

15. Hosseini SM, Boright AP, Sun L, et al. The association of previously reported polymorphisms for microvascular complications in a meta-analysis of diabetic retinopathy. Hum Genet 2015;134(2):247– 57.

16. Wilkinson CP, Ferris FL, Klein RE, et al. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology 2003;110(9):1677– 82.

17. Utsunomiya T, Nagaoka T, Hanada K, et al. Imaging of the Corneal Subbasal Whorl-like nerve plexus: more accurate depiction of the extent of corneal nerve damage in patients with diabetes. Invest Ophthalmol Vis Sci 2015;56(9):5417– 23. doi: 10.1167/ iovs.15-16609.

18. Smith AG, Kim G, Porzio M, et al. Corneal confocal microscopy is efficient, well-tolerated, and reproducible. J Peripher Nerv Syst 2013;18(1):54– 8. doi: 10.1111/ jns5.12008.

19. Szaflik JP. Comparison of in vivo confocal microscopy of human cornea by white light scanning slit and laser scanning systems. Cornea 2007;26(4):438– 45.

20. Heneghan C, Flynn J, O‘Keefe M, et al. Characterization of changes in blood vessel width and tortuosity in retinopathy of prematurity using image analysis. Med Image Anal 2002;6(4):407– 29.

21. Papanas N, Ziegler D. Corneal confocal microscopy: Recent progress in the evaluation of diabetic neuropathy. J Diabetes Investig 2015;6(4):381– 9. doi: 10.1111/ jdi.12335.

22. Misra SL, Craig JP, Patel DV, et al. 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;56(9):5060– 5. doi: 10.1167/ iovs.15-16711.

23. Dehghani C, Pritchard N, Edwards K, et al. Risk factors associated with corneal nerve alteration in type 1 diabetes in the absence of neuropathy: a longitudinal in vivo corneal confocal microscopy study. Cornea 2016;35(6):847– 52. doi: 10.1097/ ICO.0000000000000760.

24. Lovblom LE, Halpern EM, Wu T, 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– 7. doi: 10.1016/ j.jcjd.2015.02.006.

25. Asghar O, Petropoulos IN, Alam U, et al. Corneal confocal microscopy detects neuropathy in subjects with impaired glucose tolerance. Diabetes Care 2014;37(9):2643– 6.

26. Szalai E, Deak E, Modis L, et al. Early corneal cellular and nerve fiber pathology in young patients with type 1 diabetes mellitus identified using corneal confocal microscopy. Invest Ophthalmol Vis Sci 2016;57(3):853– 8. doi: 10.1167/ iovs.15-18735.

27. De Cilla S, Ranno S, Carini E, et al. Corneal subbasal nerves changes in patients with diabetic retinopathy: an in vivo confocal study. Invest Ophthalmol Vis Sci 2009;50(11):5155– 8. doi: 10.1167/ iovs.09-3384.

28. Messmer EM, Schmid-Tannwald C, Zapp D, et al. In vivo confocal microscopy of corneal small fiber damage in diabetes mellitus. Graefes Arch Clin Exp Ophthalmol 2010;248(9):1307– 12. doi: 10.1007/ s00417-010-1396-8.

29. Nitoda E, Kallinikos P, Pallikaris A, et al. Correlation of diabetic retinopathy and corneal neuropathy using confocal microscopy. Curr Eye Res 2012;37(10):898– 906. doi: 10.3109/ 02713683.2012.683507.

30. Zhivov A, Winter K, Hovakimyan M, et al. Imaging and quantification of subbasal nerve plexus in healthy volunteers and diabetic patients with or without retinopathy. PLoS One 2013;8(1):e52157. doi: 10.1371/ journal.pone.0052157.

31. Tavakoli M, Ferdousi M, Petropoulos IN, et al. Normative values for corneal nerve morphology assessed using corneal confocal microscopy: a multinational normative data set. Diabetes Care 2015;38(5):838– 43. doi: 10.2337/ dc14-2311.

32. Erie EA, McLaren JW, Kittleson KM, et al. Corneal subbasal nerve density: a comparison of two confocal microscopes. Eye Contact Lens 2008;34(6):322– 5. doi: 10.1097/ ICL.0b013e31818b74f4.

33. Petropoulos IN, Green P, Chan AW, et al. Corneal confocal microscopy detects neuropathy in patients with type 1 diabetes without retinopathy or microalbuminuria. PLoS One 2015;10(4):e0123517. doi: 10.1371/ journal.pone.0123517.

34. Patel DV, Tavakoli M, Craig JP, et al. Corneal sensitivity and slit scanning in vivo confocal microscopy of the subbasal nerve plexus of the normal central and peripheral human cornea. Cornea 2009;28(7):735– 40.

35. Mehra S, Tavakoli M, Kallinikos PA, et al. Corneal confocal microscopy detects early nerve regeneration after pancreas transplantation in patients with type 1 diabetes. Diabetes Care 2007;30(10):2608– 12.

36. Tavakoli M, Mitu-Pretorian M, Petropoulos IN, et al. Corneal confocal microscopy detects early nerve regeneration in diabetic neuropathy after simultaneous pancreas and kidney transplantation. Diabetes 2013;62(1):254– 60. doi: 10.2337/ db12-0574.

37. Gorst C, Kwok CS, Aslam S, et al. Long-term glycemic variability and risk of adverse outcomes: a systematic review and meta-analysis. Diabetes Care 2015;38(12):2354– 69. doi: 10.2337/ dc15-1188.

38. Lagali N, Poletti E, Patel DV, et al. Focused tortuosity definitions based on expert clinical assessment of corneal subbasal nerves. Invest Ophthalmol Vis Sci 2015;56(9):5102– 9. doi: 10.1167/ iovs.15-17284.

39. Edwards K, Pritchard N, Vagenas D, et al. Standardizing corneal nerve fibre length for nerve tortuosity increases its association with measures of diabetic neuropathy. Diabet Med 2014;31(10):1205– 9. doi: 10.1111/ dme.12466.

40. Barber AJ, Lieth E, Khin SA, et al. Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin. J Clin Invest 1998;102(4):783– 91.