Skip to main content

Advertisement

SpringerLink
Log in

Diabetic corneal neuropathy and its relation to the severity of retinopathy in patients with type 2 diabetes mellitus: an in vivo confocal microscopy study

  • Original Paper
  • Published:
International Ophthalmology Aims and scope Submit manuscript

Abstract

Purpose

To investigate corneal neuropathy and corneal nerve alterations in type 2 diabetes mellitus (DM) patients with different diabetic retinopathy (DR) status.

Methods

A total of 87 eyes of 87 patients with DM and 28 eyes of 28 healthy control subjects were included in the study. DM patients were further classified into 3 groups: patients without DR (NDR), patients with non-proliferative DR (NPDR), and patients with proliferative DR (PDR). PDR patients were classified into 2 groups regarding having undergone retinal argon laser photocoagulation treatment (ALP). Ocular surface disease index score (OSDI), average tear break-up time (A-BUT), corneal sensitivity and cornea nerve fiber length (CNFL), cornea nerve fiber density (CNFD), and cornea nerve branch density (CNBD) of the cornea subbasal nerve plexus (SBNP) were measured using in vivo confocal microscopy (IVCM).

Results

OSDI scores increased and A-BUT decreased in DM patients compared to the control group, but no significant difference was found between DM patient groups. Corneal sensitivity decreased in DM patients who developed DR, compared to both the controls and the NDR group. CNFD and CNFL decreased in NPDR and PDR patients compared to controls. CNFD and CNBD decreased in patients who had developed PDR, compared to all three groups. All IVCM parameters decreased with DR progression.

Conclusion

IVCM can detect early structural corneal nerve changes in diabetic patients. The presence of DM affects ocular surface parameters, especially in long-term DM patients. Corneal sensitivity loss is increased with the presence of DR. All IVCM parameters decrease with DR development and its progression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. International Diabetes Federation. IDF diabetes atlas. Seventh ed. 2015. http://www.diabetesatlas.org/

  2. Cade WT (2008) Diabetes-related microvascular and macrovascular diseases in the physical therapy setting. Phys Ter 88(11):1322–1335. https://doi.org/10.2522/ptj.20080008

    Article  Google Scholar 

  3. Avogaro A, Fadini GP (2019) Microvascular complications in diabetes: a growing concern for cardiologists. Int J Cardiol 291:29–35. https://doi.org/10.1016/j.ijcard.2019.02.030

    Article  PubMed  Google Scholar 

  4. Han SB, Yang HK, Hyon JY (2018) Influence of diabetes mellitus on anterior segment of the eye. Clin Interv Aging 14:53–63. https://doi.org/10.2147/CIA.S190713

    Article  PubMed  PubMed Central  Google Scholar 

  5. Barsegian A, Lee J, Salifu M, McFarlane S (2018) Corneal neuropathy: an underrated manifestation of diabetes mellitus. J Clin Endocrinol Diabetes. 2(1)

  6. O’Donnell C, Efron N (2012) Diabetes and contact lens wear. Clin Exp Optom 95(3):328–337. https://doi.org/10.1111/j.1444-0938.2012.00738.x

    Article  PubMed  Google Scholar 

  7. Pritchard N, Edwards K, Shahidi AM, Sampson GP, Russell AW, Malik RA, Efron N (2018) Corneal markers of diabetic neuropathy. Ocul Surf. https://doi.org/10.1016/s1542-0124(11)70006-4

    Article  Google Scholar 

  8. Yoon KC, Im SK, Seo MS (2004) Changes of tear film and ocular surface in diabetes mellitus. Korean J Ophthalmol 18(2):168–174. https://doi.org/10.3341/kjo.2004.18.2.168

    Article  PubMed  Google Scholar 

  9. Nitoda E, Kallikinos P, Pallikaris A, Moschandrea J, Amoiridis G, Ganotakis ES, Tsilimbaris M (2012) Correlation of diabetic retinopathy and corneal neuropathy using confocal microscopy. Curr Eye Res 37(10):898–906. https://doi.org/10.3109/02713683.2012.683507

    Article  CAS  PubMed  Google Scholar 

  10. Asghar O, Petropoulos IN, Alam U, Jones W, Jeziorska M, Marshall A, Ponirakis G, Fadavi H, Boulton AJ, Tavakoli M, Malik RA (2014) Corneal confocal microscopy detects neuropathy in subjects with impaired glucose tolerance. Diabetes Care 37(9):2643–2646. https://doi.org/10.2337/dc14-0279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bitirgen G, Ozkagnici A, Malik RA, Kerimoglu H (2014) Corneal nerve fibre damage precedes diabetic retinopathy in patients with type 2 diabetes mellitus. Diabet Med 31(4):431–438. https://doi.org/10.1111/dme.12324

    Article  CAS  PubMed  Google Scholar 

  12. Campagnolo M, Lazzarini D, Fregona I, Cacciavillani M, Bergamo F, Parrozzani R, Midena E, Briani C (2013) Corneal confocal microscopy in patients with oxaliplatin-induced peripheral neuropathy. J Peripher Nerv Syst 18(3):269–271. https://doi.org/10.1111/jns5.12036

    Article  PubMed  Google Scholar 

  13. Falke K, Büttner A, Schittkowski M et al (2009) The microstructure of cornea verticillata in Fabry disease and amiodarone-induced keratopathy: a confocal laser-scanning microscopy study. Graefes Arch Clin Exp Ophthalmol 247:523–534. https://doi.org/10.1007/s00417-008-0962-9

    Article  PubMed  Google Scholar 

  14. Lalive PH, Truffert A, Magistris MR, Landis T, Dosso A (2009) Peripheral autoimmune neuropathy assessed using corneal in vivo confocal microscopy. Arch Neurol 66(3):403–405. https://doi.org/10.1001/archneurol.2008.587

    Article  PubMed  Google Scholar 

  15. Mastropasqua L, Nubile M, Lanzini M, Carpineto P, Toto L, Ciancaglini M (2006) Corneal and conjunctival manifestations in Fabry disease: in vivo confocal microscopy study. Am J Ophthalmol 141(4):709–718. https://doi.org/10.1016/j.ajo.2005.11.053

    Article  PubMed  Google Scholar 

  16. Petropoulos IN, Alam U, Fadavi H, Marshall A, Asghar O, Dabbah MA, Chen X, Graham J, Ponirakis G, Boulton AJ, Tavakoli M, Malik RA (2014) Rapid automated diagnosis of diabetic peripheral neuropathy with in vivo corneal confocal microscopy. Invest Ophthalmol Vis Sci 55(4):2071–2078. https://doi.org/10.1167/iovs.13-13787

    Article  PubMed  PubMed Central  Google Scholar 

  17. Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL (2000) Reliability and validity of the Ocular Surface Disease Index. Arch Ophthalmol 118(5):615–621. https://doi.org/10.1001/archopht.118.5.615

    Article  CAS  PubMed  Google Scholar 

  18. He F, Zhao Z, Liu Y, Lu L, Fu Y (2018) Assessment of ocular surface damage during the course of type 2 diabetes mellitus. J Ophthalmol. https://doi.org/10.1155/2018/1206808

    Article  PubMed  PubMed Central  Google Scholar 

  19. Antonetti DA, Klein R, Gardner TW (2012) Diabetic retinopathy. N Engl J Med 366(13):1227–1239. https://doi.org/10.1056/NEJMra1005073

    Article  CAS  PubMed  Google Scholar 

  20. Dastjerdi MH, Dana R (2009) Corneal nerve alterations in dry eye-associated ocular surface disease. Int Ophthalmol Clin 49(1):11–20. https://doi.org/10.1097/IIO.0b013e31819242c9

    Article  PubMed  Google Scholar 

  21. Gao Y, Zhang Y, Ru YS, Wang XW, Yang JZ, Li CH, Wang HX, Li XR, Li B (2015) Ocular surface changes in type II diabetic patients with proliferative diabetic retinopathy. Int J Ophthalmol 8(2):358–364. https://doi.org/10.3980/j.issn.2222-3959.2015.02.26

    Article  PubMed  PubMed Central  Google Scholar 

  22. Nepp J, Abela C, Polzer I, Derbolav A, Wedrich A (2000) Is there a correlation between the severity of diabetic retinopathy and keratoconjunctivitis sicca? Cornea 19(4):487–491. https://doi.org/10.1097/00003226-200007000-00017

    Article  CAS  PubMed  Google Scholar 

  23. Ozdemir M, Buyukmese MA, Cetinkaya A, Ozdemir G (2003) Risk factors for ocular surface disorders in patients with diabetes mellitus. Diabetes Res Clin Pract 59(3):195–199. https://doi.org/10.1016/s0168-8227(02)00244-9

    Article  CAS  PubMed  Google Scholar 

  24. Saito J, Enoki M, Hara M, Morishige N, Chikama T, Nishida T (2003) Correlation of corneal sensation, but not of basal or reflex tear secretion, with the stage of diabetic retinopathy. Cornea 22(1):15–18. https://doi.org/10.1097/00003226-200301000-00004

    Article  PubMed  Google Scholar 

  25. Rogell GD (1980) Corneal hypesthesia and retinopathy in diabetes mellitus. Ophthalmology 87(3):229–233. https://doi.org/10.1016/s0161-6420(80)35257-3

    Article  CAS  PubMed  Google Scholar 

  26. Manaviat MR, Rashidi M, Afkhami-Ardekani M, Shoja MR (2008) Prevalence of dry eye syndrome and diabetic retinopathy in type 2 diabetic patients. BMC Ophthalmol 2(8):10. https://doi.org/10.1186/1471-2415-8-10

    Article  Google Scholar 

  27. Yu L, Chen X, Qin G, Xie HP, Lv P (2008) Tear film function in type 2 diabetic patients with retinopathy. Ophthalmologica 222:284–291. https://doi.org/10.1159/000140256

    Article  PubMed  Google Scholar 

  28. Najafi L, Malek M, Valojerdi AE, Aghili R, Khamseh ME, Fallah AE, Tokhmehchi MR, Behrouz MJ (2013) Dry eye and its correlation to diabetes microvascular complications in people with type 2 diabetes mellitus. J Diabetes Complic 27(5):459–462. https://doi.org/10.1016/j.jdiacomp.2013.04.006

    Article  Google Scholar 

  29. Lv H, Li A, Zhang X, Xu M, Qiao Y, Zhang J, Yu L (2014) Meta-analysis and review on the changes of tear function and corneal sensitivity in diabetic patients. Acta Ophthalmol 92(2):96–104. https://doi.org/10.1111/aos.12063

    Article  Google Scholar 

  30. Dogru M, Kaderli B, Gelisken O, Yücel A, Avci R, Goto E, Shimmura S, Shimazaki J, Tsubota K (2004) Ocular surface changes with applanation contact lens and coupling fluid use after argon laser photocoagulation in noninsulin-dependent diabetes mellitus. Am J Ophthalmol 138(3):381–388. https://doi.org/10.1016/j.ajo.2004.04.008

    Article  PubMed  Google Scholar 

  31. Cousen P, Cackett P, Bennett H, Swa K, Dhillon B (2007) Tear production and corneal sensitivity in diabetes. J Diabetes Complic 21(6):371–373. https://doi.org/10.1016/j.jdiacomp.2006.05.008

    Article  Google Scholar 

  32. Figueroa-Ortiz LC, Jimenez RE, García-Ben A, García-Campos J (2011) Estudio de la función lagrimal y la superficie conjuntival en pacientes diabéticos [Study of tear function and the conjunctival surface in diabetic patients]. Arch Soc Esp Oftalmol 86(4):107–112. https://doi.org/10.1016/j.oftal.2010.12.010

    Article  CAS  PubMed  Google Scholar 

  33. Di Zazzo A, Coassin M, Micera A, Mori T, De Piano M, Scartozzi L, Sgrulletta R, Bonini S (2021) Ocular surface diabetic disease: a neurogenic condition? Ocul Surf 19:218–223. https://doi.org/10.1016/j.jtos.2020.09.006

    Article  PubMed  Google Scholar 

  34. McGhee CNJ, Keller PR (1998) In vivo confocal microscopy of living tissue: the cornea at cellular level. Eyenews 5:14–20

    Google Scholar 

  35. Oliveira-Soto L, Efron N (2001) Morphology of corneal nerves using confocal microscopy. Cornea 20(4):374–384. https://doi.org/10.1097/00003226-200105000-00008

    Article  CAS  PubMed  Google Scholar 

  36. Dehghani C, Pritchard N, Edwards K, Russell AW, Malik RA, Efron N (2016) Abnormal anterior corneal morphology in diabetes observed using in vivo laser-scanning confocal microscopy. Ocul Surf 14(4):507–514. https://doi.org/10.1016/j.jtos.2016.07.004

    Article  PubMed  Google Scholar 

  37. Batawi H, Shalabi N, Joag M, Koru-Sengul T, Rodriguez J, Green PT, Campigotto M, Karp CL, Galor (2018) Sub-basal corneal nerve plexus analysis using a new software technology. Eye Contact Lens. 44(Suppl 1):S199–S205. https://doi.org/10.1097/ICL.0000000000000375

    Article  PubMed  PubMed Central  Google Scholar 

  38. dell’Omo R, Cifariello F, De Turris S, Romano V, Di Renzo F, Di Taranto D, Coclite G, Agnifili L, Mastropasqua L, Costagliola C (2018) Confocal microscopy of corneal nerve plexus as an early marker of eye involvement in patients with type 2 diabetes. Diabetes Res Clin Pract 142:393–400. https://doi.org/10.1016/j.diabres.2018.06.010

    Article  PubMed  Google Scholar 

  39. Misra S, Ahn HN, Craig JP, Pradhan M, Patel DV, McGhee CN (2013) Effect of panretinal photocoagulation on corneal sensation and the corneal subbasal nerve plexus in diabetes mellitus. Invest Ophthalmol Vis Sci 54(7):4485–4490. https://doi.org/10.1167/iovs.12-10571

    Article  PubMed  Google Scholar 

  40. Mocan MC, Durukan I, Irkec M, Orhan MF (2006) Morphologic alterations of both the stromal and subbasal nerves in the corneas of patients with diabetes. Cornea 25:769–773. https://doi.org/10.1097/01.ico.0000224640.58848.54

    Article  PubMed  Google Scholar 

  41. Dehghani C, Pritchard N, Edwards K, Russell AW, Malik RA, Efron N (2016) 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 35(6):847–852. https://doi.org/10.1097/ICO.0000000000000760

    Article  PubMed  Google Scholar 

  42. Cao J, Qu J, Odilov B, Lu B, Zhang Y, Li L, Zhang Y, Xiong Q, Hong Y, Li J, Shen Y, Hou X (2022) Corneal nerve parameter reference values for Chinese adults assessed by corneal confocal microscopy. J Diabetes Res. https://doi.org/10.1155/2022/4913031

    Article  PubMed  PubMed Central  Google Scholar 

  43. Erie JC, MacLaren JW, Hodge DO, Bourne WM (2005) The effect of age on the corneal subbasal nerve plexus. Cornea 24(6):705–709. https://doi.org/10.1097/01.ico.0000154387.51355.39

    Article  PubMed  Google Scholar 

  44. Gambato C, Longhin E, Catania AG, Lazzarini D, Parrozzani R, Midena E (2015) Aging and corneal layers: an in vivo corneal confocal microscopy study. Graefes Arch Clin Exp Ophthalmol 253(2):267–275. https://doi.org/10.1007/s00417-014-2812-2

    Article  PubMed  Google Scholar 

  45. Schiodte SN (1984) Effects on choroidal nerves after panretinal xenon arc and argon laser photocoagulation. Acta Ophthalmol 62(2):244–55. https://doi.org/10.1111/j.1755-3768.1984.tb08401.x

    Article  CAS  Google Scholar 

  46. De Cillà S, Ranno S, Carini E, Fogagnolo P, Ceresara G, Orzalesi N, Rossetti LM (2009) Corneal subbasal nerves changes in patients with diabetic retinopathy: an in vivo confocal study. Invest Ophthalmol Vis Sci 50:5155–5158. https://doi.org/10.1167/iovs.09-3384

    Article  PubMed  Google Scholar 

  47. Hossain P, Sachdev A, Malik RA (2005) Early detection of diabetic peripheral neuropathy with corneal confocal microscopy. Lancet 366(9494):1340–1343. https://doi.org/10.1016/S0140-6736(05)67546-0

    Article  PubMed  Google Scholar 

  48. 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(8):2148–2154. https://doi.org/10.2337/db07-0285

    Article  CAS  PubMed  Google Scholar 

  49. Markoulli M, Flanagan J, Tummanapalli SS, Wu J, Willcox M (2018) The impact of diabetes on corneal nerve morphology and ocular surface integrity. Ocul Surf. https://doi.org/10.1016/j.jtos.2017.10.006

    Article  PubMed  Google Scholar 

  50. Roszkowska AM, Licitra C, Tumminello G, Postorino EI, Colonna MR, Aragona P (2021) Corneal nerves in diabetes-the role of the in vivo corneal confocal microscopy of the subbasal nerve plexus in the assessment of peripheral small fiber neuropathy. Surv Ophthalmol 66(3):493–513. https://doi.org/10.1016/j.survophthal.2020.09.003

    Article  PubMed  Google Scholar 

  51. Zhivov A, Winter K, Hovakimyan M, Peschel S, Harder V, Schober HC, Kundt G, Baltrusch S, Guthoff RF, Stachs O (2013) Imaging and quantification of subbasal nerve plexus in healthy volunteers and diabetic patients with or without retinopathy. PLoS ONE 8(1):e52157. https://doi.org/10.1371/journal.pone.0052157

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  52. Chin JY, Yang LWY, Ji AJS, Nubile M, Mastropasqua L, Allen JC, Mehta JS, Liu YC (2020) Validation of the use of automated and manual quantitative analysis of corneal nerve plexus following refractive surgery. Diagnostics 10(7):493. https://doi.org/10.3390/diagnostics10070493

    Article  PubMed  PubMed Central  Google Scholar 

  53. Dehghani C, Pritchard N, Edwards K, Russell AW, Malik RA, Efron N (2014) Fully automated, semiautomated, and manual morphometric analysis of corneal subbasal nerve plexus in individuals with and without diabetes. Cornea 33(7):696–702. https://doi.org/10.1097/ico.0000000000000152

    Article  PubMed  Google Scholar 

  54. Wu PY, Wu JH, Hsieh YT, Chen LC, Cheng T, Wu PY, Hsieh BJ, Huang WL, Huang SL, Chen WL (2021) Comparing the results of manual and automated quantitative corneal neuroanalysing modules for beginners. Sci Rep 11(1):18208. https://doi.org/10.1038/s41598-021-97567-y

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  55. Polat OA, Sener H, Erkilic K (2022) Corneal nerve fiber and sensitivity loss after repeated intravitreal anti-VEGF injections: an in vivo confocal microscopy study. Cornea 41(3):317–321. https://doi.org/10.1097/ICO.0000000000002836

    Article  PubMed  Google Scholar 

Download references

Funding

The authors declare that no funds, grants, or other support was received during the preparation of this manuscript. The authors have no relevant financial or non-financial interests to disclose.

Author information

Authors and Affiliations

  1. Department of Ophthalmology, Erciyes University Medical Faculty, Kayseri, Turkey

    Zeynep Akkul, Kuddusi Erkilic, Hidayet Sener, Osman Ahmet Polat & Elif Er Arslantas

Authors
  1. Zeynep Akkul
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kuddusi Erkilic
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hidayet Sener
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Osman Ahmet Polat
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Elif Er Arslantas
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study’s conception and design. Material preparation and data collection were performed by Zeynep Akkul and Elif Er Arslantas. Formal analysis, data curation, and statistical analysis were contributed by Hidayet Sener and Osman Ahmet Polat. Writing and preparation of the first and original drafts of the manuscript were contributed by Zeynep Akkul, and review and editing were contributed by Kuddusi Erkilic, Hidayet Sener, and Osman Ahmet Polat. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Zeynep Akkul.

Ethics declarations

Conflict of interest

The authors declare that there is no conflict of interest associated with the manuscript.

Ethical approval

The study was approved by the Ethics Committee of Erciyes University Medical Faculty (number: 2022/426) and was conducted in accordance with the tenets of the Declaration of Helsinki. Informed consent was obtained from all individual participants included in the study. The authors affirm that human research participants provided informed consent for the publication of the images in Fig. 1.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Akkul, Z., Erkilic, K., Sener, H. et al. Diabetic corneal neuropathy and its relation to the severity of retinopathy in patients with type 2 diabetes mellitus: an in vivo confocal microscopy study. Int Ophthalmol 44, 108 (2024). https://doi.org/10.1007/s10792-024-03043-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10792-024-03043-7

Keywords

Search

Navigation