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Early and localized retinal dysfunction in patients with type 1 diabetes mellitus studied by multifocal electroretinogram

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Abstract

Aims

To investigate the function of localized retinal areas in highly selected type 1 diabetes mellitus patients (DM1) with no or mild signs of diabetic retinopathy (NO DR and NPDR, respectively) and its correlation with age, diabetes duration and glycemic control.

Methods

Multifocal electroretinograms (mfERG) were recorded in 35 eyes of 18 NO DR patients and 38 eyes of 19 NPDR patients. Thirty-one eyes of 17 normal subjects were enrolled as controls. N1-P1 response amplitude densities (RADs) and P1 implicit times (ITs) from isolated (R1: 0°–2.5°, R2: 2.5°–5°, R3: 5°–10°) and combined (R1 + R2, R2 + R3 and R1 + R2 + R3) annular rings and from four retinal sectors (nasal, N; temporal, T; superior, S and inferior, I) with increasing eccentricities up to 10° (S1, S2, S3, S1 + S2, S1 + S2 + S3) were measured. The statistical differences between DM1 groups and controls were tested by ANOVA. The electrophysiological data were correlated with age, duration of diabetes and glycated hemoglobin (HbA1c) level using the Pearson’s test.

Results

MfERG RADs, but not ITs, from all isolated and combined rings and sectors up to 10° of foveal eccentricity were statistically different between DM1 groups compared to controls. No significant differences were found between NO DR and NPDR patients. The mfERG abnormalities of the central retinal areas were correlated significantly with age in both DM1 groups and with diabetes duration mainly in NPDR group.

Conclusions

In DM1 patients, localized retinal dysfunction, described by reduced mfERG RAD, can be observed also in the absence of clinical signs of DR and it is related to aging.

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References

  1. Hood DC, Odel JG, Chen CS, Winn BJ (2003) The multifocal electroretinogram. J Neuroophthalmol 23:225–235

    Article  Google Scholar 

  2. Bearse MA Jr, Ozawa GY (2014) Multifocal electroretinography in diabetic retinopathy and diabetic macular edema. Curr Diab Rep 14:526

    Article  Google Scholar 

  3. Reis A, Mateus C, Melo P, Figueira J, Cunha-Vaz J, Castelo-Branco M (2014) Neuroretinal dysfunction with intact blood-retinal barrier and absent vasculopathy in type 1 diabetes. Diabetes 63:3926–3937

    Article  CAS  Google Scholar 

  4. Tan W, Wright T, Dupuis A, Lakhani E, Westall C (2014) Localizing functional damage in the neural retina of adolescents and young adults with type 1 diabetes. Invest Ophthalmol Vis Sci 55:2432–2441

    Article  Google Scholar 

  5. Querques L, Parravano M, Sacconi R, Rabiolo A, Bandello F, Querques G (2017) Ischemic index changes in diabetic retinopathy after intravitreal dexamethasone implant using ultra-widefield fluorescein angiography: a pilot study. Acta Diabetol 54:769–773

    Article  CAS  Google Scholar 

  6. Simonett JM, Scarinci F, Picconi F, Giorno P, De Geronimo D, Di Renzo A, Varano M, Frontoni S, Parravano M (2017) Early microvascular retinal changes in optical coherence tomography angiography in patients with type 1 diabetes mellitus. Acta Ophthalmol 95:e751–e755

    Article  Google Scholar 

  7. Cao D, Yang D, Huang Z, Zeng Y, Wang J, Hu Y, Zhang L (2018) Optical coherence tomography angiography discerns preclinical diabetic retinopathy in eyes of patients with type 2 diabetes without clinical diabetic Retinopathy. Acta Diabetol 55:469–477

    Article  Google Scholar 

  8. Scarinci F, Picconi F, Giorno P, Boccassini B, De Geronimo D, Varano M, Frontoni S, Parravano M (2018) Deep capillary plexus impairment in patients with type 1 diabetes mellitus with no signs of diabetic retinopathy revealed using optical coherence tomography angiography. Acta Ophthalmol 96:e264–e265

    Article  Google Scholar 

  9. Wright T, Cortese F, Nilsson J, Westall C (2012) Analysis of multifocal electroretinograms from a population with type 1 diabetes using partial least squares reveals spatial and temporal distribution of changes to retinal function. Doc Ophthalmol 125:31–42

    Article  Google Scholar 

  10. Fortune B, Schneck ME, Adams AJ (1999) Multifocal electroretinogram delays reveal local retinal dysfunction in early diabetic retinopathy. Invest Ophthalmol Vis Sci 40:2638–2651

    CAS  PubMed  Google Scholar 

  11. Robinson R, Barathi VA, Chaurasia SS, Wong TY, Kern TS (2012) Update on animal models of diabetic retinopathy: from molecular approaches to mice and higher mammals. Dis Model Mech 5:444–456

    Article  CAS  Google Scholar 

  12. Arroba AI, Alcalde-Estevez E, García-Ramírez M, Cazzoni D, de la Villa P, Sánchez-Fernández EM, Mellet CO, García Fernández JM, Hernández C, Simó R, Valverde ÁM (2016) Modulation of microglia polarization dynamics during diabetic retinopathy in db/db mice. Biochim Biophys Acta 1862:1663–1674

    Article  CAS  Google Scholar 

  13. Arroba AI, Valverde ÁM (2017) Modulation of microglia in the retina: new insights into diabetic retinopathy. Acta Diabetol 54:527–533

    Article  Google Scholar 

  14. Bogdanov P, Corraliza L, Villena JA, Carvalho AR, Garcia-Arumí J, Ramos D, Ruberte J, Simó R, Hernández C (2014) The db/db mouse: a useful model for the study of diabetic retinal neurodegeneration. PLoS One 9:e97302

    Article  Google Scholar 

  15. Bearse MA Jr, Adams AJ, Han Y, Schneck ME, Ng J, Bronson-Castain K, Barez S (2006) A multifocal electroretinogram model predicting the development of diabetic retinopathy. Prog Retin Eye Res 25:425–448

    Article  Google Scholar 

  16. Harrison WW, Bearse MA Jr, Ng JS, Jewell NP, Barez S, Burger D, Schneck ME, Adams AJ (2011) Multifocal electroretinograms predict onset of diabetic retinopathy in adult patients with diabetes. Invest Ophthalmol Vis Sci 52:772–777

    Article  Google Scholar 

  17. Adhikari P, Marasini S, Sah RP, Joshi SN, Shrestha JK (2014) Multifocal electroretinogram responses in Nepalese diabetic patients without retinopathy. Doc Ophthalmol 129:39–46 (ErratumDoc Ophthalmol 129:47)

    Article  Google Scholar 

  18. Hare WA, Ton H (2002) Effects of APB, PDA, and TTX on ERG responses recorded using both multifocal and conventional methods in monkey. Doc Ophthalmol 105:189–222

    Article  Google Scholar 

  19. Tyrberg M, Ponjavic V, Lövestam-Adrian M (2005) Multifocal electroretinography (mfERG) in insulin dependent diabetics with and without clinically apparent retinopathy. Doc Ophthalmol 110:137–143

    Article  Google Scholar 

  20. Santos AR, Ribeiro L, Bandello F, Lattanzio R, Egan C, Frydkjaer-Olsen U, García-Arumí J, Gibson J, Grauslund J, Harding SP, Lang GE, Massin P, Midena E, Scanlon P, Aldington SJ, Simão S, Schwartz C, Ponsati B, Porta M, Costa M, Hernández C, Cunha-Vaz J, Simó R, European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR) (2017) Functional and structural findings of neurodegeneration in early stages of diabetic retinopathy: cross-sectional analyses of baseline data of the EUROCONDOR project. Diabetes 66:2503–2510

    Article  CAS  Google Scholar 

  21. Laron M, Bearse MA Jr, Bronson-Castain K, Jonasdottir S, King-Hooper B, Barez S, Schneck ME, Adams AJ (2012) Association between local neuroretinal function and control of adolescent type 1 diabetes. Invest Ophthalmol Vis Sci 53:7071–7076

    Article  Google Scholar 

  22. Parisi V, Uccioli L, Parisi L, Colacino G, Manni G, Menzinger G, Bucci MG (1998) Neural conduction in visual pathways in newly-diagnosed IDDM patients. Electroencephalogr Clin Neurophysiol 108:490–496

    Article  CAS  Google Scholar 

  23. Parisi V, Uccioli L (2001) Visual electrophysiological responses in persons with type 1 diabetes. Diabetes Metab Res Rev 17:12–18

    Article  CAS  Google Scholar 

  24. Di Leo MA, Caputo S, Falsini B, Porciatti V, Greco AV, Ghirlanda G (1994) Presence and further development of retinal dysfunction after 3-year follow up in IDDM patients without angiographically documented vasculopathy. Diabetologia 37:911–916

    Article  Google Scholar 

  25. Kim SJ, Song SJ, Yu HG (2007) Multifocal electroretinogram responses of the clinically normal retinal areas in diabetes. Ophthalmic Res 39:282–288

    Article  Google Scholar 

  26. Klemp K, Larsen M, Sander B, Vaag A, Brockhoff PB, Lund-Andersen H (2004) Effect of short-term hyperglycemia on multifocal electroretinogram in diabetic patients without retinopathy. Invest Ophthalmol Vis Sci 45:3812–3819

    Article  Google Scholar 

  27. Klemp K, Sander B, Brockhoff PB, Vaag A, Lund-Andersen H, Larsen M (2005) The multifocal ERG in diabetic patients without retinopathy during euglycemic clamping. Invest Ophthalmol Vis Sci 46:2620–2626

    Article  Google Scholar 

  28. Bronson-Castain KW, Bearse MA Jr, Neuville J, Jonasdottir S, King-Hooper B, Barez S, Schneck ME, Adams AJ (2012) Early neural and vascular changes in the adolescent type 1 and type 2 diabetic retina. Retina 32:92–102

    Article  Google Scholar 

  29. Cascavilla ML, Parisi V, Triolo G, Ziccardi L, Borrelli E, Di Renzo A, Balducci N, Lamperti C, Bianchi Marzoli S, Darvizeh F, Sadun AA, Carelli V, Bandello F, Barboni P (2018) Retinal dysfunction characterizes subtypes of dominant optic atrophy. Acta Ophthalmol 96:e156–e163

    Article  CAS  Google Scholar 

  30. American Diabetes Association (2018) Classification and diagnosis of diabetes: standards of medical care in diabetes—2018. Diabetes Care 41:S13–S27

    Article  Google Scholar 

  31. Early Treatment Diabetic Retinopathy Study research group (1985) Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol 103:1796–1806

    Article  Google Scholar 

  32. Early Treatment Diabetic Retinopathy Study Research Group (1991) Grading diabetic retinopathy from stereoscopic color fundus photographs—an extension of the modified Airlie House classification. ETDRS report number 10. Ophthalmology 98:786–806

    Article  Google Scholar 

  33. Parisi V, Perillo L, Tedeschi M, Scassa C, Gallinaro G, Capaldo N, Varano M (2007) Macular function in eyes with early age-related macular degeneration with or without contralateral late age-related macular degeneration. Retina 27:879–890

    Article  Google Scholar 

  34. Parisi V, Tedeschi M, Gallinaro G, Varano M, Saviano S, Piermarocchi S, CARMIS Study Group (2008) Carotenoids and antioxidants in age-related maculopathy Italian study: multifocal electroretinogram modifications after 1 year. Ophthalmology 115:324–333

    Article  Google Scholar 

  35. Parisi V, Ziccardi L, Stifano G, Montrone L, Gallinaro G, Falsini B (2010) Impact of regional retinal responses on cortical visually evoked responses: multifocal ERGs and VEPs in the retinitis pigmentosa model. Clin Neurophysiol 121:380–385

    Article  Google Scholar 

  36. Parisi V, Ziccardi L, Centofanti M, Tanga L, Gallinaro G, Falsini B, Bucci MG (2012) Macular function in eyes with open-angle glaucoma evaluated by multifocal electroretinogram. Invest Ophthalmol Vis Sci 53:6973–6980

    Article  Google Scholar 

  37. Hood DC, Greenstein VC (2003) Multifocal VEP and ganglion cell damage: applications and limitations for the study of glaucoma. Prog Retin Eye Res 22:201–251

    Article  Google Scholar 

  38. Kurtenbach A, Langrova H, Zrenner E (2000) Multifocal oscillatory potentials in type 1 diabetes without retinopathy. Invest Ophthalmol Vis Sci 41:3234–3241

    CAS  PubMed  Google Scholar 

  39. Laron M, Bearse MA Jr, Bronson-Castain K, Jonasdottir S, King-Hooper B, Barez S, Schneck ME, Adams AJ (2012) Interocular symmetry of abnormal multifocal electroretinograms in adolescents with diabetes and no retinopathy. Invest Ophthalmol Vis Sci 53:316–321

    Article  Google Scholar 

  40. Bronson-Castain KW, Bearse MA Jr, Neuville J, Jonasdottir S, King-Hooper B, Barez S, Schneck ME, Adams AJ (2009) Adolescents with Type 2 diabetes: early indications of focal retinal neuropathy, retinal thinning, and venular dilation. Retina 29:618–626

    Article  Google Scholar 

  41. Ng JS, Bearse MA Jr, Schneck ME, Barez S, Adams AJ (2008) Local diabetic retinopathy prediction by multifocal ERG delays over 3 years. Invest Ophthalmol Vis Sci 49:1622–1628

    Article  Google Scholar 

  42. Cunha-Vaz J, Ribeiro L, Lobo C (2014) Phenotypes and biomarkers of diabetic retinopathy. Prog Retin Eye Res 41:90–111

    Article  CAS  Google Scholar 

  43. Picconi F, Parravano M, Ylli D, Pasqualetti P, Coluzzi S, Giordani I, Malandrucco I, Lauro D, Scarinci F, Giorno P, Varano M, Frontoni S (2017) Retinal neurodegeneration in patients with type 1 diabetes mellitus: the role of glycemic variability. Acta Diabetol 54:489–497

    Article  CAS  Google Scholar 

  44. Kaidonis G, Gillies MC, Abhary S, Liu E, Essex RW, Chang JH, Pal B, Sivaprasad S, Pefkianaki M, Daniell M, Lake S, Petrovsky N, Hewitt AW, Jenkins A, Lamoureux EL, Gleadle JM, Craig JE, Burdon KP (2016) A single-nucleotide polymorphism in the MicroRNA-146a gene is associated with diabetic nephropathy and sight-threatening diabetic retinopathy in Caucasian patients. Acta Diabetol 53:643–650

    Article  CAS  Google Scholar 

  45. Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820

    Article  CAS  Google Scholar 

  46. Kowluru RA, Koppolu P, Chakrabarti S, Chen S (2003) Diabetes-induced activation of nuclear transcriptional factor in the retina, and its inhibition by antioxidants. Free Radic Res 37:1169–1180

    Article  CAS  Google Scholar 

  47. Iglicki M, Zur D, Busch C, Okada M, Loewenstein A (2018) Progression of diabetic retinopathy severity after treatment with dexamethasone implant: a 24-month cohort study the ‘DR-Pro-DEX Study’. Acta Diabetol 55:541–547

    Article  CAS  Google Scholar 

  48. Hood DC, Frishman LJ, Saszik S, Viswanathan S (2002) Retinal origins of the primate multifocal ERG: implications for the human response. Invest Ophthalmol Vis Sci 43:1673–1685

    PubMed  Google Scholar 

  49. Carnevali A, Sacconi R, Corbelli E, Tomasso L, Querques L, Zerbini G, Scorcia V, Bandello F, Querques G (2017) Optical coherence tomography angiography analysis of retinal vascular plexuses and choriocapillaris in patients with type 1 diabetes without diabetic retinopathy. Acta Diabetol 54:695–702

    Article  CAS  Google Scholar 

  50. Jonsson KB, Frydkjaer-Olsen U, Grauslund J (2016) Vascular changes and neurodegeneration in the early stages of diabetic retinopathy: which comes first? Ophthalmic Res 56:1–9

    Article  Google Scholar 

  51. Scarinci F, Picconi F, Virgili G, Giorno P, Di Renzo A, Varano M, Frontoni S, Parravano M (2017) Single retinal layer evaluation in patients with Type 1 diabetes with no or early signs of diabetic retinopathy: the first hint of neurovascular crosstalk damage between neurons and capillaries? Ophthalmologica 237:223–231

    Article  Google Scholar 

  52. Vujosevic S, Midena E (2013) Retinal layers changes in human preclinical and early clinical diabetic retinopathy support early retinal neuronal and Müller cells alterations. J Diabetes Res 2013:905058

    PubMed  PubMed Central  Google Scholar 

  53. Palmowski AM, Sutter EE, Bearse MA Jr, Fung W (1997) Mapping of retinal function in diabetic retinopathy using the multifocal electroretinogram. Invest Ophthalmol Vis Sci 38:2586–2596

    CAS  PubMed  Google Scholar 

  54. Cao J, McLeod S, Merges CA, Lutty GA (1998) Choriocapillaris degeneration and related pathologic changes in human diabetic eyes. Arch Ophthalmol 116:589–597

    Article  CAS  Google Scholar 

  55. Linsenmeier RA, Braun RD, McRipley MA, Padnick LB, Ahmed J, Hatchell DL, McLeod DS, Lutty GA (1998) Retinal hypoxia in long-term diabetic cats. Invest Ophthalmol Vis Sci 39:1647–1657

    CAS  PubMed  Google Scholar 

  56. Natarajan R, Bai W, Lanting L, Gonzales N, Nadler J (1997) Effects of high glucose on vascular endothelial growth factor expression in vascular smooth muscle cells. Am J Physiol 273:H2224–H2231

    CAS  PubMed  Google Scholar 

  57. Williams B, Gallacher B, Patel H, Orme C (1997) Glucose-induced protein kinase C activation regulates vascular permeability factor mRNA expression and peptide production by human vascular smooth muscle cells in vitro. Diabetes 46:1497–1503

    Article  CAS  Google Scholar 

  58. Sone H, Kawakami Y, Okuda Y, Kondo S, Hanatani M, Suzuki H, Yamashita K (1996) Vascular endothelial growth factor is induced by long-term high glucose concentration and up-regulated by acute glucose deprivation in cultured bovine retinal pigmented epithelial cells. Biochem Biophys Res Commun 221:193–198

    Article  CAS  Google Scholar 

  59. Lombardo M, Parravano M, Serrao S, Ducoli P, Stirpe M, Lombardo G (2013) Analysis of retinal capillaries in patients with type 1 diabetes and non-proliferative diabetic retinopathy using adaptive optics imaging. Retina 33:1630–1639

    Article  Google Scholar 

  60. Lombardo M, Parravano MC, Serrao S, Bocassini B, Varano M, Stirpe M, Lombardo G (2014) Adaptive optics imaging of parafoveal cones in type 1 diabetes. Retina 34:546–557

    Article  Google Scholar 

  61. Lombardo M, Parravano M, Serrao S, Ziccardi L, Giannini D, Lombardo G (2016) Investigation of adaptive optics imaging biomarkers for detecting pathological changes of the cone mosaic in patients with Type 1 diabetes mellitus. PLoS One 11:e015138

    Article  Google Scholar 

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Acknowledgements

The authors thank Dr. Valter Valli Fiore for technical help in executing electrophysiological recordings and for collecting data. The contribution by Fondazione Bietti in this paper was supported by the Ministry of Health and Fondazione Roma.

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Correspondence to Lucia Ziccardi.

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The authors declare that they have no conflict of interest. All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements, proprietary interest), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.

Ethical approval

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national, local ethics committee: Comitato Etico Centrale IRCCS Lazio, Sezione IFO/Fondazione Bietti, Rome, Italy) and with the Helsinki Declaration of 1975, as revised in 2008.

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Ziccardi, L., Parisi, V., Picconi, F. et al. Early and localized retinal dysfunction in patients with type 1 diabetes mellitus studied by multifocal electroretinogram. Acta Diabetol 55, 1191–1200 (2018). https://doi.org/10.1007/s00592-018-1209-9

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  • DOI: https://doi.org/10.1007/s00592-018-1209-9

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