Diabetic Retinopathy as a Predictor of Systemic Micro and Macrovascular Complications

During the ASRS 2020 virtual meeting, Bobeck S Modjtahedi, and coworkers presented a retrospective study examining patients with type 2 DM for new incidents of CVA, MI, or all-cause mortality within five years of the retinal grading, excluding patients with previously diagnosed CHF, CVA and/or MI, but evaluating for the risk associated with the severity of retinopathy in addition to the known risk factors of age, gender, race, smoking status, HTN, body mass index, duration of diabetes, and hemoglobin A1c. Although the overall rates were relatively low with 2.5% suffering an MI, 3.3% a CVA, and 5.5% dying within 5 years, the severity of diabetic retinopathy was independently associated with increased risk hazards ratios ranging from 1.2 to 1.3 with mild retinopathy to 1.72 to 2.34 for the events occurring in the presence of severe retinopathy (Modjtahedi, 2020). 

This report is in line with the current recognition of diabetes as an autoimmune disorder producing system wide oxidative and inflammatory injury of organ tissues along with microvascular injury and exacerbations of macrovascular disease. Tissue apoptosis occurs of pancreas beta cells, the central and peripheral nervous system, cardiac muscle, and kidney in line with the recognition of retinal neuron injury that occurs long before the traditionally recognized microvascular lesions (Sinclair, 2020, Barber, 1998, Bui, 2009, Coughlin, 2017, Gastinger, 2008, Kern. 2008, Meshi, 2018). While AI programs assist in the photographic screening of retinopathy and monitoring progression, they rely upon detection of the traditional microaneurysm, and microvascular changes with hemorrhages, overwhelmingly only following vision loss and are poor at detecting ischemic defects of the inner retina, the exudative components of vascular leakage within the mid-retina, and the abnormalities of the retinal pigment epithelium (Duh, 2017, Gulshan, 2016, Simó, 2018, Sinclair, 2006). More recently we have come to realize that retinal neuronal injury actually precedes the microangiopathy (Araszkiewicz, 2016, Gardner, 2017, Lynch, 2017, Simo, 2018, Villarroel, 2010) paralleling similar disease processes occurring within the other organs (Sinclair 2020). 

Because of the delayed screening identification of the retinopathy and relative poor monitoring, the treatments have been focused by participating ophthalmologists solely on the treatment modalities for the end stages of the disease — intravitreal injections and laser photocoagulation for severe retinal ischemia, leakage producing edema, and neovascularization — but with poor resultant vision recovery. Among other organs the detection of the disease process and its progression are similarly delayed with the treatments directed primarily toward the end stages before organ failure (renal failure, congestive heart failure, peripheral neuropathy). Desperately needed are systemic measurements of the diabetic inflammatory process that can be used to screen in the early stages and predict the course for the individual patient. Examinations have demonstrated associations with serum C reactive protein, Cyclooxygenase 2 , ICAM-1, N-epsilon carboxymethyl lysin, AGE’s, pentraxin 3, Calgranulin C, among others (Pusparajah, 2016), and, since the photographed retina is the window to the soul, we desperately need imaging methods that will detect the process and its progression, such as with PSVue or Annexin (Mazzoni, 2019, Cordeiro, 2017). This should not only provide for the improved application of systemic treatments that will retard the process systemically, such as with minocycline, pentoxifylline, or Tie2 activator, to name a few (Suchitra, 2016, Lopes de Jesus, 2008, Rubsam, 2018) but also with localized retinal treatment, such as with super-dense micropulse laser (Luttrull, 2012). In addition, hopefully this will provide for improved warning communication from the generalist physician or endocrinologist to the ophthalmologist as well as the reverse. The specialties can no longer be focused on their own endpoints of treatment but must collaborate.

References: 

1. Araszkiewicz A, Zozulinska-Ziolkiewicz D. Retinal Neurodegeneration in the Course of Diabetes-Pathogenesis and Clinical Perspective. Curr Neuropharmacol. 2016;14(8):805-809.

2. Barber AJ, Lieth E, Khin SA, Antonetti DA, Buchanan AG, Gardner TW. Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin. J Clin Invest. 1998 Aug 15;102(4):783-91.

3. Bui BV, Loeliger M, Thomas M, Vingrys AJ, Rees SM, Nguyen CT, He Z, Tolcos M. Investigating structural and biochemical correlates of ganglion cell dysfunction in streptozotocin-induced diabetic rats. Exp Eye Res. 2009 Jun;88(6):1076-83.

4. Cordeiro, M., Normando, E., Cardoso, M., Miodragovic, S., Jeylani, S., Davis, B., . . . Bloom, P. (2017). Real-time imaging of single neuronal cell apoptosis in patients with glaucoma. Brain, 140, 1757-1767. 

5. Coughlin BA, Feenstra DJ, Mohr S. Müller cells and diabetic retinopathy. Vision Res. 2017 Oct;139:93-100.

6. Duh EJ, Sun JK, Stitt AW. Diabetic retinopathy: current understanding, mechanisms, and treatment strategies. JCI Insight. 2017 Jul 20;2(14).

7. Gardner T., Davila J. (2017). The neurovascular unit and the pathophysiologic basis of diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol, 255(1), 1-6. doi:10.1007/s00417-016-3548-y.

8. Gastinger MJ, Kunselman AR, Conboy EE, Bronson SK, Barber AJ. Dendrite remodeling and other abnormalities in the retinal ganglion cells of Ins2 Akita diabetic mice. Invest Ophthalmol Vis Sci. 2008 Jun;49(6):2635-42.

9. Gulshan V, Peng L, Coram M, Stumpe MC, Wu D, Narayanaswamy A, Venugopalan S, Widner K, Madams T, Cuadros J, Kim R, Raman R, Nelson PC, Mega JL, Webster DR. Development and Validation of a Deep Learning Algorithm for Detection of Diabetic Retinopathy in Retinal Fundus Photographs. JAMA. 2016 Dec 13;316(22):2402-2410.

10. Kern TS,  Barber AJ. Retinal ganglion cells in diabetes. J Physiol, 586, (18), 4401– 4408, 2008

11. Lopes de Jesus CC, Atallah AN, Valente O, Moça Trevisani VF. Pentoxifylline for diabetic retinopathy. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD006693.

12. Luttrull JK, Dorin G. Subthreshold diode micropulse laser photocoagulation (SDM) as invisible retinal phototherapy for diabetic macular edema: a review. Curr Diabetes Rev. 2012 Jul 1;8(4):274-84.

13. Lynch SK, Abràmoff MD. Diabetic retinopathy is a neurodegenerative disorder.Vision Res. 2017 Oct;139:101-107.

14. Mazzoni, F., Muller, C., DeAssis, J., Leevy, W., & Finnemann, S. (2019). Non-invasive in vivo fluorescence imaging of apoptotic retinal photoreceptors. Nature Scientific Reports, E, 1-9. doi:10.1038/s41598-018-38363-z.

15. Suchitra K, Tarun P. (2016). Biochemical basis and emerging molecular targets to treat diabetic retinopathy. Internat J Clin and Biomed Res, 2(1), 41-49. 

16. Meshi, A., Chen, K. C., You, Q. S., Dans, K., Lin, T., Bartsch, D.-U., . . . Freeman, W. R. (2018). Anatomical and functional testing in diabetic patients without retinopathy. Retina, electronic, 1-10. 

17. Modjtahedi, BS, Wu, J, Luong, TQ, Fong, DS, Wansu, C, Severity of diabetic retinopathy as an independent  risk factor for cerebral vascular accidents, myocardial infarctions, and all-cause mortality, ASRS 2020, 

https://www.asrs.org/content/documents/diabetic-retino_july-10.pdf

18. Pusparajah, P., Lee, L., & Kadir, K. (2016). Molecular markers of diabetic retinopathy: Potential screening tool of the future. Front in Physiol, 7(200), 1-19. doi:10.3389/fphys.2016.00200

19. Rübsam A, Parikh S, Fort PE. Role of Inflammation in Diabetic Retinopathy. Int J Mol Sci. 2018 Mar 22;19(4).

20. Simó R, Stitt AW, Gardner TW. Neurodegeneration in diabetic retinopathy: does it really matter? Diabetologia. 2018 Sep;61(9):1902-1912.

21. Sinclair SH. Diabetic retinopathy: the unmet needs for screening and a review of potential solutions. Expert Rev Med Devices. 2006 May;3(3):301-13.

22. Sinclair, S., & Schwartz, S. (2020). Diabetic retinopathy-An underdiagnosed and undertreated inflammatory, neuro-vascular complication of diabetes Prime Archives in Endocrinology (Vol. Open Access: https://videleaf.com/diabetic-retinopathy-an-underdiagnosed-and-undertreated-inflammatory-neuro-vascular-complication-of-diabetes/, pp. 1-42). Hyderabad, India: Vide Leaf.

23. Suchitra K, Tarun P. (2016). Biochemical basis and emerging molecular targets to treat diabetic retinopathy. Internat J Clin and Biomed Res, 2(1), 41-49. 

24. Villarroel M, Ciudin A, Hernández C, Simó R. Neurodegeneration: An early event of diabetic retinopathy. World J Diabetes. 2010 May 15;1(2):57-64.

More from Op-Med