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Ocular System

Diabetic retinopathy (DR)

Microvascular disorder occurring due to long term effects of diabetes, leading to vision-threatening damage to the retina, eventually leading to blindness

Microvascular disorder occurring due to long term effects of diabetes, leading to vision-threatening damage to the retina, eventually leading to blindness

  • M/C retinopathy
  • M/C cause of adult vision loss and blindness
  • M/C complication of diabetes mellitus (DM)

History:

Professor Eva Kohner exemplifies a tradition of doing the right thing for patients with diabetes. She exemplified this approach whether in the context of clinical research trials such as the United Kingdom Prospective Diabetes Study, and in her discussions of individual patients. In addition, Professor Kohner has always supported the development of young investigators, so this lecture is presented jointly by a senior (TWG) and a younger investigator (JMS). Fig. 1 shows Professor Kohner surrounded by a large group of male colleagues at the 1968 Airlie House Symposium. The Airlie House Classification of diabetic retinopathy (Goldberg & Fine, 1969) was born at this symposium and became the forerunner of the Early Treatment Diabetic Retinopathy Study classification (Anonymous, 1991, Diabetic Retinopathy Study, 1981) that has formed the basis for the important diagnostic and therapeutic trials over the last 50 years. While this classification scheme has been extremely helpful, it was designed in an era when the essential questions were about the benefit of pituitary ablation for proliferative diabetic retinopathy, and when the benefits and risks of panretinal laser therapy for proliferative diabetic retinopathy were still debated, a decade before the Diabetic Retinopathy Study results were published. Therefore, the context was the need for a structure by which to address severe blinding retinopathy. The success of that classification now brings us to the 21st century when there is the opportunity and the need for better intervention of early stage disease before patients are at risk for losing vision. The first section of this presentation focuses on the clinical characterization of diabetic retinopathy and the quantification of structural and functional changes in diabetic retinopathy. This work and the associated concepts are the product of many investigators, notably Drs. David Antonetti, Steven Abcouwer, Patrice Fort and Gregory Jackson, who are investigating distinct aspects of the neurovascular unit and its alterations in diabetes.

Attendees at the 1968 Airlie House Symposium with Professor Eva Kohner front and center
Attendees at the 1968 Airlie House Symposium with Professor Eva Kohner front and center | Goldberg, M. F., Fine, S. L. & Program U.S.P.H.S.D.a.A.C. (1969). Symposium on the Treatment of Diabetic Retinopathy: Airlie House, Warreton, Virginia, September 29 to October 1, 1968. Washington, DC: Govt. Printing Office.

Etiopathogenesis

Diabetes (DM):

  • Duration of DM (M/imp factor)
  • Glycemic control (#2/imp factor)
  • More common in type 1 diabetes

Other risk factors:

  • Hypertension
  • Nephropathy
  • Hypercholesterolemia
  • Anaemia
  • Pregnancy
Main pathogenetic events in diabetic retinopathy: Schematic representation of the main pathogenetic events in the development and progression of diabetic retinopathy (DR) depicted from healthy (left) to advanced-stage DR (right). Non-proliferative DR is characterized by vascular changes such as thickening of the basement membrane, endothelial injury that leads to the disruption of the tight junctions and pericyte loss, resulting in dot haemorrhages, microaneurysms and hard exudates. Vascular endothelial growth factor (VEGF) and pro-inflammatory cytokine production (IL-1β, tumour necrosis factor, IL-6, IL-8 and monocyte chemoattractant protein 1) by the retinal pigment epithelium (RPE), glial cells and macrophages also contribute to the vascular changes. Endothelial damage leads to vasoconstriction owing to vasoconstrictor release (endothelin 1 and thromboxane A2) and hypoxia in pre-proliferative DR, which is aggravated owing to the capillary occlusion. The severe hypoxia in end-stage DR leads to neovascularization. These new blood vessels tend to grow into the vitreous body and are prone to rupture. | GCL, ganglion cell layer; ILM, inner limiting membrane; INL, inner nuclear layer; IPL, inner plexiform layer; NFL, nerve fibre layer; OLM, outer limiting membrane; ONL, outer nuclear layer; OPL, outer plexiform layer. | Wong, T., Cheung, C., Larsen, M. et al. Diabetic retinopathy. Nat Rev Dis Primers 2, 16012 (2016). https://doi.org/10.1038/nrdp.2016.12
A model of adaptive and maladaptive stages of diabetic retinopathy development: Within the first weeks to months of diabetes, the retina adapts to a lower metabolic steady-state with reduced electrical and biosynthetic activity, adaptive autophagy and apoptosis, and impaired autoregulation. Vision remains intact and there is no clinical evidence of diabetic retinopathy. After 5–10 years of diabetes, adaptive mechanisms begin to decompensate with the appearance of mild nonproliferative retinopathy, and early impairment of vision. Aberrant repair can ensue with the onset of proliferative retinopathy and loss of vision. Regulatory strategies are currently limited to the latter two stages | T.W. Gardner, J.R. Davila The neurovascular unit and the pathophysiologic basis of diabetic retinopathy Graefes Archive for Clinical and Experimental Ophthalmology, 255 (1) (2017), pp. 1-6

Presentation

Clinical stages and main pathogenetic events of diabetic retinopathy
Clinical stages and main pathogenetic events of diabetic retinopathy: The first pathological stage that can be identified in a fundoscopic examination is non-proliferative diabetic retinopathy (DR), which can be divided into mild, moderate or severe non-proliferative DR. Diabetic macular oedema can be considered a particular subtype of non-proliferative DR in which vascular leakage involves the macula. Pre-proliferative or severe non-proliferative DR is characterized by capillary closures and non-perfused areas. The typical fundoscopic finding is the presence of ‘cotton wool’ spots and intraretinal microvascular abnormalities. Proliferative DR, in which hypoxia has an essential role, is the final stage of DR and its hallmark is the development of neovascularization. Haemovitreous (that is, bleeding in the vitreous cavity) and retinal detachment are advanced complications of proliferative DR. | Wong, T., Cheung, C., Larsen, M. et al. Diabetic retinopathy. Nat Rev Dis Primers 2, 16012 (2016). https://doi.org/10.1038/nrdp.2016.12
Classification of diabetic retinopathy and diabetic macular oedema
Classification of diabetic retinopathy and diabetic macular oedema | Sim, D. A. et al. Patterns of peripheral retinal and central macula ischemia in diabetic retinopathy as evaluated by ultra-widefield fluorescein angiography. Am. J. Ophthalmol. 158, 144–153 (2014).

Non-proliferative diabetic retinopathy (NPDR):

Increased vascular permeability and capillary occlusion
  • Microaneurysms: First clinically detectable lesions of DR located in the inner nuclear layer of the retina
  • Dot and blot hemorrhages (located in middle retinal layers)
  • Exudates (previously known as hard exudates): Located between inner plexiform and inner nuclear layers
  • Vascular changes: Beading, looping and sausage like segmentation of the veins
  • Cotton wool spots/soft exudates/nerve fiber infarcts: Result from capillary occlusion of retinal nerve fiber layer
  • Intraretinal microvascular abnormalities (IRMA): Dilated capillaries that function as collateral channels, frequently seen adjacent to the areas of capillary closure
  • Retinal edema: Accumulation of fluid between outer plexiform layer and inner nuclear layer

Proliferative diabetic retinopathy (PDR):

Characterized by pathologic preretinal neovascularization
  • Severe vision impairment when the new abnormal vessels bleed into the vitreous (vitreous hemorrhage) or when tractional retinal detachment is present.

Diabetic macular edema (DME)

Arises from diabetes-induced breakdown of the blood-retinal barrier (BRB), with consequent vascular leakage of fluid and circulating proteins into the neural retina
  • M/C cause of vision loss in patients with DR
  • ETDRS classification:
    • Clinically significant macular edema (CSME)
    • Non-CSME


Diagnosis

Fundoscopy:

Clinical signs of diabetic retinopathy on fundoscopic examination
Clinical signs of diabetic retinopathy on fundoscopic examination: a | Mild non-proliferative diabetic retinopathy (DR) with microaneurysms and haemorrhage. b | Moderate non‑proliferative DR with microaneurysms, haemorrhage and cotton wool spots. c | Proliferative DR showing new blood vessels at the optic disc. d | Diabetic macular oedema showing hard exudates at the fovea centre | Wong, T., Cheung, C., Larsen, M. et al. Diabetic retinopathy. Nat Rev Dis Primers 2, 16012 (2016). https://doi.org/10.1038/nrdp.2016.12

Optical coherence tomography (OCT):

Optical coherence tomography showing treatment outcome for diabetic macular oedema
Optical coherence tomography showing treatment outcome for diabetic macular oedema: Optical coherence tomography (OCT) images of a patient with type 2 diabetes with diabetic macular oedema (DME). a | OCT image of a patient with vision of 6/45 (vision of 6/6 is considered normal vision and 6/60 is considered legal blindness in some countries) showing fluid accumulation in cystoid spaces before intravitreal injections of ranibizumab (an anti-vascular endothelial growth factor therapy) were started. b | Vision of 6/18 (that is, vision improved from 6/45 to 6/18) was observed after three intravitreal injections of ranibizumab. c | Vision of 6/9 (that is, vision improved from 6/18 to 6/9, almost normal vision) was observed after seven intravitreal injections of ranibizumab | Wong, T., Cheung, C., Larsen, M. et al. Diabetic retinopathy. Nat Rev Dis Primers 2, 16012 (2016). https://doi.org/10.1038/nrdp.2016.12

Management

Schematic overview of the management algorithm of diabetic macular edema | OCT, optical coherence tomography; VEGF, vascular endothelial growth factor. | Wong, T., Cheung, C., Larsen, M. et al. Diabetic retinopathy. Nat Rev Dis Primers 2, 16012 (2016). https://doi.org/10.1038/nrdp.2016.12

Intravitreal anti-VEGF therapy:

Mainstay treatment
  • Pegaptanib
  • Ranibizumab
  • Aflibercept
  • Bevacizumab

Panretinal photocoagulation (PRP):

Indicated in CSME and in PDR with HRC

Vitreoretinal surgery:

For cases of nonclearing vitreous hemorrhage from PDR or cases of PDR with tractional retinal detachment to relieve fibrous attachments that may be distorting the retina and causing vision loss or metamorphopsia
Diabetic retinopathy
Diabetic retinopathy. Nat Rev Dis Primers 2, 16013 (2016). https://doi.org/10.1038/nrdp.2016.13

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