Diabetic retinopathy (DR) is the leading cause of visual impairment worldwide. It almost accounts for 2.6% of treatable blindness globally (1). It is estimated that the overall prevalence of diabetic retinopathy is 34.6 % worldwide, while the prevalence of proliferative diabetic retinopathy (PDR) is 6.96% and that of vision-threatening DR (VTDR) is computed to be 10.2% (2).
Currently, the prevalence of PDR in India is estimated to be 17% which is significantly higher compared to patients from other locations of Asia (3). Early detection and treatment is the only key to avoiding complications and risks of vision loss (4). But the major obstacle ahead of us in India is the failure to diagnose DR in early stages; as it is observed that only 18–35% of diabetics undergo ophthalmologic evaluation regularly (5).
Pathogenesis
Diabetic retinopathy is recognized as a neuro-vascular complication of diabetes. The triad of hyperglycemia, inflammation, and hypoxia along with retinal neurodegeneration is responsible for the development of DR (6).
Hyperglycemia and Hypoxia
The major culprit in the development of DR is constant hyperglycemia that causes retinal microvascular damage in the form of dilatation of blood vessels and loss of pericytes, which leads to the formation of microaneurysms(6). Hence, microaneurysms are the earliest signs of DR. Another response of retinal blood vessels to hyperglycemia is the thickening of the basement membrane(7), which contributes to the impairment of the blood-retinal barrier. Loss of pericytes (8) along with thickened basement membrane, in turn, result in capillary occlusion and ischemia, leading to the upregulation of vascular endothelial growth factor (VEGF), an integral factor involved in the development of PDR in the form of the start of neovascularization.
Inflammation
Inflammation plays an essential role in the pathogenesis of DR. Leukostasis is also recognized as a key process in the early stages of DR. With an increased duration of diabetes, Leukostasis contributes to endothelial cell loss and eventually the breakdown of the blood-retinal barrier (BRB) and forms a leukocyte-endothelial adhesion complex. Chemokines& inflammatory cytokines which normally regulate the attraction and activation of leukocytes, also play a crucial role. Chemokines such as monocytes(9), chemotactic protein-1, macrophage inflammatory protein-1alpha(MIP-1) (10) & inflammatory cytokines such as TNF-α, IL-6, IL-8, and IL-1β are significantly up-regulated in diabetics, which in turn up-regulates VEGF production in the vitreous humor, marking the start of angiogenesis(11).
Retinal Neurodegeneration
Retinal neurodegeneration is an early event during the progression of DR. Retinal ganglion cells and amacrine cells are the first neurons to succumb to diabetes-induced apoptosis, followed by the photoreceptors (12). The structural consequence of this apoptotic death is the reduced thickness of the nerve fiber layer, which can be detected by optical coherence tomography (OCT) (13).
There is growing evidence that retinal neurodegeneration can be an independent entity in the development of DR and loss of ganglion cells along with thinning of retinal nerve fiber layer is observed way before microvascular alterations (14-15).
Therefore, hyperglycemia, inflammation, and hypoxia along with neurodegeneration play a collaborative role in the development of PDR. A better understanding of pathophysiology will facilitate an efficient and specific treatment and hold better prospects in the future. The cascade of events is shown in the chart below:
Risk factors
These can be identified beforehand to predict the severity of retinopathy, anticipate the findings and stage of retinopathy (2, 16).
Risk factors can be classified into (17-19):
Unmodifiable |
Modifiable |
Genetics |
Obesity |
Ethnicity |
Hypertension |
Family History |
Poor glycemic control |
Age |
Dyslipidemia |
Longer duration of disease |
Smoking |
Anemia |
Clinical features of PDR
Presence of new vessels is the hallmark of PDR
- Neovascularization of disc.
- Neovascularization elsewhere.
- Vitreous hemorrhage
- Sub-hyaloid hemorrhage (occasionally).
- Tractional retinal detachment, which is classified as follows:
- TRD involving the macula
- Extra-macular TRD.
- Neo-vascularization of iris, angle or neovascular glaucoma (NVG) (20).
High-risk PDR is defined as any one of the following:
1. NVD ≥ 1/3 disc area
2.Any NVD with vitreous hemorrhage
3. NVE ≥ ½ disc area with vitreous hemorrhage
High-risk PDR is also defined as three or more of the following high-risk characteristics:
1.Presence of vitreous hemorrhage or pre-retinal hemorrhage
2.Presence of any active neovascularization
3. Location of neovascularization on or within one disc diameter of the optic disc
4. NVD > 1/3 disc area or NVE > ½ disc area (21).
Investigations & Examination
Prior to investigations a thorough clinical examination is essential.
This includes: Routine vision assessment (UCVA, BCVA)
IOP measurement,
Anterior segment examination.
Posterior segment evaluation including:
1. Ophthalmoscopy. Direct or indirect ophthalmoscopy remains the mainstay for the diagnosis of diabetic retinopathy.
2. Fundus photography. It is an important tool for documentation and follow up. The traditional Early Treatment Diabetic Retinopathy Study (22), ETDRS fields have been the standard for determining severity of diabetic retinopathy for ages, which evaluates the lesion of retina, using 7 stereoscopic photographs per eye (23). The newer modalities of imaging are Widefield and Ultra-wide field which represent a major advancement in imaging. Extensive PDR lesions, captured by UWF imaging outside of ETDRS fields, carry a great prognostic value (24).
3. Fundus fluorescein angiography (FFA). FFA has been the gold standard investigation for retinal diseases. The dye has a unique property to absorb blue light (peak- 465to 490nm) and produce fluorescence at yellow-green wavelengths (520-530nm) (25).
With FFA, blood circulation of retinal vessels can be accurately understood by observing their state of fluorescence, thus discovering earlier pathologies not identified by ophthalmoscopy or slit-lamp biomicroscopy. Hyperfluorescence occurs because of vascular leakage or neovascularization & hypo or blocked fluorescence due to preretinal hemorrhage or vitreous hemorrhage.
It also detects an increase in the foveal avascular zone (FAZ) or subtle maculopathy. But the downside of it is its invasive nature and potentially serious side effects. Thus, not advisable in patients on dialysis, with kidney disease or other comorbidities (26).
Optical coherence tomography (OCT): Introduction of OCT in 1991 revolutionized visualization of the vitreoretinal interface. Its noninvasive nature with high reproducibility,the cross-section of the retina could be visualized at a glance and features that normally co-exist with PDR such as intraretinal cystic changes subretinal fluid, epiretinal membrane (ERM), vitreomacular traction or macular edema which could be missed on clinical examination if subtle
Optical coherence tomography angiography: OCTA is a promising noninvasive imaging modality. It allows visualization of the FAZ with high resolution, permitting detection of ischemic alterations, and layer-by-layer analysis of the different retinal vascular arcades. OCTA also provides a scan of the mid-periphery of the retina (figure 2), highlighting significant vascular alterations, such as neovascularization or ischemic areas (26-29).
USG B Scan: It is a valuable tool in the evaluation of eyes with vitreoretinal disorders with opaque media. As it is a dynamic scan, that evaluates the degree of mobility of the echoes corresponding to the vitreous membranes or the retina. Echoes can be classified as linear echoes representing vitreous membranes or retinal detachment and dot echoes corresponding to vitreous hemorrhage (30).
Management
A multimodal approach including lifestyle modifications, medical and surgical interventions can together prevent loss of vision due to PDR.
Some of the modalities are:
Lifestyle and dietary modifications
Nutrition plays an important role in controlling the progression of diabetes. Optimizing glycemic and lipid control is one of the first-line interventions in diabetics yet a much-neglected aspect. A balanced diet rich in omega-3, PUFAs, polyphenols, flavonoids, alkaloids, and anthocyanins is recognized as a healthy diet, and shown to have protective effects against DR and slows the progression to PDR (31-32).
Laser Photocoagulation.
Laser photocoagulation has been a mainstay for the treatment of PDR, because of long term suppressive effect on retinal neovascularization. Diabetic Retinopathy Study (DRS) Research Group showed that Pan Retinal Photocoagulation (PRP) could reduce severe vision loss in PDR by more than 50% during a two year period (21).
Indications of PRP mainly are (33):
High-risk PDR
NVD
NVI or NVA
Pre proliferative retinopathy in the other eye.
In our set up, PRP (fig-2) is performed via a slit lamp laser delivery system with approx 1200-1500, 200-micronburns, separated by the width of a burn starting with the inferior quadrant first. Normally three to four such sessions are done depending upon the severity of PDR.
Some of the complications of PRP are: Pain, Vitreous hemorrhage, decreased visual field, accidental foveal burn, macular edema, raised IOP (34). Recent developments in laser such as sub-threshold, semi‐automated patterned scanning laser, navigated laser with rapid application of multiple laser spots with shorter pulse duration have lesser complications as compared to the conventional laser delivery system. (35).
Anti-VEGF drugs
Though PRP has been the mainstay for treatment of PDR for a long time now, its destructive nature and visual field constriction associated; has led to the exploration of alternative strategies. The inhibition of VEGF has emerged as a promising treatment modality in the treatment of PDR.
DRCR.net Protocol S study evaluated efficacy and safety of ranibizumab versus PRP for 2 years and concluded that though the primary outcome of visual acuity was similar in both groups, the VEGF arm had better preserved peripheral vision (36).
It also has been reported that VEGF-treated eyes show the reduced retinal thickness and lesser chances of needing vitrectomy in the future (37-38).
Aflibercept, also known as the VEGF trap, when compared with PRP proved to be more effective, showing a higher proportion of total regression of new vessels than with PRP (39).
In another significant study, PROTEUS Study (40), which compared the efficacy of ranibizumab plus PRP versus PRP alone in patients with high-risk PDR over a 12-month period, concluded that combination treatment delivered better visual acuity and anatomical outcome. As anti-VEGF provides additional benefit when macular edema co-exists with PDR.
We feel that, in the Indian scenario, customization of treatment approaches by offering either PRP alone or in combination with Anti -VEGF therapy based on patient compliance and socioeconomic considerations is necessary.
In addition, Anti-VEGFs, are also being used preoperatively to reduce intraoperative and postoperative bleeding, surgical time, and chances of resurgery in complex cases such as macula-involving TRD with active NV or vitreous hemorrhage with extensive rubeosis (41-42).
Vitrectomy
Pars plana vitrectomy as a surgical treatment for PDR was first described more than 40 years ago. PPV offers relief from vitreoretinal traction and stabilizes the vasoproliferative process. The Diabetic Retinopathy Vitrectomy Study (DRVS) showed the superiority of timely surgical intervention over observation in preserving the vision (43).
Indications for PPV are:
- Non-Resolving vitreous hemorrhage,
- Retinal detachment involving or threatening the macula.
- Combined RD (TRD with RRD).
- Pre-macular traction with macular edema.
- Epiretinal membrane with macular edema.
Key surgical steps in vitrectomy are:
Core vitrectomy after sclerotomy sites |
Opening of the posterior hyaloid and removal of hemorrhage |
Membrane peeling |
Control of bleeding |
Endolaser or Cryotherapy |
Intraoculartamponade, if needed |
After a good vitrectomy, many factors define the visual gain prognostication of the surgery (44-45).
FAVORABLE FACTORS |
UNFAVORABLE FACTORS |
The brief duration of detachment |
Initial poor VA |
Presence of previous PRP |
Macular ischemia |
Absence of vitreous hemorrhage |
DME |
ERM |
|
NVG or NVI |
These unfavorable factors can manifest as poor visual or anatomical outcomes and many times needing revision surgery for non-resolving vitreous hemorrhage, re-detachment or development of ERM.
According to the DRIVE UK Study, patients requiring revision vitrectomy, 47.2% were because of re-detachment, 38.9% for non-resolving vitreous hemorrhage, and 13.9% for epiretinal membrane. Further analysis showed that 18.60% of eyes with TRD as the primary presentation had revision surgery as compared to 36.8% who presented with a combination of TRD and VH as the primary presentation (46).
The technique and instrumentation of vitrectomy have refined over the years, the size of the vitrectomy port has reduced from 20 gauge to 25 MIVS, now to 27 gauge. Smaller gauge instruments with higher cutting rates facilitate better dissection and shaving of fibrovascular membranes, while significantly reducing the operating time, postoperative recovery period with added patient comfort (47-48). Along with reduced incidences of postoperative hypotony, scleral wound leakage, and endophthalmitis (49). With the development and use of smaller gauge instrumentation for vitrectomy, a trend shift towards earlier surgical intervention is observed that will be helpful in decreasing the therapeutic and monetary burden of monthly intravitreal injections (50).
But, in spite of all these advancements in the treatment, prevalence, and vision loss due to PDR is still not under control. Hence newer advancements in aspects of investigations, medical and operative techniques are the need of the hour for patient-specific and tailor-made treatment approaches.
Newer developments:
- Since the introduction of OCT, it has been groundbreaking in the visualization of the vitreoretinal interface. Cross-section of the retina can be visualized at a glance. To integrate this technology into the standard operating microscope is phenomenal. Microscope-integrated iOCT enables easy visualization of peripheral retinal lesions or breaks that could be missed preoperatively and enables identification of tissue planes beneath fibrovascular membranes especially in cases of TRD with VH. The iOCT system provides real-time feedback to the surgeon during the procedure which helps in the timely alteration of the surgical steps for a better surgical outcome (51-53).
- Use of artificial intelligence in medicine in an evolving technology which can be promising as a mass screening tool. DR is an ever-increasing problem, and the number of diabetics in the coming decades is expected to increase exponentially. As the patients seeking ophthalmologist opinions for DR are still very few. Early screening and timely treatment can reduce sight-threatening retinopathy and vision loss. Any tool which can aid in quick screening and minimize the requirement of trained human resources would be a boon for patients and ophthalmologists (54-55).
In conclusion, PDR management has to have a multi-disciplinary approach including ophthalmologists, diabetologists, and pathologists and a motivated patient ready to abide by the instructions to achieve a favorable outcome as a whole.
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