Diabetic Retinopathy (DR)

• The word diabetes mellitus comes from the Greek words “Diabetes” means “siphon” and mellitus which means “honey tested urine”.
• According to American Diabetes Association, the diagnosis of diabetes can be made in a person who symptomatic with polydipsia, polyphagia, polyuria, weight loss, and random plasma glucose level is >= 200 mg/dl and or fasting glucose level is >= 126 mg/dl.
• Diabetic retinopathy is a vascular complication of the disease and a leading cause of blindness worldwide.

Risk factors for the development of DR:

• Duration of diabetes
• Poor control of diabetes.
• Pregnancy
• Hypertension,
• Nephropathy
• Miscellaneous like hyperlipidemia, smoking, cataract surgery, obesity, and anemia.

Pathogenesis of DR:

Characteristic pathological Changes in DR are-

1. Pericyte Loss:

Abnormal pericytic deposition of material due to sorbitol or advanced glycation end products (AGEs) through the aldose reductase polyol pathway.

2. Basement Membrane (BM)Changes:

• Retinal Capillary Endothelium is covered by a BM, which is normally approx.0.5µ thick.
• In DR, there is an increase in the thickness of these Layers.
• This thickening may be as much as 5 folds, which results in impairment of diffusion & transfer of nutrients & metabolites.

3. Microaneurysms:

Microaneurysm is a microvascular abnormality which is characteristic but not pathognomic of DR.

Mechanism of formation of Microaneurysms:

• Pericyte loss --local weakening
• Alteration of the capillary BM
• The unrestricted proliferation of the vascular endothelial cells

4. Capillary Occlusions:

When a focal area loses its perfusion, the overlying retina suffers acute ischaemic changes, these occlusions ophthalmoscopically appears as cotton-wool spots (CWS), caused by the accumulation of axoplasmic debris n the nerve fiber layer of the ischaemic retina.

Microvascular dilatation is often found near areas of capillary obliteration & is called intraretinal microvascular abnormalities. (IRMA). IRMAs are shunts that run within the retina from arterioles to venules.

5. Neovascularization:

When a focal area loses its perfusion, the retina suffers ischemia. In response to ischemia changes the retina, retinal vessels or RPE cells secrete some vasoproliferative factors, which are thought to induce neovascularization. Some these vasoproliferative factors are:

• Vascular endothelial growth factor (VEGF),
• Platelet-derived growth factor
• Hepatocyte growth factor.

especially VEGF-A which inhibits the growth of retinal endothelial cells are implicated to induce neovascularization.

Clinical signs of DR:

Microaneurysms (MA)

• First ophthalmoscopically detectable signs of DR.
• Appears as small red dots with smooth borders & sharp edge
• FFA: tiny hyperfluorescent dots, typically more numerous than visible clinically & remain hyperfluorescent without any change in size. (hemorrhages appear as black spots due to blocked fluorescence)

• Microaneurysms are usually 12 to 100μm in size; those greater than 30μm is visible ophthalmoscopically. They are not to be larger than 125μm
• Hemorrhages are usually larger than 125μm (Early treatment DR Study)

Retinal hemorrhages:

Hard Exudates (HEs):

• HEs are a yellowish, well-circumscribed accumulation, deep to the retinal vessels in the outer plexiform nerve fiber layer.
• HE are formed by the deposition of lipid & lipoproteins and are the sign of abnormal vascular permeability
• Although HE can be found anywhere in the retina, they have a predilection to congregate in the macula. Pt may have moderate to severe loss of visual loss if the fovea is involved.
• HE occurs in two types of retinal distribution: -
• Circinate pattern: a complete or partial circle separated from the leaking vessels by a clear zone.
• Macular star: lipid accumulate in the fine layer of Henle surrounding the macula

Cotton-Wool Spots/Soft Exudates/Cytoid Bodies/Nerve Infarcts:

• Lie in the nerve fiber layers of retina.
• Represents ophthalmoscopic appearance of a microinfarct, their presence implies ischaemic microvascular disease.
• Appear initially as white fluffy patches, most commonly in the posterior pole (retinal nerve fibre layer is the thickest), become smaller & more circumscribed with time, absorbing completely after 6-8 weeks

Venous loops, venous beading:

• Indicative of extensive ischaemia of the retina and manifests as saccular bulges in the wall of the vein.
• Seen frequently adjacent to areas of nonperfusion.
• Reflects increasing retinal ischemia
• Most significant predictor of progression to PDR

Intraretinal microvascular abnormalities (IRMA)

• Often found on the borders of the nonperfused retina.
• Appears as fine, irregular, intraretinal vessels that run from arterioles to venules without crossing major blood vessels.
• FFA shows focal hyperfluorescence associated with adjacent capillary dropout areas but they don’t leak.

Diabetic maculopathy:

Abnormal permeability of the retinal vascular endothelial cells of capillaries, microaneurysm & IRMA ? extravasated lipoproteins accumulate in the extracellular space ? Retinal thickening

• Diagnosis of ME is made on the clinical finding of retinal thickening on slitlamp examination biomicroscopy using either a handheld or contact lens.
• The fluid is located between the outer plexiform and inner nuclear layers; however, it may also involve the inner plexiform and nerve fibre layers.
• Often further accumulation of fluid the fovea assumes a cystoid appearance known as cystoid macular edema.
• FFA and OCT are two important tools that are very helpful in management of diabetic maculopathy.
• FFA helps us to determine the extent of leakage as well as site of the leakage. OCT helps us to determine retinal thickening and cystoid spaces, if any. OCT is also helpful in assessment of response to treatment.
• Diabetic maculopathy can be further divided into:

Classification of DR:

The classification used in the Early Treatment Diabetic Retinopathy Study (ETDRS) is widely used internationally.

Clinically significant macular edema (CSME)

CSME can be defined as:

• Retinal thickening within 500 µm of the centre of the macula .
• Exudates within 500 µm of the centre of the macula, if associated with retinal thickening (which may be outside the 500 µm.
• Retinal thickening one disc area (1500 µm) or larger, any part of which is within one disc diameter of the centre of the macula.

Diabetic Proliferative retinopathy (PDR):

Approximately 50% of patients with very severe nonproliferative diabetic retinopathy progress to PDR within 1 year.

• Characterized by neovascularization, new vessels from retina & OD and proliferate along the retinal surface or into the vitreous with or without a fibrous component.
• Non-perfusion of at least more than one-fourth of the retina leads to the development of PDR.
• The main contributory factor for neovascularization appears to be retinal hypoxia which is clinically manifested by capillary closure & capillary drop out areas.
• The most important factor in retinal neovascularization is Vascular Endothelial Growth Factor (VEGF) which targets mainly vascular endothelial cells but can also act on RPE cells
• Three types of neovascularization of the tissues are observed in PDR:
• New vessels at the disc (NVD) refers to neovascularization on or within one disc diameter of the optic nerve head.
• New vessels elsewhere (NVE) refers to neovascularization in retina away from one disc diameter from the disc
• New vessels on the iris (NVI) or rubeosis iridis, carry a high likelihood of progression to neovascular glaucoma.
• FFA: early phases of the angiogram and shows hyperfluorescence during the later stages due to intense leakage of dye from neovascular tissue.
• Characteristics of new vessels in retina:
• All new vessels appearing in eye lack barrier properties and that's why leak fluorescein rapidly & intensively during FFA.
• New vessels are sight-threatening because they are fragile and tend to bleed to obscure the media
• They are associated with fibrosis & membrane formation which lead to traction retinal detachment

Management of Diabetic Retinopathy:

Note: This entire section on management of DR has been prepared keeping it in mind that the topic has been asked as a single question in the various examinations. However often questions are framed on a specific treatment modality like management of diabetic macular edema or PDR. In such cases it the time permits or marks allotted to that question demands, one can add the systemic control of diabetes in their write up.

Screening protocols:

A complete meticulous ophthalmic checkup is required in a diabetic patient and should include visual acuity, pupillary reactions, slit lamp examination with special attention to the presence and absence of NVI, IOP measurement and a detailed dilated fundus examination. Similarly, a proper history including duration of diabetes, information on past glycemic control of the disease, medications and a brief systemic history is very helpful.

The screening technique consists of:

• Dilated fundus examination: if performed properly this technique has a sensitivity of approx 80% and a specificity of 99% for the diagnosis of PDR.
• Stereoscopic fundus photography is an excellent tool for diagnosis, however mostly used for research purpose.
• Nonmydriatic fundus photography is used for mass screening.

Timing:

Follow up:

• Patients with minimal to no DR: annually
• Patients with mild to moderate DR without macular edema: 6-12 months
• Patients with severe nonproliferative DR: 3-4 months
• Patients with early proliferative disease & treatment is deferred: 2-3 months

Systemic control:

Hyperglycemia:

• It has been reported that every 1% reduction in HbA1C can cause approx. 35% reduction in the onset of retinopathy and its progression.
• Tight control of blood sugar level in type 1 patient has been reported to reduce the mean risk of retinopathy by 76 % and risk of progression by 54% (Diabetes Complications and Control Trial)

Blood pressure:Proper control of blood pressure helps to reduce microvascular complications in diabetes.

Hyperlipidemia: Treatment and medications (like statins) to reduce the serum lipid levels have been reported to show rapid resolution of hard exudates and to prevent the progression of DR.

Nephropathy: Diabetic nephropathy has a strong relationship with diabetic retinopathy. Proper control of albuminuria has been shown to affect the progression of DR.

Recommendations by the American Diabetic Association:

Management of a case of diabetic maculopathy or macular edema:

It can be discussed under the following heading:

A. Laser photocoagulation:

• All eyes with CSME should be treated with laser photocoagulation irrespective of the level of visual acuity, because treatment reduces the risk of visual loss by 50%. (ETDRS)
• Though in case of good visual acuity, many prefers to wait for spontaneous resolution with good glycemic control as the process of photocoagulation in such cases has its own limitation and complications.
• Photocoagulation is usually guided by FFA:
  • FFA helps to delineate the area and extent of leakage.
  • FFA also helps to detect ischaemic maculopathy,which carries a poor prognosis.(Severe form of macular ischaemia is a relative contraindication to treatment)
• The following lasers are used for the treatment of such condition
• Argon green (514.4nm) is most commonly used
• Frequency-doubled Nd: YAG (532nm) has the potential of a less destructive retinal effect than argon
• ‘Pattern Scan Laser’ (Pascal- frequency-doubled micropulse YAG )has single-shot mode or a predetermined array of up to 56 shots applied in less than a second.
• Micropulse diode laser in which short duration (microseconds) burns are applied
• Argon green and Nd: YAG is preferred as green light well absorbed by the melanin and hemoglobin.
• The treatment response is assessed after 3-4 months of laser therapy.
• In case of persistent CSME after 3 months of initial laser therapy, a repeat FFA is done and further laser procedures can be considered.
• CSME nonresponsive to more than 3 sessions of photocoagulations are considered recalcitrant and may require intravitreal pharmacotherapy.

Poor prognostic factors

Ocular factors include significant macular ischaemia, exudates involving the fovea, diffuse macular oedema, CMO and severe retinopathy at presentation.

Systemic factors include uncontrolled hypertension, renal disease, poorly-controlled blood glucose (elevated HbA1c levels).

B. Intravitreal pharmacotherapy:

B. Intravitreal pharmacotherapy:

Anti-VEGF agents:

• Four anti-VEGF agents are approved by FDA for ocular use: Pegaptanib sodium, Ranibizumab, Bevacizumab and Aflibercept
• Pegaptanib was the first anti-VEGF agent FDA approved for ocular use (approved for macular degeneration, it was also shown to have beneficial effects on DME and PDR) However, it is rarely used in the treatment of DR.

Intravitreal triamcinolone. The study described above also investigated the effect of intravitreal triamcinolone injection, finding that in pseudophakic eyes steroid injection followed by prompt laser may be as effective as ranibizumab at improving vision and reducing retinal thickening. However, there was a significant risk of an elevation of intraocular pressure. No corresponding visual benefit above laser was shown for phakic eyes, which also had a substantially increased rate of cataract surgery by 2 years.

C. Surgical approach: Pars plana vitrectomy

Indications:

1. Recalcitrant cases of diffuse macular edema with thick posterior hyaloid membrane.
2. Recalcitrant edema to both laser and intravitreal pharmacotherapy. It is believed that removal of vitreous, which is the reservoir of angiogenic and anti-angiogenic factors causing DR and CSME, will improve the progression of the DR and resolution of CSME.
3. Any traction causing macular edema

Pars plana vitrectomy may be indicated when macular oedema is associated with tangential traction from a thickened and taut posterior hyaloid. It has also been suggested that some eyes without a taut posterior hyaloid may benefit from vitrectomy. Clinically, a taut thickened posterior hyaloid is characterized by an increased glistening of the pre-macular vitreous face. FA typically shows diffuse leakage and prominent CMO, but OCT is usually the definitive assessment.

Lipid-lowering drugs may reduce the requirement for laser treatment, and studies are ongoing.

Management of a case of PDR:

Panretinal photocoagulation (PRP):

The procedure consists of photocoagulation to the all four retinal quadrants. The exact mechanism of action of the procedure is though not fully understood, some possibilities are:

• PRP decreases the production of vasoproliferative factors by converting some of the hypoxic retina to anoxic state.
• It is believed to stimulate the release of antiangiogenic factors from the retinal pigment epithelium.
• By thinning the retina, PRP increases oxygenation of the retina as it enables an increased diffusion of oxygen from the choroid and so decreases vasodilatation.

Indications

High-risk characteristics by ETDRS:

NVD> 1/3rd to 1/4th DD

NVD< 1/3rd to 1/4th DD with vitreous / preretinal haemorrhage

NVE with vitreous /preretinal haemorrhage

NVI

• PRP influences only the vascular component of the fibrovascular process. Eyes in which new vessels have regressed leaving only fibrous tissue should not be re-treated.
• If CSMO is also present, laser for this should preferably be carried out prior to PRP or at the same session; the intensity and amount of PRP should be kept to the lowest level likely to be effective, and may be spread over multiple sessions; adjunctive intravitreal steroid or an anti-VEGF agent may improve the outcome in this situation.
• Informed consent. Patients should be advised that PRP may occasionally cause visual field defects of sufficient severity to legally preclude driving a motor vehicle; they should also be made aware that there is some risk to central vision, and that night and colour vision may be affected.

PRP in PDR

In eyes with severe NVD, 3000 or more burns may be required. Occasionally complete elimination of NVD may be difficult but once the tips of the vessels start to undergo fibrosis they pose much less of a threat to vision.

Surgical Intervention

• Severe persistent vitreous haemorrhage
• Bilateral haemorrhage
• Progressive tractional RD threatening or involving the macula
• Combined tractional and rhegmatogenous RD
• Premacular subhyaloid haemorrhage,