Nonproliferative Diabetic Retinopathy (NPDR)
Diabetic retinopathy is a retinal vascular disorder characterized by typical microvascular funduscopic changes. These typical funduscopic lesions can be broadly characterized as either nonproliferative or proliferative retinopathy with varying degrees of severity in each subset. They can either precede or follow alterations in retinal function thereby highlighting the importance of timely examinations to detect incipient changes.

The characteristic fundus lesions associated with nonproliferative diabetic retinopathy include cotton wool spots, microaneurysms, dot and blot hemorrhages, retinal vascular caliber changes, hard exudate formation, retinal capillary closure, and macular edema. Microaneurysms represent saccular outpouchings of the retinal capillary bed. They can present as concentrated lesions in the posterior pole or with widespread distribution throughout the fundus. Their formation is nonspecific to diabetes and can occur in a variety of disorders including hypertension and sickle cell disease. Although their precise pathogenesis remains unknown, they are attributed to pericyte degeneration, endothelial cell proliferation, and retinal capillary closure. They represent the earliest clinical changes of the retinal vasculature in NRDR detectable with ophthalmoscopy. They are best detected with fluorescein angiography in which they typically surround areas of capillary nonperfusion.

In the earliest stages, the increase or decrease in microaneurysm formation can be used as an indicator for progression or regression of disease. The microaneurysm count at baseline examination can be used as an important predictor of progression of diabetic retinopathy. They become visually significant when there is an associated leakage of serous contents leading to macular edema. Cotton wool spots represent retinal nerve fiber layer infarcts associated with stasis of axoplasmic flow. They occur early in the course of NPDR and may be evident prior to the development of microaneurysms and retinal hemorrhages. They are evanescent in nature, usually resolving in several months though they may persist much longer. Their effect on visual acuity and the visual field is dependent on their size and location.

Although most commonly seen in diabetic retinopathy, they are also seen in a variety of retinal vascular disorders including hypertensive retinopathy, central retinal vein occlusion, and drug toxicities such as with interferon retinopathy. The presence of intraretinal microvascular abnormalities and capillary permeability may lead to the formation of retinal hemorrhages. The morphology of the hemorrhages is related to the topography of the anatomical retinal layer from which they are derived. Superficial hemorrhages assume a flame-shaped appearance due to the parallel arrangement of the nerve fiber layer to the retinal surface. Deeper hemorrhages assume a dot-andblot appearance due to the perpendicular arrangement of cells in the deeper retinal tissue. Occasionally, these hemorrhages may attain a white center, representing fibrin deposition. White-centered hemorrhages are more commonly seen in other conditions such as subacute bacterial endocarditis and acute leukemia. Intraretinal hemorrhages are significant in that they generally parallel the severity of NPDR. Intraretinal hemorrhages are not typically visually significant unless they assume a subfoveal location. Intraretinal microvascular abnormalities or IRMA are evident in NPDR.

They represent dilated vascular segments in a partially occluded capillary bed and represent intraretinal neovascularization or the formation of  shunts in areas on nonperfusion. They are clinically significant in that they may leak and cause macular edema and impart a greater risk for the development of PDR. The venous caliber abnormalities in NPDR include vascular dilation, beading, and the formation of loops. They are indicative of retinal ischemia, and may be associated with central or branch retinal venous occlusions, which are both seen more commonly in the diabetic population. The primary mechanism of visual loss in nonproliferative retinopathy is through macular edema. The edema can be a result of focal vascular leakage from microaneurysms in the macular, or via diffuse vascular leakage. The edema may be associated with hard exudates or cystoid changes in the macula. If the edema is classified as clinically significant macular edema (CSME), as outlined by the ETDRS, focal laser photocoagulation is performed to avoid precipitous vision loss. Laser photocoagulation is directed at microaneurysms for focal leakage and is applied in a grid pattern for diffuse leakage. Concomitant cardiovascular and renal disease leading to fluid retention and hypertension can further exacerbate the edema. Treatment, therefore, of systemic abnormalities using a multidisciplinary approach should be included in the care of the patient with macular edema. NPDR can be classified into mild, moderate, and severe forms, with each imparting its own degree of severity and progression to proliferative retinopathy. Mild NPDR is characterized by microaneurysms only and impart a 5% risk of developing PDR in 1 year (Fig. 21.1(1)).

Moderate NPDR is characterized by less than four quadrants of scattered microaneurysms and hemorrhages along with cotton wool spots, venous beading, or IRMA (Fig. 21.1(2)). The risk of progression to PDR within 1 year is between 12 and 27%.55 Patients with mild and moderate NPDR are treated by medically optimizing glycemic control and any associated hypertension or dyslipidemia. Patients with clinically significant macular edema are treated with focal laser therapy. These patients are not candidates for scatter laser photocoagulation. Severe NPDR is characterized by the “4-2-1” rule of four quadrants of hemorrhages and microaneurysms, two quadrants of venous caliber abnormalities, or one quadrant of IRMA (Fig. 21.1(3)). These patients are at high risk for developing PDR with a 52% risk within 1 year. These patients are candidates for panretinal photocoagulation (PRP) the timing of which is determined at the discretion of the retinal specialist.

Fig. 21.1 Stages of nonproliferative diabetic retinopathy. Mild NPDR (1) with few dot-blot hemorrhages and intraretinal lipid. Redfree photograph of moderate NPDR (2) depicting a greater number of dot-blot hemorrhages and microaneurysms with associated lipid exudation. Severe NPDR (3) characterized by extensive four quadrant distribution of intraretinal hemorrhages and lipid along with infarctions of the nerve fiber layer (cotton wool spots)

Proliferative Diabetic Retinopathy (PDR)
Proliferative diabetic retinopathy is an advanced form of diabetic retinopathy characterized by the growth of abnormal blood vessels, which extend over the surface of the retina and along the “scaffold” provided by the posterior vitreous hyaloid. These new blood vessels may present as neovascularization of the optic disc (NVD) or anywhere along the retinal periphery (NVE), vitreous hemorrhage, and fibrous proliferation. Active neovascularization commonly occurs at the border of perfused and nonperfused retina and is most severe in eyes with extensive nonperfusion. The newly formed vessels are fragile commonly resulting in vitreous hemorrhage and precipitous vision loss. The formation of new blood vessels in PDR occurs as a consequence of progressive damage to the retinal blood vessels in NPDR.

Eventually, with cumulative damage, there is capillary occlusion resulting in a relative oxygen deficient or ischemic environment. This results in the release of various angiogenic growth factors, the most significant of which is believed to be vascular endothelial growth factor or VEGF. VEGF release serves as the stimulus for the proliferation of new vessels resulting in NVD, NVE, and potential neovascularization within the anterior chamber along the surface of the iris. Neovascularization along the iris surface most commonly occurs at the pupillary margin and is significant in that these fine arborizing vessels can progress along the iris margin and into the trabecular meshwork accompanied by a fibrous membrane. Subsequent contracture of the fibrous membrane leads to synechiae within the trabecular meshwork and secondary angle closure glaucoma. Clinicians treating PDR assess for the presence of new vessels, their location, and severity when determining the timing of panretinal photocoagulation. Early PDR is that which does not meet the criteria for high-risk PDR. Patients with early PDR have a 75% risk of developing high-risk PDR within a 5-year period. Patients with early PDR and severe NPDR may require treatment with early PRP. Initiation of PRP should be considered for patients with severe NPDR with any new vessels or early PDR with elevated new vessels or NVD. High-risk PDR is characterized by any of the following:
1. NVD 1/4–1/3 disc area or more in size (Fig. 21.2(1))
2. NVD less than 1/4 disc area in size with concurrent vitreous hemorrhage
3. NVE greater than or equal to 1/2 disc area in size with concurrent vitreous hemorrhage

(Fig. 21.2(2).Patients with high-risk characteristics require prompt treatment with laser photocoagulation to prevent further progression of retinopathy. Patients with advanced PDR may require vitrectomy surgery to clear an otherwise non-clearing vitreous hemorrhage. Vitreous hemorrhage may occur as a result of vitreous traction on new vessels (Fig. 21.2(3)). Contracture of the vitreous or fibrovascular proliferation can result in the shearing of a new vessel, and subsequent vitreous hemorrhage. In time, retinal neovascularization may become fibrotic, contract, and lead to tractional retinal detachment (Fig. 21.2(4)). The fibrovascular proliferation in PDR typically occurs along the temporal vascular arcades and on the optic disc and may exhibit tractional forces resulting in macular striae and edema. The tractional retinal detachments that result can involve or spare the macula. They may be associated with both atrophic and tractional retinal breaks resulting in a combined rhegmatogenous-tractional retinal detachment. Patients with posterior tractional retinal detachments not involving the macula may be observed without vitrectomy surgery and can be stable for years. Upon encroachment of the macula, however, tractional retinal detachments can result in profound visual compromise and are therefore an indication for prompt vitrectomy. These tractional forces may be relieved with pars plana vitrectomy utilizing segmentation and delamination techniques

Fig. 21.2 Sequelae of proliferative diabetic retinopathy. Color photographs depicting neovascularization of the optic disc or NVD
(1) and neovascularization elsewhere in the retinal periphery or NVE (2). Note the development of preretinal hemorrhage in the
subhyaloidal space with progression of PDR (3). Severe proliferation of tractional membranes resulting in detachment of the macula;
tractional retinal detachment (4)

Fluorescein Angiography
Fluorescein angiography is a technique for examining the integrity of the retinal circulation using the dye-tracing method. Sodium fluorescein dye is injected into an antecubital vein and then an angiogram is obtained with multiple sequential photographs to monitor dye transit. Sodium fluorescein is a yellow-red dye with a molecular weight of 376. Daltons with a spectrum of absorption at 465–490 nm (blue wavelength) and excitation at 520–530 nm (yellow-green wavelength). The angiogram is performed with a camera with exciter and barrier filters that allow for the illumination of the retina with blue light because only yellow-green light (from the fluorescence) can reach the camera. The dye is metabolized within the liver and kidney within 24–36 h turning the patient’s urine a yellow-green color. The most common adverse reactions to fluorescein dye are mild including nausea, vomiting, and pruritus and are typically transient. However, severe reactions requiring immediate intervention such as bronchospasm and anaphylaxis can occur and must be monitored. Although there are no adverse effects reported during pregnancy, all efforts are undertaken to avoid fluorescein angiography unless deemed critical in directing diagnosis and management.

Fluorescein angiography is an invaluable tool that aids in the diagnosis and directs management in diabetic retinopathy. By allowing the clinician to identify the spectrum of funduscopic changes prevalent in diabetic retinopathy, fluorescein angiography can be used to monitor the severity of retinopathy and identify risk factors for progression. Various angiographic risk factors have been identified including fluorescein leakage, capillary dilation, and capillary loss.Diabetic retinopathy can result in both hyper- and hypofluorescent patterns of angiography and their distinction and interpretation are essential in identifying treatable lesions. In the setting of clinically significant macular edema (CSME), angiography is utilized to better identify leaking microaneurysms, which may appear as either focal or diffuse areas of permeability (Fig. 21.3(1)).

Fig. 21.3 Fluorescein angiographic characteristics. Early frame of fluorescein angiography (1) highlighting multiple areas of hyperfluorescence corresponding to microaneurysms which demonstrate prominent leakage in the late frame (2). Late frame fluorescein angiogram showing an area of hyperfluorescence along the supero-temporal arcade corresponding to retinal neovascularization and within the macula representing pronounced leakage from the perifoveal capillaries (3). Multiple areas of hyperfluorescence in the late frame angiogram (4) representing fronds of active retinal neovascularization. Hypofluorescent areas (4) seen temporally and superiorly represent ischemic zones of capillary non-perfusion

Treatment with laser photocoagulation then can be directed to the selected microaneurysms or to a cluster of microaneurysms in a grid pattern with diffuse permeability alterations (Fig. 21.3(2)). Marked ischemia can result in areas of capillary closure within the macula potentially limiting vision or further peripherally. These vascular filling defects are well delineated on angiography as hypofluorescent patches representing nonperfused segments (Fig. 21.3(4)). Furthermore, angiography can be used to identify and monitor leaf-like formation of new blood vessels referred to as fronds of neovascularization along the optic disc or elsewhere in the retinal periphery. Areas of neovascularization are easily identified in the early frames of the angiogram and exhibit late hyperfluorescence signaling leakage of dye from these newly formed, incompetent vessels (Fig. 21.3(3)). Other high-risk vascular abnormalities such as IRMA are clearly demonstrated with angiography. The use of fluorescein angiography is essential as an adjunct to clinical ophthalmoscopy in the diagnosis and management of diabetic retinopathy.

Optical Coherence Tomography (OCT)

Optical coherence tomography (OCT) captures reflected light from retinal structures to create a cross-sectional image of the retina. Optical coherence tomography (OCT) greatly enhances the ability to detect macular thickening and has brought new insights into the efficacy of various treatments. Use of this imaging modality allows for the quantitative measurement of macular thickness and objective analysis of the foveal architecture. OCT has gained widespread acceptance as an additional modality to help identify and evaluate macular pathology and allows for a reproducible way to monitor macular edema. The use of OCT with micrometer resolution was first devised by Huang et al. in 1991. The ability to obtain cross-sectional retinal images with micrometer resolution has allowed for better morphological tissue imaging  and analysis compared to other imaging modalities.

OCT utilizes the principle of low-coherence interferometry where distance information concerning various ocular structures is extracted from time delays of reflected signals. The interference pattern of light is measured over a distance of micrometers in OCT using broadband light sources. In OCT, interferometry is utilized in a noninvasive, noncontact manner to produce high-resolution crosssectional images of the retina. It is particularly useful in evaluating the extent of diabetic macular edema and in monitoring the efficacy of a given treatment (Fig. 21.4(1–4)). Topographic mapping protocol can be utilized for longitudinally monitoring and objectively quantifying the development of macular edema and for following the resolution of edema after laser treatment.

Novel Therapeutic Approaches

Various novel medical approaches in conjunction with laser photocoagulation are currently being explored for the treatment of diabetic retinopathy and diabetic macular edema. One such treatment is with ruboxistaurin, a selective PKC-b inhibitor. Hyperglycemia activates protein kinase C, and the beta-isoform of protein kinase C mediates early diabetes-induced microvascular complications, including diabetic macular edema. Animal models have suggested that ruboxistaurin ameliorates hyperglycemia-induced complications. Initial results of the 30-month data of the randomized Protein Kinase C-b Inhibitor Diabetic Macular Edema Study (PKC-DMES) indicated that treatment with 32 mg of ruboxistaurin daily did not reduce the risk of progression to sightthreatening diabetic macular  edema or focal/grid photocoagulation in diabetic patients. However, subgroupanalysis of the data revealed that those treated with ruboxistaurin daily appeared to have slower progression to sight-threatening diabetic macular edema than those taking placebo when the endpoint excluded photocoagulation, as different practitioners had different thresholds for initiating photocoagulation. Thus, the results of this clinical trial demonstrated that daily treatment with ruboxistaurin is an effective therapy for diabetic macular edema and diabetic retinopathy.

Pharmacologic inhibition of VEGF appears to be a promising strategy for diabetic retinopathy, in which breakdown of the blood–retina barrier and neovascularization play a prominent pathogenetic role. Introduction of VEGF into normal primate eyes induces the same pathologic processes as those seen in diabetic retinopathy, including microaneurysm formation and increased vascular permeability. Furthermore, elevated VEGF levels have been found from the analysis of vitreous samples from patients with diabetic macular edema. Therefore VEGF inhibition has garnered interest in ameliorating diabetic retinopathy and diabetic macular edema. Bevacizumab and ranibizumab (Genentech, Inc., South San Francisco, CA) have emerged as therapeutic options for age-related macular degeneration, with promising functional results. The rationale for evaluating their use is sound in treating patients with diabetic retinopathy and diabetic macular edema. Ranibizumab is a recombinant, humanized Fab fragment of mouse monoclonal antibody directed toward all isoforms of VEGF. Ranibizumab has been shown to significantly reduce foveal thickness and improve visual acuity in patients with diabetic macular edema. Bevacizumab is a humanized monoclonal antibody that inhibits all active isoforms of VEGF.

Intravitreal bevacizumab is a new treatment modality which is currently being tried out for use in macular edema following central retinal vein occlusion (CRVO), wet age-related macular degeneration (ARMD), rubeosis irides, proliferative diabetic retinopathy (PDR), and retinopathy of prematurity. The short-term results of various investigations demonstrate that bevacizumab is effective in improving visual acuity, reducing retinal thickness, and in causing regression of retinal and iris neovascularization in diabetic patients. Although these preliminary results are promising, the long-term outcomes from treatment with these agents remain unknown. Randomized, controlled, double-masked trials are needed to test whether intraocular injections of anti-VEGF agents provide long-term benefit to patients with DME. Further study will determine the long-term effects of pharmacologic therapies for DME and their potential utility as preventive treatments for this condition. The use of combination therapies may offer treatment advantages, particularly when the therapies approach the disease through different pathways. These novel therapeuticapproaches will likely be incorporated as adjuncts to laser photocoagulation in the future treatment of diabetic macular edema.

Fig. 21.4 Optical coherence tomography (OCT). OCT demonstrating persistent macular edema in a patient with diabetic retinopathy (1). Note the collection of cystic spaces throughout the retina. Following treatment with intravitreal bevacizumab at monthly intervals there is progressive resolution of the macular edema at 1 month (2), and 2 months (3) from baseline with ultimate restitution of the normal foveal architecture at the 3-month interval (4)

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