Diana L. Shechtman, OD, FAAO and Joseph J. Pizzimenti, OD, FAAO
Most individuals with diabetes mellitus (DM) will ultimately develop some degree of retinopathy.1,2 The earliest findings related to diabetic retinopathy (DR) are associated with the loss of capillary pericytes that in turn compromises the vessel wall, resulting in retinal leakage and ischemia.3,4 Pericytes are modified smooth muscle cells of the capillaries that help regulate retinal vascular flow.
These mural cells provide structural support for the capillaries’ endothelium and help constitute the retina’s inner blood retinal barrier. The loss of pericytes in DM contributes to decomposition of the endothelial barrier function, leading to a weakening of the capillaries, resulting in increased blood flow out of the vessel. 2 The initial clinical sign associated with this process is “outpouching(s)” of the capillary wall, known as microaneurysms (MAs). Although MAs may be noted using fundoscopic evaluation alone, fluorescein angiography (FA) can help to further assess the location and amount of vascular leakage.
Ruptured MAs and leaking capillaries manifest as intraretinal edema, exudates, and hemorrhages. Diabetic retinopathy is often associated with intraretinal hemorrhages, shaped as dots or blots. In addition to hemorrhages, yellow lipoprotein deposits (known as exudates) can also collect within the inner retinal layers and outer plexiform layer. Due to the loss of vascular support, arteriole occlusion may lead to small areas of focal infarctions, known as a cotton wool spot (CWS). Cotton wool spots represent swelling within the nerve fiber layer due to interruption of the axoplasmic flow. As the disease progresses, more severe signs can develop including venous beading and intraretinal microvascular abnormalities (IRMA). These findings indicate an enhanced risk for progression to proliferative diabetic retinopathy (PDR).
Intraretinal microvascular abnormalities represent dilated and tortuous capillaries found where no vasculature is typically observed. These fine branching capillaries may be misdiagnosed as neovascularization. Unlike neovascularization, IRMA does not represent “new” vasculature growth; it is a remodeling of the pre-existing capillaries. Thus, unlike neovascularization, IRMA will not leak profusely on an FA. In addition, IRMAs develop within the retinal layers, they will not cross over major retinal vessels or develop at the optic disc. In the presence of IRMA, there is a 15% chance of progression towards PDR within a year.5
Venous beading (VB) is a focal irregularity in the caliber of retinal veins, described as a “sausage-like” segmented venule dilation. Venous beading is commonly associated with areas of capillary dropout and retinal nonperfusion. Therefore, VB is the strongest predictor for the development of neovascularization PDR.6
Proliferative retinopathy is characterized by new vessel formation (neovascularization), affecting both the retina and optic disc. Neovascularization is a result of hypoxia, microangiopathy, and capillary occlusion. Neovascularization represents new vessel growth, and consists of fenestrated vasculature, causing extensive leakage on FA. This leakage is often described as a “hot spot” of hyperfluorescence. The lack of endothelial tight junctions predisposes neovascularization towards spontaneous bleeding. Thus, progression of neovascularization can lead to preretinal or vitreous hemorrhage (VH).7 In a patient with DM or signs associated with DR, neovascularization is always suspected in the presence of preretinal or VH, even if the neovascularization is not clearly evident fundoscopically. Proliferative retinopathy is exacerbated by a concomitant proliferation of contractile fibrous tissue, as well as vitreoretinal traction. The contraction of the fibrous tissue associated with the new vascular growths can lead to a tractional retinal detachment (TDR). In addition to the posterior segment, neovascularization may occur anteriorly, in the iris or anterior chamber angle, which may result in neovascular glaucoma (NVG). Complications associated with PDR are often linked to severe vision loss. If left untreated, 50% of patients with PDR will go blind within 5 years.8
Leakage from the perifoveal vessels may accumulate within the central macula, resulting in diabetic macular edema (DME). Accumulation of intraretinal fluid causes tissue thickening which may result in decreased visual acuity (VA).9
Diabetic macular edema manifests as swelling or thickening of the central retina. This may further be associated with intraretinal hemorrhages and/or exudates. Since the presence of DME may not necessarily be initially linked to decreased VA, all patients with exudates, hemorrhages, and/or MAs within or near the macula should be carefully evaluated for the presence of DME, regardless of the VA.
Increased prevalence of DME is linked to the duration of the disease, type of DM, as well as staging of DR.10 The Wisconsin Epidemiologic Study of Diabetic Retinopathy revealed that after 15 years of known diabetes, the prevalence of DME is approximately 20% in patients with type 1 DM, 25% in patients with type 2 DM who are taking insulin, and 14% in patients with type 2 DM who do not take insulin. In the United States, the prevalence of DME approaches 30% in adults who have had DM for 20 years or more. While the prevalence of DME in mild nonproliferative diabetic retinopathy (NPDR) is only 3%, it rises to 38% in eyes with moderate-to-severe NPDR, and 71% in eyes with PDR.11
Nonproliferative Diabetic Retinopathy
Nonproliferative diabetic retinopathy is characterized by a microangiopathy involving intraluminal, intramural, and extravascular damage. Signs associated with NPDR include dot and blot hemorrhages, MAs, IRMA, VB, hard exudates (lipid), CWS, and retinal edema. Most of these signs occur primarily within the posterior pole, but they may also affect the mid- and/or far-peripheral retina. NPDR is categorized as mild, moderate, or severe. The mild stage of the disease is depicted by the presence of MAs.6,12 CWS and/or the presence of intraretinal hemorrhages are associated with the moderate stage of the disease. The severe stage of the disease is described by applying the “4:2:1” rule.
Proliferative Diabetic Retinopathy
The hallmark of PDR is the formation of new blood vessels at the vitreoretinal interface or at the optic nerve. PDR is associated with extra-retinal fibrovascular proliferation that extends beyond the internal limiting membrane. The presence of vitreous/preretinal hemorrhage, neovascularization (NVI) of the optic nerve head/disc (NVD) or elsewhere on the retina (NVE), or anterior segment neovascularization are all sight-threatening complications of PDR.13
Neovascularization in PDR may be described as “sea fan” shaped in some cases. Fibrous tissue is often associated with longer-standing or severe neovascularization. Regression of the vessels with residual fibrovascular proliferation along the posterior hyaloid scaffold may be associated with further complications, such as TRD or combined tractional and rhegmatogenous RD. Given the fact that PDR may be asymptomatic, a careful dilated fundus examination performed at least once a year, is crucial in a patient with a history of DM.
Diabetic Macular Edema
Leakage from perifoveal vessels causes DME, which, if left untreated, may result in permanent central vision loss.14 Clinical findings in DME may be described as diffuse or focal edema localized subfoveally (center-involving) or outside the perifoveal center (noncenter-involving). DME may also be associated with cystoid macular edema (CME). Since DME can occur without VA problems, a careful stereoscopic evaluation of the macula is of utmost importance in a patient with a history of DM or signs associated with DR. Moreover, DME can occur at any stage of retinopathy and may be associated with either proliferative or nonproliferative disease. A subset of DME was defined by the ETDRS as clinically significant macular edema (CSME). CSME is defined as one or more of the following: thickening of the retina within 500 μm (or one-third of an optic disc diameter) of the center of the macula; hard exudates within 500 μm of the center of the macula with associated thickening of the adjacent retina; or at least 1 zone of retinal thickening greater than 1 optic disc diameter (DD) in size, any portion of which is within 1 DD of the center of the macula.6,13 CSME was found to be generally responsive to laser treatment, in order to decrease the chances of further vision loss.
Fluorescein angiography and optical coherence tomography (OCT) are valuable diagnostic imaging modalities for the evaluation of DME. OCT yields both qualitative and quantitative information about retinal morphology, thickness, and edema. OCT can be helpful in supporting a diagnosis of DME, represented by an increase in retinal thickening due to intraretinal fluid leakage, which appears as hyporeflective (dark) areas within the OCT cross section. This may be described as a “spongy like” swelling if the DME is diffuse. Thus, in cases where DME is suspected, a baseline OCT can aid in both the evaluation and even the monitoring of the case. OCT can be especially valuable in evaluating the efficacy of treatment or in the identification of possible recurring edema following treatment. Reimbursement issues preclude a routine baseline OCT in patients with DM without a specific objective or suspicion of DME.
Given the fact that the incidence of DM is on the rise, eye care professionals will be seeing more patients with DR. Patients with DM may not understand the importance of undergoing regular dilated retinal examinations or recognize the benefits of early detection of diabetic eye disease. The National Health Survey data indicated that only about half of patients with DM obtained an annual dilated retinal examination.16 A comprehensive eye health exam becomes even more critical, given the fact that many patients may have signs of DR without any associated symptomology. DR is a treatable condition where patient education, early diagnosis, prompt intervention, and proper treatment are crucial aspects of the management plan.
Clinical Signs of Diabetic Eye Disease
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