Diabetic Retinopathy Current Concepts and Emerging Therapy Daniel F. Rosberger,
MD, PhD, MPH
a,b
KEYWORDS Diabetic retinopathy Anti-VEGF therapy Intravitreal medications Microvascular complications of diabetes Laser photocoagulation KEY POINTS The epidemiology of diabetic retinopathy indicates that although diabetes remains the leading cause of blindness among Americans, tight glucose control and lifestyle modification can reduce its prevalence. Although laser photocoagulation remains the mainstay of treatment of both proliferative diabetic retinopathy and clinically significant macular edema, the paradigm is shifting toward treatment with intravitreal medications. Emerging therapy with anti–vascular endothelial growth factor agents, long-acting corticosteroids, protein kinase C inhibitors, tumor necrosis factor modulators, and other medications may dramatically improve the treatment of diabetic retinopathy in the coming years. The Diabetes Retinopathy Clinical Research Network is a National Institutes of Health– funded collaborative network of more than 300 physicians dedicated to multicenter clinical research of diabetic retinopathy, diabetic macular edema, and associated conditions.
INTRODUCTION
Diabetic retinopathy is a disease that eventually affects nearly all patients with longstanding diabetes mellitus. The earliest visualized lesions are generally intraretinal hemorrhages and microaneurysms. With progression, fibrovascular proliferation and neovascularization can occur. Visual loss eventually results from macular edema, macular ischemia from capillary nonperfusion, vitreous hemorrhage, fibrous distortion of the macula, neovascular glaucoma, and tractional or rhegmatogenous retinal detachments (RD). The Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) have clearly demonstrated that tight glucose control in both type 1 and type 2 diabetes can significantly delay the onset and progression of retinopathy. (Table 1 lists the commonly used abbreviations in diabetic retinopathy.) For both diabetic macular edema (DME) and proliferative diabetic
a Weill-Cornell Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA; b MaculaCare, PLLC, 52 East 72nd Street, New York, NY 10021, USA E-mail address: [email protected]
Endocrinol Metab Clin N Am 42 (2013) 721–745 http://dx.doi.org/10.1016/j.ecl.2013.08.001 0889-8529/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.
endo.theclinics.com
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Table 1 Commonly used abbreviations in diabetic retinopathy CSME
Clinically significant diabetic retinopathy
CWS
Cotton wool spot
DCCT
Diabetes Control and Complications Trial
DME
Diabetic macular edema
DRCR net
Diabetic Retinopathy Clinical Research network
DRS
Diabetic Retinopathy Study
ETDRS
Early Treatment Diabetic Retinopathy Study
FA
Fluorescein angiography
FVP
Fibrovascular proliferation
HR
High risk
IRH
Intraretinal hemorrhage
IVTA
Intravitreal triamcinolone acetonide
ma
Microaneurysm
NHR
Non–high risk
NPDR
Nonproliferative diabetic retinopathy
NVA
Neovascularization of the trabecular angle
NVD
Neovascularization of the optic disk
NVE
Neovascularization elsewhere (other than the optic disk)
NVG
Neovascular glaucoma
NVI
Neovascularization of the iris
OCT
Optical coherence tomography
POAG
Primary open angle glaucoma
PDR
Proliferative diabetic retinopathy
RD
Retinal detachment
SLE
Slit lamp examination
UKPDS
United Kingdom Prospective Diabetes Study
VH
Vitreous hemorrhage
WESDR
Wisconsin Epidemiologic Study of Diabetic Retinopathy
retinopathy (PDR), the mainstay of treatment has been laser photocoagulation. However, in the past few years, new agents and new delivery systems have been developed that are fundamentally changing the treatment paradigm. EPIDEMIOLOGY
Diabetic retinopathy remains one of the most common complications of chronic diabetes mellitus and the leading cause of new cases of blindness (defined by central visual acuity worse than 20/200) in the United States in people aged 20 to 74 years. An estimated 50 000 new cases of retinal neovascularization and macular edema occur yearly.1–3 Despite this, as many as half of the patients who would benefit from treatment remain untreated.4 The DCCT demonstrated a marked reduction in the development and progression of diabetic retinopathy in intensively treated type 1 diabetes compared with those treated conventionally.5–7 The UKPDS showed similar results in patients with type 2 diabeties.8 Much of what we know about the epidemiology of diabetic retinopathy in the United States comes from the Wisconsin Epidemiologic Study of Diabetic Retinopathy
Diabetic Retinopathy
(WESDR), which received its initial funding from the National Institutes of Health (NIH) in 1979. The primary aims of this study were to (1) describe the prevalence and severity of retinopathy and visual loss in people with diabetes and their relationship to other systemic complications and mortality, (2) quantitate the association of risk factors with retinopathy, and (3) provide information on health care delivery and quality of life in people with diabetes. Table 2 summarizes the baseline prevalence and disease severity in WESDR. In an 11-county region of southwestern Wisconsin, 452 of the 457 physicians who provided primary medical care to patients with diabetes participated by collecting lists of all the patients with diabetes they saw during the 1-year period from July 1, 1979 through June 30, 1980.9,10 A total of 10 135 patients were identified, and an initial sample of 2990 patients was selected for a baseline examination. The sample was divided into 2 groups. The first, type 1 diabetes, was referred to as younger onset and consisted of 1210 patients diagnosed with diabetes before 30 years of age who were taking insulin. The second group, referred to as older onset, consisted of a probability sample of 1780 patients taken from all eligible patients who were diagnosed with diabetes at 30 years of age or older with a postprandial serum glucose measurement of 11.1 mmol/L or more or a fasting serum glucose measurement of 7.8 mmol/L or more on at least 2 separate occasions. The older-onset group was further stratified by (1) the duration of diabetes (less than 5 years [576 patients], 5 to 14 years [579 patients], and greater than 15 years [625 patients]) and (2) insulin usage (824 patients were taking insulin and 956 were not). At the study initiation visit, approximately 70% of the younger-onset patients had some degree of diabetic retinopathy and 23% had PDR.11 In the older-onset arm, 70% of the patients taking insulin had some degree of retinopathy, whereas only 39% of the patients not taking insulin did. Moreover, 14% of the older-onset patients taking insulin and 3% of the patients who were not on insulin had PDR.12 Clinically significant macular edema (CSME) was present in approximately 6% of the younger-onset patients, 12% of the older-onset patients taking insulin, and 4% of the older-onset patients not taking insulin.13 A recent study analyzed a cross-sectional, nationally representative sample of the National Health and Nutrition Examination Survey 2005–2008 (n 5 1006).14 Among US adults with diabetes, the estimated prevalence of diabetic retinopathy and vision-threatening diabetic retinopathy was 28.5%. Retinopathy was slightly more
Table 2 Baseline prevalence and disease severity in the WESDR
Retinopathy Status
Younger Onset, (N 5 996)
Older Onset, Taking Insulin (N 5 673)
Older Onset, Not Taking Insulin (N 5 673)
None (%)
29.3
29.9
61.3
Mild NPDR (%)
30.4
30.6
27.3
Moderate and severe NPDR (%)
17.6
25.7
8.5
PDR without HR characteristics (%)
13.2
9.1
1.4
Proliferative with HR characteristics or worse (%)
9.5
4.8
1.4
CSME (%)
5.9
11.6
3.7
Abbreviations: CSME, clinically significant diabetic retinopathy; HR, high risk; NPDR, nonproliferative diabetic retinopathy.
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prevalent among men than women. Non-Hispanic blacks with diabetes had a higher crude prevalence than non-Hispanic whites of diabetic retinopathy (38.8% vs 26.4%) and vision-threatening diabetic retinopathy (9.3% vs 3.2%). Independent risk factors for the presence of diabetic retinopathy included male sex, higher hemoglobin A1c measurement, longer duration of diabetes insulin use, and higher systolic blood pressure. However, microvascular changes consistent with diabetic retinopathy can occur even before the diagnosis of diabetic retinopathy using current definitions. The Diabetes Prevention Program was a multicentered, randomized, controlled clinical trial that enrolled 3234 overweight participants that had elevated blood glucose levels but had not yet met the definitional criteria for diabetes. The study demonstrated that intensive lifestyle changes including a low-fat diet, weight loss, and increased physical activity could reduce the development of type 2 diabetes by 58% compared with placebo and that metformin (850 mg twice daily) lowered diabetes incidence by 31% compared with placebo. It also demonstrated that approximately 8% of these patients who were prediabetic already had diabetic retinopathy.15 PATHOGENESIS
The precise processes by which diabetes results in retinopathy are not completely understood; however, damage to the retinal microvasculature is clearly paramount. The molecular mechanism of microvasculature damage is likely multifactorial, with roles for hyperglycemia-induced polyol pathway activation, production of advanced glycation end products, oxidative stress, and activation of the diacylglycerol–protein kinase C (PKC) transcription pathway. Fig. 1 demonstrates the layers of the retina and the relationship of the retina to the overlying vitreous and the underlying retinal pigment epithelium (RPE). Abnormalities in most of these layers can be seen in diabetic retinopathy. Vasculature abnormalities are a prominent finding in diabetic retinopathy and can occur anywhere between the nerve fiber layer (NFL) and the outer plexiform layer. Early damage in diabetic retinopathy can be seen by light microscopic evaluation of retinal vessels as a reduction in the number of pericytes surrounding retinal capillary endothelial cells.16 Microaneurysms are the outpouching of these damaged capillaries. Microaneurysmal leakage likely plays a significant role in DME. Endothelial cell proliferation, deposition of excess basement membrane material, closing of the microaneurysm lumen, and loss of endothelial cells may lead to capillary dropout and ischemia. With progressive damage and capillary nonperfusion, arteriovenous shunts can form. Intraretinal microvascular abnormalities (IRMA) arise in areas of ischemia and can sometimes appear similar to neovascularization except that IRMA does not leak on fluorescein angiography, generally occur deeper in the retina, and are not present on the optic disk. Cotton wool spots (CWS) are seen in the NFL and under the internal limiting membrane (ILM). They are cytoid bodies and represent stasis of axoplasmic flow in the axons of ganglion cells in the NFL. Hard exudates are fat-filled, lipoidal histiocytes occurring in the outer plexiform layer. This exudation surrounds damaged retinal vasculature and microaneurysms and may appear in a circinate pattern. Venous dilatations are the result of abnormalities in the walls of retinal veins. Thickening of the capillary basement membranes and increased constriction at crossing points of retinal arteries and veins are also commonly seen. As the severity of the
Diabetic Retinopathy
Fig. 1. Layers of the retina and the relationship of the retina to the overlying vitreous and the underlying retinal pigment epithelium. (From [A] Herzlich AA, Patel M, Sauer TC, et al. Chapter 2: retinal anatomy and pathology. Retinal pharmacotherapy. Copyright Elsevier 2010; [B] The eye. Potter’s pathology of the fetus, infant and child. Copyright Elsevier 2007.)
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Fig. 1. (continued)
Diabetic Retinopathy
retinopathy progresses, beading of the retinal veins resulting from dilated venous walls and saccular aneurysmal dilatation occurs. The appearance of hemorrhages in the retina depends on the layer where the hemorrhage occurs. Intraretinal dot or blot hemorrhages occur in the inner retinal layer but can spread to the outer plexiform layer. They appear as dots because they are contained between the perpendicularly oriented cellular elements. Flame-shaped or splinter intraretinal hemorrhages spread out within the parallel elements of the NFL. Large confluent hemorrhages can involve all of the retinal layers and even break through the ILM into the vitreous space and into the subretinal space.7 Thickening of the ILM and posterior vitreous face can be seen in early retinopathy with progressive fibrotic attachment of the ILM to the vitreous as retinopathy advances with fibroblasts, fibrous astrocytes, myofibroblasts, and macrophages present in the ILM and the vitreous in patients with DME.17 Retinal neovascularization arises in regions of hypoxia, and it is thought to be mediated by the elaboration of vascular endothelial growth factor (VEGF). New blood vessels commonly arise from retinal venues at the margin of an area of capillary nonperfusion. Fibrovascular proliferation can break through the ILM and onto the surface of the retina and extend into the vitreous space. Rupture of these fragile neovascular vessels can cause extensive hemorrhage into the vitreous. As the fibrovascular process matures, fibrosis can occur on the surface of the retina causing macular distortion. With sufficient contraction, the neurosensory retina can be pulled up of the RPE creating a tractional RD. In extreme cases, the retina can rip, leading to a rhegmatogenous RD. DIAGNOSIS AND CLASSIFICATION
Despite the fact that the paradigm for treating diabetic retinopathy is moving away from laser photocoagulation (see discussion elsewhere in this article), the classification of retinopathy and, therefore, the timing of treatment and follow-up are still largely based on clinical trials of focal and panretinal laser photocoagulation. In general, diabetic retinopathy is classified as either nonproliferative (NPDR) or proliferative (PDR) based on the absence or presence of retinal vascular neovascularization. Macular edema can be present independently in either NPDR or PDR and is classified as absent, present, and clinically significant (CSME) or nonclinically significant. Correct classification is important because it gives us information about the preferred intervention and the risk of progression that will determine the appropriate follow-up. Immediate treatment is almost always recommended for macular edema once the threshold for clinical significance has been reached and for PDR once high-risk criteria are met. No treatment is generally recommended for NPDR in the absence of CSME. Classification is based on standard fundus photographs used in the Early Treatment Diabetic Retinopathy Study (ETDRS).18 NPDR Mild NPDR
Patients with mild NPDR have at least one microaneurysm; however, there are fewer intraretinal dot or blot hemorrhages than in the ETDRS standard photograph 2A (Fig. 2), and no other retinal abnormalities associated with diabetes are present. Patients with mild NPDR have only a 5% risk of progressing to PDR within 1 year and only a 15% risk of progressing to high-risk PDR necessitating panretinal laser photocoagulation within 5 years.7
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Fig. 2. Stereoscopic pairs of standard photograph 2A of the modified Airlie House classification of diabetic retinopathy illustrates a moderate degree of hemorrhages and microaneurysms. (From Aiello LM. Perspectives on diabetic retinopathy. Am J Ophthalmol 2003;136(1):131; with permission.)
Moderate NPDR
Patients with moderate NPDR have more microaneurysms or intraretinal hemorrhages than in the ETDRS standard photograph 2A (see Fig. 2) in one field; however, they are present in fewer than 4 quadrants of the retina. NFL infarctions (commonly referred to as CWS or soft exudates), undulations in the caliber of retinal veins (referred to as venous beading [VB]), and IRMA are present but less prominent than in the ETDRS standard photograph 8A (Fig. 3). Patients with moderate NPDR have a 12% to 27% risk of progressing to PDR within 1 year and a 33% 5-year risk of reaching the criteria for high-risk PDR.7 Severe NPDR
Patients with severe NPDR are defined by having one of the elements of the 4-2-1 rule. They have either 4 quadrants of intraretinal hemorrhages or microaneurysms greater than the ETDRS standard photograph 2A (see Fig. 2), 2 quadrants of significant VB, or 1 quadrant of IRMA greater than the ETDRS standard photograph 8A (see Fig. 3) and no retinal vascular neovascularization. Patients with severe NPDR have a 52% risk of progressing to PDR within 1 year and a 60% 5-year risk of reaching the criteria for high-risk PDR.7
Fig. 3. Stereoscopic pairs of standard photograph 8A of the modified Airlie House classification of diabetic retinopathy illustrates a moderate degree of IRMA. (From Aiello LM. Perspectives on diabetic retinopathy. Am J Ophthalmol 2003;136(1):131; with permission.)
Diabetic Retinopathy
Very severe NPDR
Patients with very severe NPDR have at least 2 of the elements of the 4-2-1 rule (defined earlier for severe NPDR) but have no retinal vascular neovascularization. They have a 75% risk of progressing to PDR within 1 year.7 PDR
PDR is characterized by neovascularization on the optic disk (NVD) or elsewhere (NVE) on the retina, hemorrhage present within the vitreous or trapped between the interface of the surface of the retina and the posterior margin of the vitreous body (subhyaloid hemorrhage), or fibrovascular proliferation, which can cause pulling on the retina sometimes leading to tractional or rhegmatogenous RD. PDR is defined as either early or high risk. Eyes with early PDR have a 75% 5-year risk of developing high-risk PDR. High-risk PDR is defined by the presence of NVD greater than approximately one-third of the area of the optic disk as defined by the ETDRS reference photograph 10 A (Fig. 4), or any NVD associated with vitreous or subhyaloid hemorrhage, or an area of NVE greater than one-half of the area of the optic disk with concomitant vitreous or subhyaloid hemorrhage. Early PDR includes all eyes that meet the criteria for PDR but do not meet the criteria for high risk.7 Macular Edema
Damage to the macula can occur at any level of NPDR or PDR. It may involve leakage of serosanguinous fluid from retinal vasculature damaged by diabetes or microaneurysms and result in a collection of intraretinal fluid within the macula causing the macula to become thickened or edematous. This damage may occur in a cystoid (not true cysts because there is no endothelial lining) pattern and may be associated with precipitated lipids sometimes referred to as hard exudates. Macular edema is usually defined as retinal thickening within 2 disk diameters (approximately 3 mm) of the center of the macula. Alternatively, macular damage can be the result of parafoveal capillary nonperfusion and ischemia with or without edema; fibrovascular traction on the macula causing wrinkling, distortion, or detachment of the macula; intraretinal or subhyaloid hemorrhage, which can cause a physical barrier to images reaching the macula; or the formation of macular holes. CSME
CSME is defined by the ETDRS as macular edema meeting one or more of the following 3 criteria: (1) retinal thickening occurring at or within 500 mm of the center
Fig. 4. Stereoscopic pairs of standard photograph 10A of the modified Airlie House classification of diabetic retinopathy illustrates a moderate degree of NVD. (From Aiello LM. Perspectives on diabetic retinopathy. Am J Ophthalmol 2003;136(1):131; with permission.)
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of the macula; (2) lipid precipitate deposition (hard exudates) with adjacent, associated retinal thickening at or within 500 mm of the center of the macula; or (3) a zone of retinal thickening of at least 1 disk area in size, any part of which is at or within 1 disk diameter (approximately 1.5 mm) of the center of the macula. Identifying CSME is important because patients with CSME were shown to benefit from focal laser photocoagulation in the ETDRS. Visual acuity was not a criterion for defining CSME. Although recommendations are evolving because of the increased use of intravitreal medications in the treatment of the neovascular and macular edema complications of diabetic retinopathy, recommendations for follow-up are still largely defined by the ETDRS findings regarding the progression of disease. Table 3 (progression and follow-up recommendations) summarizes the current standard recommendations regarding the appropriate follow-up of patients with various levels of retinopathy. DIAGNOSTIC MODALITIES FOR EVALUATION OF RETINOPATHY
The mainstay for diagnosis of diabetic retinopathy remains the clinical examination by a qualified examiner; however, additional diagnostic testing may often be helpful. The American Academy of Ophthalmology has developed preferred practice patterns related to the appropriate diagnosis and management of diabetic retinopathy.19 Visual acuity measurement with a standard Snellen or ETDRS chart is an easy, lowcost, and useful method of assessing visual function.20 But visual acuity was not a criterion for determining the need for laser photocoagulation in the ETDRS, and patients with extensive and sight-threatening retinopathy might maintain excellent visual acuity for periods of time. Slit lamp biomicroscopy of the anterior segment including the cornea, lens, and iris should be performed. In addition, the measurement of the intraocular pressure by any
Table 3 Risk and timing of progression of diabetic retinopathy Retinopathy Classification Mild NPDR ( ) CSME (1) CSME Moderate NPDR ( ) CSME (1) CSME
Risk of Progression to PDR in 1 y (%)
High-Risk PDR in 5 y (%)
5
15
12–27
Severe NPDR ( ) CSME (1) CSME
52
Very Severe NPDR ( ) CSME (1) CSME
75
Early PDR ( ) CSME (1) CSME
—
High-Risk PDR ( ) CSME (1) CSME
—
Recommended Follow-up
Treatment
Yearly 3 mo
No Yes
6 mo 3 mo
No Yes
4 mo 3 mo
Rarely Yes
3 mo 3 mo
Occasionally Yes
2–3 mo 2–3 mo
Occasionally Yes
2–3 mo 1–2 mo
Yes Yes
33
60
75
75
—
Diabetic Retinopathy
of several methods and gonioscopic evaluation of the iris and trabecular structures looking for signs of neovascularization of the iris and angle are necessary to diagnose primary open angle glaucoma, which may be more prevalent in patients with diabetes, and neovascular glaucoma, which is one of the most feared complications of PDR leading, in some cases, to uncontrollable increases in intraocular pressure and blindness. Stereoscopic slit lamp biomicroscopy, with the use of accessory lenses, is the preferred method for evaluating retinopathy of the posterior pole, including the optic disk and macula, as well as the retinal midperiphery.16 This technique allows for careful evaluation for the presence of macular edema, intraretinal hemorrhages, IRMA, CWS, VB, NVD, and NVE as well as epiretinal membranes and fibrovascular proliferation that can lead to tractional and rhegmatogenous RD. Binocular indirect ophthalmoscopy is used to examine the peripheral retina for NVE, vitreous hemorrhage, and RD. Alternatively, the peripheral retina can be examined with wide-angle or angledmirror lenses at the slit lamp. Dilation of the pupil is required to adequately assess the retina for the presence of retinopathy because only 50% of eyes have been shown to be accurately graded for retinopathy through undilated pupils.21 New scanning laser ophthalmoscopic imaging systems may improve visualization of the peripheral retina in undilated eyes. Ancillary testing, if used appropriately, can enhance the accuracy of diagnosis and improve patient care.14 Color fundus photography, often with stereoscopic imaging, may be a more reproducible technique than examination at the slit lamp for detecting retinopathy; but clinical examination is frequently superior for detecting macular edema and fine-caliber NVD and NVE. Photographic documentation of a previous examination, however, can be helpful in ascertaining disease progression, response to treatment, and can influence the decision as to whether or not to treat.22 Although it is not part of the routine evaluation of patients with diabetes, fluorescein angiography, in which 10% or 25% fluorescein sodium solution is rapidly injected intravenously, can be useful in identifying areas of macular and peripheral capillary nonperfusion; sources of capillary leakage, such as microaneurysms responsible for macular edema; and sometimes in visualizing subtle foci of IRMA and neovascularization. Fluorescein angiography is not needed to diagnose CSME or PDR because both of these are clinical diagnoses14; however, it is frequently used as a guide for the treatment CSME.19 Fluorescein angiography is a very safe procedure; but mild side effects, including nausea and vomiting, are not infrequent, and severe medical complications, including death (approximately 1 per 200 000 patients) can occur.23 Although adverse effects on the fetus have never been documented, fluorescein angiography is not generally recommended, other than in exceptional circumstances, during pregnancy because fluorescein dye can cross the placental barrier and enter the fetal circulation.24 B-scan ultrasonography can be very helpful in diagnosing RD in diabetic eyes with media opacities secondary to corneal clouding, cataracts, and most frequently vitreous hemorrhage. Ocular coherence tomography (OCT) provides cross-sectional imaging of the retina and macula, the vitreoretinal interface and epiretina, and the subretinal space.25 Time domain and, more recently, spectral domain instruments allow for high-resolution imaging (
MD, PhD, MPH
a,b
KEYWORDS Diabetic retinopathy Anti-VEGF therapy Intravitreal medications Microvascular complications of diabetes Laser photocoagulation KEY POINTS The epidemiology of diabetic retinopathy indicates that although diabetes remains the leading cause of blindness among Americans, tight glucose control and lifestyle modification can reduce its prevalence. Although laser photocoagulation remains the mainstay of treatment of both proliferative diabetic retinopathy and clinically significant macular edema, the paradigm is shifting toward treatment with intravitreal medications. Emerging therapy with anti–vascular endothelial growth factor agents, long-acting corticosteroids, protein kinase C inhibitors, tumor necrosis factor modulators, and other medications may dramatically improve the treatment of diabetic retinopathy in the coming years. The Diabetes Retinopathy Clinical Research Network is a National Institutes of Health– funded collaborative network of more than 300 physicians dedicated to multicenter clinical research of diabetic retinopathy, diabetic macular edema, and associated conditions.
INTRODUCTION
Diabetic retinopathy is a disease that eventually affects nearly all patients with longstanding diabetes mellitus. The earliest visualized lesions are generally intraretinal hemorrhages and microaneurysms. With progression, fibrovascular proliferation and neovascularization can occur. Visual loss eventually results from macular edema, macular ischemia from capillary nonperfusion, vitreous hemorrhage, fibrous distortion of the macula, neovascular glaucoma, and tractional or rhegmatogenous retinal detachments (RD). The Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) have clearly demonstrated that tight glucose control in both type 1 and type 2 diabetes can significantly delay the onset and progression of retinopathy. (Table 1 lists the commonly used abbreviations in diabetic retinopathy.) For both diabetic macular edema (DME) and proliferative diabetic
a Weill-Cornell Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA; b MaculaCare, PLLC, 52 East 72nd Street, New York, NY 10021, USA E-mail address: [email protected]
Endocrinol Metab Clin N Am 42 (2013) 721–745 http://dx.doi.org/10.1016/j.ecl.2013.08.001 0889-8529/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.
endo.theclinics.com
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Rosberger
Table 1 Commonly used abbreviations in diabetic retinopathy CSME
Clinically significant diabetic retinopathy
CWS
Cotton wool spot
DCCT
Diabetes Control and Complications Trial
DME
Diabetic macular edema
DRCR net
Diabetic Retinopathy Clinical Research network
DRS
Diabetic Retinopathy Study
ETDRS
Early Treatment Diabetic Retinopathy Study
FA
Fluorescein angiography
FVP
Fibrovascular proliferation
HR
High risk
IRH
Intraretinal hemorrhage
IVTA
Intravitreal triamcinolone acetonide
ma
Microaneurysm
NHR
Non–high risk
NPDR
Nonproliferative diabetic retinopathy
NVA
Neovascularization of the trabecular angle
NVD
Neovascularization of the optic disk
NVE
Neovascularization elsewhere (other than the optic disk)
NVG
Neovascular glaucoma
NVI
Neovascularization of the iris
OCT
Optical coherence tomography
POAG
Primary open angle glaucoma
PDR
Proliferative diabetic retinopathy
RD
Retinal detachment
SLE
Slit lamp examination
UKPDS
United Kingdom Prospective Diabetes Study
VH
Vitreous hemorrhage
WESDR
Wisconsin Epidemiologic Study of Diabetic Retinopathy
retinopathy (PDR), the mainstay of treatment has been laser photocoagulation. However, in the past few years, new agents and new delivery systems have been developed that are fundamentally changing the treatment paradigm. EPIDEMIOLOGY
Diabetic retinopathy remains one of the most common complications of chronic diabetes mellitus and the leading cause of new cases of blindness (defined by central visual acuity worse than 20/200) in the United States in people aged 20 to 74 years. An estimated 50 000 new cases of retinal neovascularization and macular edema occur yearly.1–3 Despite this, as many as half of the patients who would benefit from treatment remain untreated.4 The DCCT demonstrated a marked reduction in the development and progression of diabetic retinopathy in intensively treated type 1 diabetes compared with those treated conventionally.5–7 The UKPDS showed similar results in patients with type 2 diabeties.8 Much of what we know about the epidemiology of diabetic retinopathy in the United States comes from the Wisconsin Epidemiologic Study of Diabetic Retinopathy
Diabetic Retinopathy
(WESDR), which received its initial funding from the National Institutes of Health (NIH) in 1979. The primary aims of this study were to (1) describe the prevalence and severity of retinopathy and visual loss in people with diabetes and their relationship to other systemic complications and mortality, (2) quantitate the association of risk factors with retinopathy, and (3) provide information on health care delivery and quality of life in people with diabetes. Table 2 summarizes the baseline prevalence and disease severity in WESDR. In an 11-county region of southwestern Wisconsin, 452 of the 457 physicians who provided primary medical care to patients with diabetes participated by collecting lists of all the patients with diabetes they saw during the 1-year period from July 1, 1979 through June 30, 1980.9,10 A total of 10 135 patients were identified, and an initial sample of 2990 patients was selected for a baseline examination. The sample was divided into 2 groups. The first, type 1 diabetes, was referred to as younger onset and consisted of 1210 patients diagnosed with diabetes before 30 years of age who were taking insulin. The second group, referred to as older onset, consisted of a probability sample of 1780 patients taken from all eligible patients who were diagnosed with diabetes at 30 years of age or older with a postprandial serum glucose measurement of 11.1 mmol/L or more or a fasting serum glucose measurement of 7.8 mmol/L or more on at least 2 separate occasions. The older-onset group was further stratified by (1) the duration of diabetes (less than 5 years [576 patients], 5 to 14 years [579 patients], and greater than 15 years [625 patients]) and (2) insulin usage (824 patients were taking insulin and 956 were not). At the study initiation visit, approximately 70% of the younger-onset patients had some degree of diabetic retinopathy and 23% had PDR.11 In the older-onset arm, 70% of the patients taking insulin had some degree of retinopathy, whereas only 39% of the patients not taking insulin did. Moreover, 14% of the older-onset patients taking insulin and 3% of the patients who were not on insulin had PDR.12 Clinically significant macular edema (CSME) was present in approximately 6% of the younger-onset patients, 12% of the older-onset patients taking insulin, and 4% of the older-onset patients not taking insulin.13 A recent study analyzed a cross-sectional, nationally representative sample of the National Health and Nutrition Examination Survey 2005–2008 (n 5 1006).14 Among US adults with diabetes, the estimated prevalence of diabetic retinopathy and vision-threatening diabetic retinopathy was 28.5%. Retinopathy was slightly more
Table 2 Baseline prevalence and disease severity in the WESDR
Retinopathy Status
Younger Onset, (N 5 996)
Older Onset, Taking Insulin (N 5 673)
Older Onset, Not Taking Insulin (N 5 673)
None (%)
29.3
29.9
61.3
Mild NPDR (%)
30.4
30.6
27.3
Moderate and severe NPDR (%)
17.6
25.7
8.5
PDR without HR characteristics (%)
13.2
9.1
1.4
Proliferative with HR characteristics or worse (%)
9.5
4.8
1.4
CSME (%)
5.9
11.6
3.7
Abbreviations: CSME, clinically significant diabetic retinopathy; HR, high risk; NPDR, nonproliferative diabetic retinopathy.
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prevalent among men than women. Non-Hispanic blacks with diabetes had a higher crude prevalence than non-Hispanic whites of diabetic retinopathy (38.8% vs 26.4%) and vision-threatening diabetic retinopathy (9.3% vs 3.2%). Independent risk factors for the presence of diabetic retinopathy included male sex, higher hemoglobin A1c measurement, longer duration of diabetes insulin use, and higher systolic blood pressure. However, microvascular changes consistent with diabetic retinopathy can occur even before the diagnosis of diabetic retinopathy using current definitions. The Diabetes Prevention Program was a multicentered, randomized, controlled clinical trial that enrolled 3234 overweight participants that had elevated blood glucose levels but had not yet met the definitional criteria for diabetes. The study demonstrated that intensive lifestyle changes including a low-fat diet, weight loss, and increased physical activity could reduce the development of type 2 diabetes by 58% compared with placebo and that metformin (850 mg twice daily) lowered diabetes incidence by 31% compared with placebo. It also demonstrated that approximately 8% of these patients who were prediabetic already had diabetic retinopathy.15 PATHOGENESIS
The precise processes by which diabetes results in retinopathy are not completely understood; however, damage to the retinal microvasculature is clearly paramount. The molecular mechanism of microvasculature damage is likely multifactorial, with roles for hyperglycemia-induced polyol pathway activation, production of advanced glycation end products, oxidative stress, and activation of the diacylglycerol–protein kinase C (PKC) transcription pathway. Fig. 1 demonstrates the layers of the retina and the relationship of the retina to the overlying vitreous and the underlying retinal pigment epithelium (RPE). Abnormalities in most of these layers can be seen in diabetic retinopathy. Vasculature abnormalities are a prominent finding in diabetic retinopathy and can occur anywhere between the nerve fiber layer (NFL) and the outer plexiform layer. Early damage in diabetic retinopathy can be seen by light microscopic evaluation of retinal vessels as a reduction in the number of pericytes surrounding retinal capillary endothelial cells.16 Microaneurysms are the outpouching of these damaged capillaries. Microaneurysmal leakage likely plays a significant role in DME. Endothelial cell proliferation, deposition of excess basement membrane material, closing of the microaneurysm lumen, and loss of endothelial cells may lead to capillary dropout and ischemia. With progressive damage and capillary nonperfusion, arteriovenous shunts can form. Intraretinal microvascular abnormalities (IRMA) arise in areas of ischemia and can sometimes appear similar to neovascularization except that IRMA does not leak on fluorescein angiography, generally occur deeper in the retina, and are not present on the optic disk. Cotton wool spots (CWS) are seen in the NFL and under the internal limiting membrane (ILM). They are cytoid bodies and represent stasis of axoplasmic flow in the axons of ganglion cells in the NFL. Hard exudates are fat-filled, lipoidal histiocytes occurring in the outer plexiform layer. This exudation surrounds damaged retinal vasculature and microaneurysms and may appear in a circinate pattern. Venous dilatations are the result of abnormalities in the walls of retinal veins. Thickening of the capillary basement membranes and increased constriction at crossing points of retinal arteries and veins are also commonly seen. As the severity of the
Diabetic Retinopathy
Fig. 1. Layers of the retina and the relationship of the retina to the overlying vitreous and the underlying retinal pigment epithelium. (From [A] Herzlich AA, Patel M, Sauer TC, et al. Chapter 2: retinal anatomy and pathology. Retinal pharmacotherapy. Copyright Elsevier 2010; [B] The eye. Potter’s pathology of the fetus, infant and child. Copyright Elsevier 2007.)
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Fig. 1. (continued)
Diabetic Retinopathy
retinopathy progresses, beading of the retinal veins resulting from dilated venous walls and saccular aneurysmal dilatation occurs. The appearance of hemorrhages in the retina depends on the layer where the hemorrhage occurs. Intraretinal dot or blot hemorrhages occur in the inner retinal layer but can spread to the outer plexiform layer. They appear as dots because they are contained between the perpendicularly oriented cellular elements. Flame-shaped or splinter intraretinal hemorrhages spread out within the parallel elements of the NFL. Large confluent hemorrhages can involve all of the retinal layers and even break through the ILM into the vitreous space and into the subretinal space.7 Thickening of the ILM and posterior vitreous face can be seen in early retinopathy with progressive fibrotic attachment of the ILM to the vitreous as retinopathy advances with fibroblasts, fibrous astrocytes, myofibroblasts, and macrophages present in the ILM and the vitreous in patients with DME.17 Retinal neovascularization arises in regions of hypoxia, and it is thought to be mediated by the elaboration of vascular endothelial growth factor (VEGF). New blood vessels commonly arise from retinal venues at the margin of an area of capillary nonperfusion. Fibrovascular proliferation can break through the ILM and onto the surface of the retina and extend into the vitreous space. Rupture of these fragile neovascular vessels can cause extensive hemorrhage into the vitreous. As the fibrovascular process matures, fibrosis can occur on the surface of the retina causing macular distortion. With sufficient contraction, the neurosensory retina can be pulled up of the RPE creating a tractional RD. In extreme cases, the retina can rip, leading to a rhegmatogenous RD. DIAGNOSIS AND CLASSIFICATION
Despite the fact that the paradigm for treating diabetic retinopathy is moving away from laser photocoagulation (see discussion elsewhere in this article), the classification of retinopathy and, therefore, the timing of treatment and follow-up are still largely based on clinical trials of focal and panretinal laser photocoagulation. In general, diabetic retinopathy is classified as either nonproliferative (NPDR) or proliferative (PDR) based on the absence or presence of retinal vascular neovascularization. Macular edema can be present independently in either NPDR or PDR and is classified as absent, present, and clinically significant (CSME) or nonclinically significant. Correct classification is important because it gives us information about the preferred intervention and the risk of progression that will determine the appropriate follow-up. Immediate treatment is almost always recommended for macular edema once the threshold for clinical significance has been reached and for PDR once high-risk criteria are met. No treatment is generally recommended for NPDR in the absence of CSME. Classification is based on standard fundus photographs used in the Early Treatment Diabetic Retinopathy Study (ETDRS).18 NPDR Mild NPDR
Patients with mild NPDR have at least one microaneurysm; however, there are fewer intraretinal dot or blot hemorrhages than in the ETDRS standard photograph 2A (Fig. 2), and no other retinal abnormalities associated with diabetes are present. Patients with mild NPDR have only a 5% risk of progressing to PDR within 1 year and only a 15% risk of progressing to high-risk PDR necessitating panretinal laser photocoagulation within 5 years.7
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Fig. 2. Stereoscopic pairs of standard photograph 2A of the modified Airlie House classification of diabetic retinopathy illustrates a moderate degree of hemorrhages and microaneurysms. (From Aiello LM. Perspectives on diabetic retinopathy. Am J Ophthalmol 2003;136(1):131; with permission.)
Moderate NPDR
Patients with moderate NPDR have more microaneurysms or intraretinal hemorrhages than in the ETDRS standard photograph 2A (see Fig. 2) in one field; however, they are present in fewer than 4 quadrants of the retina. NFL infarctions (commonly referred to as CWS or soft exudates), undulations in the caliber of retinal veins (referred to as venous beading [VB]), and IRMA are present but less prominent than in the ETDRS standard photograph 8A (Fig. 3). Patients with moderate NPDR have a 12% to 27% risk of progressing to PDR within 1 year and a 33% 5-year risk of reaching the criteria for high-risk PDR.7 Severe NPDR
Patients with severe NPDR are defined by having one of the elements of the 4-2-1 rule. They have either 4 quadrants of intraretinal hemorrhages or microaneurysms greater than the ETDRS standard photograph 2A (see Fig. 2), 2 quadrants of significant VB, or 1 quadrant of IRMA greater than the ETDRS standard photograph 8A (see Fig. 3) and no retinal vascular neovascularization. Patients with severe NPDR have a 52% risk of progressing to PDR within 1 year and a 60% 5-year risk of reaching the criteria for high-risk PDR.7
Fig. 3. Stereoscopic pairs of standard photograph 8A of the modified Airlie House classification of diabetic retinopathy illustrates a moderate degree of IRMA. (From Aiello LM. Perspectives on diabetic retinopathy. Am J Ophthalmol 2003;136(1):131; with permission.)
Diabetic Retinopathy
Very severe NPDR
Patients with very severe NPDR have at least 2 of the elements of the 4-2-1 rule (defined earlier for severe NPDR) but have no retinal vascular neovascularization. They have a 75% risk of progressing to PDR within 1 year.7 PDR
PDR is characterized by neovascularization on the optic disk (NVD) or elsewhere (NVE) on the retina, hemorrhage present within the vitreous or trapped between the interface of the surface of the retina and the posterior margin of the vitreous body (subhyaloid hemorrhage), or fibrovascular proliferation, which can cause pulling on the retina sometimes leading to tractional or rhegmatogenous RD. PDR is defined as either early or high risk. Eyes with early PDR have a 75% 5-year risk of developing high-risk PDR. High-risk PDR is defined by the presence of NVD greater than approximately one-third of the area of the optic disk as defined by the ETDRS reference photograph 10 A (Fig. 4), or any NVD associated with vitreous or subhyaloid hemorrhage, or an area of NVE greater than one-half of the area of the optic disk with concomitant vitreous or subhyaloid hemorrhage. Early PDR includes all eyes that meet the criteria for PDR but do not meet the criteria for high risk.7 Macular Edema
Damage to the macula can occur at any level of NPDR or PDR. It may involve leakage of serosanguinous fluid from retinal vasculature damaged by diabetes or microaneurysms and result in a collection of intraretinal fluid within the macula causing the macula to become thickened or edematous. This damage may occur in a cystoid (not true cysts because there is no endothelial lining) pattern and may be associated with precipitated lipids sometimes referred to as hard exudates. Macular edema is usually defined as retinal thickening within 2 disk diameters (approximately 3 mm) of the center of the macula. Alternatively, macular damage can be the result of parafoveal capillary nonperfusion and ischemia with or without edema; fibrovascular traction on the macula causing wrinkling, distortion, or detachment of the macula; intraretinal or subhyaloid hemorrhage, which can cause a physical barrier to images reaching the macula; or the formation of macular holes. CSME
CSME is defined by the ETDRS as macular edema meeting one or more of the following 3 criteria: (1) retinal thickening occurring at or within 500 mm of the center
Fig. 4. Stereoscopic pairs of standard photograph 10A of the modified Airlie House classification of diabetic retinopathy illustrates a moderate degree of NVD. (From Aiello LM. Perspectives on diabetic retinopathy. Am J Ophthalmol 2003;136(1):131; with permission.)
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of the macula; (2) lipid precipitate deposition (hard exudates) with adjacent, associated retinal thickening at or within 500 mm of the center of the macula; or (3) a zone of retinal thickening of at least 1 disk area in size, any part of which is at or within 1 disk diameter (approximately 1.5 mm) of the center of the macula. Identifying CSME is important because patients with CSME were shown to benefit from focal laser photocoagulation in the ETDRS. Visual acuity was not a criterion for defining CSME. Although recommendations are evolving because of the increased use of intravitreal medications in the treatment of the neovascular and macular edema complications of diabetic retinopathy, recommendations for follow-up are still largely defined by the ETDRS findings regarding the progression of disease. Table 3 (progression and follow-up recommendations) summarizes the current standard recommendations regarding the appropriate follow-up of patients with various levels of retinopathy. DIAGNOSTIC MODALITIES FOR EVALUATION OF RETINOPATHY
The mainstay for diagnosis of diabetic retinopathy remains the clinical examination by a qualified examiner; however, additional diagnostic testing may often be helpful. The American Academy of Ophthalmology has developed preferred practice patterns related to the appropriate diagnosis and management of diabetic retinopathy.19 Visual acuity measurement with a standard Snellen or ETDRS chart is an easy, lowcost, and useful method of assessing visual function.20 But visual acuity was not a criterion for determining the need for laser photocoagulation in the ETDRS, and patients with extensive and sight-threatening retinopathy might maintain excellent visual acuity for periods of time. Slit lamp biomicroscopy of the anterior segment including the cornea, lens, and iris should be performed. In addition, the measurement of the intraocular pressure by any
Table 3 Risk and timing of progression of diabetic retinopathy Retinopathy Classification Mild NPDR ( ) CSME (1) CSME Moderate NPDR ( ) CSME (1) CSME
Risk of Progression to PDR in 1 y (%)
High-Risk PDR in 5 y (%)
5
15
12–27
Severe NPDR ( ) CSME (1) CSME
52
Very Severe NPDR ( ) CSME (1) CSME
75
Early PDR ( ) CSME (1) CSME
—
High-Risk PDR ( ) CSME (1) CSME
—
Recommended Follow-up
Treatment
Yearly 3 mo
No Yes
6 mo 3 mo
No Yes
4 mo 3 mo
Rarely Yes
3 mo 3 mo
Occasionally Yes
2–3 mo 2–3 mo
Occasionally Yes
2–3 mo 1–2 mo
Yes Yes
33
60
75
75
—
Diabetic Retinopathy
of several methods and gonioscopic evaluation of the iris and trabecular structures looking for signs of neovascularization of the iris and angle are necessary to diagnose primary open angle glaucoma, which may be more prevalent in patients with diabetes, and neovascular glaucoma, which is one of the most feared complications of PDR leading, in some cases, to uncontrollable increases in intraocular pressure and blindness. Stereoscopic slit lamp biomicroscopy, with the use of accessory lenses, is the preferred method for evaluating retinopathy of the posterior pole, including the optic disk and macula, as well as the retinal midperiphery.16 This technique allows for careful evaluation for the presence of macular edema, intraretinal hemorrhages, IRMA, CWS, VB, NVD, and NVE as well as epiretinal membranes and fibrovascular proliferation that can lead to tractional and rhegmatogenous RD. Binocular indirect ophthalmoscopy is used to examine the peripheral retina for NVE, vitreous hemorrhage, and RD. Alternatively, the peripheral retina can be examined with wide-angle or angledmirror lenses at the slit lamp. Dilation of the pupil is required to adequately assess the retina for the presence of retinopathy because only 50% of eyes have been shown to be accurately graded for retinopathy through undilated pupils.21 New scanning laser ophthalmoscopic imaging systems may improve visualization of the peripheral retina in undilated eyes. Ancillary testing, if used appropriately, can enhance the accuracy of diagnosis and improve patient care.14 Color fundus photography, often with stereoscopic imaging, may be a more reproducible technique than examination at the slit lamp for detecting retinopathy; but clinical examination is frequently superior for detecting macular edema and fine-caliber NVD and NVE. Photographic documentation of a previous examination, however, can be helpful in ascertaining disease progression, response to treatment, and can influence the decision as to whether or not to treat.22 Although it is not part of the routine evaluation of patients with diabetes, fluorescein angiography, in which 10% or 25% fluorescein sodium solution is rapidly injected intravenously, can be useful in identifying areas of macular and peripheral capillary nonperfusion; sources of capillary leakage, such as microaneurysms responsible for macular edema; and sometimes in visualizing subtle foci of IRMA and neovascularization. Fluorescein angiography is not needed to diagnose CSME or PDR because both of these are clinical diagnoses14; however, it is frequently used as a guide for the treatment CSME.19 Fluorescein angiography is a very safe procedure; but mild side effects, including nausea and vomiting, are not infrequent, and severe medical complications, including death (approximately 1 per 200 000 patients) can occur.23 Although adverse effects on the fetus have never been documented, fluorescein angiography is not generally recommended, other than in exceptional circumstances, during pregnancy because fluorescein dye can cross the placental barrier and enter the fetal circulation.24 B-scan ultrasonography can be very helpful in diagnosing RD in diabetic eyes with media opacities secondary to corneal clouding, cataracts, and most frequently vitreous hemorrhage. Ocular coherence tomography (OCT) provides cross-sectional imaging of the retina and macula, the vitreoretinal interface and epiretina, and the subretinal space.25 Time domain and, more recently, spectral domain instruments allow for high-resolution imaging (
