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`Diabetic Retinopathy
`
`Article  in  Diabetes Care · October 2004
`
`DOI: 10.2337/diacare.27.10.2540
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`R e v i e w s / C o m m e n t a r i e s / A D A S t a t e m e n t s
`T E C H N I C A L
`R E V I E W
`
`Diabetic Retinopathy
`
`1,2
`DONALD S. FONG, MD, MPH
`3,4
`LLOYD P. AIELLO, MD, PHD
`
`FREDERICK L. FERRIS, III, MD
`6
`RONALD KLEIN, MD
`
`5
`
`kinase C (PKC). These processes are
`thought to modulate the disease process
`through effects on cellular metabolism,
`signaling, and growth factors.
`
`O ver 135 million individuals are af-
`
`flicted with diabetes across the
`world. In the U.S., diabetes affects
`over 18.2 million people (or 6.3% of the
`total population) and 800,000 new cases
`of type 2 diabetes are diagnosed each year
`(1). Retinopathy is the most common mi-
`crovascular complication of diabetes, re-
`sulting in blindness for over 10,000
`people with diabetes per year. Epidemio-
`logical studies have described the natural
`history of and treatment for diabetic reti-
`nopathy. There is evidence that retinopa-
`thy begins to develop at least 7 years
`before the clinical diagnosis of type 2
`diabetes (2). Clinical trials have demon-
`strated the effectiveness of photoco-
`agulation, vitrectomy, and control of
`hyperglycemia and hypertension for dia-
`betic retinopathy (Table 1). The current
`review will discuss the pathophysiology,
`screening, medical treatment, and future
`research for diabetic retinopathy.
`
`Polyol accumulation
`Accumulation of polyol occurs in experi-
`mental hyperglycemia, which in rats and
`dogs is associated with the development
`of basement thickening, pericyte loss, and
`microaneurysm formation (3,4). High
`concentrations of glucose increase flux
`through the polyol pathway with the en-
`zymatic activity of aldose reductase, lead-
`ing to an elevation of intracellular sorbitol
`concentrations. This rise in intracellular
`sorbitol accumulation has been hypothe-
`sized to cause osmotic damage to vascular
`cells (5). Aldose reductase inhibitors
`(ARIs) have been evaluated for the pre-
`vention of retinal and neural damage in
`diabetes (6). However, three clinical trials
`of ARIs in humans have not shown effi-
`PATHOPHYSIOLOGY
`cacy in preventing the incidence or pro-
`Several biochemical pathways have been
`gression of retinopathy (7,8 and S. Feman
`proposed to link hyperglycemia and mi-
`[St. Louis University, St. Louis, MO], per-
`crovascular complications. These include
`sonal communication). The efficacy of
`polyol accumulation, formation of ad-
`new, more potent ARIs remains to be
`vanced glycation end products (AGEs),
`oxidative stress, and activation of protein
`evaluated in clinical trials.
`● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●
`
`From the 1Department of Ophthalmology, Southern California Permanente Medical Group, Baldwin Park,
`California; the 2Department of Research and Evaluation, Southern California Permanente Medical Group,
`Pasadena, California; 3Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts; the 4Depart-
`ment of Ophthalmology, Harvard Medical School, Boston, Massachusetts; the 5Department of Clinical
`Research, National Eye Institute, National Institutes of Health, Bethesda, Maryland; and the 6Department of
`Ophthalmology, University of Wisconsin, Madison, Wisconsin.
`Address correspondence and reprint requests to Donald S. Fong, MD, MPH, Department of Research and
`Evaluation, Southern California Permanente Medical Group, 100 S. Los Robles, Pasadena, CA 91101.
`Received and accepted for publication 9 July 2004.
`R.K. is on a steering committee for AstraZeneca and an advisory board for Eli Lilly.
`Abbreviations: ABCD, Appropriate Blood Pressure Control in Diabetes; ACCORD, Action to Control
`Cardiovascular Risk in Diabetes; AGE, advanced glycation end product; ARI, aldose reductase inhibitor;
`DCCT, Diabetes Control and Complications Trial; DIRECT, Diabetic Retinopathy Candesartan Trial; DME,
`diabetic macular edema; EDTRS, Early Treatment Diabetic Retinopathy Study; EUCLID, Eurodiab Con-
`trolled Trial of Lisinopril in Insulin Dependent Diabetes; FPG, fasting plasma glucose; NPDR, nonprolifera-
`tive diabetic retinopathy; PDR, proliferative diabetic retinopathy; PEDF, pigment epithelium– derived
`growth factor; PKC, protein kinase C; QALY, quality-adjusted life-year; ROS, reactive oxygen species; SSF,
`seven standard field; SNMDP, single-field digital monochromatic nonmydriatic photography; TGF-␤, trans-
`forming growth factor-␤; UKPDS, U.K. Prospective Diabetes Study; VEGF, vascular endothelial growth
`factor; WESDR, Wisconsin Epidemiologic Study of Diabetic Retinopathy.
`A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion
`factors for many substances.
`© 2004 by the American Diabetes Association.
`
`AGEs
`Another well-characterized pathway is
`damage resulting from accumulation of
`AGEs. High serum glucose can lead to
`nonenzymatic binding of glucose to pro-
`tein side chains, resulting in the formation
`of compounds termed AGEs (9,10). After
`26 weeks of induced hyperglycemia, the
`retinal capillaries of diabetic rats have
`marked accumulation of AGEs as well as a
`loss of pericytes. Furthermore, diabetic
`rats treated with aminoguanidine (AGE
`formation inhibitor) have reduced AGE
`accumulation and reduced histological
`changes, including microaneurysm for-
`mation and pericyte loss (11). An ongoing
`clinical trial is investigating the effect of
`aminoguanidine in humans (12). Prelim-
`inary results suggest that aminoguanidine
`reduces the progression of retinopathy
`but is associated with anemia (13).
`
`Oxidative damage
`Diabetes and hyperglycemia can also lead
`to oxidative stress and formation of reac-
`tive oxygen species (ROS), leading to vas-
`cular damage. Production of ROS (free
`radicals) may result from glucose auto-
`oxidation, protein glycation, increased
`flux through the polyol pathway, and pro-
`stanoid production (14). Normalization
`of glucose-stimulated superoxide pro-
`duction has been found to block at least
`three independent pathways of hypergly-
`cemia-induced vascular damage (15).
`Furthermore, animal studies suggest that
`antioxidants such as vitamin E may pre-
`vent some of the vascular dysfunction as-
`sociated with diabetes (16). In one study
`of patients with diabetes who had no or
`minimal retinopathy (n ⫽ 36), treatment
`for 4 months with high-dose vitamin E
`(1,600 IU/day) was found to significantly
`reverse abnormalities of retinal blood
`flow (P ⬍ 0.001) (17,18). An 88% nor-
`malization of retinal blood flow was seen,
`despite an unchanged level of glycemic
`control.
`The Heart Outcomes Prevention
`Evaluation (HOPE) trial is a randomized
`clinical trial with a 2 ⫻ 2 factorial design
`that evaluated the effects of vitamin E and
`ramipril in patients at high risk for cardio-
`vascular events (19). Patients were eligi-
`ble for the study if they were 55 years of
`age or older and if they had cardiovascular
`
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`Table 1—Outline of 1998 technical review
`(ref. 40)
`
`Epidemiology
`Impact
`Natural history
`Causes of visual loss
`Providers of eye care for patients with
`diabetes
`Provider of medical care for patients with
`diabetes
`Comprehensive eye evaluation
`Initial eye evaluation and minimal follow-up
`NPDR levels and disease progression
`PDR levels and disease progression
`Macular edema levels and disease
`progression
`Treatment objectives
`Determination of treatment efficacy
`General treatment efficacy
`Specific clinical trials outcomes
`Management of diabetic retinopathy
`Exercise
`Aspirin therapy
`Ancillary tests
`Photography and retinal screening
`Conclusions
`
`disease or diabetes with at least one addi-
`tional coronary risk factor. Patients were
`randomly allocated to daily treatment
`with 400 IU vitamin E and 10 mg ramipril
`or their respective placebos and were fol-
`lowed for an average of 4.5 years. The
`primary study outcome was the compos-
`ite of myocardial infarction, stroke, or
`cardiovascular death. Secondary out-
`comes included total mortality, hospital-
`izations for heart failure or unstable
`angina, revascularizations, overt ne-
`phropathy, and laser therapy for diabetic
`retinopathy. In the 3,654 people with di-
`abetes, vitamin E at this dose had a neutral
`effect on the primary study outcome (rel-
`ative risk 1.03, 95% CI 0.88 –1.21; P ⫽
`0.70), on each component of the compos-
`ite primary outcome, and on all pre-
`defined secondary outcomes.
`
`PKC activation
`There is increasing evidence that PKC ac-
`tivation is related to hyperglycemia-
`induced microvascular dysfunction in
`diabetes (20). Activation of PKC results in
`numerous cellular changes, including in-
`creased expression of matrix proteins,
`such as collagen and fibronectin, and in-
`creased expression of vasoactive media-
`tors, such as endothelin. The changes are
`seen as thickening of the basement mem-
`
`brane, increased retinal vascular perme-
`ability, and alterations in retinal blood
`flow. Although the activity of multiple
`PKC isoforms (␣, ␤1, ␤2, and ⑀) is in-
`creased in vascular tissues in the diabetic
`state, studies suggest that the PKC-␤2 iso-
`form preferentially mediates the patho-
`logic complications associated with
`hyperglycemia (21,22). Moreover,
`PKC-␤ has been shown to be an integral
`component of cellular signaling by vascu-
`lar endothelial growth factors (VEGFs)
`(23), important mediators of ocular neo-
`vascularization, secondary to retinal isch-
`emia and diabetic macular edema (DME)
`(24,25). Results from one clinical trial us-
`ing a PKC inhibitor will be discussed in
`the section on future directions and PKC
`inhibitors.
`
`Growth factors
`The biochemical pathways described
`above are associated with production and
`signaling of growth factors such as VEFG,
`growth hormone, IGF-I, transforming
`growth factor-␤ (TGF-␤), and pigment
`epithelium– derived growth factor
`(PEDF).
`The VEGFs are a family of proteins
`that are mitogenic for vascular endothelial
`cells and increase vascular permeability.
`VEGF is important in fetal vascular devel-
`opment, with VEGF levels diminishing af-
`ter birth. However, increased expression
`of VEGF has been demonstrated in dia-
`betic retinopathy (26). In addition, VEGF
`has been shown to be upregulated by
`hypoxia, with increasing levels of VEGF
`in the vitreous associated with increasing
`retinal ischemia. In a mouse model of hy-
`peroxic retinopathy, soluble VEGF-
`neutralizing VEGF receptor chimera was
`shown to suppress retinal neovasculariza-
`tion (27). There is increasing evidence
`that inhibition of PKC-␤ can prevent the
`neovascular and permeability effects of
`VEGF in animals (28).
`Growth hormone and IGF-I have
`been suspected of playing a role in the
`progression of diabetic retinopathy. In a
`previous era, hypophysectomy was
`shown to lead to regression of prolifera-
`tive retinopathy in a study of 100 patients
`(29). Similarly, diabetic dwarfs with low
`systemic IGF-I levels due to growth hor-
`mone deficiency have a reduced inci-
`dence of proliferative diabetic retinopathy
`(PDR) compared with age- and sex-
`matched diabetic patients. Other evi-
`dence includes observations of diabetic
`
`Fong and Associates
`
`retinopathy progression in states of ele-
`vated IGF-I, such as puberty pregnancy
`(30), and upon rapid improvement of
`metabolic control (31). Such observations
`have raised interest in the use of growth
`hormone–inhibitory and antiproliferative
`somatostatin analogs to treat severe PDR
`(32,33). In a recent small-scale study of
`adults with diabetes and PDR, however, a
`growth hormone receptor antagonist,
`pegvisomant, failed to induce regression
`of neovascularization (34). This negative
`result may have occurred because the
`treatment was initiated too late; treatment
`may need to have started prior to the de-
`velopment of PDR. In another small-scale
`trial (23 patients), octreotide (a soma-
`tostatin analog) treatment reduced the re-
`quirement for laser photocoagulation
`compared with conventional treatment in
`patients with either severe nonprolifera-
`tive diabetic retinopathy (NPDR) or early
`PDR (35). Over the 15-month study, only
`1 of 22 octreotide-treated patients re-
`quired photocoagulation compared with
`9 of 24 conventionally treated patients. A
`large clinical trial of octreotide is ongoing.
`TGF-␤ is produced by pericytes and may
`inhibit endothelial proliferation. Active
`PDR and patients with rubeosis have
`lower levels of TGF-␤ (36). Lower levels
`may promote angiogenesis by removal of
`an inhibitor. Levels of TGF-␤ are usually
`high in the vitreous of normal eyes (37).
`PEDF is produced by the retinal pig-
`ment epithelium and inhibits neovascu-
`larization (38). Systemic injection can
`reduce the development of retinal neovas-
`cularization in mouse retinopathy of a
`prematurity model (39). It has been pos-
`tulated that reduced levels of PEDF may
`contribute to diabetic retinopathy; how-
`ever, PEDF transgenic knockout mice do
`not show ocular pathology or altered neo-
`vascular responses.
`
`DIAGNOSIS
`A previous technical review published in
`Diabetes Care (40) provides an extensive
`review of the elements of comprehensive
`eye evaluation and levels of diabetic reti-
`nopathy, as well as management for diabetic
`retinopathy. The current review discusses
`1) techniques for diabetic retinopathy
`screening, 2) intervals for evaluating pa-
`tients without any retinopathy, 3) a new
`classification of diabetic retinopathy sever-
`ity, and 4) optical coherence tomography.
`Many techniques are used in the de-
`tection of diabetic retinopathy, including
`
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`Diabetic retinopathy
`
`direct and indirect ophthalmoscopy, flu-
`orescein angiography, stereoscopic digital
`and color film– based fundus photogra-
`phy, and mydriatic or nonmydriatic digi-
`tal color or monochromatic single-field
`photography. Grading of stereoscopic
`color fundus photographs in seven stan-
`dard fields (SSFs), as defined by the Early
`Treatment Diabetic Retinopathy Study
`(ETDRS) group, is a recognized standard
`for the detection of diabetic retinopathy
`(41). Although this approach is accurate
`and reproducible, it is labor intensive, re-
`quiring skilled photographers and photo-
`g r a p h r e a d e r s a n d s o p h i s t i c a t e d
`photography equipment, film processing,
`and archiving.
`Ophthalmoscopy is the most com-
`monly used technique to monitor for di-
`abetic retinopathy. However, undilated
`ophthalmoscopy, especially by non– eye
`care providers has poor sensitivity com-
`pared with stereoscopic seven-field color
`photography (42). Under typical clinical
`conditions, direct ophthalmoscopy by
`nonophthalmologists has a sensitivity of
`⬃50% for the detection of proliferative
`retinopathy (43).
`Various systems using multiple-field
`photography have been reported. Three
`groups have reported their results using
`proprietary systems, and these systems
`seem to perform well. However, the sys-
`tems are proprietary and require pupil-
`lary dilation and skilled photographers
`and may therefore be more complex than
`required for screening purposes.
`The Joslin Vision Network (44) com-
`pared stereo nonmydriatic digital-video
`color and three-field fundus photographs
`in three fields with SSF photography in 54
`patients (108 eyes) with type 1 or type 2
`diabetes (level 1 evidence). They found
`substantial agreement (␬ ⫽0.65) be-
`tween the two techniques for determina-
`tion of the clinical level of diabetic
`retinopathy. Agreement was excellent
`(␬ ⫽0.87) for referral to an ophthalmol-
`ogist for clinical examination. In addition,
`a retrospective review of a subset of pa-
`tients that had Joslin Vision Network im-
`aging showed good correlation with an
`examination by a retina specialist (45).
`The Inoveon Diabetic Retinopathy
`system (46) compared SSF photographs
`of 290 diabetic patients recorded on
`35-mm film and on their proprietary sys-
`tem. The sensitivity and specificity of the
`digital system in detecting threshold
`events were 98.2 and 89.7%, respectively.
`
`Although Inoveon’s diabetic retinopathy-
`3DT system provides highly accurate di-
`abetic retinopathy referral decisions, the
`requirement for dilation and the cost both
`reduce its usefulness as a screening tool.
`The DigiScope is a semiautomated in-
`strument that acquires fundus images,
`evaluates visual acuity, and transmits the
`data to a remote reading center through
`telephone lines (47). A pilot study in nor-
`mal eyes of normal volunteers and 17
`consecutive diabetic patients showed that
`the visualization of many retinal lesions
`present in diabetic retinopathy can be vi-
`sualized by the DigiScope. Further stud-
`ies are needed to evaluate the test
`characteristics of this technology.
`The use of single-field fundus pho-
`tography has also been used as a detection
`tool for diabetic retinopathy. Patients
`with type 1 or type 2 diabetes were se-
`quentially photographed through a non-
`pharmacologically dilated pupil by
`single-field digital monochromatic non-
`mydriatic photography (SNMDP), phar-
`macologically dilated, examined by
`ophthalmoscopy by an ophthalmologist,
`and then had 30° color stereoscopic pho-
`tographs taken in SSFs (48). There was
`excellent agreement (␬ ⫽0.97) between
`the SNMDP and SSFs for degree of dia-
`betic retinopathy using a “referral” (ET-
`DRS level ⱖ35) or “no referral” (ETDRS
`level ⱕ20) dichotomization (level 1 evi-
`dence). The sensitivity and specificity of
`SNMDP compared with SSFs were 78 and
`86%, respectively. SNMDP was superior
`to ophthalmoscopy through pharmaco-
`logically dilated pupils when compared
`with SSFs. SNMDP demonstrated 100%
`sensitivity and 71% specificity when com-
`pared with direct ophthalmoscopy. None
`of the patients identified by ophthalmos-
`copy for referral were missed by SNMDP.
`SNMDP demonstrated 25% overcalls
`(higher retinopathy levels diagnosed by
`the tested modality rather than by the
`standard) for referral compared with oph-
`thalmoscopy. However, when adjudi-
`cated against SSFs, this difference was due
`to the reduced sensitivity of ophthalmos-
`copy. With a sensitivity of 78%, SNMDP
`did miss some patients requiring referral
`based on SSFs. The lack of stereopsis also
`diminishes the ability to diagnose clini-
`cally significant macular edema in the
`absence of hard exudates or retinal hem-
`orrhages and microaneurysms. The au-
`thors emphasize that SNMDP is superior
`to dilated ophthalmoscopy. The effective-
`
`ness was confirmed in other studies
`(49,50).
`Single-field photography is not a sub-
`stitute for a comprehensive ophthalmic
`examination. However, there is evidence
`from well-designed comparative studies
`that single-field fundus photography can
`serve as an initial evaluation tool for dia-
`betic retinopathy by identifying patients
`with retinopathy for referral to ophthal-
`mic evaluation and management. The ef-
`fectiveness is demonstrated by its ease of
`use (only one photograph is required),
`cost (the cost of one photograph in most
`cases), convenience, and ability to detect
`retinopathy. None of the above ap-
`proaches, including the proprietary sys-
`tems, are able to detect other diseases
`often present in older patients with diabe-
`tes. This inability reduces the value of us-
`ing these approaches when compared
`with examination by a skilled eye care
`provider.
`
`Mydriasis and single-field
`photography
`Although most patients can be photo-
`graphed without pharmacological dila-
`tion, lens opacities in older patients can
`result in photographs that are ungrade-
`able. In the studies previously mentioned,
`Pugh et al. (50) found that 42 of 50 un-
`gradeable photographs became gradable
`after dilation. Taylor et al. (49) and Joan-
`nou et al. (50a) evaluated only dilated sin-
`gle-field photography. Based on these
`studies, eyes with ungradeable pictures
`should have dilation and repeat photog-
`raphy. Eyes with photographs that re-
`main ungradeable after dilation would be
`considered as screen positives and require
`referral to ophthalmic evaluation. With
`the advent of digital photography, the
`quality of the image taken can be re-
`viewed by the photographer and retakes
`made if necessary, possibly reducing the
`high frequency of ungradeable photo-
`graphs found in older subjects.
`
`Screening interval
`Regular dilated eye examinations are an
`effective approach to detecting and treat-
`ing vision-threatening diabetic retinopa-
`thy (51). They can help prevent blindness
`and are cost effective (52,53). Guidelines
`for systematic evaluation have been devel-
`oped because patients with retinopathy
`are often asymptomatic and because reti-
`nal photocoagulation treatment is more
`effective at reducing visual loss when ap-
`
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`plied at specific, often asymptomatic, but
`advanced stages of retinopathy (54,55).
`However, despite the recommendations
`for regular evaluation and the availability
`of effective treatment, many patients at
`risk of visual loss due to severe retinopa-
`thy are not receiving dilated eye examina-
`tions and necessary photocoagulation
`treatments (56,57).
`Guidelines for the frequency of di-
`lated eye examinations have been based
`on the severity of the retinopathy (58,59).
`These recommendations are described in
`a previously published technical review
`(40). For patients with moderate to severe
`NPDR, frequent eye examinations are of-
`ten necessary to determine when to initi-
`ate treatment. However, for patients
`without retinopathy or with only microa-
`neurysms, the need for annual dilated eye
`examinations is less clear. For these pa-
`tients, the annual incidence of either pro-
`liferative retinopathy or macular edema is
`low, suggesting that a reduced frequency
`of screening would decrease costs with-
`out increasing the risk of visual loss (60).
`Recently, some have suggested that an-
`nual screening for some patients may not
`be cost effective, and in some cases con-
`sideration should be given to increasing
`the screening interval (61). However, for
`patients where less frequent screening
`seems appropriate, there should be some
`oversight by the eye care professional to
`assure that the patient is not lost to follow-
`up. Before a less frequent screening
`schedule should be generally recom-
`mended or adopted, a better understand-
`ing of the total value of screening eye
`examinations, the potential indirect ef-
`fects of less frequent eye examinations,
`and patient preference is needed.
`Eye examinations may include other
`benefits. Older people often need eye ex-
`ams for increasing presbyopia and are at
`higher risk for cataract, glaucoma, age-
`related macular degeneration, and more,
`which may result in vision loss. Discus-
`sion by ophthalmologists with their dia-
`betic patients about medical as well as
`ophthalmic conditions certainly has
`value. For example, most primary care
`doctors tell their patients that it is impor-
`tant to control blood glucose, blood pres-
`sure, and serum lipids. During the eye
`exam these messages can be reinforced by
`the ophthalmologist at a time when pa-
`tients are particularly aware of the impli-
`cations of vision loss. Patients can also be
`reminded that controlling these parame-
`
`ters also will reduce the risk of neuropa-
`thy and nephropathy. Increased patient
`compliance will reduce the risks of these
`secondary complications of diabetes. Pre-
`vention of multiple complications is
`surely better than managing them after
`they have occurred, both for patient
`health and because of economic conse-
`quences. This value is difficult to measure
`and is often not incorporated into analy-
`ses of the costs and benefits of screening.
`Less frequent examinations may also
`have indirect effects. Long intervals be-
`tween follow-up visits may lead to diffi-
`culties in maintaining contact with
`patients. Also, patients may be unlikely to
`remember that they need an eye examina-
`tion after several years have passed. Fi-
`nally, a recommendation for follow-up
`visits at 2- or 3-year intervals may give a
`patient the impression that visual loss is
`very unlikely and therefore not a concern.
`All of these factors may result in longer-
`than-recommended intervals between ex-
`a m i n a t i o n s . A l t h o u g h a u t o m a t i c
`reminders from clinics can be helpful,
`they may be difficult to implement, espe-
`cially when patients have relocated. Until
`we have empirical evidence to confirm
`that lengthening the follow-up interval is
`not harmful, maintaining an annual fre-
`quency seems conservative.
`Patient expectations also should be
`considered. Blindness and visual loss is a
`major fear of most patients with diabetes.
`Visual loss leads to emotional distress and
`reduces functionality in daily life. The
`magnitude of this fear, the effect of blind-
`ness on functionality, and the economic
`value of these factors are hard to quantify.
`One way to assess the worth of these fac-
`tors is to determine the value of blindness
`in terms of quality-adjusted life-years
`(QALYs). Investigators have suggested
`values of 0.48 – 0.36 (52,62) for blind-
`ness, but there are no QALY values for
`visual impairment that are less than blind-
`ness. Changes in QALY values signifi-
`cantly affect the cost-effectiveness of
`screening. Analyses should include a sen-
`sitivity analysis for different values of
`QALYs before making generalized
`recommendations.
`Physicians may elect to individually
`reduce the frequency of follow-up for cer-
`tain patients without retinopathy or ne-
`phropathy who are very compliant and
`have very good control of their blood glu-
`cose, blood pressure, and serum lipids.
`However, they should not assume that ag-
`
`Fong and Associates
`
`gregate medical care costs can be reduced
`and efficiency increased by simply de-
`creasing the frequency of screening exam-
`inations for entire groups of patients.
`Until empirical data are available to show
`otherwise, the general recommendation
`that individuals with diabetes should
`have a yearly eye examination seems safe,
`conservative, and reasonable. Deviations
`from this guideline are appropriate in cer-
`tain low-risk groups but with caveats.
`Even with the current guideline, too
`many people with diabetes are needlessly
`losing vision because the opportunity to
`treat them in a timely fashion was missed.
`Relaxing the guidelines will not solve this
`problem. We think the guideline for a reg-
`ular dilated eye examination should re-
`main at 1 year rather than at 2 or 3 years.
`It is appropriate for the guideline to be
`conservative, and deviations from it
`should only be made after considering all
`of the risks.
`
`New classification
`The ETDRS severity scale was based on
`the modified Airlie House classification of
`diabetic retinopathy and was used to
`grade fundus photographs (63). Al-
`though it is recognized as the gold stan-
`dard for grading the severity of diabetic
`retinopathy in clinical trials, its use in ev-
`eryday clinical practice has not proven to
`be easy or practical. The photographic
`grading system has more levels than may
`be necessary for clinical care, and the spe-
`cific definitions of the levels are detailed,
`require comparison with standard photo-
`graphs, and are difficult to remember and
`apply in a clinical setting. In addition, in
`the past there has been no common prac-
`tical clinical standard terminology that
`has been accepted for the worldwide ex-
`change of information and data (64 – 66)
`until a new diabetic retinopathy severity
`scale was developed by the Global Dia-
`betic Retinopathy Group at the Interna-
`tional Congress of Ophthalmology in
`Sydney, Australia, in April 2002 (67).
`The levels in this new diabetic reti-
`nopathy disease severity scale are listed in
`Table 2 and consist of five scales with in-
`creasing risks of retinopathy. The first
`level is “no apparent retinopathy,” and the
`second level, “mild NPDR,” includes ET-
`DRS stage 20 (microaneurysms only). The
`risk of significant progression over several
`years is very low in both groups. The third
`level, “moderate NPDR,” includes eyes
`with ETDRS levels 35– 47, and the risk of
`
`DIABETES CARE, VOLUME 27, NUMBER 10, OCTOBER 2004
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`2543
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`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2120 Page 5
`
`

`

`Diabetic retinopathy
`
`Table 2—International Clinical Diabetic Retinopathy Disease Severity Scale (ref. 63)
`
`Proposed disease severity level
`
`Findings observable upon dilated ophthalmoscopy
`
`No apparent retinopathy
`Mild NPDR
`Moderate NPDR
`
`Severe NPDR
`
`PDR
`
`No abnormalities
`Microaneurysms only
`More than just microaneurysms but less than severe
`NPDR
`Any of the following:
`⬎20 intraretinal hemorrhages in each of 4 quadrants
`Definite venous beading in 2⫹ quadrants
`Prominent intraretinal microvascular abnormalities
`in 1⫹ quadrant
`And no signs of proliferative retinopathy
`One or more of the following:
`Neovascularization
`Vitreous/preretinal hemorrhage
`
`ence tomography measurements and vi-
`sual acuity.
`
`TREATMENT
`The technical review published in 1998
`(40) discusses the efficacy of laser photo-
`coagulation for PDR and DME and vitrec-
`tomy surgery for vitreous hemorrhage
`and active PDR. The current review dis-
`cusses medical management and experi-
`mental therapies.
`
`Glycemic control
`At present, the most effective medical
`treatment to slow the progression of dia-
`betic retinopathy is glycemic control. The
`relationship between hyperglycemia and
`retinopathy has been reported in well-
`conducted observational studies (70).
`The Diabetes Control and Complications
`Trial (DCCT) and the U.K. Prospective
`Diabetes Study (UKPDS) are two random-
`ized clinical trials that conclusively
`showed the efficacy of glycemic control in
`preventing diabetic retinopathy (71–73).
`The DCCT (74) investigated whether
`intensive treatment of glycemia would
`prevent or delay the progression of early
`NPDR (primary prevention) and whether
`intensive glycemic control would prevent
`the progression of early retinopathy to
`more advanced forms of retinopathy (sec-
`ondary intervention) (1). Patients eligible
`for the primary prevention cohort had
`type 1 diabetes for 1–5 years and no reti-
`nopathy by seven-field photography and
`for secondary intervention had type 1 di-
`abetes for 1–15 years and very mild to
`
`ity levels should result in more appropri-
`ate and consistent referrals to treatment
`centers.
`
`Optical coherence tomography
`Optical coherence tomography provides
`images by projecting a pair of near-
`infrared light beams into the eye. The re-
`sulting interference pattern from these
`beams is dependent of the thickness and
`reflectivity of the retinal structures and is
`detected by the measuring system (68).
`The images produced appear to be cross-
`sections of the retina and allow the thick-
`ness of the retina to be measured. The
`thickness of the retina may allow DME to
`be followed in a quantitative manner (69).
`An ongoing clinical trial will investigate
`the relationship between optical coher-
`
`progression increases significantly by
`level 47. Still, the fourth level, “severe
`NPDR” (ETDRS stage 53), carries with it
`the most ominous prognosis for progres-
`sion to PDR. The fifth level, “PDR,” in-
`c l u d e s
`a l l
`e y e s w i t h d e fi n i t e
`neovascularization or vitreous/preretinal
`hemorrhage. There was no attempt to
`subdivide level 5 as a function of ETDRS
`“high-risk characteristics” because signif-
`icant rates of progression are expected to
`occur in all of these cases.
`DME disease severity scale is listed in
`Table 3. The initial and most important
`designation is to separate eyes with appar-
`ent DME from those with no apparent
`thickening or lipid in the macula. Because
`there are significant variations in exam-
`iner education and availability, a two-
`tiered system was recommended. The
`first level is determined by the presence or
`absence of apparent retinal thickening or
`lipid in the posterior pole. A second level
`evaluation documents details related to
`the distance of retinal thickening and/or
`lipid from the fovea. Eyes with obvious
`foveal involvement by edema or lipid are
`categorized as “sev