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The Diagnosis of Diabetic Retinopathy
The Diagnosis of Diabetic Retinopathy
Ophthalmoscopy versus Fundus Photography Vivian S. Lee, MD, DPhil, l Ronald M. Kingsley, MD, 2 Elisa T. Lee, PhD, 3 Min Lu, MD, MPH,4 Dana Russell, MPH,4 Nabih R. Asal, PhD,s Reagan H. Bradford, Jr., MD, 2 C. P. Wilkinson, MD2 Purpose: To compare fundus photography with ophthalmoscopy in the detection of diabetic retinopathy. Methods: Ophthalmoscopy and fundus photographs with a nonmydriatic camera, both performed through dilated pupils, were compared to diagnose retinopathy in a cohort of 410 Oklahoma Indians with noninsulin-dependent diabetes mellitus. A total of 795 eyes were examined using both methods. The mean age of participants was 60.3 years, with a mean duration of diabetes of 17.3 years. Results: An overall agreement of 86.3% with a kappa statistic K of 0.74 was found between ophthalmoscopy and fundus photography with a nonmydriatic camera. For the diagnosis of proliferative diabetic retinopathy, K = 0.84 with an agreement of 98.1 %. With a total of 61 cases of proliferative retinopathy diagnosed by either method in our study, ophthalmoscopy alone detected 88.5% and fundus photography, 78.7%. When compared on a lesion-by-Iesion basis, agreement between the two diagnostic methods was highest for non proliferative retinopathy, as well as fibrous proliferation. Conclusion: The fundus photography with a non mydriatic camera, performed with mydriasis, is comparable to ophthalmoscopy for the detection of retinopathy. It may prove to be a suitable, cost-effective method for routine screening in diabetes clinics, provided ophthalmologic referral is ensured for those with a diagnosis of any form of retinopathy, questionable retinopathy, nondiabetic retinopathy, those with poor quality photographs, as well as those with acute changes in visual acuity. Ophthalmology 1993; 100: 1504-1512
With diabetes diagnosed in approximately 6.8 million persons in the United States,l diabetic retinopathy is the leading cause of new blindness in adults in the United Originally received: December 2, 1992. Revision accepted: March 29, 1993. I Department of Radiology, Duke University Medical School, Durham. 2 Dean McGee Eye Institute, Oklahoma City. 3 Center for Epidemiologic Research and Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City. 4 Center for Epidemiologic Research, University of Oklahoma Health Sciences Center, Oklahoma City.
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States?,3 Progression from nonproliferative diabetic retinopathy (non-PDR) to PDR poses one of the greatest threats to the vision of these patients. If untreated, PDR causes blindness in more than 50% of affected individuals. 4 ,5 The effectiveness of treatment with laser photocoDepartment of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City. Supported by grant ROI HL 34843 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. 5
Reprint requests to Elisa T, Lee, PhD, Center for Epidemiologic Research, College of Public Health, University of Oklahoma Health Sciences Center, PO Box 26901, Oklahoma City, OK 73190.
Lee et al . The Diagnosis of Diabetic Retinopathy agulation in lessening, though not reversing, the progression of retinopathy, maculopathy, and subsequent visual impairment emphasizes the importance of early diagnosis for early intervention. 6- s Several methods for diagnosing retinopathy are available, including fluorescein angiography, seven-field stereoscopic fundus photography with seven standard fields, fundus photography with a nonmydriatic camera, and ophthalmoscopy.9-22 While angiography and stereoscopic fundus photography are considered the gold standards,9 they are expensive and thus may not be considered feasible for routine screening nor for large-scale epidemiologic studies. Fundus photography with a nonmydriatic camera hails a new era in screening for retinopathy.ll,15-22 It is a faster, less-expensive option. The controversy surrounding the method has focused on questions of accuracy and on high rates of un gradable photographs. To date, most studies comparing the two potential screening methods, nonmydriatic fundus photography and ophthalmoscopy, have elected to perform the photography with undilated pupils. 16-20 While these methods cannot be expected to perform as well as the gold standards, they can appropriately be compared with each other as potential screening methods. As such, they should be performed under optimal conditions. Considering that patients with diabetes tend to have small pupils due to autonomic neuropathy,23,24 it is not surprising that the accuracy of nonmydriatic fundus photography has been shown to be enhanced if performed through dilated pupils. ls ,22 We thus have chosen to perform both ophthalmoscopy and fundus photography with a nonmydriatic camera through pupils dilated pharmacologically. We compare the two methods in the diagnosis and grading of diabetic retinopathy, as well as in the detection of specific ophthalmic lesions such as hemorrhages and microaneurysms, hard exudates, nerve fiber layer infarcts (soft exudates), central and peripheral new vessels, and macular edema.
Methods A cohort of 927 (571 women and 356 men) Oklahoma Indians with noninsulin-dependent diabetes were originally recruited between 1972 and 1980 for a study of the vascular complications of diabetes. 25 After an average follow-up period of 12.7 years, 410 (275 women and 135 men) participants underwent a repeat eye examination that included ophthalmoscopy and fundus photography with a nonmydriatic camera, both performed through dilated pupils. A total of 795 eyes were examined using both methods. The mean age of participants at follow-up was 60.3 (standard deviation, ±8.4) years, with a mean duration of diabetes of 17.3 (standard deviation, ±5.3) years.26
Ophthalmologic Examination At follow-up, 900 (a fundus examination lens that is used in combination with a slit-lamp microscope) and
indirect ophthalmoscopy were performed by experienced retinologists (RK, RB, CPW) after instillation of mydriatic agents, 1% tropicamide and 2.5% phenylephrine hydrochloride. The approximate numbers of dot hemorrhages and microaneurysms and larger (blot and flame) hemorrhages were recorded as well as the number of nerve fiber layer infarcts and hard exudates. In addition, the definite or questionable presence of intraretinal microvascular abnormalities, macular edema, fibrous proliferation, neovascularization (on the disc and periphery), vitreous or preretinal hemorrhage, and tractional retinal detachment were noted. Visual acuity with correction was measured by a Snellen chart. Any difficulties with visualization of retinal detail also were noted. In addition, fundus photographs of each eye were taken in duplicate using a nonmydriatic 45° camera (Canon CR4-45 non-myadric, Japan) through dilated pupils. Photographs were centered on the macula, corresponding to Standard Field #2.27 Two photographs per eye were available for 88% of the eyes, and the remaining 12% had only one photograph available. All slides were sent to the University of Wisconsin Fundus Photograph Reading Center. The grading system was based on a modification of the Airlie House Classification Scheme. 27- 3o Photographs were examined in random order to minimize possible bias. Grading involved concurrent examination of both right and left eyes. Artifacts, poor focus, and poor field definition interfering with the gradability of photographs were noted. In addition to overall retinopathy grade, the definite or questionable presence of retinal lesions, as described above for ophthalmoscopy, also was recorded. For the fundus photographs, the definition of maculopathy was limited to significant macular edema as defined by the presence of hard exudate in a configuration to suggest edema in the center of the macula or within 500 Jim of the center and at least 0.5 disc diameter in size. To simplify the comparison of grading using the two methods, three levels of retinopathy-no retinopathy, non-PDR, and PDR-were used. Non-PDR was defined by the presence of any microaneurysms, hemorrhages, hard exudates, nerve fiber layer infarcts, or intraretinal microvascular abnormalities. Proliferative diabetic retinopathy was defined by the presence of neovascularization, vitreous hemorrhage, or fibrous proliferation. The presence of lesions severe enough to satisfy the Diabetic Retinopathy Study30 criteria for high-risk proliferative retinopathy also were noted. In all cases, examiners were blinded to the initial retinopathy status at baseline examination. Fundus photographs were graded without any information on patient status or ophthalmologic examination results.
Statistical Analysis The total agreement between the two methods in diagnosing retinopathy was determined. In addition, the kappa statistic (K), an intraclass correlation coefficient, and its 95% confidence interval were computed to take into consideration the probability that the agreement between the
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Table 1. Diagnosis of Retinopathy by Ophthalmoscopy and Fundus Photography Fundus Photography
No Retinopathy
Non-PDR
PDR
Ungradable
Total
No retinopathy Non-PDR PDR Ungradable
213 51 1
0
0
35 376 8 2
5 41 2
33 19 4 5
281 451 54 9
Total
265
421
48
61
795
Ophthalmoscopy
PDR
=
proliferative diabetic retinopathy.
two methods was due to chance. 31 The kappa statistic also was used to determine the agreement between the methods for the detection of specific retinal lesions described above.
Results Quality of Examinations Of the 795 eyes examined using both diagnostic methods, 9 (1.1 %) could not be evaluated by ophthalmoscopy. In six of these eyes, poor visualization was attributable to cataracts; in the others, poor pupillary dilation, glaucoma, and severe corneal opacity were noted. In an additional 160 (20.1 %) eyes, retinal detail was noted to be at least in part difficult to visualize, again most often because of cataracts. When evaluated by the fundus photograph readers, 61 (7.7%) photographs were deemed ungradable, most often because of poor focus. Of these, 31 (50.8%) eyes were noted to have cataracts obscuring the funduscopic examination, 10 (16.4%) had severe corneal opacity, and 4 (6.6%) had vitreous opacity. (Of note, in 55 of these cases, retinal detail also was visualized poorly by ophthalmoscopic examination.) In another 84 photographs (10.6%), part of the retina was ungradable (34 of these also were visualized poorly by ophthalmoscopy). Whether associated with cataracts, corneal opacity, or technical difficulties, poor focus was the most common factor of interference with the gradability of photographs. Overall, 12.5% were considered poorly focused, and an additional 13.6% were borderline. A total of 786 eyes were gradable by ophthalmoscopy, and 734 were gradable by fundus photography with a nonmydriatic camera, both performed through dilated pupils. In all, 730 eyes were examined by both methods with gradable results.
Diagnosis of Retinopathy by the Two Methods Of the 795 eyes examined using both methods, 504 (63.4%) had some form of retinopathy diagnosed by ophthalmoscopy through dilated pupils; 469 (59.0%) had retinopathy by fundus photography through dilated pupils; and a total of 544 (68.4%) received the diagnosis by
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either method (Table 1). Proliferative diabetic retinopathy was diagnosed in 54 (6.8%) eyes by ophthalmoscopy, in 48 (6.0%) by fundus photography, and in 61 (7.7%) by either method. Of the 730 eyes that were gradable using both methods, the overall agreement between the two methods in diagnosing no retinopathy, non-PDR, or PDR, was 86.3%. To take into account the probability that agreement between the two methods was due to chance, the kappa statistic was calc;ulated. Overall, K was 0.74 (95% confidence interval [CI], 0.70-0.79; P < 0.0001), representing excellent agreement beyond chance. 31 For the diagnosis of any retinopathy, the agreement was 88.1% (K = 0.74; 95% CI, 0.69-0.79; P < 0.0001), and for the diagnosis of PDR, the agreement was 98.1% (K = 0.84; 95% CI, 0.760.92; P < 0.0001).
Characteristics of Participants by Agreement of Diagnoses Characteristics of those participants whose diagnoses using the two methods were in agreement were compared with those whose diagnoses differed. Results for the right eye only are presented in Table 2. Results for the left eye were not significantly different. Sex and duration of diabetes were not significantly different between the two groups. Not surprisingly, factors that limited the quality of examination by either method were significantly more common in the group with differing diagnoses. For example, it was more commonly reported in this group that retinal detail was not easily visualized by ophthalmoscopy (25.0% versus 11.5% in the group with diagnoses in agreement) and that fundus photographs were poorly focused (29.2% versus 13.0%) and partly ungradable (20.8% versus 10.1 %). That cataracts and visual impairment were more often observed in the group with differing diagnoses may explain the significantly greater average age of this group. Discrepancies in Diagnoses To examine the basis for discrepancies in diagnoses by the two methods, the detection of specific retinal lesions was compared. Table 3 lists the overall frequency of retinal lesions noted by fundus photography and by ophthalmoscopy. The most common lesions were hemorrhages and microaneurysms, hard exudates, and nerve fiber layer
Lee et al . The Diagnosis of Diabetic Retinopathy Table 2. Characteristics for Agreement and Disagreement between Ophthalmoscopy and Fundus Photography (right eye only) Characteristic No. Sex F M Age (yrs) . Mean ± SD Duration of diabetes (yrs) Mean ± SD Visual acuity· (%) Normal Impaired Blind % with retinal detail not easily visible by ophthalmoscopy % with cataracts % with aphakia % with artifact on photographst % with poorly focused photographs % with part of field ungradable (photograph)
so =
Agreement
p
Disagreement
316
48
210 (66.5%) 106 (33.5%)
32 (66.7%) 16 (33.3%)
0.977
59.6 ± 8.4
63.0 ± 7.6
0.009
17.2±5.1
16.9 ± 4.6
0.706
66.2 28.4 5.6
55.3 36.8 7.9
0.417
11.5 9.2 9.5 98.4 13.0 10.1
25.0 22.9 12.5 100.0 29.2 20.8
0.010 0.005 0.516 0.380 0.004
0.D31
standard deviation.
* Visual acuity is defined by the right eye only.
t Artifacts include haze, dust/dirt, lashes, uneven illumination, and central dot artifact.
infarcts. Hard exudates were more frequently detected by nonmydriatic fundus photography than by ophthalmoscopy. However, vitreous hemorrhage, tractional retinal detachment, and macular edema were more frequently detected by ophthalmoscopy. Four categories of discrepancies between diagnoses by the two methods were defined as follows: category A, any retinopathy diagnosed by fundus photography only; category B, any retinopathy diagnosed only by ophthalmoscopy; category C, PDR diagnosed by fundus photography only; and category D, PDR diagnosed only by ophthalmoscopy (Table 4). Of the 35 (4.4%) eyes with retinopathy as diagnosed by fundus photography only (category A), the most common reason was detection of hemorrhages and microaneurysms not seen by ophthalmoscopy (31/ 35). In these patients, hard exudates (14/35) and nerve fiber layer infarcts (7/35) also were more often missed by ophthalmoscopy. In all of the 52 (6.5%) eyes that had retinopathy as diagnosed by ophthalmoscopy only (category B), hemorrhages and microaneurysms were seen which were not noted by fundus photography. Also notable were findings of nerve fiber layer infarcts by ophthalmoscopy only in 24 of the 52 eyes. In all but one of the 52 eyes, non-PDR was diagnosed by ophthalmoscopy; in one case, fibrous proliferation was seen, and the patient received a diagnosis of PDR. However, this case was not referred because no new active vessels were observed. There were five (0.6%) eyes in which PDR was diagnosed by fundus photography but not by ophthalmoscopy
(category C); all five eyes had non-PDR as diagnosed by ophthalmoscopy. In none of the eyes did the proliferative retinopathy satisfy the high-risk criteria. There were nine (1.1 %) eyes in which PDR was diagnosed by ophthalmoscopy only (category D). All but one eye had non-
Table 3. Frequency of Lesions by Fundus Photography and Ophthalmoscopy Fundus Photography (n = 734) Lesion
Ophthalmoscopy (n = 786)
No.
(%J
No.
(%J
Hemorrhages and microaneurysms
396
(54.0)
263
(35.8)
Nerve fiber layer infarcts
231
(31.5)
442 164 268
(56.2)
Hard exudate Intraretinal microvascular abnormalities
(20.8) (34.1)
44
(6.0)
55
(7.0)
Neovascularization (disc)
32 18
(4.4) (2.5)
41 16
(2.0)
Neovascularization (periphery)
18
(2.5)
14
(1.8)
7 3 36
(1.0)
14
(1.8)
(0.4)
15
(1.9)
(4.9)
80
(10.2)
Fibrous proliferation
Vitreous hemorrhage Retinal detachment Macular edema
(5.2)
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Ophthalmology
Table 4. Discrepancies between Diagnoses by Ophthalmoscopy and Fundus Photography A
Lesion Hemorrhages and microaneurysms Hard exudate Nerve fiber layer infarcts Intraretinal microvascular abnormalities Fibrous proliferation Neovascularization (disc) Neovascularization (periphery) Vitreous hemorrhage Retinal detachment Macular edema
OPH:NoRet NMFP: Yes Ret (n = 35, 4.4%)
31
14 7
B OPH: Yes Ret NMFP:NoRet (n = 52, 6.5%)
D
C OPH:No PDR NMFP: Yes PDR (n = 5, 0.6%)
OPH:YesPDR NMFP:NoPDR (n = 9,1.1%)
1
6 3
52 4 24 1 1
4
4 1
4
OPH = ophthalmoscopy through dilated pupils; Ret = any retinopathy; NMFP = nonmydriatic fundus photography through dilated pupils; PDR = proliferative diabetic retinopathy.
PDR as diagnosed by fundus photography. In two eyes, neovascularization severe enough to warrant referral was seen only by ophthalmoscopy. In one of the two eyes, the entire disc and macula were ungradable by photography; the other eye was graded as having severe non-PDR by photography. Most discrepancies involved discriminating between intraretinal microvascular abnormalities versus early peripheral neovascularization or involved peripheral neovascularization outside the photographic field.
Detection of Specific Lesions Using the Two Methods We also compared the agreement rates and the intraclass correlation coefficients, K, between the two methods for the detection of specific lesions (Table 5). Agreement between the two diagnostic methods was highest for the following lesions: fibrous proliferation, hemorrhages and microaneurysms, hard exudates, and nerve fiber layer infarcts. Correlation was low for intraretinal microvascular abnormalities, tractional retinal detachment, and peripheral neovascularization. The agreement rates for vitreous hemorrhage and maculopathy were not as high as we expected. In three of the eight eyes in which vitreous hemorrhage was reported by ophthalmoscopy but not by fundus photography, the photographs were recorded as partly or completely ungradable. When tractional retinal detachment was analyzed more closely, we found that 13 of the 16 eyes with detachment were seen only by ophthalmoscopy. Of these 13 eyes, four photographs were ungradable, and six were recorded as having high-risk retinopathy and thus would still have been referred. In the remaining three eyes, fibrous proliferation was noted, although detachment was not seen. Significant macular edema was reported in only 36 (4.9%) eyes by photography, whereas maculopathy was reported in 80 (10.2%) eyes by ophthalmoscopy.
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Discussion In 1988, the American Diabetes Association issued a position statement outlining eye care guidelines for patients with diabetes mellitus 32 in which ophthalmologic examinations are recommended annually for patients older than 30 years of age and after a 5-year duration of diabetes in patients 12 to 30 years of age. Also suggested in the guidelines are more frequent examinations if there is an indication of abnormalities. American Indians in Oklahoma represent a population that can benefit from frequent screening and early therapeutic intervention. The prevalence of diabetes in adult Oklahoma Indians is thought to exceed 30%Y Diabetic retinopathy is prevalent in this population. 25 ,26,34 In our cohort, over an average 12.7-year follow-up interval, we have found a crude incidence of retinopathy to be 74.0% and ofPDR, 18.6%, based on follow-up fundus photographs. 26 The high rates of diabetic retinopathy seen in this study, though unfortunate, facilitated a statistically powerful comparison of two diagnostic methods. Moreover, the nature of this longterm follow-up study of a large population has resulted in what we consider to be a representative sample of the spectrum of diabetic retinopathy. Early diagnosis to facilitate therapeutic intervention is essential in this population at high risk for visual impairment. An accurate and cost-effective screening method is critical. Several reports from the United Kingdom have compared ophthalmoscopy with mydriasis and nonmydriatic fundus photography through undilated pupils. 15-20 Some of the studies have suggested that the high rates of ungradability of fundus photographs limit its efficacy and reliability as a screening too1. 18 Klein et al,15 however, compared nonmydriatic fundus photography with and without mydriasis and demonstrated that focus problems, as well as problems with media opacities and other artifacts, were significantly lower when photographs were
Lee et al . The Diagnosis of Diabetic Retinopathy Table
5. Agreement and Kappa Statistics for Ophthalmoscopy and Fundus Photography for Retinal Lesions Overall Agreement
Lesion
No.
(%)
Hemorrhages and microaneurysms Hard exudate Nerve fiber layer infarcts Intraretinal microvascular abnormalities Fibrous proliferation Neovascularization (disc) Neovascularization (periphery) Vitreous hemorrhage Retinal detachment Macular edema
579 598 579 656 713 712 708 721 717 671
(79.3) (81.9) (79.3) (89.9) (97.7) (97.5) (97.0) (98.8) (98.2) (91.9)
CI
=
Kappa Statistic K
(95% CI)
0.581 (0.522-0.640) 0.570 (0.508-0.632) 0.538 (0.473-0.602) 0.191 (0.074-0.309) 0.734 (0.613-0.855) 0.458 (0.247-0.669) 0.297 (0.086-0.509) 0.465 (0.170-0.760) 0.230 (-0.036-0.490) 0.440 (0.324-0.557)
P
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
confidence interval.
taken through dilated pupils; they found 12.7% and 6.8% of photographs ungradable for undilated and dilated pupils, respectively. Similarly, Mollentze et ae 2 reported that in a group of 86 black patients with an average duration of diabetes of 9.5 years, 9.9% and 3.5% of fundus photographs were ungradable before and after pupillary dilation, respectively. In our study, 7.7% of the fundus photographs were ungradable, a comparable figure. Undoubtedly, taking duplicate photographs improved our rates of gradability. Pharmacologic dilation may not only improve the gradability of fundus photographs, but also their accuracy. Klein et aIlS found a slightly higher agreement between seven-field stereoscopic fundus photography and nonmydriatic fundus photography performed through dilated pupils (86.5% agreement) than nonmydriatic photography through undilated pupils (82.5%). In the largest study to date, Taylor et al 19 compared ophthalmoscopy with mydriasis and nonmydriatic fundus photography (without mydriasis) in a total of 4312 eyes. We calculated an overall agreement for their data for the diagnosis of any retinopathy to be 76.8% (K = 0.437; P < 0.0001). Our greater agreement between the two methods may be attributable to the use of pharmacologic dilating agents before fundus photography with the nonmydriatic camera. We observed that pupillary dilation may be particularly important in the subset of older patients with smaller pupils and lens opacities. This may explain the lack of improvement in agreement with pupillary dilation in the study reported by Molleritze et al22 (62.2% versus 56.9% agreement before and after pupillary dilation, respectively). We are aware of only two studies in the literature that have compared these two screening methods, ophthalmoscopy and fundus photography, with both performed with pupils dilated. Kalm et al 21 examined 154 patients with type II diabetes in whom approximately 38.9% had background or preproliferative retinopathy, whereas 3.8% had POR. The authors estimated that the sensitivity rate
of fundus photography in detecting background retinopathy was 87%/97% (right/left eyes), significantly better than that for ophthalmoscopy (69%/61 %). In contrast, in our study, compared with a total of 517 eyes with retinopathy as diagnosed using either method, the sensitivity rates of fundus photography and ophthalmoscopy were 90% and 93%, respectively. These results, however, are not directly comparable because our cohort included a larger number of patients with severe retinopathy. In the smaller study by Mollentze et al,22 the agreement rate between the two diagnostic methods was a strikingly low 56.9%, despite the use of mydriasis. In their study, of the 51 eyes with any retinopathy as diagnosed by fundus photography, 18 (36%, corresponding to category A; Table 4) were missed by ophthalmoscopy. Similarly, of the 70 eyes with any retinopathy as diagnosed by ophthalmoscopy, 37 (51 %, category B; Table 4) were missed by photography. The discrepancies in the diagnosis of POR were even more dramatic: of the 20 eyes with POR as diagnosed by ophthalmoscopy, only 2 were diagnosed by fundus photography. An analysis of the specific lesions missed by the two methods would be useful for interpreting these results. Although we found the overall agreement between the two methods in diagnosing retinopathy to be significant, fundus photography appeared to be less sensitive than ophthalmoscopy in the detection of such lesions as intraretinal microvascular abnormalities, nerve fiber layer infarcts, peripheral neovascularization, and tractional retinal detachment. It is possible that these lesions, particularly new vessels in the periphery, may have lain outside the single field taken with the non mydriatic camera. Klein et al,15 citing unpublished data, have reported that an estimated 8% to 15% of retinopathy may be missed using this method for this reason. Similarly, we suspect that the discrepancies in diagnoses of vitreous hemorrhage may be due to the settling of hemorrhage below the field of fundus photography.
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Given the limited detection of new vessels in the periphery, neither screening method appears optimal for the diagnosis of neovascularization. In our study, of the 42 eyes with new central or peripheral vessels detected by either method, 25 (59.5%) were detected by ophthalmoscopy and 29 (69.0%) by fundus photography. Although not directly comparable, these are similar to the sensitivity rates of 77.5% for ophthalmoscopy and 65.0% for nonmydriatic fundus photography (through undilated pupils) reported by Taylor et al. I9 For eyes with high-risk diabetic retinopathy as diagnosed by ophthalmoscopy, we found only two in which fundus photography missed the diagnosis of PDR, one of which was most likely due to the poor quality of the photograph. Klein et al 15 reported that in their study none of the 14 eyes with proliferative retinopathy as diagnosed by seven-field stereoscopic photography was missed by non mydriatic fundus photography. Another study from that group II concluded that ophthalmoscopy may undercall proliferative retinopathy. Thus, there also may have been cases of PDR in our study that were not detectable by either method. 13 Without a reference method such as fluorescein angiography or sevenfield stereoscopic fundus photography, we are unable to rule out this possibility. Our finding that ophthalmoscopy is superior to fundus photography in the detection of maculopathy is in contrast to previous reports l7 ,19 which have shown non mydriatic fundus photography to be the superior method. We explain this discrepancy in part by noting that the criteria for maculopathy were different for the two methods, in that only clinically significant macular edema was recorded by the fundus photograph readers. In 13 ofthe 21 patients with discrepancies in diagnoses of macular edema not attributable to poor-quality photographs, the pattern of edema, described as diffuse or cystoid, may have been difficult to assess with the two-dimensional view by photography. Without stereoscopic views, macular edema is difficult to assess by fundus photography, especially iffew hard exudates are present. 35 We suggest that all eyes with retinopathy and deterioration in visual acuity need further retinal evaluation for macular thickening. The advantages of ophthalmoscopy through dilated pupils include the ability to examine peripheral areas of the retina which may not be photographed, even among the seven fields of stereoscopic fundus photography. Moreover, the stereoscopic view allows for a more accurate evaluation of macular thickening. 35 The disadvantages are that despite negligible costs, it requires a skill which currently appears to be satisfactory only for trained ophthalmologists and retinal specialists, 12-14 although Awh et al 14 have recently demonstrated the effectiveness of a short training course for nonophthalmologists in improving the accuracy of diagnoses by ophthalmoscopy. In addition, ophthalmoscopy only allows for a limited examination time and does not produce a permanent record for comparison in subsequent examinations. In addition to the advantages of nonmydriatic fundus photography, it provides such a permanent record, which may be useful for teaching in educational settings. 19 The images can be taken
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by trained technicians, and when necessary, photographs can be taken without dilating the pupils with less compromise to accuracy than for ophthalmoscopy.15 Given that the age and history of patients with diabetes can bias the diagnosis of diabetic retinopathy, II unbiased grading of fundus photographs can be ensured if graders are not involved in the examination. Nonmydriatic fundus photography has been deemed comparable with stereoscopic photography in terms of patient acceptance, ease of use, and time required. II The major disadvantage of nonmydriatic fundus photography compared with ophthalmoscopy is the higher rate of ungradability. These rates may be improved by taking duplicate photographs and by dilating pupils. Although the single nonstereo view limits the detection of macular edema, as well as peripheral lesions such as new vessels and vitreous hemorrhage, we have nevertheless found the method overall to be comparable with ophthalmoscopy in the diagnosis of nonproliferative and proliferative retinopathy. From our results, if any retinopathy detected by nonmydriatic fundus photography is considered as the referral criterion in a screening program, 29% (213/730) eyes would not need a full examination. The sensitivity and specificity rates were 89.2% and 85.8%, respectively, when compared with ophthalmoscopy. If this criterion is used, 52 (10.8%) eyes with retinopathy would be missed. One (1.9%) of these eyes had clinically significant macular edema and one (1.9%) had PDR. However, these two eyes were classified as having nondiabetic retinopathy by nonmydriatic fundus photography. If the referral criteria also include questionable retinopathy and nondiabetic retinopathy detected by nonmydriatic fundus photography, the sensitivity rate of detecting retinopathy would increase to 91.5%, and the specificity rate would decrease to 83.1 % when comparing with ophthalmoscopy. Only 8.5% of the eyes with retinopathy would be missed and none of the eyes with clinically significant macular edema and PDR would be missed in the screening program. In this case, 27.5% of eyes would not need a full examination in our study. Considering the high prevalence of retinopathy in our Indian population with diabetes, the latter criteria may be more favorable in a screening program using nonmydriatic fundus photography. We therefore conclude that nonmydriatic fundus photography holds great promise as a cost-effective screening method for diabetic retinopathy. As Klein et al 15 have suggested, ophthalmic technicians can be trained to carry out the American Diabetes Association-recommended screening procedures, including testing visual acuity, measuring intraocular pressure, and taking retinal photographs using a nonmydriatic camera. We propose that, unless contraindicated, fundus photography should be performed through dilated pupils for greater gradability and accuracy. In our study, all of the photographs were taken by three trained technicians, except 18 which were taken by an optometrist. In lieu of full ophthalmologic examinations, this approach may enable patients, including Oklahoma Indians with diabetes, to have access to routine screening which otherwise might not be available,
Lee et al . The Diagnosis of Diabetic Retinopathy thereby providing an opportunity to avert the tragic and costly consequences of diabetic retinopathy and other eye diseases. Taylor et al 19 have reported the success of a mobile van equipped with a fundus camera to screen thousands of patients with diabetes in the United Kingdom. A similar system would be particularly beneficial for the predominantly rural population of American Indians in Oklahoma. A referral method would have to be established for patients whose photographs suggest any form of retinopathy as well as for those with questionable retinopathy, nondiabetic retinopathy, and poor-quality fundus photographs, in addition to those suspected to be at high risk because of an acute deterioration in visual acuity. Acknowledgments. The authors thank the Oklahoma
Indian patients for their participation; Oklahoma City area Indian Health Service, staff at the Indian Health Service hospitals and clinics in Lawton, Shawnee, Anadarko, Pawnee, Clinton, Ada, White Eagle, Pawhuska, Wewoka, and Carnegie, and the Oklahoma City Urban Clinic for their cooperation and assistance; Russ Burris and Andy Wheeler of the Dean McGee Eye Institute (Oklahoma City, OK), Dr. Greg Ketcher of the Lawton Indian Hospital, and Paul Cheng for taking the fundus photographs; and Dr. Ronald Klein and his associates at the University of Wisconsin Fundus Photograph Reading Center for grading the fundus photographs.
References I. Centers for Disease Control. Prevalence and incidence of diabetes mellitus-in United States, 1980-1987. MMWR (Morb Mortal Wkly Rep) 1990;39:809-12. 2. National Society to Prevent Blindness. Operational Research Dept. Vision Problems in the U.S.: A Statistical Analysis. [New York]: The Society, 1980. 3. Klein R, Klein BEK. Vision disorders in diabetes. In: National Diabetes Data Group. Diabetes in America: Diabetes Data Compiled 1984. [Bethesda, MD]: US Dept. of Health and Human Services, 1985; chap. XIII. 4. Caird FI, Pirie A, Ramsell TG. Diabetes and the Eye. Oxford: Blackwell Scientific, 1968. 5. Herman WH, Teutsch SM, Sepe SJ, et al. An approach to the prevention of blindness in diabetes. Diabetes Care 1983;6:608-13. 6. The Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic retinopathy. Clinical application of Diabetic Retinopathy Study (DRS) findings, DRS Report Number 8. Ophthalmology 1981 ;88: 583-600. 7. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report Number I. Arch OphthalmoI1985;103:1796-1806. 8. Blankenship GW. Fifteen-year argon laser and xenon photocoagulation results of Bascom Palmer Eye Institute'S patients participating in the Diabetic Retinopathy Study. Ophthalmology 1991 ;98: 125-8. 9. The Diabetes Control and Complications Trial Research Group. Color photography vs fluorescein angiography in the detection of diabetic retinopathy in the Diabetes Control and Complications Trial. Arch Ophthalmol 1987;105: 134451.
10. Palmberg P, Smith M , Waltman S, et al. The natural history of retinopathy in insulin-dependent juvenile-onset diabetes. Ophthalmology 1981 ;88:613-18. 11. Moss SE, Klein R, Kessler SO, Richie KA. Comparison between ophthalmoscopy and fundus photography in determining severity of diabetic retinopathy. Ophthalmology 1985;92:62-7. 12. Sussman EJ, Tsiaras WG, Soper KA. Diagnosis of diabetic eye disease. JAMA 1982;247:3231-4. 13. Nathan OM, Fogel HA, Godine JE, et al. Role of diabetologist in evaluating diabetic retinopathy. Diabetes Care 1991;14:26-33. 14. Awh CC, Cupples HP, Javitt Jc. Improved detection and referral of patients with diabetic retinopathy by primary care physicians. Effectiveness of education. Arch Intern Med 1991 ;151: 1405-8. 15. Klein R, Klein BEK, Neider MW, et al. Diabetic retinopathy as detected using ophthalmoscopy, a nonmydriatic camera and a standard fundus camera. Ophthalmology 1985;92: 485-91. 16. Ryder REJ, Vora JP, Atiea JA, et al. Possible new method to improve detection of diabetic retinopathy: Polaroid nonmydriatic retinal photography. Br Med J 1985;291 :1256-
7.
17. Williams R, Nussey S, Humphry R, Thompson G. Assessment of non-mydriatic fundus photography in detection of diabetic retinopathy. Br Med J 1986;293: 1140-2. 18. Jones 0, Dolben J, Owens DR, et al. Non-mydriatic Polaroid photography in screening for diabetic retinopathy: evaluation in a clinical setting. Br Med J 1988;296: 1029-30. 19. Taylor R, Lovelock L, Tunbridge WMG, et al. Comparison of non-mydriatic retinal photography with ophthalmoscopy in 2159 patients: mobile retinal camera study. BMJ 1990;301: 1243-7. 20. Mohan R, Kohner EM, Aldington SJ, et al. Evaluation of a non-mydriatic camera in Indian and European diabetic patients. Br J Ophthalmol 1988;72:841-5. 21. Kalm H, Egertsen R, Blohme G. Non-stereo fundus photography as a screening procedure for diabetic retinopathy among patients with type II diabetes. Compared with 600 enhanced slit-lamp examination. Acta Ophthalmol 1989;67: 546-53. 22. Mollentze WF, Stulting AA, Steyn AF. Ophthalmoscopy versus non-mydriatic fundus photography in the detection of diabetic retinopathy in black patients. S Afr Med J 1990;78:248-50. 23. Smith SE, Smith SA, Brown PM, et al. Pupillary signs in diabetic autonomic neuropathy. Br Med J 1978;2:924-7. 24. Smith SA, Smith SE. Reduced pupillary light reflexes in diabetic autonomic neuropathy. Diabetologia 1983;24:330-2. 25. West KM, Erdreich U , Stober JA. A detailed study of risk factors for retinopathy and nephropathy in diabetes. Diabetes 1980;29:501-8. 26. Lee ET, Lee VS, Lu M, Russell D. Development of proliferative retinopathy in NIDDM. A follow-up study of American Indians in Oklahoma. Diabetes 1992;41:359-67. 27. Early Treatment Diabetic Retinopathy Study Research Group (ETDRS). Manual of Operations. Baltimore: ETDRS Coordinating Center, Univ. of Maryland School of Medicine, 1980. Available From: National Technical Information Service (Accession No. PB85-223006); chaps. 12,18. 28. Klein BEK, Davis MD, Segal P, et al. Diabetic retinopathy. Assessment of severity and progression. Ophthalmology 1984;91: 10-17.
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29. Klein R, Klein BEK, Moss SE, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. IX. Four-year incidence and progression of diabetic retinopathy when age at diagnosis is less than 30 years. Arch Ophthalmol 1989; 107: 237-43. 30. Diabetic Retinopathy Study Research Group. Report 7. A modification of the Airlie House classification of diabetic retinopathy. Invest Ophthalmol Vis Sci 1981 ;21 :21 0-26. 31. Fleiss JL. Statistical Methods for Rates and Proportions, 2nd ed. New York: John Wiley, 1981. 32. American Diabetes Association. Position statement. Eye care
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guidelines for patients with diabetes mellitus. Diabetes Care 1988;11:745-6. 33. West KM. Diabetes in American Indians and other native populations of the New World. Diabetes 1974;23:841-55. 34. Newell SE, Tolbert B, Bennett J, Parsley TL. The prevalence and risk of diabetic retinopathy among Indians of southwest Oklahoma. J Okla State Med Assoc 1989;82:414-24. 35. Kinyoun J, Barton F, Fisher M, et al. Detection of diabetic macular edema. Ophthalmoscopy versus photographyEarly Treatment Diabetic Retinopathy Study Report Number 5. Ophthalmology 1989;96:746-51.
Ophthalmoscopy versus Fundus Photography Vivian S. Lee, MD, DPhil, l Ronald M. Kingsley, MD, 2 Elisa T. Lee, PhD, 3 Min Lu, MD, MPH,4 Dana Russell, MPH,4 Nabih R. Asal, PhD,s Reagan H. Bradford, Jr., MD, 2 C. P. Wilkinson, MD2 Purpose: To compare fundus photography with ophthalmoscopy in the detection of diabetic retinopathy. Methods: Ophthalmoscopy and fundus photographs with a nonmydriatic camera, both performed through dilated pupils, were compared to diagnose retinopathy in a cohort of 410 Oklahoma Indians with noninsulin-dependent diabetes mellitus. A total of 795 eyes were examined using both methods. The mean age of participants was 60.3 years, with a mean duration of diabetes of 17.3 years. Results: An overall agreement of 86.3% with a kappa statistic K of 0.74 was found between ophthalmoscopy and fundus photography with a nonmydriatic camera. For the diagnosis of proliferative diabetic retinopathy, K = 0.84 with an agreement of 98.1 %. With a total of 61 cases of proliferative retinopathy diagnosed by either method in our study, ophthalmoscopy alone detected 88.5% and fundus photography, 78.7%. When compared on a lesion-by-Iesion basis, agreement between the two diagnostic methods was highest for non proliferative retinopathy, as well as fibrous proliferation. Conclusion: The fundus photography with a non mydriatic camera, performed with mydriasis, is comparable to ophthalmoscopy for the detection of retinopathy. It may prove to be a suitable, cost-effective method for routine screening in diabetes clinics, provided ophthalmologic referral is ensured for those with a diagnosis of any form of retinopathy, questionable retinopathy, nondiabetic retinopathy, those with poor quality photographs, as well as those with acute changes in visual acuity. Ophthalmology 1993; 100: 1504-1512
With diabetes diagnosed in approximately 6.8 million persons in the United States,l diabetic retinopathy is the leading cause of new blindness in adults in the United Originally received: December 2, 1992. Revision accepted: March 29, 1993. I Department of Radiology, Duke University Medical School, Durham. 2 Dean McGee Eye Institute, Oklahoma City. 3 Center for Epidemiologic Research and Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City. 4 Center for Epidemiologic Research, University of Oklahoma Health Sciences Center, Oklahoma City.
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States?,3 Progression from nonproliferative diabetic retinopathy (non-PDR) to PDR poses one of the greatest threats to the vision of these patients. If untreated, PDR causes blindness in more than 50% of affected individuals. 4 ,5 The effectiveness of treatment with laser photocoDepartment of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City. Supported by grant ROI HL 34843 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. 5
Reprint requests to Elisa T, Lee, PhD, Center for Epidemiologic Research, College of Public Health, University of Oklahoma Health Sciences Center, PO Box 26901, Oklahoma City, OK 73190.
Lee et al . The Diagnosis of Diabetic Retinopathy agulation in lessening, though not reversing, the progression of retinopathy, maculopathy, and subsequent visual impairment emphasizes the importance of early diagnosis for early intervention. 6- s Several methods for diagnosing retinopathy are available, including fluorescein angiography, seven-field stereoscopic fundus photography with seven standard fields, fundus photography with a nonmydriatic camera, and ophthalmoscopy.9-22 While angiography and stereoscopic fundus photography are considered the gold standards,9 they are expensive and thus may not be considered feasible for routine screening nor for large-scale epidemiologic studies. Fundus photography with a nonmydriatic camera hails a new era in screening for retinopathy.ll,15-22 It is a faster, less-expensive option. The controversy surrounding the method has focused on questions of accuracy and on high rates of un gradable photographs. To date, most studies comparing the two potential screening methods, nonmydriatic fundus photography and ophthalmoscopy, have elected to perform the photography with undilated pupils. 16-20 While these methods cannot be expected to perform as well as the gold standards, they can appropriately be compared with each other as potential screening methods. As such, they should be performed under optimal conditions. Considering that patients with diabetes tend to have small pupils due to autonomic neuropathy,23,24 it is not surprising that the accuracy of nonmydriatic fundus photography has been shown to be enhanced if performed through dilated pupils. ls ,22 We thus have chosen to perform both ophthalmoscopy and fundus photography with a nonmydriatic camera through pupils dilated pharmacologically. We compare the two methods in the diagnosis and grading of diabetic retinopathy, as well as in the detection of specific ophthalmic lesions such as hemorrhages and microaneurysms, hard exudates, nerve fiber layer infarcts (soft exudates), central and peripheral new vessels, and macular edema.
Methods A cohort of 927 (571 women and 356 men) Oklahoma Indians with noninsulin-dependent diabetes were originally recruited between 1972 and 1980 for a study of the vascular complications of diabetes. 25 After an average follow-up period of 12.7 years, 410 (275 women and 135 men) participants underwent a repeat eye examination that included ophthalmoscopy and fundus photography with a nonmydriatic camera, both performed through dilated pupils. A total of 795 eyes were examined using both methods. The mean age of participants at follow-up was 60.3 (standard deviation, ±8.4) years, with a mean duration of diabetes of 17.3 (standard deviation, ±5.3) years.26
Ophthalmologic Examination At follow-up, 900 (a fundus examination lens that is used in combination with a slit-lamp microscope) and
indirect ophthalmoscopy were performed by experienced retinologists (RK, RB, CPW) after instillation of mydriatic agents, 1% tropicamide and 2.5% phenylephrine hydrochloride. The approximate numbers of dot hemorrhages and microaneurysms and larger (blot and flame) hemorrhages were recorded as well as the number of nerve fiber layer infarcts and hard exudates. In addition, the definite or questionable presence of intraretinal microvascular abnormalities, macular edema, fibrous proliferation, neovascularization (on the disc and periphery), vitreous or preretinal hemorrhage, and tractional retinal detachment were noted. Visual acuity with correction was measured by a Snellen chart. Any difficulties with visualization of retinal detail also were noted. In addition, fundus photographs of each eye were taken in duplicate using a nonmydriatic 45° camera (Canon CR4-45 non-myadric, Japan) through dilated pupils. Photographs were centered on the macula, corresponding to Standard Field #2.27 Two photographs per eye were available for 88% of the eyes, and the remaining 12% had only one photograph available. All slides were sent to the University of Wisconsin Fundus Photograph Reading Center. The grading system was based on a modification of the Airlie House Classification Scheme. 27- 3o Photographs were examined in random order to minimize possible bias. Grading involved concurrent examination of both right and left eyes. Artifacts, poor focus, and poor field definition interfering with the gradability of photographs were noted. In addition to overall retinopathy grade, the definite or questionable presence of retinal lesions, as described above for ophthalmoscopy, also was recorded. For the fundus photographs, the definition of maculopathy was limited to significant macular edema as defined by the presence of hard exudate in a configuration to suggest edema in the center of the macula or within 500 Jim of the center and at least 0.5 disc diameter in size. To simplify the comparison of grading using the two methods, three levels of retinopathy-no retinopathy, non-PDR, and PDR-were used. Non-PDR was defined by the presence of any microaneurysms, hemorrhages, hard exudates, nerve fiber layer infarcts, or intraretinal microvascular abnormalities. Proliferative diabetic retinopathy was defined by the presence of neovascularization, vitreous hemorrhage, or fibrous proliferation. The presence of lesions severe enough to satisfy the Diabetic Retinopathy Study30 criteria for high-risk proliferative retinopathy also were noted. In all cases, examiners were blinded to the initial retinopathy status at baseline examination. Fundus photographs were graded without any information on patient status or ophthalmologic examination results.
Statistical Analysis The total agreement between the two methods in diagnosing retinopathy was determined. In addition, the kappa statistic (K), an intraclass correlation coefficient, and its 95% confidence interval were computed to take into consideration the probability that the agreement between the
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Volume 100, Number 10, October 1993
Table 1. Diagnosis of Retinopathy by Ophthalmoscopy and Fundus Photography Fundus Photography
No Retinopathy
Non-PDR
PDR
Ungradable
Total
No retinopathy Non-PDR PDR Ungradable
213 51 1
0
0
35 376 8 2
5 41 2
33 19 4 5
281 451 54 9
Total
265
421
48
61
795
Ophthalmoscopy
PDR
=
proliferative diabetic retinopathy.
two methods was due to chance. 31 The kappa statistic also was used to determine the agreement between the methods for the detection of specific retinal lesions described above.
Results Quality of Examinations Of the 795 eyes examined using both diagnostic methods, 9 (1.1 %) could not be evaluated by ophthalmoscopy. In six of these eyes, poor visualization was attributable to cataracts; in the others, poor pupillary dilation, glaucoma, and severe corneal opacity were noted. In an additional 160 (20.1 %) eyes, retinal detail was noted to be at least in part difficult to visualize, again most often because of cataracts. When evaluated by the fundus photograph readers, 61 (7.7%) photographs were deemed ungradable, most often because of poor focus. Of these, 31 (50.8%) eyes were noted to have cataracts obscuring the funduscopic examination, 10 (16.4%) had severe corneal opacity, and 4 (6.6%) had vitreous opacity. (Of note, in 55 of these cases, retinal detail also was visualized poorly by ophthalmoscopic examination.) In another 84 photographs (10.6%), part of the retina was ungradable (34 of these also were visualized poorly by ophthalmoscopy). Whether associated with cataracts, corneal opacity, or technical difficulties, poor focus was the most common factor of interference with the gradability of photographs. Overall, 12.5% were considered poorly focused, and an additional 13.6% were borderline. A total of 786 eyes were gradable by ophthalmoscopy, and 734 were gradable by fundus photography with a nonmydriatic camera, both performed through dilated pupils. In all, 730 eyes were examined by both methods with gradable results.
Diagnosis of Retinopathy by the Two Methods Of the 795 eyes examined using both methods, 504 (63.4%) had some form of retinopathy diagnosed by ophthalmoscopy through dilated pupils; 469 (59.0%) had retinopathy by fundus photography through dilated pupils; and a total of 544 (68.4%) received the diagnosis by
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either method (Table 1). Proliferative diabetic retinopathy was diagnosed in 54 (6.8%) eyes by ophthalmoscopy, in 48 (6.0%) by fundus photography, and in 61 (7.7%) by either method. Of the 730 eyes that were gradable using both methods, the overall agreement between the two methods in diagnosing no retinopathy, non-PDR, or PDR, was 86.3%. To take into account the probability that agreement between the two methods was due to chance, the kappa statistic was calc;ulated. Overall, K was 0.74 (95% confidence interval [CI], 0.70-0.79; P < 0.0001), representing excellent agreement beyond chance. 31 For the diagnosis of any retinopathy, the agreement was 88.1% (K = 0.74; 95% CI, 0.69-0.79; P < 0.0001), and for the diagnosis of PDR, the agreement was 98.1% (K = 0.84; 95% CI, 0.760.92; P < 0.0001).
Characteristics of Participants by Agreement of Diagnoses Characteristics of those participants whose diagnoses using the two methods were in agreement were compared with those whose diagnoses differed. Results for the right eye only are presented in Table 2. Results for the left eye were not significantly different. Sex and duration of diabetes were not significantly different between the two groups. Not surprisingly, factors that limited the quality of examination by either method were significantly more common in the group with differing diagnoses. For example, it was more commonly reported in this group that retinal detail was not easily visualized by ophthalmoscopy (25.0% versus 11.5% in the group with diagnoses in agreement) and that fundus photographs were poorly focused (29.2% versus 13.0%) and partly ungradable (20.8% versus 10.1 %). That cataracts and visual impairment were more often observed in the group with differing diagnoses may explain the significantly greater average age of this group. Discrepancies in Diagnoses To examine the basis for discrepancies in diagnoses by the two methods, the detection of specific retinal lesions was compared. Table 3 lists the overall frequency of retinal lesions noted by fundus photography and by ophthalmoscopy. The most common lesions were hemorrhages and microaneurysms, hard exudates, and nerve fiber layer
Lee et al . The Diagnosis of Diabetic Retinopathy Table 2. Characteristics for Agreement and Disagreement between Ophthalmoscopy and Fundus Photography (right eye only) Characteristic No. Sex F M Age (yrs) . Mean ± SD Duration of diabetes (yrs) Mean ± SD Visual acuity· (%) Normal Impaired Blind % with retinal detail not easily visible by ophthalmoscopy % with cataracts % with aphakia % with artifact on photographst % with poorly focused photographs % with part of field ungradable (photograph)
so =
Agreement
p
Disagreement
316
48
210 (66.5%) 106 (33.5%)
32 (66.7%) 16 (33.3%)
0.977
59.6 ± 8.4
63.0 ± 7.6
0.009
17.2±5.1
16.9 ± 4.6
0.706
66.2 28.4 5.6
55.3 36.8 7.9
0.417
11.5 9.2 9.5 98.4 13.0 10.1
25.0 22.9 12.5 100.0 29.2 20.8
0.010 0.005 0.516 0.380 0.004
0.D31
standard deviation.
* Visual acuity is defined by the right eye only.
t Artifacts include haze, dust/dirt, lashes, uneven illumination, and central dot artifact.
infarcts. Hard exudates were more frequently detected by nonmydriatic fundus photography than by ophthalmoscopy. However, vitreous hemorrhage, tractional retinal detachment, and macular edema were more frequently detected by ophthalmoscopy. Four categories of discrepancies between diagnoses by the two methods were defined as follows: category A, any retinopathy diagnosed by fundus photography only; category B, any retinopathy diagnosed only by ophthalmoscopy; category C, PDR diagnosed by fundus photography only; and category D, PDR diagnosed only by ophthalmoscopy (Table 4). Of the 35 (4.4%) eyes with retinopathy as diagnosed by fundus photography only (category A), the most common reason was detection of hemorrhages and microaneurysms not seen by ophthalmoscopy (31/ 35). In these patients, hard exudates (14/35) and nerve fiber layer infarcts (7/35) also were more often missed by ophthalmoscopy. In all of the 52 (6.5%) eyes that had retinopathy as diagnosed by ophthalmoscopy only (category B), hemorrhages and microaneurysms were seen which were not noted by fundus photography. Also notable were findings of nerve fiber layer infarcts by ophthalmoscopy only in 24 of the 52 eyes. In all but one of the 52 eyes, non-PDR was diagnosed by ophthalmoscopy; in one case, fibrous proliferation was seen, and the patient received a diagnosis of PDR. However, this case was not referred because no new active vessels were observed. There were five (0.6%) eyes in which PDR was diagnosed by fundus photography but not by ophthalmoscopy
(category C); all five eyes had non-PDR as diagnosed by ophthalmoscopy. In none of the eyes did the proliferative retinopathy satisfy the high-risk criteria. There were nine (1.1 %) eyes in which PDR was diagnosed by ophthalmoscopy only (category D). All but one eye had non-
Table 3. Frequency of Lesions by Fundus Photography and Ophthalmoscopy Fundus Photography (n = 734) Lesion
Ophthalmoscopy (n = 786)
No.
(%J
No.
(%J
Hemorrhages and microaneurysms
396
(54.0)
263
(35.8)
Nerve fiber layer infarcts
231
(31.5)
442 164 268
(56.2)
Hard exudate Intraretinal microvascular abnormalities
(20.8) (34.1)
44
(6.0)
55
(7.0)
Neovascularization (disc)
32 18
(4.4) (2.5)
41 16
(2.0)
Neovascularization (periphery)
18
(2.5)
14
(1.8)
7 3 36
(1.0)
14
(1.8)
(0.4)
15
(1.9)
(4.9)
80
(10.2)
Fibrous proliferation
Vitreous hemorrhage Retinal detachment Macular edema
(5.2)
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Ophthalmology
Table 4. Discrepancies between Diagnoses by Ophthalmoscopy and Fundus Photography A
Lesion Hemorrhages and microaneurysms Hard exudate Nerve fiber layer infarcts Intraretinal microvascular abnormalities Fibrous proliferation Neovascularization (disc) Neovascularization (periphery) Vitreous hemorrhage Retinal detachment Macular edema
OPH:NoRet NMFP: Yes Ret (n = 35, 4.4%)
31
14 7
B OPH: Yes Ret NMFP:NoRet (n = 52, 6.5%)
D
C OPH:No PDR NMFP: Yes PDR (n = 5, 0.6%)
OPH:YesPDR NMFP:NoPDR (n = 9,1.1%)
1
6 3
52 4 24 1 1
4
4 1
4
OPH = ophthalmoscopy through dilated pupils; Ret = any retinopathy; NMFP = nonmydriatic fundus photography through dilated pupils; PDR = proliferative diabetic retinopathy.
PDR as diagnosed by fundus photography. In two eyes, neovascularization severe enough to warrant referral was seen only by ophthalmoscopy. In one of the two eyes, the entire disc and macula were ungradable by photography; the other eye was graded as having severe non-PDR by photography. Most discrepancies involved discriminating between intraretinal microvascular abnormalities versus early peripheral neovascularization or involved peripheral neovascularization outside the photographic field.
Detection of Specific Lesions Using the Two Methods We also compared the agreement rates and the intraclass correlation coefficients, K, between the two methods for the detection of specific lesions (Table 5). Agreement between the two diagnostic methods was highest for the following lesions: fibrous proliferation, hemorrhages and microaneurysms, hard exudates, and nerve fiber layer infarcts. Correlation was low for intraretinal microvascular abnormalities, tractional retinal detachment, and peripheral neovascularization. The agreement rates for vitreous hemorrhage and maculopathy were not as high as we expected. In three of the eight eyes in which vitreous hemorrhage was reported by ophthalmoscopy but not by fundus photography, the photographs were recorded as partly or completely ungradable. When tractional retinal detachment was analyzed more closely, we found that 13 of the 16 eyes with detachment were seen only by ophthalmoscopy. Of these 13 eyes, four photographs were ungradable, and six were recorded as having high-risk retinopathy and thus would still have been referred. In the remaining three eyes, fibrous proliferation was noted, although detachment was not seen. Significant macular edema was reported in only 36 (4.9%) eyes by photography, whereas maculopathy was reported in 80 (10.2%) eyes by ophthalmoscopy.
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Discussion In 1988, the American Diabetes Association issued a position statement outlining eye care guidelines for patients with diabetes mellitus 32 in which ophthalmologic examinations are recommended annually for patients older than 30 years of age and after a 5-year duration of diabetes in patients 12 to 30 years of age. Also suggested in the guidelines are more frequent examinations if there is an indication of abnormalities. American Indians in Oklahoma represent a population that can benefit from frequent screening and early therapeutic intervention. The prevalence of diabetes in adult Oklahoma Indians is thought to exceed 30%Y Diabetic retinopathy is prevalent in this population. 25 ,26,34 In our cohort, over an average 12.7-year follow-up interval, we have found a crude incidence of retinopathy to be 74.0% and ofPDR, 18.6%, based on follow-up fundus photographs. 26 The high rates of diabetic retinopathy seen in this study, though unfortunate, facilitated a statistically powerful comparison of two diagnostic methods. Moreover, the nature of this longterm follow-up study of a large population has resulted in what we consider to be a representative sample of the spectrum of diabetic retinopathy. Early diagnosis to facilitate therapeutic intervention is essential in this population at high risk for visual impairment. An accurate and cost-effective screening method is critical. Several reports from the United Kingdom have compared ophthalmoscopy with mydriasis and nonmydriatic fundus photography through undilated pupils. 15-20 Some of the studies have suggested that the high rates of ungradability of fundus photographs limit its efficacy and reliability as a screening too1. 18 Klein et al,15 however, compared nonmydriatic fundus photography with and without mydriasis and demonstrated that focus problems, as well as problems with media opacities and other artifacts, were significantly lower when photographs were
Lee et al . The Diagnosis of Diabetic Retinopathy Table
5. Agreement and Kappa Statistics for Ophthalmoscopy and Fundus Photography for Retinal Lesions Overall Agreement
Lesion
No.
(%)
Hemorrhages and microaneurysms Hard exudate Nerve fiber layer infarcts Intraretinal microvascular abnormalities Fibrous proliferation Neovascularization (disc) Neovascularization (periphery) Vitreous hemorrhage Retinal detachment Macular edema
579 598 579 656 713 712 708 721 717 671
(79.3) (81.9) (79.3) (89.9) (97.7) (97.5) (97.0) (98.8) (98.2) (91.9)
CI
=
Kappa Statistic K
(95% CI)
0.581 (0.522-0.640) 0.570 (0.508-0.632) 0.538 (0.473-0.602) 0.191 (0.074-0.309) 0.734 (0.613-0.855) 0.458 (0.247-0.669) 0.297 (0.086-0.509) 0.465 (0.170-0.760) 0.230 (-0.036-0.490) 0.440 (0.324-0.557)
P
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
confidence interval.
taken through dilated pupils; they found 12.7% and 6.8% of photographs ungradable for undilated and dilated pupils, respectively. Similarly, Mollentze et ae 2 reported that in a group of 86 black patients with an average duration of diabetes of 9.5 years, 9.9% and 3.5% of fundus photographs were ungradable before and after pupillary dilation, respectively. In our study, 7.7% of the fundus photographs were ungradable, a comparable figure. Undoubtedly, taking duplicate photographs improved our rates of gradability. Pharmacologic dilation may not only improve the gradability of fundus photographs, but also their accuracy. Klein et aIlS found a slightly higher agreement between seven-field stereoscopic fundus photography and nonmydriatic fundus photography performed through dilated pupils (86.5% agreement) than nonmydriatic photography through undilated pupils (82.5%). In the largest study to date, Taylor et al 19 compared ophthalmoscopy with mydriasis and nonmydriatic fundus photography (without mydriasis) in a total of 4312 eyes. We calculated an overall agreement for their data for the diagnosis of any retinopathy to be 76.8% (K = 0.437; P < 0.0001). Our greater agreement between the two methods may be attributable to the use of pharmacologic dilating agents before fundus photography with the nonmydriatic camera. We observed that pupillary dilation may be particularly important in the subset of older patients with smaller pupils and lens opacities. This may explain the lack of improvement in agreement with pupillary dilation in the study reported by Molleritze et al22 (62.2% versus 56.9% agreement before and after pupillary dilation, respectively). We are aware of only two studies in the literature that have compared these two screening methods, ophthalmoscopy and fundus photography, with both performed with pupils dilated. Kalm et al 21 examined 154 patients with type II diabetes in whom approximately 38.9% had background or preproliferative retinopathy, whereas 3.8% had POR. The authors estimated that the sensitivity rate
of fundus photography in detecting background retinopathy was 87%/97% (right/left eyes), significantly better than that for ophthalmoscopy (69%/61 %). In contrast, in our study, compared with a total of 517 eyes with retinopathy as diagnosed using either method, the sensitivity rates of fundus photography and ophthalmoscopy were 90% and 93%, respectively. These results, however, are not directly comparable because our cohort included a larger number of patients with severe retinopathy. In the smaller study by Mollentze et al,22 the agreement rate between the two diagnostic methods was a strikingly low 56.9%, despite the use of mydriasis. In their study, of the 51 eyes with any retinopathy as diagnosed by fundus photography, 18 (36%, corresponding to category A; Table 4) were missed by ophthalmoscopy. Similarly, of the 70 eyes with any retinopathy as diagnosed by ophthalmoscopy, 37 (51 %, category B; Table 4) were missed by photography. The discrepancies in the diagnosis of POR were even more dramatic: of the 20 eyes with POR as diagnosed by ophthalmoscopy, only 2 were diagnosed by fundus photography. An analysis of the specific lesions missed by the two methods would be useful for interpreting these results. Although we found the overall agreement between the two methods in diagnosing retinopathy to be significant, fundus photography appeared to be less sensitive than ophthalmoscopy in the detection of such lesions as intraretinal microvascular abnormalities, nerve fiber layer infarcts, peripheral neovascularization, and tractional retinal detachment. It is possible that these lesions, particularly new vessels in the periphery, may have lain outside the single field taken with the non mydriatic camera. Klein et al,15 citing unpublished data, have reported that an estimated 8% to 15% of retinopathy may be missed using this method for this reason. Similarly, we suspect that the discrepancies in diagnoses of vitreous hemorrhage may be due to the settling of hemorrhage below the field of fundus photography.
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Given the limited detection of new vessels in the periphery, neither screening method appears optimal for the diagnosis of neovascularization. In our study, of the 42 eyes with new central or peripheral vessels detected by either method, 25 (59.5%) were detected by ophthalmoscopy and 29 (69.0%) by fundus photography. Although not directly comparable, these are similar to the sensitivity rates of 77.5% for ophthalmoscopy and 65.0% for nonmydriatic fundus photography (through undilated pupils) reported by Taylor et al. I9 For eyes with high-risk diabetic retinopathy as diagnosed by ophthalmoscopy, we found only two in which fundus photography missed the diagnosis of PDR, one of which was most likely due to the poor quality of the photograph. Klein et al 15 reported that in their study none of the 14 eyes with proliferative retinopathy as diagnosed by seven-field stereoscopic photography was missed by non mydriatic fundus photography. Another study from that group II concluded that ophthalmoscopy may undercall proliferative retinopathy. Thus, there also may have been cases of PDR in our study that were not detectable by either method. 13 Without a reference method such as fluorescein angiography or sevenfield stereoscopic fundus photography, we are unable to rule out this possibility. Our finding that ophthalmoscopy is superior to fundus photography in the detection of maculopathy is in contrast to previous reports l7 ,19 which have shown non mydriatic fundus photography to be the superior method. We explain this discrepancy in part by noting that the criteria for maculopathy were different for the two methods, in that only clinically significant macular edema was recorded by the fundus photograph readers. In 13 ofthe 21 patients with discrepancies in diagnoses of macular edema not attributable to poor-quality photographs, the pattern of edema, described as diffuse or cystoid, may have been difficult to assess with the two-dimensional view by photography. Without stereoscopic views, macular edema is difficult to assess by fundus photography, especially iffew hard exudates are present. 35 We suggest that all eyes with retinopathy and deterioration in visual acuity need further retinal evaluation for macular thickening. The advantages of ophthalmoscopy through dilated pupils include the ability to examine peripheral areas of the retina which may not be photographed, even among the seven fields of stereoscopic fundus photography. Moreover, the stereoscopic view allows for a more accurate evaluation of macular thickening. 35 The disadvantages are that despite negligible costs, it requires a skill which currently appears to be satisfactory only for trained ophthalmologists and retinal specialists, 12-14 although Awh et al 14 have recently demonstrated the effectiveness of a short training course for nonophthalmologists in improving the accuracy of diagnoses by ophthalmoscopy. In addition, ophthalmoscopy only allows for a limited examination time and does not produce a permanent record for comparison in subsequent examinations. In addition to the advantages of nonmydriatic fundus photography, it provides such a permanent record, which may be useful for teaching in educational settings. 19 The images can be taken
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by trained technicians, and when necessary, photographs can be taken without dilating the pupils with less compromise to accuracy than for ophthalmoscopy.15 Given that the age and history of patients with diabetes can bias the diagnosis of diabetic retinopathy, II unbiased grading of fundus photographs can be ensured if graders are not involved in the examination. Nonmydriatic fundus photography has been deemed comparable with stereoscopic photography in terms of patient acceptance, ease of use, and time required. II The major disadvantage of nonmydriatic fundus photography compared with ophthalmoscopy is the higher rate of ungradability. These rates may be improved by taking duplicate photographs and by dilating pupils. Although the single nonstereo view limits the detection of macular edema, as well as peripheral lesions such as new vessels and vitreous hemorrhage, we have nevertheless found the method overall to be comparable with ophthalmoscopy in the diagnosis of nonproliferative and proliferative retinopathy. From our results, if any retinopathy detected by nonmydriatic fundus photography is considered as the referral criterion in a screening program, 29% (213/730) eyes would not need a full examination. The sensitivity and specificity rates were 89.2% and 85.8%, respectively, when compared with ophthalmoscopy. If this criterion is used, 52 (10.8%) eyes with retinopathy would be missed. One (1.9%) of these eyes had clinically significant macular edema and one (1.9%) had PDR. However, these two eyes were classified as having nondiabetic retinopathy by nonmydriatic fundus photography. If the referral criteria also include questionable retinopathy and nondiabetic retinopathy detected by nonmydriatic fundus photography, the sensitivity rate of detecting retinopathy would increase to 91.5%, and the specificity rate would decrease to 83.1 % when comparing with ophthalmoscopy. Only 8.5% of the eyes with retinopathy would be missed and none of the eyes with clinically significant macular edema and PDR would be missed in the screening program. In this case, 27.5% of eyes would not need a full examination in our study. Considering the high prevalence of retinopathy in our Indian population with diabetes, the latter criteria may be more favorable in a screening program using nonmydriatic fundus photography. We therefore conclude that nonmydriatic fundus photography holds great promise as a cost-effective screening method for diabetic retinopathy. As Klein et al 15 have suggested, ophthalmic technicians can be trained to carry out the American Diabetes Association-recommended screening procedures, including testing visual acuity, measuring intraocular pressure, and taking retinal photographs using a nonmydriatic camera. We propose that, unless contraindicated, fundus photography should be performed through dilated pupils for greater gradability and accuracy. In our study, all of the photographs were taken by three trained technicians, except 18 which were taken by an optometrist. In lieu of full ophthalmologic examinations, this approach may enable patients, including Oklahoma Indians with diabetes, to have access to routine screening which otherwise might not be available,
Lee et al . The Diagnosis of Diabetic Retinopathy thereby providing an opportunity to avert the tragic and costly consequences of diabetic retinopathy and other eye diseases. Taylor et al 19 have reported the success of a mobile van equipped with a fundus camera to screen thousands of patients with diabetes in the United Kingdom. A similar system would be particularly beneficial for the predominantly rural population of American Indians in Oklahoma. A referral method would have to be established for patients whose photographs suggest any form of retinopathy as well as for those with questionable retinopathy, nondiabetic retinopathy, and poor-quality fundus photographs, in addition to those suspected to be at high risk because of an acute deterioration in visual acuity. Acknowledgments. The authors thank the Oklahoma
Indian patients for their participation; Oklahoma City area Indian Health Service, staff at the Indian Health Service hospitals and clinics in Lawton, Shawnee, Anadarko, Pawnee, Clinton, Ada, White Eagle, Pawhuska, Wewoka, and Carnegie, and the Oklahoma City Urban Clinic for their cooperation and assistance; Russ Burris and Andy Wheeler of the Dean McGee Eye Institute (Oklahoma City, OK), Dr. Greg Ketcher of the Lawton Indian Hospital, and Paul Cheng for taking the fundus photographs; and Dr. Ronald Klein and his associates at the University of Wisconsin Fundus Photograph Reading Center for grading the fundus photographs.
References I. Centers for Disease Control. Prevalence and incidence of diabetes mellitus-in United States, 1980-1987. MMWR (Morb Mortal Wkly Rep) 1990;39:809-12. 2. National Society to Prevent Blindness. Operational Research Dept. Vision Problems in the U.S.: A Statistical Analysis. [New York]: The Society, 1980. 3. Klein R, Klein BEK. Vision disorders in diabetes. In: National Diabetes Data Group. Diabetes in America: Diabetes Data Compiled 1984. [Bethesda, MD]: US Dept. of Health and Human Services, 1985; chap. XIII. 4. Caird FI, Pirie A, Ramsell TG. Diabetes and the Eye. Oxford: Blackwell Scientific, 1968. 5. Herman WH, Teutsch SM, Sepe SJ, et al. An approach to the prevention of blindness in diabetes. Diabetes Care 1983;6:608-13. 6. The Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic retinopathy. Clinical application of Diabetic Retinopathy Study (DRS) findings, DRS Report Number 8. Ophthalmology 1981 ;88: 583-600. 7. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report Number I. Arch OphthalmoI1985;103:1796-1806. 8. Blankenship GW. Fifteen-year argon laser and xenon photocoagulation results of Bascom Palmer Eye Institute'S patients participating in the Diabetic Retinopathy Study. Ophthalmology 1991 ;98: 125-8. 9. The Diabetes Control and Complications Trial Research Group. Color photography vs fluorescein angiography in the detection of diabetic retinopathy in the Diabetes Control and Complications Trial. Arch Ophthalmol 1987;105: 134451.
10. Palmberg P, Smith M , Waltman S, et al. The natural history of retinopathy in insulin-dependent juvenile-onset diabetes. Ophthalmology 1981 ;88:613-18. 11. Moss SE, Klein R, Kessler SO, Richie KA. Comparison between ophthalmoscopy and fundus photography in determining severity of diabetic retinopathy. Ophthalmology 1985;92:62-7. 12. Sussman EJ, Tsiaras WG, Soper KA. Diagnosis of diabetic eye disease. JAMA 1982;247:3231-4. 13. Nathan OM, Fogel HA, Godine JE, et al. Role of diabetologist in evaluating diabetic retinopathy. Diabetes Care 1991;14:26-33. 14. Awh CC, Cupples HP, Javitt Jc. Improved detection and referral of patients with diabetic retinopathy by primary care physicians. Effectiveness of education. Arch Intern Med 1991 ;151: 1405-8. 15. Klein R, Klein BEK, Neider MW, et al. Diabetic retinopathy as detected using ophthalmoscopy, a nonmydriatic camera and a standard fundus camera. Ophthalmology 1985;92: 485-91. 16. Ryder REJ, Vora JP, Atiea JA, et al. Possible new method to improve detection of diabetic retinopathy: Polaroid nonmydriatic retinal photography. Br Med J 1985;291 :1256-
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17. Williams R, Nussey S, Humphry R, Thompson G. Assessment of non-mydriatic fundus photography in detection of diabetic retinopathy. Br Med J 1986;293: 1140-2. 18. Jones 0, Dolben J, Owens DR, et al. Non-mydriatic Polaroid photography in screening for diabetic retinopathy: evaluation in a clinical setting. Br Med J 1988;296: 1029-30. 19. Taylor R, Lovelock L, Tunbridge WMG, et al. Comparison of non-mydriatic retinal photography with ophthalmoscopy in 2159 patients: mobile retinal camera study. BMJ 1990;301: 1243-7. 20. Mohan R, Kohner EM, Aldington SJ, et al. Evaluation of a non-mydriatic camera in Indian and European diabetic patients. Br J Ophthalmol 1988;72:841-5. 21. Kalm H, Egertsen R, Blohme G. Non-stereo fundus photography as a screening procedure for diabetic retinopathy among patients with type II diabetes. Compared with 600 enhanced slit-lamp examination. Acta Ophthalmol 1989;67: 546-53. 22. Mollentze WF, Stulting AA, Steyn AF. Ophthalmoscopy versus non-mydriatic fundus photography in the detection of diabetic retinopathy in black patients. S Afr Med J 1990;78:248-50. 23. Smith SE, Smith SA, Brown PM, et al. Pupillary signs in diabetic autonomic neuropathy. Br Med J 1978;2:924-7. 24. Smith SA, Smith SE. Reduced pupillary light reflexes in diabetic autonomic neuropathy. Diabetologia 1983;24:330-2. 25. West KM, Erdreich U , Stober JA. A detailed study of risk factors for retinopathy and nephropathy in diabetes. Diabetes 1980;29:501-8. 26. Lee ET, Lee VS, Lu M, Russell D. Development of proliferative retinopathy in NIDDM. A follow-up study of American Indians in Oklahoma. Diabetes 1992;41:359-67. 27. Early Treatment Diabetic Retinopathy Study Research Group (ETDRS). Manual of Operations. Baltimore: ETDRS Coordinating Center, Univ. of Maryland School of Medicine, 1980. Available From: National Technical Information Service (Accession No. PB85-223006); chaps. 12,18. 28. Klein BEK, Davis MD, Segal P, et al. Diabetic retinopathy. Assessment of severity and progression. Ophthalmology 1984;91: 10-17.
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29. Klein R, Klein BEK, Moss SE, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. IX. Four-year incidence and progression of diabetic retinopathy when age at diagnosis is less than 30 years. Arch Ophthalmol 1989; 107: 237-43. 30. Diabetic Retinopathy Study Research Group. Report 7. A modification of the Airlie House classification of diabetic retinopathy. Invest Ophthalmol Vis Sci 1981 ;21 :21 0-26. 31. Fleiss JL. Statistical Methods for Rates and Proportions, 2nd ed. New York: John Wiley, 1981. 32. American Diabetes Association. Position statement. Eye care
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guidelines for patients with diabetes mellitus. Diabetes Care 1988;11:745-6. 33. West KM. Diabetes in American Indians and other native populations of the New World. Diabetes 1974;23:841-55. 34. Newell SE, Tolbert B, Bennett J, Parsley TL. The prevalence and risk of diabetic retinopathy among Indians of southwest Oklahoma. J Okla State Med Assoc 1989;82:414-24. 35. Kinyoun J, Barton F, Fisher M, et al. Detection of diabetic macular edema. Ophthalmoscopy versus photographyEarly Treatment Diabetic Retinopathy Study Report Number 5. Ophthalmology 1989;96:746-51.