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Quantitative Grading of Nerve Fiber Layer Photographs
Quantitative Grading of Nerve Fiber Layer Photographs Harry A. Quigley, MD, Mark Reacher, MD, Joanne Katz, DSc, Ellen Strahlman, MD, Donna Gilbert, AA, Rachel Scott, BS
Purpose: The authors have developed a simple method for semi-quantitative grading of atrophy of the peripapillary nerve fiber layer (NFL) in black and white photographs. Methods: An experienced observer read sets of NFL photographs using a fourlevel grading system. Five observers with varying levels of experience at ophthalmic examination were taught the grading system in approximately 4 hours, and their readings were compared with those of the expert. Results: The reproducibility of readings by an experienced observer was excellent. The validity of the grading system was confirmed by comparisons to visual field findings, as well as to cup-to-disc ratios in the same eyes. The agreement with the expert by the five trained graders was good. Conclusions: Grading of the NFL could be useful both to monitor development of early glaucoma damage clinically and to measure progression of glaucoma damage in clinical trials research. The grading system can be taught readily to other observers. Ophthalmology 1993; 100: 1800-1807
The initial descriptions of nerve fiber layer (NFL) atrophy that are visible ophthalmoscopically in glaucoma were made by Hoyt and co-workers. 1 We2- 5 and others6- '2 have found NFL examination to be a useful additional means to monitor glaucoma damage. Defects in the NFL predicted the development of visual field damage 5 in a prospective follow-up of more than 1000 ocular hypertensive eyes. In addition, the position of NFL atrophy was correlated with the half of the field in which functional defects were to appear. In most reports of NFL assessment, the findings have been recorded as either normal or abnormal. Nerve fiber Originally received: February 19, 1993. Revision accepted: June 4, 1993. From the Dana Center for Preventive Ophthalmology and the Glaucoma Service, Wilmer Institute, Johns Hopkins University School of Medicine, Baltimore. Supported in part by PHS research grants EY 03605 and 02120 (Dr. Quigley), EY 09130 (Dr. Katz), a Senior Investigator Award from Research to Prevent Blindness, Inc, New York, and Merck Research Laboratories, Inc. Reprint requests to Harry A. Quigley, MD, Wilmer 120, Johns Hopkins Hospital, Baltimore, MD 21205.
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layer atrophy can be divided into localized atrophy (wedge defects) and diffuse atrophy of the upper or lower retina. Some have divided the area around the optic disc into sectors to quantify its abnormality.6,7, 10, II These methods have been validated by comparing them with visual field findings in the same eyes. Systems and instruments have been developed that attempt to judge the thickness of the NFL near the disc by objective and quantitative image analysisY-'6 Most of these use the shape of the NFL surface as an estimate of NFL thickness. The instruments are not readily available for clinical use and the expense involved in making measurements currently is prohibitive. One prototype system appears capable of measuring actual NFL thickness, although it has only been studied under laboratory conditions. 17 We have developed a practical method for a trained observer to distinguish three levels of severity in NFL atrophy. In this report, we evaluate how well this method can be taught to others. Five graders whose previous experience with NFL examination varied from none to extensive were tested for their agreement with standard readings by an expert. In addition, the reproducibility of this NFL grading system is assessed and it is compared with optic disc assessment and visual field findings in the
Quigley et al . Nerve Fiber Layer Photographs same eyes to evaluate its validity. We also evaluate the predictive power of such NFL assessment in a follow-up study of ocular hypertensive eyes.
Methods Subject Characteristics The persons whose photographs were used were participants in a longitudinal observation of ocular hypertension (defined as repeated intraocular pressure of more than 21 mmHg).5 They are not a population-based sample, having been recruited from ophthalmic offices and by advertisement. Each was followed for up to 12 years with annual photographs of the optic disc, NFL, and visual field testing. Initially, detailed static and kinetic fields were performed on the Goldmann perimeter. After 1984, automated Humphrey 30-2 tests were added. All subjects are adults, 75% are white, and there is an equal number of males and females. There were approximately 200 normal subjects and 800 persons with ocular hypertension in followup. Normals were defined as those with repeatedly normal visual fields, intraocular pressure below 21 mmHg, and no family history of glaucoma. In addition, more than 100 persons with visual field loss on the Goldmann perimeter due to glaucoma at entry to the study were followed. Visual field loss on the Goldmann perimeter was strictly defined as one or more of a set of abnormal findings that had to be reproducible. 5 During follow-up, more than 100 ocular hypertensive eyes have converted from normal to abnormal Goldmann field tests. We previously published the predictive power of NFL and optic disc findings in some of these eyes with documented progression using a case-control design. 18
Selection of Sets of Photographs We have a previously computerized database containing the NFL gradings for each of the approximately 1100 persons from our follow-up study. From these, we selected four sets of photographs. Three of these were for training and testing new graders and each of the three consisted of 100 upper/lower pairs of NFL photographs. These were called practice sets 1 and 2 and the test set. There were photographs from more than 200 individuals among these, so some persons contributed photographs from one or both eyes to more than one set of 100 pairs. However, no person was represented more than once among the photographs within each set of 100 pairs. These 200 individuals were selected to represent approximately onehalf normal and one-half abnormal NFL readings to facilitate training. Because the overall population of 1100 persons is not randomly selected from the population, it appears unimportant that the 200 persons were not selected randomly. The quality of the photographs from the 200 persons was similar to that of our overall collection and included some photographs of poor quality in practice
set 1 to demonstrate to new graders when to grade photographs as unreadable. The 121 individuals who contributed photographs to practice set 2 and the test set had the following personal characteristics: there were 76 white and 45 African-American persons, 56 women and 65 men, and the mean age was 66 years (range, 21-78 years). A fourth set of photographs (the case-control set) consisted of 37 eyes of 34 ocular hypertensive persons who had their first visual field defect after 5 or more years of observation (cases) and matched control ocular hypertensive persons who have not had field defects. These were described in detail in a previous publication 18 and are described further below.
Photographic Methods Photographs were taken with a Zeiss fundus camera (Carl Zeiss, New York, NY) and green light, on high contrast black and white film . Each photograph was centered either just above or just below the optic disc. They were printed on positive 35-mm transparencies and examined on a light box both with and without a lens that magnifies five times the actual size.
Grading System Readings are performed by comparing the areas above and below the optic disc to that directed toward the fovea. Three features are assessed: the brightness of the reflexes, their texture, and the degree to which the NFL obscures the view of retinal blood vessels (Table I). Based on these features, diffuse atrophy is divided into mild, moderate, and severe grades, and localized (wedge) atrophy is graded in two levels (Figs 1-3). For a final code, diffuse and wedge atrophy is combined into a single code. Based on our past comparisons of NFL and visual field findings, this is done by including milder wedge defects (called WI) with mild diffuse atrophy (0 I); more severe wedge defects are included with moderate diffuse atrophy (02). There is an inherent difficulty in setting criteria between a wide wedge defect and diffuse atrophy of upper or lower NFL. Our method of collapsing them together in this way circumvents this problem . In practice, wedge defects represent only a small proportion of all of our hundreds of photographs; hence, it is the diffuse category that is critical to grading in most eyes. For the purposes of this report, we cannot include the entire teaching manual containing details of the grading system, nor the practice and test sets of photographs. These will be published soon as a separate monograph. Reliability The reliability of the new NFL grading system was tested by having an expert read on two occasions practice set 2 and the test set (200 pairs of photographs from the upper and lower NFL, approximately half from normal eyes and half from those with atrophy). The optic disc was
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Table 1. Nerve Fiber Layer Grading System Features Nerve Fiber layer Feature
Grade DO
Grade Dl
Grade D2
Grade D3
Brightness Texture
Bright Coarse and fine striations
Less bright Fine striations
Minimally bright Barely detectable striations
Dark No texture
Blood vessels Large Medium Small
Clear or blurred Blurred Very blurred
Clear Less blurred Still blurred
Clear Clear Clear
Clear Clear Clear
covered and the observer was masked to the ocular history. The agreement between his two gradings was compared with the kappa statistic, a standard statistical technique for describing agreement. Two readings of a photograph might be the same by random chance, so this statistic gives a fractional proportion that is less than the actual agreement, using a correcting factor for the estimated effect of chance. Values between 0.4 and 0.75 are considered
Figure 1. Nerve fiber layer (NFL) photographs from the upper retina just above the optic disc, with two illustrations of normal findings (grade 0) and two of mild diffuse atrophy (grade 1). The normal photographs have their brightest white reflexes along the course of the vessels to the foveal side of a vertical line through the disc. The texture of the densest NFL zone is granular. Medium and small blood vessel outlines are blurred by the NFL that passes over them. In the mild atrophy examples, the NFL in the zone near the larger vessels is brighter than the NFL nearer to the fovea (lower portion of each photograph). The texture has changed to finer lines rather than the thick, grainy appearance of normal. The medium vessels are seen clearly because they are no longer covered by NFL.
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indicative of fair to good agreement, whereas above 0.75 is considered excellent in the kappa statistic. The expert read the photographs from the test set a third time if the first and second readings differed. The final, adjudicated reading for the 100 pairs in the test set
Figure 2. Examples of moderate (grade 2) and severe (grade 3) diffuse atrophy for comparison with those in Figure 1. Moderate atrophy is characterized by a near-total loss of white striations, no definite texture, and baring of even the smallest vessels. Severe atrophy has no striations at all. In both grades 2 and 3, the white walls oflarge vessels can sometimes be seen due to the absence of surrounding NFL white striations (see top right photograph in which arteriolar wall is visible). In a fundus with only minimal melanin pigmentation, the general brightness of the background might be superficially misinterpreted as a normal NFL (bottom right photograph). But, the lack of striations and the clear view of even small vessels show that severe diffuse atrophy is present. In addition, the NFL coming from the foveal area (arrowheads, top left and bottom right photographs) is still intact and more distinct than that of the arcuate zone above it.
Quigley et al . Nerve Fiber Layer Photographs
Figure 3. Wedge atrophy (W) is indicated in these photographs of the retina below the optic disc by a dark loss of striations flanked on either side by whiter, more normal NFL brightness. In rare examples (left), a highly localized atrophy is surrounded by normal nerve fiber layer. More commonly, a wider wedge (right) is found in an area characterized by more intact, but still moderately atrophic NFL. The margins of the wedge atrophy are marked by arrowheads.
was used to evaluate the readings of newly trained observers. Training of Observers New to the Grading System Five observers were trained to read the NFL by a standardized method of programmed instruction. They read a manual describing the NFL and its normal and abnormal appearance, as well as the features of the grading system. Next, they graded the two practice sets of 100 photographic pairs each. In practice set 1, the grading by the expert was shown on front of the photograph. For practice set 2, the grading of the expert was on the back of each slide. Finally, the five observers read the test set of 100 photographic pairs. After the first readings by each student, a training session with the expert and the practice sets was carried out, in which questions and equivocal readings were discussed. Then, the five observers read the test set again and their answers were compared with the gradings of the expert, with the agreement estimated by the weighted kappa statistic. The weighting gave full credit to perfect agreement and half credit for disagreements that were one grade apart. No credit was given for grades more than one level apart. One observer has been a glaucoma specialist for 4 years, three had just completed ophthalmic residency, and one is not an ophthalmologist and had no prior experience in examination of the NFL. Validity The case-control set of photographs was read by the expert only. This consisted of pictures from 37 eyes of 34 individuals with ocular hypertension. Each of these eyes initially had normal visual field testing on the Goldmann perimeter, and reproducible field defects developed after 5 or more years of observation. These photographs were compared with those of 37 eyes of patients with ocular
hypertension who were similarly followed for at least 5 years with continued normal fields on the Goldmann perimeter. The stable eyes were frequency-matched by age and race to those whose fields had converted to abnormal. In both groups, the annual NFL and color stereophotographs for the 5 years preceding field loss were compared by an observer masked to their history. The readings of these eyes using an NFL grading system with fewer categories has been reported. 18 The optic disc was stereophotographed with color film using the Zeiss camera. The size of the disc and the cup were measured from the 35-mm transparencies using an eyepiece micrometer. 13 The cup-to-disc ratio was calculated from these measurements without any correction for image magnification. Visual field tests on the Goldmann perimeter were performed by a detailed method described previously,S including static and kinetic presentation of at least five target size and brightness combinations. The criteria for visual field defect included nasal steps or paracentral scotomas of stated magnitudes. s Automated Humphrey 30-2 threshold tests were evaluated with the STATPAC II software indices: mean deviation, pattern standard deviation, and glaucoma hemifield test. Color photographs and NFL were compared with field findings obtained in the same 12-month period. Since we began using automated field testing in 1984, only 137 of 200 eyes in practice set 2 and the test set had automated tests performed in the same year as the photographs. Hence, in the data below, we present comparison information from visual fields on the Goldmann perimeter on 200 eyes and from Humphrey field tests on 137 eyes.
Results Gradings by an Expert The first and second gradings by the expert of the 200 upper/lower pairs in practice set 2 and the test set were identical in 339 (85%) of 400 photographs. Agreement measured by the unweighted and weighted kappa sta-
Table 2. Intraobserver Comparison of Nerve Fiber Layer Grading
Unweighted kappa 95%CI Weighted kappa" 95%CI
Upper Photograph
Lower Photograph
0.73 (0.65, 0.82) 0.78 (0.71, 0.86)
0.74 (0.66, 0.82) 0.82 (0.75,0.88)
CI = confidence interval. • Calculated by giving full credit for exact agreement and one-half credit for readings differing by one grade level.
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Table 3. Cup/Disc Ratio Compared with Nerve Fiber Layer Grade for Eyes in the Case/Control Photograph Set: Mean ± SD Vertical CjD
Nerve Fiber Layer Grade
DO (normal D1 (mild) D2 (moderate) D3 (severe)
0.48 0.51 0.57 0.67
± ± ± ±
0.14 0.18 0.19 0.18
Horizontal CjD
N*
0.47 0.48 0.49 0.61
27 10 19 9
± ± ± ±
0.15 0.17 0.17 0.19
SD = standard deviation, C/D = cup/disc ratio. • The total is fewer than 74 eyes due to unreadable color or nerve fiber layer photographs in nine eyes.
tistic was good or excellent (Table 2). The distribution of adjudicated NFL grades among the test set photographs were: normal (DO), 58%; mild atrophy (01), 10%; moderate atrophy (02), 17%; and severe atrophy (03), 15%. To judge the validity of the system, we compared the gradings to standard indicators of glaucoma injury, including cup-to-disc ratio and visual field test results. The cup-to-disc ratio and NFL data were compared for the 74 eyes in the case-control set. Of these, 65 eyes had both readable color and NFL photographs. The vertical and horizontal cup-to-disc ratios of eyes with NFL atrophy were larger than eyes with normal gradings (analysis of variance, vertical cup-to-disc ratio: P < 0.03; horizontal cup-to-disc ratio: P = 0.18; Table 3). The NFL grade was compared with the findings on visual field testing with the Goldmann perimeter in the
200 eyes of practice set 2 and the test set (Table 4). The NFL grade is presented for the retinal half corresponding to its mirror-image location in the visual field. The persons are divided into four groups: normals, two groups of patients with ocular hypertension, and those with pre-existing visual field defects. The groups of patients with ocular hypertension are divided into those in whom field defects did not develop during our follow-up study and those in whom field defects did develop (stable and converter ocular hypertension, respectively; Table 4). These are separated here to compare whether the NFL gradings differ between ocular hypertensive subgroups. Ninety percent of normal eyes were graded as NFL normal (DO), whereas 93% of eyes with a field defect were graded as NFL abnormal (01-03) (chi-square, P < 0.001; Table 4). More than half of the hemifields with field loss on the Goldmann perimeter had the most severe NFL grade. There were more eyes with higher degrees of NFL abnormality in the groups with field loss than in the normal and stable ocular hypertensive groups (chi-square, P < 0.001; Table 4). For example, of the photographic fields (upper and lower) that had the most severe NFL grade (03),69% (35/51) were in the group that entered the study with field loss. For the photographs with a grade of 02 (moderate damage), 82% (54/66) were in the two most damaged groups (converter ocular hypertension and field loss). The NFL gradings were compared with three indices that summarize automated field data: glaucoma hemifield test, pattern standard deviation, and mean deviation. In Table 5, we present the glaucoma hemifield test results of 137 eyes from practice set 2 and the test set in which we have NFL grading and threshold fields performed in the same year. There is a smooth transition in the proportion
Table 4. Visual Field* with Goldmann Perimeter Compared with Nerve Fiber Layer Grade in 200 Eyes from Practice Set 2 and Test Set Clinical Status by Field and lOP Photo Grade Upper NFL DO D1 D2 D3 Lower NFL DO D1 D2 D3 N (eyes) OH
Normal
Stable OH
Converter OH
Field Loss
74 (89)t 8 (10) 1 (1) 0
29 (74) 3 (8) 7 (18) 0
9 (26) 9 (26) 11 (33) 5 (15)
3 (7) 7 (16) 10 (23) 24 (54)
76 (92) 4 (5) 2 (2) 1 (1) 83
32 (82) 3 (8) 2 (5) 2 (5) 39
10 (29) 2 (6) 14 (41) 8 (24) 34
3 (7) 11 (25) 19 (43) 11 (25)
= ocular hypertensive; NFL = nerve fiber layer; lOP = intraocular pressure.
* Visual fields used in this comparison were performed within 12 mos of the photograph.
t
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Values in parentheses are percentages.
44
Quigley et al . Nerve Fiber Layer Photographs Table 5. Comparison of Glaucoma Hemifleld T est and NFL Grade
Table 6. Comparison of Pattern Standard Deviation and NFL Grade
Glaucoma Hemifield Test Scorer
Pattern Standard Deviation Result
NFL Grade·
Abnormal
Normal
NFL Grade"
P s 0.05
Normal
Normal Worst grade = Dl Worst grade = D2 Worst grade = D3
9 (14)t 6 (60) 19 (63) 23 (92)
56 (86) 4 (40) 11 (37) 2 (8)
Normal Worst grade = D 1 Worst grade = D2 Worst grade = D3
17 (24)t 5 (50) 20 (65) 25 (96)
53 (76) 5 (50) 11 (35) 1 (4)
Total
57
73
Total
67
70
NFL
=
nerve fiber layer.
• Each eye is placed in a category based on both hemiretinal fields examined. Normal group is those with DO in both upper and lower photographs. Worst grade = D1 includes eyes that had upper and lower grades of D1 and D1 or D1 and DO. Worst grade = D2 is all eyes the worst grade (upper or lower) of which was D2 (similarly for D3).
NFL
=
nerve fiber layer.
• Normal field group includes pattern standard deviation result fully within the normal range or with a probability of being normal of <0.1 but >0.05. Worst grade = D1, D2, and D3 defined as in Table 5.
t
Values in parentheses are percentages, as defined in Table 5.
t Values in parentheses are percentages and refer to the proportion of each NFL grade with either abnormal or normal field score.
r Normal field group includes eyes with a hemifield result of either "within normal limits" or "borderline," whereas abnormal comprises the eyes with a result of "outside normal limits." The 13 7 eyes in Practice Set 2 and the Test Set with both NFL gradings and automated field results are presented here and in Tables 6 and 7; seven eyes not listed in the table had hemifield results of either "unusually high sensitivity" or "general reduction in sensitivity" (hence, the total presented is 130).
they graded the photographs as DO or D 1 compared with D2 or D3. With this evaluation, the percent agreement with the expert averaged 87% among the five observers, and the kappa statistics (unweighted) were nearly all in the excellent range (Table 8).
Expert Grading of the Case-control Set of abnormal field results from predominately normal in the normal NFL grade (~O) to predominately abnormal in the severely atrophic NFL grade (D3) (chi-square, P < 0.001). For the pattern standard deviation and mean deviation indices, the NFL grade also follows the automated field abnormality well (chi-square tests, P < 0.001; Tables 6 and 7).
Gradings of the Test Set by Other Observers The five observers who were trained to examine the NFL were in exact agreement with the expert an average of 68% of the time. The percentage agreement for each observer for photographs from the upper and lower NFL that make up this average is given in Table 8. Exact agreement means that the observers selected the same one of the four possible grades as did the expert. The weighted kappa statistics for the five observers for upper and lower photographs also was generally in the good range (Table 8). Two of the three ophthalmologists who had recently completed residencies performed similarly to the trainee who is a glaucoma specialist. The person with no prior experience in ophthalmologic examination diQ at least as well as one of the ophthalmologists. In the clinical setting, it is most important that an observer be able to distinguish between probably normal and definitely abnormal NFL status. To simulate this distinction, we re-examined the gradings of the five observers in comparison with those of the expert regarding whether
The NFL data in 37 stable and 37 converter ocular hypertensive eyes were compared for each group at baseline (at the start of the 5-year follow-up for stable eyes and 5 years before field loss in the converters). Abnormal NFL readings were found in 62% (21/34) of converters and in only 32% (11/34) of nonconverters (chi-square test, P < 0.03; 3 of 37 in each group had unreadable photographs). Substantially more of the converters had NFL grades 2 or 3 (41%,14/34) compared with those with stable fields (26%, 9/34) (chi-square test, P < 0.04; Table 9). Table
7. Comparison of Mean Deviation Score and NFL Grade Mean Deviation Score
NFL Grade·
P s 0.05
Normal
Normal Worst grade = D 1 Worst grade = D2 Worst grade = D3
11 (16)t 3 (30) 13 (42) 25 (96)
59 (84) 7 (70) 18 (58) 1 (4)
Total
52
85
NFL
=
nerve fiber layer.
* Normal includes mean deviation scores with a probability of being nor-
mal of <0.10 but >0.05. Worst grade D1, D2, and D3 defined as in Table 5.
t
Values in parentheses are percentages as defined in Table 5.
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Table 8. Agreement between Expert and Five Observers Trained in the Nerve Fiber Layer Grading System on the Test Set Photographs Agreement with Expert Using Full Grading System
Observer
Weighted Kappa Statistic Upper Lower
Percent Agreement Lower Upper
1 2 3
4 5
69% 69Dk 64% 70% 56%
75% 74% 69% 78% 56%
0.68 (0.58, 0.67 (0.57, 0.49 (0.36, 0.61 (0.48, 0.50 (0.37,
0.78) 0.77) 0.61) 0.73) 0.63)
0.70 (0.59, 0.72 (0.63, 0.55 (0.43, 0.72 (0.61, 0.57 (0.46,
0.80) 0.82) 0.66) 0.83) 0.68)
Agreement with Expert on Ability To Distinguish DO and Dl versus D2 and D3 Unweighted Kappa Statistic Upper Lower
Percent Agreement Upper Lower
1 2 3
4 5
89% 92% 82% 86% 82%
89% 91% 82% 92% 88%
When the photographs are considered during the 5 years before field loss, 59% of converter eyes in which field loss would develop had a worsening of NFL appearance during this period, compared with 30% of stable ocular hypertensive eyes. The degree of deterioration in converter eyes was detectably more severe than that in eyes of controls. Three times as many converter eyes as stable ocular hypertensive eyes worsened by more than one grade level (e.g., Dl to D3) or worsened in both upper and lower photographs.
Discussion The evaluation of glaucoma damage would be performed optimally by objective and quantitative criteria. Parameters that describe the features of the optic disc are familiar to most ophthalmologists. The NFL examination is an additional feature that demonstrates glaucoma injury. Although this is still a technique that is performed predominately within specialized centers,2-12 it is now widely used to determine the presence and progression of glaucomatous neuropathy. Other reports have attempted to use semi-quantitative methods to determine the state of the NFL.6.7.ID.II.13 These reports have shown a reasonable degree of reproducibility, and comparisons to optic disc and visual field criteria have indicated acceptable validity of their methods. Some of these other systems divided the NFL into 4 to 12 sectors surrounding the optic nerve head, grading at each sector one or more features. We have devised a simpler system in which the normality of the NFL is evaluated by comparing the NFL appearance in the arcuate area to the
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0.73 0.81 0.51 0.64 0.61
(0.58, (0.69, (0.34, (0.47, (0.45,
0.88) 0.94) 0.69) 0.80) 0.77)
0.73 (0.58, 0.79 (0.66, 0.67 (0.51, 0.80 (0.67, 0.74 (0.61,
0.88) 0.92) 0.83) 0.93) 0.88)
foveal retina. In such a system, the relative brightness and texture of the NFL above and below compared with the central area is critical. In our experience, it is more difficult to grade the NFL in multiple sectors around the disc separately, because the relative brightness is the most practical feature to use. Absolute brightness judgments are made difficult by the varying exposures among photographs. Our system appears to be practical for both clinical management of glaucoma and for use in clinical trials of glaucoma therapy. Our NFL grading system seems to be a valid measure of glaucoma injury when judged by comparing it with observations of the optic disc and with visual field testing with the Goldmann and Humphrey instruments. Other NFL grading systems also have been shown to reflect the degree of injury in functional tests. 6 ,7,19
Table 9. NFL Readings in Case/Control Set at Start of 5-Year Follow-up Nerve Fiber Layer Grade
Converter OH
Stable OH
Normal D1 (mild) D2 (moderate) D3 (severe)
13 (35)* 7 (19) 11 (30)
23 (62) 2 (5) 9 (24)
3 (8)
0(0)
Unreadable Total OH = ocular hypertensive. • Values in parentheses are percentages.
3 (8)
37
3 (8)
37
Quigley et al . Nerve Fiber Layer Photographs Machine-based systems may have potential for the measurement of NFL atrophy in glaucoma. 13 - 17 However, currently, none of these has been validated in a prospective fashion as we have done with the NFL grading system. In addition, most require expensive equipment, are time consuming, and do not have proven, general applicability. Until these systems are further developed, methods by which to determine the state and progression of glaucoma damage are needed that are valid and practical. This is especially critical in several multi-center clinical trials now being planned. Nerve fiber layer photography is shown by the data of this study to satisfy these criteria. We used a self-instruction method for teaching the NFL assessment system to five observers. Although four of the five observers attempted to examine the NFL clinically and saw photographic examples of NFL photography before this study, the specific grading system and its criteria were new to all five persons. It was clear that some interaction with an expert was important to improve the scores after initial practice readings. However, the total learning time for these observers was approximately 4 hours. It has been inferred that NFL grading only can be performed by a few experts and that its usefulness, therefore, is limited. Motivated observers who are presented with appropriate teaching material and who devote a modest time period can detect optic nerve damage in glaucomatous eyes that is additive to information currently available. In our opinion, the examination of the NFL is no more difficult to learn than stereoscopic examination of the optic disc. It is our intention to refine the teaching program used here and to make it available to those who wish to learn it.
References I. Hoyt WF, Frisen L, Newman NM. Fundoscopy of nerve fiber layer defects in glaucoma. Invest Ophthalmol 1973; 12: 814-29. 2. Sommer A, Miller NR, Pollack I, et al. The nerve fiber layer in the diagnosis of glaucoma. Arch Ophthalmol 1977;95: 2149-56. 3. Quigley HA, Miller NR, George T. Clinical evaluation of nerve fiber layer atrophy as an indicator of glaucomatous optic nerve damage. Arch Ophthalmol 1980;98: 1564-71.
4. Quigley HA. Examination of the retinal nerve fiber layer in the recognition of early glaucoma damage. Trans Am Ophthalmol Soc 1986;84:920-66. 5. Sommer A, Katz J, Quigley HA, et al. Clinically detectable nerve fiber atrophy precedes the onset of glaucomatous field loss. Arch Ophthalmol 1991;109:77-83. 6. Drance SM, Airaksinen PJ, Price M, et al. The correlation of functional and structural measurements in glaucoma patients and normal subjects. Am J Ophthalmol 1986; 102: 612-16. 7. Airaksinen PJ, Drance SM, Douglas GR, et al. Visual field and retinal nerve fiber layer comparisons in glaucoma. Arch Ophthalmol 1985; 103:205-7. 8. Honrubia F, Calonge B. Evaluation of the nerve fiber layer and peripapillary atrophy in ocular hypertension. Int Ophthalmol 1989;13:57-62. 9. Iwata K. The earliest finding of POAG and the mode of progression. In: Krieglstein GK, Leydhecker W, eds. Glaucoma Update II. Berlin: Springer-Verlag, 1983; 133-7. [Glaucoma Society, Int'! Congress of Ophthalmology, Carmel CA, Oct 1982] 10. Jonas JB, Naumann GOH. Parapapillary chorioretinal atrophy in normal and glaucoma eyes. II. Correlations. Invest Ophthalmol Vis Sci 1989;30:919-26. II. Tuulonen A, Airaksinen PJ. Initial glaucomatous optic disk and retinal nerve fiber layer abnormalities and their progression. Am J Ophthalmol 1991;111:485-90. 12. Hitchings RA, Poinoosawmy D, Poplar N, Sheth GP. Retinal nerve fibre layer photography in glaucomatous patients. Eye 1987;1:621-5. 13. Takamoto T, Schwartz B. Photogrammetric measurement of nerve fiber layer thickness. Ophthalmology 1989;96: 1315-19. 14. Caprioli J. The contour of the juxtapapillary nerve fiber layer in glaucoma. Ophthalmology 1990;97:358-66. 15. Miller E, Caprioli J. Regional and long-term variability of fundus measurements made with computer-image analysis. Am J Ophthalmol 1991;112:171-6. 16. Dreher AW, Tso PC, Weinreb RN. Reproducibility of topographic measurements of the normal and glaucomatous optic nerve head with the laser tomographic scanner. Am J Ophthalmol 1991;111:221-9. 17. Weinreb RN, Dreher A W, Coleman A, et al. Histopathologic validation of Fourier-ellipsometry measurements of retinal nerve fiber layer thickness. Arch Ophthalmol 1990; 108:55760. 18. Quigley HA, Katz J, Derick RJ, et al. An evaluation of optic disc and nerve fiber layer examinations in monitoring progression of early glaucoma damage. Ophthalmology 1992;99: 19-28. 19. Katz J, Sommer A. Similarities between the visual fields of ocular hypertensive and normal eyes. Arch Ophthalmol 1986; 104: 1648-51.
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Purpose: The authors have developed a simple method for semi-quantitative grading of atrophy of the peripapillary nerve fiber layer (NFL) in black and white photographs. Methods: An experienced observer read sets of NFL photographs using a fourlevel grading system. Five observers with varying levels of experience at ophthalmic examination were taught the grading system in approximately 4 hours, and their readings were compared with those of the expert. Results: The reproducibility of readings by an experienced observer was excellent. The validity of the grading system was confirmed by comparisons to visual field findings, as well as to cup-to-disc ratios in the same eyes. The agreement with the expert by the five trained graders was good. Conclusions: Grading of the NFL could be useful both to monitor development of early glaucoma damage clinically and to measure progression of glaucoma damage in clinical trials research. The grading system can be taught readily to other observers. Ophthalmology 1993; 100: 1800-1807
The initial descriptions of nerve fiber layer (NFL) atrophy that are visible ophthalmoscopically in glaucoma were made by Hoyt and co-workers. 1 We2- 5 and others6- '2 have found NFL examination to be a useful additional means to monitor glaucoma damage. Defects in the NFL predicted the development of visual field damage 5 in a prospective follow-up of more than 1000 ocular hypertensive eyes. In addition, the position of NFL atrophy was correlated with the half of the field in which functional defects were to appear. In most reports of NFL assessment, the findings have been recorded as either normal or abnormal. Nerve fiber Originally received: February 19, 1993. Revision accepted: June 4, 1993. From the Dana Center for Preventive Ophthalmology and the Glaucoma Service, Wilmer Institute, Johns Hopkins University School of Medicine, Baltimore. Supported in part by PHS research grants EY 03605 and 02120 (Dr. Quigley), EY 09130 (Dr. Katz), a Senior Investigator Award from Research to Prevent Blindness, Inc, New York, and Merck Research Laboratories, Inc. Reprint requests to Harry A. Quigley, MD, Wilmer 120, Johns Hopkins Hospital, Baltimore, MD 21205.
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layer atrophy can be divided into localized atrophy (wedge defects) and diffuse atrophy of the upper or lower retina. Some have divided the area around the optic disc into sectors to quantify its abnormality.6,7, 10, II These methods have been validated by comparing them with visual field findings in the same eyes. Systems and instruments have been developed that attempt to judge the thickness of the NFL near the disc by objective and quantitative image analysisY-'6 Most of these use the shape of the NFL surface as an estimate of NFL thickness. The instruments are not readily available for clinical use and the expense involved in making measurements currently is prohibitive. One prototype system appears capable of measuring actual NFL thickness, although it has only been studied under laboratory conditions. 17 We have developed a practical method for a trained observer to distinguish three levels of severity in NFL atrophy. In this report, we evaluate how well this method can be taught to others. Five graders whose previous experience with NFL examination varied from none to extensive were tested for their agreement with standard readings by an expert. In addition, the reproducibility of this NFL grading system is assessed and it is compared with optic disc assessment and visual field findings in the
Quigley et al . Nerve Fiber Layer Photographs same eyes to evaluate its validity. We also evaluate the predictive power of such NFL assessment in a follow-up study of ocular hypertensive eyes.
Methods Subject Characteristics The persons whose photographs were used were participants in a longitudinal observation of ocular hypertension (defined as repeated intraocular pressure of more than 21 mmHg).5 They are not a population-based sample, having been recruited from ophthalmic offices and by advertisement. Each was followed for up to 12 years with annual photographs of the optic disc, NFL, and visual field testing. Initially, detailed static and kinetic fields were performed on the Goldmann perimeter. After 1984, automated Humphrey 30-2 tests were added. All subjects are adults, 75% are white, and there is an equal number of males and females. There were approximately 200 normal subjects and 800 persons with ocular hypertension in followup. Normals were defined as those with repeatedly normal visual fields, intraocular pressure below 21 mmHg, and no family history of glaucoma. In addition, more than 100 persons with visual field loss on the Goldmann perimeter due to glaucoma at entry to the study were followed. Visual field loss on the Goldmann perimeter was strictly defined as one or more of a set of abnormal findings that had to be reproducible. 5 During follow-up, more than 100 ocular hypertensive eyes have converted from normal to abnormal Goldmann field tests. We previously published the predictive power of NFL and optic disc findings in some of these eyes with documented progression using a case-control design. 18
Selection of Sets of Photographs We have a previously computerized database containing the NFL gradings for each of the approximately 1100 persons from our follow-up study. From these, we selected four sets of photographs. Three of these were for training and testing new graders and each of the three consisted of 100 upper/lower pairs of NFL photographs. These were called practice sets 1 and 2 and the test set. There were photographs from more than 200 individuals among these, so some persons contributed photographs from one or both eyes to more than one set of 100 pairs. However, no person was represented more than once among the photographs within each set of 100 pairs. These 200 individuals were selected to represent approximately onehalf normal and one-half abnormal NFL readings to facilitate training. Because the overall population of 1100 persons is not randomly selected from the population, it appears unimportant that the 200 persons were not selected randomly. The quality of the photographs from the 200 persons was similar to that of our overall collection and included some photographs of poor quality in practice
set 1 to demonstrate to new graders when to grade photographs as unreadable. The 121 individuals who contributed photographs to practice set 2 and the test set had the following personal characteristics: there were 76 white and 45 African-American persons, 56 women and 65 men, and the mean age was 66 years (range, 21-78 years). A fourth set of photographs (the case-control set) consisted of 37 eyes of 34 ocular hypertensive persons who had their first visual field defect after 5 or more years of observation (cases) and matched control ocular hypertensive persons who have not had field defects. These were described in detail in a previous publication 18 and are described further below.
Photographic Methods Photographs were taken with a Zeiss fundus camera (Carl Zeiss, New York, NY) and green light, on high contrast black and white film . Each photograph was centered either just above or just below the optic disc. They were printed on positive 35-mm transparencies and examined on a light box both with and without a lens that magnifies five times the actual size.
Grading System Readings are performed by comparing the areas above and below the optic disc to that directed toward the fovea. Three features are assessed: the brightness of the reflexes, their texture, and the degree to which the NFL obscures the view of retinal blood vessels (Table I). Based on these features, diffuse atrophy is divided into mild, moderate, and severe grades, and localized (wedge) atrophy is graded in two levels (Figs 1-3). For a final code, diffuse and wedge atrophy is combined into a single code. Based on our past comparisons of NFL and visual field findings, this is done by including milder wedge defects (called WI) with mild diffuse atrophy (0 I); more severe wedge defects are included with moderate diffuse atrophy (02). There is an inherent difficulty in setting criteria between a wide wedge defect and diffuse atrophy of upper or lower NFL. Our method of collapsing them together in this way circumvents this problem . In practice, wedge defects represent only a small proportion of all of our hundreds of photographs; hence, it is the diffuse category that is critical to grading in most eyes. For the purposes of this report, we cannot include the entire teaching manual containing details of the grading system, nor the practice and test sets of photographs. These will be published soon as a separate monograph. Reliability The reliability of the new NFL grading system was tested by having an expert read on two occasions practice set 2 and the test set (200 pairs of photographs from the upper and lower NFL, approximately half from normal eyes and half from those with atrophy). The optic disc was
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Volume 100, Number 12, December 1993
Table 1. Nerve Fiber Layer Grading System Features Nerve Fiber layer Feature
Grade DO
Grade Dl
Grade D2
Grade D3
Brightness Texture
Bright Coarse and fine striations
Less bright Fine striations
Minimally bright Barely detectable striations
Dark No texture
Blood vessels Large Medium Small
Clear or blurred Blurred Very blurred
Clear Less blurred Still blurred
Clear Clear Clear
Clear Clear Clear
covered and the observer was masked to the ocular history. The agreement between his two gradings was compared with the kappa statistic, a standard statistical technique for describing agreement. Two readings of a photograph might be the same by random chance, so this statistic gives a fractional proportion that is less than the actual agreement, using a correcting factor for the estimated effect of chance. Values between 0.4 and 0.75 are considered
Figure 1. Nerve fiber layer (NFL) photographs from the upper retina just above the optic disc, with two illustrations of normal findings (grade 0) and two of mild diffuse atrophy (grade 1). The normal photographs have their brightest white reflexes along the course of the vessels to the foveal side of a vertical line through the disc. The texture of the densest NFL zone is granular. Medium and small blood vessel outlines are blurred by the NFL that passes over them. In the mild atrophy examples, the NFL in the zone near the larger vessels is brighter than the NFL nearer to the fovea (lower portion of each photograph). The texture has changed to finer lines rather than the thick, grainy appearance of normal. The medium vessels are seen clearly because they are no longer covered by NFL.
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indicative of fair to good agreement, whereas above 0.75 is considered excellent in the kappa statistic. The expert read the photographs from the test set a third time if the first and second readings differed. The final, adjudicated reading for the 100 pairs in the test set
Figure 2. Examples of moderate (grade 2) and severe (grade 3) diffuse atrophy for comparison with those in Figure 1. Moderate atrophy is characterized by a near-total loss of white striations, no definite texture, and baring of even the smallest vessels. Severe atrophy has no striations at all. In both grades 2 and 3, the white walls oflarge vessels can sometimes be seen due to the absence of surrounding NFL white striations (see top right photograph in which arteriolar wall is visible). In a fundus with only minimal melanin pigmentation, the general brightness of the background might be superficially misinterpreted as a normal NFL (bottom right photograph). But, the lack of striations and the clear view of even small vessels show that severe diffuse atrophy is present. In addition, the NFL coming from the foveal area (arrowheads, top left and bottom right photographs) is still intact and more distinct than that of the arcuate zone above it.
Quigley et al . Nerve Fiber Layer Photographs
Figure 3. Wedge atrophy (W) is indicated in these photographs of the retina below the optic disc by a dark loss of striations flanked on either side by whiter, more normal NFL brightness. In rare examples (left), a highly localized atrophy is surrounded by normal nerve fiber layer. More commonly, a wider wedge (right) is found in an area characterized by more intact, but still moderately atrophic NFL. The margins of the wedge atrophy are marked by arrowheads.
was used to evaluate the readings of newly trained observers. Training of Observers New to the Grading System Five observers were trained to read the NFL by a standardized method of programmed instruction. They read a manual describing the NFL and its normal and abnormal appearance, as well as the features of the grading system. Next, they graded the two practice sets of 100 photographic pairs each. In practice set 1, the grading by the expert was shown on front of the photograph. For practice set 2, the grading of the expert was on the back of each slide. Finally, the five observers read the test set of 100 photographic pairs. After the first readings by each student, a training session with the expert and the practice sets was carried out, in which questions and equivocal readings were discussed. Then, the five observers read the test set again and their answers were compared with the gradings of the expert, with the agreement estimated by the weighted kappa statistic. The weighting gave full credit to perfect agreement and half credit for disagreements that were one grade apart. No credit was given for grades more than one level apart. One observer has been a glaucoma specialist for 4 years, three had just completed ophthalmic residency, and one is not an ophthalmologist and had no prior experience in examination of the NFL. Validity The case-control set of photographs was read by the expert only. This consisted of pictures from 37 eyes of 34 individuals with ocular hypertension. Each of these eyes initially had normal visual field testing on the Goldmann perimeter, and reproducible field defects developed after 5 or more years of observation. These photographs were compared with those of 37 eyes of patients with ocular
hypertension who were similarly followed for at least 5 years with continued normal fields on the Goldmann perimeter. The stable eyes were frequency-matched by age and race to those whose fields had converted to abnormal. In both groups, the annual NFL and color stereophotographs for the 5 years preceding field loss were compared by an observer masked to their history. The readings of these eyes using an NFL grading system with fewer categories has been reported. 18 The optic disc was stereophotographed with color film using the Zeiss camera. The size of the disc and the cup were measured from the 35-mm transparencies using an eyepiece micrometer. 13 The cup-to-disc ratio was calculated from these measurements without any correction for image magnification. Visual field tests on the Goldmann perimeter were performed by a detailed method described previously,S including static and kinetic presentation of at least five target size and brightness combinations. The criteria for visual field defect included nasal steps or paracentral scotomas of stated magnitudes. s Automated Humphrey 30-2 threshold tests were evaluated with the STATPAC II software indices: mean deviation, pattern standard deviation, and glaucoma hemifield test. Color photographs and NFL were compared with field findings obtained in the same 12-month period. Since we began using automated field testing in 1984, only 137 of 200 eyes in practice set 2 and the test set had automated tests performed in the same year as the photographs. Hence, in the data below, we present comparison information from visual fields on the Goldmann perimeter on 200 eyes and from Humphrey field tests on 137 eyes.
Results Gradings by an Expert The first and second gradings by the expert of the 200 upper/lower pairs in practice set 2 and the test set were identical in 339 (85%) of 400 photographs. Agreement measured by the unweighted and weighted kappa sta-
Table 2. Intraobserver Comparison of Nerve Fiber Layer Grading
Unweighted kappa 95%CI Weighted kappa" 95%CI
Upper Photograph
Lower Photograph
0.73 (0.65, 0.82) 0.78 (0.71, 0.86)
0.74 (0.66, 0.82) 0.82 (0.75,0.88)
CI = confidence interval. • Calculated by giving full credit for exact agreement and one-half credit for readings differing by one grade level.
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Table 3. Cup/Disc Ratio Compared with Nerve Fiber Layer Grade for Eyes in the Case/Control Photograph Set: Mean ± SD Vertical CjD
Nerve Fiber Layer Grade
DO (normal D1 (mild) D2 (moderate) D3 (severe)
0.48 0.51 0.57 0.67
± ± ± ±
0.14 0.18 0.19 0.18
Horizontal CjD
N*
0.47 0.48 0.49 0.61
27 10 19 9
± ± ± ±
0.15 0.17 0.17 0.19
SD = standard deviation, C/D = cup/disc ratio. • The total is fewer than 74 eyes due to unreadable color or nerve fiber layer photographs in nine eyes.
tistic was good or excellent (Table 2). The distribution of adjudicated NFL grades among the test set photographs were: normal (DO), 58%; mild atrophy (01), 10%; moderate atrophy (02), 17%; and severe atrophy (03), 15%. To judge the validity of the system, we compared the gradings to standard indicators of glaucoma injury, including cup-to-disc ratio and visual field test results. The cup-to-disc ratio and NFL data were compared for the 74 eyes in the case-control set. Of these, 65 eyes had both readable color and NFL photographs. The vertical and horizontal cup-to-disc ratios of eyes with NFL atrophy were larger than eyes with normal gradings (analysis of variance, vertical cup-to-disc ratio: P < 0.03; horizontal cup-to-disc ratio: P = 0.18; Table 3). The NFL grade was compared with the findings on visual field testing with the Goldmann perimeter in the
200 eyes of practice set 2 and the test set (Table 4). The NFL grade is presented for the retinal half corresponding to its mirror-image location in the visual field. The persons are divided into four groups: normals, two groups of patients with ocular hypertension, and those with pre-existing visual field defects. The groups of patients with ocular hypertension are divided into those in whom field defects did not develop during our follow-up study and those in whom field defects did develop (stable and converter ocular hypertension, respectively; Table 4). These are separated here to compare whether the NFL gradings differ between ocular hypertensive subgroups. Ninety percent of normal eyes were graded as NFL normal (DO), whereas 93% of eyes with a field defect were graded as NFL abnormal (01-03) (chi-square, P < 0.001; Table 4). More than half of the hemifields with field loss on the Goldmann perimeter had the most severe NFL grade. There were more eyes with higher degrees of NFL abnormality in the groups with field loss than in the normal and stable ocular hypertensive groups (chi-square, P < 0.001; Table 4). For example, of the photographic fields (upper and lower) that had the most severe NFL grade (03),69% (35/51) were in the group that entered the study with field loss. For the photographs with a grade of 02 (moderate damage), 82% (54/66) were in the two most damaged groups (converter ocular hypertension and field loss). The NFL gradings were compared with three indices that summarize automated field data: glaucoma hemifield test, pattern standard deviation, and mean deviation. In Table 5, we present the glaucoma hemifield test results of 137 eyes from practice set 2 and the test set in which we have NFL grading and threshold fields performed in the same year. There is a smooth transition in the proportion
Table 4. Visual Field* with Goldmann Perimeter Compared with Nerve Fiber Layer Grade in 200 Eyes from Practice Set 2 and Test Set Clinical Status by Field and lOP Photo Grade Upper NFL DO D1 D2 D3 Lower NFL DO D1 D2 D3 N (eyes) OH
Normal
Stable OH
Converter OH
Field Loss
74 (89)t 8 (10) 1 (1) 0
29 (74) 3 (8) 7 (18) 0
9 (26) 9 (26) 11 (33) 5 (15)
3 (7) 7 (16) 10 (23) 24 (54)
76 (92) 4 (5) 2 (2) 1 (1) 83
32 (82) 3 (8) 2 (5) 2 (5) 39
10 (29) 2 (6) 14 (41) 8 (24) 34
3 (7) 11 (25) 19 (43) 11 (25)
= ocular hypertensive; NFL = nerve fiber layer; lOP = intraocular pressure.
* Visual fields used in this comparison were performed within 12 mos of the photograph.
t
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Values in parentheses are percentages.
44
Quigley et al . Nerve Fiber Layer Photographs Table 5. Comparison of Glaucoma Hemifleld T est and NFL Grade
Table 6. Comparison of Pattern Standard Deviation and NFL Grade
Glaucoma Hemifield Test Scorer
Pattern Standard Deviation Result
NFL Grade·
Abnormal
Normal
NFL Grade"
P s 0.05
Normal
Normal Worst grade = Dl Worst grade = D2 Worst grade = D3
9 (14)t 6 (60) 19 (63) 23 (92)
56 (86) 4 (40) 11 (37) 2 (8)
Normal Worst grade = D 1 Worst grade = D2 Worst grade = D3
17 (24)t 5 (50) 20 (65) 25 (96)
53 (76) 5 (50) 11 (35) 1 (4)
Total
57
73
Total
67
70
NFL
=
nerve fiber layer.
• Each eye is placed in a category based on both hemiretinal fields examined. Normal group is those with DO in both upper and lower photographs. Worst grade = D1 includes eyes that had upper and lower grades of D1 and D1 or D1 and DO. Worst grade = D2 is all eyes the worst grade (upper or lower) of which was D2 (similarly for D3).
NFL
=
nerve fiber layer.
• Normal field group includes pattern standard deviation result fully within the normal range or with a probability of being normal of <0.1 but >0.05. Worst grade = D1, D2, and D3 defined as in Table 5.
t
Values in parentheses are percentages, as defined in Table 5.
t Values in parentheses are percentages and refer to the proportion of each NFL grade with either abnormal or normal field score.
r Normal field group includes eyes with a hemifield result of either "within normal limits" or "borderline," whereas abnormal comprises the eyes with a result of "outside normal limits." The 13 7 eyes in Practice Set 2 and the Test Set with both NFL gradings and automated field results are presented here and in Tables 6 and 7; seven eyes not listed in the table had hemifield results of either "unusually high sensitivity" or "general reduction in sensitivity" (hence, the total presented is 130).
they graded the photographs as DO or D 1 compared with D2 or D3. With this evaluation, the percent agreement with the expert averaged 87% among the five observers, and the kappa statistics (unweighted) were nearly all in the excellent range (Table 8).
Expert Grading of the Case-control Set of abnormal field results from predominately normal in the normal NFL grade (~O) to predominately abnormal in the severely atrophic NFL grade (D3) (chi-square, P < 0.001). For the pattern standard deviation and mean deviation indices, the NFL grade also follows the automated field abnormality well (chi-square tests, P < 0.001; Tables 6 and 7).
Gradings of the Test Set by Other Observers The five observers who were trained to examine the NFL were in exact agreement with the expert an average of 68% of the time. The percentage agreement for each observer for photographs from the upper and lower NFL that make up this average is given in Table 8. Exact agreement means that the observers selected the same one of the four possible grades as did the expert. The weighted kappa statistics for the five observers for upper and lower photographs also was generally in the good range (Table 8). Two of the three ophthalmologists who had recently completed residencies performed similarly to the trainee who is a glaucoma specialist. The person with no prior experience in ophthalmologic examination diQ at least as well as one of the ophthalmologists. In the clinical setting, it is most important that an observer be able to distinguish between probably normal and definitely abnormal NFL status. To simulate this distinction, we re-examined the gradings of the five observers in comparison with those of the expert regarding whether
The NFL data in 37 stable and 37 converter ocular hypertensive eyes were compared for each group at baseline (at the start of the 5-year follow-up for stable eyes and 5 years before field loss in the converters). Abnormal NFL readings were found in 62% (21/34) of converters and in only 32% (11/34) of nonconverters (chi-square test, P < 0.03; 3 of 37 in each group had unreadable photographs). Substantially more of the converters had NFL grades 2 or 3 (41%,14/34) compared with those with stable fields (26%, 9/34) (chi-square test, P < 0.04; Table 9). Table
7. Comparison of Mean Deviation Score and NFL Grade Mean Deviation Score
NFL Grade·
P s 0.05
Normal
Normal Worst grade = D 1 Worst grade = D2 Worst grade = D3
11 (16)t 3 (30) 13 (42) 25 (96)
59 (84) 7 (70) 18 (58) 1 (4)
Total
52
85
NFL
=
nerve fiber layer.
* Normal includes mean deviation scores with a probability of being nor-
mal of <0.10 but >0.05. Worst grade D1, D2, and D3 defined as in Table 5.
t
Values in parentheses are percentages as defined in Table 5.
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Table 8. Agreement between Expert and Five Observers Trained in the Nerve Fiber Layer Grading System on the Test Set Photographs Agreement with Expert Using Full Grading System
Observer
Weighted Kappa Statistic Upper Lower
Percent Agreement Lower Upper
1 2 3
4 5
69% 69Dk 64% 70% 56%
75% 74% 69% 78% 56%
0.68 (0.58, 0.67 (0.57, 0.49 (0.36, 0.61 (0.48, 0.50 (0.37,
0.78) 0.77) 0.61) 0.73) 0.63)
0.70 (0.59, 0.72 (0.63, 0.55 (0.43, 0.72 (0.61, 0.57 (0.46,
0.80) 0.82) 0.66) 0.83) 0.68)
Agreement with Expert on Ability To Distinguish DO and Dl versus D2 and D3 Unweighted Kappa Statistic Upper Lower
Percent Agreement Upper Lower
1 2 3
4 5
89% 92% 82% 86% 82%
89% 91% 82% 92% 88%
When the photographs are considered during the 5 years before field loss, 59% of converter eyes in which field loss would develop had a worsening of NFL appearance during this period, compared with 30% of stable ocular hypertensive eyes. The degree of deterioration in converter eyes was detectably more severe than that in eyes of controls. Three times as many converter eyes as stable ocular hypertensive eyes worsened by more than one grade level (e.g., Dl to D3) or worsened in both upper and lower photographs.
Discussion The evaluation of glaucoma damage would be performed optimally by objective and quantitative criteria. Parameters that describe the features of the optic disc are familiar to most ophthalmologists. The NFL examination is an additional feature that demonstrates glaucoma injury. Although this is still a technique that is performed predominately within specialized centers,2-12 it is now widely used to determine the presence and progression of glaucomatous neuropathy. Other reports have attempted to use semi-quantitative methods to determine the state of the NFL.6.7.ID.II.13 These reports have shown a reasonable degree of reproducibility, and comparisons to optic disc and visual field criteria have indicated acceptable validity of their methods. Some of these other systems divided the NFL into 4 to 12 sectors surrounding the optic nerve head, grading at each sector one or more features. We have devised a simpler system in which the normality of the NFL is evaluated by comparing the NFL appearance in the arcuate area to the
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0.73 0.81 0.51 0.64 0.61
(0.58, (0.69, (0.34, (0.47, (0.45,
0.88) 0.94) 0.69) 0.80) 0.77)
0.73 (0.58, 0.79 (0.66, 0.67 (0.51, 0.80 (0.67, 0.74 (0.61,
0.88) 0.92) 0.83) 0.93) 0.88)
foveal retina. In such a system, the relative brightness and texture of the NFL above and below compared with the central area is critical. In our experience, it is more difficult to grade the NFL in multiple sectors around the disc separately, because the relative brightness is the most practical feature to use. Absolute brightness judgments are made difficult by the varying exposures among photographs. Our system appears to be practical for both clinical management of glaucoma and for use in clinical trials of glaucoma therapy. Our NFL grading system seems to be a valid measure of glaucoma injury when judged by comparing it with observations of the optic disc and with visual field testing with the Goldmann and Humphrey instruments. Other NFL grading systems also have been shown to reflect the degree of injury in functional tests. 6 ,7,19
Table 9. NFL Readings in Case/Control Set at Start of 5-Year Follow-up Nerve Fiber Layer Grade
Converter OH
Stable OH
Normal D1 (mild) D2 (moderate) D3 (severe)
13 (35)* 7 (19) 11 (30)
23 (62) 2 (5) 9 (24)
3 (8)
0(0)
Unreadable Total OH = ocular hypertensive. • Values in parentheses are percentages.
3 (8)
37
3 (8)
37
Quigley et al . Nerve Fiber Layer Photographs Machine-based systems may have potential for the measurement of NFL atrophy in glaucoma. 13 - 17 However, currently, none of these has been validated in a prospective fashion as we have done with the NFL grading system. In addition, most require expensive equipment, are time consuming, and do not have proven, general applicability. Until these systems are further developed, methods by which to determine the state and progression of glaucoma damage are needed that are valid and practical. This is especially critical in several multi-center clinical trials now being planned. Nerve fiber layer photography is shown by the data of this study to satisfy these criteria. We used a self-instruction method for teaching the NFL assessment system to five observers. Although four of the five observers attempted to examine the NFL clinically and saw photographic examples of NFL photography before this study, the specific grading system and its criteria were new to all five persons. It was clear that some interaction with an expert was important to improve the scores after initial practice readings. However, the total learning time for these observers was approximately 4 hours. It has been inferred that NFL grading only can be performed by a few experts and that its usefulness, therefore, is limited. Motivated observers who are presented with appropriate teaching material and who devote a modest time period can detect optic nerve damage in glaucomatous eyes that is additive to information currently available. In our opinion, the examination of the NFL is no more difficult to learn than stereoscopic examination of the optic disc. It is our intention to refine the teaching program used here and to make it available to those who wish to learn it.
References I. Hoyt WF, Frisen L, Newman NM. Fundoscopy of nerve fiber layer defects in glaucoma. Invest Ophthalmol 1973; 12: 814-29. 2. Sommer A, Miller NR, Pollack I, et al. The nerve fiber layer in the diagnosis of glaucoma. Arch Ophthalmol 1977;95: 2149-56. 3. Quigley HA, Miller NR, George T. Clinical evaluation of nerve fiber layer atrophy as an indicator of glaucomatous optic nerve damage. Arch Ophthalmol 1980;98: 1564-71.
4. Quigley HA. Examination of the retinal nerve fiber layer in the recognition of early glaucoma damage. Trans Am Ophthalmol Soc 1986;84:920-66. 5. Sommer A, Katz J, Quigley HA, et al. Clinically detectable nerve fiber atrophy precedes the onset of glaucomatous field loss. Arch Ophthalmol 1991;109:77-83. 6. Drance SM, Airaksinen PJ, Price M, et al. The correlation of functional and structural measurements in glaucoma patients and normal subjects. Am J Ophthalmol 1986; 102: 612-16. 7. Airaksinen PJ, Drance SM, Douglas GR, et al. Visual field and retinal nerve fiber layer comparisons in glaucoma. Arch Ophthalmol 1985; 103:205-7. 8. Honrubia F, Calonge B. Evaluation of the nerve fiber layer and peripapillary atrophy in ocular hypertension. Int Ophthalmol 1989;13:57-62. 9. Iwata K. The earliest finding of POAG and the mode of progression. In: Krieglstein GK, Leydhecker W, eds. Glaucoma Update II. Berlin: Springer-Verlag, 1983; 133-7. [Glaucoma Society, Int'! Congress of Ophthalmology, Carmel CA, Oct 1982] 10. Jonas JB, Naumann GOH. Parapapillary chorioretinal atrophy in normal and glaucoma eyes. II. Correlations. Invest Ophthalmol Vis Sci 1989;30:919-26. II. Tuulonen A, Airaksinen PJ. Initial glaucomatous optic disk and retinal nerve fiber layer abnormalities and their progression. Am J Ophthalmol 1991;111:485-90. 12. Hitchings RA, Poinoosawmy D, Poplar N, Sheth GP. Retinal nerve fibre layer photography in glaucomatous patients. Eye 1987;1:621-5. 13. Takamoto T, Schwartz B. Photogrammetric measurement of nerve fiber layer thickness. Ophthalmology 1989;96: 1315-19. 14. Caprioli J. The contour of the juxtapapillary nerve fiber layer in glaucoma. Ophthalmology 1990;97:358-66. 15. Miller E, Caprioli J. Regional and long-term variability of fundus measurements made with computer-image analysis. Am J Ophthalmol 1991;112:171-6. 16. Dreher AW, Tso PC, Weinreb RN. Reproducibility of topographic measurements of the normal and glaucomatous optic nerve head with the laser tomographic scanner. Am J Ophthalmol 1991;111:221-9. 17. Weinreb RN, Dreher A W, Coleman A, et al. Histopathologic validation of Fourier-ellipsometry measurements of retinal nerve fiber layer thickness. Arch Ophthalmol 1990; 108:55760. 18. Quigley HA, Katz J, Derick RJ, et al. An evaluation of optic disc and nerve fiber layer examinations in monitoring progression of early glaucoma damage. Ophthalmology 1992;99: 19-28. 19. Katz J, Sommer A. Similarities between the visual fields of ocular hypertensive and normal eyes. Arch Ophthalmol 1986; 104: 1648-51.
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