an analysis of lesion size and location in newly diagnosed cy

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herent and confounds quantitative analysis. We designed a

mapping system that compensates for some of the photo-graphic distortion and that permits analysis of the concentricas well as the circumferential distribution of CMVR lesionsand their size.

Materials and Methods

Construction of the Retinal Map

The postequatorial retina was represented as a hemisphere. Theretinal surface was divided into 49 regions of equal area, eachregion containing 2.04% of the total postequatorial retinal surfacearea (PERSA; Fig 1). The central 11.6 surrounding the fovea isdefined as the macula region. The macula is surrounded by 4concentric zones, and each zone is subdivided into 12 regions. Thezone immediately surrounding the macula is referred to as thearcade zone. The most peripheral zone is referred to as the poste-quatorial zone. This hemisphere was then transposed into a flatmap to account for the distortion inherent in a flat photographicrepresentation of a curved surface. For further details on theconstruction of the retinal map, please see the Appendix.

Data Selection

Data selection was performed by a chart review of all patients withnewly diagnosed CMVR seen by one of the investigators (DVW)at the Department of Ophthalmology at Northwestern University

Medical School from 1990 through 1997. The medical records andthe Kodachrome color transparencies (Eastman Kodak Co., Roch-ester, NY) obtained at the time of diagnosis were then studied.

Data Acquisition

Kodachrome color transparencies taken at the time of diagnosis ofCMVR using a Canon model CF-60UV 60 fundus camera (CanonU.S.A., Lake Success, NY) were digitized with a Polaroid Sprint-Scan 35 (Polaroid Corp., Cambridge, MA) slide scanner usingAdobe Photoshop version 4.0 (Adobe Systems Inc., MountainView, CA). The images were then transferred to an Apple Com-puter PowerMacintosh G3/220 (Apple Computer Corp., Cuper-

tino, CA). The polar map was constructed and the CMVR lesiondata graphically plotted using the ClarisDraw graphics program1.0 version 2 (Claris Corp., Santa Clara, CA) and the Canvasgraphics software program version 5.0 (Deneba Software, Miami,FL).

Data Analysis

Each image was scaled so that the horizontal extent of each

photograph spanned 60 on the map. The anterior borders of theampullae of the vortex veins were found to extend just posterior tothe equator of the map, confirming that the images had been scaledcorrectly.

For each eye, a photographic montage of the fundus wascreated and superimposed on the flat map. Anatomic landmarkssuch as retinal blood vessels were used to align the images in themontage. The images were enlarged on a high-resolution 17-inchcolor monitor to mark the borders of CMVR. Both the active andinactive regions of CMVR were included in each lesion. Small,satellite lesions adjacent to dense, white areas of active retinitiswere considered part of the lesion and were included within theborder. The original transparencies were used to help identifylesion borders when they could not be identified definitively from

the digitized images.Lesion centers were determined by the point of intersection oflines drawn across the longest dimension, and the line drawnperpendicular to the longest dimension of the lesion. The distancefrom the fovea was determined in degrees for the center, anterior,and posterior border of all lesions, and polar coordinates for alllesion centers were computed.

Analysis of the complete extent of each lesion was such that ifpart of any lesion encroached into a region, it was said to involvethat region. Lesion size was determined by further subdividing thepolar map into regions of 0.25% PERSA. Lesion size was thengraphically estimated and rounded to the nearest whole numberpercent PERSA for each lesion.

For all lesions, the color fundus photos were compared withdetailed retina drawings on clinic notes. Six CMVR lesions were

located anterior to the equator in their entirety. These lesions wereexcluded from this study. The complete CMVR lesion border hadbeen photographed for 204 lesions included in this study; 48additional lesions were photographed to the equator; however,clinic records indicated that the lesions actually extended anteriorto the equator. Lesion centers and surface areas were computed forthese lesions by assuming that they ended at the equator. The dataset was analyzed by first including and then excluding theseadditional 48 lesions. The complete postequatorial distribution ofall 252 lesions was then analyzed.

For the overall analyses of lesion size and location, each lesionwas treated as an independent event. Two lesions from one eyewere counted the same as lesions from two different eyes or twodifferent patients.

Data analysis was performed using statistical software (SAS

Institute Inc., Cary, NC). Unless otherwise specified, categoricaldata were analyzed by chi-square test and continuous data by atwo-tailed t test or the Wilcoxon rank-sum test. Statistical signif-icance was considered P 0.05.

Results

Two hundred fifty-two lesions in 173 eyes of 130 patients (123male, 7 female) with newly diagnosed CMVR were analyzed.There were 122 right eye lesions and 130 left eye lesions. Cyto-megalovirus retinitis lesions were present in both eyes in 43 of 130patients (33%).

Figure 1. The postequatorial retina depicted as the inner surface of a

hemisphere, divided into 49 regions of equal surface area.

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There was no detectable difference in the distribution of lesionsamong regions between left and right eyes (chi-square test, P 0.27). The distribution of lesion centers for all eyes and thedistribution of the complete surface area of all lesions for all eyes

are shown in Figure 2. Analysis of the quadrantic location oflesions showed no detectable difference from a uniform distribu-tion for lesion centers (P 0.71) or for any part of a lesion (P 0.76). The distribution of lesion centers over the 49 regions was

Figure 2. An azimuth-equidistant projection of the retina model depicted in Figure 1. Fundus montages were superimposed on this map for determination

of the location and size of cytomegalovirus retinitis lesions. Polar plots illustrating the distribution of lesion centers for all eyes, as well as the distribution

of the total surface area of all lesions for all eyes, are shown. A, A right eye adjusted polar plot of all lesion centers for all eyes. The coordinates of the

lesion centers for left eyes were adjusted to match nasal and temporal orientation on a map of the right eye. The total number of lesion centers in each

region and quadrant are shown to the right. B, A right eye-adjusted polar plot of the distribution of the total surface area of all lesions. If a lesion

encroached into any part of a region, it was said to involve that region. The map for left eyes was adjusted to match nasal and temporal lesions onto the

map for right eyes. The distribution by zone is shown to the left, whereas the involvement by region and quadrant is illustrated to the right.

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not uniform (chi-square test for equal proportions, P 0.001).

The most obvious variation from a uniform distribution was thepresence of relatively few lesions in the postequatorial zone.

Analysis of the more posterior 37 regions (macula, arcade zone,

midperipheral zone, and peripheral zone) suggested a trend

away from a uniform distribution, which does not reach the

traditional level of statistical significance (P 0.09). Figure 2Asummarizes the distribution of the number of lesion centers

among all the regions. The sole outlier (more than two standard

deviations from the mean) is for the central macula region.This region accounts for 2% PERSA, but contains 6% of the

lesion centers. The greater number of lesions in the macula

region was statistically significant (P 0.001, goodness-of-fitchi-square test). If the postequatorial zone and the macular

regions are excluded, the distribution of lesion centers among

the remaining 36 regions showed no detectable difference fromwhat would be predicted by a homogeneous distribution ( P 0.33).

Figure 3 displays the distribution of lesion size. The distribu-

tion is skewed strongly toward small lesions. The median size was

3% PERSA. Fewer than one tenth of the lesions were 10% or more

PERSA. Involved eyes contained up to six lesions, but most had

just one lesion. The mean number of lesions was 1.6 per eye. The

total area of CMVR involvement (combined PERSA for all lesions

in an eye) ranged from 1% to 76% PERSA, with a median of 5%

PERSA.

There was a positive correlation between distance from the

fovea and lesion size (Pearson correlation, r 0.21, P 0.0006;Fig 4). Lesions with centers within the median distance from the

fovea were 3.8% PERSA in mean size, whereas lesions withcenters outside the median were 5.9% PERSA in mean size ( P 0.002).

Eyes of patients with unilateral retinitis had 1.3 lesions per

involved eye compared with eyes of patients with bilateral retinitis,

which had 1.6 lesions per eye (P 0.003). The mean posteriorlesion border was 24 from the fovea in unilaterally involved eyescompared with 28 in bilaterally involved eyes, a difference ofborderline statistical significance (P 0.05). Comparing eyes ofpatients with unilateral versus bilateral retinitis, there was no

difference in the distance of lesion centers from the fovea (P 0.38), individual lesion area (P 0.11), or total area of retinitis perinvolved eye (P 0.98).

Discussion

The present study provides a quantitative evaluation ofnewly diagnosed CMVR lesions by using a mapping systemthat simplified the analysis of lesion location and size andallowed statistical analysis. The results suggest that newlydiagnosed CMVR is uniformly distributed over most of theretinal surface. Variation from a uniform distribution wasfound in the postequatorial periphery, where there was arelative scarcity of lesion centers, and in the macula, whichcontained far more lesion centers than would be predictedby its relative surface area. Before considering the potentialsignificance of these results, we first discuss the advantagesas well as the limitations of the methods used.

Suitability of the Polar Map for StudyingCytomegalovirus Retinitis Lesions

There are a number of difficulties in quantitatively analyz-ing retinal lesions using fundus photographs. First, fundusimaging systems have variable magnification characteristicsthat are not only a function of the camera used, but also therefractive power of the eye photographed.16,17 Second, sizesand distances may be distorted, particularly for objects

approaching and anterior to the equator. Third, not allCMVR lesions can be photographed completely, especiallythose extending anterior to the equator.

Prior studies have outlined clever ways of measuring theoptic nerve dimensions or the size of small posterior polelesions using multiple-beam interference fringes18 or a pro-

jected ruler.19 These techniques, unfortunately, are not suit-able for studying geometrically complex CMVR lesions thatmay extend to the midperiphery or beyond.

In the present study, we attempted to devise a polar mapbased on the curved surface area of the retina. This was thentransposed to a flat representation simulating how the retina

Figure 3. A frequency histogram depicting the size distribution of indi-

vidual cytomegalovirus retinitis lesions (CMVR). The mean and median

size was 4.8% and 3% postequatorial retinal surface area (PERSA), re-

spectively. Fewer than one tenth of the lesions were 10% or more PERSA.

Figure 4. A scatterplot of lesion size versus distance from lesion center to

the fovea. The regression line demonstrates a positive correlation (Pearson

correlation, r 0.21, P 0.0006).

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would be depicted in photomontages constructed from fun-

dus photographs. Similar methods have been describedpreviously.20,21 Ideally, one would construct a different

map for each eye taking into account its refractive power.Unfortunately, this is not feasible. The model we de-

signed will slightly overestimate the retinal surface areain some patients and will undoubtedly underestimate it in

others, depending on the refractive characteristics of theeyes. All patients included in this study had been photo-

graphed on the same camera, thereby providing someuniformity in the quality as well as magnification char-acteristics of the images. The construction of our mapassumes that the postequatorial retina is a spherical sur-

face with the macula at its apex and that the photomon-tages prepared from clinical photographs represent an

azimuth equidistant representation of this spherical sur-face.21 We divided the postequatorial retina into 49

equally sized regions and transposed the boundaries ofthese regions as they would be represented on such a flatmap. By measuring lesion area as a proportion of the

whole (% PERSA), we hoped to avoid the technicaldifficulties inherent in trying to measure the absolute sizeof objects from fundus photographs.

Because lesions anterior to the equator are difficult tophotograph and are subject to the greatest distortion, welimited our study to the distribution of lesions in the poste-

quatorial retina. This method of analysis is reliable forstudying the complete postequatorial distribution of CMVR

lesions but may have some limitations with respect to de-termining the location of lesion centers for the 48 incom-

pletely photographed lesions.For 204 completely photographed lesions, the lesion

center could be determined with reasonable accuracy. For

the other 48 lesions, it was known that the true peripheralborder of the lesion was anterior to the equator, however,this border was not reliably documented. Eliminating

these lesions from the data pool would have biased thedata greatly toward more posterior lesions, because most

of these 48 lesions were anteriorly located. Instead, theselesions were measured by assuming that each lesion

ended at the equator, and these data were included in allreported analyses. Although the postequatorial retinal

surface area calculations for these lesions are valid, thelesion centers determined in this manner are more pos-

terior than they are in reality. This is a source of biastoward more posterior localization of lesions, but this

bias clearly was less than if these lesions had beenentirely excluded from the analysis. Furthermore, analy-sis of the complete surface area of all lesions confirmedthe results obtained with lesion center analysis, demon-strating fewer lesions in the postequatorial zone.

It is possible that some lesions that we counted as onemay have resulted from two or more lesions that had

coalesced. This would have resulted in undercounting oflesions and may have biased our results. Because the

median lesion size was small, we believe it is unlikelythat we undercounted a significant number of lesions inthis way.

Quantitative and Topographic Features of NewlyDiagnosed Cytomegalovirus Retinitis

In our study, the far peripheral retina (14 posterior to theequator) showed a relative scarcity of lesion centers. Thedistribution of lesions in the remainder of the postequatorialretina appeared homogeneous, with the exception of the 2%of retina centered in the macula, which contained more

lesion centers than its contribution to the retinal surface areawould predict. Some descriptions of CMVR have suggestedthat the infection has a predilection to begin around themajor vascular arcades, as may be expected based on pre-sumed hematogenous seeding of the virus. However, quan-titative analysis did not demonstrate any greater number oflesion centers in the arcade zone compared with the sur-rounding midperipheral and peripheral zones.

Previous reports of the distribution of CMVR lesionshave been predominantly descriptive or semiquantitativeand have not taken into consideration the relative area of thedifferent parts of the retina. Furthermore, these studies havenot accounted for the image distortion inherent to the var-

ious methods of data acquisition that were used. Someauthors have reported that posterior retinal involvement is aprominent feature of CMVR,35 whereas others have em-phasized the involvement of the periphery.1,6,15

The SOCA research group reported that in 337 eyes withnewly diagnosed CMVR, 50% showed zone I involvement,96% showed zone II involvement, and 84% showed zone IIIinvolvement. Involvement of the optic nerve (9%) or fovea(4%) occurred infrequently.22 The SOCA group uses astandard fundus photography protocol and a centralizedreading center. The mapping system used by SOCA dividesthe retina into three zones based on fundus landmarks,which makes it convenient for clinical classification of

lesion location but is much less suitable for quantitativeanalysis. The extent of retinal involvement is measured byplanimetry from the transparencies. It is not clear if adjust-ments are made for image distortion of peripheral retinallesions. Furthermore, SOCA has not published data local-izing lesions by a unique coordinate, such as lesion center,so only limited comparisons of our results with those re-ported by SOCA are possible.

The total area of retinal involvement in percent PERSAwas somewhat less in our patients than that reported for asimilar cohort by the SOCA research group, which found amean of 13.5% PERSA for unilaterally involved eyes.22

Bilaterally involved eyes were analyzed as the better orworse eyes. The mean percent PERSA was found to be

7.9% in the better eyes and 20.4% in the worse eyes inthe SOCA study. It appears that the bilateral eyes overall didnot differ from unilateral eyes, however, no analysis of sucha comparison was reported.22 We found the mean total areafor all involved eyes to be 10.3% PERSA, with no differ-ence between eyes for unilaterally versus bilaterally in-volved patients. In this paper, we present mean area only asa way of comparing our data with SOCA. We believe thatmedian is a more representative measure of central tendencyin this asymmetric distribution.

We found an overall distribution with more lesions lo-cated in the posterior than the peripheral zones. The more


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18. Baumbach P, Rassow B, Wesemann W. Absolute ocular fun-dus dimensions measured by multiple-beam interferencefringes. Invest Ophthalmol Vis Sci 1989;30:23149.

19. Arzabe CW, Jalkh AE, Fariza E, et al. A simple device tostandardize measurements of retinal structures in fundus pho-tographs and retinal angiograms. Am J Ophthalmol 1990;109:1078.

20. Mosier MA. Retinal cartography. Can J Ophthalmol 1982;17:21922.

21. Borodkin MJ, Thompson JT. Retinal cartography: an analysisof two-dimensional and three-dimensional mapping of theretina. Retina 1992;12:27380.

22. Foscarnet-Ganciclovir Cytomegalovirus Retinitis Trial: 5.Clinical features of cytomegalovirus retinitis at diagnosis.Studies of Ocular Complications of AIDS Research Group incollaboration with the AIDS Clinical Trials Group. Am JOphthalmol 1997;124:14157.

Appendix

Construction of the Retinal Map

A hemispheric polar map centered on the fovea was con-structed that divided the postequatorial retina into 49 re-gions of equal surface area, each region representing ap-proximately 2% of the total postequatorial retinal surfacearea (PERSA). The map was composed of a central region,surrounded by four concentric zones each divided into 12regions (Fig 1).

The postequatorial retina was represented by the innersurface of a hemisphere with the fovea at its apex. Thesurface area of a hemisphere (Ah) is:

Ah 2r2.

The area of a polar cap (Ac) of the hemisphere is

Ac 2r2(1 cos),

where represents the angle between radii drawn to theapex and to the edge of the cap.

Let P represent the ratio of the area of the spherical caprelative to the area of the entire hemisphere.

P Ac /Ah 1 cos.

Solving for ,

co s1 1 P).

In our map, we define a central cap to represent 1/49 thetotal area of the hemisphere, such that:

1 co s1 1 1/49 11.6.

The remaining polar caps are defined with P of 13/49,25/49, 37/49, and 49/49, resulting in s of 42.7, 60.7,75.8, and 90, respectively.

Each band surrounding the central cap is divided into 12equally sized segments, resulting in a total of 49 equallysized regions, each representing 1/49 or approximately 2%PERSA. Each of the 49 segments of retina is referred to asa regions, and each of the 4 bands of retina surrounding thecentral region is referred to as a zone composed of 12regions. The central region is referred to as the macula, the

innermost zone surrounding the macula is called the arcadezone, the next the midperipheral zone, then the peripheralzone, and the outermost as the postequatorial zone.

Position on the map was defined using a system analo-gous to latitude and longitude on geographic maps. Thedistance from the center of the fovea was measured indegrees (0 at the center of the fovea to 90 at the equator).Circumferential location was identified by designating the3-oclock meridian as 0 and using circular coordinates in acounterclockwise orientation (i.e., 12-oclock is 90,9-oclock is 180, 6-oclock is 270, etc.).

To account for the distortion inherent in a photographicmontage of a curved surface, a flat, equatorial, equidistant,

projection of the polar map was constructed.

20,21

In thisprojection of a hemisphere, angular distances from the pole(fovea) are directly proportional to linear distance. Thecircumferential orientation (i.e., clock-hour location) is pre-served, however, the apparent circumference becomes in-creasingly exaggerated or stretched toward the equator.


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an analysis of lesion size and location in newly diagnosed cy

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