December 2009
Volume 50, Issue 12
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Cornea  |   December 2009
Progression of Fuchs Corneal Dystrophy in a Family Linked to the FCD1 Locus
Author Affiliations & Notes
  • Danielle N. Meadows
    From the Center for Corneal Genetics, Cornea and External Disease Service, The Wilmer Eye Institute,
  • Allen O. Eghrari
    From the Center for Corneal Genetics, Cornea and External Disease Service, The Wilmer Eye Institute,
  • S. Amer Riazuddin
    the McKusick-Nathans Institute of Genetic Medicine, and
  • David G. Emmert
    From the Center for Corneal Genetics, Cornea and External Disease Service, The Wilmer Eye Institute,
  • Nicholas Katsanis
    the McKusick-Nathans Institute of Genetic Medicine, and
    the Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
  • John D. Gottsch
    From the Center for Corneal Genetics, Cornea and External Disease Service, The Wilmer Eye Institute,
  • Corresponding author: John D. Gottsch, The Wilmer Eye Institute, Johns Hopkins Hospital, Maumenee Building, Room 321, 600 N. Wolfe Street, Baltimore, MD 21287; jgottsch@jhmi.edu
  • Footnotes
    2  Contributed equally to the work and should therefore be considered equivalent authors.
Investigative Ophthalmology & Visual Science December 2009, Vol.50, 5662-5666. doi:10.1167/iovs.09-3568
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      Danielle N. Meadows, Allen O. Eghrari, S. Amer Riazuddin, David G. Emmert, Nicholas Katsanis, John D. Gottsch; Progression of Fuchs Corneal Dystrophy in a Family Linked to the FCD1 Locus. Invest. Ophthalmol. Vis. Sci. 2009;50(12):5662-5666. doi: 10.1167/iovs.09-3568.

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      © 2016 Association for Research in Vision and Ophthalmology.

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Abstract

Purpose.: Fuchs corneal dystrophy (FCD) is a progressive corneal disease marked by the development of guttae, focal excrescences of Descemet's membrane. Retroillumination photography is a useful technique for illuminating the presence of guttae and has been used to document progression of disease. This study was undertaken to quantitatively assess disease progression in a cohort of individuals with late-onset FCD linked to chromosome 13.

Methods.: Retroillumination photography was performed on 13 related individuals (26 eyes) with the FCD1 disease haplotype at a 30- to 34-month interval. Individual guttae were counted in each image and the distribution recorded. A polar coordinate system was used to delineate regional differences in development of guttae.

Results.: An increase of 29.1% was found in the total number of guttae over approximately 30 months (mean increase of 669 guttae/eye, P < 0.001) among 26 eyes. A rapid rate of progression begins at approximately age 50, representing an exponential increase (r 2 = 0.60) among individuals mildly affected for decades. Individuals with the disease haplotype but with two affected parents demonstrated an earlier disease onset. A significantly greater proportion of guttae were present in the inferotemporal quadrant of the cornea (P < 0.001), an effect that grew in significance over time.

Conclusions.: The study demonstrated quantitative progression of FCD with the use of retroillumination photography in an FCD1-linked pedigree. Comparison of severity versus age suggests a rapid increase in the number of guttae at approximately age 50. Individuals with the FCD1 disease haplotype and a second likely genetic lesion exhibit a markedly increased disease severity suggestive of genetic interaction between FCD loci.

Nearly a century ago, Ernst Fuchs first described “dystrophia epithelialis corneae,” a condition among 13 patients that included stromal edema, opacity, and loss of corneal sensation. 1 Within several years of Fuchs description, “dimples” were identified in the posterior cornea of patients with the disease. 2 Vogt described these excrescences as “drop-like,” leading to use of the term corneal guttae. 3 Histologic analysis of corneal sections in FCD confirmed the presence of guttae 4 and specular microscopy documents guttae distributed across the field. 5  
FCD typically presents in middle age as a slowly progressive 6,7 bilateral disease with greater severity in females. 1,8 A grading system to document progression of FCD was first described by Krachmer et al. 8 in 1978. In this scale, grade 1 has a minimum of 12 central, nonconfluent guttae, with grades 2 to 4 representative of increasing area of confluence and grade 5 indicating the presence of stromal or epithelial edema. We have used this scale to document the relationship of increasing age with increased severity of the disease in early- and late-onset FCD. 911  
In the early-onset form of FCD, correlated with an L450W mutation in COL8A2, 9 dense, low-elevation guttae have been documented as early as the first decade of life. 9,12 In contrast, late-onset phenotypes associated with the FCD1 (13pTel-13q12.13) 10 and FCD2 (18q21) 11 loci manifest closer to the fifth decade and are associated with coarser, more distinct guttae. 
The variability of age and severity in the clinical presentation of FCD produces a challenge in the assessment and documentation of its various phenotypes. A definitive method is needed to delineate the relationship between each phenotype and its corresponding genotype. 
Using retroillumination photography, we have demonstrated formation of new guttae in a 30-month time interval. 13 These data suggest that measurements of the number and distribution of guttae over time by this technique represent an effective, quantitative profile of disease progression, although it has been difficult to determine whether guttae distribution and rate of appearance can correlate with specific FCD-causative genetic lesions. In beginning to address this question, we used retroillumination photographs taken at 30-month intervals of affected family members in a large pedigree linked to the chromosome 13 FCD1 locus, 10 to determine whether quantitative progression of disease could be documented and correlated to FCD1 disease genotype. 
Methods
Recruitment
Previously, 34 individuals of a family with Fuchs dystrophy were genotyped to 13pTel-13q12.13. 10 Retroillumination images were acquired from 18 affected family members initially willing to participate; 13 individuals followed up by having sequential photographs taken at a 30- to 34-month interval. Those individuals in the pedigree (Fig. 1) that possess the disease haplotype were photographed at baseline and after a 30- to 34-month interval. Of these, three individuals had inherited the disease haplotype from one parent, with the other parent also affected but without the disease haplotype. 
Figure 1.
 
Subset of pedigree of family with Fuchs corneal dystrophy genotyped to 13pTel-13q13.12. 10 Individual identification numbers and corresponding ages are provided. Black: affected with haplotype. Light shading: individuals who possess haplotype and showed early signs of disease. Dark shading: affected without haplotype. White: unaffected. Question mark: unknown. Square: patient underwent transplantation before the evaluation.
Figure 1.
 
Subset of pedigree of family with Fuchs corneal dystrophy genotyped to 13pTel-13q13.12. 10 Individual identification numbers and corresponding ages are provided. Black: affected with haplotype. Light shading: individuals who possess haplotype and showed early signs of disease. Dark shading: affected without haplotype. White: unaffected. Question mark: unknown. Square: patient underwent transplantation before the evaluation.
The study protocol was approved by the Joint Committee on Clinical Investigation at The Johns Hopkins University School of Medicine and was in accordance with the tenets of the Declaration of Helsinki. Written, informed consent was obtained from all study participants after explanation of the nature and possible consequences of the study. The study is in accordance with HIPAA regulations. 
Imaging
After pupillary dilation of both eyes in each participant, retroillumination images were obtained with a photo slit lamp (Carl Zeiss Meditec, Dublin, CA), as described. 13 In summary, a digital camera (D2xs Nikon Corp., Tokyo, Japan) was used with a 12× magnification changer. Flash power averaged 460 W (range, 240–720), and the lens aperture was set between F32 and F44. A minimum of four photographs were produced of each eye: two with the retroillumination beam from the right, and two with the retroillumination beam from the left. 
Data Analysis
Images were imported into image analysis software (Photoshop CS4 Extended Package; Adobe Systems Inc., San Jose, CA). Images from individuals without disease or who did not display the disease haplotype were excluded from the analysis. 
Characteristic groups of guttae were used to align consecutive images, and a composite representation used corneal images contralateral to the beam. A polar coordinate system (Fig. 2) was developed consisting of eight concentric zones and twelve 30° divisions for a total of 96 sampled sectors. The grid was centered at the central pupil and expanded to include all potentially visible guttae. 
Figure 2.
 
Grid overlay on retroillumination image of individual III6, carrier of the FCD1 disease haplotype associated with the 13pTel-13q12.13 locus. 10 Eight concentric zones were divided into 12 angular divisions for a total of 96 sampled segments in each eye. Inferotemporal distribution of guttae continued to progress over 30 months, with inferior movement of average central guttae away from the center. Arrows: change in center of distribution of guttae. The average center of distribution in each eye progressed among right eyes (blue arrow) from sector 8C to 7E, and among left eyes (green arrow) from 6C to 6E.
Figure 2.
 
Grid overlay on retroillumination image of individual III6, carrier of the FCD1 disease haplotype associated with the 13pTel-13q12.13 locus. 10 Eight concentric zones were divided into 12 angular divisions for a total of 96 sampled segments in each eye. Inferotemporal distribution of guttae continued to progress over 30 months, with inferior movement of average central guttae away from the center. Arrows: change in center of distribution of guttae. The average center of distribution in each eye progressed among right eyes (blue arrow) from sector 8C to 7E, and among left eyes (green arrow) from 6C to 6E.
Individual gutta in each sector were identified and summated manually on computer (Photoshop Count Analysis; Adobe Systems, Inc.), and the total counts exported to a spreadsheet (Excel; Microsoft Corp., Redmond, WA) for data analysis. Differences in superior versus inferior or nasal versus temporal distribution of guttae were then assessed through statistical comparison of symmetrically opposing quadrants. Coordinates for guttae were determined, to obtain an overall trend of distribution in gutta formation. The average distance and angle of each of the 96 sectors was calculated, and the guttae in each sector summated. 
Linear and exponential regression analyses were used to examine the effect of age and density on the cumulative development of guttae (Excel; Microsoft Corp.). 
Results
Two consecutive sets of images were analyzed from each eye of 12 individuals (9 men, 3 women; average age, 47 years) who were determined to carry the disease haplotype (Fig. 1). We counted the total number of guttae throughout the cornea for all individuals (n = 136,883; Table 1). In total, we found a 29.1% increase in the number of guttae during this interval among all eyes (average increase of 669 guttae); the increase was significant (P < 0.001, paired t-test). Moreover, the total proportion of guttae in the inferior hemisphere of the cornea increased over time from 54.5% to 58.1% of total guttae, a tendency that grew stronger in significance (baseline P < 0.01, post-interval P < 0.0001). Similarly, a comparison between inferotemporal and superonasal quadrants demonstrated an increasingly significant inferotemporal distribution over time (P < 0.0009–0.0003). An example of these changes is illustrated in Figure 3. We found no significant difference in the rate of formation of guttae between right and left eyes (31.5% and 27.2%, respectively; P < 0.84). 
Table 1.
 
Total Number and Proportion of Guttae in Each Quadrant of the Cornea at Baseline and after Interval of Approximately 30 Months, across 26 Images at Each Time Point.
Table 1.
 
Total Number and Proportion of Guttae in Each Quadrant of the Cornea at Baseline and after Interval of Approximately 30 Months, across 26 Images at Each Time Point.
Baseline 30 Months
Total Guttae (n) Percentage of Total Difference vs. Inferotemporal Total Guttae (n) Percentage of Total Difference vs. Inferotemporal
Inferotemporal 17,106 29 23,384 30
Superonasal 12,823 21 P < 0.001* 15,907 21 P < 0.001*
Superotemporal 14,349 24 P < 0.02* 16,414 21 P < 0.001*
Inferonasal 15,466 26 P < 0.07 21,434 28 P < 0.017*
Figure 3.
 
Comparison of retroillumination photographs before (left) and after (right) 30-month interval in right eye of individual III6, carrier of the FCD1 disease haplotype associated with the 13pTel-13q12.13 locus. 10 Top: guttae were distributed inferiorly and temporally. Bottom: the image within the rectangle. Identical sampling regions illustrate progression after 30 months, demonstrated by the greater relative prominence of previously identified guttae (circled, white) and appearance of newly discernible guttae (circled, green).
Figure 3.
 
Comparison of retroillumination photographs before (left) and after (right) 30-month interval in right eye of individual III6, carrier of the FCD1 disease haplotype associated with the 13pTel-13q12.13 locus. 10 Top: guttae were distributed inferiorly and temporally. Bottom: the image within the rectangle. Identical sampling regions illustrate progression after 30 months, demonstrated by the greater relative prominence of previously identified guttae (circled, white) and appearance of newly discernible guttae (circled, green).
We confirmed this inferotemporal trend through averaging of coordinates for each gutta and development of a summary vector (Fig. 2). A total of 96 sectors in each of 13 images from each eye were averaged at baseline and repeated postinterval. Guttae continued to develop in an inferotemporal distribution during this interval, centered at an increasingly inferior point. 
We found density to be consistently highest in the center and increased throughout each concentric zone during this interval (P < 0.00,001, paired t-test). At both time points, distance from the center was strongly correlated with a decrease in density (r 2 < 0.96). As the guttae were increasingly distributed throughout the cornea over time, density increased at the greatest rate in the periphery, at a rate approximately 1.8 times that in the central zone. Advanced cases, representing highest density, widespread confluence and complete coverage of the cornea, experienced a relatively lower total percentage of formation of new guttae, as demonstrated in Figure 4
Figure 4.
 
Total number of guttae by age, with (A) linear and (B) logarithmic axes. Guttae developed at an exponential rate, with an increase at approximately age 50. Early onset of disease was manifested in individuals IV1, IV2, and IV4, who possessed the disease haplotype but represented offspring of two affected parents. Individual III4 demonstrated a limited rate of development of guttae, which may be due to environmental factors. Exclusion of this individual results in a factor of 0.12 and an r 2 = 0.89. (C) Percentage increase in total guttae during the interval based on the initial count. In advanced cases, density and confluence of guttae increase throughout the cornea, resulting in a decreased percentage of increase in guttae.
Figure 4.
 
Total number of guttae by age, with (A) linear and (B) logarithmic axes. Guttae developed at an exponential rate, with an increase at approximately age 50. Early onset of disease was manifested in individuals IV1, IV2, and IV4, who possessed the disease haplotype but represented offspring of two affected parents. Individual III4 demonstrated a limited rate of development of guttae, which may be due to environmental factors. Exclusion of this individual results in a factor of 0.12 and an r 2 = 0.89. (C) Percentage increase in total guttae during the interval based on the initial count. In advanced cases, density and confluence of guttae increase throughout the cornea, resulting in a decreased percentage of increase in guttae.
We also calculated the total increase in guttae in each eye (Fig. 4). A rapid rate of increase in total number of guttae was present at approximately age 50. Cumulative assessment of individuals with the disease haplotype and a single affected parent was consistent with an exponential rate (r 2 = 0.60). In a notable finding, three individuals with the disease haplotype who represent offspring of two affected parents, as indicated in the pedigree, experienced early onset of disease. 
Discussion
Using retroillumination photographic analysis, we demonstrate specific patterns of progression that correlate to the previously described FCD1-linked pedigree. 10  
All individuals had a quantitative increase in severity over time, as defined by the total number of guttae in each eye. This number increased rapidly among individuals at approximately 50 years of age, consistent with our previous findings among patients with late-onset FCD according to the Krachmer grading scale. 9 The assessment of two individuals with the disease haplotype who are mildly affected as defined by the Krachmer grading scale in the fourth to fifth decade of life suggests that rates of increase in guttae may represent an exponential pattern of progression, with earliest signs present decades before clinical presentation. Our data predict that prospective individuals with the haplotype between the ages of 20 and 30 may exhibit less than 10 corneal guttae and as such not receive a clinical diagnosis of FCD by the Krachmer scale. 
In our clinical assessment of family members, we encountered three individuals with the disease haplotype who demonstrated an earlier onset and progression of disease. We have hypothesized previously that in individuals who have inherited FCD-causing alleles from both parents, disease manifestation is accelerated by two to three decades. 10 In our present findings, we confirm disease progression in these individuals at an early age. Similar to previous findings among a family with an early-onset COL8A2 L450W phenotype, 9 the disease, once initiated, appears to progress at a rate similar to cases of later onset. In addition, we noted that one individual in the seventh decade of life experienced markedly less severe FCD than others in the family of the same age and with the same disease haplotype. This patient as an outlier may have been exposed to environmental or genetic protective effect(s). 
In this family, the majority of guttae in each eye were distributed in the inferior half of the cornea, consistent with our previous clinical observations in late-onset FCD. 13 However, quantitative measurement of the rate of development of guttae now shows that this is not only a static phenomenon, but a dynamic one that increases in significance over time. We also demonstrate a similar inferotemporal pattern of guttae formation. This distribution may be related to external environmental factors such as light exposure or related to internal aqueous dynamics. 
In summary, we used retroillumination photography to quantify and document the progression of gutta formation in a pedigree genotyped to 13pTel-13q12.13. This photographic technique may be useful in quantitatively determining the phenotypic trait of gutta formation in other genotypes identified with Fuchs dystrophy including FCD2 (18q21.2-q21.32) 11 and early-onset Fuchs dystrophy (L450W, COL8A2). 9 Differences in progression may represent a distinguishing phenotypic trait among the various genotypes of FCD. Changes in rates of progression for a given phenotype would be an essential parameter to monitor in any therapeutic clinical trial. 
Footnotes
 Supported by National Eye Institute Grant R01EY016835 (JDG), Faller Family LLC, Research Fund, and National Institute of Child Health and Development Grant R01HD04260 (NK).
Footnotes
 Disclosure: D.N. Meadows, None; A.O. Eghrari, None; S.A. Riazuddin, None; D.G. Emmert, None; N. Katsanis, None; J.D. Gottsch, None
Footnotes
 The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked “advertisement” in accordance with 18 U.S.C. §1734 solely to indicate this fact.
The authors are grateful to all family members for their enthusiastic participation in this study. The proband was initially identified by Irene Maumenee. 
References
Fuchs E . Dystrophia epithelialis corneae. Albrecht von Grafes Arch Klin Exp Ophthalmol. 1910;76:478–508. [CrossRef]
Koeppe L . Klinische beobachtungen mit der nernstspaltlampe und dem hornhaumikroskop. Albrecht von Grafes Arch Kiln Ophthalmol. 1916;91:363–379. [CrossRef]
Vogt A . Weitere Ergebnisse der Spaltlampenmikroskopic des vordern Bulbausabschnittes. Albrecht von Grafes Arch Ophthalmol. 1921;106:63–113. [CrossRef]
Vogt A . Lehrbuch und Atlas der Spaltlampenmikroskopie des lebenden Auges. 2nd ed. Berlin: Springer; 1930.
Bourne WM . Clinical specular microscopy. Trans Sect Ophthalmol Am Acad Ophthalmol Otolaryngol. 1976 81( 5): 743–753.
Kraupa E . Pigmentuerung der hornhauthinterfläche bei ‘Dystrophia epithelialis (Fuchs)’. Z Augenheilkd. 1920;44:247–250.
Friedenwald H Friedenwald JS . Epithelial dystrophy of the cornea. Br J Ophthalmol. 1925;9:14–20. [CrossRef] [PubMed]
Krachmer JH Purcell JJJr Young CW . Corneal endothelial dystrophy: a study of 64 families. Arch Ophthalmol. 1978;96:2036–2039. [CrossRef] [PubMed]
Gottsch JD Sundin OH Liu SH . Inheritance of a novel COL8A2 mutation defines a distinct early-onset subtype of Fuchs corneal dystrophy. Invest Ophthalmol Vis Sci. 2005;46:1934–1939. [CrossRef] [PubMed]
Sundin OH Jun AS Broman KW . Linkage of late-onset Fuchs corneal dystrophy to a novel locus at 13pTel-13q12.13. Invest Ophthalmol Vis Sci. 2006;47:140–145. [CrossRef] [PubMed]
Sundin OH Broman KW Chang HH . A common locus for late-onset Fuchs corneal dystrophy maps to 18q21.2-q21.32. Invest Ophthalmol Vis Sci. 2006;47:3919–3926. [CrossRef] [PubMed]
Magovern M Beauchamp B McTigue JW . Inheritance of Fuchs' combined dystrophy. Ophthalmology. 1979;86:1897–1923. [CrossRef] [PubMed]
Gottsch JD Sundin OH Rencs EV . Analysis and documentation of progression of Fuchs corneal dystrophy with retroillumination photography. Cornea. 2006;25:485–489. [CrossRef] [PubMed]
Figure 1.
 
Subset of pedigree of family with Fuchs corneal dystrophy genotyped to 13pTel-13q13.12. 10 Individual identification numbers and corresponding ages are provided. Black: affected with haplotype. Light shading: individuals who possess haplotype and showed early signs of disease. Dark shading: affected without haplotype. White: unaffected. Question mark: unknown. Square: patient underwent transplantation before the evaluation.
Figure 1.
 
Subset of pedigree of family with Fuchs corneal dystrophy genotyped to 13pTel-13q13.12. 10 Individual identification numbers and corresponding ages are provided. Black: affected with haplotype. Light shading: individuals who possess haplotype and showed early signs of disease. Dark shading: affected without haplotype. White: unaffected. Question mark: unknown. Square: patient underwent transplantation before the evaluation.
Figure 2.
 
Grid overlay on retroillumination image of individual III6, carrier of the FCD1 disease haplotype associated with the 13pTel-13q12.13 locus. 10 Eight concentric zones were divided into 12 angular divisions for a total of 96 sampled segments in each eye. Inferotemporal distribution of guttae continued to progress over 30 months, with inferior movement of average central guttae away from the center. Arrows: change in center of distribution of guttae. The average center of distribution in each eye progressed among right eyes (blue arrow) from sector 8C to 7E, and among left eyes (green arrow) from 6C to 6E.
Figure 2.
 
Grid overlay on retroillumination image of individual III6, carrier of the FCD1 disease haplotype associated with the 13pTel-13q12.13 locus. 10 Eight concentric zones were divided into 12 angular divisions for a total of 96 sampled segments in each eye. Inferotemporal distribution of guttae continued to progress over 30 months, with inferior movement of average central guttae away from the center. Arrows: change in center of distribution of guttae. The average center of distribution in each eye progressed among right eyes (blue arrow) from sector 8C to 7E, and among left eyes (green arrow) from 6C to 6E.
Figure 3.
 
Comparison of retroillumination photographs before (left) and after (right) 30-month interval in right eye of individual III6, carrier of the FCD1 disease haplotype associated with the 13pTel-13q12.13 locus. 10 Top: guttae were distributed inferiorly and temporally. Bottom: the image within the rectangle. Identical sampling regions illustrate progression after 30 months, demonstrated by the greater relative prominence of previously identified guttae (circled, white) and appearance of newly discernible guttae (circled, green).
Figure 3.
 
Comparison of retroillumination photographs before (left) and after (right) 30-month interval in right eye of individual III6, carrier of the FCD1 disease haplotype associated with the 13pTel-13q12.13 locus. 10 Top: guttae were distributed inferiorly and temporally. Bottom: the image within the rectangle. Identical sampling regions illustrate progression after 30 months, demonstrated by the greater relative prominence of previously identified guttae (circled, white) and appearance of newly discernible guttae (circled, green).
Figure 4.
 
Total number of guttae by age, with (A) linear and (B) logarithmic axes. Guttae developed at an exponential rate, with an increase at approximately age 50. Early onset of disease was manifested in individuals IV1, IV2, and IV4, who possessed the disease haplotype but represented offspring of two affected parents. Individual III4 demonstrated a limited rate of development of guttae, which may be due to environmental factors. Exclusion of this individual results in a factor of 0.12 and an r 2 = 0.89. (C) Percentage increase in total guttae during the interval based on the initial count. In advanced cases, density and confluence of guttae increase throughout the cornea, resulting in a decreased percentage of increase in guttae.
Figure 4.
 
Total number of guttae by age, with (A) linear and (B) logarithmic axes. Guttae developed at an exponential rate, with an increase at approximately age 50. Early onset of disease was manifested in individuals IV1, IV2, and IV4, who possessed the disease haplotype but represented offspring of two affected parents. Individual III4 demonstrated a limited rate of development of guttae, which may be due to environmental factors. Exclusion of this individual results in a factor of 0.12 and an r 2 = 0.89. (C) Percentage increase in total guttae during the interval based on the initial count. In advanced cases, density and confluence of guttae increase throughout the cornea, resulting in a decreased percentage of increase in guttae.
Table 1.
 
Total Number and Proportion of Guttae in Each Quadrant of the Cornea at Baseline and after Interval of Approximately 30 Months, across 26 Images at Each Time Point.
Table 1.
 
Total Number and Proportion of Guttae in Each Quadrant of the Cornea at Baseline and after Interval of Approximately 30 Months, across 26 Images at Each Time Point.
Baseline 30 Months
Total Guttae (n) Percentage of Total Difference vs. Inferotemporal Total Guttae (n) Percentage of Total Difference vs. Inferotemporal
Inferotemporal 17,106 29 23,384 30
Superonasal 12,823 21 P < 0.001* 15,907 21 P < 0.001*
Superotemporal 14,349 24 P < 0.02* 16,414 21 P < 0.001*
Inferonasal 15,466 26 P < 0.07 21,434 28 P < 0.017*
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