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Original Investigation | Clinical Sciences

Quantification of Fundus Autofluorescence to Detect Disease Severity in Nonexudative Age-Related Macular Degeneration

Ira H. Schachar, MD, MSc1; Sarwar Zahid, MD, MS1; Grant M. Comer, MD, MS1; Maxwell Stem, MD1; Asa G. Schachar, BS1; Stephen J. Saxe, MD1; Thomas W. Gardner, MD, MS1; Victor M. Elner, MD, PhD1; Thiran Jayasundera, MD1
[+] Author Affiliations
1Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan
JAMA Ophthalmol. 2013;131(8):1009-1015. doi:10.1001/jamaophthalmol.2013.4014.
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Importance  Accurate assessment of disease burden and determination of disease progression are challenging in dry age-related macular degeneration (AMD). We assessed the utility of quantified fundus autofluorescence in (FAF) the evaluation and follow-up of dry AMD.

Objective  To develop a method for quantitative FAF image analysis that is capable of stratifying severity of nonexudative AMD.

Design, Setting, and Participants  A retrospective analysis from 2008 to 2012 at a university eye center of FAF images taken of normal and nonexudative AMD eyes compared the Index of Retinal Autofluorescence (IRA) with retinal specialists’ clinical rankings of FAF images and the Age-Related Eye Disease Study (AREDS) grading scheme of corresponding color fundus photographs.

Intervention  Digital files of Heidelberg Spectralis FAF images taken of normal and nonexudative AMD eyes were analyzed. For each image, a unique horizontally oriented FAF signature composed of vertically averaged gray-scale values was generated through the fovea. A pairwise comparison of 2 signatures was performed using a modified difference of squares method, which generated a single quantitative value, the IRA.

Main Outcomes and Measures  The effects of intersession testing, cataract extraction, pupillary dilation, focal plane, and gain settings on the IRA were assessed.

Results  The FAF images taken of the same subjects at different times demonstrated low intersession variability of the IRA (intraclass coefficient = 0.75; 95% CI, 0.45-0.92). The IRA was affected by cataract severity, cataract extraction, small pupillary diameters (<5.5 mm), defocusing, and excessive high or low camera gain. The IRA values correlated with both subjective clinical rankings by retinal specialists (rs = 0.77). The IRA was positively correlated with AREDS score (rs = 0.73) and could statistically distinguish AREDS grades 3 and 4 (P < .001). Serial imaging demonstrated the utility of the method for identifying clinically meaningful disease progression.

Conclusions and Relevance  The IRA method applied to FAF digital files can quantify AMD disease severity and may be helpful in identifying AMD progression.

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Figure 1.
Fundus Autofluorescence Signature Generation

A, The signature is derived from a 400 (horizontal) × 50 (vertical)-pixel box centered on the fovea. B, All pixel values from this box are plotted. gsi Indicates gray-scale intensity. C, Pixels at the same horizontal location are averaged to yield a characteristic fundus autofluorescence signature.

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Figure 2.
Comparing Fundus Autofluorescence (FAF) Signatures to Calculate the Index of Retinal Autofluorescence

An age-related macular degeneration (AMD) FAF signature (taken from image A) is plotted against the averaged control FAF signature (B). Using a difference of squares method, the Index of Retinal Autofluorescence quantifies both hyperfluorescent (arrow) and hypofluorescent (arrowhead) changes caused by AMD. gsi Indicates gray-scale intensity.

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Figure 3.
Effect of Defocusing and Gain Setting on Index of Retinal Autofluorescence (IRA)

Focusing adequate to obtain retinal vessels measuring 15 to 25 μm (A-C) and gain settings with total sensitivities ranging from 67 (F) to 100 (G) did not significantly affect IRA reproducibility. Defocusing (D) and excessive gain (E and H) adversely affected IRA reproducibility.

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Figure 4.
Comparison of Index of Retinal Autofluorescence (IRA) Signatures of the Same Eye During Disease Progression

A, Subject with minimal clinical progression shows no appreciable increase in IRA with serial testing. gsi2 Indicates gray-scale intensity squared. B, Subject with slow clinical progression exhibits modestly increased IRA during sequential testing. C, Subject with rapidly progressive age-related macular degeneration shows large increases in IRA.

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Figure 5.
Ordering of Age-Related Macular Degeneration Fundus Autofluorescence Images by Retina Specialists and Individual Index of Retinal Autofluorescence (IRA) Values

Lower numbers represent more advanced age-related macular degeneration. A, Subjective ordering by retinal specialists is strongly correlated (rs = 0.93, Spearman rank coefficient). B, A similarly strong correlation is found between subjective ordering of fundus autofluorescence images and ordering using their respective IRA values (rs = 0.77, Spearman rank coefficient).

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Figure 6.
Box Plot of Index of Retinal Autofluorescence (IRA) Values Compared With Age-Related Eye Disease Study (AREDS) Grading

The IRA values are positively correlated with AREDS grades (rs = 0.73, Spearman rank coefficient). All AREDS grades are individually significantly different than controls (pairwise comparisons, all P < .01). The largest increase in median IRA occurs between AREDS grades 3 and 4 (P < .001).

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