September 2012
Volume 53, Issue 10
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Retina  |   September 2012
Comparison of Fundus Autofluorescence with Photopic and Scotopic Fine Matrix Mapping in Patients with Retinitis Pigmentosa: 4- to 8-Year Follow-up
Author Affiliations & Notes
  • Anthony G. Robson
    From the Moorfields Eye Hospital, London, United Kingdom; and the
    Institute of Ophthalmology, University College London, London, United Kingdom.
  • Eva Lenassi
    From the Moorfields Eye Hospital, London, United Kingdom; and the
  • Zubin Saihan
    From the Moorfields Eye Hospital, London, United Kingdom; and the
  • Vy A. Luong
    Institute of Ophthalmology, University College London, London, United Kingdom.
  • Fred W. Fitzke
    Institute of Ophthalmology, University College London, London, United Kingdom.
  • Graham E. Holder
    From the Moorfields Eye Hospital, London, United Kingdom; and the
    Institute of Ophthalmology, University College London, London, United Kingdom.
  • Andrew R. Webster
    From the Moorfields Eye Hospital, London, United Kingdom; and the
    Institute of Ophthalmology, University College London, London, United Kingdom.
  • Corresponding author: Anthony G. Robson, Electrophysiology, Moorfields Eye Hospital, 162 City Road, London EC1V 2PD, United Kingdom; anthony.robson@moorfields.nhs.uk
Investigative Ophthalmology & Visual Science September 2012, Vol.53, 6187-6195. doi:10.1167/iovs.12-10195
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      Anthony G. Robson, Eva Lenassi, Zubin Saihan, Vy A. Luong, Fred W. Fitzke, Graham E. Holder, Andrew R. Webster; Comparison of Fundus Autofluorescence with Photopic and Scotopic Fine Matrix Mapping in Patients with Retinitis Pigmentosa: 4- to 8-Year Follow-up. Invest. Ophthalmol. Vis. Sci. 2012;53(10):6187-6195. doi: 10.1167/iovs.12-10195.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose.: To assess the significance and evolution of parafoveal rings of high-density fundus autofluorescence (AF) in 12 patients with retinitis pigmentosa (RP).

Methods.: Twelve patients with autosomal recessive RP or Usher syndrome type 2 were ascertained who had a parafoveal ring of high-density AF and a visual acuity of 20/30 or better at baseline. Photopic and scotopic fine matrix mapping (FMM) were performed to test sensitivity across the macula. AF imaging and FMM were repeated after 4 to 8 years and optical coherence tomography (OCT) performed.

Results.: The size of the AF ring reduced over time and disappeared in one subject. Photopic thresholds were normal over the fovea; thresholds were elevated by 0.6 log units over the ring and by 1.2 log units external to the ring at baseline and differed by less than 0.1 log unit at follow-up. Mild photopic losses close to the internal edge of the ring were detected at baseline or follow-up in all. Mean scotopic thresholds over parafoveal areas within the ring were markedly elevated in 8 of 10 at baseline and were severely elevated in 9 of 11 at follow-up. The eccentricity of the inner edge of the AF ring corresponded closely with the lateral extent of the inner segment ellipsoid band in the OCT image.

Conclusions.: Ring constriction was largely coincident with progressive centripetal photopic threshold elevation led by worsening of rod photoreceptor function. The rate of constriction differed across patients, and a ring may reach a critical minimum before disappearing, at which stage central visual loss occurs. The structural and functional changes associated with rings of increased autofluorescence confirm that they provide an objective index of macular involvement and may aid the management of RP patients and the monitoring of future treatment efficacy.

Introduction
Fundus autofluorescence (AF) imaging has become an invaluable tool in the diagnosis and characterization of retinal disease. An absence of AF may indicate retinal pigment epithelium (RPE) atrophy, whereas abnormally high levels are consistent with an accumulation of autofluorescent material in either the RPE or subretinal space. An abnormal parafoveal ring of increased AF is commonly observed in retinitis pigmentosa (RP), with a reported incidence ranging from approximately 50% to 60% in heterogeneous groups 14 to 95% in a cohort with Usher syndrome type 2 (Saihan Z, et al. IOVS 2007; 48:ARVO E-abstract 3686). The rings may encircle central areas of largely preserved photopic function 1,2,58 and preserved outer retinal structure. 3,912 Progressive ring constriction has been reported 6,10,13 at different rates over maximum periods of up to 9.3 years. 11  
The current study addressed the relationship between ring constriction and cone and rod system sensitivity by examining longitudinal changes in AF imaging and fine matrix mapping (FMM) in a cohort of 12 patients 4 to 8 years after baseline testing. The AF and functional data at follow-up were compared with spectral-domain optical coherence tomography (OCT) measures of retinal structure. 
Methods
The protocol adhered to the tenets of the Declaration of Helsinki and was approved by the local ethics committee. Twelve patients (age range at baseline, 17–48 years; median, 28 years) underwent fundus AF imaging and FMM; eight were part of a previously published baseline study. 5 Patients underwent baseline AF and FMM on the same day (N = 9), on successive days (case 1), or within 1 month (cases 4 and 10). All had a genetic and/or clinical diagnosis of retinitis pigmentosa, supported by characteristic international standard 14 ERG changes, and a visual acuity of 20/30 or better at the time of initial AF imaging. 
Fundus AF imaging was performed with a scanning laser ophthalmoscope after mydriasis. The excitation wavelength was 488 nm. Baseline images were obtained in most by using a prototype system (SM 30-4024, barrier filter 521 nm, field of view 20°; Carl Zeiss Meditec, Oberkochen, Germany). Baseline images in four patients (cases 1, 2, 9, and 11) and all follow-up images were obtained with an HRA 2 (barrier filter 500 nm, field of view 30°; Heidelberg Engineering, Heidelberg, Germany). The background noise was greater for the Zeiss AF images than for the HRA 2, but grey scale values are closely comparable. 15  
All but one patient manifested a high-density AF ring at baseline; the one exception had a high-density arc that almost intersected the optic disc but failed to form a complete annulus The mean internal and external ring radii were computed in degrees from area measurements made by using custom software. A linear scale was determined according to the distance between the optic disc and fovea, assumed to be 15°. Areas were drawn over the digital image and quantified (mean of three measurements). Area measurements took into account radial asymmetries and irregularities in “ring” shape, but for the purposes of mean radius computation, the rings were considered circular. Additionally, vertical radii were compared with horizontal measurements. 
Fundus AF imaging and FMM were performed at follow-up on the same day (median interval, 8.0 years; range, 4.2–8.7 years). The FMM was performed under light-adapted conditions and after 40 minutes under dark adaptation, according to previously described methods. 5,16,17 In brief, a target flash subtending a visual angle of approximately 0.51° was presented randomly at 100 macular locations over a 9 × 9-degree area by using a modified Humphrey perimeter (photopic background illumination, 31.5 apostilbs). Detection thresholds were signaled with a push-button control; 25 measurements were obtained for each of four overlapping grids that were superimposed post acquisition. Central fixation was monitored with closed-circuit television and the blind spot was periodically tested; grid measurements were repeated if two or more false-positive responses were recorded. Detection sensitivity was expressed in photopic decibels and corresponding thresholds as log units (4 log units = 10,000 apostilbs). Sensitivities were shown as contour plots, illustrating the position and orientation of test matrices, and as three-dimensional threshold profiles, plotted by using interpolated values at 0.25° intervals, obtained by Gaussian filtering. 16 Averaged threshold values associated with the AF ring and areas immediately internal and external to the ring were additionally compared (without Gaussian filtering). Findings were compared with previous measurements in the same subjects and with normative data obtained in a control group of healthy individuals under light-adapted (N = 10) and dark-adapted (N = 8) conditions (Fig. 1). 
Figure 1. 
 
Normal photopic (a, b) and scotopic (c, d) fine matrix maps. Contour plots are shown for one representative normal subject; corresponding threshold plots for the same retinal locations are shown for an average of 10 healthy subjects under photopic conditions and eight under scotopic conditions. Data are shown for central (a, c) and paracentral (b, d) macular areas.
Figure 1. 
 
Normal photopic (a, b) and scotopic (c, d) fine matrix maps. Contour plots are shown for one representative normal subject; corresponding threshold plots for the same retinal locations are shown for an average of 10 healthy subjects under photopic conditions and eight under scotopic conditions. Data are shown for central (a, c) and paracentral (b, d) macular areas.
All individuals underwent spectral-domain OCT at follow-up with the Heidelberg Spectralis OCT with simultaneous recording of fundus AF to allow precise image registration. The composite image (including the scale bar) was imported into Adobe Photoshop CS4 (Adobe Systems Inc., San Jose, CA) and the lateral extent of the inner segment/outer segment (IS/OS; inner segment ellipsoid) junction, external limiting membrane (ELM), and outer nuclear layer (ONL) were measured along each of six radial axes (0°, 30°, 60°, 90°, 120°, and 150°) intersecting the fovea with the “Ruler” tool. The AF ring diameter was measured by using the same scale (in μm) along the same OCT scan planes. 
Results
Clinical Findings and AF Ring Parameters
The clinical and genetic details are summarized in Table 1. All had sporadic or autosomal recessive RP including six with Usher syndrome type 2, genetically confirmed in five families including two sibships (cases 1 and 11; 2 and 9).Visual acuity (VA) was 20/30 or better at baseline in all patients and was unchanged at follow-up in 10 of 12 subjects. Mild VA deterioration occurred in case 10 and was associated with the development of cystoid macular edema (CME). Severe VA reduction to hand movements occurred in case 12, associated with disappearance of the ring of AF and the development of patchy foci of low and high density. 
Table 1. 
 
Clinical and Genetic Details of the 12 Patients with RP
Table 1. 
 
Clinical and Genetic Details of the 12 Patients with RP
Case Figure Age at Baseline, y Follow-up Period, y VA at Baseline VA at Follow-up Nyctalopia Field Loss Bone Spicules Attenuated Vessels Genetic Diagnosis Other Symptoms/Signs
1 2a–d, 6a 26 5.3 20/20 20/20 +(9) + + + USH2A Cellophane membrane superior to fovea BE.
20/16 20/20
2 2e–h, 6b 20 4.4 20/20 20/20 +(12) + + + USH2A
20/20 20/20
3 28 8.1 20/30 20/30 +(20) + + Usher type 2 clinically. Mild cataract. High myope. RPE thin.
20/20 20/30
4 3e–h 38 8.0 20/20 20/30 +(15) + + + Photopsia. Vitreous opacities. Treated for glaucoma.
20/20 20/30
5 31 8.6 20/30 20/30 +(15) + + + Mild lens opacity BE. Hearing loss associated with adenoids.
20/30 20/20
6 48 8.7 20/30 20/30 + + + + Disc pallor BE. Myopia. Perivascular pigmentation.
20/30 20/30
7 31 8.0 20/20 20/20 +(30) + + +
20/20 20/20
8 41 8.6 20/30 20/40 +(35) + + + USH2A Pseudophakic BE. Pale discs. Widespread retinal degeneration.
20/30 20/30
9 17 4.2 20/20 20/30 +(10) + + + USH2A
20/20 20/30
10 23 8.6 20/16 20/40 +(11) + + + Developed CME; present at time of follow-up testing.
20/20 20/80
11 3a–d 27 5.5 20/30 20/30 +(12) +- + + USH2A Bilateral ERMs.
20/30 20/30
12 4a–d 28 7.9 20/30 HM +(17) + + AF ring gave way to high- and low-density foci over central macula.
20/30 HM
Night blindness was the presenting symptom in all cases (age of presentation, 12–32 years). Most had peripheral or midperipheral visual field loss, bone-spicule pigmentation, and attenuated retinal blood vessels. Qualitative assessment of fundus autofluorescence over central areas within the ring revealed no obvious abnormality in any case at baseline. In some individuals with small rings at baseline (N = 4) or follow-up (N = 9), the area immediately surrounding the ring was of visibly lower AF intensity than adjacent eccentric areas, giving an impression of concentric rings. Isolated foci of low density or patches of RPE atrophy were visible over the most eccentric areas of the AF images at baseline in six individuals and in 10 at follow-up, including eight cases in which atrophic changes encroached upon the region of the vascular arcades. 
The mean radius to the inner edge of the high-density AF ring ranged from 1.9° to 8.0° and the mean radius to the external edge of the ring ranged from 3.0° to 10.5° (area of annular hyperfluorescence within the internal and external borders of the ring, 17.3 to 191.7 degrees2). At follow-up 11 of 11 cases with a ring showed a reduced area of annular hyperfluorescence (mean rate of reduction, 0.2–39.2 deg2/y). Inner ring radius reduction varied from 0.2° to 3.0° at a mean rate of between 0.03 and 0.63 deg/y (mean, 0.23 deg/y); outer ring radius reduction varied between 0.30° and 5.4° at a mean rate of between 0.03 and 1.30 deg/y (mean, 0.37 deg/y; see Table 2 for a summary and Figs. 2, 3 for typical examples). The vertical radius was on average 16% smaller than the horizontal radius at baseline and 33% smaller at follow-up. In one patient the ring disappeared and was replaced by foci of high- and low-density AF (case 12; Fig. 4). 
Figure 2. 
 
Contour plots and corresponding three-dimensional threshold plots in subjects 1 (ad) and 2 (ef) under photopic (rows 1 and 2) and scotopic (rows 3 and 4) conditions at baseline (rows 1 and 3) and follow-up (rows 2 and 4). Three-dimensional plots show thresholds above normal obtained by subtracting the values shown in Figure 1 for corresponding retinal locations. Abscissa: retinal location in degrees; ordinate: threshold in log units (4 log units = 10,000 apostilbs).
Figure 2. 
 
Contour plots and corresponding three-dimensional threshold plots in subjects 1 (ad) and 2 (ef) under photopic (rows 1 and 2) and scotopic (rows 3 and 4) conditions at baseline (rows 1 and 3) and follow-up (rows 2 and 4). Three-dimensional plots show thresholds above normal obtained by subtracting the values shown in Figure 1 for corresponding retinal locations. Abscissa: retinal location in degrees; ordinate: threshold in log units (4 log units = 10,000 apostilbs).
Figure 3. 
 
Contour plots and corresponding three-dimensional threshold plots in subjects 11 (ad) and 4 (eh) under photopic (rows 1 and 2) and scotopic (rows 3 and 4) conditions at baseline (rows 1 and 3) and follow-up (rows 2 and 4). Three-dimensional plots show thresholds above normal in a through d; absolute thresholds are shown without subtraction of normal values in e through h. Abscissa: retinal location in degrees; ordinate: threshold in log units (4 log units = 10,000 apostilbs).
Figure 3. 
 
Contour plots and corresponding three-dimensional threshold plots in subjects 11 (ad) and 4 (eh) under photopic (rows 1 and 2) and scotopic (rows 3 and 4) conditions at baseline (rows 1 and 3) and follow-up (rows 2 and 4). Three-dimensional plots show thresholds above normal in a through d; absolute thresholds are shown without subtraction of normal values in e through h. Abscissa: retinal location in degrees; ordinate: threshold in log units (4 log units = 10,000 apostilbs).
Figure 4. 
 
Contour plots and corresponding three-dimensional threshold plots in subject 12 tested under photopic (columns 1 and 2) and scotopic (columns 3 and 4) conditions at baseline (row 1) and follow-up (row 2). Three-dimensional plots show absolute thresholds without subtraction of normal values. Abscissa: retinal location in degrees; ordinate: threshold in log units.
Figure 4. 
 
Contour plots and corresponding three-dimensional threshold plots in subject 12 tested under photopic (columns 1 and 2) and scotopic (columns 3 and 4) conditions at baseline (row 1) and follow-up (row 2). Three-dimensional plots show absolute thresholds without subtraction of normal values. Abscissa: retinal location in degrees; ordinate: threshold in log units.
Table 2. 
 
AF Ring Dimensions at Baseline and Changes over Time
Table 2. 
 
AF Ring Dimensions at Baseline and Changes over Time
Case Area within the Internal and External Edges of the Ring at Baseline (Area of the Annulus), deg2 Mean External Radius of Ring at Baseline, deg2 Central Area Surrounded by the Ring at Baseline, deg2 Mean Internal Radius of Ring at Baseline, deg Reduction in Area within the Internal and External Edges of the Ring, deg2; Mean Rate Of Change, deg2/y Reduction in Central Macular Area Surrounded by the Internal Edge of the Ring, deg2; Mean Rate of Change, deg2/y Reduction in Mean External Ring Radius, deg; Mean Rate of Reduction, deg/y Reduction in Mean Internal Ring Radius, deg; Mean Rate of Reduction, deg/y
1 37.4 5.9 73.4 4.8 11.5; 2.1 30.0; 5.4 1.2; 0.23 1.1; 0.20
2 60.0 6.6 75.3 4.9 35.0; 7.9 43.9; 9.9 2.3; 0.53 1.7; 0.39
3 36.2 4.5 27.6 3.0 24.2; 3.0 16.5; 2.0 1.8; 0.22 1.1; 0.10
4 43.4 4.8 29.9 3.1 22.4; 2.8 12.3; 1.5 1.3; 0.17 0.7; 0.10
5 54.6 8.6 175.6 7.5 32.8; 3.8 49.9; 5.8 1.7; 0.20 1.2; 0.13
6 21.4 5.1 60.7 4.4 8.6; 1.0 42.8; 4.9 2.0; 0.23 2.0; 0.23
7 22.9 4.6 42.5 3.7 0.77; 0.2 15.3; 1.9 0.6; 0.07 0.7; 0.10
8 17.3 3.0 11.1 1.9 2.07; 0.3 2.5; 0.3 0.3; 0.03 0.2; 0.03
9 191.7 9.4 87.7 5.3 163.4; 39.2 65.7; 15.8 5.4; 1.30 2.6; 0.63
10 141.5 10.5 201.7 8.0 116.5; 13.6 124.9; 14.6 4.8; 0.55 3.0; 0.36
11 131.2 8.1 76.3 4.9 105.1; 16.8 39.2; 6.3 3.6; 0.58 1.5; 0.24
12 119.0 6.7 20.0 2.5 - - - -
Photopic FMM
Photopic fine matrix maps in 10 healthy subjects (Fig. 1) show an almost flat threshold profile across the central macula, with mean foveal values ranging from 0.44 log units (standard deviation [SD], 0.25) at the fovea to 0.63 log units (SD, 0.19) at the most eccentric macular location tested (6.4° from the fovea). 5 Foveal thresholds were normal in all 11 RP patients at baseline (<1.5 SDs of the normal mean). There was a steep gradient of threshold elevation that largely overlapped with the area of high-density arc (Figs. 21552 4); threshold values external to the ring were severely elevated by up to 3.1 log units (16.2 SDs). The mean of photopic threshold values within areas encircled by the rings was normal (Fig. 5a) but there was some variability; gradients of sensitivity loss extended into areas immediately internal to the ring at some retinal locations in most patients (Figs. 2a, 2b, 2f, 3b, 3e, 3f, 4a), whereas in others, hyperfluorescence was associated with shallower gradients of change (Figs. 2e, 3a). Figure 5a summarizes photopic threshold values obtained from 10 patients over different areas of AF intensity. 
Figure 5. 
 
Mean photopic (a) (N = 10 subjects; 1000 measurements) and scotopic (b) (N = 6 subjects; 600 measurements) thresholds measured within the central macular area surrounded by the ring (inside ring), across the ring itself (on ring) and external to the outside edge of the ring (outside ring) at baseline and follow-up. Threshold values were averaged without Gaussian filtering (see text for details). Horizontal broken lines show 2 standard deviations above the mean of normal thresholds for the central 9 × 9-degree areas. Error bars show one standard deviation either side of the mean for each retinal zone. Follow-up data from case 10 are excluded owing to development of CME and in case 12, owing to ring dispersion.
Figure 5. 
 
Mean photopic (a) (N = 10 subjects; 1000 measurements) and scotopic (b) (N = 6 subjects; 600 measurements) thresholds measured within the central macular area surrounded by the ring (inside ring), across the ring itself (on ring) and external to the outside edge of the ring (outside ring) at baseline and follow-up. Threshold values were averaged without Gaussian filtering (see text for details). Horizontal broken lines show 2 standard deviations above the mean of normal thresholds for the central 9 × 9-degree areas. Error bars show one standard deviation either side of the mean for each retinal zone. Follow-up data from case 10 are excluded owing to development of CME and in case 12, owing to ring dispersion.
The ring was no longer detectable at follow-up in one patient (case 12); visual acuity had severely deteriorated from 20/30 to hand movements and there was concomitant severe threshold elevation (Fig. 4). One patient with CME (case 10) showed mild-moderate threshold elevation over the central macula and was excluded from the group analysis at follow-up. Foveal thresholds showed minimal change in nine cases and increased by 2.5 SDs in two cases with small rings (cases 3 and 6). The patient with the smallest AF ring had a normal foveal threshold (case 8). There was progressive centripetal threshold elevation associated with ring constriction (Figs. 2, 3). Mean photopic thresholds over areas within, across, and outside the high-density arc were stable (Fig. 5a), in spite of ring constriction. However, contour and threshold plots (Figs. 2, 3) show that the spatial association between thresholds and the ring could change. Figures 2f and 2e show closer correspondence between gradients of sensitivity loss and the AF ring at follow-up than at baseline, and Figures 3e and 3f show greater correspondence with the external edge of the ring at baseline and internal edge at follow-up. 
Scotopic FMM
Normal scotopic thresholds are maximal at the rod-free foveola (mean, 3.06 log units; SD, 0.37) and show a steep decline with increasing eccentricity (0.92 log units at 6.4° eccentricity; SD, 0.45). 5 Patient data at baseline showed that at this most eccentric location, dark-adapted thresholds were normal in two patients with the largest rings (cases 5 and 10) but were markedly elevated in others (Figs. 21552 4). There was severe widespread scotopic threshold elevation that included areas within the ring in all cases tested, and which at follow-up was more severe and more widespread than photopic threshold elevation. Scotopic threshold elevation encroached upon the innermost parafoveal areas in 9 of 11 patients. Figure 5b shows the averaged scotopic FMM data in patients that underwent follow-up examinations over identical retinal areas centered on the fovea (excluding case 10 with CME). 
Optical Coherence Tomography
The dimensions of the ring at follow-up were compared with those of the photoreceptor IS/OS band, ELM, and ONL, measured with spectral-domain OCT along each of six radial axes intersecting the fovea in nine patients (Fig. 6). The inner edge of the AF ring corresponded closely with the lateral extent of the preserved IS/OS band. The diameter of the ring (inner edge) correlated with the diameter of the IS/OS band (r 2 = 0.97, slope = 1.00, N = 9) and with the diameter of the ELM (r 2 = 0.95, slope = 0.92); correlation was weaker when compared with the diameter of the ONL (r 2 = 0.42, slope = 0.42). The diameter of the outer edge of the ring correlated with but extended beyond that of the IS/OS band (r 2 = 0.90, slope = 0.97, N = 11) and ELM (r 2 = 0.93, slope = 0.90); correlation was weaker when compared with the ONL (r 2 = 0.46, slope = 0.46). All correlations described above were statistically significant (P < 0.01). The ONL tapered beyond the external edge of the ring in 11 of 11 cases. The OCT in patient 12 (ring dispersed) showed evidence of severe outer retinal thinning and loss of the IS/OS and ONL bands. 
Figure 6. 
 
OCT scans were obtained along each of six radial axes and representative examples are shown for patients 1 (a) and 2 (b). The central area is additionally magnified in each case for clarity. The lateral extent of different outer retinal OCT bands measured along each of six radial scan planes, compared with the internal (c) and external (d) dimensions of the high-density AF arc, measured along the same radial axes (N = 9 patients; total = 54 scans). Data from subject 10 are excluded owing to development of CME.
Figure 6. 
 
OCT scans were obtained along each of six radial axes and representative examples are shown for patients 1 (a) and 2 (b). The central area is additionally magnified in each case for clarity. The lateral extent of different outer retinal OCT bands measured along each of six radial scan planes, compared with the internal (c) and external (d) dimensions of the high-density AF arc, measured along the same radial axes (N = 9 patients; total = 54 scans). Data from subject 10 are excluded owing to development of CME.
Discussion
This longitudinal study monitored changes in parafoveal rings of high-density AF and detailed psychophysical measures of cone and rod system sensitivity in a group of patients with RP and good visual acuity. Together with the spectral-domain OCT, the findings provide unique insight into the functional and structural significance of macular AF changes in RP. The novel data presented demonstrated that ring constriction is associated with progressive photopic threshold elevation led by centripetal worsening of rod photoreceptor function. Disappearance of a ring of increased AF, associated with severe visual acuity worsening, was also described. 
High-density AF rings are common in patients with RP 14 but only a few recent reports document changes with time 6,4,13 and only one has monitored changes in excess of 4 years. 11 The current study demonstrated how ring parameters evolve over periods of up to 8.7 years. Disappearance of the ring occurred in one case, as documented recently, 11 and was associated with visual acuity loss and severe widespread sensitivity loss (Fig. 4). Disappearance of the ring has been reported in one other patient. 13 In other patients, progressive ring constriction was partly related to ring size at baseline; both the inner and outer edges tended to constrict more rapidly than small rings (Table 2), broadly consistent with nonlinear visual field constriction that has been well documented in other RP patients. 18,19 Additional serial images are necessary to determine possible changes in the rate of ring constriction (nonlinear progression), and whether that may help predict future progression. 
The study confirms a spatial association between the internal edge of progressive ring constriction and advancing photopic sensitivity loss (Figs. 2, 3, 5a). This spatial association was initially speculated following electrophysiologic assessments of macular function 1 and is consistent with a preliminary report of ring constriction associated with progressive pattern ERG reduction and visual field constriction demonstrated by Humphrey perimetry. 6 The baseline photopic and scotopic FMM data suggested that the increased hyperfluorescence may reflect progressive photopic visual field constriction led by an encroaching edge of rod photoreceptor dysfunction. 5 The current study is the first direct demonstration of this phenomenon (Figs. 2, 3). Spatial concordance between the ring and photopic sensitivity loss may differ between baseline and follow-up, and progressive cone dysfunction and ring constriction may occur at slightly different rates. This is consistent with recent reports of localized photopic sensitivity loss within AF rings. 20,12 It is also notable that severe macular rod dysfunction can precede abnormal accumulation of detectable AF fluorophore by several years (Figs. 2, 3). Central loss of photopic sensitivity is also broadly in keeping with the demonstration by adaptive optics that increased cone spacing and progressive cone loss can occur in RP without profound loss of function and without reduction in visual acuity. 21,22 No report of adaptive optics of a ring of high-density AF has been published to date. 
Serial perimetry may be used to estimate the rate of visual field constriction, but perimetric measurements are subject to significant test–retest variability, 2325 which may worsen with advancing disease. 26 FMM involves Gaussian filtering, whereby threshold values incorporate a weighted average of surrounding measurements (Figs. 14). The technique is specifically designed to optimize longitudinal assessments and can dramatically improve test–retest variability 16 as well as provide parameters of rarely measured macular rod system function. Fixation was monitored subjectively and measurement grids were repeated in cases of false positives, but coregistration of AF would be an obvious improvement. 12 Gaussian filtering may partly mask abrupt changes in sensitivity, for example, in the presence of sharply demarcated macular atrophy, 27 but this does not occur over the areas tested in the RP patients. The sensitivity gradients illustrated in Figures 2, 3, and 4 are consistent with the averaged threshold values that are plotted in Figure 5
Spectral-domain OCT measures of outer retinal structure show close correspondence between the lateral extent of the IS/OS (inner segment ellipsoid 28 ) band and that of the internal edge of the ring of high-density AF. 3,912,20,29 The current study corroborated and extended these findings, showing an almost 1:1 relationship between the eccentricity of these two parameters along multiple orientations and scan planes. Selective thinning or abolition of visible OCT bands may influence future treatment strategies. For example, the ONL extending beyond the ring may be amenable to functional rescue at a stage before photoreceptor degeneration. Spectral-domain OCT was not available at baseline but the follow-up data are consistent with studies that have shown reduction in the width of the IS/OS band that is proportionate to AF ring constriction. 10  
Background AF was visibly preserved in areas immediately concentric and external to the ring and appeared to be reasonably stable over the long follow-up periods in most patients, despite severe eccentric outer retinal disruption evident in the OCT at follow-up. However, quantification of AF intensity may be needed to detect small changes. Fundus AF has been attributed to lipofuscin (A2E) accumulation in the RPE, resulting from outer segment turnover and degradation of retinoids, but lipofuscin has also been shown to degrade rapidly when exposed to light in vitro. 30 Previous studies have proposed that RPE AF implies continuing outer segment shedding and metabolic demand. 7,31 The loss of outer retinal structure detailed above suggests that normal background AF outside the ring is not dependent on continued retinoid recycling; the fluorescent half-life of lipofuscin may be prolonged in vivo or there may be other more stable fluorophores, resistant to light and enzyme degradation. 32  
The data suggest that rod system dysfunction in RP progressively encroaches upon central macular areas with consequent cone dysfunction and progressive visual field constriction. This chronic photoreceptor dysfunction likely results in progressive fluorophore accumulation and the development of a ring of increased AF, at a time and location that is closely coincident with advancing cone system dysfunction. 
The value of AF will be further enhanced when the ability to quantify AF levels objectively 33,34 becomes more widely available. The combination of spectral-domain OCT and AF imaging is likely to have a profound influence on the future management of RP patients. 
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Footnotes
 Supported by The Special Trustees of Moorfields Eye Hospital, The Foundation Fighting Blindness, The National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital National Health Service (NHS) Foundation Trust and University College London (UCL) Institute of Ophthalmology.
Footnotes
 Disclosure: A.G. Robson, None; E. Lenassi, None; Z. Saihan, None; V.A. Luong, None; F.W. Fitzke, None; G.E. Holder, None; A.R. Webster, None
Figure 1. 
 
Normal photopic (a, b) and scotopic (c, d) fine matrix maps. Contour plots are shown for one representative normal subject; corresponding threshold plots for the same retinal locations are shown for an average of 10 healthy subjects under photopic conditions and eight under scotopic conditions. Data are shown for central (a, c) and paracentral (b, d) macular areas.
Figure 1. 
 
Normal photopic (a, b) and scotopic (c, d) fine matrix maps. Contour plots are shown for one representative normal subject; corresponding threshold plots for the same retinal locations are shown for an average of 10 healthy subjects under photopic conditions and eight under scotopic conditions. Data are shown for central (a, c) and paracentral (b, d) macular areas.
Figure 2. 
 
Contour plots and corresponding three-dimensional threshold plots in subjects 1 (ad) and 2 (ef) under photopic (rows 1 and 2) and scotopic (rows 3 and 4) conditions at baseline (rows 1 and 3) and follow-up (rows 2 and 4). Three-dimensional plots show thresholds above normal obtained by subtracting the values shown in Figure 1 for corresponding retinal locations. Abscissa: retinal location in degrees; ordinate: threshold in log units (4 log units = 10,000 apostilbs).
Figure 2. 
 
Contour plots and corresponding three-dimensional threshold plots in subjects 1 (ad) and 2 (ef) under photopic (rows 1 and 2) and scotopic (rows 3 and 4) conditions at baseline (rows 1 and 3) and follow-up (rows 2 and 4). Three-dimensional plots show thresholds above normal obtained by subtracting the values shown in Figure 1 for corresponding retinal locations. Abscissa: retinal location in degrees; ordinate: threshold in log units (4 log units = 10,000 apostilbs).
Figure 3. 
 
Contour plots and corresponding three-dimensional threshold plots in subjects 11 (ad) and 4 (eh) under photopic (rows 1 and 2) and scotopic (rows 3 and 4) conditions at baseline (rows 1 and 3) and follow-up (rows 2 and 4). Three-dimensional plots show thresholds above normal in a through d; absolute thresholds are shown without subtraction of normal values in e through h. Abscissa: retinal location in degrees; ordinate: threshold in log units (4 log units = 10,000 apostilbs).
Figure 3. 
 
Contour plots and corresponding three-dimensional threshold plots in subjects 11 (ad) and 4 (eh) under photopic (rows 1 and 2) and scotopic (rows 3 and 4) conditions at baseline (rows 1 and 3) and follow-up (rows 2 and 4). Three-dimensional plots show thresholds above normal in a through d; absolute thresholds are shown without subtraction of normal values in e through h. Abscissa: retinal location in degrees; ordinate: threshold in log units (4 log units = 10,000 apostilbs).
Figure 4. 
 
Contour plots and corresponding three-dimensional threshold plots in subject 12 tested under photopic (columns 1 and 2) and scotopic (columns 3 and 4) conditions at baseline (row 1) and follow-up (row 2). Three-dimensional plots show absolute thresholds without subtraction of normal values. Abscissa: retinal location in degrees; ordinate: threshold in log units.
Figure 4. 
 
Contour plots and corresponding three-dimensional threshold plots in subject 12 tested under photopic (columns 1 and 2) and scotopic (columns 3 and 4) conditions at baseline (row 1) and follow-up (row 2). Three-dimensional plots show absolute thresholds without subtraction of normal values. Abscissa: retinal location in degrees; ordinate: threshold in log units.
Figure 5. 
 
Mean photopic (a) (N = 10 subjects; 1000 measurements) and scotopic (b) (N = 6 subjects; 600 measurements) thresholds measured within the central macular area surrounded by the ring (inside ring), across the ring itself (on ring) and external to the outside edge of the ring (outside ring) at baseline and follow-up. Threshold values were averaged without Gaussian filtering (see text for details). Horizontal broken lines show 2 standard deviations above the mean of normal thresholds for the central 9 × 9-degree areas. Error bars show one standard deviation either side of the mean for each retinal zone. Follow-up data from case 10 are excluded owing to development of CME and in case 12, owing to ring dispersion.
Figure 5. 
 
Mean photopic (a) (N = 10 subjects; 1000 measurements) and scotopic (b) (N = 6 subjects; 600 measurements) thresholds measured within the central macular area surrounded by the ring (inside ring), across the ring itself (on ring) and external to the outside edge of the ring (outside ring) at baseline and follow-up. Threshold values were averaged without Gaussian filtering (see text for details). Horizontal broken lines show 2 standard deviations above the mean of normal thresholds for the central 9 × 9-degree areas. Error bars show one standard deviation either side of the mean for each retinal zone. Follow-up data from case 10 are excluded owing to development of CME and in case 12, owing to ring dispersion.
Figure 6. 
 
OCT scans were obtained along each of six radial axes and representative examples are shown for patients 1 (a) and 2 (b). The central area is additionally magnified in each case for clarity. The lateral extent of different outer retinal OCT bands measured along each of six radial scan planes, compared with the internal (c) and external (d) dimensions of the high-density AF arc, measured along the same radial axes (N = 9 patients; total = 54 scans). Data from subject 10 are excluded owing to development of CME.
Figure 6. 
 
OCT scans were obtained along each of six radial axes and representative examples are shown for patients 1 (a) and 2 (b). The central area is additionally magnified in each case for clarity. The lateral extent of different outer retinal OCT bands measured along each of six radial scan planes, compared with the internal (c) and external (d) dimensions of the high-density AF arc, measured along the same radial axes (N = 9 patients; total = 54 scans). Data from subject 10 are excluded owing to development of CME.
Table 1. 
 
Clinical and Genetic Details of the 12 Patients with RP
Table 1. 
 
Clinical and Genetic Details of the 12 Patients with RP
Case Figure Age at Baseline, y Follow-up Period, y VA at Baseline VA at Follow-up Nyctalopia Field Loss Bone Spicules Attenuated Vessels Genetic Diagnosis Other Symptoms/Signs
1 2a–d, 6a 26 5.3 20/20 20/20 +(9) + + + USH2A Cellophane membrane superior to fovea BE.
20/16 20/20
2 2e–h, 6b 20 4.4 20/20 20/20 +(12) + + + USH2A
20/20 20/20
3 28 8.1 20/30 20/30 +(20) + + Usher type 2 clinically. Mild cataract. High myope. RPE thin.
20/20 20/30
4 3e–h 38 8.0 20/20 20/30 +(15) + + + Photopsia. Vitreous opacities. Treated for glaucoma.
20/20 20/30
5 31 8.6 20/30 20/30 +(15) + + + Mild lens opacity BE. Hearing loss associated with adenoids.
20/30 20/20
6 48 8.7 20/30 20/30 + + + + Disc pallor BE. Myopia. Perivascular pigmentation.
20/30 20/30
7 31 8.0 20/20 20/20 +(30) + + +
20/20 20/20
8 41 8.6 20/30 20/40 +(35) + + + USH2A Pseudophakic BE. Pale discs. Widespread retinal degeneration.
20/30 20/30
9 17 4.2 20/20 20/30 +(10) + + + USH2A
20/20 20/30
10 23 8.6 20/16 20/40 +(11) + + + Developed CME; present at time of follow-up testing.
20/20 20/80
11 3a–d 27 5.5 20/30 20/30 +(12) +- + + USH2A Bilateral ERMs.
20/30 20/30
12 4a–d 28 7.9 20/30 HM +(17) + + AF ring gave way to high- and low-density foci over central macula.
20/30 HM
Table 2. 
 
AF Ring Dimensions at Baseline and Changes over Time
Table 2. 
 
AF Ring Dimensions at Baseline and Changes over Time
Case Area within the Internal and External Edges of the Ring at Baseline (Area of the Annulus), deg2 Mean External Radius of Ring at Baseline, deg2 Central Area Surrounded by the Ring at Baseline, deg2 Mean Internal Radius of Ring at Baseline, deg Reduction in Area within the Internal and External Edges of the Ring, deg2; Mean Rate Of Change, deg2/y Reduction in Central Macular Area Surrounded by the Internal Edge of the Ring, deg2; Mean Rate of Change, deg2/y Reduction in Mean External Ring Radius, deg; Mean Rate of Reduction, deg/y Reduction in Mean Internal Ring Radius, deg; Mean Rate of Reduction, deg/y
1 37.4 5.9 73.4 4.8 11.5; 2.1 30.0; 5.4 1.2; 0.23 1.1; 0.20
2 60.0 6.6 75.3 4.9 35.0; 7.9 43.9; 9.9 2.3; 0.53 1.7; 0.39
3 36.2 4.5 27.6 3.0 24.2; 3.0 16.5; 2.0 1.8; 0.22 1.1; 0.10
4 43.4 4.8 29.9 3.1 22.4; 2.8 12.3; 1.5 1.3; 0.17 0.7; 0.10
5 54.6 8.6 175.6 7.5 32.8; 3.8 49.9; 5.8 1.7; 0.20 1.2; 0.13
6 21.4 5.1 60.7 4.4 8.6; 1.0 42.8; 4.9 2.0; 0.23 2.0; 0.23
7 22.9 4.6 42.5 3.7 0.77; 0.2 15.3; 1.9 0.6; 0.07 0.7; 0.10
8 17.3 3.0 11.1 1.9 2.07; 0.3 2.5; 0.3 0.3; 0.03 0.2; 0.03
9 191.7 9.4 87.7 5.3 163.4; 39.2 65.7; 15.8 5.4; 1.30 2.6; 0.63
10 141.5 10.5 201.7 8.0 116.5; 13.6 124.9; 14.6 4.8; 0.55 3.0; 0.36
11 131.2 8.1 76.3 4.9 105.1; 16.8 39.2; 6.3 3.6; 0.58 1.5; 0.24
12 119.0 6.7 20.0 2.5 - - - -
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