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PURPOSE. In patients diagnosed with Best vitelliform macular dystrophy (BVMD), quantitative fundus autofluorescence (qAF), near-infrared fundus autofluorescence (NIR-AF), and spectraldomain optical coherence tomography (SD-OCT) were used to elucidate pathogenic mechanisms.METHODS. Fourteen patients heterozygous for BEST1 mutations were recruited. qAF was analyzed using short-wavelength fundus autofluorescence (SW-AF) images. Mean gray levels (GL) were determined in nonlesion areas (7 to 98 eccentricity) and adjusted by GL measured in an internal fluorescent reference. NIR-AF images (787 nm; sensitivity of 96) were captured and saved in non-normalized mode. Horizontal SD-OCT images also were acquired and BVMD was staged according to the OCT findings. RESULTS.In the pre-vitelliform stage, NIR-AF imaging revealed an area of reduced fluorescence, whereas in the vitelliruptive stage, puncta of elevated NIR-AF signal were present. In both SW-AF and NIR-AF images, the vitelliform lesion in the atrophic stage was marked by reduced signal. At all stages of BVMD, nonlesion qAF was within the 95% confidence intervals for healthy eyes. Similarly, the NIR-AF intensity measurements outside the vitelliform lesion were comparable to the healthy control eye. SD-OCT scans revealed a fluid-filled detachment between the ellipsoid zone and the hyperreflectivity band attributable to RPE/Bruch's membrane.CONCLUSIONS. NIR-AF imaging can identify the pre-vitelliform stage of BVMD. Mutations in BEST1 are not associated with increased levels of SW-AF outside the vitelliform lesion. Elevated SW-AF within the fluid-filled lesion likely reflects the inability of RPE to phagocytose outer segments due to separation of RPE from photoreceptor cells, together with progressive photoreceptor cell impairment. 2012This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from iovs.arvojournals.org on 07/16/2020 FIGURE 10. Semiquantitative NIR-AF intensity profiles. Mean (solid lines) and 95% confidence intervals (dashed lines); 28 eyes. Gray lines represent healthy control eyes and red lines indicate BVMD patients. Black vertical lines are the limits of the lesion, and the yellow vertical lines are the approximate limits of the halo. Upper right, within the halo mean GLs in the control versus BVMD eyes are significantly different (P ¼ 0.031).

PURPOSE. To ascertain cellular constituents within islands of preserved retina in choroideremia (CHM) by multimodal imaging. METHODS. CHM probands (16) and female carriers (9) of CHM were studied. Near-infrared autofluorescence (NIR-AF; 787-nm excitation; emission, >830 nm), short-wavelength autofluorescence (SW-AF; 488-nm excitation, 500-to 680-nm emission), and spectral-domain optical coherence tomography (SD-OCT) images were acquired with a confocal scanning laser ophthalmoscope. SW-AF intensities were measured by quantitative fundus autofluorescence (qAF), and NIR-AF intensity profiles were analyzed. Retinal thicknesses and visual acuity were measured. RESULTS. In 19 of 31 eyes of affected males, islands of preserved NIR-AF signal were also visible as fluorescence signal in SW-AF images. Notable in 12 eyes were areas of speckled SW-AF that was hypoautofluorescent in the NIR-AF image. Islands of preserved NIR-AF and SW-AF signal were often associated with the presence of visible but thinned outer nuclear layer and discontinuous interdigitation zone, ellipsoid zone, and external limiting membrane. NIR-AF profiles revealed that even in areas of preserved retina, the NIR-AF signal from retinal pigment epithelium (RPE) melanin is greatly reduced. qAF was reduced overall. The fundus of carriers was characterized by a mosaicism in which patches of reduced NIR-AF colocalized with reduced SW-AF. CONCLUSIONS. In CHM-affected males, the presence of RPE was indicated by an NIR-AF signal and the absence of hypertransmission of OCT signal into the choroid. RPE preservation was associated with better visual acuity. In carriers, patches of reduced SW-AF colocalized with decreased NIR-AF and qAF was severely reduced.

To increase our understanding of the mechanisms underlying hydroxychloroquine (HCQ) retinopathy, analyses by quantitative fundus autofluorescence (qAF) and near-infrared fundus autofluorescence (NIR-AF) were compared to results obtained by recommended screening tests. METHODS. Thirty-one patients (28 females, 3 males) were evaluated with standard automated perimetry and spectral domain optical coherence tomography (SD-OCT); 28 also had multifocal electroretinography (mfERG). Measurement of short-wavelength fundus autofluorescence (SW-AF) by qAF involved the use of an internal fluorescent reference and intensity measurements in eight concentric segments at 7°to 9°eccentricity. For semiquantitative analysis of NIR-AF, intensities were acquired along a vertical axis through the fovea. RESULTS. Four of 15 high-dose (total dose >1000 g, daily dose >5.0 mg/kg) patients and one of 16 low-dose (total dose <1000 g, daily dose 4.4 mg/kg) patients were diagnosed with HCQ-associated retinopathy based on abnormal 10-2 visual fields, SD-OCT, and SW-AF imaging. Three of the high-dose patients also had abnormal mfERG results. Of the five patients exhibiting retinopathy, two had qAF color-coded images revealing higher intensities inferior, nasal, and lateral to the fovea. The abnormal visual fields also exhibited superior-inferior differences. Mean NIR-AF gray-level intensities were increased in four high-dose patients with no evidence of retinopathy. In two patients with retinopathy, NIR-AF intensity within the parafovea was below the normal range. One high-dose patient (6.25 mg/kg) had only abnormal mfERG results. CONCLUSIONS. These findings indicate that screening for HCQ retinopathy should take into consideration superior-inferior differences in susceptibility to HCQ retinopathy.

Mutations in retinaldehyde-binding protein 1 (RLBP1), encoding the visual cycle protein cellular retinaldehyde-binding protein (CRALBP), cause an autosomal recessive form of retinal degeneration. By binding to 11-cis-retinoid, CRALBP augments the isomerase activity of retinoid isomerohydrolase RPE65 (RPE65) and facilitates 11-cis-retinol oxidation to 11-cis-retinal. CRALBP also maintains the 11-cis configuration and protects against unwanted retinaldehyde activity. Studying a sibling pair that is compound heterozygous for mutations in RLBP1/CRALBP, here we expand the phenotype of affected individuals, elucidate a previously unreported phenotype in RLBP1/CRALBP carriers, and demonstrate consistencies between the affected individuals and Rlbp1/Cralbp−/− mice. In the RLBP1/CRALBP-affected individuals, nonrecordable rod-specific electroretinogram traces were recovered after prolonged dark adaptation. In ultrawide-field fundus images, we observed radially arranged puncta typical of RLBP1/CRALBP-associated disease. Spectral domain-optical coherence tomography (SD-OCT) revealed hyperreflective aberrations within photoreceptor-associated bands. In short-wavelength fundus autofluorescence (SW-AF) images, speckled hyperautofluorescence and mottling indicated macular involvement. In both the affected individuals and their asymptomatic carrier parents, reduced SW-AF intensities, measured as quantitative fundus autofluorescence (qAF), indicated chronic impairment in 11-cis-retinal availability and provided information on mutation severity. Hypertransmission of the SD-OCT signal into the choroid together with decreased near-infrared autofluorescence (NIR-AF) provided evidence for retinal pigment epithelial cell (RPE) involvement. In Rlbp1/Cralbp−/− mice, reduced 11-cis-retinal levels, qAF and NIR-AF intensities, and photoreceptor loss were consistent with the clinical presentation of the affected siblings. These findings indicate that RLBP1 mutations are associated with progressive disease involving RPE atrophy and photoreceptor cell degeneration. In asymptomatic carriers, qAF disclosed previously undetected visual cycle deficiency.

Fundus autofluorescence (FAF) imaging is crucial to the diagnosis and monitoring of recessive Stargardt disease (STGD1). In a retrospective cohort study of 34 patients, we compared FAF imaging platforms varying in field size (30° and 55°: blue/SW-AF and NIR-AF; 200°: ultrawide-field, UWF-AF), excitation wavelength (488 nm, blue/SW-AF; 532 nm, UWF-AF and 787 nm, NIR-AF) and image processing. Due to reduced absorption of 532 nm and 787 nm light by macular pigment, foveal sparing was more readily demonstrable by green/UWF-AF and NIR-AF imaging. Prominent in green/UWF-AF images is a central zone of relatively elevated AF that is continuous inferonasal with a demarcation line bordering lower AF nasally and higher AF temporally. This zone and border are more visible in STGD1 than in healthy eyes and more visible with green/UWF-AF. With the development of AF flecks, inferonasal retina is initially spared. Central atrophic areas were larger in NIR-AF images than in blue/SW-AF and green/UWF-AF images and the presence of a contiguous hyperAF ring varied with imaging modality. Flecks visible as hyperAF foci in blue/SW-AF images were also visible in green/UWF-AF but were often hypoAF in NIR-AF. Since disease in STGD1 often extends beyond the 30° and 55° fields, green/UWF-AF has advantages including for pediatric patients. The imaging platforms examined provided complementary information.

We analyze disease progression in retinitis pigmentosa (RP) according to mode of inheritance by quantifying the progressive decrease of the ellipsoid zone (EZ) line width on spectral domain optical coherence tomography (SD-OCT) and of the dimensions of the hyperautofluorescent ring on short-wave fundus autofluorescence (SW-FAF). In this retrospective study of 96 patients, average follow-up time was 3.2 ± 1.9 years. EZ line width declined at a rate of −123 ± 8 µm per year, while the horizontal diameter and ring area declined at rates of −131 ± 9 µm and −0.5 ± 0.05 mm 2 per year, respectively. Disease progression was found to be slowest for autosomal dominant RP and fastest for X-linked RP, with autosomal recessive RP progression rates between those of adRP and XLRP. EZ line width and ring diameter rates of disease progression were significantly different between each mode of inheritance. By using EZ line width and horizontal diameter as parameters of disease progression, our results confirm that adRP is the slowest progressing form of RP while XLRP is the fastest. Furthermore, the reported rates can serve as benchmarks for investigators of future clinical trials for RP and its different modes of inheritance.

The purpose of this paper was to discuss manifestations of primary mitochondrial dysfunctions and whether the retinal pigment epithelium or the photoreceptors are preferentially affected. METHODS. A retrospective analysis was performed of patients with clinically and laboratory confirmed diagnoses of maternally inherited diabetes and deafness (MIDD) or Kearns-Sayre syndrome (KSS). Patients underwent full ophthalmic examination, full-field electroretinogram, and multimodal imaging studies, including short-wavelength autofluorescence, spectral domain-optical coherence tomography, and color fundus photography. RESULTS. A total of five patients with MIDD and four patients with KSS were evaluated at two tertiary referral centers. Mean age at initial evaluation was 50.3 years old. Nascent outer retinal tubulations corresponding with faint foci of autofluorescence were observed in two patients with MIDD. Characteristic features of this cohort included a foveal sparing phenotype observed in 13 of 18 eyes (72%), global absence of intraretinal pigment migration, and preserved retinal function on full-field electroretinogram testing in 12 of 16 eyes (75%). One patient diagnosed with MIDD presented with an unusual pattern of atrophy surrounding the parapapillary region and one patient with KSS presented with an atypical choroideremia-like phenotype. CONCLUSIONS. MIDD and KSS are phenotypically heterogeneous disorders. Several features of disease suggest that primary mitochondrial dysfunction may first affect the retinal pigment epithelium followed by secondary photoreceptor loss. Similarities between primary mitochondrial degenerations and retinal disorders, such as age-related macular degeneration may suggest a primary role of mitochondria in the pathogenesis of these oligogenic disorders.