High Resolution Imaging in Patients with Retinal Dystrophies
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1 High Resolution Imaging in Patients with Retinal Dystrophies Ophthalmic Photographers Society Annual Midyear Meeting April 2, 213 Jacque Duncan, M.D. UCSF Department of Ophthalmology How can retinal imaging help me evaluate patients? Can t see vision cells Typically: Measure visual acuity, visual field sensitivity New tools let us study retinal structure and function with high-resolution Testing Retinal Function Subjectively Visual Acuity Visual Field Testing: Perimetry Humphrey Visual Field Goldmann Visual Field Fundus-guided Microperimetry SLO used to provide infrared fundus image to track fundus landmarks Resolution on the order of several degrees Fundus-guided Microperimetry Normal values are 2 within 4 degrees of the fovea Able to demonstrate tiny central and paracentral scotomas Evaluation of Macular Structure Color fundus photos Fundus Autofluorescence Infrared fundus photos Fluorescein angiography Optical Coherence Tomography (OCT) Non-invasive method of creating cross-sectional images in vivo Fundus photos: a view to the back of the eye Color: represents what can be seen on exam Fundus Autofluorescence: Short wavelength light excites fluorescent compounds in the RPE (Lipofuscin) Most prevalent fluorophore is A2E Accumulates in RPE with photoreceptor outer segment degradation Infrared: uses long wavelength light to visualize melanin and melanolipofuscin Left Eye Color fundus photo Left eye fundus autofluorescence
2 OCT: measures retina in cross-section Like ultrasound: Instead of differences in acoustic backscattering, OCT uses differences in reflectivity of light to image different tissues High resolution: 2-1 m Necessary to image retinal structures No contact with eye required Ideally suited to imaging ocular structures Ultrasound Resolution: 15 m OCT Resolution: 2-3 m Left eye infrared fundus photo OCT: Cross-sectional image resembles histology Useful way to measure retinal structure quantitatively in vivo Spectral Domain Optical Coherence Tomography (OCT) Cross-sectional images of retinal structure in vivo Non-invasive; doesn t require perfectly clear media Axial resolution 3-4 um with spectral-domain systems Horizontal OCT across normal fovea ONL ELM EZ: ISe or IS/OS JXN IZ: OS/RPE JXN Scanning Laser Ophthalmoscopy (SLO): Confocal images of retinal planes Can image autofluorescence from lipofuscin in RPE Poor axial resolution (3um) Lateral resolution limited by aberrations induced by optics of cornea/lens Adaptive Optics Correct Aberrations Increasing Pupil Size Adaptive Optics Scanning Laser Ophthalmoscope Yuhua Zhang Austin Roorda AO + SLO = AOSLO No AO (defocus and astigmatism corrected) Adding Adaptive Optics
3 AO + SLO = AOSLO AO + SLO = AOSLO Adaptive Optics Scanning Laser Ophthalmoscopy (AOSLO) No AO (defocus and astigmatism corrected) Single frame with AO No AO (defocus and astigmatism corrected) Single frame with AO Multiple frames with AO Overcomes blur from optical aberrations Shack-Hartmann wavefront sensor Deformable mirror Image individual cones with high resolution The left image is taken after best correction of defocus and astigmatism, but not high order aberrations. The second frame is a single frame taken after AO correction. The third frame is a coadded set of 1 frames which have been corrected for distortions due to eye movements. Signal magnitude, resolution and contrast are improved after AO correction and virtually every cone is resolved in the registered frame. 45 microns Cone Spacing Increases with Eccentricity in Normal Eyes Cone spacing (microns) Distance from fovea (degrees) AOSLO data from 2 normal eyes best fit (+/- 95% limits) histological data (+/- 2 sd) Curcio CA et al. J Comparative Neurology 199; 292: Cone Spacing (arcminutes) Cone Spacing is Similar in Normal Eyes Aged Open Squares: < 4 yo Black Squares: 4-55 yo Red Squares: > 55 yo Eccentricity (degrees) Duncan et al, IOVS, 27 AOSLO in Retinal Degenerations Progressive loss of photoreceptors causes vision loss Can we image macular cones in patients with diseased photoreceptors? Are diseased cones different in patients with different types of degeneration? Do certain phenotypes correlate with specific genetic mutations? Stargardt Disease Stargardt Disease 1/1, patients in the U.S. Central vision loss due to macular degeneration of photoreceptors and RPE cells ABCA4 mutations identified in up to 8% Abnormal accumulation of autofluorescent lipofuscin in RPE cells Flecks, dark choroid on fluorescein angiography Evaluate macular cone structure in 8 STGD patients using high-resolution retinal imaging (AOSLO) Correlate cone structure with visual function using fundus-guided microperimetry (MP-1)
4 Stargardt Disease: SD-OCT Findings A B Normal subject: Vertical OCT across anatomic fovea Central scotomatous region Superiorly shifted fixation to Transition Zone with IZ present D 1 C F3P1: Vertical OCT across fixation and anatomic fovea Chen YM et al. Invest Ophthalmol Vis Sci 211; 52: Chen YM et al. Invest Ophthalmol Vis Sci 211; 52: Cone Spacing in Stargardt Disease: Lessons Learned from AOSLO Regions of increased cone spacing correlated with reduced visual sensitivity Cone structure was closest to normal at the location of eccentric fixation Cone structure was preserved in the parapapillary region AOSLO may provide a sensitive measure of cone survival and disease progression Age-Related Macular Degeneration Age-Related Macular Degeneration (AMD) Leading cause of vision loss among elderly in the US Deposits under the RPE (drusen) eventually kill photoreceptors Directly: geographic atrophy Indirectly: choroidal neovascularization AOSLO provides opportunity to study cones at the margin of geographic atrophy in AMD Cones Preserved at the Border of GA
5 Diagnostic Dilemmas: Vision loss of unknown etiology Atypical cases of common diseases New tools to explore the macula allow assessment of cone structure and function Fundus-guided Microperimetry Spectral Domain OCT AOSLO images of macular cones 48 year old man Complains of blind spots in both eyes, gradually progressing over the past 2-3 years First noticed trouble locating mouse pointer OS 5 years ago, then OD Reports difficulty with glare at night, vision in shadows and recognizing pastel colors Denies photosensitivity or reduced side vision Past medical history: unremarkable Medications: none No prior chloroquine, hydroxychloroquine, thioridazine Family history: Mother developed reduced central vision in her 3s, stopped driving at age 38 and is now legally blind; her deceased sister and mother also had vision problems Some vision problems Eye Examination Vision loss in her early 3s c/o vision loss in his early 4s Still driving, age 7 Significant vision loss in her early 4s No known Consanguinity BCVA: 2/25 OD, 2/4 OS IOP 19 OU No APD Anterior Segment: Trace NS OU, no vitreous cell Dilated Fundus Examination: Humphrey Visual Fields
6 Goldmann Visual Fields Differential Diagnosis? Early-onset AMD? Myopic Degeneration? Multifocal choroiditis? Histoplasmosis? Late-onset Stargardt Disease? Pattern Dystrophy? Adult Vitelliform? Central Areolar Choroidal Dystrophy? No drusen, young Not myopic No signs of inflammation No peripapillary or peripheral changes No dark choroid, old, AD family history AD history, no patterns No vitelliform lesions +AD, +atrophy Fluorescein Angiogram Fundus Autofluorescence OCT Genetic Testing Carver Nonprofit Genetic Testing Laboratory ( Fee for service testing for many mutations DNA sequencing of the entire coding sequence of the RDS gene revealed a heterozygous CGG>TGG nucleotide substitution Amino acid change of Arg172Trp in the peripherin/rds gene Peripherin/RDS gene Chromosome 6p (human), 17 (mouse) In mice: retinal degeneration, slow (RDS) Photoreceptor disc membrane-associated glycoprotein, essential for outer segment disc stabilization; forms complex with ROM1 In humans: mutations can cause ADRP, pattern dystrophy, adult vitelliform, central areolar choroidal dystrophy, RP albescens, CRD, and AD macular dystrophy Sometimes RP, pattern and fundus flavimaculatus all in same family Weleber RG, Carr RE, Murphey WH et al., Arch Ophthalmol 1993; 111: Conclusions: AMD vs. Hereditary Maculopathy Earlier onset, bilateral, symmetric macular lesions Implications for other family members Take a family history Consider genetic testing: eyegene How can retinal imaging help me take care of my patients? Often the cause of vision problems is not obvious from examination alone Advances in retinal imaging can shed light on diagnosis and implicate photoreceptors as source of vision loss SDOCT provides high resolution cross-sectional retinal images AOSLO images individual photoreceptors
7 AOSLO in Retinal Disease: The Present High resolution images of cone photoreceptors on a microscopic scale Cones are preserved in regions with preserved visual function and around the optic disc in STGD Cones are visible at the border of geographic atrophy and over drusen AOSLO in Retinal Disease: The Future Promising new technology for vision science May provide a sensitive measure of cone survival during degeneration and in response to therapy May yield insight into mechanism of cell death in several different types of retinal diseases Acknowledgements Reema Syed, UCSF Shiri Soudry, UCSF Moreno Menghini, UCSF Kavitha Ratnam, UCSF Katherine Talcott, UCSF Yingming Chen, University of Toronto Austin Roorda, UC Berkeley Brandon Lujan, UC Berkeley Pavan Tiruveedhula, UC Berkeley Yuhua Zhang, University of Alabama, Birmingham Radha Ayyagari, UCSD Acknowledgements The Foundation Fighting Blindness Research to Prevent Blindness Jahnigen Career Development Scholars Award (American Geriatrics Society) American Health Assistance Foundation Macular Degeneration Fund Hope for Vision Karl Kirchgessner Foundation That Man May See, Inc. The Bernard A. Newcomb Macular Degeneration Fund NIH BRP Adaptive Optics Instrumentation for Advanced Ophthalmic Imaging (PI: David Williams)
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