Fundus Autofluorescenceclinical applications
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1 Northwestern University Feinberg School of Medicine Fundus Autofluorescenceclinical applications Amani A. Fawzi, MD Associate Professor of Ophthalmology Northwestern University, Feinberg School of Medicine Financial disclosure None Origin of Fundus Autofluorescence Lipofuscin accumulates in the RPE Undigestible remnants of photereceptor outer segments not degraded by lysosomes Over age of 70, ¼ of the cytoplasmic space RPE cells is occupied by lipofuscin and melano-lipofuscin (product of LF and melanin) webeye.ophth.uiowa.edu/.../ Mullins/index.htm 1
2 Source of Lipofuscin PHOTORECEPTORS RPE cslo 488nm laser Imaging Fundus Autofluorescence Exciting light Fundus camera band pass filter: nm Macular pigment: Acts as filter ( only in cslo) Lipofuscin autofluorescence : > 500nm Fluorescein excitation Ocular pigment absorption interaction with AF imaging cslo excitation 488nm laser Lipofuscin emission Fundus camera excitation filter: nm Fundus camera barrier filter: nm 2
3 Normal Autofluorescence Autofluorescence signal intensity is 2 order magnitude lower than background of FA at most intense transit To improve signal to noise ratio: High sensitivity cameras averaging of multiple images Image alignment 3
4 Best s disease: pseudohypopyon 4
5 Spaide, Ophthalmology, 2006 Adult Onset Foveal Pigment Epithelial Dystrophy (AOFPED) - Adult vitelliform Variant of pattern dystrophy Peripherin RDS>>Bestrophin Later onset (40-60) Smaller lesion (1/3 dd) Pigment spot EOG preserved Variable family history Reading vision DDx: BLD-vitelliform Drusenoid PED Courtesy of Dean Eliott, MD AOFPED Courtesy of Dean Eliott, MD 5
6 Pattern dystrophies Midlife, asymptomatic to mild AD, peripherin/rds AOFPED butterfly Reticular Fundus pulverulentus (coarse pigment mottling) Overlapping, can evolve, closely related Metamorphopsia, sl decrease VA Borderline EOG Reading VA in at least 1 eye Butterfly Pattern 6
7 Reticular Pattern Dystrophy Fish net pattern Courtesy of Stephen Tsang, MD,PhD 7
8 Reticular pattern--autofluorescence Fish net pattern Courtesy of Stephen Tsang, MD,PhD Which pa3ern? 8
9 9
10 Bie6 s Macular Dystrophy Heritable crystalline macular dystrophy Autosomal recessive/cyp4v2 chromosome 4 Encodes for a protein in the cytochrome P450 pathway Defect leads to accumulation of glittering crystals in the fundus & peripheral cornea Rare autosomal dominant form Disease more frequent in East Asia, China and Japan Diff dx crystals: oxalosis, cystinosis, exposure to tamoxifen, methoxyflurane, canthaxanthine and talc Bie6 s crystalline dystrophy Presenta<on: bilateral, slowly progressive nightblindness and paracentral scotomas Legally blind by 5-6 th decade Gli3ering crystals in fundus, cornea Cytoplasmic lipid inclusions found in circula<ng lymphocytes and fibroblasts 10
11 Bie6 s: tes<ng ERG: minimally abnormal, nondiagnos<c FA: loss of choriocapillaris AF: areas of hypoautofluoresence associated with with RPE atrophy, sca3ered hyperfluorescent spots OCT: deposits preferen<ally in the outer re<na (OPL/RPE) with RPE hyperplasia which progresses to atrophy 06/2012 FAF NIR 06/
12 A3243G Mutation The single-point mutation of the mitochondrial DNA (mtdna); adenine to guanine transition at position 3243 of mtdna (A3243G) in a transfer RNA leucine (trna Leu(UUR) ) encoding region Originally described in association with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) Variety of other clinical disorders Maternally Inherited Diabetes And Deafness (MIDD) Cardiomyopathy, Chronic Progressive External Ophthalmoplegia (CPEO) Myopathy GI Dysmotility Renal Failure Variability linked to load of mutant mtdna, which also varies from tissue to tissue within an individual. Higher mutant mtdna load associated with more severe disease. Goto. Nature 1990 Chinnery. J Med Genet 1999 Manouvrier. J Med Genet 1985 Chinnery. Brain 1997 A3243G Mutation Estimated prevalence of mitochondrial mutation in diabetics: 0.13% to 2.8%.! "(Vionnet, Lancet 1999; Kadowaki, NEJM 1994)! Clinical/subclinical hearing loss: most common feature associated with A3243G mutation! Hypothesis: mitochondrial dysfunction à ATP à ion imbalance à hair cell and stria vascularis cell death! Patients/relatives with progressive hearing loss à eye exam to r/o retinal abnormalities! Patients with A3243G-associated macular features à audiological testing, even in the absence of diabetes or self-reported hearing loss.! Negative screen for the A3243G mtdna mutation does not exclude carrier status! A3243G mutation load in blood reduces over time (Frederiksen, J Med Genet 2006) à mutation-negative still warrants ophthalmologic and audiological assessment! MIDD Maternal inherited diabetes and deafness (MIDD) may present with diabetes mellitus, neurosensory hearing loss, and retinal dystrophy. First reported in 1992 Caused by the mtdna point mutation A3243G. Prevalence: 1% to 2% of diabetics 86% of MIDD patients: bilateral macular pattern dystrophy: RPE hyperpigmentation surrounding the macula and/or optic disc (Massin, Ophthalmology 2009) Massin classified progression of dystrophy into: 1. Grade 1: Tiny pigment deposits in macula and around disc 2. Grade 2: Annular and radiate pattern of pigmentary changes 3. Grade 3 : Atrophic areas of RPE and choriocapillaris surrounding the macula 12
13 MELAS MELAS frequently associated with a A3243G point mutation Prevalence : 0.95 to 236: # (Chinnery Ann Neurol 2000; Manwaring, Mitochondrion 2007; Elliott, Am J Hum Genet 2008) CRVO reported once with G13513A mitochondrial mutation with MELAS like syndrome:. Hsieh YT. Ophthalmic Genet Latkany et al. (AJO 1999): Ocular findings in 4 family members with MELAS syndrome caused by A3243G mutation Ophthalmoplegia Neurosensory deafness Reduced photopic and scotopic ERG b-wave Myopathy Slowly progressive geographic macular RPE atrophy Jones et al. (AJO 2004) : only 1/570 patients with early or late AMD +ve for A3243G mutation FAF Two Reported Patterns 1. Discontinuous circumferentially oriented perifoveal atrophy 2. Pattern dystrophy phenotype, diffuse speckled appearance of the macula Rath. Characterisation of the macular dystrophy in patients with the A3243G mitochondrial DNA point mutation with fundus autofluorescence. BJO Different Phenotypes Michaelides, Archives 2008 Macular Dystrophy Associated With the A3243G Mitochondrial DNA Mutation: Distinct Retinal and Associated Features, Disease Variability, and Characterization of Asymptomatic Family Members" 13
14 14
15 Banded type Trickling type Progression 15
16 Progression CASE EXAMPLES RPE rips: what is the VA? 16
17 Summary Fundus Autofluorescence is a non-invasive, rapid and useful imaging modality Reflects metabolic changes in the RPE High risk characteristics Monitoring disease progression in geographic atrophy/amd Clinical trials for GA Role in neovascular AMD still uncertain 17
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