Retina Imaging Conference

Jinghua Chen, MD, PhD

University of Louisville

Department of Ophthalmology and Visual Sciences

February 5, 2015

HistoryCC: Blurred vision OD for five months.

HPI: 40 year old African American Female complained of

blurred vision in OD for 5 months. She denied eye pain, flashes, floaters, headache, jaw

claudication, temporal tenderness.

Past Medical HistoryPOH: Primary open angle glaucoma

NIDDM without diabetic retinopathy PMH: HTN, NIDDM, anxiety, depression, arthritisAllergy: Lisinopril, LatexFH: Mom was blind due to glaucomaSurgeries: Splenectomy, tubal ligation, knee surgeryMedication: Timolol, HCTZ, losartan, cyanocobalamin,

ferrous sulfate, fluticasone, xorelto, cymbolta, citalopram

ExamOD OS

BCVA: 20/40 20/40Refraction -1.75+0.75 ×130 -1.25+0.75×90 Pupils: 42 42RAPD: Negative OUIOP: 17 14EOM and CVF: Full OUAnterior segment: Normal OU

Fundus Photos

Auto Fluoresence Photos

FA Photos

14s 20s15s

32s 46s

Spectral Domain OCT OD

Spectral Domain OCT OS

Central 24-2 Threshold Test 2012

Diagnosis and DifferentialsAssessment:

40 year old African American Female complained of blurred vision in OD for 5 months.

Diagnosis: FundoscopyFAFundus autofluorescenceOCT

Impression: Stargardt’s DiseaseDifferential Diagnosis

1) Fundus albipunctatus2) Fundus flavimaculatus (a milder condition)3) Familial drusen 4) Fleck retina of Kandori5) Retinitis punctata albescens6) Alport's syndrome7) Tamoxifen or Canthaxanthin

Incidence and Epidemiology

of Stargardt Disease The most common childhood recessively inherited macular dystrophy. It was first described by German ophthalmologist Karl Stargardt, in 1909. 7% of all retinal degenerations, grossly affecting 1 per 10.000 individuals. STGD is an autosomal-recessively inherited condition often associated with

mutations in ABCA4. Autosomal dominant forms have been reported. ABCA4 (1p21-p23) gene mutation (Autosomal recessive), which encodes an

ATP-binding cassette (ABC) transporter protein expressed by rod and cone disc membrane and is involved in the transport of vitamin A derivatives to RPE. (ABCA4 also have been implicated in cone dystrophy, cone-rod dystrophy, and ‘‘retinitis pigmentosa.’’)

Other phenotype: 1p21-p22 (STGD1), 4p(STGD4), 6q14(STGD3) and ELOVL4, which encodes a phtoreceptor-specific component of the fatty acid elongation system

http://eyewiki.aao.org/Stargardt_disease/Fundus_flavimaculatus

PAS stain discloses hypertrophic RPE cells with PAS positive cytoplasmicgranules containing lipofuscin-retinal flecks.

In advanced stages of Stargardt disease, geographic RPE atrophy with loss of the photoreceptor cell layer may be observed.

Choroidal Hyperreflective Foci in Stargardt Disease

The mean numbers of hyperreflective foci in each retinal/choroidal layer in decreasing frequency were as follows: Bruch membrane/retinal pigment epithelial (RPE) complex,

78.22 (24.39); Choriocapillaris, 25.77 (17.57); Sattler layer, 18.59 (12.89); Outer retina, 16.64 (6.96); Inner retina, 0.95 (1.58); Haller layer, 0.73 (0.87).

Piri N, Nesmith BL, Schaal S. JAMA Ophthalmol. 2015 Jan 15

Disease Course Slowly progressive 50% have at least 20/40 VA in one eye by age 19 22% have 20/40 vision by age 39 After age 40 more rapid progression to 20/200 -counting fingers

Fujinami K, Zernant J, Chana RK, et al. Ophthalmology. 2015 Feb;122(2):326-34.

Westeneng-van Haaften SC, Boon CJ, Cremers FP, et al. Clinical and genetic characteristics of late-onset Stargardt's disease. Ophthalmology. 2012 Jun;119(6):1199-210.

Developing macular flecks

Central atrophy with no visible flecks at baseline (fundus grade 3a), with AF imaging showing a localized low AF signal surrounded by subtle foci of high AF signal at the macula .

Six years later, there are marked and increased macular flecks, also clearly seen on AF imaging .

Fujinami K, Zernant J, Chana RK, et al. Ophthalmology. 2015 Feb;122(2):326-34.

Clinical Polymorphism of Stargardt Disease

Polymorphism of Stargardt Disease; El Matri et al 2003

Autofluorescence images of One Stargardt patients

Spread of hyperautofluorescent fleck lesions in a centrifugal “wave” centered on the fovea.

Arch Ophthalmol. 2012 February ; 130(2): 171–179.

Management

Gene screening and genetic consult (ABCA4 genotyping microarray; arrayed primer extension (APEX) technology)

Gene therapy of ABCA4-Associated Diseases Stem cell therapy: transfected modified mRNA in

human embryonic stem cell-derived RPE cells.

References BSCS 2014-2015 Book 12, Retina and Vitreous: 234-236 Piri N, Nesmith BL, Schaal S.Choroidal Hyperreflective Foci in Stargardt Disease Shown by

Spectral-Domain Optical Coherence Tomography Imaging: Correlation With Disease Severity. JAMA Ophthalmol. 2015 Jan 15

Allikmets R, Singh N, Sun H, et al. A photoreceptor cellspecific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet. 1997;15:236–246.

Michaelides M, Chen LL, Brantley MA Jr, et al. ABCA4 mutations and discordant ABCA4 alleles in patients and siblings with bull’s-eye maculopathy. Br J Ophthalmol. 2007; 91:1650–1655.

Fujinami K, Zernant J, Chana RK, et al. Clinical and Molecular Characteristics of Childhood-Onset Stargardt Disease.Ophthalmology. 2015 Feb;122(2):326-34.

El Matri L, Ouechtati F, Chebil A, et al. Clinical polymorphism of stargardt disease in a large consanguineous tunisian family; implications for nosology. J Ophthalmic Vis Res. 2013 Oct;8(4):341-50.

Catherine A. Cukras, Wai T. Wong, Rafael Caruso, et al. Centrifugal Expansion of Fundus Autofluorescence Patterns in Stargardt Disease Over Time Arch Ophthalmol. 2012 February ; 130(2): 171–179.

Auricchio A, Trapani I, Allikmets R. Gene Therapy of ABCA4-Associated Diseases Cold Spring Harb Perspect Med. 2015 Jan 8.

Magnus L. Hansson, Silvia Albert, et al. Efficient delivery and functional expression of transfectedmodified mRNA in human Embryonic Stem Cell-derived Retinal Pigmented Epithelial cells. J BiolChem. 2015 Jan 2.

Westeneng-van Haaften SC, Boon CJ, Cremers FP, et al. Clinical and genetic characteristics of late-onset Stargardt's disease. Ophthalmology. 2012 Jun;119(6):1199-210.