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Posterior Segment

C/D: 0.3/0.2, bilateral temporal pallor

Macula: diffuse, irregular hyperpigmentation OS>OD, with large, round area increased tessilation from choroid, consistent with RPE loss

Vessels: arteriolar narrowing OU

Periphery: flat/attached OU

Anterior Segment

LLL: wnl OU

C/S: w/q OU

K: clear OU

AC: d/f OU

Iris: r/f OU

Lens: 1+ NS OU

On Exam...

dVAsc: OD CF@3 ft PH NI

OS 20/80 PH 20/50

Pu: 5->4 mm OU, no RAPD

IOP: 17/17

CVF: decreased symmetrically OD

Full to finger count OS

EOM: full OU

Differential Diagnosis

1. Central Areolar Macular Dystrophy

2. Stargardt disease

3. AMD/geographic atrophy

4. Toxoplasmosis

5. North Carolina macular dystrophy

6. Retinitis Pigmentosa Inversa

Central Areolar Choroidal Dystrophy (CACD)

1. Review anatomical features of the RPE and choroid

2. List differential diagnosis for focal macular dystrophy

3. Define clinical and radiological features of CACD

4. Detail gene mutations of CACD and associated features

5. Distinguish CACD from Stargardt disease, AMD, toxoplasmosis, North Carolina Macular Dystrophy, and Retinitis Pigmentosa Inversa

Differential Diagnosis?

Patient Background

PMHx: None

POHx: None

POSx: None

FHx: +CVA, no family history of vision loss

Soc hx: negative

Medications: visine prn

All: NKDA

ROS: +hearing loss

Patient Presentation

48 yo Hispanic male presenting with slowly progressive vision loss since age 20. Denies eye pain, double vision. Has not been seen by a PCP in many years. Referred to HEI by Optometry clinic.

What additional imaging study should you consider ordering?

North Carolina Macular Dystrophy

CACD

vs.

image from http://webeye.ophth.uiowa.edu/eyeforum/atlas/pages/north-carolina-macular-dystrophy.htm

Retina Pigment Epithelium

- Developed from outer layer of optic cup (neuroectoderm)

- Continuous with ciliary body and iris pigment epithelium

- Defects in RPE --> photoreceptor degradation

A brief review of retinal anatomy

-Heterogeneous AD macular degeneration with onset in infancy

-Yellow macular lesions of RPE that congregate over time-> can progress to retinal atrophy, staphylomatous-like lesions

-Disease progression stabilizes in teens

-100% penetrance but variable expressivity

-vision generally better than expected based on exam findings - 20/20-20/200

Sources

Image from: Strauss O. The Retinal Pigment Epithelium in Visual Function. Physiological Reviews. 2005;85(3);845-881.

Sources

17. Yanagihashi S, Nakazawa M, Kurotaki J, Sato M, Miyagawa Y, Ohguro H. Autosomal dominant central areolar choroidal dystrophy and a novel Arg195Leu mutation in the peripherin/RDS gene. Arch Ophthalmol. 2003 Oct;121(10):1458-61.

18. Lotery AJ, Ennis KT, Silvestri G, Nicholl S, McGibbon D, Collins AD, Hughes AE. Localisation of a gene for central areolar choroidal dystrophy to chromosome 17p. Hum Mol Genet. 1996 May;5(5):705-8.

19. Hughes AE, Lotery AJ, Silvestri G. Fine localisation of the gene for central areolar choroidal dystrophy on chromosome 17p. J Med Genet. 1998 Sep;35(9):770-2.

20. Hughes AE, Meng W, Lotery AJ, Bradley DT. A novel GUCY2D mutation, V933A, causes central areolar choroidal dystrophy. Invest Ophthalmol Vis Sci. 2012 Jul 12;53(8):4748-53.

21. http://webeye.ophth.uiowa.edu/eyeforum/atlas/pages/north-carolina-macular-dystrophy.htm

22. Butler N, Furtado J, Winthrop K. Ocular toxoplasmosis II: clinical features, pathology, management. Clin Experiment Ophthalmol. 2013 Jan-Feb; 41(1): 95-108.

23. Ortiz S et al. Ocular toxoplasmosis: a case report. International Journal of Clinical Medicine. 2013. 4(1);1-2. DOI 10.4236/ijcm.2013.41001

24. Nash et al. Retinal dystrophies, genomic applications in diagnosis and prospects for therapy. Translational pediatrics. April 2015:4(2);139-163.

25. Hoyng CB, van Rijn, Deutaman AF. Central areolar choroidal dystrophy and slowly progressive hearing loss. Acta Ophthalmol Scand. 1996 Dec;74(6):639-41.

26. http://www.eyerounds.org/atlas/pages/Stargardt-disease-13.htm

27. http://imagebank.asrs.org/file/3342/stargardt-disease-case-3-fa-le

28. http://imagebank.asrs.org/file/5123/late-stage-stargardt-disease

Acknowledgments

Dr. Huddleston

Dr. Juliet Kim

Dr. Rocio Diaz

Steve Moser

1. http://www.siumed.edu/~dking2/ssb/EE020b.htm

2. Basic Anatomy. In L. B Cantor, C. J. Rapuano, and G. A. Cioffi (eds.), Retina and Vitreous. 2016-2017 Basic and Clinical Science Course. pp. 7-19. San Francisco, CA: American Academy of Ophthalmology.

3. Strauss O. The Retinal Pigment Epithelium in Visual Function. Physiological Reviews. 2005;85(3):845-881.

4. Nickla D, Wallman J. The Multifunctional Choroid. Prog Retin Eye Res. 2010 Mar; 29(2): 144-168.

5. Ramrattan RS, van der Schaft TL, Mooy CM, de Bruijn WC, Mulder PG, de Jong PT Invest Ophthalmol Vis Sci. 1994 May; 35(6):2857-64.

6. G. Klintworth and T. Cummings. 2007. Normal Eye and Ocular Adnexa. In S. Mills (ed.) Histology for the Pathologist, 3rd edition. Lippincott Williams & Wilkins.

7. Hereditary Retinal and Choroidal Dystrophies. In L. B Cantor, C. J. Rapuano, and G. A. Cioffi (eds.), Retina and Vitreous. 2016-2017 Basic and Clinical Science Course. pp. 215-238. San Francisco, CA: American Academy of Ophthalmology.

8. Klevering BJ, van Driel M, van Hogerwou AJ, van De Pol DJ, Deutaman AF, Pinckers AJ, Cremers FP, Hoyng CB. Central areolar choroidal dystrophy associated with dominantly inherited drusen. Br J Ophthalmol 2002;8691- 96

9. Piguet B, Héon E, Munier FL, Grounauer PA, Neimeyer G, Butler N, Schorderet DF, Sheffield VC, Stone EM. Full characterization of the maculopathy associated with an Arg-172-Trp mutation in the RDS/ peripherin gene. Ophthalmic Genet 1996;17175- 186

10. Noble K. Central Areolar Choroidal Dystrophy. American Journal of Ophthalmology. Sept 1977. 84(3);310-318.

11. Hughes AE, Lotery AJ, Silvestri G. Fine localisation of the gene for central areolar choroidal dystrophy on chromosome 17p. J Med Genet. 1998 Sep;35(9):770-2.

12. Hoyng CB Deutman AF. The development of central areolar choroidal dystrophy. Graefes Arch Clin Exp Ophthalmol. 1996;234:87–93.

13. Smailhodzic D, Fleckenstein M, Theelen T, Boon C, van Huet R, van de Ven J, Den Hollander A, Schmitz-Valckenberg S, Hoyng C, Weber B, Holz F, Kleverin B. Central areolar choroidal dystrophy (CACD) and age-related macular degeneration (AMD): differentiating characteristics in multimodal imaging. Invest Ophthalmol Vis Sci. 2011 Nov 21;52(12):8908-18.

14. Gundogan FC, Tas A, Sobaci G. Multifocal electroretinogram and central visual field testing in central areolar choroidal dystrophy. European Journal of Ophthalmology, Volume 20, Number 5, 2010.

15. Reig C, Serra A, Gean E, Vidal M, Aruni J, De la Calzada MD, Antich J, Carballo M. A point mutation in the RDS-peripherin gene in a Spanish family with central areolar choroidal dystrophy. Ophthalmic Genet. 1995 Jun;16(2):39-44.

16. Hoyng CB, Heutink P, Testers L, Pinckers A, Deutman AF, Oostra BA. Autosomal dominant central areolar choroidal dystrophy caused by a mutation in codon 142 in the peripherin/RDS gene. Am J Ophthalmol. 1996 Jun;121(6):623-9.

Choroid

-Develops from mesenchyme surrounding optic vesicle at 2 months gestation

- Contains blood vessels, melanocytes, fibroblasts, immune cells, elastic and connective tissue

- Functions = supply O2 and nutrients to outer retina

light absorption

thermoregulation

aqueous drainage (uveoscleral)

Image from: G. Klintworth and T. Cummings. 2007. Normal Eye and Ocular Adnexa. In S. Mills (ed.) Histology for the Pathologist, 3rd edition. Lippincott Williams & Wilkins.

CACD vs. Retinitis Pigmentosa Inversa

-Both macular RP and CACD associated with PRPH2 mutations

-RP a/w choroidal degeneration, pigment migration, bone spicule formation in macula

-RP is classically associated with waxy pallor of optic nerve, arteriolar narrowing

-thinning of photoreceptor OS on OCT

CACD vs. AMD

image from Smailhodzic et al. Central areolar choroidal dystrophy (CACD) and age-related macular degeneration (AMD): differentiating characteristics in multimodal imaging. Invest Ophthalmol Vis Sci. 2011 Nov 21;52(12):8908-18.

image from http://www.siumed.edu/~dking2/ssb/EE020b.htm

Questions?

Four Clinical Stages of CACD

image from Nash et al. Retinal dystrophies, genomic applications in diagnosis and prospects for therapy. Translational pediatrics. April 2015:4(2);139-163.

1. Focal parafoveal pigmentary RPE changes

2. Round-oval area of mild hypopigmented atrophy, seen on FAF

3. One or more extra-foveal regions of circumscribed RPE atrophy

4. #3 + foveal involvement with decreased VA

Genetics of CACD

STAGE 1 CACD

Central Areolar Choroidal Dystrophy (CACD)

image from Smailhodzic et al. Central areolar choroidal dystrophy (CACD) and age-related macular degeneration (AMD): differentiating characteristics in multimodal imaging. Invest Ophthalmol Vis Sci. 2011 Nov 21;52(12):8908-18.

1. RDS/Peripherin gene (PRPH2) on chromosome 6

- cell surface glycoprotein- mediates signal transduction

stabilizes outer segment

- Arg172Trp, Arg142Trp, Arg195Leu substitutions

- Arg = highly charged, substitution changes protein character

2. Chromosome 17p13

-1996: linked to Chromosome 17p13

-1998: Localized specific CACD gene to Chr 17p13 between microsatellites D17S1810 and GATA7B03

-2012: single-base substitution in guanylate cyclase 2D, membrane (retina-specific) gene (GUCY2D)

-associated with genes for multiple proteins involved in retinal health and function

STAGE 2 CACD

- First described by E. Nettleship (1884) - "Central senile areolar dystrophy"

- Sporadic, AD, AR macular dystrophy

- Reported in patients of European, Asian, Middle Eastern descent

- Onset after second decade, most profound vision loss noted during fourth decade

- Early S/S = central scotoma

fine mottled macular depigmentation

- Bilateral, well-circumscribed, symmetric atrophy of RPE, choriocapillaris, and neurosensory retina

- Associated with drusen-like deposits in some reported cases

image from Smailhodzic et al. Central areolar choroidal dystrophy (CACD) and age-related macular degeneration (AMD): differentiating characteristics in multimodal imaging. Invest Ophthalmol Vis Sci. 2011 Nov 21;52(12):8908-18.

-Both associated with drusen, atrophy in late stages

-Smailhodzic et al. 2011

-CACD a/w younger age (53.2 vs. 77.1), stronger Fhx (80% vs. 9.4%)

-FAF: CACD more associated with well-demarcated speckling than AMD (85% vs. 5.6%)

-SD-OCT: higher frequency of sub-RPE deposits in AMD (36.8% vs. 2.1%). Reticular drusen in AMD only, not in CACD

-limitations: small sample

PRPH2 mutation only

STAGE 3 CACD

image from Smailhodzic et al. Central areolar choroidal dystrophy (CACD) and age-related macular degeneration (AMD): differentiating characteristics in multimodal imaging. Invest Ophthalmol Vis Sci. 2011 Nov 21;52(12):8908-18.

STAGE 4 CACD

image from Smailhodzic et al. Central areolar choroidal dystrophy (CACD) and age-related macular degeneration (AMD): differentiating characteristics in multimodal imaging. Invest Ophthalmol Vis Sci. 2011 Nov 21;52(12):8908-18.

Image from Gundogan FC, Tas A, Sobaci G. Multifocal electroretinogram and central visual field testing in central areolar choroidal dystrophy. European Journal of Ophthalmology, Volume 20, Number 5, 2010.

Stargardt Disease vs. CACD

Why not Usher Syndrome?

-Most common juvenile macular dystrophy

-AR, a/w mutations in ABC4 and/or PRPH2

-Engorgement of RPE cells with lipofuscin-like matter

-DFE = Central foveal atrophy surrounded by pisciform flecks at RPE - "fundus flavimaculatus"

-FA = Dark choroid

-FAF = central macular hypoautofluorescence

expanding pattern of hyperfluorescent flecks

image from http://imagebank.asrs.org/file/5123/late-stage-stargardt-disease

Image from http://www.eyerounds.org/atlas/pages/Stargardt-disease-13.htm

image from http://imagebank.asrs.org/file/3342/stargardt-disease-case-3-fa-le

Acquired Toxoplasmosis

Photo from: Ortiz S et al. Ocular toxoplasmosis: a case report. International Journal of Clinical Medicine. 2013. 4(1);1-2. DOI 10.4236/ijcm.2013.41001

-Classically characterized by unilateral necrotizing retinitis with variable vitritis with adjacent CRS, often in the macula

-higher incidence of macular involvement in congenitally acquired cases

-Retinitis resolves spontaneously in 1-2 mo regardless of treatment in immunocompetent hosts

-Recurrences are common

-Diagnose by PCR

Hearing loss and CACD

-Hoyng et al. 1996: two cases of hearing loss associated with CACD in middle-aged patients

-CACD confirmed with FA, ERG

-sensorineural hearing loss confirmed with audiometry testing

-Genetic link?

Back to our patient...

-referred to low vision clinic

-RTC 1 year

A Choroid Splotched and Bespeckled

Financial Disclosures:

None

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