Differential Diagnosis of Atypical Bulls-Eye

Abstract: This report describes an atypical bilateral bulls-eye maculopathy in a healthy young Caucasian male. Differentials include cone dystrophy and maculopathy secondary to Accutane toxicity.

Case Report

A 25 year old Caucasian male presented to our clinic on July 28th, 2011. He was referred from an optometrist in private practice. His chief complaint was worsening in his right eye for the past month, more evident when reading than when looking in the distance. The patient complained of being more stressed recently due to upcoming major examinations, but reported no current illness or infection. The patient had no significant ocular history and hi medical history was significant only for acne. He had started Accutane therapy 3 months prior to his visit, but discontinued the medication when his visual symptoms began. His other medications included Ambien and Acetaminophen. His family history was non-contributory and he had no known allergies. He was well oriented to time, place and person.

The patient’s uncorrected was 20/40+ OD and 20/20- OS. Pinhole acuities improved to 20/25- OD and remained at 20/20- OS. testing showed blurring of the central grid OD and OS, but no metamorphopsia and no scotomas. His pupils were equally round and reactive to light. External ocular muscles were full and unrestricted with no pain or diplopia. Color vision testing using the Ishihara color plates was normal OD and OS. Anterior segment evaluation revealed an internal hordeolum on the right upper eyelid. His bulbar and palpebral conjunctiva was white and quiet, his iris was flat and even, his cornea was clear and the anterior chamber was deep and quiet OD and OS. Pressures were 16mmHg OD and 16mmHG OS with Goldmann applanation tonometry.

The patient was dilated with 1% Tropicamide and 2.5% Phenylephrine. Posterior segment evaluation revealed no lenticular or vitreal opacities OD or OS. Fundus assessment showed small discs and c/d ratios, a flat macula with a positive foveal reflex OD and OS. There were no other clinically significant retinal findings.

Topcon and Zeiss OCT imaging studies showed parafoveal defects in the photoreceptor integrity layer (PIL) in both eyes. OCT images also showed a significantly thinner than the normative database OD and OS. Microperimetry was performed using a custom setting to test the central 10 degrees with a few added points. The patient had normal foveal sensitivity with a surrounding annulus of reduced sensitivity in both eyes. Fundus autoflurorescent photos showed a hyperautofluorescent bulls-eye pattern around his fovea OD and OS. The bulls-eye was bilateral and symmetric. The patient had a normal fluorescein angiogram (FA) results from a previous examination.

At a follow-up visit on August 9th, 2011, the patient reported no change in his ocular complaints or medical status. His best corrected vision improved to 20/20 OD and remained 20/20 OS. Full flash electroretinography (ERG) was performed using the VERIS system. The patient’s scotopic, photopic and flicker responses were within normal limits. Primary Differential Diagnosis

• Cone Dystrophy • Accutane-related Toxicity

Other Differential Diagnosis

• Early Cone-rod Dystrophy • Chloroquine (Plaquenil) maculopathy • Benign concentric macular dystrophy • Fenestrated sheen macular dystrophy • Stargardt’s disease

Diagnosis and Discussion

This patient’s bilateral symmetric presentation suggests either a hereditary macular dystrophy, or a toxic reaction to a systemic medication. The bulls-eye maculopathy seen in this patient looks strikingly similar to plaquenil maculopathy. Plaquenil cause symptoms of blurred vision, nyctalopia, loss of color vision and central/paracentral scotomas, among other symptoms1,2. However, our patient has never taken plaquenil.

Benign concentric macular dystrophy is an autosomal dominant disease that presents in adulthood with mild central vision loss1. It is associated with bulls-eye maculopathy and mild vascular attenuation. Visual fields will show a paracentral ring scotoma much like the defect in our patient. Prognosis is usually good, although some develop progressive vision loss and reduced night vision. Although our patient has the maculopathy and visual field defect, he has no family history of eye disease and normal retinal vasculature.

Stargardt’s can cause bulls-eye maculopathy, central vision loss and present in the first to second decade of life. Inheritance is autosomal recessive and it the most common form of juvenile-onset macular dystrophy. The photopic ERG in these patients is normal to subnormal while scotopic response is normal. In advanced cases the EOG is abnormal. The fundus shows a characteristic “dark choroid” with fluorescein angiography, due to build up of lipofuscin deposits in the RPE. Stargardt’s is a progressive disease with poor prognosis for visual acuity. While this is a possibility our patient has no family history of eye disease. His fundus also lacks the piscifom lesions associated with Stargardt’s ,and he has a normal fluorescein angiogram.

Fenestrated sheen macular dystrophy is an extremely rare condition with strong autosomal dominant inheritance3. Central vision is generally preserved, but there is a red-green sheen to the macula with a distinct bull’s-eye pattern. The sheen appears to be made up of multiple irregular window defects, or fenestrations allowing for a view of the underlying RPE and choroid. Mild red-green color vision defects have been noted but ERG and FA studies are normal. The rare autosomal dominant nature of the disease makes it unlikely to be the cause of our patient’s complaints.

Cone-rod dystrophy generally presents in the second decade with central vision loss and color vision loss. As the disease progresses there is profound night vision loss, pigmentary bone-spicule-like depositions, and there can be bulls-eye maculopathy. The characteristic ERG has shows a reduced cone response and can show a reduce rod response. As previously stated, our patient had a normal ERG, no complaints with night vision and a negative family history.

Cone dystrophy presents in the first to second decade of life with progressive bilateral central vision loss and severe color vision defects1, 2. In the later stages of the disease there can be photophobia and pendular nystagmus. Inheritance is usually autosomal dominant, although it can be autosomal recessive, x-linked or sporadic. The macula is thinned and can have a granular appearance or demonstrate a bull’s-eye maculopathy. The characteristic ERG in cone dystrophy shows a significantly reduced photopic response and normal to subnormal scotopic response. Though this fits well with the symptoms and signs, our patient has normal color vision and a normal scotopic and photopic ERG. He also reports no family history of color vision defects or vision loss. Cone dystrophy remains a primary differential diagnosis due to the appearance of the fundus, the patient’s symptoms and the fact that it can often occur sporadically.

The only drug on the patient’s list of medications with known ocular side effects is Accutane. The patient’s symptoms began after taking this medication. Isotretinoin (Accutane) is a retinoid used to treat severe recalcitrant nodular acne. The active ingredient, 13-cis retinoic acid, inhibits sebaceous gland function and keratinization; however, the exact mechanism of action is unknown4. There are numerous known ocular side effects include blepharoconjunctivitis, reduced night vision, and pseudotumor cerebri. Fraunfelder et al compiled 1741 case reports of ocular side effects of isotretinoin5. They listed 25 cases or retinal pigment disturbance, but did not specify the pattern, or retinal location. Isotretinoin is known to slow the regeneration of rhodopsin by inhibiting 11 cis- retinaldehyde, thus reducing dark adaptation. Other biochemical effects of this drug on the retina are unknown. It is hypothesized that isotretinoin competes with retinol for binding sites on cell surfaces or transport molecules on the retinal pigment epithelium (RPE)6, or interferes with retinol storage or detoxification7. Isotretinoin has been also shown to inhibit the growth of human RPE cells in vitro and in animal models8. The effect of this medication on the retina is well documented, although there are limited reports in the literature of maculopathy.

Sanchez–Chicharro et al9 published a case report of an 18 year old male with a bull’s-eye maculopathy after using Accutane for 6 months. The young man in their case had a family history of oculodermal albinism and a history of refractive amblyopia in childhood that completely resolved. Their patient presented with reduced visual acuity OS (20/200) and bilateral symmetric bulls-eye maculopathy visible with fundoscopy. They called the pattern an “inverted bulls-eye” because it had a hypo-pigmented center and hyperpigmented annulus. Sanchez-Chicharro’s patient had normal color vision, OCT and ERG test results. His electrooculography (EOG) results were borderline on the right eye and normal in the left eye. After discontinuing Accutane therapy the patient’s visual acuity eventually recovered to 20/20 but the bull’s-eye maculopathy remained. Sanchez-Chicharro’s differentials listed many of the macular dystrophies mentioned above. However, Accutane toxicity was a primary differential.

Differences between Sanchez-Chicharro’s patient and our patient include the severity of the vision loss, the length of time the patient was taking Accutane, the normal OCT, the abnormal FA and the fact that their patient had a family history of oculodermal albinism. The authors did not specify whether spectral domain OCT was used. Therefore it is possible that the defect in the photoreceptor integrity line was present but not detected. They also did not obtain fundus autofluorescent retinal photos. Even with these differences, the symptoms and signs are very similar.

One must also consider that there could be multiple factors causing the retinal disturbance in these patients. It is possible that a weakened retina due to early macular dystrophy was exacerbated by Accutane usage. Environmental factors such as UV exposure and nutrition could also factor into the diagnosis. Further testing and careful observation over time is needed to make that determination.

The next step for our patient will be to get a multi-focal ERG and to undergo genetic testing for cone dystrophies and other genetically inherited retinal diseases. Other options for testing could be an EOG. It is important to rule out the most common known causes of bull’s-eye retinal lesions before attributing this to retinal toxicity. Observation over time will also be diagnostic. Progressive vision loss would suggest dystrophy while no change suggests toxicity. Unlike plaquenil, Accutane is not known to cause progressively worse ocular side effects once the drug is stopped. Observing the patient over time may give us the best clue about the etiology of his ocular condition.

References

1 Kanski, Jack J.Clinical Ophthalmology 6th Ed. Oxford. Butterworth-Heinemann Elsevier 2007, pg. 667 2 Friedman, Neil J., Kaiser, Peter K., Pineda, Roberto. The Massachusetts Eye and Ear Infirmary Illustrated Manual of Ophthalmology 3rd Ed. Saunders 2009. Pg 449. 3 O’Donnel, F.E., Welch, R.B. Fenestrated sheen macular dystrophy – A new autosomal dominant maculopathy. Archives of Ophthalmology July 1970; 97: 1292-1296. 4 Roche Accutane Package Insert. 5 Fraunfelder, F.T., Fraunfelder, F.W. and Edwards, R. Ocular side effects possibly associated with isoretinoin usage. American Journal of Ophthalmology Sept 2001; 132(3): 299-305. 6 Weleber, R.G, Denman, S.T., Hanifin, J.M., and Cunningham, W.J. Abnormal retinal function associated with isotretinoin therapy for acne Archives of Ophthalmology June 1986; 104(6): 831-837. 7 Ball MD, Furr HC, Olson JA: Enhancement of acyl coenzyme A:retinol acyltransferase in rat liver and mammary tumor tissue by retinyl acetate and its competitive inhibition by N-(4-hydroxyphenyl)retinamide. Biochem Biophys Res Commu 1985;128:7-11. 8 Wu WC, Hu DN, Mehta S, Chang YC. Effects of retinoicacid on retinal pigment epithelium from excised membranes from proliferative vitreoretinopathy. J Ocul Pharmacol Ther 2005;21:44 –54. 9 Sanche. Pastor, J.C., Lopez Galvez, M.I., Coco Martin, R.M. and Asensio, R.C. Diagnostic and therapeutic challenges. Journal of Retinal and Vitreous Diseases. 2008; 28(1): 174-179.