Case of the Month

Edited by Robert N. Johnson, MD

Case #97: July, 2017

A 17-year-old female presents with decreased vision in both eyes.

Presented by Judy Chen, MD

Figure 1: Color montage of the right eye. Note the  multiple pisciform-shaped flecks in a circinate pattern around the macula and optic nerve, as well as central mottling of the RPE.

Figure 2: Color montage of the left eye. Note a similar pattern of multiple pisciform-shaped flecks in the posterior pole but with more prominent RPE mottlng and hyperplasia centrally than what is present in the right eye.

Case History

A 17-year-old Hispanic female presented with a 2-year history of decreased vision in both eyes.  She described having difficulty reading small print since the age of 14, reduced color vision particularly with the color green, and worse vision at night than during the day.  Her past ocular history was significant for myopia, for which she wears corrective lenses. Past medical history, family history and review of systems were noncontributory and she was taking no medications.   Of note, both her two brothers and her parents had normal vision.

On examination, her best-corrected visual acuity was 20/63 in both eyes. Ocular motility, pupillary examination, intraocular pressure, and anterior segment examinations were normal in both eyes.  The posterior segment examination of the right eye revealed multiple flecks, mostly surrounding the central macula in a circinate pattern but also in a semicircular pattern around the optic nerve, as well as central mottling of the retinal pigment epithelium (RPE) (Figure 1).  Dilated fundus examination of the macula in the left eye showed similar flecks in a circular pattern around an area of RPE mottling and geographic atrophy (Figure 2). RPE hyperplasia was present in the left macula.

Fundus auto fluorescence (FAF) imaging of the right and left eyes depicted hyperautofluorescent spots corresponding to the pisciform flecks and mottled parafoveal hypoautofluorescence, denser centrally, corresponding to the areas of RPE mottling and geographic atrophy (Figure 3 & 4).  Optical coherence tomography (OCT) scans of the right eye revealed significant loss of the outer retina and RPE in the parafoveal region (Figure 5).  OCT scans of the left macula exhibited extensive loss of the outer retina in the macula, extending nearly to the peripapillary region, associated with RPE hypertrophy and scarring subfoveally (Figure 6).

Figure 3: Fundus auto fluorescence of the right eye. Note the hyperautofluorescent spots corresponding to the flecks and mottled parafoveal hypoautofluorescence, denser centrally.

Figure 4: Fundus auto fluorescence of the left eye. Note the similar hyperautofluorescent spots seen in the right eye corresponding to the flecks and mottled parafoveal hypoautofluorescence, denser centrally.

Figure 5: Spectral Domain OCT scan of the right eye. Note the significant loss of the outer retina and RPE in the parafoveal region

Figure 6: Spectral Domain OCT scan of the left eye. Note the extensive loss of the outer retina in the macula, extending nearly to the peripapillary region, associated with RPE hyperplasia and scarring subfoveally.

What is your Diagnosis?

Differential Diagnosis

Pattern dystrophy with flecks (RDS/peripherin mutation), Age-related macular degeneration with peripheral drusen, Familial drusen (EFEMP1 mutation), Best’s disease and Autosomal recessive bestrophinopathy (BEST1 mutation), Sjögren-Larsson syndrome, Retinitis pigmentosa (Retinitis punctate albescens, Bothnia/Newfoundland dystrophy), Cystinosis, Familial benign flecked retina, Autosomal dominant Stargardt-like macular dystrophy, Stargardt’s disease.

 

Additional Case History

The patient underwent electrophysiologic testing including electro-oculogram, full-field electroretinogram (ERG), and multifocal ERG.  The electro-oculogram and full-field ERG testing results were within normal limits (Figure 7).  Multifocal ERG, however, revealed a decrease in waveform amplitudes of at least 3-4 standard deviations below normal within the central 5-10 degrees eccentric to fixation, with delayed timing in each eye (Figure 8).

Based on the clinical and electrophysiologic testing results, genetic testing was sent.  The patient was found to have multiple missense mutations in the ABCA4 gene, consistent with Stargardt's.  At final 10-year followup, the patient’s best-corrected visual acuity had declined to 20/200 in both eyes and an increased number of pisciform flecks were noted on posterior segment examination, but the patient was otherwise stable.

 

Figure 7: Full-field electroretinogram of both eyes were normal.

Figure 8: Multifocal electroretinograms of the right (A) and left (B) eyes revealed a significant decrease in waveform amplitudes within the central 5-10 degrees.

Discussion

Stargardt‘s disease was first described in 1909 by Karl Stargardt.1 It is the most common macular degenerative disease in patients under the age of 50, and is characterized by a progressive, bilateral macular atrophy associated with the subretinal deposition of lipofuscin-like material.2 Although its usually diagnosed before the age of 20, a later age of onset is associated with a more favorable visual prognosis.

The pathophysiology of Stargardt’s disease is related to a dysfunction in the processing of retinoids in the outer retina, resulting in accumulation of lipofuscin A2E within the retinal pigment epithelium. Ophthalmoscopic findings can vary from a normal fundus, especially in early disease, to the classic findings of light-colored pisciform flecks with RPE mottling and geographic atrophy centered around the macula.3,4 Fluorescein angiography (FA) reveals a dark, silent or masked choroid, consistent with blockage of the underlying choroidal fluorescence by lipofuscin accumulation within the RPE (Figure 9). FAF imaging now largely supercedes FA for the diagnosis of Stargardt’s due to its high sensitivity for early changes, ease of image acquisition, and lower side effect profile. Characteristic patterns of FAF involve areas of increased FAF in flecks scattered around the macula and areas of decreased FAF corresponding to RPE atrophy or loss. OCT provides cross-sectional views of progressive photoreceptor and RPE atrophy. New imaging techniques, such as adaptive optics scanning light ophthalmoscopy (AOSLO), allows for in vivo imaging of rods and cones and creates photoreceptor mosaics mapping areas of loss.4

 A recent report has shown that electrophysiologic testing, specifically full-field ERG, has important prognostic implications.5 Three functional groups have been characterized based on ERG: 1) abnormal multifocal or pattern ERG with normal scotopic and photopic full-field ERG, 2) abnormal photopic but normal scotopic full-field ERG characterizing generalized cone dysfunction, and 3) abnormal photopic and scotopic ERG. Groups 2 and 3 were found to have a more severe phenotype associated with loss of both central and peripheral vision, leading to complete blindness.

Stargardt’s disease is inherited in an autosomal recessive pattern and has been found to be caused by mutations in the ABCA4 gene on chromosome 1p13-p21.6 Currently, more than 900 pathologic mutations have been identified.4 The ABCA4 gene encodes for the photoreceptor-specific ATP-binding cassette transporter 4, which plays an indispensible role in the clearance of all-trans-retinal from the disk membranes.2 Loss of function of this transporter leads to the accumulation of toxic substances, including lipofuscin A2E, and the subsequent death of RPE cells and photoreceptors.

Current treatment regimens for inherited retinal degenerations such as Stargardt’s centers around supportive measures to maximize the patient’s vision, such as low vision rehabilitation, visual training, corrective lenses or magnification devices. Retrospective studies of the dietary habits of Stargardt’s patients have suggested that low vitamin A intake (<600 ug RAE/day) may slow visual decline by decreasing the rate of metabolism in RPE cells, and thereby arrest the accumulation of toxic metabolites.7 Novel therapies, including gene therapy, retinal prosthetics, optogenetics, and cellular therapy are currently under investigation.

Figure 9: Fluorescein angiogram of the left eye from a different patient with Stargardt’s disease demonstrating the classic dark choroid appearance.

Take Home Points

  • While a dark choroid on fluorescein angiography is classic and virtually pathognomonic, fundus autofluorescence testing has largely superceded FA in the diagnosis of Stargardt’s.
  • Full-field ERG testing divides Stargardt’s patients into three functional groups, which have important prognostic implications.
  • Stargardt’s disease is caused by a mutation in the ABCA4 gene on chromosome 1p13-p21, of which more than 900 pathologic mutations have been identified thus far.

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References

  1. Stargardt K. Über familiäre, progressive degeneration under makulagegend des auges. Albrecht von Graefes Arch Ophthalmol 1909;71:534–550.
  2. Sahel J-A, Marazova K, Audo I. Clinical characteristics and current therapies for inherited retinal degenerations. Cold Spring Harb Prospect Med 2015;5:a017111.
  3. Ryan S. Retina, 5th ed. 2013: 864-874.
  4. Tanna P, Strauss RW, Fujinami K, Michaelides M. Stargardt disease: clinical features, molecular genetics, animal models and therapeutic options. Br J Ophthalmol 2017;101:25-30.
  5. Lois N, Holder GE, Bunce C, Fitzke FW, Bird AC. Phenotypic subtypes of Stargardt macular dystrophyfundus flavimaculatus. Arch Ophthalmol 2001;119:359–369.
  6. Allikmets R, Singh N, Sun H, Shroyer NF, et al. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet 1997;15:236–246.
  7. Sofi F, Sodi A, Franco F, Murro V, et al. Dietary profile of patients with Stargardt’s disease and retinitis pigmentosa: is there a role for a nutritional approach? BMC Ophthalmol 2016;16:13.

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