Case of the Month

Edited by Robert N. Johnson, MD

Case #104, Feb, 2018

Presented by Joseph Alsberge, MD

A 33-year-old woman with blurry vision in both eyes since age 7

Figures 1 and 2: Fundus photo of the right eye. Note the discrete area of atrophy in the right eye associated with some subretinal fibrosis and the presence of yellowish subretinal material inferotemporal to the fovea. The peripheral retina is most unremarkable.

Figures 3 and 4: Fundus photographs of the left eye. Note atrophic macular lesion, similar to what is present in the right eye. A few chorioretinal scars are seen inferiorly as well as a circumferential band of pigmentation temporally

Case History

A 33-year-old woman presented for evaluation of constant blurry central vision in both eyes over the last 26 years.

On examination, visual acuity was 20/40 in the right eye and 20/80 in the left eye. The anterior segment examination was normal in both eyes.

Examination of the right macula revealed a round area of chorioretinal atrophy with central fibrous tissue centered on the fovea, surrounding pigment, and an adjacent, ovoid, yellow, subretinal lesion with associated subretinal fluid located temporally (Figure 1). The retinal periphery in the right eye was unremarkable aside from a small, faint, round area of focal chorioretinal atrophy located inferonasally (Figure 2). Examination of the left macula revealed a large round area of excavated chorioretinal atrophy located at the fovea with associated pigment and a ring of subretinal fibrous tissue (Figure 3). The left retinal periphery showed multiple round areas of pigmented chorioretinal atrophy located temporally, arranged in a circumferential pattern (Figure 4).

Wide-field fundus autofluorescence (WF-FAF) of the right eye showed a central area of hypoautofluorescence in the macula and an adjacent area of hyperautofluorescence corresponding to the yellow subretinal lesion seen on clinical exam (Figure 5). WF-FAF of the left eye showed a large central area of hypoautofluorescence in the macula and multiple focal areas of hypoautofluorescence in the temporal periphery (Figure 6).

Fluorescein angiography (FA) of the right eye revealed central blocked fluorescence from fibrous tissue with a surrounding halo of window-defect hyperfluorescence, as well as an area of blocked fluorescence temporal to the fovea corresponding to the yellow subretinal lesion see clinically (Figure 7). FA of the left eye showed central visibility of the larger choroidal vessels due overlying RPE and choriocapillaris atrophy, and a surrounding ring of hypofluorescence due to blockage from fibrous tissue and pigment (Figure 8). There was no late leakage consistent with choroidal neovascularization in either eye.

Spectral domain optical coherence tomography revealed chorioretinal atrophy, a dense central area of subretinal hyper-reflective material, and a pocket of temporal subretinal fluid in the right eye; and a central area of chorioretinal excavation and atrophy with a surrounding annulus of subretinal hyper-reflective material in the left eye (Figures 9 and 10, respectively).

Figure 5: Wide-field fundus autofluorescence of the right eye. Note the reduced autofluorescence in the central macula corresponding to the atrophic lesion seen on the color photographs. Some increased autofluorescence is noted at the edges of the lesion.

Figure 6: Wide-field fundus autofluorescence of the left eye. Note the reduced autofluorescence in the central macula corresponding to the atrophic lesion. The peripheral lesions are mostly hypoautofluorescent.

Figure 7:Fluorescein angiogram of the right eye: Note the central blocked fluorescence from fibrous tissue with a surrounding halo of window-defect hyperfluorescence, as well as an area of blocked fluorescence temporal to the fovea corresponding to the yellow subretinal lesion seen clinically.

Figure 8: Fluorescein angiogram of the left eye: Note the central visibility of the larger choroidal vessels due overlying RPE and choriocapillaris atrophy, and a surrounding ring of hypofluorescence due to blocking from fibrous tissue and pigment.

Figure 9: SD-OCT of the right eye. Note the area of subretinal fluid temporal to fovea and the dense hyperrefledtive changes centrally consistent with the fibrotic and RPE hyperplastic changes seen on the fundus photo.

Figure 10: SD-OCT of the left eye. Note the central area of atrophy with a ring of subretinal fibrosis.

What is your Diagnosis?

Differential Diagnosis

Best disease, North Carolina Macular Dystrophy, Stargart disease, central areolar retinochoroidal dystrophy, congenital infection (e.g., toxoplasmosis).

 

Additional History and Diagnosis

The patient’s family history included macular dystrophy in her mother and grandmother, diagnosed elsewhere. An electrooculogram was performed and found to be normal with an Arden ratio of 4.6 in the right eye and 4.4 in the left eye. The patient then underwent genetic testing and was found to be heterozygous for a missense mutation (Arg218-to-Leu) in the BEST1 gene, confirming the diagnosis of Best disease. None of the genetic variations that have been associated with North Carolina Macular Dystrophy were present in the patient.

 

Discussion

Best disease is an autosomal dominant macular dystrophy that was first described by Friedrich Best in 1905, and is classically characterized by bilateral vitelliform (i.e., egg-yolk-like) central macular lesions.1 It is caused by mutations in the BEST1 gene, and is one of the most common macular dystrophies.1

The clinical features of Best disease can be varied, but the characteristic finding is a solitary, round or ovoid, yellow, subretinal lesion that is bilateral and centered on the fovea.2 Over time, the subretinal yellow material may gravitate inferiorly to develop a “pseudohypopyon” appearance, and then later break up to produce a so-called “scrambled-egg” lesion (sometimes termed the “vitelliruptive” stage). In later stages of the disease, patients can develop central chorioretinal atrophy and plaques of subretinal fibrous tissue, as in the case presented here. These patients are at risk of developing choroidal neovascularization.2

The electro-oculogram (EOG) in Best disease is typically markedly abnormal, with an Arden ratio (ratio of the light peak to dark trough) of less than 1.5, even prior to the development of the vitelliform lesions, reflecting widespread retinal pigment epithelial (RPE) disturbance.1 However, one series found a normal EOG in 20% of patients with the Best disease phenotype and BEST1 mutations, as was the case for the patient reported here.3 Full-field electroretinography is typically normal in Best disease.

The BEST1 gene is located on the long arm of chromosome 11, and encodes the protein product Bestrophin, which is located on the basolateral membrane of the RPE.4 Bestrophin regulates ionic flow across the RPE and may play a role in the normal adhesion of the RPE and neurosensory retina.1 Over 100 mutations in BEST1, typically missense variants, have been associated with the Best disease phenotype.1 Other phenotypes that have been associated with BEST1 mutations include autosomal dominant vitreoretinochoroidopathy and autosomal recessive bestrophinopathy.2

Patients with Best disease should be monitored for the development of choroidal neovascularization, which can be treated with intravitreal anti-VEGF agents.5

Take Home Points

  • Best disease is an autosomal dominant macular dystrophy caused by mutations in the BEST1 gene, and is characterized by bilateral egg-yolk-like central macular lesions, which in later stages may become atrophic.
  • A normal EOG does not exclude Best disease.
  • Choroidal neovascularization may develop, which can be treated with intravitreal anti-VEGF agents.

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References

  1. Sohn EH, Mullins RF, Stone EM. Macular Dystrophies. In: Ryan SJ, Schachat AP, Sadda SR, eds. Retina. Fifth ed. Elsevier:852-906.
  2. Agarwal, AA. Heredodystrophic Disorders Affecting the Pigment Epithelium and Retina. In: Agarwal, AA. Gass’ Atlas of Macular Diseases. Fifth ed. Elsevier:240-436.
  3. Meunier I, Sénéchal A, Dhaenens C-M, et al. Systematic Screening of BEST1 and PRPH2 in Juvenile and Adult Vitelliform Macular Dystrophies: A Rationale for Molecular Analysis. Ophthalmology 2011;118:1130–1136.
  4. Marmorstein AD, Marmorstein LY, Rayborn M, et al. Bestrophin, the product of the Best vitelliform macular dystrophy gene (VMD2), localizes to the basolateral plasma membrane of the retinal pigment epithelium. Proc Natl Acad Sci USA 2000;97:12758-12763.
  5. Querques G, Bocco MC, Soubrane G, et al. Intravitreal ranibizumab (Lucentis) for choroidal neovascularization associated with vitelliform macular dystrophy. Acta Ophthalmol 2008;86:694-695.