Ophthalmic Surgery, Lasers and Imaging Retina

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Case Report 

Diffuse Retinal Pigment Epithelial Disease in an Adult with Cystic Fibrosis

Jordana F. Goren, MD; Sumit P. Shah, MD; Grant P. Janzen, MD; Nicole E. Gross, MD; Jay S. Duker, MD

Abstract

An adult with cystic fibrosis presented for decreased vision in the right eye of several months’ duration. Biomicroscopy and fluorescein angiography demonstrated bilateral large subretinal drusenoid deposits concentrated temporal to the fovea, as well as a small subretinal hemorrhage associated with focal leakage of fluid within the macula in the right eye. Optical coherence tomography demonstrated subretinal fluid consistent with choroidal neovascular membrane in the right eye with the absence of fluid in the left eye. The retinal manifestations of bilateral diffuse drusen associated with choroidal neovascular membrane may be consistent with autosomal dominant drusen, age-related macular degeneration, and type II glomerulonephritis, or alternatively may be a unique finding associated with cystic fibrosis. To the authors’ knowledge, these findings have not previously been described in association with cystic fibrosis.

Abstract

An adult with cystic fibrosis presented for decreased vision in the right eye of several months’ duration. Biomicroscopy and fluorescein angiography demonstrated bilateral large subretinal drusenoid deposits concentrated temporal to the fovea, as well as a small subretinal hemorrhage associated with focal leakage of fluid within the macula in the right eye. Optical coherence tomography demonstrated subretinal fluid consistent with choroidal neovascular membrane in the right eye with the absence of fluid in the left eye. The retinal manifestations of bilateral diffuse drusen associated with choroidal neovascular membrane may be consistent with autosomal dominant drusen, age-related macular degeneration, and type II glomerulonephritis, or alternatively may be a unique finding associated with cystic fibrosis. To the authors’ knowledge, these findings have not previously been described in association with cystic fibrosis.

Diffuse Retinal Pigment Epithelial Disease in an Adult with Cystic Fibrosis

From Tufts Medical Center (JFG, SPS, GPJ, JSD), Department of Ophthalmology, Boston, Massachusetts; and Manhattan Eye and Ear Infirmary (NEG), Department of Ophthalmology, New York, New York.

Dr. Duker is a consultant for Alcon, Genentech, and Ophthotech, is a scientific advisor for Paloma Pharmaceuticals, and receives research support from Opti-Vue and Carl Zeiss Meditec. The remaining authors have no financial or proprietary interest in the materials presented herein.

Address correspondence to Jordana F. Goren, MD, Tufts Medical Center, Department of Ophthalmology, 800 Washington Street, Box 450, Boston, MA 02111. E-mail: jgoren@tuftsmedicalcenter.org

Received: January 11, 2011
Accepted: April 26, 2011
Posted Online: June 09, 2011

Introduction

Cystic fibrosis is a disease caused by a mutation in the cystic fibrosis transmembrane receptor (CFTR). The effects of cystic fibrosis on the airway and gastrointestinal system have been extensively studied; however, reports on the ophthalmic manifestations of the disease are rare. We report a case of an adult with cystic fibrosis and large diffuse subretinal drusenoid deposits associated with choroidal neovascular membrane initially diagnosed at age 31 years.

Case Report

A 40-year-old woman presented with decreased vision in the right eye of several months’ duration. Her medical history was noteworthy for cystic fibrosis diagnosed in childhood without additional complications such as diabetes mellitus or renal failure. Her medications included levofloxacin, albuterol, zolpidem, dornase alpha, fluticasone, bupropion, and alprazolam. Her ophthalmic history was significant for a bilateral macular drusen diagnosed initially at age 31 years and a choroidal neovascular membrane diagnosed several months prior to examination, for which she had been offered a bevacizumab injection but declined pending a second opinion.

Visual acuity with correction was 20/50 in the right eye and 20/30 in the left eye. Anterior segment examination was unremarkable. Dilated funduscopic examination revealed bilateral diffuse medium to large subretinal drusenoid deposits concentrated temporal to the fovea with a small subretinal hemorrhage within the macula of the right eye (Fig. 1A). Optical coherence tomography demonstrated disruption of the retinal pigment epithelium (RPE) with intraretinal fluid in the right eye (Fig. 1B). Fluorescein angiography demonstrated early blockage, with late focal leakage consistent with a choroidal neovascular membrane (Figs. 1C and 1D). Color photographs, optical coherence tomography, and fluorescein angiography of the left eye were similar with absence of choroidal neovascular membrane and subretinal fluid (Fig. 2).

(A) Color Fundus Photograph Demonstrating Diffuse Medium to Large Confluent Subretinal Drusen Deposits Associated with Small Subretinal Hemorrhage and Choroidal Neovascular Membrane. (B) High-Resolution Optical Coherence Tomography Demonstrating Disruption of the Retinal Pigment Epithelium with Subretinal Fluid. (C and D) Fluorescein Angiography Demonstrating Leakage Associated with Choroidal Neovascular Membrane.

Figure 1. (A) Color Fundus Photograph Demonstrating Diffuse Medium to Large Confluent Subretinal Drusen Deposits Associated with Small Subretinal Hemorrhage and Choroidal Neovascular Membrane. (B) High-Resolution Optical Coherence Tomography Demonstrating Disruption of the Retinal Pigment Epithelium with Subretinal Fluid. (C and D) Fluorescein Angiography Demonstrating Leakage Associated with Choroidal Neovascular Membrane.

(A) Color Fundus Photograph Demonstrating Diffuse Medium to Large, Confluent Subretinal Drusen Deposits. (B) Fluorescein Angiography Demonstrating Diffuse Retinal Pigment Epithelial Mottling Without Leakage. (C) High-Resolution Optical Coherence Tomography Demonstrating Disruption of the Retinal Pigment Epithelial with Drusen, Without Associated Subretinal Fluid.

Figure 2. (A) Color Fundus Photograph Demonstrating Diffuse Medium to Large, Confluent Subretinal Drusen Deposits. (B) Fluorescein Angiography Demonstrating Diffuse Retinal Pigment Epithelial Mottling Without Leakage. (C) High-Resolution Optical Coherence Tomography Demonstrating Disruption of the Retinal Pigment Epithelial with Drusen, Without Associated Subretinal Fluid.

The patient was treated with intravitreal bevacizumab in the right eye. Over the next 2 years, she developed choroidal neovascular membrane in the left eye and was also treated with intravitreal injections of anti-vascular endothelial growth agents. Most recent visual acuity was 20/20 in the right eye and 20/25 in the left eye with absence of subretinal fluid.

Discussion

The retinal manifestations in this patient are consistent with dominant drusen, age-related macular degeneration, or drusen associated with type II membranoproliferative glomerulonephritis.1 However, the patient’s young age at initial observation (noted at age 31 years by the referring ophthalmologist) makes age-related macular degeneration unlikely, and normal renal function without a history of glomerulonephritis or renal transplant makes drusen associated with type II glomerulonephritis extremely unlikely. Dominant drusen is a rare autosomal dominant disorder with variable expression and age-dependent penetrance. The drusen in this disorder are typically diffuse, present in the third or fourth decade of life, and extend peripherally to involve the macula and retina nasal to the optic disc.2 This case may be consistent with dominant drusen, but the lack of a positive family history and distinctive pattern on funduscopy point away from this diagnosis and suggest the possibility that this may be a unique finding associated with cystic fibrosis.

Cystic fibrosis is a disease resulting from a mutation in the CFTR. The CFTR is one of a growing list of chloride channels that is expressed in many fluid-transporting epithelial tissues, including the airway, pancreas, and intestine.3 CFTR is a twelve transmembrane domain protein, which recently has been localized to the cornea, retina, and ciliary body.4,5 Patients with cystic fibrosis are well known to have complications including poor ciliary motility with increased risk of lung and upper airway infections, as well as pancreatic insufficiency and malabsorption.

The RPE is a monolayer of cells that transport metabolites, ions, and fluids between the neural retina and the choroid. The photoreceptor outer segments and the apical membrane of the RPE are separated by a potential subretinal space, and it is the movement of ions that maintains the volume and chemical composition of this space. Chloride absorption across human RPE is mediated by entry across the apical membrane via a Na+-K+-2Cl-co-transporter and passive exit through chloride channels in the basolateral membrane.4,6 In the RPE, the CFTR functions as a cyclic AMP activated chloride channel, presumably at the basolateral membrane. CFTR has been proposed to enhance RPE fluid transport indirectly by ATP release and autocrine signaling and directly by mediating the fast oscillation component of the electrooculogram.7,8

One hypothesis for the findings in this patient is that a mutation in the CFTR could alter the chemical composition and volume of the subretinal space and result in failure of the RPE to function properly. This metabolic imbalance might then lead to the accumulation of drusen-like deposits with disruption of the RPE/Bruch’s membrane complex, and the subsequent formation of a choroidal neovascular membrane. Now that there are genetic tests available to test for autosomal dominant drusen, it would be prudent to send this patient’s blood for testing if she returns for follow-up to rule out dominant drusen as a cause of her disease. Regardless, investigation into the ophthalmic manifestations of cystic fibrosis should be further explored.

References

  1. D’souza Y, Short CD, McLeod D, Bonshek RE. Long-term follow-up of drusen-like lesions in patients with type II mesangiocapillary glomerulonephritis. Br J Ophthalmol. 2008;92:950–953. doi:10.1136/bjo.2007.130138 [CrossRef]
  2. Deutman AF, Hansen LMAA. Dominantly inherited drusen of Bruch’s membrane. Br J Ophthalmol. 1970;54:373–382. doi:10.1136/bjo.54.6.373 [CrossRef]
  3. Pilewski JM, Frizzell RA. Role of CFTR in airway disease. Physiol Rev. 1999;79(1 suppl):S215–S255.
  4. Levin M, Verkman AS. Aquaporins and CFTR in ocular epithelial fluid transport. J Membrane Biol. 2006;210:105–115. doi:10.1007/s00232-005-0849-1 [CrossRef]
  5. Sheppard DM, Welsh MJ. Structure and function of the CFTR chloride channel. Physiol Rev. 1999;79(1 suppl):S23–S45.
  6. Kennedy BG. Na(+)-K(4)-Cl-cotransport in cultured cells derived from human retinal pigment epithelium. Am J Physiol. 1990;259:29–34.
  7. Reigada D, Mitchell CH. Release of ATP from retinal pigment epithelial cells involves both CFTR and vesicular transport. Am J Physiol. 2005;288:C132–C140.
  8. Blaug S, Quinn R, Quong J, Jalickee S, Miller SS. Retinal pigment epithelial function: a role for CFTR?Doc Ophthalmol. 2003;106:43–50. doi:10.1023/A:1022514031645 [CrossRef]
Authors

From Tufts Medical Center (JFG, SPS, GPJ, JSD), Department of Ophthalmology, Boston, Massachusetts; and Manhattan Eye and Ear Infirmary (NEG), Department of Ophthalmology, New York, New York.

Dr. Duker is a consultant for Alcon, Genentech, and Ophthotech, is a scientific advisor for Paloma Pharmaceuticals, and receives research support from Opti-Vue and Carl Zeiss Meditec. The remaining authors have no financial or proprietary interest in the materials presented herein.

Address correspondence to Jordana F. Goren, MD, Tufts Medical Center, Department of Ophthalmology, 800 Washington Street, Box 450, Boston, MA 02111. E-mail: jgoren@tuftsmedicalcenter.org

10.3928/15428877-20110602-04

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