Article

Hereditary Retinal Degenerations and Cystoid Macular Edema

Part 2 of a 3-part series on cystoid macular edema.

By JOON-BOM KIM, MD • MINA M. CHUNG, MD • AJAY E. KURIYAN, MD, MS

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Cystoid macular edema (CME) is a well-described feature of certain hereditary retinal degenerations, including retinitis pigmentosa (RP), juvenile X-linked retinoschisis (XLRS), enhanced S-cone syndrome (ESCS), choroideremia, and gyrate atrophy.1 It can affect the central VA of patients who may already have severely constricted peripheral visual fields. The pathogenesis of CME in hereditary retinal degenerations is poorly understood. Breakdown of the blood-retinal barrier, dysfunction of the retinal pigment epithelium (RPE) pumping mechanism, Müller cell dysfunction, disruption of the retinal architecture by defects in cell-to-cell adhesion, antiretinal antibodies, and vitreous traction are thought to contribute to CME in RP.2 Fluorescein angiography (FA) shows minimal or no leakage into these cystoid spaces, suggesting that vascular leakage does not play a role in this clinical setting.3 While there is no known therapy to halt the progression of photoreceptor degeneration, we review here the options for the treatment of CME in hereditary retinal degenerations.

Joon-Bom Kim, MD, is a vitreoretinal resident with the Flaum Eye Institute, University of Rochester, in New York. Mina M. Chung, MD, and Ajay E. Kuriyan, MD, MS, are vitreoretinal specialists with the Flaum Eye Institute. Dr. Kim reports no related disclosures. Dr. Chung reports consultancy to Santen, Inc., and Wave Life Sciences and research grant support from Lowy Medical Research Institute. Dr. Kuriyan reports consultancy to Allergan and Alimera Sciences. Reach Dr. Kuriyan at ajay.kuriyan@gmail.com.

RETINITIS PIGMENTOSA

Retinitis pigmentosa encompasses a complex group of hereditary retinal dystrophies characterized by the degeneration of rod-greater-than-cone photoreceptors. Early symptoms include nyctalopia and insidious progressive peripheral visual field loss that can culminate in central vision loss and complete blindness.4 Hallmark funduscopic features include attenuated retinal arterioles, RPE atrophy and hyperplasia with bone spicule pigmentation, and optic nerve pallor (Figure 1). Electroretinography (ERG) typically shows diminished responses under scotopic greater than photopic conditions, but results can range from near-normal to undetectable depending on disease severity. The prevalence of CME in RP patients has been reported to be between 20% and 50%, with more recent studies showing higher rates of CME found on optical coherence tomography (OCT) than previously reported with FA.5-8

Figure 1. Color fundus photograph of a 70-year-old man with end-stage retinitis pigmentosa showing attenuated retinal arterioles, RPE atrophy, hyperplasia with bone spicule pigmentation, and waxy optic nerve pallor.
COURTESY OF AJAY E. KURIYAN, MD.

JUVENILE X-LINKED RETINOSCHISIS

Juvenile X-linked retinoschisis is an early-onset retinal degeneration affecting males. Patients typically present around school age with bilateral mild to moderate central vision loss. Fundus examination shows a spoke-wheel pattern of macular schisis in the inner retinal layers in 98% to 100% of patients (Figure 2). Less than 50% of patients additionally develop peripheral retinoschisis, characterized by a sharply delineated separation of the inner retinal layer usually in the temporal peripheral retina, but it can extend to the macula. Spectral-domain OCT (SD-OCT) has identified that foveomacular schisis occurs due to splitting of the inner nuclear layer (INL) (Figure 2C), and extramacular schisis is present in the INL, outer nuclear layer, and ganglion cell layer.9 The characteristic ERG is “electronegative,” with the a-wave larger than the b-wave.10 Multifocal electroretinography (mfERG) demonstrates widespread central and peripheral cone-system dysfunction.11

Figure 2. Color fundus photograph of an 8-year-old boy with juvenile X-linked retinoschisis. Visual acuity was 20/40 in the right eye and 20/25 in the left eye (A). Red-free fundus photograph accentuates spoke-wheel pattern of macular schisis in both eyes (B). SD-OCT of foveomacular schisis shows splitting within the inner nuclear layer (C).
COURTESY OF MINA M. CHUNG, MD.

ENHANCED S-CONE SYNDROME

Enhanced S-cone syndrome, also called Goldmann-Favre syndrome, is an autosomal recessive vitreoretinal degeneration related to mutations in the NR2E3 gene, also called photoreceptor-specific nuclear receptor (PNR).12,13 Patients present with night blindness and visual field deficits. Fundus examination typically shows nummular pigmentary deposition at the level of the RPE along the vascular arcades (Figure 3),14,15 and in more severe cases, it may show fibrillar vitreous degeneration, chorioretinal atrophy, a sharply demarcated circumferential pigmentary retinal degeneration, macular and/or peripheral retinoschisis, presenile cataracts and hyperopia.13,16

Figure 3. Color fundus photograph of a 42-year-old woman with enhanced S-cone syndrome showing circumferential RPE pigmentary deposition along the vascular arcades.
COURTESY OF MINA M. CHUNG, MD.

Electroretinogram recordings show severe reduction in rod function and relatively enhanced function of short wavelength-sensitive cones. The prevalence of CME in ESCS is difficult to estimate due to the rarity of the condition; however, in a case series of 19 ESCS patients, 9 had foveal schisis-like changes, 4 of whom with foveal cysts on OCT.14

TREATMENT OF CME IN HEREDITARY RETINAL DEGENERATIONS

Carbonic Anhydrase Inhibitors

Carbonic anhydrase inhibitors (CAIs) act on membrane-bound carbonic anhydrase (CA) IV receptors on the apical and basolateral cell membrane of the RPE, and they decrease standing potential of RPE and acidify the subretinal space by increasing chloride ion transport. The resulting increase in the rate of subretinal fluid absorption across the RPE to the choroid improves CME.17 Several studies have shown improvement in RP-CME with oral and topical CAIs (Figure 4).18-24 In the largest retrospective series studying RP-CME treated with CAIs, among 81 RP patients (157 eyes) with CME, 40% of eyes treated with topical dorzolamide (Trusopt, Merck) and 28% of eyes treated with oral acetazolamide (Diamox, Duramed) showed objective improvement in CME on OCT.20 Rebound CME in RP patients has been reported after discontinuation of CAIs, but reintroduction of CAI restored treatment response in these patients.24

Figure 4. Spectral-domain OCT of a 16-year-old boy with retinitis pigmentosa with bilateral CME. Visual acuity was 20/100 in the right eye and 20/80 in the left eye (A). He was started on topical dorzolamide, and 1 year later, there was improvement in central macular thickness in both eyes (B). Visual acuity was 20/150 in the right eye and 20/80 in the left eye.
COURTESY OF MINA M. CHUNG, MD.

Carbonic anhydrase inhibitors have been used for treatment of CME in XLRS patients with positive response in several studies.25-27 In the largest retrospective study of the therapeutic effect of topical CAIs on CME in XLRS, in 29 eyes (15 patients) with XLRS treated with topical dorzolamide, 20 (69%) of 29 eyes had anatomic improvement, and 16 eyes (55%) showed improvement in VA.27

Cystoid macular edema in ESCS has shown mixed response to CAIs. Iannaccone et al reported a case of CME in an adult ESCS patient treated with oral acetazolamide, whose VA improved from 20/200 to 20/20.28 However, Busic et al reported a case of a 7-year old patient with ESCS with CME treated with topical dorzolamide with no reduction in thickness or improvement in BCVA.29 These reports suggest either different mechanisms of CME in adults and children with ESCS or, more likely, variable response to CAIs in ESCS.

Anti-VEGF

Vascular endothelial growth factor (VEGF) is an important promoter of vascular permeability and an inhibitor of endothelial barrier function, which can cause CME. Using this rationale, anti-VEGF agents have been tried for the treatment for CME in RP patients with varying results.30-34 Several small case series studying the effect of intravitreal bevacizumab (Avastin; Genentech), ranibizumab (Lucentis; Genentech), and aflibercept (Eylea; Regeneron) have demonstrated improvement in macular edema and/or VA.30-33 However, another study of 2 eyes in 2 patients treated with a single injection of intravitreal bevacizumab demonstrated no anatomic or functional improvement.34

Steroids

Inflammatory cell proliferation and migration can contribute to blood-retina barrier dysfunction, resulting in CME. Various intravitreal corticosteroids have been studied for the treatment of CME in RP patients who are believed to have an impaired blood-retina barrier due to dysfunction of RPE pumping mechanism. A prospective, nonrandomized trial comparing 20 eyes of 20 RP patients who received intravitreal injection of triamcinolone acetonide and 20 eyes of 20 patients who declined treatment found improvement in central macular thickness in the treatment group but no significant change in vision.35 A multicenter, retrospective case series of 45 eyes from 34 patients with RP and CME treated with intravitreal dexamethasone implant (Ozurdex; Allergan) found improvement in VA in 27 (60%) of 45 eyes after 4 months.36 Fourteen eyes required multiple injections, and seven patients developed visually significant cataracts.36

SUMMARY

Cystoid macular edema can cause significant visual impairment. Treatment interventions such as CAIs, anti-VEGF, and corticosteroids have been used with varying success, and no standard of care has been established. Further research to better understand retinal degenerations and the pathogenesis and mechanism of CME will aid in the development of targeted, effective treatment. RP

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