Study Background

Central serous chorioretinopathy (CSC), characterized by an idiopathic serous neurosensory retinal detachment, affects the central vision of working-age adults.(Liu et al., 2016) Choroidal hyperpermeability demonstrable on Indocyanine green (ICG) angiography and retinal pigment epithelial (RPE) dysfunction has been suggested as the possible mechanisms.(Gass, 1967; Iida et al., 1999; Yannuzzi, 2010) Unrecognized corticosteroid use has been implicated in the pathogenesis of CSC.(Ge et al., 2020) Altered corticosteroid metabolism linked to Cathedrin 5 gene is believed to be associated.(Schubert et al., 2014)

While the benign self-limiting nature of acute CSC is known, treatment challenges remain for chronic and recurrent disease. The stagnated fluid at the macula, both the cause and effect of permanent RPE decompensation unless treated aggressively, cause irreversible photoreceptor damage and vision loss.(Haga et al., 2017; Iida et al., 2003; Piccolino et al., 2005)

The traditional therapeutic strategies include thermal and photochemical lasers (Photodynamic therapy – PDT).(Lim et al., 2014; Robertson & Ilstrup, 1983)  Thermal lasers targeting extrafoveal angiographic leaks are most efficacious when the leaks are focal but may be ineffective in widespread RPE involvement represented by poorly defined angiographic leaks. Symptomatic scotoma and choroidal neovascularization (CNV) are undesirable complications of multiple laser sessions in chronic disease.(Ross et al., 2011) Yellow sub-threshold micropulse lasers are the other alternative options, but the need for confluent treatment spots in the absence of visible burns continues to be a challenge.(van Dijk et al., 2018) Large trials in recent years have shown encouraging results with yellow micropulse laser.(Scholz et al., 2016) PDT is safer for wide area treatment of diffuse RPE decompensation.(Yannuzzi et al., 2003) The high price, limited access to the photosensitizing dye, time taken for resolution, light exposure restrictions after the procedure and post-laser complications like choroidal ischemia, transient worsening of CSC and choroidal neovascularization has curbed the acceptance of this treatment option.(Colucciello, 2006; Lee et al., 2009; Ma et al., 2014)Eplerenone, a mineralocorticoid receptor antagonist widely used in treating chronic CSC has run into deliberations on its usefulness – a large randomized controlled trial did not find its use convincingly superior to placebo.(Lotery et al., 2020)

As systemic corticosteroids may precipitate or aggravate the disease in susceptible individuals, avoidance or discontinuation of corticosteroids in all forms is recommended.(Ge et al., 2020) This incriminatory role of corticosteroids in CSC causation had kept its intravitreal therapeutic value unexplored until the efficacy and safety of DEX implant as a novel treatment approach in complex CSC was demonstrated in our proof-of-concept study (CTRI/2022/01/039632). A favourable outcome in complex CSC in the study indirectly implicated inflammation (or retinal para inflammation) in chronic CSC pathogenesis. Evidence of inflammatory cytokines such as IL1, IL6, IL 10, and TNFa, in the aqueous humour of CSC eyes, and the known action of DEX in their downregulation support the hypothesis.(Rodríguez Villanueva et al., 2017; Shin & Lim, 2011). Demonstration of inflammatory cytokines in vitreous in cCSC may validate the use of intravitreal corticosteroids  in cCSC.  (Karska-Basta et al., 2021; Shin & Lim, 2011)

Rationale of study design:

The primary comparative endpoint at week 8 was determined based on the expected treatment benefit with DEX implant shown in our proof-of-concept study. The results in this study have shown that patients with cCSC treated with intravitreal Ozurdex injection of 0.7 mg dexamethasone had a rapid resolution of IRF and SRF in 66% of eyes by 6 weeks. The results will be compared with YMPL, the alternate care aimed at treating the choroid in chronic CSC in the absence of PDT.

Rationale of dose/ regimen, duration of treatment:

DEX is readily available in 0.7mg dose. The standard laser parameters for YMPL will be followed. An extramacular test burn with a 500micron spot will be used to titrate the laser. Using a duty cycle of 5% and frequency of 500Hz, confluent ablations to the regions of choroidal vascular hyperpermeability on ICGA will be done, limiting the treatment to 2 disc areas from the center of macula. The fovea will be spared – 500 microns from center of fovea. Both the treatment modalities are expected to show their peak result by 8 weeks. Like acute CSC, cCSC also runs a waxing and waning course. In this milieu, the treatment efficacy of a particular intervention is difficult to judge. A placebo arm is expected to throw light on the natural history of the disease albeit over a short span of 2 months.

Rationale for choice of comparator:

In view of the non-availability of the photosensitizing dye for PDT, YMPL is the second best preferred method to treat chronic CSC.

Reference:

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