Non-damaging Retinal Laser Therapy for Central Serous ChorioRetinopathy

Principal Investigator: Peter Karth
Scientific Advisor: Daniel Palanker
Stanford Ophthalmic Reading Center (STARC): Theodore Leng, Director
Byers Eye Institute at Stanford: Darius Moshfeghi, Steven Sanislo
Federal University de Rio Grande de Sol (Porto Alegre, Brazil): Daniel Lavinsky
Kangwon National University, Korea: Seungjun Lee

            Central serous chorioretinopathy (CSCR) is the fourth most common non-surgical retinopathy behind age-related macular degeneration (AMD), diabetic retinopathy, and branch retinal vein occlusion [1]. The peak prevalence of this disease is at 45 years of age [2], and risk factors include corticosteroids, uncontrolled hypertension, sympathomimetic agents, type A personality, and psychological stress [3,4].
            CSCR is characterized by serous detachments of the neurosensory retina and/or retinal pigmented epithelium (RPE), associated with leakage on fluorescein angiography [1].  CSCR can either spontaneously resolve, with reabsorption of subretinal fluid and near total restoration of visual acuity within three months of the symptoms onset, or progress to chronic CSCR with persistent sub-retinal fluid, leading to permanent visual disturbance [1].
           The pathophysiology of CSCR has been attributed to hyper-permeable choroidal vessels, impaired choroidal vascular autoregulation, and dysfunction of the RPE barrier and pumping, causing fluid leakage into the sub-retinal space, leading to detachment of the neurosensory retina or RPE [5].  There is still no FDA approved medication nor treatment widely considered the standard of care. Treatment options for CSCR include modification of risk factors, such as stopping all exogenous steroids, photodynamic therapy (PDT), various forms of retinal laser therapy, and a host of oral medications with limited clinical evidence and possible side effects. Anti-vascular endothelial growth factor (anti-VEGF) therapy is generally thought not to be effective, unless a concomitant choroidal neovascular membrane (CNVM) is present.
          Photodynamic therapy (PDT) with verteporfin reduces choroidal perfusion, narrows choroidal vasculature and decreases choroidal hyperpermeability, a key factor in CSCR6.  PDT at full dose [7], half dose [8], and half fluence [9] has been shown to be efficient in cases of acute, chronic, and recurrent CSCR, and may be applied within the parafoveal zone. While the risks of PDT decrease upon decreasing the dose of verteporfin or laser fluence, possible side effects still include choroidal ischemia [10], neuroretinal thinning [11], and rarely RPE tears [12] when large pigment epithelial detachments are treated. Injection of verteporfin makes PDT an invasive intervention with potential systemic complications such as temporary vision loss, tissue damage from dye extravasation, or skin damage from excessive exposure to sunlight.
Retinal laser photocoagulation was the historic treatment of choice for CSCR [13], and remains a viable treatment option in cases of focal angiographic leakage outside of the parafoveal zone [14,15]. While photocoagulation accelerates the resolution of fluid, it permanently damages retinal tissue at the site of laser application and precludes retreatments in case of recurrence or insufficient response. 
         To reduce collateral retinal damage by photocoagulation, “sub-threshold” laser therapy has been developed, which includes the more specific classification of sub-visible and non-damaging retinal laser therapy (NRT). Two primary types of the clinically available non-damaging lasers are: (1) micropulse lasers (810 nm or 577nm wavelength) which deliver 100-300ms bursts of pulses of 0.1-0.3ms in duration, with the average power set below detectable tissue damage, and (2) PASCAL lasers with Endpoint Management algorithm to reduce pulse energy into the window of cellular response [16]. Selective destruction of RPE using microsecond or nanosecond pulses (SRT) results in RPE proliferation and migration, and it was found efficient in treatment of CSCR, however it is not truly non-damaging [17]. Resolution of subretinal fluid in chronic CSCR after NRT
         Retinal response to non-damaging retinal laser therapy (transient hyperthermia below damage threshold) includes the upregulation of heat shock proteins expression which initiates cellular repair [18] and alters cytokine production. NRT avoids the excessive heating and associated necrosis while providing similar clinical benefits as conventional laser coagulation in diabetic macular edema [19] and CSCR [20]. However, reliable titration is required for each patient to ensure the adequate amount of laser energy in the treatment. If laser settings are too low, the treatment will be sub-therapeutic, whereas if the settings are too high, there is a danger of tissue damage, especially ominous when treating near the fovea. These issues are reflected in variability of results in micropulse laser studies and have prevented broad acceptance of this technology in clinical practice.
        We have developed the titration protocol, called EndPoint Management, for PASCAL laser, which ensures that pulse energy is within the range of clinical response, but does not exceed the tissue damage threshold [16], in every patient. Initial clinical results with this protocol demonstrated its safety and efficacy in treatment of chronic CSCR [21], as illustrated in an examplary figure above. We are testing this treatment protocol in patients with CSCR in a randomized controlled trial to improve visual acuity, resolve subretinal fluid, and prevent permanent visual dysfunction.


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16           Lavinsky, D. et al. Retina 34, 87-97 (2014).
17           Framme, C. et al. Ophthalmologica 234, 177-188 (2015).
18           Sramek, C. et al. Invest Ophthalmol Vis Sci 52, 1780-1787 (2011).
19           Sivaprasad, S., et al. Clin Experiment Ophthalmol 35, 640-644 (2007).
20           Lavinsky, D. et al. IOVS 52, 4314-4323 (2011).
21           Lavinsky, D. & Palanker, D. Retina 35, 213-222 (2015).

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