Subthreshold Micropulse Laser Photocoagulation in the Management of Central Serous Chorioretinopathy
Central serous chorioretinopathy (CSCR) is a condition characterized by a serous neurosensory detachment, with or without retinal pigment epithelial (RPE) detachment, and is typically associated with one or more leakage points in the choriocapillaris that lead to fluid accumulation in the subretinal space [1, 2]. It is primarily seen in young healthy males in the fourth or fifth decades of life, but can also affect elderly patients. Although there is no clear racial predilection, it occurs more frequently in Caucasians, Asians and Hispanics. CSCR classically presents unilaterally and is characterized by blurred vision; other symptoms include metamorphopsia, relative central scotoma, micropsia, mild dyschromatopsia, and reduced contrast sensitivity [2, 3].A diagnosis of CSCR is made utilizing a combination of clinical history, ophthalmoscopic examination, enhanced-depth imaging optical coherence tomography (EDI-OCT), fluorescein angiography (FA), and indocyanine green angiography (ICG) . Biomicroscopic examination typically reveals the presence of serous detachment of the neurosensory retina in the posterior pole. EDI-OCT may assist in confirming the location and quantity of subretinal fluid as well as choroidal thickening. FA often shows a pinpoint leak at the level of the RPE, although multiple leaks can be observed, especially in atypical or recurrent cases .
While the choroid, RPE, and hormonal factors presumptively all play a role in the pathogenesis of CSCR, its etiology remains unknown. One recent publication postulates that CSCR results from choroidal vascular hyperpermeability related to stasis, ischemia, inflammation, or a combination of all three factors [2, 4]. Corticosteroids also alter the regulation of epithelial water and ion transport, which may impair the barrier function of the RPE [2, 5].
Central serous chorioretinopathy can be classified into acute or chronic forms. Acute CSCR often manifests as a single neurosensory retinal detachment lasting less than six months. Patients generally have a good prognosis with minimal visual sequelae . Chronic CSCR is often characterized by multiple foci of neurosensory detachments and leakage points on FA . Chronic CSCR patients have a poorer visual prognosis and often have persistent or recurrent disease leading to RPE atrophy, which contributes to inefficient resorption of subretinal fluid [2, 4]. One third to one half of all CSCR patients will experience a recurrence of the condition in their lifetime, and up to 5% of patients will suffer from severe vision impairment .
As 90% of CSCR cases resolve spontaneously within 2 to 3 months, treatment is usually initiated only after three months without resolution . Given the association between corticosteroids and CSCR, physicians should counsel all patients to eliminate or reduce stress and corticosteroid-containing medications [6, 8]. For patients with persistent disease, a variety of treatments has been studied; these are discussed below, followed by a review of an emerging treatment modality, subthreshold
diode micropulse (SDM) therapy.
Focal laser photocoagulation
Focal laser photocoagulation occludes vessels at the site of exudation and allows RPE cells to pump fluid back into the choriocapillaris . In a prospective, randomized trial of 67 patients with CSCR, average time to recovery-defined by retinal flattening and absence of leakage on FA-was only 6 weeks compared to a 16-week recovery time in the control group . Laser photocoagulation can lead to scotomas and choroidal neovascularization (CNV) formation ; precise targeting of the laser beam can also prove challenging. The NAVILAS focal photocoagulation system (NAVILAS; OD-OS GmbH, Teltow, Germany) aims to minimize the latter by utilizing a retinal by utilizing a retinal eye-tracking laser delivery system with integrated digital color fundus photographs, red-free and infrared imaging, and fluorescein angiography that can be visualized in real-time. It was found to be effective in treating diabetic macular edema in a small series where patients experienced improved visual acuity and decreased central foveal thickness . Chhablani, et al. evaluated the use of the NAVILAS system in CSCR patients in a prospective study found that FA-guided treatment to leakage points resulted in complete resolution of subretinal fluid in 15 out of 16 eyes in the study, although a change in visual acuity was not observed .
Indocyanine green angiography-guided photodynamic therapy
Indocyanine green angiography (ICG)-guided photodynamic therapy (PDT) induces temporary hypoperfusion of choroidal vessels . In a prospective case series of 26 refractory CSCR patients, patients treated with PDT were observed to have a more rapid resolution of CSCR compared to their counterparts treated with laser photocoagulation, but no visual acuity difference was seen between the two groups . Some believe that complications of PDT—which include RPE atrophy, choroidal ischemia, and CNV—may be minimized by using halffluence PDT and half-dose verteporfin [6, 14].
Anti-vascular endothelial growth factors
Although elevation of VEGF levels has not been found in CSCR patients compared to controls, the utility of intravitreal anti-VEGF agents has been evaluated . A prospective, controlled study of 30 patients with chronic CSCR found that all 15 of the 15 patients treated with bevacizumab had stable or improved vision at 6 months as compared to only 10 of the 15 untreated patients . In contrast, a randomized controlled trial of 12 patients by Lim, et al. found no significant differences in visual acuity, central retinal thickness, or remission duration between treated and control groups .
The potential role of mineralocorticoid receptor activation in CSCR pathophysiology has long been explored . A non-randomized case series of 13 chronic CSCR patients given oral eplerenone, a mineralocorticoid receptor antagonist, demonstrated a significant decrease in subretinal fluid and improvement of visual acuity .
Cytochrome p450 inducer rifampin is thought to accelerate the metabolism of endogenous steroids in the liver. Steinle, et al. reported a case study where one patient with chronic CSCR was treated with oral rifampin. After one month, all subretinal fluid resolved, and the patient had improved visual acuity .
Ketoconazole inhibits endogenous cortisol synthesis by blocking both the conversion of cholesterol to pregnenolone and 11β-deoxycortisol to cortisol. In a controlled study of 30 patients with chronic CSCR, the treatment arm had improved visual acuity and decreased RPE detachment at 1 month compared with controls, but the difference was not statistically significant .
Glucocorticoid receptor inhibitor mifepristone given orally to chronic CSCR patients for 12 weeks produced improvements in visual acuity in 7 patients in a case series conducted by Nielson, et al. Although all patients demonstrated a reduction in macular edema on OCT, mifepristone treatment did not resolve subretinal exudates in all patients .
Carbonic anhydrase inhibitors appear to enhance retinal adhesiveness and subretinal fluid absorption in animal models . In a prospective, non-randomized comparative trial of 22 patients, acetazolamide reduced subretinal fluid and accelerated resolution onset, but had no effect on CSCR recurrence or final visual acuity .
Adrenergic receptor inhibitors
Inhibition of adrenergic receptors has been evaluated in the treatment of chronic CSCR. In two case studies by Tatham, et al., both patients treated with propranolol experienced resolution of symptoms and macular edema. One patient had a recurrent episode of CSCR, which resolved when retreated with propranolol .
Subthreshold Diode Micropulse Laser
Subtheshold diode micropulse laser treatment consists of short, repetitive pulses of diode laser (0.1-0.3 microseconds), which releases low energy per pulse as opposed to argon or diode lasers (e.g. 100-200 ms) which apply continuous energy . These micropulses deliver a sublethal cellular thermal effect that does not spread laterally to other neuroretinal cells [25-27]. SDM does not cause retinal blanching nor does it leave a visible scar [25, 26]. SDM has been used for the treatment of macular edema, branch retinal vein occlusion, glaucoma, and diabetic retinopathy [27-30]. Its long-term safety profile, with no ophthalmoscopically detectable laser lesions based on ANSI Z136.1 laser safety standards, was supported by Luttrull, et al. who applied SDM (800-950 mW, 0.1-0.3 ms pulse duration) in a confluent pattern over areas of retinal thickening in patients with diabetic macular edema [30, 31].
The use of SDM in the treatment of CSCR was pioneered by Bandello, et al. in 2003 . Five eyes with CSCR were treated with SDM laser and demonstrated complete resorption within one month with no recurrence at the 4 month follow-up visit. Subsequent studies support that SDM laser provides therapeutic benefits similar to those of continuous wave laser without causing CNVM lesions or laser-related scotomas [26, 32-34].
In a prospective, randomized, double-blind sham controlled pilot study, five patients were placed in the sham group, and 10 patients were treated with subthreshold 810-nm diode micropulse laser. At the three month follow-up, mean BCVA improved from 35.4 letters ± 11.6 at baseline to 47.9 letters ± 8.0 at three months (P=0.06) in the treatment group with no significant improvement in the sham group .
Behnia, et al. conducted a randomized, controlled interventional trial of 37 acute CSCR patients experiencing symptoms for less than one month . 18 patients were assigned to the control group and 19 to the experimental group, and follow-up visits were scheduled at 1 and 6 months post-treatment with micropulse laser. At each follow-up visit, contrast sensitivity was tested using CSV1000 grating charts in spatial frequencies of 3, 6, 12, and 18 cycles per degree (CPD). Six-month post-treatment contrast sensitivity in the experimental group was significantly improved as compared to the controls for spatial frequencies of 6 and 12 CPD. The treatment arm scored 5.54 0.66, and the control arm scored 4.7 0.95 (p=0.021) at 6 CPD. At 12 CPD, the treatment arm scored 4.77 0.73 while the control arm scored 3.9 0.88 (p=0.017).
In a retrospective, interventional case series, 11 eyes with CSCR were treated with low-intensity/high-density subthreshold 810-nm micropulse diode laser to areas of leakage seen on FA and to areas of neurosensory detachment and/or pigment epithelial detachments. There was a significant decrease in the macular thickness (mean=97 μm, p=0.0046) and an overall improvement in visual acuity from 39.2 letters pre-treatment to 45.4 letters post-treatment (p-value not reported) with no evidence of post-treatment RPE damage . This study provides evidence that low-intensity/high-density SDM laser treatment is safe and effective for CSCR treatment.
Chen, et al. treated 26 eyes with chronic CSCR and juxtafoveal leakage on FA in a prospective, non-comparative interventional case series . The eyes were divided into 3 groups—focal leakage with no associated RPE atrophy (group 1), focal leakage with RPE atrophy (group 2) and diffuse RPE decompensation with indeterminate source leakage (group 3). Group 1 patients had complete resolution after 1 SDM treatment. In group 2, eight eyes had total subretinal retinal fluid (SRF) reabsorption after 1 to 3 SDM sessions, while 1 patient had persistent SRF. In group 3, however, 5 of 11 eyes with diffuse juxtafoveal leakage required supplemental PDT laser therapy to achieve full resolution of SRF. The average preoperative foveal thickness at the six month follow-up was reduced by more than half of its original thickness. 15 eyes (57.7%) gained three or more lines of vision while 6 eyes (23.1%) gained one to three lines. The authors conclude that while SMD laser is beneficial for patients with point source leakage, it has limited use for those with RPE atrophy or diffuse RPE decompensation who likely require PDT for SRF resolution.
CSCR is often self-limited, but for persistent or recurrent disease, treatment should be considered. Although there have been many studies evaluating various pharmacological agents in the treatment of CSCR, most lack statistical power due to small sample sizes, lack of controls to diminish the effect of confounding variables, and failure to randomize patients.
Variable success has been observed with mineralocorticoid inhibitors, rifampin, ketoconazole, mifepristone, acetazolamide, vascular endothelial growth factor inhibitors, and adrenergic receptor inhibitors; no definitive evidence exists that they are superior to observation alone.
The principal advantage of SDM over other laser treatment modalities is a decreased risk for scotoma or CNVM formation. SDM may also be beneficial in the treatment of refractory cases of CSCR, as suggested by Lanzetta, et al . One study demonstrated that SMD-treated CSCR patients had improved contrast sensitivity over untreated controls . Large-scale, randomized controlled trials are needed in order to determine the true therapeutic benefit of SDM compared to observation or other treatment modalities. Perhaps the greatest limitation of SMD therapy is the difficulty in titrating the treatment dose given the absence of an ophthalmoscopically visible mark. This makes it extremely challenging for the surgeon to guide laser application, although staining RPE cells with ICG dye has been suggested as a potential solution [34, 36].
While data supporting the potential benefits of SDM laser therapy in CSCR is growing, the use of this treatment modality remains limited. This may be due to the fact that SDM laser machines are not widely available. Additionally, SDM laser has not yet proven to be more efficacious than focal laser for extrafoveal lesions, and there is no evidence that it is safer than PDT when there is a juxtafoveal RPE leak. It shares a similar drawback with focal argon laser in that its efficacy diminishes when there is diffuse RPE leakage [25, 26]. Due to incomplete understanding of SDM’s exact mechanism of action, no well-defined treatment protocol exists in regards to the optimal laser irradiance (power per unit of area) that should be delivered to the retina .
In summary, subthreshold diode micropulse therapy may be a useful treatment modality for idiopathic chronic CSCR. Its inherent property of utilizing less energy and thereby minimizing chorioretinal disruption is appealing. However, randomized controlled trials are needed to establish long-term efficacy, identify which patients may benefit most from SDM treatment, and determine whether SDM is in fact superior to alternative treatment approaches. Given the limited but promising data thus far, further investigation is merited.
- RoismanL, Magalhães F P, Lavinsky D, Moraes N, Hirai FE et al. Micropulse diode laser treatment for chronic central serous chorioretinopathy: a randomized pilot trial. Ophthalmic Surgery, Lasers & Imaging Retina. 2013, 44(5): 465-470.
- Nicholson B, Noble J, Forooghian F, Meyerle C. Central serous chorioretinopathy: update on pathophysiology and treatment. Survey of Ophthalmology. 2013, 58(2): 103-126.
- Liegl R, Ulbig M W. Central serous chorioretinopathy. Ophthalmologica. Journal International d’ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde. 2014, 232: 65-76.
- Yannuzzi L A. Central serous chorioretinopathy: a personal perspective. American Journal of Ophthalmology. 2010, 149(3): 361-363.
- Haimovici R, Rumelt S, Melby J. Endocrine abnormalities in patients with central serous chorioretinopathy. Ophthalmology. 2003, 110(4): 698-703.
- Liew G, Quin G, Gillies M, Fraser-Bell S. Central serous chorioretinopathy: a review of epidemiology and pathophysiology. Clinical & Experimental Ophthalmology. 2013, 41(2): 201-214.
- Ross A, Ross A H, Mohamed Q. Review and update of central serous chorioretinopathy. Current Opinion in Ophthalmology. 2011, 22(3): 166-173.
- Wang M, Munch I C, Hasler P W, Christian Pru¨nte, Michael Larsen. Central serous chorioretinopathy. Acta Ophthalmologica. 2008, 86: 126-145.
- Leaver P, Williams C. Argon laser photocoagulation in the treatment of central serous retinopathy. The British Journal of Ophthalmology. 1979, 63(10): 674-677.
- Samy C N, Gragoudas E S. Laser photocoagulation treatment of central serous chorioretinopathy. International Ophthalmology Clinics. 1994, 34(3): 109-119.
- Jung J, Gallego-Pinazo R, Lleo-Perez A, Jonathan I. Huz, Irene A. Barbazetto. NAVILAS Laser System Focal Laser Treatment for Diabetic Macular Edema-One Year Results of a Case Series. The Open Ophthalmology Journal. 2013, 7: 48-53.
- Chhablani J, Rani P, Mathai A, Subhadra Jalali,Igor Kozak . Navigated focal laser photocoagulation for central serous chorioretinopathy. Clin Ophthalmology. 2014, 8: 1543-1547.
- Lim J W, Kang S W, Kim Y T, Chung SE, Lee SW. Comparative study of patients with central serous chorioretinopathy undergoing focal laser photocoagulation or photodynamic therapy. The British Journal of Ophthalmology.2011, 95(4): 514-517.
- Chan W M, Lam D S, Lai T Y, et al. Photodynamic therapy with verteporfin for symptomatic polypoidal choroidal vasculopathy: one-year results of a prospective case series. Ophthalmology. 2004, 111(8): 1576-1584.
- Lim J W, Kim M U, Shin M C. Aqueous humor and plasma levels of vascular endothelial growth factor and interleukin-8 in patients with central serous chorioretinopathy. Retina. 2010, 30(9): 1465-1471.
- Artunay O, Yuzbasioglu E, Rasier R, Sengul A, Bahcecioglu H. Intravitreal bevacizumab in treatment of idiopathic persistent central serous chorioretinopathy: a prospective, controlled clinical study. Current Eye Research. 2010, 35(2): 91-98.
- Zhao M, Célélier I, Bousquet E, Jeanny JC, Jonet L et al. Mineralocorticoid receptor is involved in rat and human ocular chorioretinopathy. The Journal of Clinical Investigation. 2012, 122(7): 2672-2679.
- Bousquet E, Beydoun T, Zhao M, Hassan L, Offret O et al. Mineralocorticoid receptor antagonism in the treatment of chronic central serous chorioretinopathy: a pilot study. Retina. 2013, 33(10): 2096-2102.
- Steinle N C, Gupta N, Yuan A, Singh RP. Oral rifampin utilisation for the treatment of chronic multifocal central serous retinopathy. The British Journal of Ophthalmology. 2012, 96(1): 10-13.
- Golshahi A, Klingmuller D, Holz F G, Eter N. Ketoconazole in the treatment of central serous chorioretinopathy: a pilot study. Acta Ophthalmologica. 2010, 88(5): 576-581.
- Nielsen J S, Bachhawat A, Jampol L M. A case of chronic severe central serous chorioretinopathy responding to oral mifepristone: update. Retina. 2008, 28(9): 1363.
- Wolfensberger T J, Chiang R K, Takeuchi A, M F Marmor. Inhibition of membrane-bound carbonic anhydrase enhances subretinal fluid absorption and retinal adhesiveness. Graefe’s Archive for Clinical and Experimental Ophthalmology. Albrecht von Graefes Archiv fur Klinische und Experimentelle Ophthalmologie. 2010, 238: 76- 80.
- Pikkel J, Beiran I, Ophir A, Miller B. Acetazolamide for central serous retinopathy. Ophthalmology. 2002, 109(9): 1723-1725.
- Tatham A, Macfarlane A. The use of propranolol to treat central serous chorioretinopathy: an evaluation by serial OCT. Journal of Ocular Pharmacology and Therapeutics : The Official Journal of the Association for Ocular Pharmacology and Therapeutics. 2006, 22(2): 145-149.
- Quin G., Liew G, Ho I V, Gillies M, Fraser-Bell S. Diagnosis and interventions for central serous chorioretinopathy: review and update. Clinical & Experimental Ophthalmology. 2013, 41(2): 187-200.
- Chen S N, Hwang, J F, Tseng L F Lin C J. Subthreshold diode micropulse photocoagulation for the treatment of chronic central serous chorioretinopathy with juxtafoveal leakage. Ophthalmology. 2008, 115(12): 2229-2234.
- Parodi M B, Spasse S, Iacono P, Di Stefano G, Canziani T et al. Subthreshold grid laser treatment of macular edema secondary to branch retinal vein occlusion with micropulse infrared (810 nanometer) diode laser. Ophthalmology. 2006, 113(12): 2237-2242.
- Moorman C M, Hamilton A M. Clinical applications of the MicroPulse diode laser. Eye. 1990,13 ( Pt 2): 145-150.
- Laursen M L, Moeller F, Sander B, A K Sjoelie. Subthreshold micropulse diode laser treatment in diabetic macular oedema. The British Journal of Ophthalmology. 2004, 88(9): 1173-1179.
- Luttrull J K, Musch D C, Mainster M A. Subthreshold diode micropulse photocoagulation for the treatment of clinically significant diabetic macular oedema. The British Journal of Ophthalmology. 2005, 89(1): 74-80.
- Malik K J, Sampat K M, Mansouri A, Steiner JN, Glaser BM. Low- intensity/high-density subthreshold micropulse diode laser for chronic central serous chorioretinopathy. Retina. 2015, 35(3): 532-536.
- Lanzetta P, Furlan F, Morgante L, Veritti D, Bandello F. Nonvisible subthreshold micropulse diode laser (810 nm) treatment of central serous chorioretinopathy. A pilot study. European Journal of Ophthalmology. 2008, 18(6): 934-940.
- Gupta B, Elagouz M, McHugh D, Chong V, Sivaprasad S. Micropulse diode laser photocoagulation for central serous chorio-retinopathy. Clinical & Experimental Ophthalmology. 2009, 37(8): 801-805.
- Ricci F, Missiroli F, Regine F, Grossi M, Dorin G. Indocyanine green enhanced subthreshold diode-laser micropulse photocoagulation treatment of chronic central serous chorioretinopathy. Graefe’s Archive for Clinical and Experimental Ophthalmology = Albrecht von Graefes Archiv fur Klinische und Experimentelle Ophthalmologie. 2009, 247(5): 597-607.
- Behnia M, Khabazkhoob M, Aliakbari S, Abadi AE, Hashemi H et al. Improvement in visual acuity and contrast sensitivity in patients with central serous chorioretinopathy after macular subthreshold laser therapy. Retina. 2013, 33(2): 324-328.
- Sivaprasad S, Elagouz M, McHugh D, Shona O, Dorin G. Micropulsed diode laser therapy: evolution and clinical applications. Survey of Ophthalmology. 2010, 55(6): 516-530.