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Current Therapeutic Approaches to Chronic Central Serous Chorioretinopathy.

Introduction

Central serous chorioretinopathy (CSCR) is characterized by serous neurosensory retinal detachment (NSD) accompanied by retinal pigment epithelium (RPE) detachment in some cases, and is the second most common maculopathy after diabetic maculopathy between the third and fifth decades of life. (1,2,3) Clinically, CSCR has a good prognosis and usually resolves spontaneously within the first 3 months. (2,3) However, approximately 5% of cases can become chronic. (1,4) Refractory NSD, which can develop in chronic CSCR, may lead to photoreceptor damage, diffuse RPE changes, RPE atrophy, and subsequent permanent vision loss. (1,2,3)

Studies on the subject have demonstrated that the two main factors involved in the pathogenesis of CSCR. The first is alterations in the autoregulatory mechanisms of choroidal circulation and the subsequent choroidal ischemia, and the second is irregularities in RPE pump function. (5,6,7) Choroidal stasis, inflammation, and ischemia due to dysregulation of regulatory proteins (glucocorticoids, mineralocorticoids, epinephrine, norepinephrine) in the choroidal circulation leads to an increase in choroidal permeability. (7,8,9,10) This hypothesis is corroborated by the presence of local and/or diffuse leakage in fundus fluorescein angiography (FFA) and indocyanine green angiography (ICGA), which are important diagnostic methods for CSCR. (5,10,11,12,13) Due to the multifactorial and complex mechanism of CSCR pathophysiology, several treatment options, such as conventional laser (CL) and verteporfin photodynamic therapy (PDT) have been tried, particularly in the treatment of the chronic type; however, CL was reported to have no significant effect on the final visual acuity or recurrence rate and to have toxic effect on the RPE and photoreceptors. (14,15) Although successful results were obtained with the standard protocol (full-dose, full-fluence) PDT (SP-PDT), this treatment was also observed to have toxic effects on the RPE and photoreceptors. (16,17,18) The adverse effects of CL and SP-PDT have prompted studies in recent years on the safety and efficacy of subthreshold micropulse laser (SML), verteporfin PDT with different parameters (half-dose [HD] or half-fluence [HF]), glucocorticoid antagonists, mineralocorticoid receptor (MR) antagonists, and anti-VEGF agents (Figure 1). (19,20,21,22)

This review evaluated current treatment approaches to chronic CSCR based on randomized and nonrandomized studies that accepted symptom duration of at least 3 months as chronic disease and included at least a case series (more than 3 cases).

Treatment Options

Subthreshold Micropulse Diode and Yellow Laser

Although it has long been used in the treatment of CSCR, the permanent RPE damage and scarring caused by CL led to the adoption of SML, which minimizes RPE damage with repetitive short pulses (0.1-0.2 ms) that allow the use of less energy. This feature of EML enables the laser to be applied to areas much closer to the fovea.

One drawback of applying SML with repetitive short pulses (0.1-0.2 ms) was that the laser burns were too faint to see with the eye. Ricci et al. (23) claimed that this problem could be eliminated by applying micropulse diode laser under ICGA guidance to directly visualize the affected area.

In their prospective interventional study, Chen et al. (24) observed a visual acuity increase of 3 or more letters in 15 of 26 eyes with chronic CSCR that had leakage in the juxtafoveal area and underwent SML therapy (810-nm diode laser), while 5 of the 11 eyes with widespread juxtafoveal RPE leakage required rescue PDT for subretinal fluid resorption. Similarly, Lanzetta et al. (25) observed subretinal fluid resorption at 1 month in 65% and at the end of the follow-up in 75% of 24 eyes treated with SML (810-nm diode laser) and followed for an average of 14 months. Abd Elhamid (26) achieved subretinal fluid resorption after treatment in 73% of 15 eyes with CSCR treated with SML (577-nm yellow laser). In addition, the authors specifically noted that in 9 cases, the leakage was in foveal avascular zone.

Of the comparative studies conducted to date, Scholz et al. (27) applied SML (577-nm yellow laser) to 42 eyes and HD verteporfin PDT (HD-PDT) to 58 eyes diagnosed with chronic CSCR and reported subretinal fluid resorption in 36% of the eyes subjected to SML and 21% of the eyes subjected to PDT at 6 weeks, which was not a statistically significant difference.

In contrast, Maruko et al. (28) treated 29 eyes with CSCR and typical focal leakage persisting more than 3 months, 15 with CL and 14 with SML (577-nm yellow laser), and compared their efficacy in terms of complete subretinal fluid resorption and their safety in terms of RPE damage assessed by fundus autofluorescence imaging. Their results showed no significant difference in efficacy between CL and SML (66.7% vs. 64.3%, respectively). However, RPE damage was observed in all eyes with successful outcomes after CL therapy but only in one eye treated successfully with SML. Their study highlighted that SML was at least as efficient as CL and much safer than CL in terms of RPE damage. The authors also stated that their higher success rates compared to the study by Scholz et al. (27) may be attributed to their exclusion of cases with diffuse leakage from the study. In a comparative study by Ozmert et al. (29), no statistically significant difference in rates of complete resorption of subretinal fluid was observed between HF-PDT in 18 eyes and SML (577-nm yellow laser) therapy in 15 eyes with chronic CSCR (72.2% vs. 80%, respectively). In a comparative, controlled prospective study by Koss et al. (20), SML (810-nm diode laser) therapy was performed on 16 eyes and intravitreal bevacizumab treatment was performed on 10 eyes with chronic CSCR, and 26 eyes were followed as a control group. The highest rate of complete subretinal fluid resorption at 10 months post-treatment was observed in the SML group, followed by the bevacizumab group, and the differences were statistically significant (SML vs. bevacizumab vs. control: 87.5% vs. 40% vs. 8%). A summary of studies on SML in chronic CSCR is presented in Table 1.

Intravitreal Anti-VEGF Therapy

Although it is known that choroidal neovascularization (CNV) is not a primary factor in the pathophysiology of CSCR, (30,31) some authors argue that anti-VEGF agents, which are the popular and effective options for treating CNV may be effective in resolving the disease by reducing pooling and hyperpermeability in the choroidal vessels. (21,32,33) There is only one randomized controlled study on the efficacy of anti-VEGF in chronic CSCR in the literature. In this study, performed in Turkey by Artunay et al. (22), 15 eyes with a history of CSCR persisting longer than 3 months were treated with the anti-VEGF agent bevacizumab and 15 eyes were followed for 6 months without any intervention. They reported complete resorption of subretinal fluid in 80% (n=12) of the treated eyes and 53.3% (n=8) of the untreated eyes (p<0.01). Furthermore, visual acuity was unchanged or improved in all treated eyes and 10 eyes in the follow-up group (p<0.01).

In one of the nonrandomized, prospective comparative studies, Kim et al. (34) treated 30 eyes with chronic CSCR with bevacizumab. The researchers grouped eyes that did not respond to the first three injections as anti-VEGF-resistant and the eyes that responded as anti-VEGF-sensitive. Compared to the treatment-resistant group, the treatment-sensitive group showed greater subfoveal choroidal thickness and more choroidal vessel dilation in ICGA before treatment and greater reduction in choroidal thickness after treatment. Based on these findings, the authors noted the importance of the ability to predict response to anti-VEGF therapy before treatment based on subfoveal choroidal thickness and hyperpermeability. In addition to this information, Yannuzzi (35) stated that the presence of fibrin observed in the fovea on fundus examination indicates leakage from abnormal choroidal vessels and emphasized that PDT in such cases can cause severe RPE damage due to excessive energy accumulation over the fibrin structure. In light of this, anti-VEGF agents may be a better treatment option in terms of preventing potential complications in patients with subretinal fibrin accumulation. A recent meta-analysis of studies concerning anti-VEGF therapy in CSCR resulted in several recommendations.

Recommended indications for anti-VEGF in chronic CSCR (2,36,37)

1. Patients with subfoveal fibrin accumulation in which focal laser or PDT can be inconvenient

2. When CSCR is complicated by CNV

Corticosteroid Antagonists

1. Glucocorticoid Antagonists

Elevated serum cortisol levels in CSCR patients have been demonstrated previously. (9,38) Therefore, investigation began into the efficacy of anti-glucocorticoids such as ketoconazole, mifepristone, and finasteride, though only as case series. (39,40)

Some studies have also demonstrated elevated testosterone levels in CSCR. (41,42) This information prompted research into the therapeutic efficacy of finasteride, an inhibitor of 5-reductase, an enzyme that is involved in the synthesis of the hormone dihydrotestosterone (which is more potent than testosterone). In a comprehensive study on the efficacy of finasteride, Moisseiev et al. (43) administered 5 mg/day oral finasteride to 23 patients diagnosed with chronic CSCR (>3 months). After a mean follow-up time of 14.7 months, complete resolution was observed in 75.9% of the patients, while 37.5% had recurrence after discontinuing treatment. However, studies conducted with glucocorticoid antagonists were not randomized or controlled, and therefore, there is still no reliable information on the efficacy of this class of drugs.

2. Mineralocorticoid Receptor Antagonists

Several studies have demonstrated that glucocorticoids and mineralocorticoids are co-expressed in the retinal Muller cells and choroidal vessels. With higher circulating levels, these hormones bind to glucocorticoid receptors (GR) and MRs and cause alterations in retinal and choroidal homeostasis, which is considered the most likely factor in the pathophysiology of CSCR. (44,45) In a randomized controlled comparative study of MR antagonists, Pichi et al. (46) established 3 groups of 20 patients with chronic CSCR (average duration of 8 months) and administered oral spironolactone to group 1, oral eplerenone to group 2, and placebo to group 3 for the first month. For the second month, they gave eplerenone to group 1 and spironolactone to groups 2 and 3, then discontinued treatment and followed the patients for 2 more months. The authors reported that spironolactone was statistically superior in terms of visual acuity gain and subretinal fluid resolution. They attributed this difference to eplerenone having a 20-fold lower affinity for MR; however, in comparison of adverse effect profiles, they stated that eplerenone exhibits fewer progestinic effects because of its selectivity for MR. The results of other studies of MR antagonists are presented in Table 2. In summary, the MR antagonists spironolactone and eplerenone can be effective options in the treatment of CSCR. However, conducting more randomized controlled studies with these drugs will provide more reliable information regarding both treatment efficiency and adverse effect profile.

Verteporfin-Photodynamic Treatment

1. SP-PDT

The known limitations of argon laser therapy in CSCR and the roles of choroidal vessel dilation and hyperpermeability in CSCR pathophysiology have led to investigation of the efficacy and safety of verteporfin PDT, which was previously proven effective in wet AMD patients (TAP protocol), (47) in the treatment of CSCR. In the first trial evaluating the efficacy and safety of SP-PDT, carried out by Yannuzzi et al. (48) subretinal fluid resorption was observed in 60% of 20 chronic CSCR patients after a mean of 6 months. In a study by Cardillo et al. (49) in which 20 eyes with chronic CSCR were treated with SP-PDT, vision improved in 6 eyes and was unchanged in 14 eyes after an average follow-up period of 12 months, and 81% of the eyes showed complete resorption of subretinal fluid.

Ruiz-Moreno et al. (18) performed SP-PDT in 82 eyes with chronic CSCR and observed complete resorption of subretinal fluid in all eyes and a statistically significant increase in mean visual acuity (1.9[+ or -]2.4 Snellen lines) after an average follow-up period of 12 months. In the same study, reactivation (recurring NSD) occurred in 2 eyes, CNV secondary to treatment in 2 eyes (2%), and reactive RPE hyperplasia in 9 eyes (10%). In a study including a total of 42 eyes with chronic CSCR, Reibaldi et al. (16) treated 19 with SP-PDT and 23 with HF-PDT and reported juxtafoveal CNV at 3 months in only 1 eye (2%) in the SP-PDT group. A summary of studies on SP-PDT in chronic CSCR is presented in Table 3.

2. HD-PDT and HF-PDT

Adverse effects such as focal RPE losses, CNV secondary to treatment, chronic choroidal hypoperfusion, and pigmentary changes observed after SP-PDT with verteporfin prompted clinicians to consider modifying the standard treatment protocol.

Of the clinical studies in the literature investigating the efficacy of verteporfin-PDT in CSCR, only two were done in chronic cases. Bae et al. (50) randomized 16 eyes with CSCR into two equal groups and treated one group with HF-PDT and the other with intravitreal ranibizumab injection (consecutive monthly injections); at the end of a 3-month follow-up period, they observed complete resorption of subretinal fluid in 6 eyes (75%) in the PDT group and 2 eyes (25%) in the injection group. In the same study, 4 eyes with incomplete resorption after ranibizumab injection underwent rescue HF-PDT and 2 of them showed complete resorption of subretinal fluid. No complications occurred in either group. In another randomized controlled study, Semeraro et al. (51) gave intravitreal bevacizumab (1.25 mg) injections to 12 eyes and performed HF-PDT in 10 eyes diagnosed with CSCR persisting for an average of more than 3 months, with 9 months of follow-up. At the end of the follow-up period, there were no statistically significant differences between the two groups in terms of mean central macular thickness or change in visual acuity. However, because the number of eyes with complete subretinal fluid resorption was not reported in that study, their results could not be compared in detail with those of other studies. There were also no complications secondary to treatment reported in either group in that study.

Among the studies on HD-PDT and HF-PDT, Chan et al. (19) treated 48 eyes with chronic CSCR with HD-PDT (3 mg/[m.sup.2] verteporfin) and reported complete resorption of subretinal fluid in all eyes after 12 months of follow-up and recurrence in 4 eyes (8.3%). Mean visual acuity of the patients increased by 2 lines. No complications occurred in any of the eyes in their study. In another study, Nicolo et al. (52) performed HD-PDT on 38 eyes with chronic CSCR and observed complete resorption of subretinal fluid in all eyes and recurrence in 5 eyes (13.2%) after a mean follow-up of 14.2 months, and no complications were reported. Senturk et al. (53) performed HD-PDT on 24 eyes with chronic CSCR and reported complete resorption of subretinal fluid in all of the eyes at 6 months and emphasized that no complications occurred in any of the eyes.

Of the studies comparing SP-PDT and PDT with different parameters, Reibaldi et al. (16) treated 42 eyes with chronic CSCR with SP-PDT or HF-PDT. At a mean of 12 months, they reported complete resorption of subretinal fluid in 79% of the eyes treated with SP-PDT and 91% of the eyes treated with HF-PDT. In the SP-PDT group they also observed new atrophy in the treated area on FFA in 1 eye (5%) and juxtafoveal CNV in 1 eye (5%) at 12 months post-treatment. A summary of studies on HD-PDT and HF-PDT in chronic CSCR is presented in Table 4.

In conclusion, publications on PDT in CSCR are still at the level of case series and nonrandomized comparative studies. Randomized controlled clinical trials with much larger samples are needed to evaluate the efficacy and safety of this therapy. A systematic review by Erikitola et al. (54) in 2014 evaluated results concerning SP-PDT, HD-PDT, and HF-PDT from randomized controlled studies and qualitative observational studies that met at least 70% of the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) criteria (Table 5).55 They concluded that of various parameters, HD-PDT was the treatment option with the lowest adverse event and recurrence rates. In 4 (42.9%) of 7 studies on HD-PDT, complete resorption of subretinal fluid was observed with no recurrence in any of the eyes. (56,57,58,59) The overall recurrence rate of CSCR in the review varied between 3%-24%, though it was noted that these results were obtained from studies with small sample sizes.

Conclusion

An evaluation of the literature data regarding current treatment options for chronic CSCR, such as SML, anti-VEGF, MR antagonists, and PDT, suggests that SML is superior to CL in terms of adverse effects and comparable to PDT in terms of efficacy. Assessing the effectiveness of SML using longer-term follow-up data will provide more reliable information for comparison with the effectiveness of PDT. In addition, similar to CL, the ineffectiveness of SML in diffuse RPE leakages is considered an additional disadvantage. Although the valuable prospective randomized study by Artunay et al. (22) offered promising results, studies on anti-VEGF have usually been reports of a few cases, which limits the power of these studies. Therefore, performing randomized studies with larger sample sizes will yield more reliable results. Moreover, the most probable pathogenesis of the disease is not closely related to the mechanism of action of anti-VEGF, which suggests that these agents may not be very effective. Studies on MR antagonists have shown that these are effective treatment options; however, the results indicate that these short acting agents are more disadvantageous in terms of patient compliance and in comparison with treatment options with more permanent effects such as PDT and SML. Studies with longer follow-up will also provide more definitive data regarding the effectiveness of MR antagonists. Finally, although PDT is known to be more costly than CL, studies indicate that verteporfin PDT is superior to and safer than CL therapy in terms of effectiveness and adverse event profiles, particularly in chronic, subfoveal, and juxtafoveal involvement. In particular, the fact that PDT at different parameters (HD-PDT, HF-PDT) minimized adverse effects such as choroidal ischemia and CNV supports this treatment as an effective and safe treatment option for chronic CSCR.

Ethics

Peer-review: Externally and internally peer-reviewed.

Authorship Contributions

Surgical and Medical Practices: Samet Gulkas, Ozlem Sahin, Concept: Samet Gulkas, Ozlem Sahin, Design: Ozlem Sahin, Data Collection or Processing: Samet Gulkas, Analysis or Interpretation: Samet Gulkas, Ozlem Sahin, Literature Search: Samet Gulkas, Writing: Samet Gulkas.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.

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(60.) Karacam Z. Epidemiyolojide gozlemsel arastirma raporu yaziminin guclendirilmesi icin bir rehber. Anadolu Hemsirelik ve Saglik Bilimleri Dergisi. 2014;17:64-72.

(61.) Bousquet E, Beydoun T, Zhao M, Hassan L, Offret O, Behar-Cohen F. Mineralocorticoid receptor antagonism in the treatment of chronic central serous chorioretinopathy: a pilot study. Retina. 2013;33:2096-2102.

(62.) Chin EK, Almeida DR, Roybal CN, Niles PI, Gehrs KM, Sohn EH, Boldt HC, Russell SR, Folk JC. Oral mineralocorticoid antagonists for recalcitrant central serous chorioretinopathy. Clin Ophthalmol. 2015;9:1449-1456.

(63.) Leisser C, Hirnschall N, Hackl C, Plasenzotti P, Findl O. Eplerenone in patients with chronic recurring central serous chorioretinopathy. Eur J Ophthalmol. 2016;26:479-484.

(64.) Cakir B, Fischer F, Ehlken C, Buhler A, Stahl A, Schlunck G, Bohringer D, Agostini H, Lange C. Clinical experience with eplerenone to treat chronic central serous chorioretinopathy. Graefes Arch Clin Exp Ophthalmol. 2016;254:2151-2157.

(65.) Singh RP, Sears JE, Bedi R, Schachat AP, Ehlers JP, Kaiser PK. Oral eplerenone for the management of chronic central serous chorioretinopathy. Int J Ophthalmol. 2015;8:310-314.

(66.) Silva RM, Ruiz-Moreno JM, Gomez-Ulla F, Montero JA, Gregorio T, Cachulo ML, Pires IA, Cunha-Vaz JG, Murta JN. Photodynamic therapy for chronic central serous chorioretinopathy: a 4-year follow-up study. Retina. 2013;33:309-315.

(67.) Sakalar YB, Keklikci U, Unlu K, Alakus MF, Kara IH. Effects of photodynamic therapy with verteporfin for the treatment of chronic central serous chorioretinopathy: An uncontrolled, open-label, observational study Curr Ther Res Clin Exp. 2010;71:173-185.

(68.) Lim SH, Chang W, Sagong M. Efficacy of half-fluence photodynamic therapy depending on the degree of choroidal hyperpermeability in chronic central serous chorioretinopathy. Eye (Lond). 2013;27:353-362.

[iD] Samet Gulkas (*), [iD] Ozlem Sahin (**)

(*) Sanliurfa Training and Research Hospital, Ophthalmology Clinic, Sanliurfa, Turkey

(**) Marmara University Faculty of Medicine, Department of Ophthalmology, Istanbul, Turkey

Address for Correspondence: Samet Gulkas MD, Sanliurfa Training and Research Hospital, Ophthalmology Clinic, Sanliurfa, Turkey

Phone: +90 531 943 89 31 E-mail: drsametgulkas@gmail.com ORCID-ID: orcid.org/0000-0002-1698-7060

Received: 28.03.2018 Accepted: 06.09.2018

DOI: 10.4274/tjo.galenos.2018.49035
Table 1. Major studies of subthreshold micropulse laser in the
treatment of central serous chorioretinopathy

Authors               Study                    Mean duration of symptoms
                      Designdesign

                      Prospective,
Abd Elhamid (26)      uncontrolled case           4.6 months
                      series

                      Prospective,
Lanzetta et al. (25)  uncontrolled case        [greater than or equal
                      series                   to]6 months

                      Prospective,
Chen et al. (24)      uncontrolled case          >4 months
                      series

Ozmert et al. (29)    Retrospective,             13 months
                      comparative case series

Authors               Number of  Follow-up    Result
                      Eyeseyes   Timetime

                                              Functional success:
                                              (mean increase in BCVA) -
                                              27%
Abd Elhamid (26)      15          6 months    Anatomic success:
                                              Complete response - 86.6%
                                              Recurrence rate - NA

                                              Functional success:
                                              (Mean increase in BCVA) -
                                              30%
Lanzetta et al. (25)  24         14 months    Anatomic success:
                                              Complete or partial
                                              response - 75%
                                              Recurrence rate - NA

                                              Functional success:
                                              (mean increase in BCVA) -
                                              66%
Chen et al. (24)      26          9.5 months  Anatomic success:
                                              Complete response - 73%
                                              Recurrence rate - 31%

                                              Functional success:
                                              (mean increase in BCVA) -
                                              5%
Ozmert et al. (29)    15         12 months    Anatomic success:
                                              Complete response - 80%
                                              Recurrence rate - 13.3%

Table 2. Major studies on mineralocorticoid receptor antagonist therapy
(eplerenone) in central serous chorioretinopathy

                                                 Eplerenone
Authors               Study design               dose

                                                 25 mg/g (1 week),
                      Prospective, uncontrolled  followed by 50
Bousquet et al. (61)  case series
                                                 (1-3 months)

Chin et al. (62)      Retrospective case series  50 -100 mg/g

Leisser et al. (63)   Retrospective case series  25 mg/g

                                                 25 mg/g (1 week),
                                                 followed by 50
Cakir et al. (64)     Retrospective case series  mg/g
                                                 (5 weeks)

Singh et al. (65)     Retrospective case series  25-50 mg/g

                      Number of  Treatment
Authors               eyes       duration     Outcome

                                              Functional success: 94%
                                              (Significant rate of
                                              increase in BCVA)
                                              Anatomic success:
Bousquet et al. (61)  13          4-12 weeks  Complete response - 64%
                                              Partial response - 18%
                                              No response - 18%

                                              Functional success:
                                              Unspecified
                                              Anatomic success:
Chin et al. (62)      23          4 months    Complete/Partial response
                                              - 52.2%
                                              No response - 47.8%

                                              Functional success: 73%
                                              (Significant rate of
                                              increase in BCVA)
Leisser et al. (63)   11         10 weeks     Anatomic success:
                                              Complete response - 36.4%
                                              Partial response - 27.2%
                                              No response - 36.4%

                                              Functional success: 66%
                                              (Significant rate of
                                              increase in BCVA)
Cakir et al. (64)     24         15 months    Anatomic success:
                                              Complete response - 29%
                                              Partial response - 33%
                                              No response - 25%

                                              Functional success:
                                              Unspecified
                                              Anatomic success:
Singh et al. (65)     17         Unspecified  Complete response - 35.3%
                                              Partial response - 11.8%
                                              No response - 47.1%

BCVA: Best corrected visual acuity

Table 3. Major studies on standard-protocol verteporfin-photodynamic
therapy in central serous chorioretinopathy

Authors                  Study design               Mean duration of
                                                    symptoms

                         Prospective, uncontrolled
Yannuzzi (35)            case series                       111 months

Cardillo et al. (49)     Prospective, uncontrolled  [greater than or
                         case series                equal to]6 months

Ruiz-Moreno et al. (18)  Retrospective case series          28 months

Silva et al. (66)        Retrospective case series           8.5 months

Sakalar et al. (67)      Retrospective case series  [greater than or
                                                    equal to]6 months

Authors                  Number of  Follow-up     Outcome
                         eyes       time

                                                  Functional success:
                                                  (mean increase in
                                                  BCVA) - 53%
Yannuzzi (35)            20          6.8 months   Anatomic success:
                                                  Complete response -
                                                  60%
                                                  Recurrence rate - 10%

                                                  Functional success:
                                                  (Mean increase in
                                                  BCVA) - 35%
Cardillo et al. (49)     16          6-12 months  Anatomic success:
                                                  Complete response -
                                                  76%
                                                  Recurrence rate: 15%

                                                  Functional success:
                                                  (mean increase in
                                                  BCVA) - 30%
Ruiz-Moreno et al. (18)  82         Success rate  Anatomic success:
                                                  Complete response -
                                                  100%
                                                  Recurrence rate - 2.4%

                                                  Functional success:
                                                  (mean increase in
                                                  BCVA) - 33%
Silva et al. (66)        46         56.8 months   Anatomic success:
                                                  Complete response -
                                                  100%
                                                  Recurrence rate - 8.6%

                                                  Functional success:
                                                  (mean increase in
                                                  BCVA) - 84%
Sakalar et al. (67)      17         13 months     Anatomic success:
                                                  Complete response -
                                                  100%
                                                  Recurrence rate - 0%

BCVA: Best corrected visual acuity

Table 4. Major studies on half-dose and half-fluence
verteporfin--photodynamic therapy in central serous chorioretinopathy

Authors               Study Designdesign        Mean duration of
                                                symptoms

                      Prospective,
Chan et al. (19)      uncontrolled case series     8.2 months
                      (HD-PDT)

                      Prospective,
Nicolo et al. (52)    uncontrolled case series  [greater than or equal
                      (HD-PDT)                  to]6 months

                      Prospective,
Senturk et al. (53)   uncontrolled case series     4-6 months
                      (HD-PDT)

                                                Severe hyperfluorescence
                      Prospective,              group
Lim et al. (68)       comparative case series     13.2 months
                      (HF-PDT)                  Mild hyperfluorescence
                                                group
                                                  11.9 months

                      Prospective,
Reibaldi et al. (16)  comparative case series      8.5-9 months
                      (SP-PDT vs. HF-PDT)

Authors               Number of  Follow-up time  Outcome
                      eyes

                                                 Functional success:
                                                 (mean increase in BCVA)
                                                 - 51%
Chan et al. (19)      48         12 months       Anatomic success:
                                                 Complete response -
                                                 89.6%
                                                 Recurrence rate - 8.3%

                                                 Functional success:
                                                 (mean increase in BCVA)
                                                 - 38%
Nicolo et al. (52)    38         14.2 months     Anatomic success:
                                                 Complete response -
                                                 92.1%
                                                 Recurrence rate - 13.2%

                                                 Functional success:
                                                 (mean increase in BCVA)
                                                 - 40%
Senturk et al. (53)   24          6 months       Anatomic success:
                                                 Complete response -
                                                 100%
                                                 Recurrence rate - 0%

                                                 Functional success:
                                                 (Mean increase in BCVA)
                                                 Intense
                                                 hyperfluorescence group
                                                 - 53%
                                                 Weak hyperfluorescence
                                                 group - 41%
                                                 Anatomic success:
Lim et al. (68)       30          6 months       Complete response
                                                 Intense
                                                 hyperfluorescence group
                                                 - 100%
                                                 Weak Hf group - 100%
                                                 Recurrence rate
                                                 Intense
                                                 hyperfluorescence group
                                                 - 0%
                                                 Weak hyperfluorescence
                                                 group - 7.1%

                                                 Functional success:
                                                 (Mean increase in BCVA)
                                                 SP group - 37%
                                                 HF group - 65%
                                 SP group        Anatomic success:
Reibaldi et al. (16)  42          8.5 months     Complete response
                                 HF group        SP group - 79%
                                  8.9 months     HF group - 91%
                                                 Recurrence rate
                                                 SP group - 11%
                                                 HF group - 5%

BCVA: Best corrected visual acuity, Hf: Hyperfluorescence, SP: Standard
protocol, HD: Half-dose, HF: Half-fluence

Table 5. Strengthening the Reporting of Observational Studies in
Epidemiology (STROBE) criteria (47,54,55,60)

                      Item no  Recommendation

Title and abstract             (a) Indicate the study's design with a
                               commonly used term in the title or the
                               abstract
                       1       (b) Provide in the abstract an
                               informative and balanced summary of what
                               was done and what was found
Introduction
Background/rationale   2       Explain the scientific background and
                               rationale for the investigation being
                               reported
Objectives             3       State specific objectives, including any
                               prespecified hypotheses
Methods
Study design           4       Present key elements of study design
                               early in the paper
Setting                5       Describe the setting, locations, and
                               relevant dates, including periods of
                               recruitment, exposure, follow-up, and
                               data collection
                               (a) Cohort study - give the eligibility
                               criteria, and the sources and methods of
                               selection of participants. Describe
                               methods of follow-up
                               Case-control study - give the eligibility
                               criteria, and the sources and methods of
                               case ascertainment and control selection.
                               Give the rationale for the choice of
Participants           6       cases and controls
                               Cross-sectional study - give the
                               eligibility criteria, and the sources and
                               methods of selection of participants
                               (b) Cohort study - for matched studies,
                               give matching criteria and number of
                               exposed and unexposed
                               Case-control study - for matched studies,
                               give matching criteria and the number of
                               controls per case
Variables              7       Clearly define all outcomes, exposures,
                               predictors, potential confounders, and
                               effect modifiers. Give diagnostic
                               criteria, if applicable
Data sources/          8       For each variable of interest, give
measurement                    sources of data and details of methods of
                               assessment (measurement). Describe
                               comparability of assessment methods if
                               there is more than one group
Bias                   9       Describe any efforts to address potential
                               sources of bias
Study size            10       Explain how the study size was arrived at
Quantitative          11       Explain how quantitative variables were
variables                      handled in the analyses. If applicable,
                               describe which groupings were chosen and
                               why
                               (a) Describe all statistical methods,
                               including those used to control for
                               confounding
                               (b) Describe any methods used to examine
                               subgroups and interactions
Statistical methods            (c) Explain how missing data were
                               addressed
                      12       (d) Cohort study - if applicable, explain
                               how loss to follow-up was addressed
                               Case-control study - if applicable,
                               explain how matching of cases and
                               controls was addressed
                               Cross-sectional study - if applicable,
                               describe analytical methods taking
                               account of sampling strategy
                               (e) Describe any sensitivity analyses
Results
                               (a) Report numbers of individuals at each
                               stage of study - e.g. numbers potentially
                               eligible, examined for eligibility,
                               confirmed eligible, included in the
                               study, completing follow-up, and analysed
Participants          13       (b) Give reasons for non-participation at
                               each stage
                               (c) Consider use of a flow diagram
                               (a) Give characteristics of study
                               participants (e.g., demographic,
                               clinical, social) and information on
                               exposures and potential confounders
Descriptive data      14       (b) Indicate number of participants with
                               missing data for each variable of
                               interest
                               (c) Cohort study - summarise follow-up
                               time (e.g., average and total amount)
                               Cohort study - report numbers of outcome
                               events or summary measures over time
Outcome data          15       Case-control study - report numbers in
                               each exposure category, or summary
                               measures of exposure
                               Cross-sectional study - report numbers of
                               outcome events or summary measures
                               (a) Give unadjusted estimates and, if
                               applicable, confounder-adjusted estimates
                               and their precision (e.g., 95% confidence
                               interval). Make clear which confounders
                               were adjusted for and why they were
                               included
Main results          16       (b) Report category boundaries when
                               continuous variables were categorized
                               (c) If relevant, consider translating
                               estimates of relative risk into absolute
                               risk for a meaningful time period
Other analyses        17       Report other analyses done - e.g.,
                               analyses of subgroups and interactions,
                               and sensitivity analyses
Discussion
Key results           18       Summarise key results with reference to
                               study objectives
Limitations           19       Discuss limitations of the study, taking
                               into account sources of potential bias or
                               imprecision. Discuss both direction and
                               magnitude of any potential bias
Interpretation        20       Give a cautious overall interpretation of
                               results considering objectives,
                               limitations, multiplicity of analyses,
                               results from similar studies, and other
                               relevant evidence
Generalisability      21       Discuss the generalisability (external
                               validity) of the study results
Other information
Funding               22       Give the source of funding and the role
                               of the funders for the present study and,
                               if applicable, for the original study on
                               which the present article is based
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Author:Gulkas, Samet; Sahin, Ozlem
Publication:Turkish Journal of Ophthalmology
Date:Jan 1, 2019
Words:6626
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