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Micropulse Diode Laser Treatment for Chronic Central Serous Chorioretinopathy: A Randomized Pilot Trial Luiz Roisman, MD; Fernanda Pedreira Magalhães, MD; Daniel Lavinsky, MD; Nilva Moraes, MD, PhD; Flávio E. Hirai, MD, PhD; José Augusto Cardillo, MD, PhD; Michel Eid Farah, MD, PhD INTRODUCTION
BACKGROUND AND OBJECTIVE: To evaluate 810nm subthreshold diode micropulse (SDM) laser in patients with chronic central serous chorioretinopathy (CSC). PATIENTS AND METHODS: Prospective, randomized, double-blind, sham-controlled pilot trial. Patients were randomized to SDM laser treatment (group 1) or sham procedure (group 2). Primary outcome measure was change in best corrected visual acuity (BCVA); secondary outcome was central macular thickness after 3 months. Laser treatment was performed along the detached area. At the 3-month visit, all patients were evaluated for re-treatment if they met re-treatment criteria. RESULTS: Fifteen patients were included in this study: five patients in the sham group and 10 in the treatment group. At 3 months, BCVA was significantly enhanced in the treatment group (P = .006) compared with the sham group (P = .498). All patients from the sham group needed treatment after 3 months. An improvement in central macular thickness and leakage on fluorescein angiography was noted in all treated patients (in both groups). CONCLUSION: In this limited-size, short-term exploratory study, SDM laser was effective in treating chronic CSC. There was no evidence of retinal damage induced by treatment. [Ophthalmic Surg Lasers Imaging Retina. 2013;44:465-470.]
Central serous chorioretinopathy (CSC) is characterized by serous detachment of the neurosensory retina and/or the retinal pigment epithelium (RPE), secondary to one or more leakage points at the RPE level.1,2 There are two main forms of disease presentation: acute CSC, most commonly seen in early adulthood, manifests as a round retinal sensory detachment lasting less than 6 months and usually has a self-limiting course, whereas chronic CSC is characterized by multifocal widespread RPE changes associated with varying degrees of leakage observed on fluorescein angiography.1,3 The diagnosis of CSC is based on a clinical history of blurred vision and metamorphopsia with relative central scotoma, ophthalmologic examination, and fluorescein angiography. Optical coherence tomography (OCT) aids in diagnosing shallow serous detachments and is especially useful in the follow-up of affected patients.4 Fundus autofluorescence offers indirect information concerning the metabolic activity of the RPE5 and could be a noninvasive tool for monitoring RPE changes in CSC.6 In most cases of acute CSC, retinal detachment resolves spontaneously within 3 months of onset. After 3 months without resolution of acute CSC or in chronic CSC, continuous wave laser photocoagulation or photodynamic therapy should be considered. Direct threshold photocoagulation treatment with continuous wave laser can shorten the duration of the serous detachment,7 but it is not appropriate for juxtafoveal or subfoveal leakage points because it leads to retinal burn scars.
From the Department of Ophthalmology, Federal University of São Paulo, São Paulo, Brazil (LR, FPM, DL, NM, FEH, JAC, MEF); and the Araraquara Eye Hospital, Araraquara, Brazil (JAC). Originally submitted March 20, 2013. Accepted for publication July 18, 2013. The authors have no financial or proprietary interest in the materials presented herein. Address correspondence to Luiz Roisman, MD, Department of Ophthalmology, Federal University of São Paulo, Botucatu St. 820, São Paulo 04023, Brazil; (55) (11) 5085-2010; email:
[email protected]. doi: 10.3928/23258160-20130909-08
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Figure. Fluorescein angiography, fundus autofluorescence, and spectral-domain OCT of a treated patient. (A) Fluorescein angiogram at baseline. (B) OCT infrared thickness map illustrating the area of thicker retina corresponding to the detached neurosensory retina, where the laser treatment was performed. (C) Fluorescein angiogram at 3 months. (D) Spectral-domain OCT at baseline. (E) Spectral-domain OCT at 3 months.
Photodynamic therapy has been used as an alternative in the treatment of juxtafoveal and subfoveal leakage.8 However, it can cause adverse effects, including RPE atrophy, choroidal hypoperfusion with choriocapillaris ischemia, and choroidal neovascularization.9,10 The classic photocoagulation treatment strategy consists of applying laser energy to obtain a confluent coagulation lesion of moderate intensity covering the leakage point.1 An alternate hypothesis for the photocoagulation mechanism of action suggests that its therapeutic benefits are secondary to biological activation, which does not necessarily occur in laser-necrotized tissue but in still-viable cells stimulated by sublethal thermal stress directly produced with subthreshold diode micropulse (SDM) laser exposure or indirectly caused by the equilibrating thermal wave from the laser burn.11 Subvisible photocoagulation can potentially localize laser photothermal effects and decrease chorioretinal damage.9 SDM laser treatment using a 810-nm diode laser may limit the damage to the neural retina by raising the RPE temperature to just below the protein-denaturation threshold so that the thermal wave that reaches the neural retina is insufficient to cause either damage or a clinically visible endpoint.12 This
therapeutic laser modality offers the possibility of minimizing iatrogenic retinal lesions. SDM delivers laser energy as a train of repetitive short diode pulses, with an “on” time and an interpulse “off” time with a sublethal cellular thermal effect.13 The ratio between “on” time and the total time is the duty cycle percentage, which can be adjusted to control heat intensity and spread. This study aimed to evaluate the safety and therapeutic response of micropulse diode 810-nm laser treatment in patients with chronic CSC.
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PATIENTS AND METHODS
This prospective, randomized, double-masked, sham-unstratified, controlled pilot exploratory trial was conducted at the Retina Service of the Federal University of São Paulo. After approval from the university’s investigational review board, 15 patients with CSC lasting more than 6 months were enrolled. Informed consent was obtained from all subjects, and the study adhered to the tenets of the Declaration of Helsinki. The 15 patients were randomized 2:1 through double-masked random draw into two groups: 10 patients in group 1 received subthreshold 810-nm diode micropulse laser (FastPulse laser; Opto, Brazil)
treatment, and five patients in TABLE 1 group 2 underwent sham treatBaseline Clinical Data of Treatment and Sham Groups ment. The baseline examination included ETDRS best corrected Sham Group Treatment Group P Value visual acuity (BCVA), slit-lamp examination of the anterior segGender, male (%) 60 70 .566 ment, indirect ophthalmoscopy, Age (years) 44.2 ± 5.8 39.5 ± 7.7 .243 color fundus photography using Median (range) 45 (38-52) 40.5 (26-51) Topcon TRC-50DX (Topcon OpDuration of symptoms 31.8 ± 24.3 13.3 ± 7.7 .040 tical, Tokyo, Japan) or Visucam (months) (Carl Zeiss Meditec, Jena, GermaMedian (range) 24 (12-72) 11 (6-24) ny), fluorescein angiography (FA), and fundus autofluorescence usOCT central macular 349.6 ± 61.3 419.6 ± 111.8 .270 thickness (µm) ing HRA-2 (Heidelberg Retina Angiograph; Heidelberg Engineering, Median (range) 324 (301-454) 417 (259-575) Heidelberg, Germany). Baseline BCVA (letters) 26.6 ± 6.8 35.4 ± 11.2 .110 macular thickness was evaluated Median (range) 28 (16-34) 34.5 (18-55) by spectral-domain OCT using BCVA (logMAR) 0.568 ± 0.135 0.392 ± 0.223 .110 Spectralis (Heidelberg Engineering, Heidelberg, Germany). The Median (range) 0.54 (0.42-0.78) 0.41 (0-0.74) SD-OCT macular thickness meaOCT = optical coherence tomography; BCVA = best corrected visual acuity; logMAR = logarithm of the sures included subretinal fluid if minimum angle of resolution. present. The SDM laser treatment was performed over the neurosensory retinal detachment area seen at the moment of the Statistical analyses were performed using the Wilprocedure (Figure). The main outcome measure was coxon and Fisher tests for comparison between the visual acuity after 3 months, and the secondary out- two groups for continuous and categorical variables, come measure was change in central macular thick- respectively. The Wilcoxon signed-rank test was used ness. At the 3-month visit, patients from group 2 were for paired analysis of data before and after intervenevaluated to cross over and undergo laser treatment tion. Linear regression models using generalized estiif they met two of the three criteria considering the mating equations (GEE) were used to evaluate longimain outcome measures: decreased visual acuity of tudinal changes in visual acuity in both groups. The at least one line from baseline, macular subretinal Kolmogorov-Smirnov normality test and Dunnett’s fluid on OCT, and significant leakage on angiography. test for multiple comparisons were carried out to evalRe-treatment was reconsidered every 3 months for all uate the sham-treated patients after the cross-over. A patients. P value of less than 0.05 was considered statistically Best corrected visual acuity (EDTRS chart), color significant. The analysis was performed with Stata fundus photography, fundus autofluorescence, and version 10 (StataCorp, College Station, TX) and Prism SD-OCT were performed at 1, 3, 4, and 6 months in version 5 (GraphPad, San Diego, CA). both groups. FA was performed at 3 and 6 months in both groups and at 9 and 12 months in patients treat- RESULTS ed in a later stage of the study. A micropulse diode Fifteen eyes from 10 men and five women were laser was used for SDM photocoagulation using the divided into two groups for treatment (10 eyes) or Mainster standard contact lens (Ocular Instruments, sham (five eyes). The baseline clinical data are sumBellevue, WA). A spot size of 125 mm was used. The marized in Table 1. The average age was 44.2 ± 5.8 power was initially adjusted in the nasal retina to years for the sham group and 39.5 ± 7.7 years for the minimum threshold value for a visible burn in the treatment group (P = .243). The mean duration a continuous wave mode and 300-ms duration. The of symptoms (in months) was 31.8 ± 24.3 for the device was then changed to micropulse mode with a sham group and 13.3 ± 7.7 for the treatment group duty cycle of 15%, and the power was increased by (P = .040). There was no statistically significant dif1.2× threshold. The number of laser envelopes, laser ference considering baseline central macular thickpower energy, SDM photocoagulation sessions, and ness (OCT) and visual acuity between groups. The recurrences were recorded. median follow-up period was from 10.2 ± 2.7 and
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quired another laser treatment at the Best Corrected Visual Acuity Relative to Baseline 3-month follow-up. Considering the BCVA (letters) first stage of the study, from baseBaseline 1 Month 3 Months 6 Months 12 Months line to 3 months of Sham group 26.6 ± 6.8 26.8 ± 7.6 25.6 ± 8.9 31.0 ± 8.8 39.2 ± 7.1 follow-up, mean best P value .584 .498 .225 .042 corrected visual acuTreatment group 35.4 ± 11.1 44.4 ± 8.1 47.9 ± 8.0 50.0 ± 6.8 ity improved from 35.4 letters (20/49 P value 0.011 0.006 0.008 Snellen equivalent) BCVA = best corrected visual acuity. ± 11.6 at baseline to 47.9 letters (20/27 Snellen) ± 8.0 at 3 TABLE 3 months (P = .006) in the treatment group. Central Macular Thickness Relative to Baseline In the sham group, BCVA changed from OCT Central Macular Thickness 26.6 (20/73 Snellen) Baseline 1 Month 3 Months 6 Months 12 Months ± 6.8 letters at baseSham group 349.6 ± 61.3 351.4 ± 94.4 289.6 ± 77.7 283.6 ± 66.5 235.8 ± 66.0 line to 25.6 (20/77 P value 1.00 0.225 0.500 0.079 Snellen) ± 8.9 letters at 3 months (P Treatment group 419.6 ± 111.8 306.9 ± 55.3 265.4 ± 98.1 247.2 ± 105.4 = .498). Continued P value 0.052 0.091 0.008 follow-up revealed a BCVA of 50.0 (20/25 OCT = optical coherence tomography. Snellen) ± 6.8 letters at 6 months (P = 6.4 ± 3.2 months for the sham and treatment groups, .008) in the treatment group, 31.0 (20/60 Snellen) ± respectively. The mean power used for the continu- 8.8 letters at 6 months in the sham group (P = .225), ous wave laser to titration was 370 mW (range: 250 and 39.2 (20/41 Snellen) ± 7.1 letters at 12 months to 550 mW), and the mean power for the micropulse in the sham group (P = .042) (Table 2). Multivariate laser was 444 mW (range: 300 to 660 mW). The mean analysis showed that laser treatment led to a mean number of laser shots considering all treatments per- improvement of 15 letters (three ETDRS lines or formed was 456.9 (range: 299 to 674). double the angle of vision unit) compared with the On fluorescein angiography at baseline, all pa- sham group, regardless of age, gender, or duration of tients in the sham treatment group had a juxtafoveal symptoms. leakage point, and three showed a posterior pole winMean central macular thickness was correlated dow defect, corresponding to RPE atrophy areas. In with baseline measurements, where it ranged in the the treatment group, two patients had an extrafoveal treatment group from 419.6 ± 111.8 mm at baseline to leakage area, two had diffuse leakage with a juxtafo- 265.4 ± 98.1 mm at 3 months (P = .091) and 247.2 ± veal source of leakage, and six patients had a juxta- 105.4 mm at 6 months (P = .008). In the sham group, foveal leakage point. Five patients showed posterior mean central macular thickness was 349.6 ± 61.3 mm pole window defect areas on angiography. at baseline, 289.6 ± 77.7 mm at 3 months (P = .225), All five patients from the sham treatment group 283.6 ± 66.5 mm at 6 months (P = .500), and 235.8 ± required treatment during the follow-up period: three 66.0 mm at 12 months (P = .079) (Table 3). patients at the 3-month visit and two at the 6-month Patients in the sham group were also paired chronvisit. One patient treated at the 3-month visit required ologically from the cross-over, using as baseline data re-treatment at the 6-month follow-up, and one treat- the OCT macular thickness and visual acuity at the ed at the 6-month visit was re-treated at the 9-month time of initial laser treatment. We used the data from follow-up. In the treatment group, one patient re- the 3-month follow-up in three patients and from the TABLE 2
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6-month follow-up in two patients, TABLE 4 which is when treatment was initiChronologically Paired Mean Central Macular Thickness ated. and BCVA of Sham Group After Cross-over Mean BCVA improved from 27.40 ± 9.40 letters at baseline to 36.00 ± Paired Baseline 3 Months 6 Months 10.07 letters at 3 months and 39.60 ± 7.37 letters at 6 months (P < .05) in Central Macular 340.20 ± 45.65 252.00 ± 78.75* 233.60 ± 65.98** the sham group (Table 4). Thickness (µm) P < .05 P < .01 Mean central macular thickness BCVA (letters) 27.40 ± 9.40 36.00 ± 10.07 39.60 ± 7.37* ranged from 340.20 ± 45.65 mm at baseline to 252.00 ± 78.75 mm at 3 P < .05 months (P < .05) and 233.60 ± 65.98 *P < .05 compared to baseline. mm at 6 months (P < .01) in the sham **P < .01 compared to baseline. group after the cross-over (Table 4). BCVA = best corrected visual acuity. No laser scars could be seen on funduscopy or on FA at the end of follow-up, as expected with the SDM technique. Two patients, one in each group, had sub- group (P = .006) compared with no significant visual retinal fluid at the end of the study, but they did not improvement observed in the sham group (P = .498). present with re-treatment criteria. In fact, a marked improvement in BCVA was noted in the first month in the treatment group (P = .011). DISCUSSION There was improvement in central macular thickness Diode laser with micropulsed emission without a on OCT and leakage on fluorescein angiography in all visible burn endpoint appears to reduce the risk of originally treated patients and in the patients of both structural and functional retinal laser damage, allow- groups who were treated later in the course of the ing treatment of subfoveal lesions.14 It has been suc- study. Of 15 patients, three needed to be re-retreated cessfully used for diabetic macular edema and seems without reported complications and no evidence of to be as effective as conventional argon laser with retinal changes on fundus indirect ophthalmoscopy theoretical advantages.15,16 examination either on fluorescein angiography or In 2003, Bandello et al were the first to propose fundus autofluorescence in any patient. SDM photocoagulation for the treatment of CSC, Recognizing the limitations of a small sample size, showing positive results in a series of five cases.17 To a significant baseline difference was found in the dudate, studies on the treatment of chronic CSC have ration of symptoms between the sham (31.8 ± 24.3 shown that SDM can provide therapeutic benefits months) and treatment groups (13.3 ± 7.7 months), similar to those obtainable with standard-threshold which might explain the differential effect of the dicontinuous-wave laser photocoagulation, but without ode laser or any treatment modality in this chronic causing discernible chorioretinal lesions,12,13,18,19 al- condition. However, all patients in group 2 crossed lowing almost confluent therapy and re-treatment of over to treatment during the study follow-up, and persistent or new leaking points. they showed a significant improvement in visual acuThe greatest limitation of the SDM laser procedure ity and macular thickness after laser. is the difficulty of titrating the treatment without the In summary, this trial provides evidence that subfeedback of an ophthalmoscopically visible mark.14 threshold diode micropulse laser treatment can lead The absence of an apparent endpoint may interfere to early resolution of serous retinal detachment in with the selective treatment, but ICG-stained RPE chronic CSC, with significant functional improvecells could be an option to guide the surgeon.18 ments and without leaving any sign of laser-induced In the present pilot study, besides the small sam- lesions. The safety of SDM enables treatment closer ple size, SDM laser treatment was first of all compared to the fovea over extensive areas of RPE decompensato placebo, considering the possible influence of the tion and re-treatment over the same area as needed. type A personality related to this condition. The pa- Further research and a large clinical trial, including tients were divided into two groups for the laser or direct comparison with green laser and PDT, must be sham treatment at baseline. At the 3-month follow- performed to provide more evidence-based clinical up, BCVA significantly improved in the treatment data.
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