Central serous chorioretinopathy (CSC) is a relatively common condition among middle-aged individuals. CSC predominantly affects males and is characterized by serous detachment of the central retina, choroidal thickening, and retinal pigment epithelium (RPE) dysfunction.1 The prognosis for CSC is generally good because the subretinal fluid (SRF) often resolves spontaneously with complete visual rehabilitation; thus, the management of CSC typically starts with observation for 3 months to 6 months.2 Non-resolved CSC visual symptoms may include relative scotomas, micropsia, metamorphopsia, and abnormal color vision.3 Moreover, long-standing non-resolved CSC is associated with degenerative changes of the outer retina, RPE atrophy, and choroidal neovascularization and can result in a poor final visual outcome even after complete SRF resolution.4,5
Non-therapeutic treatment options for CSC aim to stop focal or diffuse leakage and require topical identification of an area of leakage or a leakage point. At the same time, diagnosis of CSC typically can be established with optical coherence tomography (OCT) (including OCT angiography for exclusion of choroidal neovascularization [CNV]). Thus, in noncomplicated patients with CSC, fluorescein angiography (FA) or indocyanine green angiography is only necessary when planning treatment. From this point of view, FA-free identification of the leakage point could be a step toward a completely noninvasive approach to CSC management. It could also be an option for patients with contraindications for intravenous angiography.
In our previous paper, we proposed an approach for the OCT-based identification of the leakage point without FA in noncomplicated CSC cases.6 We found that a pigment epithelium detachment (PED) localized in the upper half of neurosensory detachment with photoreceptor outer segments (PROS) thinning above this PED typically coincided with the leakage point.6 We therefore supposed that such PED, when small enough, could be used as a target for FA-free focal laser to block the leakage point with which it coincided.
In this case series, we demonstrate the practical utility of FA-free OCT-guided navigated focal laser photocoagulation (FLP) in treating patients with noncomplicated non-resolving CSC.
Patients and Methods
The study followed the ethical standards stated in the Declaration of Helsinki and was approved by the local ethics committee. Written informed consent was obtained from all patients after they were informed about the nature and potential advantages and disadvantages of the procedure.
Only symptomatic patients with non-resolved CSC (lasting more than 3 months) were included in this prospective interventional case series. CSC was confirmed by the presence of a serous detachment of the central retina associated with a single small PED. Any other causes of neurosensory detachment except for presumed CSC were excluded.
Patients underwent FA-free OCT-guided FLP if they met the following criteria: (1) CSC duration greater than 3 months; (2) the presence of a single PED detected by OCT less than 500 μm at the maximum dimension; (3) the single PED located in the upper half of the neurosensory detachment area; and (4) the presence of the PROS thinning area (defined as PROS layer thinner than that of a lower part of the neurosensory detachment of 20 μm or more) overlapping the single PED.
Exclusion criteria were as follows: any previous treatment for CSC (including mineralocorticoid receptor antagonist, FLP, micropulse laser therapy [MLT], or photodynamic therapy [PDT]); symptoms lasting less than 3 months or more than 12 months; and signs of any other active retinal disease in the study eye. Patients who had a flat, irregular PED, global RPE disruption masking individual PED, complete atrophy of PROS layer, or suspicion of CNV on OCT-angiography (available with Copernicus REVO [Optopol, Zawiercie, Poland]) were also considered to be not appropriate for FA-free OCT-guided FLP. In cases of bilateral CSC, only one eye was included in the study.
All patients underwent comprehensive ophthalmic examinations, including measurement of best-corrected visual acuity (BCVA), slit-lamp examination, and indirect ophthalmoscopy.
Optical Coherence Tomography and Treatment Planning
In all patients, an OCT examination was performed to assess the number and position of PEDs as well as the presence of PROS thinning area. Two spectral-domain OCT systems were used in this study. Three-D reference scan (7 mm × 7 mm with 141 B-scans each of 385 A-scans) of RTVue-100 (Optovue, Fremont, CA) and three-dimensional volume scan (7 mm × 7 mm with 163 B-scans each of 320 A-scans) of the Copernicus REVO were used to identify leakage points. The central retinal thickness (CRT) was obtained using the macular thickness map. The height of SRF was measured manually between the outer border of the PROS layer and the RPE at the foveal center. In cases of eccentric neurosensory detachment, the maximum height of SRF was used for analysis.
En face images from RTVue-100 were produced with a slab thickness of 20 μm to 40 μm at the level of the RPE. In cases in which relatively high PEDs were present (the hyporeflective space between the RPE and Bruch's membrane being clearly visible), PED was defined on en face images as a hyporeflective (black) area with sharp borders, which was considered the presumed leakage point. In cases of poor visualization of PED on the en face image (the presence of relatively flat PED), the presumed leakage point was indicated at the intersection of the x- and y-scans using OCT software. Using Copernicus REVO, a presumed leakage point was indicated on the fundus reconstruction image as the position of A-scan at the center of PED responsible for leakage. The PROS thickness was evaluated on cross-sectional scans using a built-in caliper tool of the OCT system software (Figure 1).
Representative example of fluorescein angiography (FA)-free optical coherence tomography (OCT)-guided navigated focal laser photocoagulation of a leakage point without FA (Case 8). (A) En face image with a noted presumed leakage point superimposed on the baseline fundus image. (B) Focal laser photocoagulation treatment plan included three laser spot marks placed at the pigment epithelium detachment (PED). The white line represents the position of the cross-sectional OCT scan. (C) Cross-sectional OCT scan demonstrated a focal PED (asterisk) in the upper part of the neurosensory detachment area and photoreceptor outer segments layer thinning (arrowheads) above this PED.
En face or fundus reconstruction images with the noted leakage points were imported into the Navilas 532 (OD-OS, Teltow, Germany) system, superimposed onto the baseline image (the Navilas color fundus image), and utilized for treatment planning. An initial test burn was performed outside of the neurosensory detachment area to find the parameters for the treatment laser shots. Laser spot marks were placed at the site of the presumed leakage point with spot size of 100 μm, burn spacing of 0.5 to 1.0 burn-widths apart, and a pulse duration of 100 ms (Figure 1).
Retinal treatment began with the titration of the laser power outside the macular region to a minimally visible retinal lesion endpoint. Laser treatment was performed with a 0-power contact lens using topical anesthesia with 0.5% proxymetacaine (Alcaine; Alcon Couvreur NV, Puurs, Belgium).
Postoperatively, OCT examination was performed weekly until the complete resolution of the neurosensory detachment and monthly after that. The primary outcome measure was complete SRF resolution on OCT at 2 months after intervention. The secondary outcome measures included BCVA score at 2 months after FLP and the total number of shots per leakage point. The minimum duration of follow-up was 6 months.
Statistica 10.0 (StatSoft, Tulsa, OK) was used for statistical analysis. The results are expressed as mean ± SD for continuous variables. Wilcoxon signed-rank test was used to assess changes in baseline BCVA, CRT, and height of SRF at 2 months after FLP.
Thirty consecutive patients with unilateral acute non-resolving symptomatic CSC were enrolled in this prospective interventional case series; from those, 16 patients (53.3%) met the criteria to be selected for FA-free navigated focal laser photocoagulation. The patient profiles are shown in Table 1. Of 16 eyes, seven were emmetropic, seven were hyperopic, and two were myopic. Two patients (Cases 13 and 15) had no foveal involvement but had complaints about a paracentral relative scotoma.
Baseline Characteristics and Clinical Outcomes of Patients Undergoing Optical Coherence Tomography-Guided Focal Laser Photocoagulation of Leakage Points Without Fluorescein Angiography
Each patient received an average of 3.1 ± 0.44 laser burns targeting the PED responsible for the leakage. One patient (Case 13) received two sessions of FA-free FLP. The first session with three laser shots (shot power of 60 mW, pulse duration of 70 ms) did not result in change of SRF at 1 month after treatment. One month after the first session, the second session was performed using the same treatment plan with a higher laser power (shot power of 90 mW, pulse duration of 70 ms) followed by complete resolution of SRF at 1 month after FLP (Figure 2). One patient without foveal involvement (Case 15) had two eccentric neurosensory detachments, one of which was symptomatic. In this case, only symptomatic neurosensory detachment met the criteria for FA-free OCT-guided FLP (Figure 3) and was treated. At the moment of complete resolution of treated neurosensory detachment, as well as at the end of follow-up, SRF in the nontreated neurosensory detachment persisted.
Optical coherence tomography (OCT)-guided navigated focal laser photocoagulation of a leakage point without fluorescein angiography (Case 13). (A) Retinal thickness map showed increased central retinal thickness associated with neurosensory detachment. (B) Cross-sectional scan through the presumed leakage point (represented by the black line on the retinal thickness map) coinciding with a pigment epithelium detachment (PED) (arrowhead) demonstrated significantly thinner photoreceptor outer segments (PROS) layer compared with the lower part of neurosensory detachment. (C) Cross-sectional scan through the center of the macula (represented by blue line) demonstrated that thickness of PROS layer across the detached retina progressively increases from the presumed leakage point in the upper part of neurosensory detachment toward the lower part of neurosensory detachment. (D) Cross-sectional scan through the lower part of neurosensory detachment (represented by red line) showed thick PROS layer. (E) The focal laser photocoagulation treatment plan with en face image superimposed on baseline image. The position of the presumed leakage point was indicated in the intersection of x- and y-scans and targeted with three laser spot marks. The black dashed line outlines the area of neurosensory detachment. (F) En face OCT revealed irregular (ellipsoid) neurosensory detachment with the PED (asterisk) in the upper part of the detachment area. (G) Retinal thickness map showed normal central retinal thickness 1 month after second session of OCT-guided navigated focal laser photocoagulation. (H) Cross-sectional scan through the site of former leakage point (represented by black line) showed retinal pigment epithelium irregularities resulting from laser burns. (I) Cross-sectional scan through the center of the macula (represented by blue line) demonstrated normal retina appearance with little attenuation of the PROS layer. (K) Cross-sectional scan through the lower part of neurosensory detachment (represented by red line) revealed complete resolution of subretinal fluid. Minimal attenuation of PROS layer is also noticeable.
Optical coherence tomography (OCT)-guided navigated focal laser photocoagulation of a leakage point without fluorescein angiography in a patient with two neurosensory detachments (Case 15). (A) Montaged retinal thickness map showed two areas (dashed lines) of neurosensory detachments. Only temporal neurosensory detachment was symptomatic. (B) Cross-sectional scan through the presumed leakage point (represented by black line on retinal thickness map) coinciding with pigment epithelium detachment (PED) (arrowhead) demonstrated significant thinning of the photoreceptor outer segments (PROS) layer compared with the lower part of neurosensory detachment. (C) Cross-sectional scan through the asymptomatic nasal neurosensory detachment (represented by red line) demonstrated no PEDs and regular PROS layer. (D) Cross-sectional scan through the lower part of the symptomatic temporal neurosensory detachment (represented by blue line) showed thick PROS layer. (E) The focal laser photocoagulation treatment plan with fundus reconstruction image superimposed on baseline image. Presumed leakage point was indicated as the position of A-scan and targeted with three laser spot marks. (F) En face OCT revealed irregular (ellipsoid) shape of neurosensory detachment with PED (asterisk) in the upper part of the neurosensory detachment area. (G) Montaged retinal thickness map 3 weeks after focal laser photocoagulation showed normal retinal thickness in the area of the temporal neurosensory detachment. Note that nasal neurosensory detachment (dashed line) persisted. (H) Cross-sectional scan through the site of former leakage point (represented by black line) showed thinning of outer retinal layers. (I) Cross-sectional scan through the asymptomatic nasal neurosensory detachment (represented by red line) demonstrated no changes compared with baseline. (K) Cross-sectional scan through the lower part of neurosensory detachment (represented by blue line) revealed complete resolution of subretinal fluid and thinning of outer retinal layers.
Fourteen of 16 patients (87.5%) achieved complete resolution of SRF at 2 months after FLP. For all the patients, the mean time for complete resolution of SRF after FLP was 6.5 weeks ± 1.8 weeks. The mean BCVA statistically significantly increased from 0.08 ± 0.09 (20/25 Snellen equivalent) at baseline to 0.0 ± 0.04 (20/20) at 2 months after FLP (P = .0005). Both the mean CRT and the mean height of SRF decreased statistically significant (P < .001) from 395.3 μm ± 146.3 μm and 225.1 μm ± 104.4 μm, respectively, at baseline to 234.4 μm ± 37.2 μm and 10.5 μm ± 30.3 μm, respectively, at 2 months after FLP. The final CRT after complete resolution of SRF was 227.5 μm ± 28.0 μm.
During the follow-up, there were no adverse events associated with laser application. In one patient (6.25%) (Case 14), SRF recurrence occurred at 3 months after FLP and resolved spontaneously 3 weeks after onset.
In this prospective case series, we showed that focal leakage (leakage point) could be identified with OCT and successfully treated without FA in a significant number of CSC patients.
The FA-free approach described in this study was based on the relatively well-known fact that PED is frequently present at the leakage point in CSC patients.7–9 However, this fact alone does not allow focal laser targeting PED to be performed because noncoincidence of leakage point and PED is possible. However, two additional OCT findings may allow us to verify the presence of leakage at the particular PED. The first finding is PROS thinning in the area of PED, which was found in 89.3% of PEDs coinciding with leakage points.6 The second finding was that the leakage point was typically associated with a PED located in the upper half of the neurosensory detachment area.6
Based on this consideration, the steps of the OCT-based algorithm for the identification of presumed leakage points in patients with CSC include: (1) the visualization of all PEDs within the neurosensory detachment area; (2) the exclusion of the PEDs localizing in the lower half of the neurosensory detachment area; and (3) an analysis of the PED and PROS thinning area colocalization. Nevertheless, we theorize that patients with multiple PEDs could be treated, as well, if they demonstrate only one PED in the upper half of the neurosensory detachment and / or noticeable focal PROS thinning. To minimize risk of misidentification of the presumed leakage point, in this study we excluded patients who demonstrated more than one PED on OCT.
Although this study had no control group, it prospectively demonstrated no failures in identification of presumed leakage point in a specific cohort of patients with CSC. Interestingly, in the patient who had two neurosensory detachments (Case 15), only the one treated demonstrated resolution of SRF, while the nontreated detachment continued to persist. An “inner control” (a nontreated neurosensory detachment) presented in this case supports effectiveness and the sufficient precision of FA-free OCT-guided identification of leakage point because it allows us to exclude self-resolution of the treated neurosensory detachment. In one patient (Case 13), the first session of FLP did not result in SRF resolution. Because the second session of FLP was performed using the same treatment plan, we believe that the first session could be considered a “sham” FLP (due to the low laser energy used) and excludes self-resolution of SRF. This case therefore also advocates for practical effectiveness of FA-free OCT-guided FLP.
Because CSC is a self-limiting condition, treatment is recommended only for non-resolving cases with a duration of more than 3 months. Treatment of CSC cases uncomplicated by CNV may include laser photocoagulation of the leakage points,10 PDT with verteporfin,11 or subthreshold MLT.12 Although all three methods result in the resolution of SRF and an increase in visual acuity, none reduce the risk of CSC recurrence. Moreover, all three methods are not without disadvantages. Conventional FLP can be performed only if focal leakage is found on FA and is considered to be an inappropriate procedure for chronic CSC cases associated with diffuse leakage. Potential adverse effects of PDT are associated with overtreatment of the choroidal vasculature, choroidal ischemia, and CNV.13 Further, intravenous administration of verteporfin is generally safe but may have potential systemic complications. At the same time, the advantages of MLT over FLP or PDT are still debated.12,14 In contrast with FLP, both PDT and MLT share a common advantage because these procedures have demonstrated effectiveness in chronic CSC cases with diffuse leakage.14
Navigated laser therapy used in this study has been shown to be effective and safe for FLP in patients with non-resolved CSC.15,16 The navigated approach improves the accuracy of the application of laser burns and reduces the risk of damage to the foveal avascular zone.17 The FA-free OCT-guided approach for conventional FLP may be challenging because of significant differences in appearance between the ophthalmoscopic view and the en face image used for treatment planning. This disadvantage is completely solved by planning with a navigated laser system, allowing us to superimpose an en face image on a baseline image of the eye fundus.
As was reported earlier, the resolution of the SRF in patients with CSC can be achieved with the application of a single laser spot for each single leak with minimum iatrogenic damage to the retina.16 In our treatment protocol, we used 3.3 ± 0.5 laser spots per presumed leakage point because in the majority of cases, targeting PED was significantly larger than the typical leakage point. The application of more than one laser burn per presumed leakage point was not associated with any adverse event during the follow-up as demonstrated by Mastropasqua et al. in an earlier study.15 Thus, in our cohort of patients, FA-free FLP appears to be non-inferior to conventional FA-guided focal laser in terms of tissue sparing. Our study also demonstrated similar to conventional FLP success rate as well as the rates of both SRF resolution and SRF recurrence in patients with CSC who underwent FA-free OCT-guided FLP of leakage points.15–17
A concern about the FA-free approach is the potential possibility of the misidentification of presumed leakage points. However, strict adherence to the algorithm of identification of presumed leakage points as well as adequate patient selection minimizes the failure rate. Moreover, modern laser therapy is generally safe and, if performed correctly, is associated with a minimum risk for adverse events such as CNV or central scotoma.
The effectiveness and safety of FA-free OCT-guided approach for navigated FLP were demonstrated in this study. Nevertheless, the selection of patients and strict adherence to the algorithm of identification of the presumed leakage points are critical for this procedure. This procedure was easy to perform using a navigated laser system and can also be replicated by most laser surgeons using conventional laser systems. We believe that this surgical technique is a good option for a significant number of patients with CSC. Additionally, the FA-free OCT-guided approach can also be used for MLT or PDT because the precision of these procedures is inferior to that of FLP. Nevertheless, further studies should be conducted to verify this suggestion.
- Daruich A, Matet A, Dirani A, et al. Central serous chorioretinopathy: Recent findings and new physiopathology hypothesis. Prog Retin Eye Res. 2015;48:82–118. doi:10.1016/j.preteyeres.2015.05.003 [CrossRef]
- Mehta PH, Meyerle C, Sivaprasad S, Boon C, Chhablani J. Preferred practice pattern in central serous chorioretinopathy. Br J Ophthalmol. 2017;101(5):587–590. doi:10.1136/bjophthalmol-2016-309247 [CrossRef]
- Liew G, Quin G, Gillies M, Fraser-Bell S. Central serous chorioretinopathy: A review of epidemiology and pathophysiology. Clin Exp Ophthalmol. 2013;41(2):201–214. doi:10.1111/j.1442-9071.2012.02848.x [CrossRef]
- Breukink MB, Dingemans AJ, den Hollander AI, et al. Chronic central serous chorioretinopathy: Long-term follow-up and vision-related quality of life. Clin Ophthalmol. 2017;11:39–46. doi:10.2147/OPTH.S115685 [CrossRef]
- Lee WJ, Lee JH, Lee BR. Fundus autofluorescence imaging patterns in central serous chorioretinopathy according to chronicity. Eye (Lond). 2016;30(10):1336–1342. doi:10.1038/eye.2016.113 [CrossRef]
- Maltsev DS, Kulikov AN, Chhablani J. Topography-guided identification of leakage point in central serous chorioretinopathy: A base for fluorescein angiography-free focal laser photocoagulation. Br J Ophthalmol. 2018;102(9):1218–1225. doi:10.1136/bjophthalmol-2017-311338 [CrossRef]
- Fujimoto H, Gomi F, Wakabayashi T, Sawa M, Tsujikawa M, Tano Y. Morphologic changes in acute central serous chorioretinopathy evaluated by fourier-domain optical coherence tomography. Ophthalmology. 2008;115(9):1494–1500, 1500.e1–2. doi:10.1016/j.ophtha.2008.01.021 [CrossRef]
- Kim HC, Cho WB, Chung H. Morphologic changes in acute central serous chorioretinopathy using spectral domain optical coherence tomography. Korean J Ophthalmol. 2012;26(5):347–354. doi:10.3341/kjo.2012.26.5.347 [CrossRef]
- Roisman L, Lavinsky D, Magalhaes F, et al. Fundus autofluorescence and spectral domain OCT in central serous chorioretinopathy. J Ophthalmol. 2011;2011:706849. doi:10.1155/2011/706849 [CrossRef]
- Robertson DM, Ilstrup D. Direct, indirect, and sham laser photocoagulation in the management of central serous chorioretinopathy. Am J Ophthalmol. 1983;95(4):457–466. doi:10.1016/0002-9394(83)90265-9 [CrossRef]
- Lim JI, Glassman AR, Aiello LP, et al. Collaborative retrospective macula society study of photodynamic therapy for chronic central serous chorioretinopathy. Ophthalmology. 2014;121(5):1073–1078. doi:10.1016/j.ophtha.2013.11.040 [CrossRef]
- Ambiya V, Goud A, Mathai A, Rani PK, Chhablani J. Microsecond yellow laser for subfoveal leaks in central serous chorioretinopathy. Clin Ophthalmol. 2016;10:1513–1519. doi:10.2147/OPTH.S112431 [CrossRef]
- Erikitola OC, Crosby-Nwaobi R, Lotery AJ, Sivaprasad S. Photodynamic therapy for central serous chorioretinopathy. Eye (Lond). 2014;28(8):944–957. doi:10.1038/eye.2014.134 [CrossRef]
- Salehi M, Wenick AS, Law HA, Evans JR, Gehlbach P. Interventions for central serous chorioretinopathy: A network meta-analysis. Cochrane Database Syst Rev. 2015;(12):CD011841.
- Mastropasqua L, Di Antonio L, Toto L, Mastropasqua A, Di Iorio A, Carpineto P. Central serous chorioretinopathy treated with navigated retinal laser photocoagulation: Visual acuity and retinal sensitivity. Ophthalmic Surg Lasers Imaging Retina. 2015;46(3):349–354. doi:10.3928/23258160-20150323-09 [CrossRef]
- Chhablani J, Rani PK, Mathai A, Jalali S, Kozak I. Navigated focal laser photocoagulation for central serous chorioretinopathy. Clin Ophthalmol. 2014;8:1543–1547. doi:10.2147/OPTH.S67025 [CrossRef]
- Kozak I, Oster SF, Cortes MA, et al. Clinical evaluation and treatment accuracy in diabetic macular edema using navigated laser photocoagulator NAVILAS. Ophthalmology. 2011;118(6):1119–1124. doi:10.1016/j.ophtha.2010.10.007 [CrossRef]
Baseline Characteristics and Clinical Outcomes of Patients Undergoing Optical Coherence Tomography-Guided Focal Laser Photocoagulation of Leakage Points Without Fluorescein Angiography
|Patient||Age (Years)||Gender||Duration of Symptoms (Weeks)||Refraction||Baseline CRT (μm)||CRT at 2 Months (μm)||Baseline SRF Height (μm)||Height of SRF at 2 Months (μm)||Baseline BCVA logMAR (Snellen Equivalent)||Final BCVA logMAR (Snellen Equivalent)||Resolution of SRF (Weeks)||No. of Laser Burns||Follow-Up (Weeks)|
|1||33||M||12||E||548||227||353||0||0.10 (20/25)||0.00 (20/20)||6||3||33|
|2||48||F||32||E||403||228||169||0||0.05 (20/22)||0.00 (20/20)||7||3||72|
|3||45||M||12||E||277||179||218||0||0.22 (20/33)||0.05 (20/22)||8||3||43|
|4||47||M||13||E||340||296||247||0||0.10 (20/25)||0.00 (20/20)||7||3||38|
|5||37||M||16||H||278||216||169||57||0.10 (20/25)||0.05 (20/22)||9||4||48|
|6||37||M||12||H||552||231||375||0||0.00 (20/20)||−0.08 (24/20)||8||4||32|
|7||60||M||20||E||508||234||194||0||0.30 (20/40)||0.00 (20/20)||7||3||29|
|8||43||M||12||H||437||252||238||0||0.15 (14/20)||0.00 (20/20)||6||3||27|
|9||39||M||14||H||692||233||446||111||0.05 (20/22)||−0.08 (24/20)||9||3||25|
|10||50||M||16||H||483||265||204||0||0.00 (20/20)||0.00 (20/20)||7||3||28|
|11||48||M||13||H||239||195||87||0||0.00 (20/20)||0.00 (20/20)||8||2||24|
|12||48||M||12||H||337||206||126||0||0.00 (20/20)||−0.08 (24/20)||6||3||24|
|13||31||M||12||M||540||231||333||0||0.10 (20/25)||−0.08 (24/20)||4||3||30|
|14||44||F||12||M||256||226||210||0||0.10 (20/25)||0.00 (20/20)||4||3||31|
|15||38||M||12||E||198||197||154||0||0.00 (20/20)||0.00 (20/20)||3||3||29|
|16||30||F||12||E||237||225||78||0||0.00 (20/20)||0.00 (20/20)||5||3||52|
|42.4 ± 8.0||14.5 ± 5.2||395.3 ± 146.3||234.4 ± 37.2||225.1 ± 104.4||10.5 ± 30.3||0.08 ± 0.09 (20/25)||0.0 ± 0.04 (20/20)||6.5 ± 1.8||3.1 ± 0.44||35.3 ± 12.9|