Subthreshold Micropulse Laser (577 nm) Treatment in Chronic Central Serous Chorioretinopathy

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1 Originl Pper Received: Mrch 24, 2015 Accepted fter revision: August 17, 2015 Published online: September 26, 2015 Subthreshold Micropulse Lser (577 nm) Tretment in Chronic Centrl Serous Chorioretinopthy Pul Scholz Lebriz Ersoy Cmiel J.F. Boon b Ssch Fuser Deprtment of Ophthlmology, University Hospitl of Cologne, Cologne, Germny; b Leiden University Medicl Center, Leiden, The Netherlnds Key Words Centrl serous chorioretinopthy Subthreshold micropulse lser Photodynmic therpy Abstrct Purpose: To ssess tretment with 577-nm subthreshold micropulse lser (SML) in ptients with chronic centrl serous chorioretinopthy (ccsc). Methods: This retrospective study included 38 ptients treted with 577-nm SML (Supr Scn; Quntel Medicl) for ccsc. We included subgroup of 18 ptients with persistent subretinl fluid (SRF) fter photodynmic therpy (PDT). Assessment included visul cuity (VA), centrl retinl thickness (CRT) nd resolution of SRF. Results: At the lst follow-up (men 5 months), 74% of ptients responded to therpy. The CRT decresed fter tretment (men CRT 115 μm, p < 0.001) nd VA improved (men logmar 0.06, p = 0.039). No lser burns were detected with ny imging modlity. In the subgroup of ptients resistnt to PDT, 61% of ptients responded to therpy with decrese in CRT (men CRT 75 μm, p = 0.019). Conclusions: The 577-nm SML is n effective tretment for ccsc even in ptients without sufficient improvement fter PDT S. Krger AG, Bsel Introduction Centrl serous chorioretinopthy (CSC) is chrcterized by vision loss due to serous detchment of the neurosensory retin [1]. Clinicl evidence from multimodl imging, such s choroidl congestion nd thickening nd hyperpermebility of the choroid, suggests tht choroidl dysfunction is n importnt underlying cuse for retinl pigment epithelium (RPE) dysfunction nd subretinl fluid (SRF) lekge in CSC [2, 3]. Two min subtypes of CSC cn be distinguished: cute nd chronic CSC (ccsc). In cute CSC, the detchment is cused by focl lek ( hot spot ) in the RPE. The SRF usully resolves spontneously within few weeks, nd visul cuity (VA) recovers to (ner-) norml in cute CSC [4]. However, ccsc cn led to permnent structurl dmge nd often pronounced loss of centrl vision [5 7]. These ptients show irregulr mildly trophic RPE chnges nd choroidl bnormlities which often occur without single focl hot spot but with more diffuse lekge. So fr, there is no gold stndrd tretment for CSC. For extrfovel lekge, the conventionl suprthreshold rgon lser photocogultion cn be used, which cn ccelerte resolution of SRF [6, 8]. Potentil side effects in- E-Mil krger@krger.com S. Krger AG, Bsel /15/ $39.50/0 Ssch Fuser Deprtment of Ophthlmology, University Hospitl of Cologne Kerpener Strsse 62 DE Cologne (Germny) E-Mil uk-koeln.de

2 Fig. 1. ICGA of ptient showing inkblot lekge pttern nd diffuse RPE bnormlities typicl for ccsc. b A schemtic illustrtion of the micropulse lser tretment. b clude choroidl neovsculriztion [9] nd reduction of contrst sensitivity [10]. Furthermore, this lser tretment is not suitble for diffuse or centrl lekge s it cuses scotoms. Another tretment option is photodynmic therpy (PDT) which cn be pplied even to juxtfovel nd subfovel lesions. However, even when using reduced tretment settings, PDT lso hs potentil side effects, such s RPE trophy, choroidl neovsculriztion, choriocpillris ischemi, nd trnsient reduction of mculr function [11 15]. Subthreshold micropulse lser (SML) tretment without ny visible endpoint seems to be promising lterntive tretment strtegy. In SML, energy is pplied in very short lser pulses seprted by enough time to llow het dissiption nd minimize therml dmge to the trget tissue nd its surrounding structures. It is ssumed tht retinl dmge my not be needed to chieve therpeutic effect [16]. After SML tretment, no lser spots on clinicl exmintion cn be detected. Severl studies with micropulse diode lser (810 nm) showed some efficcy in CSC ptients with subfovel nd extrfovel lekge sites [17 20]. We hve now evluted new 577-nm micropulse lser which potentilly llows better titrtion of lser power s the individul threshold cn be clibrted in the micropulse mode in the more peripherl retin s the power cn be incresed high enough to produce visible burns. This my llow more effective tretment while mintining subthreshold tretment. In this study, we retrospectively reviewed the effect of 577-nm SML tretment in ptients with ccsc. Ptients nd Methods Dt of ptients treted with the Supr Scn 577-nm lser (Quntel Medicl, Cedex, Frnce) for ccsc were retrospectively nlyzed. The dignosis of ccsc with multimodl imging ws bsed on n extensive ophthlmologic exmintion, including fundoscopy, spectrl domin opticl coherence tomogrphy (SD- OCT), fluorescein ngiogrphy (FA), nd indocynine green ngiogrphy (ICGA) (Spectrlis, Heidelberg Engineering, Heidelberg, Germny). The definition of ccsc used in this study ws bsed on the currently vilble literture, tking the following chrcteristics into ccount (ll hd to be present): serous SRF on SD-OCT, 1 res of multifocl diffuse lekge on FA, nd corresponding hyperfluorescence on ICGA, s described previously [21]. Ptients with evidence of other retinl dignoses, such s choroidl neovsculriztion or polypoidl choroidl vsculopthy, were excluded. If both eyes of ptient were treted, only one rndomly chosen eye ws included in this nlysis. We included ptients with persistent SRF for t lest 6 weeks who were treted with SML between November 2013 nd December Ptients with previous PDT tretments were included s long s the lst tretment ws more thn 3 months prior to SML. Lser spots were pplied with the Are Centrlis contct lens (lser spot mgnifiction 0.94; Volk Opticl Inc., Mentor, Ohio, USA). Stndrdized tretment prmeters were used. The spot size ws 160 μm, the exposure time 0.2 s, nd duty cycle of 5% ws used. We chose duty cycle of 5% becuse this llows for the het production time to be shorter thn the therml relxtion time for the spce between the RPE nd the neurl retin, which results in xil confinement of the increse in het t the RPE [22]. To chieve confluent lser tretment, the multispot mode, without spcing between the spots, ws chosen ( fig. 1 ). The individul power for the ptient ws titrted t norml re of the retin, ner the ffected re in the monospot micropulse mode. The power titrtion ws strted t 700 mw nd then grdully incresed until just visible burn ws seen. When this threshold ws reched, the power ws reduced by 50%. With this power, the SML tretment of the hyperfluorescent res on mid-phse ICGA nd 2 Scholz/Ersoy/Boon/Fuser

3 the corresponding hot spots on mid-phse FA ws performed. The tretment outcome ws evluted using the best-corrected VA (BCVA), centrl retinl thickness (CRT) nd resolution of SRF. The CRT ws mesured using the utomted segmenttion progrm of the Heidelberg Eye Explorer softwre. All scns were checked for correct segmenttion nd correct positioning of the scn on the fove nd, if necessry, mnully djusted. The existence of SRF ws ssessed in the volume scns. Sttisticl Anlysis SPSS (IBM SPSS Sttistics, version 22) ws used for the sttisticl nlysis. The VA nd the CRT before nd fter SML were compred using the Wilcoxon signed-rnk test. The Spermn correltion coefficient ws used to evlute the correltion between the gin in BCVA nd the reduction in CRT fter SML tretment. Kpln-Meier curves were clculted for morphologicl nd functionl response. Results Thirty-eight eyes of 38 consecutive ptients (29 men nd 9 women) were included in the nlysis. The men ge of the ptients ws 51 yers (rnge 32 69). The men durtion of disese before SML tretment ws 4 yers (rnge 4 months to 19 yers). In this study, 17 eyes received one SML tretment, 15 eyes two, nd 6 eyes three SML tretments. BCVA t bseline ws 0.36 (SD ±0.24) men logrithm of the minimum ngle of resolution (logmar). CRT ws 402 (SD ±139 μm). The men follow-up fter the first SML tretment ws 5.0 months (SD ±3.7). Tretment Outcome At 6 weeks, in 5 out of 38 eyes (13%), the SRF hd disppered completely nd in 19 eyes (50%), the SRF ws reduced but hd not completely disppered. Fourteen eyes (37%) showed no improvement in SRF. The CRT decresed significntly 6 weeks fter tretment (men CRT before SML: 402 ± 139 μm, fter SML: 309 ± 86 μm, p < 0.001), but BCVA showed no significnt increse (men logmar before: 0.36 ± 0.24, fter SML: 0.33 ± 0.24). At the 3-month visit, in 7 out of 23 eyes (30%), the SRF hd disppered completely, nd in 13 eyes (57%), the mount of SRF ws reduced. In 3 eyes (13%), the mount of SRF incresed. The CRT decresed significntly (men CRT before SML: 410 ± 155 μm, fter SML: 263 ± 57 μm, p < 0.001). BCVA showed no significnt improvement (men logmar before: 0.33 ± 0.27, fter SML: 0.27 ± 0.26). At the 6-month visit, 2 out of 14 eyes (14%) showed no SRF nd 9 eyes (64%) showed less SRF. In 3 eyes (21%), the SRF incresed. The CRT remined significntly decresed (men CRT before SML: 496 ± 175 μm, fter SML: 276 ± 46 μm, p = 0.005). BCVA showed no significnt improvement (men logmar before: 0.36 ± 0.23, fter SML: 0.29 ± 0.19). At the lst follow-up (5.0 ± 3.7 months fter SML), in 9 eyes (24%) the SRF hd disppered completely, nd in 19 eyes (50%) the SRF ws reduced. Ten eyes (26%) showed no improvement. The CRT decresed significntly fter tretment (men CRT before SML: 402 ± 139 μm, fter SML: 287 ± 75 μm, p < 0.001), nd BCVA showed significnt increse (logmar before: 0.36 ± 0.24, fter SML: 0.30 ± 0.25, p = 0.039). The BCVA improved in 17 out of 38 eyes (45%) by one or more lines (in 8 eyes by one line, in 5 eyes by two lines nd in 4 eyes by three or more lines). Fourteen eyes (37%) mintined vision, nd 7 eyes (18%) lost one or two lines (5 eyes one nd 2 eyes two lines). There ws significnt correltion between the gin in BCVA nd the reduction in CRT fter SML tretment (p = 0.036). Kpln-Meier curves were clculted for morphologicl response (improvement in CRT of t lest 15 μm) nd functionl recovery (increse in BCVA of t lest one line) ( fig. 2 ). In most cses, the functionl response set in erly, while BCVA improved over longer period of time. Disese Recurrence One eye with complete resolution of SRF fter 3 months hd recurrence 10 months fter the initil tretment. Five eyes with persistent SRF 6 weeks fter the first tretment showed complete resolution of SRF fter second SML tretment nd styed dry until the lst follow-up. Four eyes showed complete resolution of SRF t the 6-week visit nd styed dry during the follow-up period of up to 8 months. Pretretment with PDT The subgroup of ptients who did not respond sufficiently to one or more hlf-dose PDT tretments in the pst (n = 18) ws nlyzed. In this group, 2 eyes (11%) showed complete resolution of SRF t the lst follow-up, in 9 eyes (50%) the SRF ws reduced, nd 7 eyes (39%) showed no improvement. The CRT decresed significntly fter tretment (men CRT before SML: 357 ± 131 μm, fter SML: 282 ± 54 μm, p = 0.019). BCVA showed no significnt increse (men logmar before: 0.37 ± 0.20, fter SML: 0.33 ± 0.19). The reduction in CRT ws smller (CRT: 75 ± 140 μm; BCVA: 0.03 ± 0.1 logmar) thn in the group of previously untreted ptients (CRT: Micropulse Lser in Centrl Serous Chorioretinopthy 3

4 Ptients without improvement in CRT fter tretment Decrese in CRT Censored Ptients without improvement in BCVA fter tretment Increse in BCVA Censored Time fter tretment (weeks) b Time fter tretment (weeks) Fig. 2. Kpln-Meier plots on tretment response fter SML tretment. Time point when ptients showed reduction in CRT of t lest 15 μm. b Time point when ptients showed n improvement in BCVA of t lest 1 line. 152 ± 144 μm; BCVA: 0.09 ± 0.2 logmar), lthough the difference ws not sttisticlly significnt. Nonresponse to SML Tretment In the group of ptients who did not respond to the SML tretment, the verge ge ws significntly higher thn in the group of responders (men ge nonresponders: 56.0 yers, SD ±8.7; responders: 47.9 yers, SD ±7.8, p = 0.013). Regrding the disese durtion nd number of lekge points, there ws no significnt difference between the two groups (p = nd p = 0.489, respectively). However, diffuse RPE decompenstion with or without dditionl point source lekge ws found in 100% of the nonresponders, wheres this ws found in only 52% of the responders (p = 0.009). Sfety No lser spots were detected fter tretment by biomicroscopy, SD-OCT, fundus utofluorescence, infrred reflectnce imge, or FA nd ICGA. Ptients with up to three SML tretments lso did not show ny structurl lser dmge. We only detected lser spots from the titrtion procedure in the retinl periphery by incresed utofluorescence. Discussion In this study, SML tretment with 577-nm lser ws ssocited with disppernce or significnt reduction of SRF in 75% of ptients with ccsc. As ll ptients hd t lest 4 months of persistent SRF, the effect ws likely ttributble to the lser tretment effect nd not to spontneous resolution of fluid in most cses. Overll, we sw smll improvement of BCVA tht ws correlted with the reduction in CRT. However, our cohort hd n often long-stnding history of CSC of up to 19 yers with possibly permnent structurl dmge tht precluded mrked visul improvement. However, even ptients without BCVA improvement will probbly benefit from resolution of the serous neuroretinl detchment becuse of prevention of further retinl trophy nd stbiliztion of visul function [23]. It is lso importnt to note tht even severe, long-stnding cses could show reduction or resolution of SRF. Nonresponse ws ssocited with diffuse RPE decompenstion nd higher ge but not with the durtion of disese. A resolution or reduction of SRF my still be chieved with SML therpy in ccsc ptients who did not respond to prior hlf-dose PDT tretments. This does not men tht PDT ws inferior per se but tht some ptients might be more suitble 4 Scholz/Ersoy/Boon/Fuser

5 to either PDT or SML or tht there my even be synergistic effect when combining both methods. Kpln-Meier nlysis showed tht morphologicl improvements tend to set in erlier thn functionl recovery. In previous studies with 577-nm SML, complete resolution in 33 75% nd t lest prtil resolution in 100% of ptients with ccsc were reported [24, 25]. However, these studies used other inclusion criteri nd some ptients with more cute CSC who re more inclined to dry up spontneously. In our study, 24% of ptients dried up completely nd 75% showed t lest prtil resolution of fluid. However, this less fvorble outcome is possibly due to the severity of the disese in our cohort with phenotype of diffuse lekge, very long-stnding disese, or being refrctory to previous tretment with PDT. As there is no visible endpoint in SML tretment, there is risk of undertretment. Therefore, we used confluent tretment of the ffected retinl nd choroidl re nd individully djusted the lser power by the titrtion procedure described bove. Despite this, severl ptients needed repetition of the SML which then further decresed SRF. Nevertheless, even fter three tretments, no structurl lser dmge ws seen. Overll, we did not observe ny dverse events in the whole cohort. Tretment very close to the fove ws lso sfe. This indictes tht 577-nm SML tretment cn be performed sfely nd repetedly, lthough long-term follow-up studies re required to confirm this on the long run. Although there seems to be cler tretment effect of SML therpy in our retrospective cse series, only minority of eyes (24%) hd complete resolution of SRF t the finl follow-up, but nother 51% of eyes showed significnt reduction of SRF ccumultion. Our dt indicte tht SML generlly chieves its grdul effect on SRF reduction nd resolution over severl months, nd it is uncler to wht extent ccsc ptients benefit visully from SRF reduction without SRF resolution. Bsed on the vilble lrgely retrospective literture on hlf-dose PDT nd other PDT strtegies using reduced settings, PDT my be ble to chieve fster nd complete resolution in lrger proportion (60 100%) of ccsc ptients [13, 14]. However, there re benefits of SML tretment over PDT tretment in CSC. Unlike PDT, which uses the intrvenously dministered light-ctivted verteporfin, there is no need fter SML tretment to be protected from bright light in the first dys fter tretment. In ddition, choroidl neovsculriztion nd RPE trophy hve been described in smll subgroup of PDT-treted CSC ptients [14, 15] but hve thus fr not been described in SML. It is generlly ssumed tht more thn two PDT tretments, even when using reduced dosge, fluence, or time settings, crry higher risk of complictions such s RPE trophy. SML tretment presumbly cn be repeted more often in sfe mnner. This difference is possibly due to the fct tht the effect of PDT tretment lens on suprthreshold effect on the choriocpillris tht my result in structurl chnges, wheres SML tretment is by definition subthreshold nd is imed t the RPE. However, the precise mechnisms of the possible therpeutic effect of SML re uncler. SML tretment using 577-nm wvelength pulses is reltively new technique, nd SML tretment using 810-nm wvelength hs been previously described s possible tretment in CSC [17 20]. It is uncler which SML wvelength is more effective nd/or sfer. In rbbit study, similr duty cycle-dependent histologicl effects were seen in 810- nd 532-nm SML strtegies [26]. Limittions of the present study re the bsence of control group nd reltively short follow-up time with nonstndrdized follow-up periods becuse of the retrospective nture of the study. Without rndomized tril including control group, we cnnot rule out spontneous resolution of SRF fter the SML, lthough the longstnding disese in ll ptients mkes this possibility less likely. In ddition, the lck of visible endpoint fter SML tretment complictes decision mking in choosing the optiml tretment settings to chieve the mximl effect. Tretment settings with this reltively new 577-nm SML lser modlity should therefore be subject of further study. In conclusion, this cse series indictes tht 577-nm SML tretment cn be n effective nd sfe tretment for ccsc with persistent SRF, even in subgroup of ptients who did not respond to prior PDT tretment. As there re no known side effects nd no clerly detectble structurl dmge fter SML, erly SML tretment could be considered nd might help to void permnent structurl dmge nd lsting visul impirment in ccsc ptients. The role of SML tretment in CSC should be further exmined becuse multicenter rndomized controlled tretment trils on this topic re lcking thus fr. We re currently performing such multicenter prospective rndomized controlled tril compring hlf-dose PDT with highdensity SML s primry tretment for ccsc (EudrCT No , NCT ). Disclosure Sttement The uthors hve no proprietry or commercil interest in ny mterils discussed in this rticle. Micropulse Lser in Centrl Serous Chorioretinopthy 5

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