Current Eye Research 2002, Vol. 25, No. 5, pp.
0271-3683/02/2505-287$16.00 © Swets & Zeitlinger
Indocyanine green-mediated photothrombosis as a new technique of treatment for persistent central serous chorioretinopathy
Rogério A. Costa1,2, Luciana Scapucin1, Nilva S. Moraes1, Daniela Calucci1, Luiz A. Melo Jr.1, José A. Cardillo1,2 and Michel E. Farah1 Instituto da Visão – IPEPO, Department of Ophthalmology, Federal University of São Paulo, Brazil; 2Consultores de Retina e Associados, Araraquara, São Paulo, Brazil
Purpose. To evaluate the potential beneﬁt and complications of indocyanine green-mediated photothrombosis (IMP) in the management of patients with persistent central serous chorioretinopathy (CSC). Methods. Interventional noncomparative case series. Eleven patients with CSC presenting with persistent subretinal ﬂuid in optical coherence tomography (OCT) four months after presentation and decrease in visual acuity (VA) were submitted to a single IMP session with 2 mg/kg body weight ICG and application of 5.6 W/cm2 light at 810 nm. A continuous follow-up was provided with best-corrected ETDRS VA assessment, and angiographic and OCT documentation 72 hours before and at 2 days, 1 and 2 weeks, 1, 3, 6, and 12 months after treatment. Results. Pretreatment VA levels ranged from 20/32 - 1 to 20/100 (mean, 20/63 + 2 [logMAR equivalent, 0.460 ± 0.155]); post treatment levels ranged from 20/25 - 2 to 20/20 (mean, 20/20 - 2 [logMAR equivalent, 0.038 ± 0.048]). Ten out of eleven patients presented with VA levels of ≥20/25 2 weeks after treatment; the mean logMAR VA change of 0.345 at that time was statistically signiﬁcant (p < 0.05, Friedman test). OCT disclosed resolution of persistent subretinal ﬂuid in all eyes. No recurrence was observed after 12 months of follow-up. Complications included transient retinal whitening in two patients, and associated occlusion of retinal capillaries in one. Conclusions. Photothrombosis using low-intensity 810 nm light to direct laser energy continuously at the active leakage sites after intravenous ICG infusion induced rapid VA recovery in patients with persistent CSC; accordingly, restoration of the macular architecture was evidenced on OCT, and no recurrence was noted 12 months after IMP. Keywords: hyperthermia; indocyanine green; laser; optical coherence tomography; photodynamic therapy; thermotherapy
Central serous chorioretinopathy (CSC) is a disorder of unknown origin characterized by a serous detachment of the sensory retina affecting the macular region of healthy young adults, generally between the ages of 20 and 50 years.1,2 Symptoms related to the disease such as mild loss of central vision, micropsia, metamorphopsia, and impaired dark adaptation are generally transient and resolve spontaneously in 3 to 4 months.2–4 Fluorescein angiography demonstrates focal leaks at the level of the retinal pigment epithelium whereas areas of choroidal hyperpermeability are identiﬁed in indocyanine green (ICG) angiography.5 Although a good visual outcome is generally expected, several studies suggest that the presence of persistent pigment epithelial detachment and/or subretinal ﬂuid observed in some patients with CSC is related with reduced ﬁnal visual acuity (VA).6–8
Drs. Costa, Cardillo, and Farah are consultants to Akorn, Inc., a United States manufacturer of indocyanine green. Any kind of ﬁnancial support was herein provided by the company since consulting agreement has just been settled.
Received: August 25, 2002 Accepted: November 18, 2002 Correspondence: Rogério Alves Costa, MD, Rua Itália, 1905, Apto 74, Araraquara, SP 14801-350, Brazil. Tel./Fax: 55 (16) 3331 2197, E-mail: firstname.lastname@example.org
a second IV injection of the remaining ICG solution (2 ml) was administered. Buffalo Grove.10.288
R. and all participants gave written informed consent before participating in the study. (3) had an allergy to ﬂuorescein. Twenty minutes after ﬁrst light delivery. ICGmediated photothrombosis was applied in a prospective. Patients were also excluded if they (1) were unable to cooperate for the laser procedure. The drug at a dose of 2 mg/Kg body weight was dissolved in 4 ml of distilled water and administered IV as follows: a loading dose of 2. 1 and 2 weeks after treatment.20–22 ICG-mediated photothrombosis is a novel. as well as at
. however. coupled with the fact that ICG uptake is increased in areas of ALS in CSC patients. Inc.0-ml saline ﬂush. Based on these results. followed by a 5. noninvasive laser-dye modality used to achieve selective vascular occlusion with minimal or no damage to adjacent neural structures. and OCT evidence of serous retinal detachment involving the macular region. Akorn. The resultant 2. Patients were evaluated using a standardized regimen at 72 hours before treatment and 2 days.5 mm spot per treatment. Bellevue. Brazil) emitting light at 810 nm and an irradiance of 5. USA) as a sensitizer. or any other ophthalmic disorder that might affect visual function. The single spot size used in this series was sufﬁcient to provide complete area coverage in all patients despite minimal movements during the extended procedure.0 ml of the ICG solution was infused as a bolus. USA) was used for visualization. (4) had previously undergone laser photocoagulation. A fundus contact lens of 1. All patients received a complete evaluation before and after a single treatment session using a standardized regimen and were seen at regular intervals with documentation according to a deﬁned protocol.A. Costa et al. as well as best-corrected VA. Puerto Rico 2001). All ﬂuorescein and ICG angiography studies and OCT evaluations were performed by an experienced certiﬁed ophthalmic technician (DC). and exudative changes in OCT evaluation were documented at initial presentation. Patient selection The patient enrollment period was from January through July 2001. A diode laser (Trimode-L. twenty minutes after the loading dose. Light was applied over an interval of 90 seconds with a single 1.23 Recently. (2) were unable to comprehend the nature of the procedure or the study to give an informed consent. and improvement in vision. They were informed orally and in writing of the potential beneﬁts and risks of the procedure and all signed a written form stating that they understood and consented to ICG-mediated photothrombosis. Patients were not offered enrollment in the study if they had drusen. uveitis. Evaluation 4 months after initial presentation was considered as the baseline evaluation for eleven patients who met the eligibility criteria for the study. The angiographic appearance. or iodine. OPTO.6 W/cm2 was used for ICG photoactivation. The indica-
Patients with best-corrected VA £ 20/32 secondary to persistent subretinal ﬂuid involving the macula 4 months after initial presentation were offered to IMP. resolution of serous retinal detachment and macular edema. since no angiographic damage is commonly detected in the normal tissues involved in the treatment spot (Costa et al.. Ocular Instruments. or (5) had opacity that obstructed laser access to the macular area. followed immediately by a 5.0-ml saline ﬂush.25 mm spot was placed directly on the center of the ALS. a second (and last) laser application using identical parameters was performed. interventional case series to eleven patients with persistent CSC. peripapillary changes with atrophic or pigmented “punched out” chorioretinal lesions. ICG. Documentation
Investigators have been seeking to abbreviate the duration of symptoms in patients with CSC by treating the active leakage site (ALS) detected on ﬂuorescein angiography with laser application of different wavelengths and light intensity. Candidates were patients with CSC with angiographic identiﬁcation of areas of ALS. the use of such modality for the management of choroidal neovascularization in patients with age-related macular degeneration achieved selective lesion regression..9–19 The general consensus from these studies is that laser application shortens the course of the disease with no related complication.
Patients and methods
The clinical study protocol was approved by the local Institutional Review Board before patient enrollment at the Retina & Vitreous section of the Ophthalmology Department at the Federal University of São Paulo began. Light exposures were started 2 minutes after the end of the second IV infusion. São Carlos. tion for the therapeutic intervention was based on the presence of macula-involving subretinal ﬂuid on OCT evaluation as well as the best-corrected ETDRS VA of 20/32 or less four months after initial presentation. All participants had to be available for follow-up visits at regular intervals for up to 1 year after the treatment. – Vitreous Society Annual Meeting. All treatments were performed by a single retinal specialist (RAC). polypoidal lesions. some authors reported signiﬁcant loss of contrast sensitivity and iatrogenically produced choroidal neovascularization after laser treatments in eyes with CSC. Inc.5 ¥ magniﬁcation (Mainster wideﬁeld. Retreatments were not performed. 72 hours prior to treatment (baseline evaluation) and during follow-up for as long as 1 year. ICG-mediated photothrombosis (IMP) IMP was performed using ICG (IC-Green.24 The therapeutic effect are thought to arise rather from the photochemical reactions between pathologic areas with increased ICG uptake and laser rather than the heat generated after RPE light absorption.
Data on adverse ocular events were obtained from case records forms and inspection of ﬂuorescein and ICG angiography and OCT documentation. and R). Dublin.1 (mean. 10 and 20 minutes after IV administration of 25 mg ICG solution (approximately 0.05). ICG angiography conﬁrmed selective hypoperfusion of the leakage area.3 (±0. All ALS identiﬁed with ﬂuorescein angiography in these patients demonstrated increased ICG uptake on ICG angiography.3 lines) was noted at 3 months (mean best-corrected VA = 20/20 .00 mm in length centered on the foveal region at 0° and 270° and a 7. Topcon. In the remaining 3 patients abnormal decrease in retinal thickness over the former ALS was observed in one
. Humphrey Instruments. For ICG angiography. Two patients missed the 6 month follow-up visit. 5. pictures were taken before and at 10 seconds to 2 minutes. all patients had some degree of RPE mottling in the site previously identiﬁed as the leakage area.1. We found that the
active leakage area on ICG angiograms was never larger than 1600 microns.155]). For ﬂuorescein angiography. Vision change observed in the eleven eyes during the study is summarized in Table 2 and Figure 1. Marked RPE damage was observed in two patients who presented mild retinal whitening at the end of the IMP session placed within the papillomacular bundle. All but one patient presented vision restoration to 20/25 levels or more 1 month after treatment. Two weeks after IMP. in 3 patients in whom the laser was applied within the foveal region. 2). images were taken before and at 10 seconds to 2 minutes.
Ten out of eleven patients who were enrolled completed the 1-year study. At one week after treatment. 4).4 (±1.460 ± 0. The greatest VA change from baseline (+4. Fluorescein angiography indicated that all patients had decrease in the extent of active leakage 1 week after treatment.3) lines over baseline was statistically signiﬁcant (p < 0. best-corrected VA had improved from a mean of 20/63 + 2 at baseline to a mean of 20/32 . and 12 months after the IMP session. associated retinal capillary obliteration with some degree of staining of the retinal vessels wall over the center of the ALS was also noted in one case.3 mg/Kg body weight).00 scan positioned along the greatest linear dimension of the serous macular detachment. No further signiﬁcant changes in vision were noted during the followup visits 6 and 12 months after IMP. Best-corrected VA at baseline ranged from 20/100 to 20/32 .8) lines. the remaining three eyes had direct treatment within the papillomacular bundle. 6. 0. The three women and eight men ranged in age from 30 to 47 (mean. Fluorescein and ICG angiography and OCT showed that at baseline. the mean VA increase of 3. 2. The 2. At the end of the IMP session mild retinal whitening was observed in two eyes that had laser application within the papillomacular bundle. Best-corrected visual acuity was measured using a retroilluminated Lighthouse for the Blind distance visual acuity test chart (using modiﬁed Early Treatment Diabetic Retinopathy Study charts 1. CA) consisted of two linear scans 5. in the remaining nine eyes. OCT ﬁndings agreed with those of ﬂuorescein and ICG angiography in showing a gradual decrease in retinal elevation due to reduced or absent of leakage after IMP in all eyes as early as 1 week. however. representing a mean change in VA from baseline of 2. regardless of the size of the macular detachment. all study eyes had persistent symptoms associated solely with CSC and that all eyes had increased retinal elevation caused by subretinal ﬂuid accumulation. IMP-induced damage in these patients at the RPE level respected the limits of previously areas identiﬁed on ICG baseline angiograms as the ALS in spite of the use of a laser spot quite larger than these areas (Fig. The non-parametric Friedman test with multiple comparisons was used for statistical analysis of the mean change in VA since the data was not normally distributed. In two patients the leakage area was located within the juxtafoveal or subfoveal area. and 10 minutes after IV administration of 5 ml of a 10% sodium-ﬂuorescein solution. Japan) was used. Tokyo. San Leandro. CA) was performed at the 3 month follow-up visit. Choroidal occlusion after IMP was restricted to the area previously identiﬁed as the ALS in all patients. 38) years.05.2). 5. We should mention that in no case the area of RPE alteration increased in size over the follow-up period. The signiﬁcant level adopted was 0. Any loss in VA after the procedure was considered signiﬁcant when evaluating the treatment response. 3). Fluorescein angiography showed the characteristic focal leak at the level of the RPE in all 11 cases on baseline examination. On follow-up OCTs. and no detectable angiographic alterations in the normal choriocapillaris and choroidal vessels in the vicinity of the ALS included in the treatment spot was seen (Fig. The areas evidenced in ICG angiography were signiﬁcant larger than those identiﬁed on ﬂuorescein angiography. Interestingly. a better demarcation of the ALS was noted in 4 cases with ICG angiography. 2. At the ﬁnal (12-month) follow-up visit. For ﬂuorescein and ICG angiography a fundus camera (TRC-50IA/IMAGEnet.ICG-mediated photothrombosis in persistent CSC 3.25 mm (measured on the retina) laser spot used for the IMP procedure was applied within the foveal region in three eyes and in the macular area sparing the fovea in ﬁve others. the ALS was located in the papillomacular bundle (n = 4) or elsewhere in the posterior pole (n = 5) (Table 1). Measurement of the visual ﬁeld using Humphrey ﬁeld analyzer 10–2 program (Zeiss Humphrey. no detectable alteration was noted in the reﬂective bands corresponding to the retinal layers and RPE/choriocapillaris complex in 8 patients (Fig. 20/63 + 2 [logMAR equivalent. Optical coherence tomography evaluation (OCT 2000. Outcome measurements Follow-up best-corrected VA determinations and change in vision from baseline were used to evaluate the effects of the procedure.
32 0.155177 Day 2 20/80 + 1 0. laser application 1.4 0.053955 Month 12 20/20 .3 0. (Snellen / LogMAR) Baseline 20/100 + 1 0. RE.2 0.18 20/20 .12 0.06 0 0.58 20/50 . BCVA = best-corrected visual acuity.1 0. J = juxtafoveal. F.038 0.68 20/63 .46 0. ALS.1 0.02 20/25 .174231 Week 1 20/40 .32 20/40 + 2 0. M.46 0.56 0.290
Table 1.26 0.2 0.46 0.1 0.2 20/20 .08 0. PB 8.2 0. EPP Mean BCVA ±1 standard deviation
ALS = active leakage site location. F.1 0. S.66 0.1 0. EPP 11.04671 Month 6 20/20 0 20/25 + 2 0.56 0.22 0.1 0. RE.5 20/100 0.114545 0.42 0.2 20/25 . PB. LE.2 0.A.46 0.2 20/100 + 2 0.02 20/20 0 20/25 + 2 0.1 20/20 .1 0. PB. J.54 * 0.34 0.32 20/32 0.02 20/25 + 2 0. F.2 0.14 20/40 0.1 0.193261 Month 12 0. S = subfoveal.08 20/20 .2 20/63 + 2 0. EPP 7. RE. LE.04 20/20 0 20/20 0 20/20 .34 20/32 0.18 0.36 0.134191 Month 1 0.6 20/25 .66 0.46 0.1 20/25 .1 20/25 + 2 0. PB.048488
Patient number.2 0.04 0.1 20/20 0 20/20 .2 0. 33.423333 0.1465
Patient number 1 2 3 4 5 6 7 8 9 10 11 Mean ±1 standard deviation
* No visual acuity measurement for this interval.26 0.4 0.06 20/25 .3 0.28 * 0. EPP 6.02 20/20 . M.174189 Week 2 20/25 0. M.2 0. gender.03 0. 42.08 0. LE. LE = left eye.32 20/40 0.02 20/32 0.2 0.028889 0. Costa et al.2 0. 31. LE.1 0.1 0.4 0.66 20/32 + 1 0. M.46 0.1 0.38 0. RE.4 0.66 0.4 0.1 0. RE.68 0.54 0. 47.
.22 20/50 0. EPP.44 20/32 .04 20/20 0 20/20 0 20/20 .06 20/20 0 20/20 0 20/25 + 2 0.3 20/32 0.18 0.46 0.063636 0. EPP.3 0. 39.091134 Month 3 20/20 .2 0. * No visual acuity measurement for this interval. 42.7 20/40 0.16 * * 20/20 0 20/20 0 20/20 0 20/20 . 42. F = female.52 20/63 + 2 0. study eye.28 0. 43.44 20/40 .
Visual acuity change (LogMAR) from baseline by visit.06 20/20 0 20/20 0 20/25 0.46 0.041429 Week 1 0.381818 0.4 20/40 0.2 0.2 0. PB 5.48 0.1 0.14 20/20 0 20/25 + 1 0. F = foveal.22 0.138643 Month 6 0.169255 Month 1 20/20 .56 0.58 0.22 0.2 0.04 0.032727 0.3 0.04 20/40 .28 0. RE.2 0.7 20/50 .232727 0. Day 2 0.08 0.078182 0.418 0. RE.
Table 2. age.2 0.396364 0.088667 Week 2 0. 30. 38. EPP. EPP = elsewhere in posterior pole. M. RE = right eye.
Baseline characteristics and best-corrected visual acuity (Snellen / LogMAR). M = male.1 0.14 0. PB.2 0.04 20/20 0 20/25 .44 0. EPP.117241 Month 3 0.04 20/20 0 20/32 + 2 0.18 0.26 0.5 20/80 + 2 0. 32.26 20/50 + 1 0.3 20/25 0.46 0.14 20/25 0. F 10.14 20/25 0. PB 3.2 0.427273 0.345455 0. M.14 20/80 0.36 0.22 0.06 20/20 0 * * 20/20 .04 0.3 20/63 + 2 0.34 0.46 * 0.24 0. EPP.1 0.1 20/20 .46 0. M.1 0.12 20/32 .
R.06 20/20 0 20/20 0 * * 20/20 .56 20/100 0. F 2.02 20/20 0 20/20 0 20/20 .2 0.46 20/63 0.46 0.34 0.28 20/63 0.46 20/40 + 1 0.1 0.1 20/40 . F 4.12 0.04 20/25 .02 20/25 + 2 0.3 20/25 0. M.56 0.1 0.28 0. PB = papillomacular bundle. EPP 9.227273 0.42 0.
The measurement of the central visual ﬁeld in patients who had laser treatment over the foveal region 3 months after IMP. demonstrated normal foveal sensibility (35. retinal distortion. Although claimed quite safe and effective.14. continuous application of 810-nm laser and ICG we have already demonstrated that effective and relatively selec-
. IMP led to rapid improvement in visual function. with no signiﬁcant complications. we analyzed ﬂuorescein and ICG angiograms at initial and baseline evaluations and found that: (1) an increase in ICG uptake existed in ALS identiﬁed on ﬂuorescein angiograms. this is the ﬁrst study to propose continuous 810 nm laser and intravenous ICG infusion as a treatment for persistent CSC. have been also reported. Indication for laser therapy is based on its high rate of success in decreasing symptoms duration.6–8 Results of alternative therapeutic modalities have been controversial and so far no deﬁnite proven method is generally accepted. The improvement in vision was strongly related to decreased activity and leakage cessation from the former ALS as documented by ﬂuorescein and ICG
angiography leading to restoration of the macular architecture as seen on OCT evaluations. and choroidal neovascularization. skin photosensitivity reactions. 35. the treatment did not cause any systemic photosensitivity complications.26 We believed we could overcome these last. Of the various reports about the use of different laser treatments for the management of CSC. Second. limitations to laser photocoagulation of CSC just discussed.9–22 In the prospective case series we report. Although only a few patients were included in this series.22. in all patients with persistent CSC who underwent the procedure. signiﬁcant loss of contrast sensitivity.
eye. Overall. to address the factors previously mentioned that have been reported to have a negative impact on the success of high intensity (W/cm2) laser treatments. or major ocular adverse events such as nonperfusion in retinal vessels.9–22 no deﬁnitive agreement existed among the real beneﬁts induced by laser photocoagulation. and its minimal damage induced by the treatment (usually limited to the extrafoveal area). and 37 dB) and absence of central scotoma.13. the presence of persistent pigment epithelial detachment and/or subretinal ﬂuid have been suggested to be related with reduced ﬁnal VA.ICG-mediated photothrombosis in persistent CSC
Figure 1. By the use of lowintensity. and increased reﬂectivity from choroid consistent with some RPE atrophy in two eyes. we proposed a new approach to ALS treatment.
Visual acuity change (LogMAR) from baseline by visit. or recurrent CSC variants that were associated with persistent subretinal ﬂuid and central RPE atrophy.2–4 Nevertheless. particularly because of the favorable visual outcome commonly observed after spontaneous disease remission. and (2) ALS were greater and easier to delineate in 4 out of the eleven patients in ICG angiograms.
Laser treatment for the management of exudative manifestations in CSC remains a controversial issue. First. as documented by change in best-corrected VA. and some others. the mean change in vision was statistically signiﬁcant as early as 2 weeks after the procedure (p < 0. As far as we are aware.05).25 In addition. laser treatments achieved limited results in the management of chronic. complications related to laser photocoagulation such as accidental foveal damage. severe.
0 W/cm2. Retinal vessels over the ALS remained perfused and with no angiographic signs of damage. The fact that the laser used for IMP is the same utilized for hyperthermic treatments (TTT) might generate some doubts about the mechanisms of action involved in the pro-
cedure. Mainster and Reichel suggested that irradiances of up to 11. Consequently. the absorption center lies outside the vessel lumen.A.0 W/cm2 can be safely delivered to the fundus over 60 seconds for the treatment of occult subfoveal CNV. In addition. When using a blood-borne exogenous pigment in IMP.
tive occlusion of the choriocapillaris23 and neovascular lesions complicating AMD24 could be achieved. Taken together. Studies on tumor vessel damage after laser-induced hyperthermia demonstrated an increased vessel permeability and extreme edema of vascular endothelial cells.29 Because near-infrared wavelength is not absorbed by hemoglobin. but certainly not exclude.
Figure 2. (D) Indocyanine green angiography revealed an irregular hypoﬂuorescent area corresponding to the former ALS. vascular damage is likely to occur by indiscriminate and unpredictable heat transmission from the endogenous pigmented targets of the radiation (RPE cells and choroidal melanocytes).292
R.27 and Connolly et al. (B) A well-deﬁned irregular area of hyperﬂuorescence corresponding to the active leakage site (ALS) surrounded by an area of presumed choroidal hyperpermeability was seen on indocyanine green angiography. (C) One week after treatment subretinal ﬂuid resolved and extensive RPE alteration was seen on ﬂuorescein angiography. this heat generation (arising from endogenous pigments) by the use of lower intensities laser irradiations for
. utilizing a similar diode laser. (A) Typical focal leak at the level of the retinal pigment epithelium was still seen on ﬂuorescein angiography four months after initial presentation. and the vascular endothelium is damaged by heat radiating from endogenous pigments toward the vessel wall. Note that in spite of the large rounded spot utilized for treatment no damage was evidenced on the presumed normal choroidal tissues involved in the laser spot. Costa et al. these points establish the rationale of IMP for the treatment of persistent CSC. we could minimize. Doted line represents the 2.28 described limited outer retinal changes or no damage at all by histopathologic study in otherwise normal retinal tissue in human eyes after prolonged irradiances of 9.25 mm spot used for laser application.
we theoretically maximized photochemical effects at the desired target as follows: (1) ﬁrst ICG infusion
(“loading dose”) leads to ICG staining of the walls of the choroidal vessels which present abnormal permeabiity leading to breakdown of the outer blood-retinal barrier as demonstrated by the results of the angiographic studies herein and by Guyer et al. (C) One week after treatment minimal alterations at the retinal pigment epithelium level was seen and almost complete restoration of the macular architecture was observed. (B) Indocyanine green angiography delineated two areas of active leakage and multiple areas of hyperﬂuorescence consistent with presumed choroidal hyperpermeability. F) Note that in spite of the large spot used for laser application over the foveal region.. (A) Increased serous macular detachment caused by a well deﬁned active leakage area (ALS) was seen on ﬂuorescein angiography four months after initial presentation. Therefore the absorption center lies within the region that present higher concentrations of the dye whose peak absorption matches the laser light wavelength. (E.5 (2) second ICG infusion leads to a high concentration of the dye in the choroidal intravascular
. (D) Indocyanine green angiography demonstrated selective occlusion of the ALS previously identiﬁed.
the procedure. twenty minutes apart.ICG-mediated photothrombosis in persistent CSC
Figure 3. no corresponding scotoma was seen three months after treatment in 10–2 visual ﬁeld measurement. By dividing the ICG injections in two dye-bolus infusions. Foveal sensibility at that time was normal (35 dB).
We could have achieved an even higher effect with the laser application initiating seconds after the second infusion because of the rapid ICG clearance. (C¢) When no dye is used in continuous 810 nm laser application (TTT). Prior to treatment the choroidal vessels that present abnormal permeability leading to ﬂuid extravasation and retinal elevation (active leakage site [ALS]) are represented in yellow. and 1 month after indocyanine green-mediated photothrombosis (White bar = 250 micras).00 mm scans of another patient who had treatment over the foveal region. (A) Sequential 5. (B) Second ICG infusion 2 minutes prior to laser application leads to a high concentration of the dye in the choroidal intravascular compartment (green circles). and the vascular endothelium is damaged by heat radiating from endogenous pigments toward the vessel wall (blue). vascular damage is likely to occur by indiscriminate and unpredictable heat transmission (red dots) from the endogenous pigmented targets of the radiation because near-infrared wavelength is not absorbed by hemoglobin. similarities among IMP and hyperthermia (TTT) are restricted to the fact that both use the same laser wavelength for continuous light application and similar
doses of light (J/cm2). Experimental observations and theoretical models have suggested that intensity is the main factor contributing to temperature changes in laser-treated tissues. Optical coherence tomography (OCT) performed 72 hours before treatment and 2 days. 1 and 2 weeks.294
R. (B) 7. Costa et al. 5). (A) First ICG infusion (“loading dose”) leads to ICG staining of the walls of the choroidal vessels which present abnormal permeability after 20 minutes (green rings). Although the second ICG injection promotes random intravascular distribution after two minutes (when light delivery initiates) a higher photochemical effect occurs rather in those vessels/areas involved in the treatment spot that have been formerly “ICG-loaded” (the ALS in this series) than in the normal choroidal vessels that presents minimal or no ICG residual up-take from the ﬁrst ICG injection. (D) The absorption center lies within the region that present higher concentrations of the dye whose peak absorption matches the laser light wavelength.A. Even though this level could have caused side effects such as irreversible damage to the inner retinal layers of the fundus in the targeted area. furthermore a greater heat generation is expected to occur since higher laser intensity is used in such procedure. Thus.
Figure 4. Schematic sequence in indocyanine green (ICG) mediated photothrombosis and hyperthertmic treatment.
Figure 5. and this is borne out by the
. (D¢) The absorption center lies outside the vessel lumen. but a two-minute interval was chosen to allow some decrease in ICG concentration of the retinal circulation.00 mm horizontal OCT scans demonstrated rapid and gradual restoration of the macular architecture as evidenced by the resolution of the subretinal ﬂuid as well as decrease in retinal thickness.
compartment. inducing a higher photochemical effect (blue) in those areas that were formerly “ICG-loaded”. The procedure sequence and laser irradiance used in this series (5.6 W/cm2) were chosen based on preliminary results of the studies using IMP in exudative AMD (Vitreous Society Meeting 2001). A similar course was observed and no alteration at the level of the retinal pigment epithelium and choriocapillaris hyperreﬂective band was seen. in theory the desired induced effect in TTT is considered an adverse effect in IMP (Fig. (C) The use of a bloodborne exogenous pigment (ICG) minimized the heat generation (red dots) arising from endogenous pigments by the use of lower intensities 810 nm laser irradiations. we believed that the risk of this effect was lower with IMP because the intensity we used in this study was at least 100 times lower than that regularly used for laser photocoagulation.
the increase in the retinal irradiance (to compensate the lower maximum human tolerated ICG dose) necessary to induce a clinical observed effect in the clinical scenario make impossible to determine exactly how thermal or photodynamic was the generated response.ICG-mediated photothrombosis in persistent CSC relative effects of various lasers used clinically. the molecule’s absorbed energy can be converted to heat (internal conversion) and transferred to other molecules (photooxidation type I).23 however. Apparently. in 3 patients who had treatments placed over the foveal region.13 of patients with CSC approximately 33% to 50% experienced recurrences after the primary episode. Recovery of vision was strongly related to macular subretinal ﬂuid resolution in all patients. This is in fact the reason of the change in the initial terminology proposed to the procedure (i-PDT). Even if the spot size used for light delivery was larger than the ALS in all cases. we have demonstrated that with the use of IMP. In conclusion. with subsequent retinal capillary occlusion in one. ICG-mediated photodynamic effects were already demonstrated in vitro31 and in vivo. and approximately 50% of the recurrences occur within one year of the ﬁrst episode.19 We can not compare these results to those observed in our patients because of signiﬁcant study differences.7) who presented a delayed recovery of the VA caused by late resolution of the subretinal ﬂuid. which can cause irreversible destruction of biologic substrates.1 as early as 1 month following treatment. laser-dye-induced effects on the RPE and choroidal tissues were not sufﬁcient to induce clinically signiﬁcant perceptible damage at these levels. In the remaining 2 patients. More important than clarify the exact mechanism of action is to point out that induced effects are mainly related to the biodistribution of the dye within the irradiated area. different responses can be achieved. signiﬁcant and rapid short-term improvement in VA can be achieved in patients with persistent CSC. Furthermore. the dye’s absorbed energy can be transferred to molecular oxygen (photooxidation type II) via a triplet state. No recurrences were observed in the one year follow-up period with all but one (loss of follow-up visit) patient retaining vision at that time. Nevertheless. Apparently if the retinal layers were not primarily affected during laser application. Although some degree of inner blood-retinal barrier breakdown was also seen in ﬂuorescein angiography after treatment.32. and by the end of the 1-month study VA levels of 20/25 was observed in 10 out the 11 patients.19 absence of recurrences in our study might be related to the use of large spot for laser application. as shown by the use of ICG for tissue welding. In studies reported by Klein et al.3 and Gilbert et al. furthermore.25 mm retinal spot centered on the ALS used may have lead to unintentional treatment of small leakage areas impossible to detect on ﬂuorescein angiography. OCT ﬁndings agreed with the clinical outcome. the presence of ﬂuid over the ALS was essential to achieve optimal results as demonstrated for instance. The photochemical reactions after ICG photoactivation in addition to somewhat heat generated by laser-endogenous pigment interaction induced undesirable effects mostly
caused by the close relation between the choroidal ALS and external retinal layers in these eyes. Both patients had the ALS located in the papillomacular bundle.32 Depending on speciﬁc dye properties and laser settings for its photoactivation. The clinical and OCT course following IMP was quite similar among patients with the exception of one patient (n. no patient experienced new CSC episode during the 12 months period of follow-up.30 Alternatively. Taking into consideration the greater ALS observed on ICG angiograms in 36% of the patients in our study.33 Damage induced by singlet oxygen formation is restricted to the immediate vicinity of the photoactivated drug because it possesses a reactive distance of only 0. mild retinal whitening over the ALS was observed immediately after the end of IMP session.27 Another issue to be addressed is related to the photochemical response of ICG under the conditions herein proposed. and at the edge of the serous macular detachment within an area of attached retina. ﬂuorescein and ICG angiography or optical coherence tomography in 9 out of 11 patients. such as singlet oxygen. We hypothesized over a mixed type I and II photooxidation therapy to explain the observed effects in IMP. Our study has several lim-
. For the IMP procedure a 2. thus minimizing undesirable effects in the normal tissues. Notable VA change occurred after IMP in all patients in this small series.4 lines was observed as rapid as two weeks within treatment. thereby damaging cells by raising their intracellular temperature.13. a dye molecule that has absorbed laser light energy can reach the ground state by either radiative or non-radiative decay. the foveal sensibility was ≥35 dB and no evident scotoma was demonstrated in the additional 10.. Following laser photoactivation. a simple outpatient procedure with minimal risks and relatively low cost.1 mm. A mean statistically signiﬁcant recovery of 3. the 2. no evidence of damage to the nerve ﬁber layer was noted. it is difﬁcult to determine whether the recurrence is due exacerbation of a previous leakage. IMP-induced effects led to VA levels of 20/20 or 20/20 . as demonstrated by the rapid and gradual resolution of the subretinal ﬂuid evidenced after treatment. In non-radiative decay. an entirely new leakage point or incomplete identiﬁcation of the original ASL. coupled with the fact that the new leakage site is located within a distance no greater than 1 mm of the original ALS in 80% of recurrent cases.2 visual ﬁeld measurement performed in all three patients 3 months after the procedure.31 which then interacts with oxygen and other compounds to form reactive intermediates. the results herein presented suggest that a selective effect occurred and no deleterious effects could be evidenced in presumably normal tissues within the treatment area by clinical examination.25 mm spot was chosen for laser application. A faster and more intense increase in tissue temperature occurs when conventional photocoagulation is used than when much higher energy (measured in J/cm2) is delivered in a continuous pulse with lower intensity (measured in W/cm2) as used for thermotherapy for exudative age-related macular degeneration for example.
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