Choroidal neovascularization was thought to be the only cause of exudative age-related macular degeneration. Recently, in a subset of eyes with exudative age-related macular degeneration, an intraretinal source of neovascularization was found to be the cause of the exudates and decrease in visual acuity. The term retinal angiomatous proliferation (RAP) has been given to this new subset, which may be present in 10% to 15% of newly diagnosed cases of age-related macular degeneration. RAP is usually associated with intraretinal edema.1
RAP lesions have been divided into a three-stage classification. Stage 1 presents as an intraretinal neovascularization, a capillary proliferation within the retina originating from the deep capillary plexus in the para-macular area. Intraretinal edema and multiple small intraretinal hemorrhages are also seen. In stage 2, the intraretinal neovascularization extends posteriorly into the subretinal space, forming a subretinal neovascularization. In stage 3, choroidal neovascularization is also present, often accompanied by a retinal pigment epithelial detachment.1 At Retinal AAO 2004, Dr. Robert Murphy subdivided RAP lesions into four morphological groups with the percentage of frequency. The lesions may be focal (45%), circular (25%), geometric (10%), or complex or multifocal (25%). At the same meeting, he proposed the use of the Iridex green 510-nm laser (Iridex Corporation, Mountain View, CA) in the pulsed mode for treatment.2
In 2001, Costa presented a case report on the use of indocyanine green (ICG) dye together with the 810-nm infrared laser to treat choroidal neovascularization.3 In 2002, Flower proposed the use of indocyanine green dye-enhanced photocoagulation (ICG-DEP) for the closure of feeder vessels deep in the choroid. The energy of the 810-nm infrared laser penetrated more easily and deeper into the retina and choroid than did that of the argon laser, but was less well absorbed within the feeder vessels. He added an intravenous bolus of ICG dye (0.3 mL of 65 mg/mL) 30 seconds prior to the use of the infrared laser such that the energy of the infrared laser was absorbed within the feeder vessels, causing its coagulation. When the ICG dye was observed in the feeder vessel, the 810-nm infrared laser was used to coagulate the feeder vessel, interrupting blood flow to the choroidal neovascularization.4
The authors adopted a modified ICG-DEP technique to close five RAP lesions using a long exposure protocol of repetitive laser pulses at gradually increased irradiance5 for the purpose of creating and maintaining the long-lasting thermal elevation required to achieve a complete thrombosis in highly perfused RAP lesions.
On the day of treatment, the patient first has a diagnostic ICG angiogram to verify the patency of the RAP lesion and the time it takes the RAP lesion to fill with ICG. A whole bottle of ICG (25 mg) is diluted with 3 cc of glucose and a bolus of 1 cc (8.3 mg) of ICG followed by a bolus of 5 cc of physiologic solution is used for the angiogram. If the RAP lesion is open, the treatment is done immediately. A bolus of 3 cc (25 mg) of ICG followed by a bolus of 5 cc of physiologic solution is given. After 3 to 4 minutes, depending on the filling time of the previous ICG angiogram, the laser treatment is begun. The power of the IRIS Medical OcuLight SLx laser (Iridex Corporation) is set at 350 mW and in the millipulsed mode, the first train of 50 to100 laser pulses is delivered to the RAP lesion, for an exposure duration of 10 to 20 seconds (with the repetition rate of 5 pulses per second). Two or three trains at this subthreshold level are given.
The power is then increased by steps of 50 to 100 mW and another train of 50 to 100 pulses is delivered. This sequence of trains of laser pulses at step-increased power is continued until a light retinal edema is observed, normally between 450 and 850 mW. The number of pulses delivered can vary between 500 and 1,000 in total. An ICG angiogram is then repeated 20 minutes after the treatment with one-third of a bottle of ICG (8.3 mg). If the RAP lsion is closed, the patient has a repeat ICG angiogram in 2 weeks. If it is still open, additional trains of laser pulses at increasingly higher power are immediately administered, taking advantage of the presence of ICG in the RAP lesion from the diagnostic ICG angiogram.
A 72-year-old man was seen in June 2004 with a 2-month history of decreased vision and metamorphopsia in the right eye. He had renal insufficiency and received oral steroids for 2 months. He had age-related macular degeneration in both eyes for more than 10 years. His visual acuity was 20/100 in the right eye and 20/20 in the left eye. A fluorescein angiogram showed a paramacular hyperfluorescence that extended into the foveola. The ICG angiogram revealed a circular intra-retinal neovascularization with distinct margins (Fig. 1). Intraretinal edema and scattered intraretinal hemorrhages were also present. The diagnosis of a stage 1 circular RAP was made.
Indocyanine green angiogram of the right eye in case 1 demonstrating a stage 1 circular retinal angiomatous proliferation.
The RAP was treated with ICG-DEP using two-thirds of a bottle of ICG (16.6 mg) intravenous followed by a bolus of 5 mL of physiologic solution. Only 16.6 mg of ICG was used because the patient had renal insufficiency and refused a higher dose. After 3 minutes, a Goldmann contact lens was placed in the right eye and the 810-nm infrared laser was used to directly photocoagulate the intraretinal neovascularization using a 75-μm diameter spot. The laser energy was pulsed, delivered in the millipulsed mode using trains of repetitive pulses (100 ms “ON” time separated by 100 ms inter-pulse “OFF” time). Each train was approximately 100 pulses and the power was increased 50 to 100 mW for each new train of laser pulses. The treatment went from 350 mW through 850 mW, until an area of light retinal edema was created (830 cumulative laser pulses). An ICG angiogram with one-third of a bottle (8.3 mg) of ICG was repeated after 20 minutes, showing complete closure of the lesion.
At 2 weeks following treatment, the intraretinal neovascularization was closed with a reduction of the retinal edema and a disappearance of the hyperfluorescence in the foveola. The visual acuity in the right eye improved from 20/100 to 20/35 over 2 months. After 1 year, the patient had phacoemulsification and intra-ocular lens implantation in the right eye with visual acuity of 20/35. After 3 years, the RAP was still closed and the visual acuity had decreased to 20/40 because of retinal pigment epithelial changes (Fig. 2).
Fluorescein angiogram of the right eye in case 1 showing hyperfluorescence due to retinal pigment epithelial changes.
A 72-year-old man was seen on October 2003 with a best-corrected visual acuity of 20/70 and metamorphopsia in the right eye for 1 month. The left eye had a large macular scar with visual acuity of counting fingers. The fluorescein angiogram, ICG angiogram, and optical coherence tomography revealed a focal stage 2 RAP lesion in the right eye. Over a period of 9 months, he received four argon laser treatments and five photo-dynamic therapy treatments, all directed to the RAP.
On July 2004, the RAP lesion was still open with a large pigment epithelial detachment and visual acuity of 20/100. The RAP had now become a focal stage 3 lesion with a small choroidal neovascularization (Fig. 3). The macula had a large area of edema with a large circinate exudate in the posterior pole. ICG-DEP with a whole bottle of ICG (25 mg) was performed directly to the RAP lesion in mid July 2004. A repeat ICG angiogram with one-third of a bottle of ICG (8.3 mg) 20 minutes after treatment revealed closure.
Indocyanine green angiogram of the right eye in case 2 demonstrating a stage 3 focal retinal angiomatous proliferation.
Two weeks later, the RAP lesion reopened and ICG-DEP was repeated with a whole bottle of ICG (25 mg). A repeat ICG angiogram 20 minutes later showed closure of the RAP lesion. The small choroidal neovascularization remained inactive and the RAP lesion remained closed for 8 months with resolution of the pigment epithelial detachment. The visual acuity improved to 20/70 and the circinate exudates and edema gradually decreased.
At 8 months after treatment, a retinal choroidal anastamosis formed to the choroidal neovascularization and this grew again. Three sessions of the argon laser directly to the anastamosis closed it along with the choroidal neovascularization. The RAP lesion itself never reopened. After another 6 months, the anastamosis reopened and the choroidal neovascularization grew, but the intraretinal portion of the RAP lesion remained closed (Fig. 4). The patient refused further laser treatment. Bevacizumab therapy was not available at that time and the patient had a photodynamic therapy to the choroidal neovascularization with loss of visual acuity to 20/200.
Indocyanine green angiogram of the right eye in case 2 demonstrating the retinal choroidal anastamosis to the choroidal neovascular membrane without the focal retinal angiomatous proliferation.
A 87-year-old woman had a 3-month decrease in vision in her right eye. On examination in November 2004, visual acuity was counting fingers in the right eye. The fluorescein angiogram, ICG angiogram, and optical coherence tomography revealed a stage 2 complex RAP with two separate lesions in the right eye (Fig. 5).
Indocyanine green angiogram of the right eye in case 3 revealed a stage 2 complex retinal angiomatous proliferation with two separate lesions.
She had ICG-DEP (25 mg of ICG) treatment directly to the two focal lesions in the right eye. A repeat ICG angiogram with one-third of a bottle of ICG (8.3 mg) 20 minutes after treatment revealed incomplete closure of one of the RAP lesions in the right eye. The ICG-DEP was immediately repeated to an end point of a dense white retinal edema. This second ICG-DEP treatment was done using the residual dye in the RAP from the diagnostic ICG angiogram. A second intravenous injection of ICG prior to this second ICG-DEP treatment was not done because there was sufficient dye in the RAP lesion from the diagnostic ICG angiogram.
At 2 weeks after treatment, one of the RAP lesions in the right eye was closed but a subretinal neovascularization was noted adjacent to the other RAP lesion. It was treated and closed with another ICG-DEP treatment. At 2 months after treatment in mid January, both of the RAP lesions and the subretinal neovascularization were closed, her visual acuity had improved to 20/200, and the edema was decreasing. In February 2005, she noted decreased visual acuity to 20/200 in the left eye with a stage 1 geometric RAP lesion inferior nasal to the fovea in the left eye (Fig. 6). It was closed with ICG-DEP. In September 2005, visual acuity was 20/200 in the right eye and 20/70 in the left eye. The fluorescein angiogram of the right eye (Fig. 7) and the left eye (Fig. 8) showed hyperfluorescence at the margins of the laser scars.
Indocyanine green angiogram of the left eye in case 3 revealed a stage 1 geographic retinal angiomatous proliferation inferior nasal to the fovea.
Fluorescein angiogram of the right eye in case 3 showing hyperfluorescence at the margins of the laser scars.
Fluorescein angiogram of the left eye in case 3 showing hyperfluorescence at the margins of the laser scar.
In December 2005, visual acuity in the right eye decreased to 20/400 and ICG angiography revealed a third and new geographic RAP lesion at the 3:30 clock position nasal to the fovea in the right eye. She refused further treatment. In February 2007, the visual acuity was unchanged in both eyes with the RAP lesion open in the right eye and still closed in the left eye.
Flower originally proposed ICG-DEP to treat the choroidal feeder vessels to a choroidal neovascularization.4 He used an intravenous injection of a bolus of 0.3 mL of 65 mg/mL of ICG dye (19.5 mg of ICG in total) followed by a bolus of 5 mL of physiologic solution. When the dye reached the feeder vessel in the arterial phase, he used the 810-nm infrared laser because its infrared wavelength can penetrate deeper in the choroid than can the visible wavelength of the 514-nm argon laser. However, once in the choroid, the 810-nm infrared laser energy is not well intraluminally absorbed by the blood in the feeder vessels. To enhance the intraluminal absorption of the 810-nm laser energy and production of heat within the feeder vessels, he proposed the addition of ICG inside the vessel as an exogenous chromophore with strong absorption characteristics at 810 nm. He estimated an 86% increase in the 810-nm energy absorption, facilitating the vessel coagulation.
Flower and Staurenghi use this technique to treat feeder vessels. Approximately 30 seconds after the intravenous bolus of ICG, under direct visualization of the dye in the feeder vessels, they treat and close the feeder vessels with a few laser spots at a power of approximately 600 to 800 mW and a time of 0.5 to 1.0 sec.4,6
In our ICG-DEP treatment protocol, we decided to use a whole bottle of ICG (25 mg) diluted to 3 mL with glucose, achieving an ICG concentration of 8.3 mg/mL. The whole 3 mL of ICG dye (25 mg) was rapidly injected intravenously and immediately followed by a bolus of 5 mL of physiologic solution. The authors then waited 3 to 4 minutes before the laser treatment to allow time for the ICG dye accumulation in the RAP lesion, as determined by the ICG angiography. In the case of choroidal feeder vessels, the laser treatment is started after approximately 30 seconds because the ICG dye arrives quickly in the arterial phase and remains only for a short time at its highest concentration. Conversely, the ICG dye arrives later in the RAP, in accordance with retinal blood perfusion, and waiting for 3 to 4 minutes allows for dye accumulation within and around the lesion with a better chance of closure by photothermal thrombus formation.
With RAP, there is usually a large amount of retinal edema with some hemorrhage. Retinal edema will create light scattering to the laser light. The shorter the wavelength, 514 nm versus 810 nm, the more light scattering and the more energy needed to penetrate the edema.7 The authors believe that it was more difficult for the 514-nm argon laser to penetrate the retinal edema and more energy is needed to coagulate a deep retinal lesion with more inherent damage to the surrounding tissue. The 810-nm infrared laser penetrates the retinal edema more easily and the presence of the ICG dye in the RAP facilitates selective energy absorption and heat production at the lesion, leading to effective closure with less damage to surrounding tissues.
In dermatology, to treat skin lesions, laser treatments are often pulsed (eg, 100 ms “ON” and 100 ms “OFF”). The interval of 100 ms “OFF” allows for a period of tissue cooling or thermal relaxation between laser pulses for the purpose of preserving the optical characteristics of the tissue, creating less tissue edema. Less tissue edema is created with a pulsed laser allowing for longer treatment sessions with more laser energy absorption in a lesion.8 Furthermore, a sustained low thermal elevation, below the threshold of visible coagulation necrosis, acts as a thermal preconditioning that increases the thermotolerance of the retinal tissue.9 Beginning with laser pulses below threshold creates this cytoprotective effect and elevates the resistance to thermal injury and to burn formation of the RAP lesion, which can continue the absorption of the laser energy and the production of heat until complete thrombosis occurs. With the RAP, after a brief period of subthreshold treatment, the laser power can be increased. At that point, as the blood flow is interrupted, an area of mild white retinal edema is created and this is the visible endpoint of the treatment.
To use the advantages of thermal relaxation and thermotolerance, the authors adopted Murphy’s pulsed laser treatment for RAP lesions. He uses a long exposure protocol with trains of laser pulses at gradually increased irradiance.5 The authors use the IRIS Medical OcuLight SLx laser in the millipulsed, not micropulsed, mode. Using a retinal spot diameter of 80 μm (75 μm aerial setting delivered with a 0.93× Goldmann fundus lens), a long-lasting thermal elevation is created and maintained, delivering trains of repetitive 810-nm laser pulses (100 ms “ON” time, spaced by 100 ms inter-pulses “OFF” time, 50% duty cycle, 5 pulse/second repetition rate). The treatment is started at a low irradiance of 350 mW (below the thresh-old of visible tissue reaction) and gradually increased until closure of the RAP lesion is observed.
The above described modified ICG-DEP technique together with Murphy’s pulsed laser at increasing irradiance has proven to be an useful method to treat RAP lesions outside the foveal area. The energy of the 810-nm infrared laser penetrates the retinal edema well and, in the presence of ICG dye, is absorbed by the RAP lesion with minimal damage to the surrounding retinal tissue.
- Yannuzzi LA, Negrào S, Iida T, et al. Retinal angiomatous proliferation in age-related macular degeneration. Retina. 2001;21:416–434. doi:10.1097/00006982-200110000-00003 [CrossRef]
- Murphy RP. High-speed ICG feeder vessel treatment of CNV. Presented at: Retina AAO. ; October 22–23, 2004. ; New Orleans, LA. .
- Costa RA, Farah ME, Cardillo JA, Belfort R Jr, . Photodynamic therapy with indocyanine green for occult subfoveal choroidal neovascularization caused by age-related macular degeneration. Curr Eye Res. 2001;23:271–275. doi:10.1076/ceyr.23.4.271.5449 [CrossRef]
- Flower RW. Optimizing treatment of choroidal neovascularization feeder vessels associated with age-related macular degeneration. Am J Ophthalmol. 2002;134:228–239. doi:10.1016/S0002-9394(02)01579-9 [CrossRef]
- Murphy RP. The treatment of CNV’s feeder vessels. Presented at: 19th Annual Squaw Valley Retinal Symposium. ; January 27–30, 2000. ; Olympic Valley, CA. .
- Staurenghi G. Fotocoagulazione dye-enhanced per la CNV. Presented at: Simposio della Fondazione per la Macula-Macula update, 85th Congresso Nazionale SOI. ; November 23–26, 2005. ; Milan, Italy. .
- Ludwig K, Lasser T, Sakowski H, et al. Photocoagulation in the edematous and non-edematous retina with the cw-laser of different wavelengths. Ophthalmologe. 1994;91:783–788.
- Kimel S, Svaasand LO, Cao D, et al. Vascular response to laser photothermolysis as a function of pulse duration, vessel type, and diameter: Implications for port wine stain therapy. Lasers Surg Med. 2002;30:160–169. doi:10.1002/lsm.10016 [CrossRef]
- Schushereba ST, Bowman PD, Stuck BE. Protection of ARPE-19 cells against thermal injury: evaluation of thermal preconditioning and Herbimycin A treatment by cell viability and cDNA arrays. Invest Ophthal Vis Sci. 2003;44:ARVO E-Abstract 2281.