Laser-dye hybrid shows potential for various CNV forms

In a study, patients treated for CNV in pathologic myopia required no re-treatments after 48 weeks follow-up.

A hybrid laser-dye procedure that combines aspects of photothermal therapy and photodynamic therapy has shown some clinical efficacy as a treatment for various forms of choroidal neovascularization, according to the technique’s developer.

Called indocyanine green-mediated photothrombosis (i-MP), the procedure uses an 810-nm diode laser (Opto Eletronica SA), similar to transpupillary thermotherapy (TTT). However, the laser is used with the primary intention of photoactivating a high concentration of indocyanine green (ICG) within a neovascular lesion, similar to the photoactivation of Visudyne (verteporfin for injection, Novartis Ophthalmics) as in standard photodynamic therapy (PDT).

Sixty-nine-year-old patient with AMD with an ill-defined neovascular lesion with subfoveal involvement who was submitted to standard ICG-mediated photothrombosis. A. Fluorescein blockage from sub-retinal and sub-RPE hemorrhage as well as some areas of stippled hyperfluorescence was seen at baseline (BCVA = 20/800+1). B. Twenty-four weeks after treatment, fluorescein staining of the quiescent neovascular lesion and no leakage from previous CNV was observed (BCVA = 20/160+2). Note that no clear angiographic damage was evident in the presumably normal choroidal and retinal tissues involved in the large (4.5-mm spot) treatment area (dashed circular line).

Rogério Alves Costa, MD, PhD, one of the developers of the technique, told Ocular Surgery News that the procedure does not rely on the laser interacting with endogenous pigment to produce a thermal effect. Rather, the laser is used in a manner to optimize ICG photoactivation while minimizing random heat generation from RPE.

Also, unlike standard PDT, i-MP has shown some efficacy for all forms of choroidal neovascularization (CNV) irrespective of the cause, lesion type or fluorescein angiography classification, he said. Dr. Costa has used i-MP to treat neovascular lesions in conditions including age-related macular degeneration (AMD), pathologic myopia and angioid streaks as well as conditions from inflammatory and idiopathic causes (Figures 1, 2).

“This is in fact one of the major advances of (i-MP). You do not have to get stuck on a complicated angiographic lesion classification system. If you perform ICG angiography and an increased uptake of ICG is seen in the neovascular lesion, then it really does not matter whether it is a predominantly or minimally classic or occult lesion,” he said. “The basic principle is that the targeted lesion must have an increased uptake of ICG. If this takes place, it’s OK and treatment may be attempted.”

Dr. Costa used the technique on more than 150 patients as part of the initial i-MP clinical protocol at the Federal University of São Paulo, Brazil. He has treated about another 60 patients at his clinic, he said.

“Considering the entire CNV scenario, I believe that the treatment may work a little better than PDT, but it is just an impression since no comparative study had been done,” he said.

The technique may be altered depending on the lesion being treated, he noted. For example, a CNV in which identification of the neovascular vessels is possible would be treated using a procedure similar to a feeder vessel technique, he said. The same principles are incorporated, but the procedure uses smaller laser spot size and higher laser intensity. The laser is also applied only to the ingrowth site of the lesion (Figures 3, 4). Dr. Costa called this modified technique neovascular ingrowth site photothrombosis.

Standard technique

Dr. Costa said the standard i-MP technique is similar to verteporfin PDT. After injecting the photosensitive dye, a large laser spot about 6.45 mm in diameter is applied to the retina at an irradiance of approximately 2 W/cm².

Because the ICG is concentrated mainly in the neovascular lesions, normal choroidal and retinal tissues involved in the treatment area are not significantly affected, he said.

He noted the procedure was initially called i-PDT because preliminary studies involving rabbits showed that a pure photodynamic effect could be attained using ICG instead of verteporfin.

However, because ICG is a weak photosensitizer, the procedure required a high dose of the dye to achieve a pure photodynamic effect. This dose had to be lowered in human studies, which reduced that effect, he said.

Dr. Costa explained that the maximum recommended dose of ICG in humans is 2 mg/kg, which is too low to generate a pure photodynamic effect, according to preliminary studies in humans. To compensate for this, the laser intensity was increased. This results in not only a photodynamic effect (photooxidation type 2) but also the generation of some heat (photooxidation type 1) after ICG photoactivation.

“The important issue about the technique is that the laser is used with the sole purpose to photoactivate the dye,” he said. He noted that because of this, the effectiveness of the treatment depends upon the location and uptake of the dye within the neovascular lesion.

Optical coherence tomography evaluation of the same patient shown in Figure 1. Rapid resolution of the exudative manifestations was disclosed by horizontal 6-mm scans as early as 1 week after standard ICG-mediated photothrombosis. Considerable restoration of the macular architecture was seen in the subsequent follow-up visits 12 and 24 weeks after treatment.

Dr. Costa said that although the maximum recommended dose is used, there are no concerns over toxicity or dose-related complications. He said ICG has been in use for approximately 30 years and has a good safety profile. At one point, cardiologists used the dye at concentrations of up to 5 mg/kg, he said.

Dr. Costa said another difference between TTT and i-MP is that i-MP uses a lower retinal irradiance, which allows the laser to be applied to an area for a longer period.

“This is an important issue. When we are dealing with heat generation between the interaction of the laser and the endogenous pigment, laser intensity is one of the most important factors,” he said. “You can deliver more energy (100% more) by just lowering the laser intensity by 12% to 15%.”

In i-MP, the retinal irradiance is varied between 2 W/cm² and 5.2 W/cm² and is applied twice for 100 seconds. TTT uses retinal irradiance between 7.5 W/cm² and 11.2 W/cm², depending on the spot size.

Like PDT, though, patients may require multiple i-MP applications. Based on the preliminary analysis, patients receiving i-MP require an average of two treatments during the first year. For maximum effect, patients treated with PDT require an average of 3.4 treatments during the first year, Dr. Costa said.

Pathologic myopia

Dr. Costa noted that he has used a modified version of i-MP to treat some neovascular lesions resulting from pathologic myopia, which he said would normally not be treated because conflicting information exists about the natural history of the disease.

He said the Verteporfin in Photodynamic Therapy trial demonstrated PDT was effective for preventing moderate visual loss in patients with pathologic myopia. However, the effect was statistically significant in the first year and lost significance during the second year, he said.

“It is quite hard to treat pathologic myopia because the natural history is not as bad as in AMD,” he said. “They normally have a good visual prognosis depending on the age of disease onset, which is not as good in AMD, for example.”

Dr. Costa said the patients he has treated with standard i-MP technique generally have preserved vision, with very few patients continuing to lose vision.

Thirty-eight-year-old patient with subfoveal choroidal neovascularization associated with multifocal choroiditis submitted to ingrowth site ICG-mediated photothrombosis. A. Hyperfluorescent areas of classic and occult choroidal neovascularization as well as dark regions of elevated blocked fluorescence (pigment and thick blood) were seen 48 hours prior to treatment. B. Thirty minutes after the procedure, non-perfusion of the entire neovascular complex was seen. Note that no significant retinal damage was demonstrated by fluorescein angiography over the juxtafoveal ingrowth site in which a 500-µm spot (dashed line) was positioned for continuous 810-nm laser application.

According to his study, published in the American Journal of Ophthalmology, six patients with CNV secondary to pathologic myopia were treated with a feeder vessel technique of i-MP (neovascular ingrowth site photothrombosis).

Using an 800-µm spot size, laser energy at an irradiance of 30 W/cm² was continuously applied for 80 seconds to the ingrowth site of the neovascular lesion. A second laser application was applied using the same parameters 10 minutes after the first laser application.

According to the study, patients had a mean baseline best-corrected visual acuity (BCVA) of 20/160, which improved to a mean of 20/125 at 1 week follow-up. All showed no leakage.

At 24 weeks follow-up, two patients had minimal leakage within the area of the CNV, and the remaining four patients had no leakage. No further change in lesion activity was seen at 48 weeks follow-up, and patients had a mean improvement in vision of 2.7 ± 2.1 lines from baseline at last visit.

Optical coherence tomography evaluation of the same patient shown in Figure 3. Prior to treatment, retinal elevation caused by massive intraretinal and subretinal fluid accumulation was disclosed by 6-mm vertical OCT scan. Note the rapid resolution of the exudative manifestations in the subsequent visits 1 and 4 weeks after neovascular ingrowth site photothrombosis.

Angioid streaks

Neovascular ingrowth site photothrombosis also appears effective for treating CNV related to angioid streaks, according to a separate study performed by Dr. Costa and colleagues.

The study, published in Ophthalmology, included five patients between 41 and 62 years of age who had active CNV extending under the geometric center of the foveal avascular zone. All eyes also had fluid accumulation causing increased retinal thickness or retinal elevation.

At baseline, patients had an average BCVA of 20/500. All patients received a modified i-MP application identical to the ingrowth site treatment used for patients with pathologic myopia.

According to the study, at 1 week follow-up, BCVA improved a mean of 3.2 ± 1.4 ETDRS lines from baseline, making the average BCVA 20/250+1.

At 48 weeks follow-up, mean visual acuity had improved 6.1 ± 1.6 lines, with the fifth patient experiencing an improvement of 8.6 lines, the authors wrote.

According to the study, all patients had at least a 4-line improvement in visual acuity at final follow-up.

The authors note that the laser irradiance used, 30 W/cm², is higher than that used for standard i-MP, but it was considered necessary to attain definitive and localized vascular occlusion.

Searching for a sponsor

Although indocyanine green-mediated photothrombosis has shown some preliminary promise as a treatment for numerous forms of choroidal neovascularization, the ophthalmic industry seems hesitant to sponsor a clinical trial, according to Rogério Alves Costa, MD, PhD. Dr. Costa, one of the developers of the laser technique, told Ocular Surgery News that he and colleagues have been trying to initiate a clinical trial of the procedure for the past 2 years. However, no companies have been willing to put up the necessary funds for a large-scale, randomized clinical study, which he noted some companies calculated would cost approximately $20 million. After failing to gain support in the United States, Dr. Costa said they are now trying to gain support for a multicenter trial in Brazil. However, he said it is unlikely any of the participating surgeons would be paid for their work. “It is going to be really difficult to set it up,” he said. “But I believe that … we are really going to have some centers that would like to participate in a study to address important issues pertinent to i-MP.”

For Your Information:

• Rogério Alves Costa, MD, PhD, can be contacted at Rua Italia 1905, Apto 74, Araraquara-Sáo Paulo, 14801-350, Brazil; (55) 16-236-5210; fax: (55) 16-236-5210 or (55) 16-236-99-28; e-mail: rog.retina@uol.com.br. Dr. Costa has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.
• Opto Eletronica SA, maker of the diode laser used in Indocyanine green-mediated photothrombosis (i-MP), can be reached at Rua Joaquim Augusto Ribeiro de Souza, 1071, Jardim Santa Felícia, Caixa, Postal 706, CEP 13563-330, São Carlos SP Brasil; (55) 16-3373-7000; fax: (55) 16-3373-7001; Web site: www.opto.com.br.

References:

• Costa RA, Calucci D, et al. Selective occlusion of subfoveal choroidal neovascularization in angioid streaks using a new technique of ingrowth site treatment. Ophthalmology. 2003;110:1192-1203.
• Costa RA, Calucci D, et al. Selective occlusion of subfoveal choroidal neovascularization in pathologic myopia using a new technique of ingrowth site treatment. Am J Ophthalmol. 2003;135: 857-866.
• Costa RA, Farah ME, et al. Choriocapillaris photodynamic therapy using indocyanine green. Am J Ophthalmol. 2001;132:557-565.
• Costa RA, Farah ME, et al. Photodynamic therapy with indocyanine green for occult subfoveal choroidal neovascularization caused by age-related macular degeneration. Curr Eye Res. 2001;23:271-275.
• Costa RA, Meirelles RL, et al. Retinal capillary hemangioma treatment by indocyanine green-mediated photothrombosis. Am J Ophthalmol. 2003;135:395-398.
• Costa RA, Rocha KM, et al. Neovascular ingrowth site photothrombosis in choroidal neovascularization associated with retinal pigment epithelium detachment. Graefes Arch Clin Exp Ophthalmol. 2003;241:245-250.
• Costa RA, Scapucin L, et al. Indocyanine green-mediated photothrombosis as a new technique of treatment for persistent central serous chorioretinopathy. Curr Eye Res. 2002;25:287-297.
• Navajas EV, Costa RA, et al. Indocyanine green-mediated photothrombosis combined with intravitreal triamcinolone for the treatment of choroidal neovascularization in serpiginous choroiditis. Eye. 2003;17:563-566.