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INDOCYANINE GREEN ANGIOGRAPHY IN AGE-RELATED MACULAR DEGENERATION
GAURAV K SHAH
Barnes Retina Institute, 1600 South Brentwood Boulevard, 8th Floor, St. Louis, MO 63144.
Verteporfin is a medication that has been approved for use with photodynamic therapy. It is valuable in treating choroidal neovascularization from age-related macular degeneration where it reduces the risk of visual loss. In primary ocular histoplasmosis and myopia it has been shown to stabilize and even improve vision in selected cases. This review article explains the mechanism of action, summarizes the results of clinical trials and discusses the side-effects of photodynamic therapy.
INTRODUCTION
Photodynamic therapy (PDT) has been used in many medical specialities but had its roots in cancer research. The goal of photodynamic therapy is selective treatment to a particular disease process. This was most applicable in the 1970s to cancer research. Unfortunately, the response was often limited by toxicity issues and skin photosensitivity.[1]
In the mid-1980s, porphyrin-based sensitizing agents were investigated and studied. These compounds had absorption peaks at longer wavelengths and less skin phototoxicity, which allowed them to be both safe and efficacious.
In the early 1990s, attention was turned to the treatment of pathologic ocular neovascularization. Early studies were done in animal models which paved the way for use in humans.
Verteporfin is medication that has been approved for use with photodynamic therapy in patients with macular degeneration, ocular histoplasmosis, myopia, and idiopathic choroidal neovascularization. MECHANISM OF ACTION
The mechanism of action has been thought to work by causing direct endothelial cell damage, with platelet adhesion and degranulation leading to localized vascular thrombosis and occlusion. Typically, closure of the choroidal neovascular membrane (CNVM) can be seen by angiography with nonperfusion of the CNVM and hypoperfusion in the area where the neovascular complex resides. Unfortunately, however, by about 12 weeks some degree of reperfusion is noted, most likely from vascular recannulization.
The mechanism of action of PDT is thought to be a result of singlet oxygen and other free radical production. The photosensitising dye is typically excited from the electronic ground state to a higher level, and as this photosensitivity returns to its ground state it releases energy to surrounding oxygen and other elementary compounds to create singlet oxygen and other charged particles that can lead to vascular thrombosis and occlusion.[2,3]
There are numerous factors that determine the effectiveness of treatment. They typically include wavelength, the metabolic profile of the dye, and vehicle used in the dye. The technique of photodynamic therapy is involved and typically has a two-step process that involves infusion of the photosensitizing dye followed by application of appropriate wavelength light to the target tissue. The dye is administered intravenously by standard infusion pump over a range of approximately 5 to 25 minutes, the exact duration depending upon the specific characteristics of the dye and specific dose. The dose of the dye is calculated by the patient’s weight and total body surface area. Once the dye is injected, there is a waiting period between the end of the infusion and the application of treatment. The treatment is typically done for 83 seconds for the laser part. The specific time interval allows the maximum amount of dye to be present in the choroidal neovascular membrane. This is done since later application while the dye is still present in the retinal vessels can cause untoward and unwanted neovascular occlusion and neurosensory infarction. The predetermined amount of light energy and size of the lesion is calculated on the fluorescein angiogram. A continuous wide beam of up to 500 microns of low thermal energy laser is applied by the delivery system. The size of the beam is adjusted to extend at least 500 microns beyond the margins of the neovascular complex. Typically, no changes are seen at the time of the treatment, unlike thermal laser. Results of Clinical Trials
Verteporfin and Visudyne is a compound that has been often used in animal models and to date has been approved for photodynamic therapy. In the Phase I and Phase II studies of verteporfin and PDT, the goal was to look at the proper dye and light doses necessary to close CNVM in patients with subfoveal CNVM. This study demonstrated that treatment was effective in achieving short-term cessation of fluorescein leakage from CNVM without the loss of visual acuity from CNVM. It also showed that multiple photodynamic treatments were safe and effective and that the area of fluorescein leakage appeared to be decreased with successive treatments. In 1996, the Phase III clinical trial, known as the treatment of age-related macular degeneration with photodynamic therapy study (TAP) was conducted. The primary outcome was a greater proportion of eyes with fewer than 15 letters lost (less than 3 lines of vision lost). PDT was administered every three months for a period of two years in eyes that had recurrent CNVM fluorescein leakage. The data from the TAP shows a statistically significant benefit from PDT. All outcome values, including visual acuity, contrast sensitivity and fluorescein angiogram outcomes were better in the treated eyes than in the placebo eyes at every follow-up examination.[4,5] The effect was greatest in eyes that had predominantly classic CNVM, with the classic CNVM being 50% or more of the entire lesion. For lesions that had less than 50% classic CNV, no difference in visual acuity was found between the PDT and placebo control groups. Currently, trials for both lesions less than 50% CNVM and occult are ongoing and the results pending.
Previously reported series from three institutions for subfoveal histoplasmosis showed that CNVM from histoplasmosis can be safely treated with PDT.[6]Patients with ocular histoplasmosis are at significant risk for developing CNVM.[7-9] With the natural history in cases with CNVM the prognosis is guarded, with more than 75% of eyes with subfoveal lesions developing 20/200 or worse vision over a two-to three-year period. The MPS and other groups showed that thermal laser and krypton laser were effective in treating extrafoveal, juxtafoveal and peripapillary CNVM.[10-13] The MPS demonstrated longer-term benefit with thermal laser in patients with subfoveal CNVM from age-related macular degeneration. This treatment has not been evaluated for histoplasmosis, given the loss of central visual acuity.
The use of submacular surgery for subfoveal CNVM in POHS has yielded variable results and continues to be investigated.[14-19] Rosenfeld and others have demonstrated preliminary results that PDT with Verteporfin was effective in studies with subfoveal CNVM.[20] Our results at the Barnes Retina Institute on 41 eyes of 41 patients showed significant benefit of PDT in eyes that had undergone previous submacular surgery (Table 1).
Visual acuity results in eyes with POHSPreoperative visual acuity
Mean : 20/80
Median : 20/163
Range : 20/20-20/800Postoperative visual acuity
Mean : 20/60
Median : 20/127
Range : 20/20-20/600Change in visual acuity (Preoperative versus Postoperative)
Mean change : 0.92 lines improvement (95%)
(CI : -0.22 lines to 2.06 lines)
Median change : 1 line improvement
26 of 38 patients (68.42 %; 95% CI:51.34-82.49)
improved or stayed the same
17 of 38 patients (44.73%; 95% CI:28.62-61.70)
improved 2 or more lines
10 of 38 patients (26.31%; 95% CI:13.40-43.10)
improved 4 or more lines
In our study, nearly 70% of the patients with CNVM secondary to POHS had visual stabilization or improvement following photodynamic therapy with Verteporfin. Data obtained from the retrospective analysis suggested that photodynamic therapy is a viable option for patients with CNVM from ocular histoplasmosis, at least in the short term. When comparing the natural history of the disease process, eyes treated with PDT in this study appeared to be more likely to have stabilization or improvement in vision, as did eyes that undergone previous submacular surgery, although the sample sizes were too small for subgroup analysis. This merits further investigation as the question of submacular surgery after PDT has become more relevant in patients with recurrent or persistent membranes requiring additional treatment options. We also performed a similar study on patients who had CNVM from pathologic myopia and found patients to have stabilization and improvement of vision following treatment with photodynamic therapy, with a mean preoperative visual acuity of 20/90 (Figs. 1A-4C).
As with any retrospective review, there are certain study limitations. First, data were abstracted by researchers who knew that patients had received photodynamic therapy. In situations where researchers are not masked, it is possible for investigator bias to be introduced into the results. Secondly, the decision to initiate treatment, the number of treatments and the decision to terminate treatment were performed in a non-standardized fashion.
Side Effects of PDT
Side effects of PDT are few but can be serious. Extravasation of the dye can cause localized tissue inflammation and injection, and infusion-related problems were reported in about 15% of patients who underwent PDT in the past study.
Photosensitivity reactions occur in about 3% of patients undergoing PDT. There was mild to moderate sunburn in patients who had sun exposure within 24 hours of dye infusion.
Another peculiar side effect is back pain at the time of infusion. This back pain may be related to possible changes or fluctuations in blood pressure. This typically resolves as the patient stands up during the treatment.
SUMMARYPDT therapy is important in the armamentarium for treatment of age-related macular degeneration. It is valuable in the treatment of choroidal neovascularization from age-related macular degeneration, primary ocular histoplasmosis, and myopia. In patients with age-related macular degeneration, it has been shown to significantly reduce the risk of visual loss, while in POHS and myopia it has actually been shown to stabilize and even improve vision in selected cases. In order to maintain visual benefit, re-treatments are necessary in all these circumstances. The best visual outcomes are typically obtained with these disease processes in the early stages of development. During the next millennium PDT will allow clinicians to embark on improving the management largely in patients in whom choroidal neovascularization causes visual loss. Although conventional laser photocoagulation is the gold standard and preferred treatment for non-subfoveal CNVM, PDT may soon become the gold standard for treating CNVM in many different disease conditions.
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