Transpupillary Thermotherapy: a Developing Approach in the Treatment of Occult Subfoveal Choroidal Membranes during Age-related Macular Degenera- Tion

Transpupillary thermotherapy (TTT) of choroidal neovascularization is a developing treatment modality. It uses large spot size, low irradiance and long exposure times with infrared laser to deliver hyperthermia to the choroid and retinal pigment epithelium. TTT has been originally used in the treatment of ocular tumors such as choroidal melanoma and choroidal hemangioma. Histologic studies showed secondary vascular sclerosis of irradiated vessels. Most of treatments of choroidal neovascularization have been conducted in eyes with symptomatic subfoveal occult lesions. The rationale for the treatment of choroidal neovascularization is to induce moderate hyperthermia sufficient to produce CNV thrombosis without major collateral retinal damages. Preliminary results from a number of pilot studies showed that TTT can safely reduce the risk of vision loss in patients with occult CNV secondary to AMD. A placebo-controlled, multi-center trial (TTT4CNV) evaluating the long-term efficacy and visual implications of TTT in occult CNV is underway. The basic principle of TTT and the results of the initial studies are described in this review. Introduction Choroidal neovascularization is a leading cause of blindness in the western world. It causes 90% of the visual loss in age-related macular degeneration (AMD).1 It also occurs during pathologic myopia (PM), which is the seventh leading cause of blindness in the United States,2 ocular histoplasmosis syndrome, angioid streaks, or idiopathic causes. Laser photocoagulation treatment can reduce the incidence of severe visual loss in cases of classic extrafoveal and juxtafoveal CNV. However laser photocoagulation damages the overlying neural retina and results in immediate visual loss when the CNV is subfoveal.3 There is also a high recurrence rate after laser photocoagulation.4 Additionally only 13% of cases of neovascular AMD are eligible for laser treatment under the present guidelines, because the CNV is occult, or subfoveal and large.5 Currently, there are no indications for the treatment of occult subfoveal CNV. Therefore, there is a need for alternative treatment modalities for CNV. Recently, photodynamic therapy (PDT) has shown promising results in the treatment of classic subfoveal CNV.6 Photodynamic therapy has also shown modest benefits in the treatment of a subgroup of occult CNVs with smaller lesions (4 disc areas or less) or lower levels of visual acuity (approximate Snellen equivalent of 20/50 or less).4 A number of other new treatments (radiotherapy, systemic thalidomide and other antiangiogenic agents, macular translocation, submacular membrane excision) are under investigation. Preliminary experiences have shown the benefit of TTT for the treatment of subfoveal CNV. Reichel et al.7 and Newsom et al.8 demonstrated a high closure rate and resolution of the neovacular membranes in patients with AMD without deleterious side effects. Principle and modality of application of transpupillary termotherapy Transpupillary therapy offers a potentially selective treatment for CNV secondary to AMD and other diseases. TTT is a low retinal irradiance, large spot size, long-pulse infrared diode laser photocoagulation treatment. The near infrared wavelength is absorbed by melanin contained into RPE cells and choroidal melanocytes. The aim of the treatment is to induce leakage reduction and exudate resorption. In this event fovea flattens and, potentially, vision stabilizes or improves. Whereas PDT and hyperthermia use exposures of one minute or longer, standard laser photocoagulation is applied with exposures of less than 100 times. Standard laser photocoagulation uses irradiances more than 10 times higher than TTT. Retinal irradiance is less than 1W per square centimeter in PDT and more than 10 times higher with hyperthermia. With PDT there is no temperature increase at the retina, while standard laser photocoagulation gives a temperature rise of about 45° with complete protein denaturation. Conversely to suprathreshold standard laser irradiation, the endpoint of TTT is not tissue coagulation but a controlled gradual maximal temperature raise of 10° C at the level of the lesion.10 In general no retinal color change should be obtained during laser exposure. Usual setting for a 60-second exposure on occult lesion is a power/diameter ratio of about 250 mW per mm. A spot size of 3 mm micron requires a power of 800 mW with a Goldmann lens. The Goldmann type lens magnification factor is 0.93X, so the actual laser spot at the retina is obtained 136 Journal of the Bombay Ophthalmologists’ Association Vol. 11 No. 4 dividing the diameter in air for the lens magnification (table 1). Before treatment, an accurate measurement of the lesion on fluorescein and indocyanine angiogram should be obtained in order to avoid irradiation of healthy tissue. The large laser spot is set to extend at least 100 micron beyond its margins. For the purpose of producing and maintaining the same level of hypertermia with different spot diameters (ie. constant power/diameter ratio), TTT of smaller lesions need higher irradiances due to the faster heat dissipation. This is an apparent paradox according to the constant irradiance or power/area ratio normally used in conventional photocoagulation. Infact, for any given pigmentation, temperature rise depends on both laser irradiance and spot size. The spot size, however, determines the thermally affected volume of tissue irradiated. Irradiance is directly proportional to the cooling rate and inversely proportional to the thermally affected volume. Transpupillary thermotherapy is a laser procedure but ophthalmoscopic and angiographic features differ significantly from the typical features of conventional laser theraphy. 12 The challenge of TTT is also related to the proper selection of laser power levels that are not too low nor excessive but are sufficient to alter the natural history of the lesions and trigger the pathophysiologic response resulting in a therapeutical beneficial effect. The absence of a visible endpoint during TTT leaves the physician with no tangible sign of achieved proper threshold for a positive outcome. Angiographic characteristics Although histologic studies of TTT-treated choroidal melanomas demonstrated extensive thrombosis of tumor vessels after treatment,9,11 the mechanisms of TTT-induced vascular damage and occlusion of CNV are not yet fully understood. Fluorescein and indocyanine green angiography are valuable tools to document the direct effect of TTT on the vascular integrity of CNV and collateral choroid. The changes that occur in the first weeks after TTT may provide some useful information to explain, predict and compare the effects in treated patients. Early angiographic images immediately after treatment might provide the treating ophthalmologist with a proof of a non-sham, and hopefully beneficial treatment. Recently we examined initial morphological alteration of CNV after treatment of occult and classic lesions. 13 Digital fluorescein angiography (FA)and indocyanine green angiography (ICGA) were performed at baseline and after TTT within 1 hour, and at 1 week. Within 1 hour after TTT of CNV, 67% of observed eyes showed a hyperfluorescent area correspondent to the laser spot (fig. 1). Increased leakage activity was evident originating from CNV and collateral choroid included into the treatment spot. Similar angiographic findings can be appreciated after PDT of CNV. 14 The treatment with PDT is followed by early intensive increase in vascular permeability consistent with a loss of barrier function. In 54% of cases observed, follow-up at 1 week after TTT of CNV demonstrated homogeneous choroidal hypofluorescence covering the entire size of the laser spot with absence of angiographic leakage (fig. 2). Hypofluorescence by ICGA angiography was not as deep as seen by fluorescein angiography, with larger choroidal vessels still seen. Late phases of ICGA angiography demonstrated reperfusion of the choroid with a ringshaped hyperfluorescence of the collateral choroid included into the irradiated area. The retinal vessels were intact and physiologically perfused in all cases except the one that showed retinal whitening during treatment. Similarly to TTT, hypofluorescence of the light-exposed area has been described at one week after photodynamic therapy of CNV. 14 Our results clearly showed that vascular damage and remodelling are consequences of TTT of CNV. The observation of hyperfluorescence and hypofluorescence after TTT derives from a combination of damage within the microvasculature and the stimulated responses. OCT imaging of CNV treated with TTT TTT induces a dynamic sequence on CNV during the early post-operative period. Many of the biomicroscopic and angiographic signs of exudative AMD can be visualized and quantified with OCT. 21-23 OCT may be also of aid in understanding the rapid response to treatment in the research and clinical setting. 24 Subfoveal CNV can be identified as a highly or moderately reflective mass that protrudes through Table 1. TTT indications for initial laser power setting 60 second laser exposure time Spot diameter in air (mm) Power mW Irradiance (W/cm2) Power/Diameter Ratio (mW/mm)