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Table 1. 
Follow-up and Retreatment of the Original 69 Patients*
Follow-up and Retreatment of the Original 69 Patients*
Table 2. 
Visual Acuity
Visual Acuity
Table 3. 
Comparison of Visual Acuity Results to Other Treatment Trials*
Comparison of Visual Acuity Results to Other Treatment Trials*10,11,1620,25,15,13
1.
Ferris  FL  IIIFine  SLHyman  L Age-related macular degeneration and blindness due to neovascular maculopathy. Arch Ophthalmol. 1984;1021640- 1642Article
2.
Macular Photocoagulation Study Group, Argon laser photocoagulation for senile macular degeneration: results of a randomized clinical trial. Arch Ophthalmol. 1982;100912- 918Article
3.
Macular Photocoagulation Study Group, Krypton laser photocoagulation for neovascular lesions of age-related macular degeneration: results of a randomized clinical trial. Arch Ophthalmol. 1990;108816- 824Article
4.
Macular Photocoagulation Study Group, Laser photocoagulation of subfoveal neovascular lesions in age-related macular degeneration: results of a randomized clinical trial. Arch Ophthalmol. 1991;1091220- 1231Article
5.
Vogl  ABirngruber  R Temperature profiles in human retina and choroid during laser coagulation with different wavelengths ranging from 514 to 810 nm. Lasers Light Ophthalmol. 1992;59- 16
6.
Brancato  RPratesi  R Applications of diode laser in ophthalmology. Lasers Ophthalmol. 1987;1119- 129
7.
Puliafito  CADeutsch  TFBoll  JTo  K Semiconductor laser endophotocoagulation of the retina. Arch Ophthalmol. 1987;105424- 427Article
8.
Shields  CShields  JCater  J  et al.  Transpupillary thermotherapy for choroidal melanoma: tumor control and visual results in 100 consecutive cases. Ophthalmology. 1998;105581- 590Article
9.
Oosterhuis  JAKorver  HG Journee-deKakebeeke-Kemme  HMBleeker  JC Transpupillary thermotherapy in choroidal melanomas. Arch Ophthalmol. 1995;113315- 321Article
10.
Reichel  EBerrocal  AMIp  M  et al.  Transpupillary thermotherapy of occult subfoveal choroidal neovascularization in patients with age-related macular degeneration. Ophthalmology. 1999;1061908- 1914Article
11.
Newsom  RSMcAlister  JCSneed  MMcHugh  JD Transpupillary thermotherapy (TTT) for the treatment of choroidal neovascularization. Br J Ophthalmol. 2001;85173- 178Article
12.
Holladay  JTPrager  TC Mean visual acuity [letter]. Am J Ophthalmol. 1991;111372- 374
13.
Treatment of Age-Related Macular Degeneration With Photodynamic Therapy(TAP) Study Group, Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials—TAP report 1. Arch Ophthalmol. 1999;1171329- 1345Article
14.
Bressler  NMTreatment of Age-Related Macular Degeneration With Photodynamic Therapy(TAP) Study Group, Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials—TAP report 2. Arch Ophthalmol. 2001;119198- 207
15.
Verteporfin in Photodynamic Therapy Study Group, Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization—vertiporfin in photodynamic therapy report 2. Am J Ophthalmol. 2001;131541- 560Article
16.
Park  CHDuker  JSMainster  MA  et al.  Transpupillary thermotherapy (TTT) of occult choroidal neovascularization: a retrospective, noncomparative case series of fifty-seven eyes. Semin Ophthalmol. 2001;1666- 69Article
17.
Friberg  TRPandya  ANazari  K Transpupillary thermotherapy (TTT) for age-related macular degeneration. Semin Ophthalmol. 2001;1670- 80Article
18.
Ahuja  RMBenner  JDSchwartz  JC  et al.  Efficacy of transpupillary thermotherapy (TTT) in the treatment of occult subfoveal choroidal neovascularization in age-related macular degeneration. Semin Ophthalmol. 2001;1681- 85Article
19.
Kim  JEPerkins  SLSchwiesow  T  et al.  Transpupillary thermotherapy of occult choroidal neovascularization in age-related macular degeneration. Semin Ophthalmol. 2001;1686- 89Article
20.
Algvere  PVLibert  CSeregard  S Transpupillary thermotherapy of occult CNV with no or minimally classic CNV in age-related macular degeneration. Semin Ophthalmol. 2001;1690- 96Article
21.
Mainster  MAReichel  E Transpupillary thermotherapy for age-related macular degeneration: long-pulse photocoagulation, apoptosis, and heat shock proteins. Ophthalmic Surg Lasers. 2000;31359- 373
22.
Welch  AJWissler  EHPriebe  LA Significance of blood flow in calculations of temperature in laser irradiated tissue. IEEE Trans Biomed Eng. 1980;27164- 166Article
23.
Korver  JG Journee-deOosterhuis  JAde Wolff-Rouendaal  DKemme  H Histopathological findings in human choroidal melanomas after transpupillary thermotherapy. Br J Ophthalmol. 1997;81234- 239Article
24.
Lanzetta  PMichieletto  PPirracchio  ABandello  F Early vascular changes induced by transpupillary thermotherapy of choroidal neovascularization. Ophthalmology. 2002;1091098- 1104Article
25.
Stevens  TSBressler  NMMaguire  MG  et al.  Occult choroidal neovascularization in age-related macular degeneration: a natural history study. Arch Ophthalmol. 1997;115345- 350Article
26.
Thompson  JT Retinal pigment epithelial tear after transpupillary thermotherapy for choroidal neovascularization. Am J Ophthalmol. 2001;131662- 664Article
Clinical Sciences
June 2003

Large–Spot Size Transpupillary Thermotherapy for the Treatment of Occult Choroidal Neovascularization Associated With Age-Related Macular Degeneration

Author Affiliations

From the Retinal Consultants of Arizona, Phoenix.

Arch Ophthalmol. 2003;121(6):817-820. doi:10.1001/archopht.121.6.817
Abstract

Objective  To describe the outcome of patients with occult choroidal neovascularization in age-related macular degeneration treated with transpupillary thermotherapy.

Design  Prospective, nonrandomized, nonmasked case series.

Methods  All patients with age-related macular degeneration with a predominantly occult choroidal neovascular membrane and an initial visual acuity of 20/400 or better were offered treatment using transpupillary thermotherapy. The treatment consisted of using a diode laser, a spot size of about 3000 to 6000 µm delivered over 60 seconds, and a power of 600 to 1000 m W.

Main Outcome Measures:  A stable, improved, or worsened visual acuity and the need for additional treatment.

Results  Sixty-nine patients were treated. All patients have been followed up for at least 6 months. At the 6-, 9-, and 12-month follow-up visits, 71% of patients have stable or improved visual acuity and 29% have lost 2 or more lines of visual acuity on the Snellen letter chart.

Conclusion  Large–spot size transpupillary thermotherapy is effective in stabilizing the visual acuity in those patients who have occult choroidal neovascularization due to age-related macular degeneration.

AGE-RELATED MACULAR degeneration (AMD) is one of the leading causes of blindness in the Western world. The most common cause of visual loss is the formation of choroidal neovascularization (CNV).1 Compared with the natural history, thermal laser treatment is more effective in preventing significant loss of visual acuity in patients with extrafoveal and juxtafoveal CNV.2,3 In patients with neovascularization under the fovea, the prognosis is much more guarded. Thermal lasers have been the mainstay of treatment for subretinal neovascular membranes. Unfortunately, thermal lasers cause damage to the neurosensory retina resulting in a permanent scotoma. For those patients with subfoveal neovascularization, the Macular Photocoagulation Study Group4 showed a small benefit by treating these lesions with a thermal laser.

The diode laser has a theoretical advantage over other wavelengths of light because there is little absorption in the xanthophyll layer and, thus, damage to the nerve fiber layer is minimized. Additionally, compared with the argon laser, the diode laser is poorly absorbed by hemoglobin5,6 allowing an improved ability to treat through preretinal and subretinal hemorrhage. The wavelength of the diode laser (810 nm) is mainly absorbed by melanin at the level of the retinal pigment epithelium and choroid, enabling treatment of choroidal lesions.7 Long-duration, low-irradiance diode laser has been used to treat choroidal melanomas8,9 and, in preliminary trials, to treat CNV (transpupillary thermotherapy [TTT]).10,11 The recent reports on the use of TTT for subfoveal CNV show some success in the treatment of both classic and occult CNV. Because occult neovascular membranes are often difficult to precisely define and may originate from more than one foci, we used a large–spot size diode laser to ensure that the treatment area would cover large, multifocal or diffuse occult CNV. We investigated the use of large-spot size TTT for occult CNV in patients who had AMD.

METHODS

All patients in this study were initially treated between October 1, 2000, and December 31, 2000. Patients were 55 years of age and older and diagnosed as having occult subfoveal CNV secondary to AMD.

At the initial visit and all subsequent visits the patient had a Snellen visual acuity measured and underwent a general ophthalmologic examination, to include biomicroscopic examination of the macula. Fluorescein angiography was performed at the initial visit and at each subsequent 3-month visit. The patients were informed of the results of preliminary trials that had been published and given the option of observation vs treatment.

Transpupillary thermotherapy (TTT) was delivered via a slitlamp using an infrared diode laser at 810 nm. The spot size was set at 3000 µm. Topical 0.5% proparacaine hydrochloride was applied to the eye prior to placement of an area centralis lens (magnification of laser spot, ×0.94) or a quadraspheric lens (×1.97 magnification of laser spot, resulting in a spot size of 5910 µm) (Volk Optical Inc, Mentor, Ohio). Continued observation through the lens ensured proper fixation. The treatment consisted of a single spot with a duration of 60 seconds. The power used ranged from 600 to 1000 m W. The power was begun at 750 m W for the area centralis lens and at 1000 m W for the quadraspheric lens and was adjusted downward if there was any retinal whitening noted, if the patient experienced any pain or a burning sensation, or if the patient or physician heard a popping sound.

The patient was seen 6 weeks after treatment and 3 months after treatment, then every 3 months thereafter. Retreatment was performed at 3-month intervals if there was persistent leakage noted in the late stages of the fluorescein angiogram. The average visual acuity was obtained by calculating the logarithm of the minimal angle of resolution (ie, Snellen visual acuity), taking the mean of these figures, and converting the antilog of the mean to a Snellen visual acuity.12

RESULTS

Sixty-nine patients (18 men [26%] and 51 women [74%]) elected to undergo treatment with TTT. The average age was 78 years (age range, 66-91 years). Review of the fluorescein angiogram showed that all 69 lesions were predominantly occult. Two patients developed a retinal pigment epithelial tear after TTT, but no other complications were noted. The laser spot size was about 6000µm in 65 patients (94%) and about 3000 µm in 4 patients (6%).

Table 1 gives the duration of follow-up visits and the retreatment of the original 69 patients. All patients had at least 6 months of follow-up (some patients returned for a 9- or 12-month follow-up visit but had not returned for the 6-month follow-up visit). Each patient had an average of 1.93 treatment sessions in the first year (range, 1-3 treatment sessions). Twenty-one patients (30.4%) had 1 treatment, 32 patients(46.4%) had 2 treatments, and 16 patients (23.2%) had 3 treatments (Table 1).

The mean visual acuity at the initial visit was 20/177, at the 3-month visit it was 20/208, at the 6-month visit it was 20/230, at the 9-month visit it was 20/208, and at the 12-month visit it was 20/229. The visual acuity at each of the follow-up visits was compared with the initial visual acuity. Stable or improved visual acuity was defined as a loss of 1 line on the Snellen letter chart, any improvement in visual acuity, or no change in visual acuity. Worsened visual acuity was defined as a loss of 2 or more lines of visual acuity on the Snellen letter chart. At the 3-month visit 56 (81%) of the 69 patients had stabilized or improved visual acuity. At the 6-, 9-, and 12-month visit 46, 36, and 20 (71%) of the 65, 51, and 28 patients, respectively, had stable or improved visual acuity (Table 2).

COMMENT

Until recently the only options available to patients with AMD and subfoveal CNV were observation or thermal laser treatment of the lesion. Few patients meet the strict guidelines established by the Macular Photocoagulation Study Group for treatment of a subfoveal CNV and those treated often had an immediate decrease in the visual acuity.4 Photodynamic therapy offers treatment of subfoveal CNV without the immediate loss of central vision induced by the thermal laser. Unfortunately, photodynamic therapy, as it is used, has been found to be beneficial for patients with a predominantly classic CNV or a purely occult CNV.1315 For those patients with a predominantly occult CNV, there have been recent trials that indicate that TTT is effective in stabilizing CNV and stabilizing visual acuity.10,11,1620 Our study shows that large–spot size TTT is effective in stabilizing visual acuity in those patients who had an occult CNV due to AMD.

Thermal lasers cause a heat-induced denaturation of chorioretinal proteins. The thermal lasers used in AMD tend to be in the visible spectrum, be of short duration (<1 second), and have a small spot size (<500 µm) raising the tissue temperatures as much as over 40°C. Photodynamic therapy, on the other hand, creates a photochemical reaction in which a long-pulse, very low-irradiance laser activates a chemical photosensitizer that has been absorbed in the target tissue causing damage to and closure of the CNV. Transpupillary thermotherapy uses a long pulse and large spot size to induce hyperthermia and apoptosis.21 Transpupillary thermotherapy raises tissue temperatures about 10°C.21 For very long exposures, heat convection, because of choroidal blood flow, moderates the chorioretinal temperature rise.22 When used in patients who have AMD, it delivers the light at a threshold or subthreshold level with a barely visible or an invisible lesion in the retina and choroid. It is thought that raising the temperature 5°C will cause heat shock, protein denaturation, and cell death.21 Melanin in the retinal pigment epithelium and choroid is the primary light absorber in retinal photocoagulation.5,6 These factors should help to limit the damage to the neurosensory retina. A histopathologic study done on TTT-treated eyes with a choroidal melanoma showed thrombosis of the tumor vessels.23 Fluorescein angiography shows hypofluorescence and diminished leakage at 1 and, to a lesser extent, 4 weeks after TTT. This closure of the choroidal vasculature may be caused by endothelial damage due to hyperthermia at the target tissue.24

The results from our study show that visual acuity is stabilized in 71% of patients at the 6-, 9- and 12-month follow-up visits (Table 2). Although statistically there was not a significant improvement in visual acuity, neither was there a significant decrease in visual acuity. This compares favorably with the results of other studies on TTT in which 63% to 86% were stable, with variable follow-up, 10,11,1620 and with the natural history of occult CNV in which only 38% of patients were stable after 9 to 12 months (Table 3).25 Photodynamic therapy for purely occult CNV did not seem to fare any better than the natural history studies.15 In patients treated with photodynamic therapy for occult CNV, only 34% of those treated had stable or improved visual acuity at 12 months. In the control group, 23% of those treated had stable or improved visual acuity. Comparing the results of these studies has its limitations as each study had its own inclusion and exclusion criteria, vastly different forms of treatment, variable methods of measuring visual acuity, and different follow-up periods.

The ideal laser settings for TTT have not been determined. The previous studies using TTT for CNV in AMD have used different settings.10,11,1620 The spot size varied from 800 to 3000 µm. The power used was 300 to 1000m W, and the number of spots varied from 1 to an average of 4.25 per treatment session. The goal in all of the studies is to have minimal or no retinal whitening. In our study we used a large spot size of about 6000 µm in most of our patients. The large spot size was used to cover a broad area as the full extent of an occult CNV may not be able to be determined on fluorescein angiography alone. Often an occult CNV will have several points of origin. The patients in our study were treated with 600 to 1000 m W of power. None of the patients developed any clinical evidence of retinal whitening, but the power was adjusted downward only when the patient felt pain or a burning sensation or when the physician or patient heard an audible pop. The audible pop or retinal whitening indicates a suprathreshold treatment level. Of the 133 treatment sessions completed, the power was lowered for 12 patients (9%) because of pain or a burning sensation or an audible pop.

We had 2 patients (3%) who developed a tear in the retinal pigment epithelium after TTT. Thompson26 has also reported a tear in the retinal pigment epithelium after TTT. Others have reported a complication rate as low as a 0% and as high as 9%.10,11,1620 Other complications noted to occur after TTT for a choroidal melanoma include vascular occlusion, macular edema, retinal neovascularization, and optic nerve edema. The increased risk of TTT complications in patients with a choroidal melanoma may be due to the higher-power settings used for these patients.

The use of large–spot size TTT seems to be an effective treatment of occult CNV membranes in AMD. Our results are comparable to the results of other studies using smaller spot sizes.10,11,1620 When compared with photodynamic therapy for predominantly occult CNV, TTT seems to have a better success at stabilizing visual acuity, although there have not been any controlled studies with TTT. Other than the results of apparent improved visual acuity, TTT does not require the time and cost of photodynamic therapy and because no medication is needed, there are fewer adverse effects from TTT.

Although our study was prospective, we did not use standardized visual acuity charts (eg, Early Treatment Diabetic Retinopathy Study chart) and we used only historical controls. These factors may have induced bias in our analysis. The exact role of TTT in patients with subfoveal CNV in AMD and the laser treatment variables will only be answered after a large randomized, prospective, multicenter treatment trial is conducted.

Corresponding author and reprints: Allen B. Thach, MD, Retinal Consultants of Arizona, PO Box 32530, Phoenix, AZ 85064-2530.

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Article Information

Submitted for publication August 2, 2002; final revision received January 26, 2003; accepted February 12, 2003.

References
1.
Ferris  FL  IIIFine  SLHyman  L Age-related macular degeneration and blindness due to neovascular maculopathy. Arch Ophthalmol. 1984;1021640- 1642Article
2.
Macular Photocoagulation Study Group, Argon laser photocoagulation for senile macular degeneration: results of a randomized clinical trial. Arch Ophthalmol. 1982;100912- 918Article
3.
Macular Photocoagulation Study Group, Krypton laser photocoagulation for neovascular lesions of age-related macular degeneration: results of a randomized clinical trial. Arch Ophthalmol. 1990;108816- 824Article
4.
Macular Photocoagulation Study Group, Laser photocoagulation of subfoveal neovascular lesions in age-related macular degeneration: results of a randomized clinical trial. Arch Ophthalmol. 1991;1091220- 1231Article
5.
Vogl  ABirngruber  R Temperature profiles in human retina and choroid during laser coagulation with different wavelengths ranging from 514 to 810 nm. Lasers Light Ophthalmol. 1992;59- 16
6.
Brancato  RPratesi  R Applications of diode laser in ophthalmology. Lasers Ophthalmol. 1987;1119- 129
7.
Puliafito  CADeutsch  TFBoll  JTo  K Semiconductor laser endophotocoagulation of the retina. Arch Ophthalmol. 1987;105424- 427Article
8.
Shields  CShields  JCater  J  et al.  Transpupillary thermotherapy for choroidal melanoma: tumor control and visual results in 100 consecutive cases. Ophthalmology. 1998;105581- 590Article
9.
Oosterhuis  JAKorver  HG Journee-deKakebeeke-Kemme  HMBleeker  JC Transpupillary thermotherapy in choroidal melanomas. Arch Ophthalmol. 1995;113315- 321Article
10.
Reichel  EBerrocal  AMIp  M  et al.  Transpupillary thermotherapy of occult subfoveal choroidal neovascularization in patients with age-related macular degeneration. Ophthalmology. 1999;1061908- 1914Article
11.
Newsom  RSMcAlister  JCSneed  MMcHugh  JD Transpupillary thermotherapy (TTT) for the treatment of choroidal neovascularization. Br J Ophthalmol. 2001;85173- 178Article
12.
Holladay  JTPrager  TC Mean visual acuity [letter]. Am J Ophthalmol. 1991;111372- 374
13.
Treatment of Age-Related Macular Degeneration With Photodynamic Therapy(TAP) Study Group, Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials—TAP report 1. Arch Ophthalmol. 1999;1171329- 1345Article
14.
Bressler  NMTreatment of Age-Related Macular Degeneration With Photodynamic Therapy(TAP) Study Group, Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials—TAP report 2. Arch Ophthalmol. 2001;119198- 207
15.
Verteporfin in Photodynamic Therapy Study Group, Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization—vertiporfin in photodynamic therapy report 2. Am J Ophthalmol. 2001;131541- 560Article
16.
Park  CHDuker  JSMainster  MA  et al.  Transpupillary thermotherapy (TTT) of occult choroidal neovascularization: a retrospective, noncomparative case series of fifty-seven eyes. Semin Ophthalmol. 2001;1666- 69Article
17.
Friberg  TRPandya  ANazari  K Transpupillary thermotherapy (TTT) for age-related macular degeneration. Semin Ophthalmol. 2001;1670- 80Article
18.
Ahuja  RMBenner  JDSchwartz  JC  et al.  Efficacy of transpupillary thermotherapy (TTT) in the treatment of occult subfoveal choroidal neovascularization in age-related macular degeneration. Semin Ophthalmol. 2001;1681- 85Article
19.
Kim  JEPerkins  SLSchwiesow  T  et al.  Transpupillary thermotherapy of occult choroidal neovascularization in age-related macular degeneration. Semin Ophthalmol. 2001;1686- 89Article
20.
Algvere  PVLibert  CSeregard  S Transpupillary thermotherapy of occult CNV with no or minimally classic CNV in age-related macular degeneration. Semin Ophthalmol. 2001;1690- 96Article
21.
Mainster  MAReichel  E Transpupillary thermotherapy for age-related macular degeneration: long-pulse photocoagulation, apoptosis, and heat shock proteins. Ophthalmic Surg Lasers. 2000;31359- 373
22.
Welch  AJWissler  EHPriebe  LA Significance of blood flow in calculations of temperature in laser irradiated tissue. IEEE Trans Biomed Eng. 1980;27164- 166Article
23.
Korver  JG Journee-deOosterhuis  JAde Wolff-Rouendaal  DKemme  H Histopathological findings in human choroidal melanomas after transpupillary thermotherapy. Br J Ophthalmol. 1997;81234- 239Article
24.
Lanzetta  PMichieletto  PPirracchio  ABandello  F Early vascular changes induced by transpupillary thermotherapy of choroidal neovascularization. Ophthalmology. 2002;1091098- 1104Article
25.
Stevens  TSBressler  NMMaguire  MG  et al.  Occult choroidal neovascularization in age-related macular degeneration: a natural history study. Arch Ophthalmol. 1997;115345- 350Article
26.
Thompson  JT Retinal pigment epithelial tear after transpupillary thermotherapy for choroidal neovascularization. Am J Ophthalmol. 2001;131662- 664Article
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