Transpupillary thermotherapy and photodynamic therapy for neovascular age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among elderly in industrialized nations, and promises to extract an even greater toll with the imminent demographic shift. Neovascular AMD (wet AMD) often develops quickly and involves the growth of new blood vessels under the retina (choroidal neovascularization, CNV). These new blood vessels tend to be fragile and often leak blood and fluid. The blood and fluid elevates the macula, the central part of the retina, causing rapid visual loss. Without treatment the prognosis is poor with profound impact on an individual s ability to perform daily tasks.

Photodynamic therapy (PDT) has been the most common treatment for neovascular AMD. PDT uses a cold laser to seal the leaking blood vessels. This involves injecting a lightsensitive drug that reaches and coats the abnormal blood vessels via the blood stream. The drug is then activated by light leading to a local occlusion of new vessels.

Transpupillary thermotherapy (TTT) is technique in which a laser-induced subretinal vascular occlusion can be created through a small temperature elevation but without any photosensitive drugHowever, there has been a controversy about the optimal TTT laser intensity and controlled clinical trails demonstrating efficacy in neovascular AMD have been lacking.

The first two studies of the thesis demonstrate that PDT as well as TTT can reduce experimental CNV, without causing damage to the surrounding tissue. A cellular damage in surroundning tissues was however seen at higher dosage. The therapeutic window is thus narrow for both treatments underscoring the importance minimizing treatment doses. We also found that both TTT and PDT induce an immediate thrombosis and cessation of perfusion in CNV areas, but after PDT some areas remained vascularised while after TTT the closure of the abnormal vessels proceeded for at least one week.

The third and fourth studies of the thesis were on a prospective clinical study, randomizing 98 patients with neovascular AMD (occult CNV) to either low-dose TTT or PDT. During a follow-up of 12 months, no significant differences between the two groups emerged. The proportion of patients with stabilized visual acuity was approximately 75% in both groups and the two treatments were equally potent at stabilizing patient-reported visual function.

Recently intravitreal anti-VEGF has become the first line treatment for neovascular AMD demonstrating superior efficacy for all forms of neovascular AMD. However, anti-VEGF is expensive and requires repeated injections. The use of PDT as an adjuvant to anti-VEGF therapy has been suggested to decrease both the cost and the need for repeated injections. Also this combination may prove beneficial regarding control of lesion growth. The results of this thesis, showing that low dose TTT may be equipotent to PDT, suggests that TTT may be a cost-effective adjuvant to intravitreal anti-VEGF treatment.

List of scientific papers

I. Ming Y, Algvere PV, Odergren A, Berglin L, van der Ploeg I, Seregard S, Kvanta A (2004). "Subthreshold transpupillary thermotherapy reduces experimental choroidal neovascularization in the mouse without collateral damage to the neural retina." Invest Ophthalmol Vis Sci 45(6): 1969-74
https://pubmed.ncbi.nlm.nih.gov/15161865

II. Odergren A, Ming Y, Kvanta A (2006). "Photodynamic therapy of experimental choroidal neovascularization in the mouse." Curr Eye Res 31(9): 765-74
https://pubmed.ncbi.nlm.nih.gov/16966149

III. Odergren A, Algvere PV, Seregard S, Kvanta A (2008). "A prospective randomised study on low-dose transpupillary thermotherapy versus photodynamic therapy for neovascular age-related macular degeneration." Br J Ophthalmol 92(6): 757-61. Epub 2008 Mar 20
https://pubmed.ncbi.nlm.nih.gov/18356266

IV. Odergren A, Algvere P, Seregard S, Libert C, Kvanta A (2008). "Vision-related function after low dose transpupillary thermotherapy (TTT) versus photodynamic therapy (PDT) for neovascular age-related macular degeneration." (Submitted)