Selective laser trabeculoplasty

Argon laser trabeculoplasty

The application of lasers on the trabecular meshwork (TM) was pioneered by Worthen and Wickham in 1973.1,2 They described the use of a continuous wave argon laser to photocoagulate the TM, resulting in a significant reduction in intraocular pressure (IOP). The technique was called argon laser trabeculotomy and the results were temporary, lasting only several months. In 1979, Wise and Witter3 described the use of a low energy argon laser not to penetrate the TM, but rather to create a series of superficial scars circumferentially with the end result of decreased IOP. Their work paved the way for the widespread use of lasers in the treatment of open-angle glaucoma. This technique became known as argon laser trabeculoplasty (ALT).

Selective laser trabeculoplasty

Despite the proven success of ALT, its use has been limited by several factors. Most important of these is the underlying coagulative damage to the TM induced by the procedure. Such changes in the architecture of the TM may ultimately result in trabecular fusion and/or occlusion of the trabecular spaces, possibly leading to obstruction of aqueous outflow.

In 1995, using a procedure they called selective laser trabeculoplasty (SLT), Latina and Park4 demonstrated that coagulative damage to the TM is not necessary for achieving IOP reduction. Initial in vitro studies were conducted to evaluate the possibility of selectively targeting the pigmented TM cells without damaging the architecture of the TM.5

This was achieved using a Q-switched, frequen-cy- doubled Nd:YAG laser at energy fluences of 30-1000 mJ/cm². A subsequent study using owl monkeys (sp. Aotus trivirgatus) confirmed actual selective targeting of pigmented TM cells in vivo, and evaluated the safety and morphological effects of the procedure in a living system (unpublished data presented at ARVO; Latina MA, Sibayan S: S408, 1996). Light and electron microscopy revealed only disruption of pigmented TM cells with an intact structural architecture and no damage to the trabecular collagen beams. Endothelial membrane formation on the TM, which is usually found in ALT-treated eyes, was not seen.

These results were confirmed by Kramer and Noecker6 Using scanning and transmission electron microscopy to compare acute morphological changes in the TM of freshly enucleated human eye bank eyes, they demonstrated crater formation, coagulative damage, fibrin deposition, and disruption of trabecular beams and endothelial cells after ALT, while eyes treated with SLT showed none of these findings. SLT preserved the architecture of the TM.

Mechanism of selective laser trabeculoplasty

The in vitro and in vivo findings after SLT are observed because the pulse duration of the Q- switched, frequency-doubled (532 nm) Nd:YAG laser is shorter than the thermal relaxation time of melanin.4 Thermal relaxation time defines the absolute time required by a chromophore to convert electromagnetic energy into thermal energy. Melanin has a thermal relaxation time in the microsecond range, while the pulse duration of the Nd:YAG

laser ranges from 3-10 nsec. This means that the pulse duration of this laser is too short for the melanin to convert the laser energy into heat. This spares the surrounding non-pigmented tissues from any coagulative damage.

The demonstrable clinical efficacy of SLT suggests that it works on the cellular level, either through migration and phagocytosis of TM debris by the macrophages,7 or by stimulation of the formation of healthy trabecular tissue which may enhance the outflow properties of the TM.8,9 Alvarado10 observed a fiveto eight-fold increase in the number of monocytes and macrophages present in the TM of monkey eyes treated with SLT, compared with untreated controls. He theorized that injury to the pigmented TM cells after SLT results in the release of factors and chemoattractants which recruit monocytes. These are activated and transformed into macrophages upon interacting with the injured tissues, and engulf and clear the pigment granules from the TM before exiting the eye to return to the circulation via Schlemm’s canal.11

Clinical efficacy of selective laser trabeculoplasty

A pilot study evaluating the IOP lowering effect of SLT in 53 patients whose IOPs could not be controlled by medication, or who had failed traditional ALT, demonstrated the safety and efficacy of SLT.5 The patients were followed for 26 weeks and a mean IOP reduction of 18.7% (4.6 mmHg) with minimal adverse effects was noted. Furthermore, 66% of patients who had previously failed ALT showed an average reduction of IOP of 5.9 mmHg, without any significant adverse effects.

In a longer term, randomized, prospective clinical study comparing the effects of SLT versus ALT on the IOP of patients with open-angle glaucoma on medication, Damji et al.7 noted a mean IOP reduction of 6.5 mmHg at 12 months in those patients treated with SLT over 180°. Eyes treated with ALT achieved an IOP reduction of 6.03 mmHg, which was not statistically different from the SLTtreated eyes.

Indications for selective laser trabeculoplasty

Almost all forms of open-angle glaucoma are candidates for treatment with SLT. However, caution should be used with conditions not amenable to ALT, such as juvenile open-angle glaucoma and secondary inflammatory glaucomas.

Selective laser trabeculoplasty as initial therapy

The Glaucoma Laser Trial (GLT), demonstrated that initial treatment with ALT was shown to have

a greater pressure lowering effect than medication (timolol maleate 0.5%) at two years of follow-up. The GLT study indicated that initial treatment with ALT in patients with primary open-angle glaucoma was at least as effective as intervention with timolol.15

In a similar fashion, SLT has been demonstrated to be safe and efficacious as a first line therapy for open-angle glaucoma. In a study of 26 previously untreated pseudoexfoliative and primary open-angle glaucoma patients, Latina and Smith showed a 30month cumulative probability of successfully remaining off medication of 70% without significant adverse effects after SLT (unpublished data presented at the AAO. Latina MA, Smith J: 2001).

Preoperative assessment

The preoperative evaluation should include the assessment of corneal clarity and gonioscopy. Corneal clarity is necessary in the delivery of energy. Opacifications in the cornea from edema, scarring, or dystrophy must be noted and appropriate interventions performed.

Gonioscopy performed preoperatively will facilitate the laser procedure. Narrow angles may require laser gonioplasty or iridotomy to deepen the angle. Peripheral anterior synechiae should be noted. Extensive synechiae may preclude an effective procedure.

Operative technique

The operative technique is similar to ALT. Even though SLT is not associated with large IOP spikes, apraclonidine or brimonidine should be given to minimize post-laser IOP elevation. A topical anesthetic such as proparacaine, given immediately prior to the procedure, will also be helpful.

A Goldmann three-mirror lens or a Ritch lens may be used, but a Latina lens, optically tuned for the 532 nm wavelength, is preferred for SLT. Goniosolution is placed on the contact lens and the lens is placed on the eye.

The aiming beams should be focused on the TM through the center of the mirror of the contact lens in order to ensure a round beam and to maximize energy delivery. The 400-µm aiming beam is large enough to cover the antero-posterior breadth of the TM.

SLT has a fixed spot size of 400 µm – as large as the aiming beam. Treatment is begun at 0.8 mJ and increased or decreased in 0.1 mJ increments until the threshold energy is reached. This can be identified by the formation of a cavitation bubble. Treatment is consummated just below the threshold energy. Approximately 50 laser shots are delivered to cover 180° of TM. SLT treatment should be confluent, but non-overlapping.

Postoperative period

An increased anterior chamber reaction can be expected during the first hour after treatment.5,7 This quickly resolves and usually disappears by the fifth day. A wide variety of anti-inflammatories has been used successfully as post-treatment medication, including indomethacin 0.1% t.i.d. for ten days,16 dexamethasone-neomycin q.i.d. for seven days,17 and prednisolone acetate 1% q.i.d. for seven days.7

Without pre-treatment with apraclonidine, Latina et al. reported IOP spikes of 8 mmHg or greater in 9% of treated eyes, and IOP spikes of 5 mmHg or greater in only 24% of treated eyes.5 Pretreament with apraclonidine 1% resulted in a mean drop of 1.4 mmHg at one hour.7 An IOP spike occurred in only three of 18 treated eyes (maximum, 4 mmHg) in the same study.

Within two hours, up to 40% IOP decrease has been observed.16 This was maintained at 24 hours. Gracner reported a 22.6% or 5.12 mmHg mean reduction in IOP at one day, which still remained at six months.17 However, there were cases in which a less precipitous drop in IOP occurred. Hence, clinical decisions regarding repeat treatment should be deferred for at least six weeks.

Repeat treatments

If IOP reduction is inadequate after six weeks, treatment of the untreated 180° may be contemplated. Because of its non-destructive nature, multiple treatments with SLT are theoretically possible. Repeat treatment with SLT has been found to be safe and effective (unpublished data presented at the AAO. Latina MA, Smith J: 2001).

Conclusions

In summary, SLT is safe and effective in lowering IOP. Moreover, clinical studies have demonstrated that SLT treatment following failed ALT has a success rate similar to that seen in patients who have not had prior laser treatment. The treatment may be repeated because of the lack of coagulation damage to the TM. Furthermore, it can be considered as a primary treatment option, especially in patients who are medication-intolerant or in those who will not comply with their glaucoma medication, without interfering with the success of future surgery.

Due to its non-destructive properties and low

complication rate, SLT has the potential to become an ideal first line treatment for open-angle glaucoma.

References

1.Worthen DM, Wickham MG: Laser trabeculotomy in monkeys. Invest Ophthalmol Vis Sci 12:707-711, 1973

2.Worthen DM, Wickham MG: Argon laser trabeculotomy. Trans Am Acad Ophthalmol Otolaryngol 78:371-375, 1974

3.Wise JB, Witter SL: Argon laser therapy for open-angle glaucoma: a pilot study. Arch Ophthalmol 197:319-322, 1979.

4.Latina M, Park C: Selective targeting of trabecular meshwork cells: in vitro studies of pulse and continuous laser interactions. Exp Eye Res 60:359-372, 1995

5.Latina MA, Sibayan SA, Shin DH, Noecker RJ, Marcellino G: Q-switched 532-nm Nd:YAG laser trabeculoplasty (selective laser trabeculoplasty). Ophthalmology 105:20822090, 1998

6.Kramer TR, Noecker RJ: Comparison of the acute morphologic changes after selective laser trabeculoplasty and argon laser trabeculoplasty in human eye bank eyes. Ophthalmology 108:773-779, 2001

7.Damji KF, Shah KC, Rock WJ et al: Selective laser trabeculoplasty vs argon laser trabeculoplasty: a prospective randomised clinical trial. Br J Ophthalmol 83(6):718722, 1999

8.Dueker DK, Norberg M, Johnson DH et al: Stimulation of cell division by argon and Nd:YAG laser trabeculoplasty in cynomolgous monkeys. Invest Ophthalmol Vis Sci 31:115124, 1990

9.Bijlsma SS, Samples JR, Acott TS, Van Buskirk EM: Trabecular cell division after argon laser trabeculoplasty. Arch Ophthalmol 106:544-547, 1988

10.Alvarado JA: Mechanical and biochemical comparison of ALT and SLT. Ocul Surg News March 7-10, 2000

11.Alvarado JA, Murphy CG: Outflow obstruction in pigmentary and primary open angle glaucoma. Arch Ophthalmol 110: 1769-1778, 1992

12.Glaucoma Laser Trial Research Group: Acute effects of argon laser trabeculoplasty on intraocular pressure. Arch Ophthalmol 107:1135-1142, 1989

13.Glaucoma Laser Trial Research Group: The Glaucoma Laser Trial II: Results of argon laser trabeculoplasty versus topical medicines. Ophthalmology 97:1403-1413, 1990

14.Glaucoma Laser Trial Research Group: The Glaucoma Laser Trial VI: Treatment group differences in visual field changes. Am J Ophthalmol 120:10-22, 1995

15.Glaucoma Laser Trial Research Group: The Glaucoma Laser Trial VII: The glaucoma laser trial (GLT) and glaucoma laser trial follow-up study results. Am J Ophthalmol 120:718731, 1995

16.Lanzetta P, Menchini U, Virgili G: Immediate intraocular pressure response to selective laser trabeculoplasty. Br J Ophthalmology 83:29-32, 1999

17.Gracner T: Intraocular pressure response to selective laser trabeculoplasty in the treatment of primary open-angle glaucoma. Ophthalmologica 215:267-270, 2001

Introduction

Potential treatments for retinal disease are becoming more diverse as the pathogenic mechanisms underlying retinal disease are better understood and laser-tissue interactions better refined. At present, lasers are used in photomechanical, photothermal, photochemical, and photodynamic modalities specific for disease entities. The range of laser treatments is likely to increase with the possibility of adjunctive therapies to enhance treatments. Within this chapter, we aim to discuss developments in laser and photodynamic therapy for age-related macular degeneration.

Photocoagulation

Background

Photocoagulation relies on the conversion of light energy to heat by retinal chromophores (Tables 1 and 2).1,2 The total energy released depends on light wavelength (λ), irradiance (power per unit area), and retinal chromophore concentrations.3 Threshold retinal photocoagulation occurs when the retinal temperature is raised by 20°C for ten seconds, or by 39°C for 0.1 seconds.4 Clinically, lasers are used at suprathreshold levels, raising retinal temperatures between by 40-60°C.5 The energy needed to achieve threshold coagulation increases in proportion to pulse length. During longer pulses, proportionally more heat is conducted from irradiated tissues.6,7 The highest temperatures generated occur at the center of the laser spot, while temperatures at the burn periphery are lower, due to light scatter, heat conduction and eye movements.8 The effects of tem-

Table 1.

Table 2.

perature gradients along a laser spot are minimized with short 0.1-0.5-second exposures.9

Retinal pigment epithelium (RPE) melanin is the primary chromophore during photocoagulation. Retinal hemoglobin and xanthophyll, absorbing light between 400-550 nm, are key chromophores for argon green (514 nm) and frequency-doubled YAG

(532 nm) lasers. RPE and choroidal melanin absorb longer wavelengths of light between 600 and 1000 nm.10 Thus, the inner retina is heated more with shorter wavelengths and the outer retina/choroid with longer wavelengths.11 Histological studies12 show argon blue-green lasers (488 and 514 nm) cause full thickness burns, and argon green lasers (514 nm)13 and frequency-doubled YAG lasers form cone shaped burns mainly effecting photoreceptors and RPE.14 Krypton (647 nm) and diode lasers (810 nm) cause outer retina coagulation, since most of their energy passes unabsorbed through macular xanthophyll and hemoglobin.15,16 However, at suprathreshold levels, all the aforementioned lasers can cause full thickness retinal burns.

When treating choroidal neovascularization (CNV), light energy is converted to heat energy, which denatures proteins within the surrounding tissue and causes intravascular capillary coagulation. Green.17 found histological evidence of CNV obliteration following photocoagulation, but also evidence of recurrence in nine (75%) lesions. A scar comprised of hyperplastic retinal pigment epithelium was noted. Inner retinal layers were preserved following krypton photocoagulation, however, blue-green argon caused full-thickness destruction of the retina.17 RPE cells at the edge of the lasered site react by spreading, migrating,18,19 and releasing inhibitory growth factors.20 CNV resolution may also depend on altering growth factor expression.21 Studies of RPE following photocoagulation show up-regulation of TGF-β, VEGF, IL-8, and ETS-1.22,23 However, several weeks following treatment of CNV, VEGF down-regulation occurs, due to increased retinal oxygenation from the choroidal circulation.24

The damaging collateral effects of retinal photocoagulation have driven laser research to target specific retinal layers. Lowering laser irradiance with micropulsed treatments or subthreshold levels avoiding retinal coagulation and photoreceptor loss are gaining acceptance (Table 3).5,8,25,26

be targeted using laser pulses shorter in duration than the thermal relaxation time of a given tissue (adiabatic heating).25 However, very short pulses may generate micro-explosions and other thermomechanical effects offsetting the beneficial effects of shorter pulse duration. Thermomechanical effects of shortpulsed lasers can be prevented using lower power micropulses. An animal model of argon laser micropulsing was developed,25 and is now used for diode laser applications. Initial studies reported positive results for treatment of diabetic macular edema, showing improvement in 29% and stabilization of acuity in 69%.26 Other authors reported that micropulsed lasers were less painful and clinically effective in treating macular edema.27 Friberg and Karatza28 observed clinical resolution of macular edema from branch retinal vein occlusion in 92% of eyes, with visual acuity stabilizing in 77%. Subthreshold treatment by placing the laser in continuous wave (cw) mode has also been shown to reduce energy transmitted to the retina, thus avoiding photocoagulation.5

Judging the endpoint of subthreshold treatments is difficult, due to the lack of a visible retinal reaction. Some investigators have suggested using suprathreshold treatment to adjacent tissue as a guide to titrating laser power, followed by a 50% power reduction when treating the intended choroidal lesion.27 However, retinal chromophore composition may vary over a short distances, so that laser uptake may differ between the two sites, leading to variable laser reactions. This form of photocoagulation has been criticized, as it tends to create variable response in the retinal pigment epithelium.29

Subthreshold laser treatment of retinal disease may mirror the trend to use lower power lasers in other medical applications such as low power laser irradiation (LPLI). LPLI in the visible and infrared regions causes bio-stimulation of cellular processes which clinically accelerates wound healing and tissue repair. Similar tissue reactions may occur following sub-threshold retinal laser treatments.

Subthreshold photocoagulation

Attempts at limiting collateral retinal damage from suprathreshold laser photocoagulation have led to a focus on subthreshold techniques. Initial animal studies demonstrated that specific retinal layers could

Current indications for photocoagulation

Age-related macular degeneration prophylaxis

Prophylactic laser photocoagulation of soft drusen is a controversial treatment intended to stimulate

drusen re-absorption and theoretically diminish the risk of CNV. In 1973, Gass first reported his observation that laser applied to drusen.35 This initial finding was corroborated by other reports demonstrating a beneficial effect of laser to drusen. Little et al.36 reported on 27 patients with bilateral drusen. Laser photocoagulation was applied to drusen in one eye with the second eye acting as a control. All 27 eyes treated with laser demonstrated resolution of the drusen with an associated 1.2-line improvement in visual acuity. Seven percent of treated eyes progressed to CNV, compared with 15% in the control group.

While the results of these individual reports appear to be impressive, an associated increased incidence in laser-induced CNV appears to be a complication of this treatment. Guymer et al.37 observed CNV following photocoagulation in patients with drusen. In these patients, histology demonstrated choroidal endothelial processes breaching the elastic lamina, possibly representing early changes prior to choroidal neovascularization. In 1998, the Choroidal Neovascularization Prevention Trial Research Group found that CNV occurred in 5% of treated eyes compared to 2% in control eyes.38 With this degree of controversy surrounding photocoagulation treatment to drusen, Olk et al.39 explored the use of subthreshold micropulsed diode laser to drusen. Six- ty-five percent of patients had drusen resorption with an improvement in vision. No increased incidence in the formation of CNV was reported.39

Although this latest modality appears to be promising, studies of drusen prophylaxis will need to be re-evaluated in the light of recent (AREDS) study, which showed vitamins C and E, beta-carotene and zinc could reduce progression of visual loss and neovascular events in late age-related macular degeneration (AMD) by an odds ratio of 0.72.40

Current indications for photocoagulation of choroidal neovascularization

Extrafoveal CNV

The macular photocoagulation study (MPS) demonstrated a beneficial effect of treating extrafoveal choroidal neovascularization with argon laser photocoagulation in eyes with AMD.41 Lesions in this group occurred a minimum of 200 µm from the geometric center of the foveal avascular zone (FAZ). Forty-five percent of the treated group, compared with 63% of the untreated group, suffered severe visual loss (a loss of six or more lines measured on an ETDRS chart) at three years. This trend was observed to continue at five years, with 46% of treated eyes and 64% of observed eyes showing severe visual loss (SVL). At five years, treated eyes had lost 5.2 lines and untreated eyes 7.1 lines of visual acuity. Recurrent CNV proved to be a major problem with laser photocoagulation, occurring in 54%

of laser treated eyes at five years. Seventy-five percent of recurrent CNV occurred within the first year following photocoagulation, with 80% of these eyes suffering SVL.41

Photocoagulation of CNV secondary to non-AMD etiologies fared better. In lesions secondary to presumed ocular histoplasmosis (POHS), 10% of the treated group compared with 43% of the control group lost six or more lines of vision. Patients with idiopathic CNV also fared better, since 23% of the treated group compared to 48% of the control group lost six or more lines of visual acuity at five years, with most of the vision loss occurring within the first six months.41

Juxtafoveal CNV

Treatment results were less clear for classic juxtafoveal CNV occurring between 1 and 199 µm from the geometric center of the FAZ. Severe vision loss in the treated group compared to the control group was 55% versus 65%.42 In this trial, 54% of patients suffered recurrence at one year and 78% at five years. The median visual acuity was 20/200 in the treated group compared to 20/250 in the control group. The mean number of lines lost in the treated group was 5.5, compared to 6.5 in the control group.

Patients with juxtafoveal CNV secondary to POHS fared better than eyes with AMD, since they exhibited fewer recurrences and better preservation of vision. SVL occurred in 12% of the treated group compared to 28% of the control group. The mean change in acuity was a loss of 0.1 lines in the treatment compared to 2.1 lines in the control group. The eyes in the idiopathic CNV group exhibited similar results, with 21% of the treated group compared to 34% of the control group experiencing SVL at five years.

For extrafoveal and juxtafoveal classic lesions, laser photocoagulation remains the standard of treatment. Although the TAP Study43 focused on subfoveal disease, a small subgroup of patients with juxtafoveal classic lesions was included in the clinical trial. It is interesting to note that these patients tended to show a greater visual benefit than those patients who had true subfoveal lesions, suggesting a role for photodynamic therapy in treating juxtafoveal CNV. However, a randomized clinical trial is necessary to prove this point.

Subfoveal CNV

Photocoagulation for classic, subfoveal choroidal neovascularization has demonstrated modest prevention of SVL compared to the natural history of classic CNV.44 Three months following enrollment, 20% of the treated eyes, compared to 11% of the control eyes, had lost six or more lines of visual acuity. Fortyeight months following randomization, the efficacy of treatment was realized with 23% of the treated group losing six or more lines of acuity compared

to 45% of the control group. A mean of 3.5 lines was lost in the treated group compared to 5.0 lines in the control group.

The limiting feature of foveal ablation for subfoveal CNV is an immediate and marked decline in visual acuity. With this technique, there is generally a four-line decline in visual acuity immediately following treatment. Despite a statistically significant difference in visual acuity between treated and untreated eyes, conventional photocoagulation of subfoveal CNV has not gained wide acceptance. Techniques aimed at treating subfoveal CNV, while sparing the surrounding neurosensory retina, are gaining in popularity. Photodynamic therapy (PDT) and transpupillary thermotherapy (TTT) offer, for the first time, treatments that rely on gradual involution of CNV while sparing the neurosensory retina.

Transpupillary thermotherapy

Transpupillary thermotherapy (TTT) treats CNV by producing a mild rise in retinal temperature that has been calculated to be between 4 and 10°C using biophysical models developed by Mainster.8 The choroid acts as a heat sink by dissipating excessive heat produced, thus preventing excessive temperature elevations and retinal coagulation.8 An elevation of temperature to 41°C leads to the inhibition of DNA, RNA, protein synthesis, and respiratory enzymes. Above a temperature of 43°C, extensive free radical release and protein denaturation occurs.8 Heat shock proteins (Hsps) are theoretically produced during TTT. Hsps may protect cells against the deleterious effects of hyperthermia, radiation, ischemia, hypoxia, cytokines, oxygen free radicals, and metabolic poisons.48-50 However, the primary role of Hsps is as a molecular chaperon aiding in the folding of unstable newly translated proteins.51-53 In heat stressed cells, they bind thermally denatured proteins and play an important role in generating thermotolerance.53 They also prevent apoptosis (programmed cell death) inhibiting the action of the capsase cascade.49

HSP 70, a specific Hsps, is present in all retinal layers, except the outer segments.54 The primary site of synthesis of Hsps following hyperthermia is the photoreceptor layer,55 since they protect the retina against phototoxicity. Following diode laser TTT, HSP 70 is expressed in the RPE and choroidal vessels45 controlling apoptotic events within the RPE and choroidal vessels.

Several reports have demonstrated positive results of TTT for the treatment of occult subfoveal CNV. Reichel et al.46 reported on 16 eyes of 15 patients with symptomatic visual loss from occult CNV secondary to AMD. Three eyes (19%) showed a two or more line improvement in visual acuity. Visual acuity remained stable (no change or one-line improvement) in nine treated eyes (56%). The remaining four eyes (25%) showed a decline of one or more

lines of visual acuity. Fifteen eyes (94%) demonstrated decreased exudation on fluorescein angiography and optical coherence tomography.46 Newsom et al.47 demonstrated similar results in eyes with occult CNV. Treatment of classic CNV was also evaluated in this study, with 80% of eyes demonstrating stable vision within two lines of their pretreatment visual acuity. Most investigators have found that between 70% and 80% of patients with occult CNV demonstrate stabilization, with similar results for classic CNV. While the follow-up in these studies is relatively short compared to publications evaluating argon laser photocoagulation, TTT appears to decrease the rate of recurrent CNV. The scope of the usefulness of TTT continues to broaden. Investigators have shown that TTT is effective among different racial groups. TTT has also been used to treat CNV associated with myopia, angioid streaks, and idiopathic etiologies, and in individuals with idiopathic polypoidal choroidal vasculopathy.

Reported complications from TTT are rare. Corneal burns and cataract do not appear to be a significant complication. TTT may cause transient visual loss in 2-5% of patients, and has been shown to temporarily reduce choroidal blood flow similar to PDT.56 There have been reports of negative outcomes in patients with serous PED treated with TTT,57 though this complication has been observed in patients who have been treated with conventional photocoagulation and photodynamic therapy.

In some reported series, 10% of occult CNV converted to classic lesions following TTT. These patients can be effectively treated with PDT.58 In natural history studies, 30-50% of occult lesions demonstrate the development of classic lesions. While conversion to classic lesions following TTT may merely represent the natural history of occult CNV, TTT may accelerate this process. The ‘TTT4CNV’ study, a multicenter, randomized, blinded trial comparing TTT with sham therapy for occult subfoveal lesions, will provide more information regarding occult conversion to classic and the effectiveness of TTT compared with the natural history of disease.

Practical considerations

Thermal modelling has provided additional information with regard to TTT. For long exposures and large spot sizes, the energy required is proportional to the diameter of the spot size. The calculation of the spot size at the retina is critical in attaining therapeutic retinal irradiances.8 The authors have found that a 1.0 × magnification lens is useful for lesions of up to 3000 µm in diameter and a 2 × magnification lens for lesions of up to 6000 µm. Power settings are increased proportionally to the laser spot diameter. However, in lesions greater than 4000 µm in diameter, the calculated power may have to be reduced by 20-40%. Maintenance of beam circularity is important for preventing astigmatism and ensuring equal retinal irradiance.59 Avoidance of exces-

sive ocular pressure by the contact lens, during TTT is crucial for successful treatment. Increased pressure on the globe may diminish choroidal blood flow, reducing the capacity of the choroid to dissipate generated heat that may result in retinal coagulation.

The endpoint of treatment with TTT is to visualize no retinal whitening. Subtle retinal changes can be observed by viewing the retina with a narrow slit beam centered on the red circular aiming beam. Variations in retinal pigmentation must be considered when treating with TTT. Darkly pigmented fundi produce higher temperatures for a given irradiance than paler fundi, which can lead to over treatment. Similarly, pigment clumps in the RPE following previous laser photocoagulation may cause focal hyperthermia and retinal coagulation, potentially giving rise to recurrent CNV in that area.5 The presence of subretinal blood also increases diode laser uptake, leading to overtreatment. Shallow serous retinal elevation may also require lower power settings, since they may be at a higher risk for retinal damage. If whitening is observed, then treatment should be stopped and the patient closely monitored postoperatively. The time taken to reach a stable temperature is approximately 0.2 seconds, so if the TTT treatment is interrupted for any reason,60 only the remaining time is needed to complete the treatment.

Re-treatments of TTT are necessary in 2050% of occult membranes.46-47 Following TTT, CNV membranes slowly close and re-treatments are not usually performed before six weeks for classic membranes and three months for occult membranes.46-47 Different properties of classic CNV compared to occult CNV may explain the need for earlier and more frequent re-treatments using TTT.

TTT is an emerging treatment with great potential. Clinical experience has shown there is variability in reaction to TTT possibly due to variations in blood flow and chromophore concentrations. Developing techniques to monitor individual responses to this subthreshold treatment will be important in developing this technology.

Photodynamic therapy

Photodynamic therapy has revolutionized the treatment of classic, subfoveal CNV. Verteporfin, a benzoporphyrin derivative monoacid ring A,61-63 is an intravenously injected drug that is infused over a tenminute period, followed by a five-minute pause. Verteporfin accumulates in areas of neovascularization and normal blood vessels by binding to low-density lipoproteins (LDL) receptors that are expressed on endothelial and tumor cells.62,64,65 Fifteen minutes after the start of intravenous infusion, the verteporfin is activated by a low power laser (λ 689 nm). When treating CNV, the spot size used is 1000 µm larger than the greatest linear dimension of the lesion. Involution of the CNV occurs through the

production of free radicals (type 1 reaction) and the formation of singlet oxygen (type II reaction) after light activation of the photosensitizing agent.63 Tissue damage is characterized by membrane peroxidation,66 nuclear damage, protein denaturation, organelle and apoptotic mechanism damage.66 Lesions treated with PDT demonstrate histological evidence of vascular occlusion, endothelial cell damage, platelet aggregation, histamine, tumor necrosis factor-a (TNF-a), and cytokine release.67-72

Preclinical trials have shown that liposomal preparations and intravenous preparations were effective in closing experimental CNV.65 The Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) Study Group reported positive outcomes for patients with predominately classic CNV (classic component of CNV equal to or greater than 50% of the lesion) treated with PDT using verteporfin. Moderate visual loss (MVL), consisting of a loss of three or more lines Snellen acuity or 15 or more ETDRS letters, was reduced from 62% in treated eyes and 47% in control eyes 24 months after randomization.43 Severe visual loss was reduced from 30% in the control group to 18% in the treated group. However, patients with prior laser treatment, older age (greater than 75 years), and lesions with fibrosis showed no benefit from PDT.

Results for occult CNV without evidence of classic CNV were reported in the Verteporfin in Photodynamic Therapy (VIP) Study Group. The results were not as dramatic as those reported by the TAP study group. Fifty-five percent of the treated group compared to 68% of the control group had MVL at two years.73 Only one subgroup of patients, those having either lesions greater than four disc areas in size or relatively poor vision (less than 65 ETDRS letters), showed benefit at two years. A sudden decrease in vision following verteporfin treatment occurred in 4.4% of eyes, due to subretinal bleeding or choriocapillaris occlusion. Fifty percent of these affected eyes regained some vision. These study findings have been corroborated by the authors’ clinical experience with verteporfin.

The VIP study group similarly reported positive results for the treatment of subfoveal CNV secondary to myopia. Twelve months following randomization, 14% of the verteporfin treated eyes compared to 33% of the placebo-treated eyes had lost more than 15 letters (p < 0.01).74 Two years after randomization, no statistical benefit between verteporfintreated eyes and control eyes could be identified.

One drawback of PDT is that many patients needed multiple treatments (five on average in both the TAP and VIP studies).43,73 Other potentially life-threat- ening reactions have been reported, as well as local intravenous site complications.75 Ocular complications include pigment epithelial rips following the treatment of classic CNV.76 It is important to note that the prevention of severe vision loss in treating classic CNV is no different from when compared to conventional laser photocoagulation after two years’ follow-up.43,44

Similarities exist between the effects of TTT and PDT. Both induce involution of CNV while avoiding photocoagulation of the neurosensory retina, thereby stabilizing visual acuity. Transient interruption of choroidal blood flow is observed angiographically.70 TTT and PDT both release free radials within the choroidal blood vessels and injure the vascular endothelium, resulting in closure of the CNV. However, one difference is that PDT closes membranes within 24 hours of treatment.70 These usually re-open and require re-treatment. Membranes treated with TTT appear to close in more gradually, which appears to protect against revascularization of the treated CNV. Therefore, TTT-treated lesions appear to require fewer retreatments compared to PDT. Post-treatment angiographic changes are subtle following both treatments, and may be difficult to interpret. Membranes may take several weeks to regress and continue to stain even after stabilization. Subretinal fibrosis is identified clinically, by redfree photos, and on angiography when the treated lesion develops a scalloped edge. Our experience is that serial OCT images are useful in monitoring the progression of the CNV when angiographic features become quiescent.77 This enables the ophthalmologist to monitor the activity of the CNV through the presence or absence of subretinal and intraretinal fluid collection.

The treatment of serous pigment epithelial detachments (PED) has not been established, however, PDT or TTT may be of use when CNV can be demonstrated on ICG. There is a high risk of rips in the retinal pigment epithelium with either procedure. Feeder vessel photocoagulation before or after PDT/ TTT may also have possible therapeutic advantages in that laser energy can be targeted directly to a few abnormal vessels.78 Again, however, the problems of damage to Bruch’s membrane and suprathreshold photocoagulation mean that there can be a relatively high rate of recurrence in CNV treated in this manner.

Conclusions

Macular photocoagulation for subfoveal and juxtafoveal CNV is associated with high rates of visual loss and recurrence of CNV. New therapies such as TTT and PDT treat CNV with less injury to the surrounding neurosensory retina. PDT has demonstrated good efficacy for classic CNV associated with AMD and presumed ocular histoplasmosis, and moderate efficacy for occult CNV. Initial reports for TTT have been supportive for the treatment of both occult and classic CNV. Further developments in subthreshold laser treatments may also be useful for the prophylactic treatment of early AMD. However, without a clearly observable endpoint, new techniques for evaluating laser tissue interactions may be necessary before this treatment becomes widespread. Huge strides in our understanding of laser

tissue interactions have allowed laser treatments to be refined and tailored to individual conditions, however, adjunctive therapies may hold the final answer for challenging retinal conditions such as AMD.

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