Laser uveoscleroplasty: basic mechanisms and clinical experience

Abstract

A morphological study using 12 cynomolgus monkeys demonstrated that severe burn pars plana photocoagulation with a cw Nd:YAG laser produced an enlarged extracellular space from the anterior chamber to the suprachoroidal space, which could enhance uveoscleral outflow. Histopathological study of human autopsy eyeballs showed that moderate burn lesions using diode and cw Nd:YAG lasers produced coagulation necrosis of the ciliary epithelium and stroma. Severe burn lesions produced additional coagulation necrosis of the inner layer of the sclera. Eight eyes of eight patients with primary openangle glaucoma were treated by means of moderate burn pars plana photocoagulation using a diode laser, and were followed up for two to 18 months. Intraocular pressure was maintained lower than 20 mmHg, except in one eye. Ultrasound biomicroscopy demonstrated that an enlarged supraciliary space was produced between the burn lesions, with cyclitic membrane formation. These findings indicate that moderate burn pars plana photocoagulation using a diode laser holds promise in the treatment of primary open-angle glaucoma.

Introduction

The ocular hypotensive mechanism in connection with destructive surgery of the pars plicata of the ciliary body is generally considered to involve the decrease of aqueous formation. The ocular hypotensive approach used in some current laser and surgical techniques could partially work by enhancement of the uveoscleral outflow, and this modification might possibly lead to further enhancement of the uveoscleral outflow. Photocoagulation of the pars plana or an even more posterior site, could decrease the intraocular pressure (IOP) by means of other mechanisms, such as an increase of the uveoscleral outflow.1-6

In this report, we demonstrate morphologically the mechanism of laser uveoscleroplasty. On the basis of this morphological study, we will discuss our clinical experience with laser uveoscleroplasty.

Basic mechanisms of laser uveoscleroplasty

Material and methods

Animals

Twelve eyes of 12 cynomolgus monkeys (weighing 2.5-3.5 kg) were used, including one control eye. The animals were anesthetized by intravenous injection of Nembutal® (20 mg/kg; Abbott Laboratories, North Chicago, IL).

Cyclophotocoagulation procedures

Contact transscleral cyclophotocoagulation was performed using a cw Nd:YAG laser (model YC11; Nidek, Gamagoori, Japan) with a sapphiretipped contact probe (2.2 mm in diameter; SLT Japan, Tokyo, Japan). The energy of each laser burn was 3.2 J (16 applications at equal intervals on the circumference). The anterior edge of the tip of the contact probe was placed at a distance of 3.0 mm from the limbus of the left eye.

Observations

After cyclophotocoagulation, IOP and flare in the anterior chamber were measured periodically by means of a pneumotonometer (PTG; Alcon, Forth Worth, TX) and a laser flare cell meter (FC-1000; Kowa, Tokyo, Japan). The eyes were enucleated for histological investigation either immediately after coagulation, or at one, three, five, 12 or 24 weeks thereafter.

Tracer particle perfusion

Before enucleation, all eyes had tracer particles introduced into the anterior chamber. Two cannulas (23G 5/8-inch needles) were inserted into the anterior chamber. One cannula was connected to an irrigating solution (Opeguard MA®; Senju Pharmaceutical, Osaka, Japan). The level of the irrigating solution was set 18 cm above the eye in order to prevent any increase of IOP while the perfusions were being carried out. The other cannula was connected to the tracer solution. The tracer particles were composed of latex spheres (0.1, 0.5, and 1.0 µm in diameter). The tracer solution consisted of 2.5% latex sphere solution for each size (Polysciences, Warrington, FL) and 6% gelatin in Opeguard MA. Every 20 minutes, 0.3 ml of this solution was perfused into the anterior chamber within five seconds. Two hours after the initial perfusion, the monkey was killed using an overdose of Nembutal®. Then, 4.0% glutaraldehyde solution was perfused into the anterior chamber through the same syringe, and enucleation was performed.

Histopathology

The eyeballs were immersed for two days in a fixative solution of 4.0% glutaraldehyde in 0.05 M phosphate buffer (pH 7.4). After fixation, the eyeballs were dissected through the equator. The anterior hemisphere was dissected through the

meridional line. One half was embedded in glycol methacrylate for light microscopic examination. The other half was dissected into several meridional wedges, postfixed in 1.0% osmium tetroxide, and embedded in Epon. The 1-µm thick sections were stained with Azure II for light microscopic examination, and the 100-nm-thick sections were prepared with uranyl acetate and lead citrate for electron microscopic examination.

Results

Intraocular pressure and anterior chamber inflammation

The changes in IOP are shown in Figure 1. Elevation of IOP was shown immediately after cyclophotocoagulation. A decrease in IOP was noted after 24 hours and reached its lowest value seven days after coagulation. A gradual increase in IOP occurred from the second weeks, but IOP remained lower than the preoperative value up to the end of the observation period.

The flare in the anterior chamber is also shown in Figure 1. Increase of the flare in the anterior chamber was shown immediately after cyclophotocoagulation. Eight eyes shows exudative material and hyphema, which interfered with the investigation after the first week. A decrease in the protein concentration in the anterior chamber was observed with time.

Gross examination

The lesions were localized to the pars plana. Depigmented circular lesions of approximately 1.5 mm in diameter were observed immediately after coagulation. Evaporation of tissues and vitreous hemorrhage frequently occurred in the center of the lesion. After three weeks, some grayish-white ingrowing tissue had extended into the vitreous cavity.

Light microscopic examinations

Immediately after treatment, coagulation necrosis was noted in the nonpigmented epithelium, the pigmented epithelium, and in a whole layer of the stroma (Fig. 2). Tissue defects were observed in the center of the lesions. Vitreous hemorrhage and ablation of the stroma were frequent, with coagulation necrosis in the inner portion of the sclera.

Macrophages migrated into the damaged area, phagocytosing cell debris and melanosomes, one week after coagulation. Fibroblasts and nonpigmented epithelium had covered the entire damaged area within one week.

The cellular proliferation of the nonpigmented epithelium and fibroblasts replaced the damaged stroma and progressed to the vitreous cavity three to five weeks after coagulation (Fig. 3). Compared

to the active regeneration of the fibroblastic nonpigmented epithelium, regeneration of the pigmented epithelium and capillaries was slight.

Three to six months after coagulation, proliferated tissue still covered the damaged area, and abundant collagen fibers had accumulated around the fibroblastic tissue. There was no sign of retinal detachment during the observation period.

The extracellular space at the stroma between two coagulated scar lesions was enlarged, and the ciliary muscle had separated from the sclera after three weeks (Fig. 3). The inner portion of the sclera had been replaced by fibroblastic tissue.

Electron microscopic examination

In the inner portion of the pars plana lesions, two cell types proliferated (Fig. 4). One had an elongated or indented nucleus, well-developed cytoplasmic organelles, and microfilaments, indicating the proliferation of fibroblasts. The other cells had basal laminae, indicating proliferated nonpigmented epithelium. Few intercellular junctional complexes could be found. There was no evidence of latex sphere leakage in this region.

Accumulation of latex spheres was recognized in the trabecular meshwork and in the anterior portion of the space between the bundles of ciliary

muscle in both control and photocoagulated eyes. Also, many spheres had gained access to the posterior chamber through the pupillary opening and had accumulated along the base of the vitreous cavity. The trapezoid part of the ora serrata region was examined carefully. In control eyes, the suprachoroidal space in the ora serrata region was closed, and few latex spheres could be detected in this region. On the other hand, the extracellular space of the stroma was enlarged, and the suprachoroidal space was widely opened three weeks to six months after coagulation. Latex spheres of all three sizes could be recognized at the extracellular space of the stroma and opened suprachoroidal space (Fig. 5). Some spheres had been phagocytosed by macrophages.

Discussion

Schubert and Federman7 observed that a more intense flare was closely related to lower IOP. Crawford and Kaufman8 suggested that inflammatory mediators, such as prostaglandin F2a, enhance aqueous drainage via the uveoscleral pathway. Elevated prostaglandin (PG) levels have been found in the aqueous humor of humans after various laser9 and surgical10 procedures in the anterior segment. Increased aqueous PGs are capable of enhancing uveoscleral outflow, but the resultant ocular hypotension wears off with time, and this might be related to a decrease of endogenous PGs. On the other hand, the long-term effects of IOP reduction may be related to the absence of the barrier that permits aqueous humor to pass through the enlarged spaced between the coagulated scars, enhancing the total volume of the uveoscleral outflow routes.

Our basic study showed the same relationship between flare intensity and lower IOP during the acute stage. Electron microscopic examination of the proliferated fibrous scars of pars plana lesions showed no evidence of tracer particle leakage through this region. This is because of the connection from the hyaloideoorbicular space of Hannover to the photocoagulated lesions, which interfered with the tracer particles gaining access to the proliferated scars. The possibility that water and small molecules can pass through these fibroblastic scars cannot be denied, because the proliferated tissue lacks intercellular junctional complexes after pars plana photocoagulation. The characteristic change of the uveoscleral outflow pathway after pars plana photocoagulation was the opening of extracellular and suprachoroid spaces surrounding the coagulated lesions. These pathological changes may be similar to other disorders that result in enlargement of the extracellular space of the stroma and of the suprachoroidal space, which would be expected to increase the uveoscleral outflow. Examples of these include iridocyclitis or ciliocho-

roidal detachment with edema of the ciliary muscle. As usual, the narrow space between the longitudinal muscle and suprachoroid allows small-sized latex spheres to pass through. Thus, large-sized latex spheres were not seen in the ora serrata region. On the other hand, large-sized latex spheres passed through the trabecular meshwork and entered the open extracellular space of the stroma to reach the suprachoroidal space after pars plana photocoagulation. This phenomenon indicates that the enlargement of these spaces allows free communication of aqueous humor between the anterior chamber and the suprachoroidal space, leading to the decrease of IOP after pars plana photocoagulation. This seems to be a reasonable explanation of enhancement of the uveoscleral outflow.

The pathological features of pars plana photocoagulation were necrosis followed by active proliferation. Necrosis of the epithelium, stroma, and inner portion of the sclera occurred immediately after photocoagulation. Severe destruction of the stroma and sclera stimulated an active fibroblastic reaction. The proliferated tissue covered the damaged area within one week, and extended further into the vitreous cavity. This proliferated tissue may pull on the surrounding tissue in order to increase the extracellular space among the bundles of ciliary muscle and the suprachoroid space at the chronic stage.

In conclusion, contact transscleral cw Nd:YAG laser photocoagulation applied to the pars plana could decrease IOP. Enhancement of the uveoscleral outflow pathway is certain, as shown by the fact that the tracer particles pass through the uveoscleral meshwork and enter the widely opened extracellular and suprachoidal spaces. As pars plana photocoagulation requires less energy (a moderate burn instead of the severe burn needed for pars plicata photocoagulation) and also leaves the ciliary process intact, this procedure could be beneficial for the treatment of open-angle glaucoma without damage to the anterior chamber angle.

Parameters for laser uveoscleroplasty

Material and methods

Material

Three Japanese autopsy eyeballs with brown colored irises were kept in a 37°C water bath during the procedure.

Cyclophotocoagulation procedures

Contact transscleral cyclophotocoagulation was performed using a cw Nd:YAG laser (model YC11; Nidek, Gamagoori, Japan) with a sapphiretipped contact probe (2.2 mm in diameter; SLT, Tokyo, Japan), and a diode laser (model SLx, Iris Medical Instruments, Mountain View, CA) with a G-probe. The anterior edge of the tip of the contact

probe was placed at a distance of 4.0-5.0 mm from the limbus. The exposure time was set at one or two seconds, and the exposure power was changed from 1.0 to 6.0 W, as appropriate.

Gross examination and histopathology

The laser-exposed eyeballs were immersed for one day in a fixative solution of 2.5% formaldehyde and 1.0% glutaraldehyde in 0.15 M phosphate buffer (pH 7.4). After fixation, the eyeballs were dissected through the equator. Photographs of the anterior hemisphere were taken with a macrophotograph camera. The photocoagulation lesions were dissected into meridional wedges, postfixed in 1.0% osmium tetraoxide, and embedded in Epon. The 1- µm-thick sections were stained with Azure II for light microscopic examination.

Results

Grading of photocoagulated lesions

Mildly photocoagulated lesions had a whitish, round appearance and were approximately 1.0 mm in diameter. Coagulation necrosis was noted histologically in the nonpigmented and pigmented epithelia. Moderately photocoagulated lesions had a white, round appearance and were approximately 2.0 mm in diameter. Coagulation necrosis was noted histopathologically in the nonpigmented and pigmented epithelia, and in a whole layer of the stroma. In severely photocoagulated lesions, evap-

oration of the tissue occurred in the center of a white circular lesion of approximately 2.0 mm in diameter. Tissue defects were observed histopathologically in the center of the lesions. Ablation of stroma occurred with coagulation necrosis in the inner portion of the sclera.

Exposure power and time

In mildly, moderately and severely burned lesions, the correlation between the exposure power and time is shown in Figure 6. The moderate lesions needed 40-45% more power than the mild lesions, and the severe lesions required 43-50% more power than the moderate ones.

Discussion

On laser uveoscleroplasty, the laser photocoagulated lesions are placed at equal intervals on the pars plana. The anterior edge of the tip of the contact probe is placed clinically at a distance of 4.0-5.0 mm from the limbus. Photocoagulation at 3 and 9 o’clock must be avoided in order to prevent damage to the long posterior ciliary artery and nerve. Figure 7 shows the location of the photocoagulated lesions. These are placed at equal intervals on the circumference of a 19-mm diameter circle. The size of the moderately and severely photocoagulated lesions is approximately 2.0 mm in diameter. The interval between the photocoagulated lesions is approximately 1.3 mm, and these spaces may enhance the uveoscleral outflow which helps in the decrease of IOP.

Moderately photocoagulated lesions produce coagulation necrosis of the ciliary epithelium and stroma, followed by scar formation. Severely photocoagulated lesions add coagulation necrosis of the

Fig. 6. Relationship between exposure power and time in autopsy eye pars plana photocoagulation.

Fig. 7. Location of the pars plana photocoagulated lesion is indicated by the black circles. The two dotted circles at 3 and 9 o’clock have been avoided in order to escape damage to the long posterior ciliary nerve and artery.

inner layer of the sclera to moderately photocoagulated lesions, and produce more proliferative tissue in the vitreous, followed by cyclitic membrane formation. In order to take advantage of its hypotensive value, moderate rather than severe photocoagulation is preferable for clinical use.

Clinical experience with laser uveoscleroplasty

Subjects and methods

Subjects

Eight eyes were studied of eight patients with primary open-angle glaucoma (POAG). The mean age of the patients was 71 years (range, 41-79 years).

Cyclophotocoagulation procedures

Contact transscleral cyclophotocoagulation was performed using a diode laser (model SLx; Iris Medical Instruments, Mountain View, CA) with a G-probe. The anterior edge of the tip of the contact probe was placed at a distance of 4.0-5.0 mm from the limbus. The laser exposure power and time were adjusted to fit the moderately photocoagulated lesions (2.2 W, 1.0 seconds). Sixteen photocoagulated lesions were placed at equal intervals, except at the 3 and 9 o’clock positions (Fig. 7).

Observations

The postoperative observation period was two to 18 months (mean, ten months). The medical score was estimated at one point for each eye drop and two points for carbonic anhydrase inhibitor medication.

After cyclophotocoagulation, IOP and flare in the anterior chamber were measured periodically by means of a Goldmann applanation tonometer and a laser flare cell meter (FC-1000; Kowa, Tokyo, Japan). Best-corrected visual acuity was tested using the Snellen chart before and every six months after coagulation. Visual fields were assessed by either kinetic Goldmann or static peri-

metric analysis before and every six months after coagulation.

Ultrasound biomicroscopy (Rion; Tokyo, Japan) was used to detect any enlargement of the supraciliary space between the photocoagulated lesions.

Results

Intraocular pressure and anterior chamber inflammation

The changes in IOP are shown in Figure 8 and Table 1. No elevation of IOP was shown immediately after photocoagulation, but a decrease of IOP was noted within seven days. A gradual increase in IOP occurred after the second week. It remained lower than 20 mmHg up to the end of the observation period, except in Case 8. The changes of flare in the anterior chamber can be seen in Figure 9. A gradual increase of flare was seen one to three days after photocoagulation, which decreased within two weeks.

Ultrasound biomicroscopy

Figure 10 shows the pars plana lesion at a distance of 4.5 mm from the limbus four months after cyclophotocoagulation. The inner layer of sclera is brighter than the outer layer at the photocoagulated lesion. The stroma of the ciliary body is slightly thicker than the surrounding area. The ciliary epithelia are covered by the cyclitic membrane at the burned lesion. In the region between the photocoagulated lesions, enlargement of the supraciliary space can be seen. The diameter of the photocoagulated lesions is approximately 2.0 mm, and the distance between the photocoagulated lesions about 1.0 mm.

Visual acuity and visual field

The stages of visual field loss in terms of the Aulhorn-Greve classification were: stage 6 (three cases); stage 5 (one case); stage 4 (one case); stage 3 (one case); and stage 2 (two cases). No significant changes were noted in visual acuity or visual field during the observation period.

Fig. 10. Ultrasound biomicroscopic image at a distance of 4.5 mm from the limbus, four months after cyclophotocoagulation. The photocoagulated lesion is shown between the large arrows. The medium-sized arrows indicate the separation of the supraciliary space. The small arrows show the formation of the cyclitic membrane.

Medication score

Table 1 shows the medication score before and after laser uveoscleroplasty. A decrease in this score was seen during the observation period.

Complications

There was no severe eye pain during cyclophotocoagulation. No transient increases in IOP were seen after cyclophotocoagulation. Neither the formation of peripheral anterior synechia, hypotony, nor severe anterior chamber inflammation were encountered.

Conclusions

We investigated the mechanism of laser uveoscleroplasty morphologically. On the basis of this study, we demonstrated our clinical experience with laser uveoscleroplasty. The prolonged lowering effect of IOP was achieved by both severe photocoagulation in the monkey pars plana and moderate photocoagulation in the human pars plana. The flare in the anterior chamber of the monkey eyes was ten times stronger than that in human POAG eyes. On the other hand, cyclitic membrane formation was achieved in both the severely and the moderately cyclophotocoagulated lesions.

There are no reported controlled, randomized, prospective studies on pressure-lowering treatment in POAG that measure the outcome in terms of optic disc or visual field progression, although most authorities advocate lowering the IOP with medication, laser techniques, or surgery. Topical medical treatment alone does not usually produce a significant decrease in IOP in most POAG patients, if the side-effects are tolerable. Laser trabeculoplasty reduces IOP significantly in approximately half the patients who are initially treated by laser.11 Argon laser trabeculoplasty is often an appropriate first therapy, especially in eyes with

significant pigmentation of the posterior trabecular meshwork.

In general, filtration surgery is indicated when medical and laser therapy is insufficient to control the glaucoma, and when the rate of deterioration of visual function is rapid enough to damage the patient’s quality of life. Filtering surgery alone or in combination with medical therapy reduces IOP to a satisfactory range in approximately 85-95% of cases in the early postoperative follow-up period.12 However, loss of IOP control and progression of glaucoma damage may occur over time, despite the initial success during the first year.13 Trabeculectomy may decrease IOP to 15 mmHg or lower, trabeculotomy to 15 mmHg or higher.14 The IOP lowering effect produced by laser uveoscleroplasty could be equivalent to that of trabeculotomy. Laser uveoscleroplasty should be recommended for POAG patients in whom IOP control is not good, despite maximum medication. Moreover, laser uveoscleroplasty would seem to be indicated in cases of normal-tension glaucoma.

It is suggested that laser uveoscleroplasty is an effective and safe procedure for POAG, on the basis of limited experience. Laser uveoscleroplasty could be considered an appropriate first procedure instead of a second or repeated one, because the intact spaces between the photocoagulation lesions play an important role in its application. Further investigations are necessary to establish its clinical applications.

References

1.Klapper RM, Wandel T, Donnenfeld E, Perry HD: Transscleral neodymium, YAG thermal cyclophotocoagulation in refractory glaucoma. Ophthalmology 95:719-722, 1988

2.Schubert HD: Noncontact and contact pars plana transscleral

neodymium:YAG laser cyclophotocoagulation in postmortem eyes. Ophthalmology 96:1471-1475, 1989

3.Schubert HD, Federman JL: A comparison of cw Nd:YAG contact transscleral cyclophotocoagulation with cyclocryopexy. Invest Ophthalmol Vis Sci 30:536-542, 1989

4.Schubert HD: Effects of exposure time in cw Nd:YAG contact transscleral photocoagulation and photofiltration. Lasers Light Ophthalmol 3:53-59, 1990

5.Schubert HD, Agarwala A, Arbizo V: Changes in aqueous outflow after in vitro neodymium:yttrium aluminum garnet laser cyclophotocoagulation. Invest Ophthalmol Vis Sci 31:1834-1838, 1990

6.Liu G-J, Mizukawa A, Okisaka S: Mechanism of intraocular pressure decrease after contact transscleral continuous Nd:YAG laser cyclophotocoagulation. Ophthalmic Res 26: 65-79, 1994

7.Schubert HD, Federman JL: A comparison of cw Nd:YAG contact transscleral cyclophotocoagulation with cyclocryopexy. Invest Ophthalmol Vis Sci 30:536-542, 1989

8.Crawford K, Kaufman PL: Pilocarpine antagonizes pros-

taglandin F2α induced ocular hypotension in monkey. Arch Ophthalmol 105:1112-1116, 1989

9.Sato G, Altafani R, Doro D: Prostaglandin E2 and intraocular pressure (IOP) after argon laser trabeculoplasty in piroxicam

pre-treated patients. II. Boll Oculist 66:183-187, 1987

10.Miyake K, Sugiyama S, Norimatsu I, Ozawa T: Prevention of cystoid macular edema after lens extraction by topical indoethacin. III. Radioimmunoassay measurements of extraction procedures. Graefe’s Arch Clin Exp Ophthalmol 209:83-88, 1978

11.Glaucoma Laser Trial Research Group: The Glaucoma Laser Trial (GLT) and Glaucoma Laser Trial Follow-up. 7. Results. Am J Ophthalmol 120:718-731, 1995

12.Nouri-Mahdavi K, Brigatti L, Weitzman M, Caprioli J: Outcome of trabeculectomy for primary open-angle glaucoma. Ophthalmology 102:1760-1769, 1995

13.Chen TC, Wilenskey JT, Viana MA: Long-term follow-up of initially successful trabeculectomy. Ophthalmology 104:1120-1125, 1997

14.Tanihara T, Negi A, Akimoto M et al: Surgical effects of trabeculotomy ab externo on adult eyes with primary open angle glaucoma and pseudoexfoliation syndrome. Arch Ophthalmol 111:1653-1661, 1993

Abstract

Background: The physical laws that should be considered for the optimal photothermal treatment of solid and vascular tumors are studied, as well as other vascular anomalies of the retina and choroid of various etiology. Optimal irradiation therapy should take into account the distribution of both radiant and thermal energy in tumors such as retinoblastomas, malignant melanomas, and vascular malformations. Strict confinement of the extent of photothermal damage is critical, since such pathological entities are frequently located close to the macula or optic nerve head.

Methods: A formal way of treating the optical quantities related to these requirements is presented. In this analysis, the following topics are analyzed: Arrhenius’s law, the kinetics of protein denaturation, electromagnetic radiation field, wavelength, laser pulse duration (exposure time), optical properties of tissue, photocoagulation, and thermotherapy.

Results: Generally, conditions are best fulfilled when using radiation in the near-infrared range of the electromagnetic spectrum, such as that emitted by the diode (810 nm) and Nd:YAG (1064 nm) lasers, because of the good optical penetration properties of this radiation in the tissues. The xenon arc lamp was a very effective and particularly appropriate energy source for such purposes, and its withdrawal from the world market may have been untimely. Short wavelength sources of radiation, such as the argon ion (488, 514 nm) or the fre- quency-doubled Nd:YAG (532 nm) lasers, are unsuitable for the irradiation of large vascular structures, as they have poor penetration depths. However, for vascular formations with a short path length (1 mm or less), short wavelength sources appear to be the most appropriate choice. Optical

coupling of radiant energy to the eye by means of indirect ophthalmoscopic systems or contact lenses to the eye is crucial. Strong positive lenses may lead to severe constriction of the laser beam, leading to high irradiance within the anterior segment, and increasing the chances of its being damaged; with negative contact lenses, such as the -64 D Goldmann type, this danger is reduced.

Conclusions: Photothermotherapy is not without risk unless the temperature field can be well adapted to the tumorous structure, since temperature elevations outside a small therapeutic range that affect vital structures are considered to be a risk factor.

Introduction

The xenon arc lamp was the first energy source introduced by Meyer-Schwickerath et al.1-5 for the treatment of retinal and choroidal tumors, as well as vascular malformations. It is still used today by some specialists,6-11 although, for most specialists, it has largely been replaced by various lasers, such as the argon ion, krypton and Nd:YAG. Shields,12 Lommatzsch and Wessing,13 and Zweng et al.14 have carried out comprehensive surveys of the indications and principles of the photic treatment of malignant retinal and choroidal tumors. In this review, the physical laws that need to be considered for optimal photothermal treatment of solid and vascular tumors, as well as other sanguineous anomalies of various etiology within the retina and choroid, are surveyed. The optimal irradiation therapy should take into account the distribution of both radiant and thermal energy in the ocular media, as well as throughout tumors, which include retinoblastomas, malignant melanomas, and neovascular structures. Strict confinement of the extent

of tissue damage is critical, since such entities are frequently located close to the macula or optic nerve head.

The limited local confinement of irradiation damage can therefore be considered to be one of the most prominent, undesirable features of a number of treatment modalities, particularly radiation therapy, including gamma and beta radiation and external irradiation using charged particles such as protons15 or helium ions16 (see Shields12 for an extensive review). Despite new techniques targeted at the localization and estimate of the size of the tumors,17-29 many and varied damage effects have been described by a number of authors.19,30-32 In contrast, photothermal therapy, if properly administered, does not as a rule cause such generalized damage effects. For this reason, photothermal therapy has been recommended for the treatment of tumors near the posterior pole, particularly when they are situated in the immediate vicinity of the optic disc, where blindness due to radiotherapy must be expected in about one-fourth of all cases treated.30 Therefore, photothermal therapy has been recommended as the treatment of choice for small melanomas situated close to the macula or optic nerve.33 Photodynamic therapy is another technique that has been investigated,34,35 based on the uptake of specific sensitizers that induce a localized cytotoxic photochemical process. This technique may eventually become the treatment of choice, once a highly selective affinity for neoplastic tissues has been achieved.

Despite its claimed superiority, photothermal therapy may not always be without risk. The aim of this report was to analyze those photothermal treatment strategies that could guarantee a minimum of photothermal damage outside the target area. Apart from a number of basic considerations, this analysis emphasizes the following topics: Arrhenius’s law, the kinetics of protein denaturation, radiation field, thermal distribution, wavelength, laser pulse duration (exposure time), optical properties of tissue, photocoagulation, and thermotherapy. Details can also be found Rol et al.36

Basic aspects

Arrhenius’s law: dynamics of protein denaturation

Elevations in ambient temperature induce a change of conformation in various proteins, which denature at a characteristic temperature specific to the protein species.37-39 Denaturation may be seen as the common development that leads to cell necrosis. It has been described as a phase change (which occurs at some particular temperature) by Flory and Garret40 and, in terms of catastrophe theory, by Benham and Kozak,41 but the most successful treatment methods discuss the process in terms of thermochemical rate equations, where the detailed

temperature history determines the extent of denaturation. Glasstone et al.42 presented a rigorous statistical model describing the process of thermal damage, and others have developed this approach further.43,44 Some authors offer more heuristic accounts, such as in Wood45 and Birngruber.46 As developed in Rol et al.,36 the loss rate of undamaged molecules is simply described by a tempera- ture-dependent rate constant, or loss rate ω(T) whose integral over time Ω has been called the damage integral and is a measure of the damage produced. When Ω = 1, there is 63% damage, which was defined by Henriques47 as the endpoint of the complete necrosis of thermally damaged pig basal epidermis. It is taken by Birngruber as being the threshold for denaturation, this threshold or endpoint being characterized by a whitish tissue discoloration. On this basis, the efficiency of denaturation as a function of the various parameters can be estimated.36 For a constant temperature exposure, the relationship between temperature and denaturation time τdenat (exposure duration for a given endpoint Ω) may be written:

Therefore, in the case of a constant temperature laser exposure, the pulse duration τp must at least

equal the denaturation time τdenat in order to reach the given endpoint Ω.

Henriques47 derived values for A and ∆E by applying Equation (5) to his experimental data, and concluded that for the basal epidermis of pig skin, ∆E = 6.3.105 J.mol-1 and A = 3.1.1098 s-1. Other workers have suggested different values for the constants A and ∆E in different proteins.48-51 Using the constants suggested by Birngruber for the retina46,52 mentioned in Rol et al.,36 the variation of

the denaturation time τdenat with temperature is shown in Figure 1 for Ω = 1. It can be seen that the

exponential dependence of τp on temperature T will have a strong influence on the thermotherapy of tumors, in so far as the efficiency, i.e., the time to reach threshold denaturation, can be drastically reduced by relatively small temperature elevations. In order to determine these temperature changes, precise knowledge (as far as possible) of the temperature distribution in tissue as a function of various laser parameters (such as wavelength, thermal relaxation time, exposure duration, power, and energy density) is necessary. For this purpose, light and heat transfer mechanisms have to be studied.

Light transfer of radiated energy

The efficiency of photic tumor destruction methods depends on the absorption of the radiated energy in both the surrounding media and in the tumor itself. However, calculation of absorbed and scattered light by heterogeneous tissues is a very complex task. Solving the fundamental electromagnetic equations is unrealistic because such a solution

would require detailed information on the locations and optical properties of all local structures in the tissue. Therefore, several approximate analytical methods have been applied using global tissue parameters such as the absorption coefficient µa and the scattering coefficient µs. From these models based on the classic Boltzmann transport equation, the Kubelka-Munk model and several models based on optical diffusion theory have been obtained.53-57

The Boltzmann transport equation is, in principle, an analytical model that calculates the number of photons lost from the direction of beam propagation due to absorption and scattering, taking into account the number of photons scattered back into this particular direction through multiple scattering. In practice, however, only approximate numerical solutions of the Boltzmann equation are obtainable. The diffusion theory, which can be obtained through a series expansion of the more general transport equations, is valid when the light is scattered to an almost isotropic distribution. A net flux of diffuse photons is then expected to flow from regions with a high optical fluence rate to regions with a lower fluence rate. This flow occurs in a manner similar to the situation when heat flows from a high temperature region to surrounding locations at lower temperatures. In this case, an effective attenuation coefficient, µeff, applies in tissue, as introduced by Ishimaru.58

where µs is the scattering coefficient, µa is the absorption coefficient and µa<<µs. The Kubelka-Munk

method is a one-dimensional model of heuristic structure. In the most simplified version, two diffuse photon fluxes are considered: one flux propagating in a forward direction and the other in a backward direction. The spatial variations of these two fluxes are assumed to be caused by either absorption or by scattering between the fluxes. This most simple version of this analysis has been enhanced to three-dimensional space by adding transversal or/and collimated fluxes.

Most of the time, however, only approximate numerical solutions can be obtained, due to the complexity of the models. For that reason, numerical solutions can also be used. The Monte Carlo model is one such solution, based on computer tracking of individual photons. The computer basically follows each photon through a large number of scattering and absorption events. This kind of simulation has gained wide acceptance because of its versatility, especially with regard to the approximate geometry of tissue. However, its use is limited by the computing time needed to generate accurate radiation distributions within the tissue.

In addition, temperature-dependent changes of the optical properties are common and further complicate the process in various tissues.59-46 The increased stray light in the coagulated retina and choroid decreases denaturation efficiency and increases heat contamination of the tissue surrounding the target.65-67

Heat transfer of radiated energy

When the conduction of heat is neglected, the tem-

perature difference ∆Tnoconduction of the medium above a baseline (e.g., 0 or 37°C) at the end of a pulse

duration τp can be estimated by:

where P is the irradiating power, c the specific heat capacity, ρ the density of the medium, and Ø the diameter of the irradiated spot on the tissue.

However, when the thermal diffusivity of the medium α is taken into account, the final temperature difference is decreased. According to the first approximation described in Rol et al.,36 this fall-off can be evaluated considering no thermal loss for the fraction F of the energy remaining available for target heating when the energy is delivered as a constant power pulse of duration τp:

where τr is the relaxation time of the irradiated tissue. The final temperature difference decreases with increasing τp/τr. The variation of F, i.e., the

ratio between ∆T and ∆Tnoconduction is displayed in Figure 2 as a function of the ratio τp/τr. Therefore,

for a pulse duration τp, much shorter than the thermal relaxation time τr, the temperature elevation in the target can be approximated by Equation (3), while for a pulse duration τp, much longer than the thermal relaxation time τr, the temperature elevation in the target can be written as

It can therefore be assumed that, even for pulse durations longer than the relaxation time, the temperature remains quasi constant during the pulse so that the formalism developed in Rol et al.36 for Arrhenius’s law can be used. Consequently, the thermal relaxation time and absorption coefficient of a given tissue are good predictors of the extent of the damage.

McKenzie68 determined the thermal relaxation time for a Gaussian-shaped temperature profile beneath the surface of a slab of soft tissue, and found that the characteristic time for heat diffusion to a depth d, is

Furzikov69 quotes a general expression similar to Equation (6):

Fig. 2. Fraction F of the energy that remains available for heating a target displaying a relaxation time τr when the energy is delivered at a constant power during a pulse duration of τp. For τp << τr, F approaches 1 (100%), while for τp >> τr F tends to 0.

where L is a characteristic linear dimension of the tissue volume being heated. He considers tissue with an attenuation coefficient µa irradiated by a laser source as having a diameter Ø. Two extreme situations can be identified: (1) radially dominated heat diffusion, where µa-1, the laser radiation penetration depth, is much greater than Ø/2, so that L = Ø/2; and (2) axially dominated heat diffusion, where the penetration depth is much less than the spot diameter, so that L = µa-1. In the latter case, therefore,

which is the same relationship as that given by Hayes and Wolbarsht70,71 and Wolbarsht.57 This theme has been generalized by van Gemert and Welch,72 who consider a ‘parallel circuit’ of axial and radial heat loss, so that the effective time constant τeffective, is given by:

It should be appreciated that it is not always appropriate to use the penetration depth d as the characteristic dimension. For example, it will be seen later that some targets may have dimensions larger than the penetration depth, because they are heated by conduction rather than radiation. Other targets, such as microvasculature and organelles, may be smaller than the penetration depth. In these cases, the more general Equation (7) may be more appropriate.

Application of physical data to the laser therapy of retinal and choroidal tumors

In this section, the effects of various types of radiation, such as that emitted by the Nd:YAG laser (1064 nm), diode laser (810 nm), argon laser (514 nm), or frequency-doubled Nd:YAG (532 nm) laser are compared.

Energy transfer through pretumoral media

According to Geeraets and Berry,73 absorption in the media in juvenile eyes amounts to 2.9, 5, and 35% for argon (average of the 488 and 514 nm emission lines), diode and Nd:YAG laser radiation, respectively (Fig. 3). Inaccuracies in Geeraets and Berry’s values were later found by Van den Berg,74 who pointed out that, because of the great fluctuation of transmission measurement values, it would make more sense to refer to the absorption values of water: 3, 4.5, and 25% for argon, diode and Nd:YAG laser radiation, respectively. The five-fold stronger absorption of Nd:YAG laser light compared to diode laser light in pretumoral media was considered by Oosterhuis et al. to be a decisive disadvantage for chorioretinal irradiation tasks.75 However, this argument only remains valid in clear media. While the absorption values mentioned above are relevant to young eyes, transmission through both the cornea (Fig. 4) and the crystalline lens decreases as a function of age (Fig. 5). Because there is much higher absorption in the short wavelength range, the crystalline lens assumes a yellowish color with advancing age.76-78 In addition, age-related accumulation of multiple fluorophores and pigments occurs, with selective concentration between the lens cortex and nucleus.79 Apart from such age effects, scatter and absorption both increase in cataractous eyes. Furthermore, vitreous opacities as a function of pathology may

Fig. 3. Transmission spectra for various components of the dioptric media of the human eye. (Adapted from Van den Berg and Spekreijse74 by courtesy of the publisher.)

Fig. 4. Transmission of the human cornea. (Adapted from Lerman79 by courtesy of the publisher.)

Fig. 5. Transmission of the crystalline lens at various ages for various wavelengths. (Adapted from L’Esperance124 by courtesy of the publisher.)

have to be accounted for. Therefore, transmission at short wavelengths may be heavily reduc- ed.73,76,77,80-89 In vitro, stray light due to cataracts was found to decrease monotonically from 400700 nm.90 Generally, due to the heterogeneity of such disturbances, the wavelength dependence of absorption and scatter is not known. Nevertheless, the transmission for long wavelengths is better than that for short wavelengths in all cases.91

Energy transfer in tumors

Because tumorous tissue is heterogeneous, its absorption is not well known except, in a number of experimental tumors.92 Figure 6 shows the optical penetration depth of a Greene’s experimental ame-

lanotic tumor for wavelengths of 1064, 834, and 633 nm.93 Table 1 shows the optical penetration depths for a human retinoblastoma and a B-16 melanotic melanoma implanted into the eye of an athymic mouse.92 With low pigmentation, the optical penetration depth is 4.2 and 5.1 mm for diode and Nd:YAG laser light, respectively. For a melanotic tumor, the penetration depth decreases to 0.5 and 1.4 mm for diode and Nd:YAG laser light, respectively. These examples emphasize the important role played by melanin absorption, and illustrate the fact that the optical penetration depth is better for the Nd:YAG laser than for the diode, in particular when some pigmentation is present in the tissue. This may be of clinical importance when thick or pigmented tumors are irradiated. When absorption is low, scattering is of major importance in determining the distribution of thermal damage. In 1982, Van der Zypen and Fankhauser94 determined a sevento eight-fold greater penetration depth for the Nd:YAG laser in trabecular tissue compared to the argon laser. Despite the fact that energy absorption by chromophores is a desirable

feature for tumor destruction, penetration depth is obviously equally as important. They are, however, mutually exclusive. Furthermore, it is not known whether differences in penetration depth between the wavelengths of 816 and 1064 nm (e.g., 0.9 mm, as derived from Table 1, for both retinoblastoma and melanotic melanoma) are clinically relevant. Penetration depth decreases in necrotic tumors, which may have clinical relevance.

There is a quantity of data for the optical constants in individual tissues,95-99 some of which are summarized in Table 2. A comparable diversity may be assumed for retinal and choroidal tumors.92,93 While the values in this Table are variable, a clear trend emerges: in non-pigmented tissues, the absorption coefficient is much less than the scattering coefficient for the visible and nearinfrared wavelengths, whereas both coefficients are comparable in pigmented tissue.

Considering thermal parameters of tissues, Takata et al.100 obtained relationships between ρ, c, and β from the data of Spells.101 Table 3 shows the values of ρ, c, β, and α for a 70% water content

Table 2. Approximate absorption, µa, and scattering, µs, coefficients in pigmented and non-pigmented tissues at 1064 nm

Table 3. Values of variables relating to the diffusion of heat in a medium composed of 70% water and pure water

and for pure water at 0° and 37°C. Most workers use values within this range.

Fig. 7. Absorption of deoxygenated blood with a hemoglobin concentration of 150 g/L as a function of wavelength for various blood layer thicknesses. The number of erythrocytes is 4.9 × 106mm-3. Absorption at wavelengths beyond 1000 nm are extrapolated. (Adapted from Welsch et al.102 by courtesy of the publisher.)

Angiomas and neovascular structures

Structures containing blood are characterized by the ratio of oxygenated and deoxygenated blood whose absorption is shown in Figures 7 and 8. Optical penetration depths are given in Table 4.102 It should be noted here that the yellow line of the Krypton ion laser (568 nm) corresponds with the highest absorption by blood and, therefore, to the shortest penetration depth. Because it has been stated,95 but not proven, that oxygenated blood deoxygenates with increasing temperature, there is a fair degree of uncertainty as to which absorption spectrum is of relevance when blood is heated. Apart from the oxygenation status of the hemoglobin molecule, the optical properties of heated blood, compared to normal blood, are not well known.103,104 For example, the agglutination status of erythrocytes105 will greatly influence absorption.54,106 At present, the detailed mechanisms of photothermal hemothrombosis are still largely unknown. Ultrastructural clinically-oriented studies relating to the interaction of blood and Nd:YAG laser energy have been presented by Fankhauser107 and Van der Zypen.104,108-110 A more detailed survey of some hemostatic mechanisms is presented in Rol et al.36.

Some recent results concerning the effects of

Fig. 8. Absorption of oxygenated blood with a hemoglobin concentration of 150 g/L as a function of wavelength for various blood layer thicknesses. The number of erythrocytes is 5.2 × 106mm-3. Values for absorption at wavelengths beyond 1000 nm are extrapolated. (Adapted from Welsch et al.102 by courtesy of the publisher.)

irradiated choroidal angiomas were described in extenso by Lanzetta et al.111 and Brancato and Menchini.112 The effects of laser radiation upon the vessels feeding the angioma and upon the angioma itself will generally be speculative at best, as the

total volume, volume flow, and flow velocity, as well as the precise geometry, will only be known approximately. The following empirical rules may be of relevance: the wavelengths (or the penetration depths) to be used may be adapted to the diameters of the angiomas or vascular structures to be irradiated. (For such evaluations, Figs. 7 and 8 or Table 4 may be helpful.) Correspondingly, vascular structures with small diameters should be irradiated with short wavelengths, while vascular structures with large diameters should be treated with long wavelength radiation.104,107-109,113

Discussion

Melanomas and retinoblastomas not extending as far as the ciliary body and not exceeding 30° (equivalent to 8 mm), and with a thickness of about 3 mm, are suitable for irradiation with the xenon arc lamp,3 or with lasers of an appropriate wavelength. For primary therapy, phototherapy is recommended for tumors situated close to the macula or the optic nerve.30,114 The argon laser is the principal energy source to date (488 and 514 nm). The choice of phototherapy rather than radiotherapy for the treatment of tumors located close to the macula and optic nerve reflects the concept that the extent of the damage with this method is considered small and well controllable.12

The discussion above and in Rol et al.36 defines the physical conditions that guarantee total tumor destruction with strict confinement of the thermally damaged zone, as far as this is possible. The physical parameters that control both the optimal radiation distribution and thermal energy distribution critically depend on parameters such as thermal conductivity, thermal diffusivity, specific heat capacity, density as well as pigmentation, and homogeneity (or heterogeneity) of the tumor tissue. This is where the problems start, since the sizes, physical constants, and variables of specific tumors are, at best, only known approximately or not at all. Despite these uncertainties, the basic principles are obvious: (a) the laser beam should have a sufficient penetration depth to induce total necrosis of the tumor; and (b) the lateral spread of the thermal effect should be precisely controllable because of the vicinity of vital structures and the low thermal resistance of non-neoplastic cells.

Short wavelength laser light, such as argon (488 and/or 514 nm) or frequency-doubled Nd:YAG (532 nm), has a limited optical penetration depth and therefore does not satisfy (a) and (b) well. Radiation from xenon arc lamps, semiconductor lasers and, depending on the tumor volume, perhaps even better, Nd:YAG lasers satisfies (a) very well, due to their longer wavelengths. Both axial and lateral heat propagation is controlled by the thermal relaxation time. Laser pulses longer than the relaxation time induce heat waves that extend

beyond the tumor during the pulse and contaminate non-neoplastic, normal tissues.

One further parameter requires consideration: changes in reflectance occurring with denaturation at high temperature levels (coagulation) decrease efficiency as they increase light scattering, and have a short time constant.65-67 Taking this into account, irradiation duration should not exceed 100-200 msec with small spot sizes, as otherwise the induced temporal temperature profile could be impaired.

The higher transmission of ocular media at semiconductor wavelengths compared to Nd:YAG wavelengths should not be overestimated, as the temperatures induced in the clear media by the Nd:YAG laser are small, provided an appropriate contact lens is used.36 Apart from this, two arguments act in favor of the Nd:YAG laser: its high transmission through turbid media and the retina’s higher safety limit for Nd:YAG laser light. According to the safety standard ANSI Z136.1 (1993), the tolerance in fluence rate (= power density = irradiance) is about ten times greater for Nd:YAG laser light (1064 nm) than for diode laser light at 810 nm.

When using positive wide-angle contact or noncontact ophthalmic lenses, constriction of the beam waist at the plane of the cornea or the pupil may be a matter of concern since, depending on pulse energy, spot-size setting, and refractive power of the lens, the safety limit of 2 J mm-2 can easily be exceeded.36 An additional factor when using positive optics is the dependence of the radiation field on the refraction of the eye being considered. Negative lenses of -60 D, such as the Goldmann contact lens, do not suffer from this dependence,115 which greatly simplifies calculation of the spatial irradiance in the radiation field, and therefore enhances safety.

When irradiating angiomas, the absorbing volume is the critical quantity. For angiomas, neovascularizations, or other abnormalities of the vascular system with a narrow blood column (small volume), short wavelength laser radiation (such as the argon ion or frequency-doubled Nd:YAG laser) with high absorption in the blood is indicated. When thick columns (large blood volume) are treated, which can occur, for example, in Von Hippel-Lindau’s disease, long wavelength radiation (such as that emitted by the diode or Nd:YAG laser) is indicated. In contrast to melanin, blood is a chromophore whose absorption spectrum changes dramatically as a function of temperature,103 and is also dependent on a number of other factors, such as the erythrocyte density105 (see Rol et al.36 for more information on this subject).

Transpupillary thermotherapy, i.e., methods utilizing long exposure durations, is a novel clinical method recently introduced by Oosterhuis et al.75 which has received some interest.116 Oosterhuis et al. used the following: wide-angle contact lenses

(Panfundoscope, Mainster, Transequator and Quadraspheric) and a diode laser beam with a diameter (focal spot) of between 2.0 and 4.5 mm. For tumors close to the macula or optic nerve, diameters between 2.0 and 2.5 mm were chosen. The exposure duration was 60 seconds, and the endpoint of the irradiation procedure was a grayish discoloration, although they state that: “The early appearance of a whitish coagulation is considered an adverse effect’. Irradiances varying from 5-12.5 W.cm-2 were used.

Shields et al.114 prefer an indirect ophthalmoscopic argon laser delivery system. The space surrounding the tumor is irradiated using beam diameters of 0.2-0.5 mm for durations of between 0.5 and 1.0 seconds and irradiances of between 100 and 300 mW. The tumor is then irradiated directly with spots of the same diameter, although with irradiances of between 200 and 500 mW and durations of between 1.0 and 16 seconds.

Investigating photodynamic therapy, SchmidtErfurth et al.34,35 also successfully treated intraocular tumors of between 3 and 5 mm in diameter. They used a dye laser emitting at 692 nm with an irradiance of 0.15 W/cm² for about 530 seconds.35 This irradiance is 20-80 times smaller than that used by Oosterhuis et al., but the absorption coefficient was increased by the use of a photosensitizer (benzoporphyrine). Therefore, the possibility that photothermal denaturation (low temperature elevation with a long exposure time) made a contribution to the positive results could not be ignored.35

While relaxation times are exceeded in the two first procedures,12,75 and while the threat of the heat wave emitted by the heated tissue causing damage as it propagates cannot be ignored, the clinical significance of this effect needs to be evaluated quantitatively. Also, according to the parameters given above, the radiation fields obtained with po-

sitive lenses cannot be considered ideal (see Rol et al.36). While the 488/514 or 532 nm wavelengths seem to be attractive, due to their low absorption in clear pre-focal media, their inferior penetration depth in tumorous tissue appears to be a disadvantage. The reduced heating of the media expected due to the lower absorption at the 488, 514, 532, and 810 nm wavelengths compared to the 1064 nm Nd:YAG laser,75 may be of secondary importance when unsuitable radiation fields are used, as is the case with high-power ophthalmoscopic or positive contact lenses.

The combination of large retinal laser spot sizes (up to 4.5 mm)75 and high-power, wide-angle, positive lenses appears to be most dangerous for structures in the anterior segment of the eye. The 488/514/532-nm wavelengths can be considered the most unsuitable wavelengths for chorio-retinal tumor therapy because of their poor penetration both in tumors and large vascular structures. In addition, scattering in the media greatly increases with age and may lead to unwanted heating of opacified media, simultaneously reducing irradiance at the laser spot and the tumor.

As an example, the temperature reached in the target tissue varies linearly with the irradiating power (Equation (3)). Figures 9 and 10 show the in vivo effects of a cw Nd:YAG laser pulse on the retina and choroid of a pigmented rabbit using the ‘fast denaturation’ strategy presented above. In Figure 9, the irradiation parameters were a power of 0.8 W, pulse duration of 0.2 seconds (pulse energy 0.16 J), and laser spot diameter in air of 100 µm. Damage is restricted to the pigment epithelium and the outer sensory retina. The profile of the impact is sharply defined and is clearly characterized by a coagulation region with minimal structural distortions, although it displays predominant swelling and disruptive phenomena. Intense coagu-

Fig. 10. TEM of an acute lesion of the choroid of a pigmented rabbit following irradiation with a cw Nd:YAG laser (CF2 normal, CF1 coagulated collagen fibrils; Fb: coagulated fibroblasts). Negative magnification: × 3600. (Reproduced by courtesy of Dr C. England, Institute of Anatomy, University of Bern, Switzerland.)

lation effects have caused swelling and disruptive alterations in the meridional direction. These effects were observed to be limited to the outer granular layer, as can be concluded from the reduced cell density. In Figure 10, the power is increased from 0.8-1.4 W (pulse energy 0.28 J), while the pulse duration and spot size remain the same (0.2 seconds and 100 µm, respectively). This results in pronounced choroidal damage. At a number of sites, endothelial cells have become detached from their origin, while thrombocytes have migrated to these sites and have built a new barrier. The survival time of these experiments was 20 minutes.117 The collagen fibrils are either destroyed or show severe thermal damage. These alterations to the collagen fibrils serve as a measure of the extent of the thermal damage. The vascular apparatus also exhibits severe thermal damage.

In conclusion, for the treatment of tumors with a short path length (1 mm or less), short wavelength sources of radiation, such as the argon ion (488, 514 nm) or frequency-doubled Nd:YAG (532 nm) laser, appear to be the most appropriate choice. However, these are unsuitable for the irradiation of large vascular structures, as they have poor penetration depths. For that purpose, long wavelength sources such as the diode or Nd:YAG laser should be used. Summing up the pros and cons of semi-

conductor and Nd:YAG lasers: when all the other parameters are kept constant, their similarities could be much greater than their differences, as long as the irradiation time is longer than the denaturation time. It should be mentioned that model calculations based on physical data have not yet proved the superiority of a specific method, although this work permits rational planning of photothermal tissue effects. Whatever the wavelength used, the combination of a large retinal spot size with positive high-power ophthalmic lenses should be avoided in order to protect the ocular structures in the anterior segment of the eye.

Like other methods, thermotherapy,75 and in particular photodynamic therapy,34,92,93,118 is promising, although one which will require further improvements. Factors limiting hyperthermia include long exposure durations and the small difference in sensitivity between normal and neoplastic cells.93,118-121

Improved diagnostic methods122,123 to define the physical properties of tumor tissue more accurately than is currently possible, together with precise temperature measuring devices for use during irradiation, may eventually define the ideal photothermal tumor therapy.

Conclusions

Phototherapy by means of various laser energy sources is not without risk unless the temperature field is adapted to the tumorous structures. Temperature elevations outside a small therapeutic range that affect vital structures, are considered to be a risk factor. Dedicated mathematical models for computation of the distribution of light energy in the retina and various tumors are provided, as well as models related to temperature fields. Important parameters for photic tumor therapy are laser wavelength and configuration of the optics for energy delivery. The Nd:YAG laser has the greatest penetration depth in various tumors, followed by the diode wavelength. Delivery systems, such as highpower positive contact lenses, or those dependent on indirect ophthalmoscopy, may lead to dangerous temperature elevations in the pretumoral media.

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