Hemostasis, hemodynamics, photodynamic therapy, transpupillary thermotherapy: controversial aspects

Abstract

The authors have studied the physical and biological mechanisms required for the deeper understanding of laser-induced thermothrombosis. They analyze the absorption of radiated energy by the blood and endogenous absorbers. Hemostasis embraces hemodynamic and clotting mechanisms, leading to photothrombosis. The authors take a critical look at the working mechanisms of photodynamic therapy, transpupillary thermotherapy, and also analyze the effects of thermal and photochemical energy upon the vascular structures, resulting in thrombosis. Laser safety and the effects of immediate and late damage following laser irradiation are also reviewed.

Introduction

Hemostasis, leading to the obliteration of ocular and periocular vessels, including angiomas of various origin, can be achieved with various lasers, including the argon, potassium titanium phosphate (KTP), krypton, diode, Nd:YAG laser, etc.1 The critical parameters that should be observed in photo-oblitera- tion are absorption and optical penetration by the vascular structures, volume and velocity of the blood flow, and the presence or absence of endogenous and/or exogenous absorbers.

Small blood volumes such as, for example, various structures to be treated during proliferative neovascular diabetic retinopathy, or capillary malformations of the retina and choroid or of the skin of the face, should optimally be treated by laser wavelengths that have high absorption by hemoglobin, such as are emitted argon green (514 nm), krypton yellow (568 nm), and KTP (532 nm) lasers.

Blood vessels that transport very small volumes of blood and that have poor absorption, or where a

selective effect is required, depend upon exogenous absorbers such as photodynamic substances or indocyanine green. Even then, the selective photothrombosis of small blood vessels is difficult.

In contrast, for angiomas, which transport large volumes of blood, laser wavelengths are required that have good tissue penetration, such as those of the diode or the Nd:YAG lasers. Here too, the photoobliteration of large angiomas, particularly when they are perfused by a rapidly-moving blood column, is a demanding task.

Since photothermal thrombosis depends upon achieving intravasal temperatures of about 60-100°C during a critical interval, sufficient energy and power are required. It is difficult to photothrombose vessels that have a high volume flow, because thermal energy is carried away by heat convection. Structures of this kind cannot be thermo-obliterated unless the thrombosis is induced in a step-wise fashion during repeated sessions and/or by taking advantage of exogenous absorbers and, as in the case of, for example, vascular abnormalities of the face, by supplementary measures such as the injection of vaso-obliterating substances or the ligation of large vessels.

Photodynamic therapy (PDT) is another choice of therapy that can be used to induce localized photochemical thrombosis in senile, neovascular, exudative maculopathy.2 Here, photochemical energy is required, which is several times less than that necessary to induce thermal photothrombosis. However, due to the progressive nature of this disease, it cannot be claimed that this method is any more than palliative.

Selective ablation of various cells, such as ablation of the retinal pigment epithelium (RPE), which should not involve thermal damage to the collateral

structures, can be achieved by ultra-short pulses, and may, for example, be used to remove pigment cells that are presumably diseased, in the hope that they will be replaced by vital, functionally intact, cells, or that such ablation will be sufficient to induce, as in selective laser trabeculoplasty (SLT), a functional result without any collateral damage, the mechanism of which is not known.

Growth factors are causally related to the pathology of parts of or the whole functional unit, consisting of the neurosensory retina, RPE, Bruch’s membrane, and the choriocapillaris, whose functional integrity is intimately associated with the success of any selective interventional procedure. As a distant goal, a therapy could be conceived that relies upon restoring the normal function of the metabolism of growth factors, which, once achieved, could be preferable to any photochemical or thermal laser intervention.

Immediate or induced radiation damage is a serious occurrence, which may be followed by blindness, and should be avoided by having an understanding of its basic mechanisms, and therefore being able to avoid them.

The physics of photothermal and photochemical vascular thrombosis

Radiated energy can be absorbed by endogenous absorbers, such as blood and melanin, contained in pigmented cells, from where the thermal energy generated can be conducted to the lumen of the vessels. The interaction of thermal energy with elements of the blood (e.g., plasma, erythrocytes and thrombocytes) and/or the vessel wall (e.g., endothelial cells) induces thermothrombosis by biological multiple-step interaction.3 Exogenous dyes, such as, for example, indocyanine green (ICG), or photodynamic substances reinforce the biological interaction by adding thermal or photochemical energy to the clotting mechanism, but these dyes probably do not change the basic pattern of thrombosis,3 al-

Fig. 1. Scheme summarizing the various physical and biological effects operating to produce blood flow stasis in (A) choroidal and (B) mesenteric vessels irradiated with a cw Nd:YAG laser.

Fig. 2. Vascular lamina of the choroid; rabbit eye 20 minutes after irradiation with an Nd:YAG laser (pulse energy: 100 mJ). Longitudinal section through a venule. Endothelial cells, E, have been damaged. Aggregation of platelets, P, within the vessel lumen. Transmission electron micrograph. Negative magnification × 9000. (Reproduced from Fankhauser et al.13 by courtesy of the publisher.) Corresponding to mechanism A

B

Fig. 3. Segment of a rabbit mesenteric artery (diameter: 33 µm; focal spot diameter: 70 µm; pulse energy: 1 J; pulse duration: 20 msec). Between the thickly layered protein coagulates, P, blood shadows, Er, can be seen, which are the remnants of the exploded erythrocytes. The endothelial cells, E, exhibit vacuolization of the endoplasmic reticulum, as well as lytic degeneration of the filaments and ribosomes. The smooth muscle cells, M, and internal elastic membrane, B, appear to be morphologically intact. Transmission electron micrograph. Negative magnification × 5000. (Reproduced from Van der Zypen et al.12 by courtesy of the publisher.) Corresponding to mechanism B

Fig. 4. Rabbit mesenterium capillary (diameter: 8 µm) approximately 100 µm away from an irradiated larger vessel (focal spot diameter: 80 µm); pulse energy: 1 J; pulse duration: 100 msec. Sawtooth deformed erythrocytes, E, are in marked apposition to morphologically unaltered endothelial cells (arrows). Transmission electron micrograph. Negative magnification × 14,000. (Reproduced from Fankhauser et al.13 by courtesy of the publisher.) Corresponding to mechanism A or B

Fig. 5A. Absorption of deoxygenated blood with a hemolytic concentration of 150 g/l as a function of wavelength for various thicknesses of blood layers. The number of erythrocytes is 4.9 × 106 mm-3. Absorption at wavelengths beyond 1000 nm is extrapolated. (Adapted from Rol et al.1 by courtesy of the publisher.)

Fig. 5B. Absorption of oxygenated blood with a hemoglobin concentration of 150 g/l as a function of wavelength for various thicknesses of blood layers. The number of erythrocytes is 5.2 x 106 mm-3. Values for absorption at wavelengths beyond 1000 nm are extrapolated. (Reproduced from Rol et al.1 by courtesy of the publisher.)

though they may have a more selective effect upon small vessels.

Broadly speaking, two basic clotting patterns can be differentiated: A. energy such as heat, mechanical or electric (Joule heat), can damage the vessel and trigger the clotting cascade (Fig. 2); B. excessive energy overpowers the clotting cascade and induces the immediate arrest of the blood volume by coagulating the blood proteins (Fig. 3). This is the mechanism utilized in laser surgery. It is simply a question of the power density delivered to the vessels which leads to either A or B (Figs. 1, 2 and 3). The photothrombosis observed in the capillaries (Fig. 4) can follow either mechanism A or B.

Absorption of laser radiation by the blood is a complex event that cannot simply be understood by a ‘dye-radiation absorption concept’, although pri-

Fig. 6. Graphic display of the relevant physical quantities responsible for photic vessel occlusion. (Reproduced from Fankhauser et al.9 by courtesy of the publisher.)

mary absorption of radiation by hemoglobin is important (Figs. 5A and 5B).1,4 The effective ‘thrombogenic temperature’ is thought to be about 60-100°C. Deposited thermal energy is either transported to the vessel once it has been absorbed by pigmented cells, or absorbed directly by hemoglobin and other constituents contained in the vessel. Depending on blood flow velocity, this thermal energy is then carried away to a greater or lesser extent by the blood flow. Obviously, the greater the blood volume irradiated and the greater the blood flow velocity, the lesser the increase in intravasal temperature and, hence, the energy-dependent hemostatic effect.5,6

Virchow7 stated that thrombosis follows stasis of the blood column. This is obviously a feedback process: the slower the blood flow, the more efficiently used the radiated energy, inducing stasis, and vice versa, i.e., the higher the temperature induced, the more efficiently it will delay blood flow and induce stasis. This qualitative concept has been used in a model9 (Fig. 6) which has been helpful in planning in vitro laser-dependent experiments,6 and in developing other theoretical concepts.5,8

Figure 6 shows that slowing down the blood flow is the main parameter leading to blood stasis. In Equation (1) and Figure 6, V0 is the flow velocity at an intact vessel; V1 is the velocity at the non-con- stricted site and V2 that at the constricted site of an irradiated vessel. The lumen-narrowing effect can be characterized by various factors γ and δ; γ being the ratio of the narrowed to the non-narrowed vessel diameter. δ defines the fraction L0 of the narrowed vessel. D is the diameter of the vessel.

Figure 6 and Equation (1) show that, at the start of a localized thrombotic event, acceleration of blood flow velocity can be seen. This can be significant and correlates with the in vitro observation that the start of a thrombotic effect is the most critical, and

that fluid flow must be overcome by more intense thrombosis-stimulating energy, while later, when thrombosis becomes effective, the energy demand leads asymptomatically towards zero.5,6

When the vessel is gradually obstructed over its entire length, Equation (1) is reduced to:

which shows the strong dependence of flow velocity upon the narrowed vessel diameter. For example, when the vessel is narrowed to half its diameter, the blood flow velocity falls to a quarter of its initial value. Equations (1) and (2) are only valid for vessel segments in which the pressure drop is constant. For this model, a Newtonian fluid is assumed for purposes of simplification.

We have found this model to be suitable for describing the blood flow in photothrombotic events in arteries and veins. However, it is probably not suitable for describing flow phenomena in the capillaries. A unique phenomenon has been observed here. Erythrocytes and other cellular blood components that showed definite heat damage were observed beyond the sites of the impact of radiation within capillaries that did not show any heat damage, thereby enlarging the region of vascular impairment (Fig. 4).13

The absorption of radiated energy by hemoglobin and melanin

The melanin contained in the RPE and in the choroidal melanophores absorbs laser radiation more strongly than either hemoglobin (Hb) or oxyhemoglobin (HbO), when comparing different light absorbing materials of equal thickness.10,11

It has been shown that, at a wavelength shorter than about 625 nm, and for a subretinal vascular membrane in contact with the RPE and about 10 µm thick, Hb absorption is much lower than pigment epithelium absorption.11 For this reason, the effects of laser irradiation upon thin layers of blood may be almost entirely neglected, unless heat is conducted from a neighboring melanin absorption site to the lumen of the vessel. However, this will almost infallibly lead to heat contamination of the surrounding tissues, which is one of the main problems facing photocoagulation. At nonpigmented sites, the heating of a vessel due to the absorption of light energy by blood alone, and without damage to the surrounding structures, may only be possible if chromophores, such as organic dyes (e.g., ICG) or photodynamic substances, are added to the blood.

The heat generated upon the absorption of light energy must be transported from the absorber (RPE or choroidal chromatophores) to the target blood vessel. Along the way, the temperature drops as the distance increases. This can be calculated for both equilibrium temperatures and finite exposure dura-

Fig. 7. a: η, the efficiency factor, as a function of time τ, exposure time, and distance from the pigment epithelium x. In a., the distance x is 0.5 mm. b: x is 1 mm. c. x is 2 mm. t is exposure duration. (Reproduced from Bebie et al.5 by courtesy of the publisher.)

tions (Figs. 7, 8, and 9). For example, it can be shown that the efficiency factor (see Bebie et al.5 for details) responsible for energy transmission from the RPE to a vascular structure, at various exposure durations, decreases exponentially as the vessel distance increases. At large vessel-absorber distances, the heat effect upon a vessel becomes very small or, conversely, high temperatures, contaminating neighboring structures by heat, are needed. This is illustrated by the difficulties encountered when, for

:

Fig. 8. Intravascular temperature increase (°C) by direct absorption within a vessel with a diameter (D) of 80 µm, irradiated by an argon laser bundle with a diameter (L) of 100 µm and a power of 200 mW, as a function of the velocity of blood flow. (Reproduced from Bebie et al.5 by courtesy of the publisher.)

Fig. 9. Factor β indicating the fraction of the temperature that is reached within a vessel when blood flow velocity (v) is greater than zero. The three stripes represent vessel diameters

(D) of 40, 60, and 100 µm. The upper borders of the stripes correspond to beam diameters of L = 600 µm, the lower borders to L = 300 µm. (Reproduced from Bebie et al.5 by courtesy of the publisher.)

example, irradiating preretinal neovascularizations or intravitreal vessels, or when the distance from the vessel to the RPE is great. This emphasizes the importance of intraluminal absorption by exogenous dyes.

The temperature within an irradiated vessel will always be the result of the energy balance between, on the one hand, heat generated by direct absorption by blood and heat conduction from the irradiated chromophores (RPE, choroidal chromatophores) towards a vessel, and, on the other, heat loss due to heat diffusion and convection.

Due to the very high absorption of the argon laser radiation temperature in an 80-µm vessel irradiated by a laser bundle of 100 µm in diameter, theoretical temperatures are very high at, for example,

a motionless blood column (about 300°C), while a rapid collapse of temperature is shown when flow velocity increases (to about 40°C at a flow velocity of 9 cm/s) (Fig. 8). This emphasizes the great importance of reducing flow velocity by the clotting apparatus and/or by any other means (e.g., compression of the vessel). These computations5 should not be taken too literally, because a number of factors have been ignored for the sake of simplification. Moreover, the temperature of the blood will not exceed 100°C. Even so, the critical influence of heat due to conduction is well predicted by the model.

The increase in temperature will eventually lead to coagulation of blood plasma, and finally to arrest of the blood column. The experimental and clinical effects have been described previously.12-15

The vascular effects of photodynamic therapy

A wide range of effects has been observed after light activation of photochemically active molecules. In general, in PDT, light treatment of tissue-localizing photosensitizers results in damage to several cellular targets, including plasma membranes, lysosomes, mitochondria, and DNA,16-18 broadly following the general pattern of ‘normal’ intravascular clotting.3 The study of the time course of blood-flow deceleration (Fig. 10),18 or the dynamics of blood-vessel narrowing (Fig. 11),16 has been shown to be a powerful instrument for understanding the parameters related to PDT-conditioned blood flow arrest.

Various techniques for PDT-conditioned flow measurement have been used so far. These include radiolabelled microsphere injection,20,21 direct visualization through transparent sandwich observation

Fig. 10. Effect of 100 J/cm2 light fluence on the intraoperative blood flow of malignant tissue in situ in six different patients who all received aminolevulinic acid (ALA), 60 mg/kg, p.o. Blood flow was measured immediately before and eight minutes after PDT. The origin and location of the tumor, as well as the time of PDT after receipt of ALA, is indicated for each patient. The mean decrease in blood flow was 51.8 ± 2.7% (p = 0.001). (Reproduced from Moan et al.18 by courtesy of the publisher.)

Fig. 11. Microvascular response to PDT using Photofrin. Animals were injected with 25 mg/kg Photofrin 24 hours before light treatment. Light treatment consisted of 135 J/cm2, 630 nm wavelength light to the entire cremaster muscle containing a chondrosarcoma tumor during the first 30 minutes of observation. Vessel diameters were recorded for an additional one hour after completion of the light treatment (–y–): change in the diameter of 20-30 µm tumor microvasculature (y---y): change in the diameter of 20-30 µm microvasculature in normal tissues. Points are the means of five experiments, calculated as a percentage of the initial vessel diameter. Bars represent the mean + 2 SEM. (Reproduced from Fingal16 by courtesy of the publisher.)

chambers,22 intra-arterial fluorescein injection,23 injection and extraction of 86RbCl,24,25 magnetic resonance spectroscopy using D2O,26-28 measurement of oxygen tension, microscopic measurement of changes in blood vessel diameter, ocular angiography, laser Doppler flowmetry,19,28-30 etc.19

Actually, in clinical practice, it is known that shortwavelength laser radiation (argon, KTP, krypton yellow) is optimal for the photo-obliteration of small vessels measuring about 1-2 mm (Fig. 12), while vascular structures larger than about 2 mm (Fig. 13) should preferably be irradiated with mediumor longwave radiation (diode, Nd:YAG).1

The ultrastructure of laser-induced thermothrombosis

As indicated earlier, hemostasis produced by highpower radiation induces abrupt stasis due to instantaneous coagulation in the vessel lumina (mechanism B), leading to permanent occlusion, unless the intravasal pressure is able to ‘push’ the clot downstream. In contrast, hemostasis due to a lesser energy interaction has a protracted time course following the clotting cascade (mechanism A) (Fig. 1). Photochemical interactions will also follow this second mechanism, at least in part.16 A particular thrombogenic event, which may also be observed during PDT, is observed in the capillaries (Fig. 4); here, apart from direct thrombosis in the focal area, heatdamaged blood cells can be seen to obstruct nondamaged capillaries beyond the focal area.

Fig. 12. Port-wine angioma of the face. A: Before and B: after irradiation with a KTP laser. (By courtesy of M.W. Berns.)

Fundus anomalies

Most fundus and retinal vascular anomalies can be treated with laser radiation (Table 1). According to the above, small lesions such as Group 1 malforma-

Fig. 13. A: Rapidly growing capillary/cavernous hemangioma of the forehead, upper eyelid, and nose. B: Three months after Nd:YAG laser photocoagulation and injection of steroids. C: Following Nd:YAG laser photocoagulation using a sapphire tip; good resection of the hemangioma can be seen, with improvement of color, contour, and symmetry. (Reproduced from Apfelberg et al.70 by courtesy of the publisher.)

tions (Table 2) can be treated with short-wavelength laser radiation, while Group 2 and 3 malformations (Table 2) can pose considerable problems when these wavelengths are used. In these cases, long-wave- length laser radiation is vastly superior to shortwavelength radiation. Classic examples are Von Hippel-Lindau angiomas, which are notoriously resistant even to xenon arc radiation and Nd:YAG or diode laser light, but which can be tackled by a repetitive strategy using these wavelengths.

There are strong analogies to skin tumors of the face. Capillary vascular anomalies such as capillary angiomas of the face respond very well to short-

Table 1. Classification of fundus vascular anomalies

Vascular dilatation

Retinal arterial macroaneurysms: focal dilatation of a retinal artery

Idiopathic juxtafoveal retinal telangiectasis: dilatation of retinal parafoveal capillaries

Retinal venous macroaneurysms: focal dilatation of a retinal vein

Coats’ disease: dilatation of retinal arteries, capillaries, and veins

Retinal cavernous hemangiomas: tumors of dilated retinal vessels

Choroidal hemangiomas: tumors of dilated choroidal vessels

Arteriovenous shunting

Arteriovenous malformations: large retinal vessel communications

Retinal capillary hemangiomas: small retinal vessel communications

(Adapted from Asdourian71 by courtesy of the publisher)

Table 2. Classification of retinal arteriovenous malformations

Group 1 A small arteriovenous malformation is present with a capillary network between a normal caliber artery and vein

Group 2 A direct communication exists between an artery and a vein without an intervening capillary network

Group 3 Large convoluted arteries and veins are present without an intervening capillary network

(Adapted from Archer et al.72 by courtesy of the publisher)

wavelength radiation (Fig. 12), while large angiomas (Fig. 13) may pose huge problems, which can only be overcome by supplementary measures such as ligation of large arterial feeder vessels and the injection of steroids.

Transpupillary thermotherapy

(see Newsom RSB, Rogers AH and Reichel E: this book)

Transpupillary thermotherapy (TTT) is a novel treatment method for CNV related to senile maculopathy, introduced by Reichel et al.31,32 and others.33 With this method, the macular area is irradiated by diode laser light (810 nm) for one minute, resulting in a ‘faint retinal graying’. Various irradiances varying from 6-47 W/cm2 and beam diameters of 800-3000 µm can be used.33 The estimated temperature rise at the retina is 4-9°C above body temperature, resulting in an absolute rise of 41-46°C.34 A retrospective study claimed that, after six months, closure rates are superior to PDT (Table 3).

Table 3. Closure rates with CNV, and visual acuity results at six months for TTT33 and PDT

Without proof, photochemical mechanisms or hyperthermia, or both, are claimed to be the basic mechanism relating to this novel therapy. The ophthalmology community is awaiting the results of forthcoming, prospective, randomized studies.

Mechanisms and controversial aspects related and controversal aspects to photodynamic therapy

So far, very little is known about the ultrastructural effects of PDT in humans, and ultrastructural studies are limited to the initial findings in specimens of choroidal neovascular membranes obtained after macular surgery. The complexity of such membranes is huge, and their components are listed in Table 4 and displayed in Figures 13 and 14.

So far, conclusions relating to the effects of PDT have only been drawn from fluorescein angiography, light microscopial and ultrastructural findings following animal experiments.37,38,43 However, it appears to be impossible to apply these results to human pathology, and the interaction between photochemical energy and the various elements found in neovascular lesions is purely speculative (Table 4, Figs. 13, 14).

Studies of flow in theoretical models5 or in analogues of flow models in small vessels, mirroring choroidal flow, is one way of understanding the complexities of PDT-based hemostasis.

Rationale of photodynamic therapy (PDT), photo-thermolysis (PTL), transpupillary thermotherapy (TTT), and selective laser trabeculoplasty (SLT)

The two-year results of the Age-Related Macular Degeneration Study indicated that, on average, Verte-

Table 4. Cellular and extracellular components of surgicallyexcised CNV specimens with age-related macular degeneration

Fig. 13. A vascular channel in a surgically excised membrane is surrounded by loosely arranged collagen and fibrin, lined by endothelium (end), and an erythrocyte (rbc). The endothelium displays a basal lamina (arrowhead) and intercellular juntions (arrow). Several pigment-containing macrophages (mac) are present in the membrane (original magnification, ×5510; inset, original magnification, ×160). From35 with permission of the publisher.

Fig. 14. Basal laminar deposit (bld) lies between the retinal pigment epithelium (rpe) and the inner aspect of Bruch’s membrane in this choroidal neovascular membrane excised from a patient with age-related macular degeneration. Wide-spaced collagen is in the basal laminar deposit and scarred choroid versus a component of the choroidal neovascular membrane (asterisk) are present within Bruch’s membrane (original magnification, ×10,440; inset, original magnification, ×400). From35 with permission of the publisher.

porphin therapy requires five treatments during a 24month period in order to control the effects of agerelated macular degeneration.37 Schmidt-Erfurt et al.,38 Peyman et al.,40,41 and Reinke et al.42 have discussed the possible ramifications of numerous retreatments on the healthy choroid and retina. When using Verteporphin in healthy monkeys, Kramer et al. found, at the lowest effective dose applied, damage to the RPE only, or REP + slight photoreceptor changes + occasional pyknosis in the outer nuclear layer, with or without closure of the choriocapillaris.43 Nakashizuka et al.,44 using the photosensitizer NPe6, noted damage confined to the RPE and choriocapillaris in normal, nonhuman primates.

Data from a one-year study showed that the results of contrast sensitivity and fluorescein angiographic

studies were better in eyes treated with Verteporphin than in those treated with placebo.38 In a subgroup analysis of this study, the benefits of treatment were found to be greatest in the subgroup with predominantly classic CNV. In this subgroup, 67% of eyes treated with Verteporphin lost fewer than 15 letters of visual acuity (approximately three lines), compared to 39% of those given placebo (p = 0.001). The beneficial effects of Verteporphin therapy were maintained over a two-year period, when 53% of Verteporphin-treated eyes had lost fewer than 15 letters of visual acuity compared to 38% of those given placebo. Again, this beneficial effect was greater in the predominantly classic subgroup, with 59% of the eyes treated with Verteporphin losing fewer than 15 letters compared with 31% of the eyes receiving placebo (p = 0.001). Verteporphin therapy was also reported to be well tolerated over a twoyear period, with few ocular or systemic adverse events resulting from the treatment. In a more recent report39 it was found that vision outcomes for verteporfin-treated patients with predominantly classic lesions at baseline remained relatively stable from month 24 to month 36, although only approximately one third of the verteporfin-treated patients originally enrolled with this lesion composition had a month 36 examination. From these results, the TAP Study Group identified no safety concerns to preclude repeating photodynamic therapy with verteporfin. Additional treatment was judged likely to reduce the risk of further vision loss. Caution appears warranted in the absence of comparison with an untreated group during the extension and since not all patients in the TAP Investigation participated in the TAP Extension.

In contrast to these good results, the mechanism of action is still far from being understood. Obviously the results of irradiation in healthy animals are only of limited help for the interpretation of human behaviour. The idea of obliterating newly formed vessels in diseased humans may make sense when juxtaor extramacular areas, with a chorioretinal anatomy that still retains some function, are available. Even here, it is not understood how the obliteration of newly formed vessels can make sense, when even in experimental animals, the least therapeutical effect following PDT therapy caused damage to the RPE and choriocapillaris.43,44 Van den Bergh and Bellini (this book) also describe damage to the choriocapillaris following PDT. Such experimental findings are not compatible with the claimed pronounced selectivity of PDT for neovascular choroidal vessels in human pathology, but rather emphasize the fact that the selectivity of newly formed vessels and neighboring structures is limited. Even less is known about the effect of the transfer of photochemical energy and related physical phenomena upon its surroundings in genuine neovascular membranes. From the appearance of excised human neovascular membranes, it would not appear to be possible that any vision could be retained in areas of established neovascular, exudative degen-

Fig. 15. Troglitazone (TRO) decreases the thickness of laserinduced CNV membranes in the rat. A: Control CNV membrane in which neovascular channels (arrows) and intervening stromal cells can easily be identified. B: TRO treated animals showed significantly thinner CNV membranes. The membranes appeared to contain fewer neovascular channels and fewer stromal cells. Horizontal bar: 25 µm. (Reproduced from Murata et al. by courtesy of the publisher.)73

erative maculopathy. (Figures 13 and 14) This is compatible with the microperimetric results of Bunse et al., in which an absolute central scotoma with adjacent relative contrast loss was shown.47 It could perhaps be that the PDT-dependent intervention slows pathology down for a time in the juxtacentral region.

While most experimental treatments aim to destroy the newly formed vessels, the goal of basic cellular and growth mechanisms and functions related to receptors, interphotoreceptor matrix, RPE, Bruch’s membrane, and the choriocapillaris in age-related, neovascular maculopathy, needs to be more clearly understood (see Appendix). Such mechanism may be the final key of the problems.

Photothermolysis (PTL), oriented towards the selective destruction of functionally-disturbed ‘senile’ RPE cells, depends on the identification of such functionally-disturbed RPE cells, because the destruction of normal RPE cells does not make sense. Also, the functional integrity of newly formed RPE cells, should they be produced, is not known. Nevertheless, the clinical application of selective PTL in retinal pathology appears to show promise. (see Roider J, Brinkman R, Birngruber R. this book)

The logical basis of TTT still has to be determined. In PTL, PDT, and SLT, an understanding of the complexities of cell mechanisms and growth factors

would appear to be imperative. Vascular endothelial growth factor may be considered to be one of the most important growth factors.57 This and others will be considered in the Appendix. Despite the complexities of the basic mechanisms, there appears to be progress (Fig. 15).

Finally, a rebirth of the classical ‘feeder-vessel coagulation technique’ ought to be reconsidered.45,46 Also, other mechanisms that are being used in the treatment of age-related macular degeneration should be considered.58

Retinal temperature elevations

However TTT uses treatment temperatures which may reach 47°C during 60s.65,66 The therapeutic index of hyperthermia is rather narrow,59 for example, above 44°C the thermal sensitivity of normal cells rapidly approaches that of neoplastic or other rapidly growing cells. Neuron damage is well documented at 43°C. In normal and neoplastic cells, the DNA synthetic portion of the cell (S phase) seems to be relatively more selectively heat-sensitive.61 In light of these facts, temperature elevations in TTT (up to 47°C)90 should be reconsidered.31-33

Retinal photocoagulation and photodynamic therapy

The risks of macular photocoagulation are well known, and have been discussed in numerous papers. The late effects of retinal photocoagulation have been studied by Tso and Fine69 (see Appendix). Four years following mild argon photocoagulation of the monkey retina, they noted serious degenerative changes.

Collateral damage is cumulative with repeated verteporphin PDT treatments.42,43

TTT may have the same problem as PDT, insofar as the interaction of radiated energy i.e. the interaction of radiated with the complexities of macular pathology is enigmatic. Retinal radiant exposure is less in PDT than in TTT (0.59 versus 9.2 J/cm2).67 This however may have little relevance as long as the basic energy transfer mechanisms are not known. Collateral damage of TTT has been observed.68 General aspects of laser safety are discussed by D. Sliney (this book).

Conclusions

We have described the basic mechanisms, based on model assumptions, affecting blood-flow stasis. It becomes clear that localized damage to vascular structures is only possible by adding exogenous absorbers to the vessels to be obliterated, because endogenous absorber blood does not absorb enough energy to be sufficiently effective for thermo-oblit- eration, unless collateral damage is accepted. Such damage may (plastic surgery) or may not (irridation of organellas of the eye) be acceptable. In addition

to other exogenous substances, photodynamic substances, indocyanine green and others could be an approach to the problem. Nevertheless, despite successful clinical results, it follows that photodynamic energy, despite clinical efficiency, concluding from anatomical evidence, is not able to destroy neovascular structures in the retina selectively. Laser radiation in TTT, related to tissue temperature elevations, may be an immediate threat to retinal neurons and may be harmful.

The relative clinical value of PDT and TTT remains to be determined. Studies related to intraoperative monitoring of retinal temperatures are in course.66

Appendix

An Appendix covering the time span up to December 31, 2002, including selected titles, can be found on the Internet at www.kuglerpublications.com.

References

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