Ординатура / Офтальмология / Английские материалы / Retinal Vascular Disease_Joussen, Gardner, Kirchhof_2007

Fig. 13.5. Laser lesion replaced by scar tissue

of area destroyed, but cannot change the irreversible destruction of the photoreceptors itself [59, 62].

To summarize, photocoagulation is an unspecific method. Using common laser parameters, the RPE, the choriocapillary layer, the photoreceptors and to a certain degree more distant structures are damaged. The coagulated area is replaced by unspecific scar tissue, which leads to irreversible visual field loss.

13.2.2 Mechanisms of Treatment

In proliferative diabetic retinopathy one of the first explanations of the effect of laser coagulation was the destruction of the oxygen consuming photoreceptors, while the relation between need for oxygen and

a

posed by Marshall et al. [40], who showed after coagulation of porcine eyes proliferative dividing cells of venous capillaries. These cell activities were seen even in the inner retinal layers, suggesting a long distance effect of a biological substance. This substance likely is a vascular endothelial growth factor (VEGF), which is released oxygen dependently and which can be detected both after retinal ischemia and in ocular neovascularization. VEGF is a strong angiogenic factor [25]. To explain the beneficial effects of retinal laser photocoagulation, Wilson et al. examined gene expressions of retina, RPE and choroid in mice eyes 3 days after retinal laser coagulation [78]. Among 265 differentially classified genes, an increased expression of angiotensin II type 2 receptor was found, which is involved in inhibition of VEGF expression and VEGF-induced angiogenesis. The same study also found a decreased expression of calcitonin receptor-like receptor (CRLR) precursor, interleukin-1 (IL)-1m, the fibroblast growth factors (FGF-14 and FGF-16), and plasminogen activator inhibitor II (PAI2), which may also contribute to the anti-angiogenetic effects of laser therapy. Ogata et al. showed an upregulation of pigment epitheliumderived factor (PEDF) in cultured human retinal pigment epithelial cells after photocoagulation [53].

b

PEDF was recently shown to be a potent inhibitor of ocular angiogenesis [14]. Ogata et al. found not only that anti-angiogenic factors but also angiogenic factors were upregulated transiently after laser photo-

13 II coagulation in cultured RPE cells. Via reverse transcription polymerase chain reaction a significant increase in the expression level of basic fibroblast growth factor (bFGF) was detected, with a maximum 6 h after photocoagulation and a decreasing level after 72 h to less than before photocoagulation. bFGF is a strong angiogenic factor [52] which also accelerates wound healing [45]. Therefore, its use has been suggested to promote the proliferation of laser injured RPE cells in culture. Among the angiogenetic factors, Ogata et al. also found increased expression after 6 h of kinase insert domain-containing recep- tor-1 (KDR/flk-1), Ets-1, which is a transcription factor expressed in endothelial cells during angiogenesis, and nuclear factor kappa B (NF-κB), which may regulate the initiation of angiogenesis [63, 64] as well as VEGF [52]. Interestingly, after 72 h KDR/flk-1, Ets-1, NF-κB and VEGF gradually decreased to a level lower than that before photocoagulation. These experimental findings in cultured RPE cells indicate that not only the detection of various growth factors, but also their time dependent course must be taken into account in complex explanation models, which are not yet fully understood.

13.3Standards and Indications for Panretinal Laser Coagulation

13.3.1Full Scatter Panretinal Laser Coagulation

13.3.1.1 Diabetes

The present guidelines for panretinal laser coagulation are mainly based on experience in diabetic retinopathy. The treatment of proliferative diabetic retinopathy is based on the Diabetic Retinopathy Study (DRS) [67, 68]. The DRS Study was a prospective, randomized and multicenter trial. A total of 1,700 patients with proliferative and non-proliferative diabetic retinal changes were examined between 1972 and 1975, looking into whether a retinal xenon or argon laser coagulation of the retina has a beneficial effect in comparison to the natural cause. The treatment parameters were exposure times of 100 ms and spot diameters of between 500 and 1,000 μm. In one session 500 – 1,000 laser spots were applied. With such intense destruction of retinal tissues the risk of severe loss of vision within 2 years could be reduced by 50 %. Therefore the study was stopped in favor of treatment for all patients. The systematic analysis of the retinal changes showed four high risk factors for

acute loss of sight, which are generally accepted as indications for a dense (full scatter) panretinal laser coagulation. While eyes with only one risk factor are at a relative risk of 4.2 – 6.8 % of severe loss of vision, the risk in eyes with four risk factors rises to 37 %. The risk factors/indications are:

Presence of vitreous or preretinal hemorrhage Location of new vessels on or near the optic disk (NVD)

Presence of new vessels “elsewhere” (NVE) Severity of new vessels (proliferation area greater than one-fourth of the optic disk size)

13.3.1.2 Central Retinal Vein Occlusion

Another indication for a full scatter panretinal laser coagulation arises from central retinal vein occlusion (CRVO). The main complications of a central vein occlusion apart from macular edema are neovascularizations of the retina and of the iris. The incidence of retinal neovascularizations is correlated highly with the degree of ischemia [27]. The guidelines for treatment of CRVO are based on the central retinal vein occlusion study, which was performed from 1988 until 1992 [13]. It showed that macular edema could be reduced after grid laser coagulation, and also that there was no improvement in visual acuity. There was also no effect of prophylactic panretinal laser coagulation to prevent neovascularizations of the iris. But if neovascularizations of the retina or of the iris exist, the treated eyes clearly benefit from full scatter panretinal laser coagulation.

Guidelines for the Clinic

Suitable exposure times are 100 – 200 ms and a spot size of 500 μm. The laser application should lead to a mild white retinal lesion. The distance between the laser spots should be 0.5 – 1 laser spot. In patients with four diabetic risk factors the range of laser spots varies between 1,000 and 2,000 depending on the spot size. It is recommended to apply laser lesions in two to four sessions, e.g., 2 weeks apart, to avoid serous choroidal detachment and patient discomfort [16]. It should be remembered not to laser onto intraretinal bleedings, as absorption of the laser beam by the hemoglobin in the inner retinal layers may lead to overcoagulation and damage of the retinal layer. In central retinal vein occlusion with proliferation and neovascularization, often even more laser spots are necessary. Regression of neovascularization can be expected after 4 – 6 weeks.

13.3.1.3 Branch Retinal Vein Occlusion

The natural course of branch retinal vein occlusions is characterized by macular edema and vitreous hemorrhage from retinal neovascularizations. About 30 – 50 % of patients with branch retinal vein occlusion (BRVO) recover to visual acuities of 0.5 or even

better without therapy [26, 49]. Cases with poor visual acuity are caused by ischemia. In two-thirds of patients a macular edema leads to loss of vision. Neovascularization can develop if there are large areas of ischemia. The treatment guidelines for BRVO are based on the Branch Vein Occlusion Study [11, 51]. It showed that visual acuity was better in the treatment group after 3 years and also proved that the risk of development of neovascularization could be reduced by a modified sector laser coagulation.

Guidelines for the Clinic

Retinal laser coagulation should be done not earlier than 3 – 6 months after the appearance of a branch retinal vein occlusion. Laser photocoagulation should be done only if retinal hemorrhage has significantly cleared. Otherwise the inner layer of the retina will be destroyed. For the treatment of macular edema, exposure times of 100 ms and a spot size of 100 μm are recommended. The distance between spots should be 2 – 3 spot diameters. The area of the edema should be treated in a dense grid. After occurrence of neovascularizations a sector retinal laser coagulation as described in Sect. 13.3.1 is indicated.

nopathies. For classification of a severe non-prolif- erative diabetic retinopathy the 4:2:1 rule has been proven [29]:

A severe non-proliferative diabetic retinopathy is present:

If either intraretinal bleeding occurs in 4 quadrants Or if venous beading occurs in at least 2 quadrants Or if intraretinal microvascular abnormalities (IRMA) occur in at least one quadrant

Guidelines for the Clinic

A mild scatter panretinal laser coagulation is carried out similarly to the full scatter panretinal laser coagulation except for the amount of laser spots: In total 600 laser spots of 500 μm at greater distances are applied.

13.3.2Mild Scatter Panretinal Laser Coagulation

The treatment guidelines for non-proliferative diabetic retinopathy are to be regarded as the results of the Early Treatment Diabetic Retinopathy Study (ETDRS) [17 – 19]. Similarly to the DRS it was a multicenter, prospective and randomized trial

Complications of Panretinal Laser Coagulation

Depending on the retinal area destroyed, visual field loss and disturbances of dim vision are the most frequent complications. If the area outside the arcades is destroyed, visual field is only about 20 degrees. In rare cases macular edema can lead to a loss of visual acuity after coagulation. These possible complications indicate overtreatment should be avoided. A reason for the failure of the laser therapy is often an

Fig. 13.7. Fundus image of a patient with severe non-prolifera- tive diabetic retinopathy: Severe venous beading (see asterisk) is conceivable

Fig. 13.8. Acute lesions after mild scatter panretinal laser coagulation 1 h after treatment

insufficient coagulation with too small and too few spots.

A therapeutic effect after panretinal laser coagulation can be seen usually not earlier than 6 weeks 13 II after coagulation. If there is no regression of the risk factors, an additional laser coagulation is to be carried out. However, the DRS studies showed that in proliferative diabetic retinopathy the risk of severe loss of vision can be avoided only in 50 %, even if laser treatment is extensive and appropriately per-

formed.

13.4 Focal Laser Application

The ETDRS demonstrated that focal laser coagulation in diabetic macular edema reduces the risk of moderate loss of vision. There was a significant loss of vision in 5 % of the treated eyes, compared to 8 % in not treated eyes after 1 year. After 2 years the loss of vision averaged out at 7 % in treated vs. 16 % in untreated eyes, and after 3 years it was 12 % vs. 24 % [17]. The diagnosis of clinically significant macular edema (CSM) is made by fundoscopy. It is present and should be treated by focal laser coagulation if:

There is a clinical retinal thickening within 500 μm distance from the center of the macula

There is hard exudation within 500 μm distance from the center of the macula with retinal thickening in the bordering retina

There is a retinal thickened area by the size of at least one papilla diameter within the distance of one papilla diameter from the center of the macula

Fig. 13.9. Diabetic patient with clinically significant macular edema

Guidelines for the Clinic

Focal laser coagulation and its complications:

The placement of the laser coagulation spots has to be decided by fluorescein angiography. Areas with edema should be treated close to the leakage. Suitable exposure times are 100 ms and a spot size of 100 μm. The beginning power should not exceed 70 – 80 mW. The laser application should lead to a mild gray retinal lesion. The first spots should be placed distant from the fovea to adjust the power. The distance between the laser spots should be one laser spot apart. Clinical results can be expected not before 3 months after treatment. The most frequent complication is a disturbance of reading by irreversible destruction of photoreceptors. To reduce the risk of complications a modified grid laser coagulation can be performed alternatively in widespread diffuse macular edema. The modified grid laser coagulation is performed similarly to the focal laser coagulation, but the distance between spots should be 2 – 3 spot diameters, treating the whole area of the edema. A rare complication can be secondary CNV development

13.5Subthreshold Laser Coagulation for Retinal Disease

The benefit of retinal laser treatment has traditionally been attributed to the destruction of retinal tissue as described above. Heat conduction from the irradiated RPE into the retina in a typical laser lesion leads to irreversible thermal denaturation of the outer and inner segments [7, 76, 77]. For a variety of retinal diseases, which are probably associated with a destruction of the RPE, selective treatment of the RPE might be sufficient. Thus the overlying photoreceptors can be spared in order to avoid visual field loss, which is especially useful in the macula. If the damaged RPE was regenerating in the healing process, due to migration and proliferation of the adjacent RPE, minimal, destructive, selective RPE treatment might be optimal.

Heat diffuses out of the absorbing RPE layer at a speed of roughly 1 μm/μs. Hence, traditional laser exposures of 100 ms and more result in considerable heat conduction. The spatial and temporal temperature distribution can be calculated by mathematical models, and can be verified experimentally [4, 56]. Only a small temperature difference exists between the RPE and the neural retina after a 100-ms exposure. This difference is about 18 % from the RPE to 5 μm into the retina. The pulse duration needed to spare the neural retina can be estimated by the thermal relaxation time or the time interval required for the heat to diffuse out of an absorbing tissue [1, 4, 57]. Considering a size of an RPE cell of about 10 μm, high temperatures can be limited to the RPE cell itself, if the exposure time is of the order of microseconds rather than the customary millisecond settings. Since no more laser energy is delivered at the end of a laser pulse, the temperature quickly smooths out. If the tissue between repetitive laser pulses has suffi-

Fig. 13.10. Histology of the retina 2 h after selective RPE treatment. The RPE is significantly destroyed

Fig. 13.11. Temperature-time course within the RPE and the retina during application of repetitive ms-laser pulses. Despite significant temperature elevations within the RPE the average temperature in the retina is low, sparing the photoreceptors

cient time to cool down completely to baseline, high temperatures can be achieved inside the RPE, keeping temperatures low in the adjoining photoreceptors at the same time. Figure 13.10 shows the histological effect after exposure to a chain of 500 repetitive 5-μs laser pulses.

In animal experiments, it has been shown that the RPE may respond in several different ways after injury. Adjacent RPE cells are able to spread out to fill defects with hypertrophy. This has been shown in rabbits after photocoagulation and after surgically induced RPE defects and in monkeys after retinal detachment [30]. A new RPE barrier is quickly restored. In treatment of diabetic macular edema, the beneficial effect of laser coagulation is thought to be mediated by restoration of a new RPE barrier [12]. Similar is the rationale of therapy in central serous retinopathy (CSR). Another possible target is the therapy of drusen. Drusen disappear after photocoagulation of the surrounding tissues. The value of prophylactic treatment of drusen is actually being studied by several groups [21, 22, 28]. In a first clini-

cal pilot study, the focus of treatment was on three pathological conditions: diabetic macular edema, central serous retinopathy, and drusen in age-related macular degeneration (AMD). Treatment was per-

formed using a chain of repetitive laser pulses with a II 13 frequency-doubled Nd:YLF laser. In a pilot study, the selectivity of retinal pigment epithelium treatment

was investigated. Microperimetry was performed directly on top of laser lesions during a follow-up period of up to 1 year. A repetitive pulsed Nd:YLF laser was applied in 17 patients, using pulse energies of 20 – 130 μJ. To find the necessary energy, test exposures were performed in the inferior macular region. Seventy-three of 179 test lesions were followed at various times by performing microperimetry directly on top of the laser lesions. All test lesions were at the threshold of RPE disruption and none of the laser effects was visible by means of ophthalmoscopy during photocoagulation. After exposure with 500 pulses, retinal defects could be detected in up to 73 % of patients (100 μJ) after the first day. Most defects were no longer detectable after 3 months. After exposure with 100 pulses, no defects could be detected with 70 and 100 μJ after 1 day, and the neural retina remained undamaged during the follow-up period. Thus selective retinal pigment epithelium damage could be achieved. In a multicenter clinical trial visual and morphologic outcome of patients with focal DMP treated with SRT was evaluated [20].

Sixty eyes in 60 patients were treated with SRT using a frequency doubled Q-switched Nd:YLF laser (527 nm). Each laser exposure contained a train of 30 pulses, each with a duration of 1.7 μs, at a repetition rate of 100 Hz. The SRT laser lesions were not visible ophthalmoscopically during treatment, but were detectable by fluorescein angiography. Median foveal retinal thickness, measured by optical coherence tomography (OCT), was 244 μm and 230 μm at baseline at 6 months. The maximum retinal thickness measured by radial OCT scans in the treated edematous macula area decreased from 351 μm at baseline to 330 μm after 6 months. FA leakage decreased in 31.1 %, remained stable in 52.1 % and increased in 15.8 % of the patients after 6 months. Visual acuity results at 6 months showed that 39.6 % of patients had an improvement of greater than 1 line, 49.1 % demonstrated a stabilization of VA within ±1 line and 11.3 % had a reduction of greater than 1 line. According to these first clinical results, SRT offers the potential for earlier treatment and the possibility of treating closer to the fovea without side effects associated with conventional argon laser treatment. Based on these findings, SRT has also shown that the destruction of the photoreceptors is not always necessary and laser treatment has to be individually adapted to the underlying diseases.

13 II

a

c

Fig. 13.12. a Focal diabetic macular edema before treatment by SRT. b The same fundus 2 h after SRT – the lesions are visible only in the fluorescein angiogram and show the pattern of treatment. c Fundus image 6 months after SRT. The hard exudates have resolved

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II 14

Photodynamic therapy (PDT) with verteporfin has significantly improved functional outcome in the treatment of choroidal neovascularization (CNV) in various clinical disorders [86]. While CNV due to age-related macular degeneration [4, 53, 76 – 80, 84] and pathologic myopia [83, 85] was the primary focus, several studies showed that the treatment effects of PDT were not only restricted to these two underlying disorders. Recently, several clinical studies observed PDT as a treatment modality of CNV due to ocular histoplasmosis syndrome [52, 55, 68], choroiditis [71, 89], angioid streaks [31, 37, 68], Stargardt’s disease [81], symptomatic choroidal hemangioma [30, 61, 82] and other causes [15, 72]. While PDT has become an established treatment modality for various choroidal disorders, its role in the treatment of retinal diseases remains to be determined.

This chapter reports on the molecular and biophysical mechanisms of photodynamic therapy, the characteristics of the photosensitizer verteporfin, the steps required to complete the PDT, and current treatment results for various retinal disorders.

14.2 Photodynamic Therapy

Photodynamic therapy is a non-thermal, photochemical, two-step treatment modality; this allows the treatment of a vascularized target tissue with preferential selectivity. It requires the application of a non-toxic photoactivable compound (photosensitizer), the preferential accumulation of the photosensitizer in the target tissue, oxygen and the activation of the photosensitizer by non-thermal light

eral authors suggested that this light dose may be not sufficiently effective for the treatment of angiomas and hemangiomas and recommended a light dose of 100 J/cm2 The effects of PDT on retinal lesions are at least in part limited by the small number of cases and case series. However, the incidence of most of these diseases may be low PDT may represent an alternative treatment modality for retinal capillary hemangiomas (RCAs) located in the periphery, with significant exudation, which may not be evaluable for laser coagulation

In addition, treatment effects due to PDT have been observed on vasoproliferative tumors resolving the exudation

However, PDT may not be useful for treating parafoveal teleangiectasis without any CNV

exposure of a specific wavelength. This procedure results in a sequence of photochemical and photobiological effects in the target tissue. The selectivity of this treatment modality is achieved by a preferential accumulation of the photosensitizer in the target area and the light exposure, which meets the absorption maximum of the photosensitizer and is confined to the target area [14].

14.2.1 Effects of Light on Biological Tissue

The therapeutic effects of light on biological tissues in ophthalmology may be transmitted by photomechanical, photothermal, and photochemical means. Photodisruption uses light of high power applied in very short-term pulses and very small light spots to irradiate a small tissue volume [73]. These highintensity electric fields to a small focal laser volume are able to generate a plasma of positively and negatively charged ions which induce a shock wave when applied with durations of nanoseconds or shorter [73]. These shock waves mechanically disrupt tissue in the vicinity of the target volume [8]. Photodisruption with nanosecond Nd:YAG laser pulses is applied for laser iridotomies and capsulotomies of the posterior capsule. Photocoagulation induces thermal effects with light pulses of high energy and short duration. A non-selective coagulation necrosis is achieved in biological tissues with light absorbing fundus chromophores (melanin of the retinal pigment epithelium, hemoglobin). It is associated with irreversible protein denaturation and cellular injury and involves the structure and function of adjacent tissues (e.g., retina). Thermal effects are applied by, e.g., laser photocoagulation for the treatment of