Ординатура / Офтальмология / Учебные материалы / Retinal Vascular Disease Joussen Springer

Fig. 14.2. Photodynamic therapy consisting of intravenous administration of the photosensitizing agent (Ia), the distribution and accumulation of the photosensitizing agent (Ib), particularly within the target tissue, and the light application to the target tissue (II). Both steps are necessary to induce effects of photodynamic therapy within the target tissue

II. Light application on the target tissue

Effects within the target tissue only

extrafoveal CNVs to achieve an obliteration of the neovascular tissue [10]. Their restrictions in the treatment of subfoveal lesions are well known and have emphasized the search for modalities resulting in less impairment of retinal function (Fig. 14.1a). In contrast, photodynamic therapy represents a photochemical procedure [14]: It involves first the (intravenous) administration of a target tissue localizing a photosensitizing agent, followed by activation of the photosensitizer in the target tissue with a light of a wavelength that is specific for absorption by the photosensitizing agent. Both steps are a precondition for the photosensitized reactions in the target tissue and are depicted in Fig. 14.2. While these photosensitizing reactions do not require any light doses with

thermal or mechanical effects, the involvement of oxygen in the target tissue is essential. Therefore, compared to the findings after laser coagulation of a CNV, PDT does not reveal any signs that would be visible within the area of the CNV immediately after the treatment procedure, when performed with low light doses in a therapeutic range (Fig. 14.1b). The preconditions necessary for PDT comprise the following:

(Intravenously applied) photosensitizer

Light of a wavelength specific for the absorption by the photosensitizer

Oxygen!

Non-thermal and photochemical reaction

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II 14

under investigation. Nevertheless, verteporfin is the only photosensitizer currently approved for clinical use in clinical ophthalmology.

14.3.1 Characteristics

Verteporfin, benzoporphyrine derivative monoacid ring A (BPD-MA), is a second generation porphyrin derivative and consists of two regioisomers, which differ only in the location of the carboxylic acd and methyl ester on the C and D rings of the chlorinetype molecule. BPD-MA consists of a reduced porphyrin cycle with a cyclohexadiene ring fused at ring A. This cyclohexadiene ring may be responsible for the high photosensitizing potency. There are two absorption peaks, at 400 nm and at 692 nm, respectively. However, in order to avoid possible light toxicity, only the absorption peak at 692 nm has relevance for therapeutic use. Light at specific wavelengths can be efficiently absorbed by verteporfin 4 – 10 times more than hematoporphyrin [50]. In addition, this peak at 692 nm is free from competition for light by

hemoglobin, which absorbs light below 600 nm [50]. It has a half-life of 5 – 6 h, a fast clearance rate and is metabolized in the liver to inactive metabolites, where the monoacid regioisomers are metabolized to a diacid. Only 4 % are cleared via kidneys. Verteporfin does not cause any significant photosensitivity of the skin 24 h after intravenous injection [49, 50].

A 10to 70-fold increased cytotoxicity toward non-adherent human cell lines (leukemia cells, human lymphocytes, mouse mastocytoma cells) was found to develop compared with hematoporphyrin [48, 49].

It is lipophil which facilitates the accumulation in cell membranes, tumor cells improving the efficacy of the photosensitizer BPD-MA. To increase the selective localization and photodynamic action in the target tissue, BPD-MA was coupled to human low-density lipoprotein, suggesting that LDL metabolism is increased in neovascular tissue and tumor cells [2, 57]. Therefore, for clinical use, verteporfin has a liposomal delivered formulation, to facilitate binding to plasma lipoproteins, enhance the phototoxic effects in the target tissue and internalize verteporfin into the target cells via LDL-receptor mediated binding [2, 57 – 59].

14.3.2 Effects of PDT in Animal Experiments

Fluorescein microscopy detected BPD-MA in the RPE and choroids 5 min after the injection, with increasing concentrations within 20 min and staining including the photoreceptor outer segments. Therefore, it is detected rapidly in the vessels of the retina and choroids, and the RPE. However, in the retina and choroid, it is detected for no longer than 2 h, confirming the fast elimination time of BPD-MA [22]. Kramer et al. [34] observed BPD-MA in the CNV within 1 – 30 min after injection of 2 mg/kg, persisting for up to 2.5 h. Fluorescence in the normal choroidal and retinal vessels occurred and faded earlier: 5 min for choroidal vessels and 20 min for retinal vessels. However, traces of fluorescence were observed in the RPE up to 24 h after infusion [34].

Experimental CNV was induced in cynomolgus monkeys following argon laser coagulation and using a laser injury model by Ryan [54]. Effective closure of the CNV demonstrated by fundus photography, fluorescein angiography and electron microscopy could be observed [38] following intravenous injection of 1 – 2 mg/kg BPD-MA for 5 min. BPD-MA was activated 1 – 81 min after completion of dye injection using a light dose of 50, 75, 100, and 150 J/ cm2 at an irradiance of 150, 300, and 600 mW/cm2, respectively. The endothelial cells of the CNV were necrotic or missing. The vessels were filled with platelets, neutrophils, erythrocytes and fibrin. The

pericytes were vacuolized. Associated damage and loss of photoreceptors was also noted. Damage to the RPE, pyknotic nuclei in the outer nuclear layer, and loss of photoreceptors was noted, while the inner retina appeared almost unchanged.

Husain et al. [25] used BPD-MA at a dose of 0.375 mg/kg, infused for 10 min (fast infusion rate) and 32 min (slow infusion rate). Irradiation was followed 32 – 105 min after beginning infusion with a fluence of 150 J/cm2 at 600 mW/cm2. CNV was closed as demonstrated by fluorescein angiography 24 h after PDT, when irradiation was performed 32 min (fast infusion rate) and 32 – 55 min (slow infusion rate) after the start of the infusion. Histological examination revealed that the choriocapillaris was closed under the CNV. Histopathologic examination 4 weeks after PDT showed that the underlying choriocapillaris was reopened and the overlying neurosensory retina had some separation of the outer segments, swelling of the outer plexiform layer and pyknosis of cells from the outer nuclear layer. Selectivity of the PDT effects to normal retina and choriocapillaris was investigated. It demonstrated some damage to the RPE and choriocapillars and some damage to the photoreceptors in all of the illuminated eyes. The neurosensory retina showed up to 40 % of pyknosis in the outer nuclear layer, when treated 30 – 40 min after start of infusion at a fast infusion rate. At a slow infusion rate and illumination within 65 min after start of infusion damage to the choriocapillaris, the RPE and disarray of the photoreceptors and up to 20 % pyknosis of the outer nuclear layer was observed, while larger choroidal vessels remained intact.

Kramer et al. [34] further investigated the dye dosimetry and optimal treatment parameters, including time of laser irradiation after dye injection, to achieve selective closure of an experimentally induced CNV in the cynomolgus monkey. Dye doses of 0.25, 0.375, 0.5 and 1 mg/kg were studied. The light parameters were kept constant (irradiance 600 mW/cm2, fluence 150 J/cm2). Closure of CNV was observed at all dye doses: The lower the dose, the shorter the time interval after the injection in which the illumination induced an occlusion of the CNV. The experiments revealed optimal treatment parameters at a dye dose of 0.375 mg/kg, which correlates approximately to 6 mg/kg body surface area, with an illumination applied at 20 – 50 min after start of infusion. Eighty-five percent of the CNVs were closed using these treatment parameters. Investigating the effects on normal structures revealed damage of the RPE and some misalignments of the photoreceptor outer segments and nuclei at all dye doses. Damage of the larger choroidal vessels or retinal vessels or significant pyknosis of the outer nuclear layer was

observed at a dose of 1 mg/kg, 0.5, and 0.375 mg/kg, when illuminated within 50 min, 20 min, and 10 min after start of bolus injection, respectively. Therefore, the selectivity of the PDT with BPD-MA to the CNV

may be reduced, when the time between illumination II 14 and start of infusion is short: Damage to retinal and

larger choroidal vessels was observed, when illumination was performed within 5 min of the infusion, because the dye concentration may be equal in the normal choroid, retinal vessels and the CNV, respectively.

The effects of PDT (0.375 mg/kg BPD-MA, fluence 150 J/cm2, irradiance 600 mW/cm2) on experimentally induced CNVs in cynomolgus monkeys were observed in the long term, when follow-up was performed for 4 and 7 weeks: CNV was closed in 71 % 4 weeks after PDT, while the damage to the normal RPE, choriocapillaris and photoreceptors histologically showed some recovery with preservation of the neurosensory retina 7 weeks after PDT [26]. These effects on CNV and normal structures have been observed with bolus injection, and infusion over 10 and 32 min. The effects of repeated treatments at 2 weekly intervals on cynomolgus monkeys have been observed using different doses of BPD-MA (6, 12, 18 mg/m2 body surface area) at a fluence of 100 J/ cm2 and an irradiance of 600 mW/cm2 20 min after administration of the drug. Damage to the normal retina and choroids was only minimal at a dose of 0.47 mg/kg (corresponding to 6 mg/m2 body surface area), while higher doses increased the risk of significant damage to normal structures [47].

14.3.3Effects of PDT in (Normal) Human Tissue

Following the findings in the animal experiments, the effects of PDT on CNVs due to age-related macular degeneration, pathologic myopia, angioid streaks and presumed ocular histoplasmosis syndrome have been investigated in a phase I/II trial as a proof of principle [39, 60, 68]. Fluorescein leakage was completely absent 1 week after PDT, and only minor leakage was found 4 weeks after PDT. Compared to the findings prior to PDT, leakage was present in the majority of patients and at least in part reduced in most patients 12 weeks after PDT, when illumination was performed 15 – 20 min after start of the infusion. Nevertheless an increase in size of the CNV was observed in some patients, particularly when light was applied 30 min after start of the infusion. Therefore, the interval between start of the infusion and illumination was reduced. Multiple treatments did not appear to have significant side effects on visual function. In this study, significant effects of PDT on the CNV were observed using light doses within a

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14 II

tion and separation from Bruch’s membrane. However, no effects of the PDT on photoreceptors, capillaries of the retina and the optic nerve and the ganglion cell layer were observed with light doses of

50J/cm2 and 100 J/cm2, respectively (Table 14.2).

14.3.4Toxic Effects and Adverse Effects of PDT with Verteporfin

One of the major side effects is the increased photosensitivity particularly of the skin as long as the photosensitizing agent is circulating in its active form in the organism [14]. The clearance and the retention

Table 14.3. Adverse effects and visual loss of 6 lines and more judged as clinically relevant observed within the TAP, VIP and VIM multicenter studies

% of eyes

TAP, 2001 VIP, 2001 VIP, 2001 VIM, 2004j

The numbers represent the percentage of eyes with adverse effects observed in the verteporfin group

a Visual disturbances included reports of abnormal vision, decreased vision and visual field defects of the verteporfin group

bTAP study group after 24 months including abnormal vision (10.2 %), decreased vision (14.4 %), and visual field defects

(6 %) of the verteporfin subgroup

cVIP study group after 24 months including abnormal vision (20 %), decreased vision (30 %), and visual field defects (15 %)

of the verteporfin subgroup

d VIP study group, CNV in pathologic myopia, after 24 months including abnormal vision (9 %), decreased vision (16 %), and visual field defects (4 %) of the verteporfin subgroup

e Visual loss of at least 4 lines within 7 days after the treatment f Percentage of the verteporfin subgroup with occult CNV in AMD including extensive subretinal exudation (0.4 %), subretinal RPE hemorrhage (1.3 %), and no obvious cause (2.6 %) g Percentage of the verteporfin subgroup with occult CNV in

AMD

h TAP study 3 of 402 patients of the verteporfin subgroup

iInjection site adverse effects include pain, edema, extravasation, inflammation, hemorrhage, hypersensitivity, discolor-

ation, and fibrosis

jNumbers are presented for the two subgroups with reduced and standard light doses of 25 J/cm2 and 50 J/cm2, respectively

time of a photosensitizer may at least in part determine the risk of phototoxic side effects on the skin [49, 50]. Using a dose of 6 mg/m2 verteporfin, no phototoxic effects on the skin were observed 24 h and

more after infusion [76, 77]. II 14 The spectrum of possible side effects after PDT

with verteporfin has been observed in several prospective, double-masked, randomized, multicenter, placebo-controlled studies [76, 77, 83, 84, 87]. Adverse effects evaluated to be clinically relevant and observed for the verteporfin subgroup of the multicenter studies are listed in Table 14.3.

Visual disturbances included reports of abnormal vision, decreased vision and visual field defects observed in 10.2 %, 14.4 % and 6 % for the verteporfin group of the TAP study, respectively [77]. They were detected more for lesions with occult CNV [83, 84] than for lesions with classic CNV [77]. An acute severe loss of visual acuity within 7 days after PDT was observed more for patients with occult CNV compared to patients with lesions consisting of predominantly classic CNV.

Allergic reactions, infusion related pain, reactions of the injection site due to infusion of verteporfin and photosensitivity of the skin may be additional systemic adverse effects observed in the multicenter studies. A severe visual loss of 6 lines and more during the complete follow-up time was observed for 18 %, 29 %, 11 % and 13 – 18 % of the verteporfin subgroup patients in the TAP study, VIP study (occult CNV), VIP study (CNV due to pathologic myopia) and VIM study, respectively.

The results of the phase I/II human trial showed an occlusion of retinal vessels using a light dose of 150 J/cm2 applied 15 min after infusion of verteporfin (6 mg/m2 body surface area) [68]. However, no effects on retinal vessels, the ganglion cell layer and photoreceptors have been observed by histopathologic studies after PDT with light doses of 100 J/cm2 and 50 J/cm2 [56, 62].

In addition, alterations of the RPE following a treatment session of PDT have been reported in several case series and prospective studies (Fig. 14.6). They have been observed particularly in young patients (females) with classic CNV and in the presence of choroidal hemangiomas [30, 61], respectively. While the pigment mottling and focal atrophy of the RPE correlated with the size of the treatment spot, the retinal function of these areas was not significantly affected. Enhanced photochemical effects on the RPE, an increased sensitivity of the RPE, focal atrophy of the RPE following occlusion of the choroid, inherent effects of the RPE and hormonal status of these patients have been discussed as possible causes of these reactions [45, 90].

14.4 Current Treatment Recommendations

The current treatment recommendations of CNV are based on experimental animal studies and on prospective multicenter studies for the treatment of lesions due to age-related macular degeneration [76, 77, 85, 86] and pathologic myopia [83 – 85]: Verteporfin is administered intravenously at a dose of 6 mg/ m2 body surface area over a period of 10 min. Five minutes after the cessation of infusion, light exposure (laser emitting light of 692 nm) with an irradiance of 600 mW/m2 is started, delivering 50 J/cm2 within 83 s. The size of the light spot should completely cover the lesion consisting of CNV, and features that can occlude the boundaries of the CNV like hemorrhages, blocked hypofluorescence due to RPE, blood or fibrosis, and serous detachments of the RPE [86].

Based on the reports about treatment of choroidal hemangioma, light exposure with a light dose of 100 J/cm2 over an interval of 166 s has been applied by the majority of authors for the treatment of angiomatous retinal lesions. Some authors performed the first PDT session with a light dose of 50 J/cm2 and observed recurrent exudation during the fol- low-up [5 – 7]. However, treatment sessions with a light dose of 100 J/cm2 have been reported to be more effective according to the resolution of exudation, regression of angiomatous lesions, stabilization of visual function and number of recurrences, respectively [5 – 7].

14.5Verteporfin in Retinal Vascular Disease

The positive effects of PDT with verteporfin in the treatment of CNV of various causes have stimulated trials for the treatment of retinal disorders. However, most of these trials represent at least in part prospective case series, while the incidence of most of these diseases is low compared to the incidence of exudative AMD.

Retinal capillary hemangioma

Vasoproliferative tumor

Parafoveal teleangiectasis

14.5.1 Retinal Capillary Hemangioma

14.5.1.1 Characteristics

Retinal capillary hemangiomas (RCH) may occur as a solitary tumor or as the most frequent and earliest manifestation of the systemic von Hippel-Lin- dau (VHL) syndrome [43, 67]. Clinically, the majority of RCH are localized in the (temporal) periphery of the retina as a reddish-pink tumor (Fig. 14.7). However, a minority of the VHL gene carriers have juxtapapillary presentations of RCH. Intraretinal and subretinal exudation may result in exudative retinal detachment involving the macula, the juxtapapillary area and loss of visual acuity. In addition, tractional detachment of the retina, epiretinal membranes, hemorrhages of the vitreous

and the retina may be observed in RCH [67]. The typical dilated arterial feeder vessel and the draining retinal venous vessels may not be present and difficult to detect in smaller RCH and RCH of the optic disk, respectively. Fluorescein angiography gives rapid filling via a retinal feeder vessel in the early phases and staining with fluorescein leakage of the RCH in the late phases, respectively (Fig. 14.8).

14.5.1.2 Treatment Options

Treatment depends on the size, location and secondary complications due to the RC. It includes laser photocoagulation only of small RC with a lesion size of less than 1.5 mm in diameter [69], cryotherapy [66, 69] of small anterior localized RCA (external beam, plaque), radiotherapy [35], and vitreoretinal surgery [28]. Juxtapapillary RC

may be a therapeutic challenge, because of the high risk of causing irreversible injuries to the optic nerve, the nerve fiber layer and retinal vessels. Therefore, treatment of juxtapapillary lesions is recommended only when central retinal function may be reduced [36].

14.5.1.3 Effects of PDT on Retinal Angiomas

Treatment of RCA with PDT has been reported in small case series with RC [1, 5, 6, 51, 74]. PDT may be a treatment option particularly for RCA with a peripheral localization. The majority of authors have used a light dose of 100 J/cm2 5 min after intravenous administration of verteporfin (6 mg/kg body surface area).

Peripheral RCA

The effects of PDT on RCA of the periphery during the follow-up are shown in Figs. 14.8 – 14.12. The 14 II subretinal exudation clearly increased after the first treatment due to a transient decompensation of the endothelium and the vessels of the angiomatous lesion (Fig. 14.9). However, 1 week after PDT (Fig.

14.10), occlusion of the RCA documented by fluorescein angiography and resolution of the subretinal exudation was observed at least in part, which resulted in an increase in the visual acuity. Partial recanalization of the RCA may occur during the 3-month

follow-up examinations and may lead to a repetition of the PDT session. Occlusion of the RCA without significant exudation was observed 3 months after the final PDT. As shown in Fig. 14.11, some exudation was present 6 months after the first PDT, while the diameter of the RCH decreased compared to the baseline. The effects of the second PDT are depicted in Fig. 14.12, consisting of an area of hypofluorescence around the RCH and some exudation detected by fluorescein angiography.

Laser photocoagulation of small RCA has been reported to be very effective. PDT may be an alternative and effective treatment option and at least in