Selective visualization of choroidal neovascular membranes.

PURPOSE: Laser-targeted angiography has unique advantages over conventional angiography of the fundus. Its efficacy in visualizing choroidal neovascular membranes was tested in a rat model and compared to that of fluorescein angiography. METHOD: Laser-targeted angiography was performed in rats with choroidal neovascularization (CNV) by injecting heat-sensitive carboxyfluorescein liposomes intravenously, locally releasing a bolus of dye in the choroid with a weak laser pulse, and recording advancement of the bolus on a video camera. Conventional fluorescein angiography also was performed. RESULTS: Laser-targeted angiography revealed CNV as an abnormal pattern of brightly fluorescent vessels. The flow pattern of the bolus and histology, performed in some cases, confirmed the choroidal nature of the vessels. The angiographic visualization was not dependent on dye leakage through the vessels or staining of their walls. Laser-targeted angiography also provided visualization of new vessels that could not be diagnosed by fluorescein angiography. It demonstrated that blood flow was typically more sluggish in CNV than in normal choriocapillaris. Fluorescein angiography failed to demonstrate flow dynamics in all cases of CNV. CONCLUSIONS: This study, in an animal model of CNV, shows that laser-targeted angiography demonstrates CNV and its flow dynamics in a manner not provided by conventional fluorescein angiography. It holds clinical promise as a method to delineate CNV considered difficult or impossible to detect by fluorescein angiography. The method also may permit selective photocoagulation of feeding vessels in the choroid, thereby limiting damage to the overlying retina.

Noninvasive visualization of the choriocapillaris and its dynamic filling.

PURPOSE: The choroidal microvasculature and its circulation are inadequately assessed by presently available techniques. Laser-targeted delivery was applied to generate local, repetitive angiograms of the choriocapillaris in primates. METHODS: Carboxyfluorescein was encapsulated in heat-sensitive liposomes and injected intravenously in monkeys. The liposome contents were then released locally in the choroid by application of a short heat pulse provided by an infrared laser. The bolus of dye spread rapidly downstream from the underlying arterioles into clusters of lobules. Video angiograms were generated with excitation illumination provided by an argon laser. RESULTS: Laser-targeted delivery choroidal angiography performed on three monkeys indicated that the fluorescence was emitted mainly from the choriocapillaris. Clusters of irregular shape with well-defined margins were observed. Adjacent arteries typically supplied separate clusters that fit together like a jigsaw puzzle. The dynamic filling and emptying patterns, recorded at video rate, revealed that macular lobules were filled by a central arteriole and drained by a venous annulus. The average dye transit time through a lobule (n = 10) was 118 +/- 26 msec (mean +/- SD), and the dye transit velocity was 2.53 +/- 0.55 mm/sec. CONCLUSIONS: This study clearly documents the segmental nature of the primate choroidal microvasculature. It also illustrates that choroidal angiography by laser-targeted dye delivery provides information useful for studying the response of the choriocapillaris to physiological and pathologic changes.

Noninvasive visualization of blood flow in the choriocapillaris of the rat.

PURPOSE: The rat has been used to generate models of various eye diseases. However, methods to study the choriocapillaris noninvasively have been inadequate in this species. Laser-targeted angiography was applied to generate local, repetitive angiograms of the choriocapillaris in the rat and to assess the similarity between the choriocapillaris of the rat and that of the subhuman primate. METHODS: Carboxyfluorescein was encapsulated in heat-sensitive liposomes and injected intravenously in rats. The liposome contents were then released locally in the choroid by the application of a short, noncoagulating heat pulse provided by an argon laser. Videoangiograms of the downstream spread of the bolus of dye were generated with excitation illumination provided by another output from the argon laser. RESULTS: Laser-targeted angiography demonstrated that the bolus of dye perfused the choriocapillaris. Clusters of choriocapillaris lobules were observed and appeared similar to those described in the primate. Dynamic filling and emptying patterns also were similar to those of the primate. Lobules were filled by a central arteriole and drained by a venous annulus. CONCLUSIONS: This study demonstrates the feasibility of noninvasively studying the choriocapillaris of the living rat using the technique of laser-targeted angiography. It demonstrates as well the similarity between the rat and the primate choriocapillaris, thus indicating that the rat is an acceptable and convenient model for the study of physiological and pathologic changes in the choroidal vasculature.

Feasibility of laser-targeted photoocclusion of the choriocapillary layer in rats.

PURPOSE: A new method, laser-targeted photoocclusion, was developed to occlude choroidal neovascularization while minimizing damage to the overlying retina. The ability to occlude normal choriocapillary layer in rats was evaluated as a first test of the feasibility of treating choroidal neovascularization with this method. METHOD: A photosensitive agent, aluminum phthalocyanine tetrasulfonate, encapsulated in heat-sensitive liposomes, was administered intravenously along with carboxyfluorescein liposomes. A low-power argon laser (retinal power density of 5.7 W/cm2) locally released a photosensitizer bolus, monitored by the simultaneous release of carboxyfluorescein. A diode laser (operating at 675 nm with a retinal power density of 0.27 W/cm2) activated the photosensitizer with its release. RESULTS: Vessels in the choriocapillary layer were occluded at day 3 after laser treatment and remained unchanged during the 30-day follow-up. Larger choroidal vessels and retinal capillaries remained perfused. Control experiments excluded possible effects of heat or activation of free photosensitizer. Pilot histologic studies showed no damage to the retinal pigment epithelium. CONCLUSIONS: Laser-targeted photoocclusion caused selective occlusion of normal choriocapillaries while sparing overlying retinal pigment epithelium and retinal vessels. The method has potential as a treatment of choroidal neovascularization that may minimize iatrogenic loss of vision.

Feasibility of laser targeted photo-occlusion of ocular vessels.

AIMS/BACKGROUND: Neovascularisation occurs in many major ocular diseases such as diabetes, age-related macular degeneration, and sickle cell disease. Laser photocoagulation is typically used to obliterate the vessels but it also causes severe damage to adjacent normal tissues. This is a very significant limitation especially in the treatment of choroidal neovascularisation which often covers large areas of the posterior pole and the fovea. A method, laser targeted delivery, has been developed capable of releasing drugs locally and non-invasively in the choroidal or retinal vasculature. This method could be used to target a photo-sensitiser to neovascular membranes and cause their selective occlusion by irradiating them. The targeting properties of the method promise to yield a treatment for neovascularisation that does not damage adjacent tissues and thus preserves vision. The purpose of the present study was to test the feasibility of occluding ocular vessels with this method. METHOD: The iris vessels of the albino rat were chosen because the treatment could be assessed unequivocally and followed with time. Aluminium phthalocyanine tetrasulphonate was encapsulated in heat sensitive liposomes and administered systemically. The iris vessels were irradiated with a yellow laser to raise their temperature to 41 degrees C, cause a phase transition in the liposomes and thereby locally release the photosensitiser. The laser was also used to excite the released photosensitiser and cause occlusion. The effect was monitored immediately and for 8 months thereafter. Controls for the effect of the laser and the unencapsulated drug were conducted. RESULTS: The results demonstrated that occlusion can be achieved and sustained for the period of follow up. The controls showed that the effect was not due to heat or to the activation of the low dose of free drug. CONCLUSION: These preliminary findings indicate that laser targeted photo-occlusion is a promising new method for the treatment of neovascularisation.

Systemic toxicology and laser safety of laser targeted angiography with heat sensitive liposomes.

Angiography is currently limited by its lack of local and tissue specificity. The dye rapidly fills both the retinal and choroidal vessels and leaks out of the vessels thus hampering visualization of small vascular beds such as occult choroidal neovascularization. We have developed a method of laser targeted delivery based on encapsulating the dye in heat sensitive liposomes, administering the liposomes intravenously and causing them to release their content by noninvasively warming the target tissue with a laser pulse delivered through the pupil. The local release yields a bright fluorescent bolus which selectively highlights retinal or choroidal vessels. A preliminary investigation of the potential side effects of the method is presented. In rats the systemic toxicity of carboxyfluorescein-entrapped liposomes was compared with that of the free dye. No significant difference was found between the two. Non-human primates exposed to repeated laser targeted angiography were monitored over time and no significant side effects were observed. The safety of the laser exposures was assessed by conventional fluorescein angiography and histopathology. Choroidal laser targeted angiography was achieved without damage. Retinal laser targeted angiography was accompanied by mild and local damage in an area remote from the fovea. The study indicates that laser targeted choroidal angiography can be performed safely and holds promise for diseases such as age related macular degeneration with occult choroidal neovascularization. Further improvements are needed to ensure that no side effects accompany retinal laser targeted angiography.

Management of bleb leaks after glaucoma filtering surgery. Use of autologous fibrin tissue glue as an alternative.

PURPOSE: To study the nature of bleb leaks after contemporary glaucoma filtering surgery as well as to evaluate various treatment modalities, including autologous fibrin tissue glue (AFTG) prepared in a modified manner. METHODS: Patients who presented to a Glaucoma Service during a 1-year period with a postoperative bleb leak were studied. Evaluation of various treatment modalities, including AFTG, was performed. RESULTS: Thirty-five episodes of bleb leaks were encountered in 25 eyes of 22 patients in a 1-year period. There was no statistically significant association between late or early leaks and the age or the race of the patient, previous eye surgery, or the use of antimetabolites at the time of filtering surgery. Eleven (31.4%) of the leaks were refractory to nonsurgical treatment modalities, 8 or them being of the late type. Successful healing of the leaks was obtained in 9 of the 12 episodes in which AFTG was used. However, there were no statistically significant differences between AFTG and the other treatment modalities. CONCLUSION: Bleb leaks are a common complication of contemporary glaucoma filtering surgery. Various nonsurgical and surgical modalities can be used in the treatment. In early as well as late bleb leaks, AFTG offers an alternative nonsurgical treatment and is at least as efficacious and may, in some ways, be superior to other nonsurgical modalities of treatment.