Atrophy in Neovascular Age-Related Macular Degeneration: Age-Related Eye Disease Study 2 Report Number 15.

PURPOSE: To identify the development and progression of macular retinal pigment epithelial atrophy in eyes with neovascular (CNV) age-related macular degeneration (AMD) and to correlate with visual acuity (VA). DESIGN: Cohort study. PARTICIPANTS: Age-Related Eye Disease Study 2 (AREDS2) participants with intermediate AMD enrolled in a randomized controlled clinical trial of oral supplements. Analyses were conducted in the subset of AREDS2 participants who were also enrolled in the fundus autofluorescence ancillary (FAF) ancillary study. METHODS: Color photographs and FAF images were evaluated in eyes that developed CNV. Presence of geographic atrophy (GA) prior to the incidence of CNV and the development of macular atrophy following incident CNV were assessed. Areas of hypoautofluorescence representing atrophy were measured for area and macular involvement. Enlargement rate of atrophy and change in visual acuity over time were analyzed. MAIN OUTCOME MEASURES: incidence and enlargement rate of atrophy and VA changes in eyes with incident CNV. RESULTS: Incident CNV developed in 334 (9.2%) of eyes evaluated in the AREDS2 FAF substudy. Of these, 40% had macular atrophy at incidence of CNV with half of these attributable to pre-existing GA. Atrophy developed in 14.7 % of eyes over 4 years of follow-up. Mean area of atrophy was largest in eyes with pre-existing GA and CNV (5.17 mm2, p<0.001), and atrophy involved the center of the macula in > 65% of eyes. Mean VA letter score at the annual visit in which CNV was documented was similar in the three groups with atrophy; eyes with CNV and pre-existing GA, incident atrophy at the first visit with CNV, and atrophy during follow up (60 letters). Enlargement rate of atrophy was also similar in eyes in the three groups (1.23 - 1.86 mm2, p = 0.47). Eyes with macular atrophy lost more visual acuity compared to eyes without atrophy, particularly after 2 years of follow-up (-10.9 vs. - 3.6 letters, p = 0.07). CONCLUSION: Atrophy is commonly seen in neovascular AMD and often can be attributed to pre-existing GA. Macular atrophy and GA appear to be a continuum of the same disease process and are both associated with poor vision.

Microvascular retinopathy in the Zucker diabetic fatty rat.

PURPOSE: To determine if quantifiable morphometric signs of retinopathy occur in the Zucker diabetic fatty rat (ZDF/Gmi-fa, formerly designated ZDF/Drt), a partially inbred strain in which the genetic propensity for diabetes is only expressed in obese males. METHODS: Retired diabetic (ZDF/Gmi-fa) and control lean Zucker (fa/+) breeder rats were examined for quantifiable evidence of microvascular changes of the retinal capillaries by gross examination, trypsin digestion of retinal vessels, and transmission electron microscopy. RESULTS: Gross examination of retinas and trypsin digestion of capillaries revealed no differences. Quantitative assessment of capillary cell nuclear density showed that diabetic retinas were hypercellular compared to lean rats (3.888 +/- 0.041 versus 3.304 +/- 0.046 nuclei per 100 microns (mean +/- SE), P = 0.0042). Transmission electron microscopic analysis of retinal capillary basement membrane thickness demonstrated thicker measurements in diabetic animals (mean thickness 21% greater in diabetic rats, P = 0.0307). CONCLUSIONS: This model may be useful for pharmacologic intervention studies because it is naturally and severely non-insulin-dependent diabetic, there are quantifiable retinal vascular changes, and same-sex litter mates can be used as controls.

HRP/trypsin technique for studies of the retinal vasculature.

The HRP/trypsin technique is a new histologic method for the light microscopic study of the retinal blood vessels. A two-stage procedure, the first step results in a retinal whole amount preparation which permits visualization of the three-dimensional architecture of perfused vessels and their relationship within the retina. This allows analysis of gross vessel morphology and differentiation of deep and superficial vascular beds. The second step involves digesting the whole mount with trypsin and staining with hematoxylin. This permits detailed evaluation of the density of retinal capillary endothelial cells and pericytes, recognition of basement membrane ghosts, microaneurysms, and other intraretinal microvascular abnormalities, with intravascular horseradish peroxidase as a perfusion marker. This technique has been employed with success in studies of the retinal vasculature in both normal and RCS rat retinas, and in a monkey model of branch retinal vein occlusion.

Inhibition of intraocular neovascularization caused by retinal ischemia in pigs by PKCbeta inhibition with LY333531.

OBJECTIVE: The authors tested the antiangiogenic properties of an orally administered protein kinase-Cbeta inhibitor, LY333531, in a pig model of preretinal neovascularization caused by retinal branch vein occlusion to determine the effectiveness of this therapy in preventing intraocular neovascularization from an ischemic stimulus. METHODS: In 20 eyes of 10 pigs, branch retinal vein occlusions were created in a standardized manner using photodynamic thrombosis with rose bengal dye and thermal burns from an argon laser with green light. Five animals received 1 mg/kg LY333531 daily in two oral doses, and five animals were untreated. The eyes were followed clinically for 12 weeks with ophthalmoscopy, fundus photography, and fluorescein angiography. A standardized grading system permitted masked assessment of disc proliferations using stereo fundus photographs. After the pigs were killed, all neovascularization was confirmed histopathologically in a masked fashion and a final grade was assigned to each eye. The Mann-Whitney test was used for statistical analysis of the median values of the unpaired data between the two eyes of each animal (data were rounded up). RESULTS: Significant inhibition of neovascularization was observed in eyes from animals treated with the study drug (P = 0.03). Although some of the treated eyes demonstrated no clinically evident new vessels, histopathologic and photographic analysis demonstrated fine new vessels on the optic disc in all eyes (mean grade 1.9). All the untreated eyes developed clinically evident neovascularization (mean grade 3.1). The oral drug was well tolerated, and no side effects were documented. CONCLUSIONS: A specific protein kinase-Cbeta inhibitor, LY333531, effectively inhibited preretinal and optic nerve head neovascularization in the pig model of branch retinal vein occlusion. This was consistent with the known pathways of signal transduction by growth factors in activated cells and suggested that inhibition of this key regulatory isozyme is effective in the treatment of ischemia-mediated neovascular diseases.

Transpupillary thermotherapy for subfoveal occult choroidal neovascularization: effect on ocular perfusion.

PURPOSE: To perform a descriptive analysis of the effects on ocular blood flow of transpupillary thermotherapy (TTT) for occult subfoveal choroidal neovascular membranes (CNVMs) in age-related macular degeneration (AMD). METHODS: Eleven subjects with occult subfoveal CNVM due to AMD were assessed in a masked fashion by color Doppler imaging (CDI) within 24 hours before, 24 hours after, and 1 month after undergoing TTT. RESULTS: In the posterior ciliary arteries (PCAs), there were no statistically significant changes observed in the peak systolic velocity (PSV), end diastolic velocity (EDV), or resistive index (RI) at 24 hours. At 1 month, the mean EDV decreased 36% (P = 0.0105) and the mean RI increased 3.8% (P = 0.0305) in the nasal PCA. Although there was a similar trend in the temporal PCA, the differences did not reach statistical significance. In the central retinal artery (CRA), the mean PSV decreased 16% (P = 0.0137), and the mean EDV decreased 21% (P = 0.0222) at 24 hours after treatment. There were no statistically significant differences in the CRA blood flow indices at 1 month after treatment. In the ophthalmic artery, there were no statistically significant differences observed in the mean PSV, EDV, or RI at 24 hours or 1 month after treatment. CONCLUSIONS: TTT is associated with transiently decreased volumetric blood flow in the retinal circulation 24 hours after treatment. In the posterior ciliary arteries that supply the choroid, there were no changes observed at 24 hours, but at 1 month, there was a decrease in the mean EDV and an increase in the RI in the nasal and temporal PCAs, reaching statistical significance in the nasal PCA only. This study suggests that TTT could lead to alterations in choroidal blood flow, as assessed by CDI. Further study is warranted.

Flow dynamics of extrusion needle vacuuming in a closed vitrectomy system.

The dynamics of pressure, flow, and ocular volume relationships were examined with respect to extrusion needle use in simulated vitrectomy. Glass-stoppered bottles used with infusion lines with drip chambers lowered the intraocular pressure 4 to 7 inches below the fluid level in the bottle, varying with the amount of fluid in the bottle. Compared with flow rates using the regular tip needle with the steel infusion cannula, the disposable infusion cannula lowered the flow rate by about 25% and the tapered tip extrusion needle decreased outflow by 40% to 50%. Tracer dilution rates were decreased by the use of the disposable infusion port or the aphakic model eye; however, 2 minutes of infusion at a 30-inch bottle height dilution was still sufficient to wash out the tracer to less than 5% of the original concentration.

Preretinal and optic nerve head neovascularization induced by photodynamic venous thrombosis in domestic pigs.

OBJECTIVE: To develop a reliable model of ischemic preretinal and optic nerve head neovascularization in young male domestic pigs. METHODS: Using laser-induced branch retinal venous obstruction assisted by photodynamic thrombosis with rose bengal, 15 of 15 treated eyes developed neovascularization of the optic nerve head and retina. All cases of neovascularization were followed up clinically for up to 12 weeks. RESULTS: Clinical, fluorescein angiographic, and histopathologic features were consistent with neovascular proliferation into the vitreous. CONCLUSIONS: Further evaluation of the long-term natural history, role of the degree of ischemia, and the effect of interventions for various types of ischemic retinopathy (eg, panretinal photocoagulation) is warranted. This model is simple and relatively inexpensive and allows easy clinical assessment.

Intravitreal triamcinolone acetonide inhibits choroidal neovascularization in a laser-treated rat model.

OBJECTIVE: To determine if intravitreal triamcinolone acetonide (TAAC) inhibits experimental choroidal neovascular membranes induced by laser trauma in a rat model. METHODS: Nineteen anesthetized male Brown Norway rats received a series of 8 krypton red laser lesions per eye (647 nm, 0.05 seconds, 50 microm, and 150 mW in 17 rats, and 200 mW in 2 rats). One eye received an intravitreal injection of triamcinolone acetonide (20 microL, 0.8 mg) and the other eye received an injection of isotonic sodium chloride solution. Fundus and fluorescein angiography examinations occurred just before euthanasia and tissue processing for histopathology on day(s) 0, 1, 3, 7, 14, 21, 28, and 35. RESULTS: From the control eyes that underwent photocoagulation at 150 mW, 57 discrete lesions with definitive fibrovascular proliferations were observed at 21, 28, and 35 days, arising from a total of 72 spots placed (79% yield). From the control eyes that underwent photocoagulation at 200 mW, 11 discrete lesions with definitive fibrovascular proliferations were observed at 28 days, arising from a total of 16 spots placed (69% yield). In the TAAC-treated group, no fibrovascular proliferations were observed in the 72 lesions and in the 16 lesions created with 150 mW and 200 mW, respectively. CONCLUSION: Intravitreal TAAC is a potent inhibitor of fibrovascular proliferations in a rat model of choroidal neovascular membranes induced by laser trauma. CLINICAL RELEVANCE: This study corroborates previous investigations that propose TAAC as a potential treatment for choroidal neovascular membranes in humans.

Age-related macular degeneration: a review of experimental treatments.

Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in the USA. Laser photocoagulation of choroidal neovascular membranes (CNVMs) in exudative AMD is currently the only well-studied and widely accepted treatment modality. It is beneficial for only a small minority of patients who show well-demarcated "classic" CNVMs, and it destroys normal retinal tissue, creates a scotoma, and is associated with an unacceptably high CNVM persistence and recurrence rate. Consequently, investigators have attempted to develop new modalities for treatment of CNVMs. These treatment modalities can be grouped into four major categories: photodynamic therapy; pharmacologic inhibition of CNVM formation with antiangiogenic agents; surgical intervention, including excision of subfoveal CNVMs; and radiation therapy. All of these experimental treatment modalities are directed toward destroyiing CNVMs, the end result of the exudative process, and all have limitations. The ideal treatment of the future must be based on the pathogenesis of the disease at a stage well before CNVMs develop. Investigations in nonexudative AMD are currently focusing on several major areas. Epidemiologic factors, such as genetics, sunlight, and nutrition, are being evaluated in several large studies, including the Age-Related Eye Disease Study, with the possibility of ultimately limiting the risk of AMD through behavior modification. Laser treatment of drusen is being evaluated as a means of limiting the risk of CNVM formation, although mixed results have been reported in the small number of studies to date. Choroidal perfusion abnormalities have been described in AMD, and some investigators postulate that altering blood flow may limit the risk of CNVM formation. No perfusion-treatment trials have been completed to date.

Phototoxic reactions caused by sodium fluorescein.

PURPOSE: To report three cases of phototoxic reactions to intravenous fluorescein for retinal angiography and to describe provocative testing in a volunteer. METHODS: Three patients with phototoxic reactions were interviewed, and one volunteer underwent a controlled challenge test by applying a potent sunscreen and exposing skin areas to direct sunlight before and after fluorescein administration. RESULTS: All patients experienced marked cutaneous erythema, edema, and pain to sun-exposed areas within 1 hour of exposure. The reaction faded during a variable period of time, and one case resulted in mild epidermal desquamation and prolonged discomfort. We noted minimal skin changes in the volunteer who was exposed to the sun before fluorescein administration; however, marked blanching erythema and pain were noted after fluorescein administration and sunlight. CONCLUSIONS: Consistent with its in vitro properties as a photodynamic dye, fluorescein may rarely act as a phototoxic agent in humans at doses employed for fluorescein angiography.

Iatrogenic central retinal vein occlusion and hyperviscosity associated with high-dose intravenous immunoglobulin administration.

PURPOSE: To describe a patient with iatrogenically induced central retinal vein occlusions secondary to serum hyperviscosity from intravenous immunoglobulin administration. METHOD: Case report. RESULTS: The patient developed bilateral central retinal vein occlusions in association with high-dose intravenous immunoglobulins. The central retinal vein occlusions resolved when the immunoglobulins were withheld and serum hyperviscosity decreased. CONCLUSION: Administration of high-dose intravenous immunoglobulins can be associated with hyperviscosity syndrome manifested by central retinal vein occlusion.

Comparison of intraocular to plasma HIV-1 viral burden in patients with cytomegalovirus retinitis.

PURPOSE: To determine the relationship between plasma and intraocular human immunodeficiency virus-1 (HIV-1) viral loads in 12 consecutive patients undergoing ganciclovir implant surgery for cytomegalovirus (CMV) retinitis. METHODS: Aqueous and vitreous specimens were assayed for HIV-1 viral load by polymerase chain reaction analysis (Roche Amplicor HIV Monitor; Roche Diagnostics Systems, Inc, Branchburg, New Jersey). RESULTS: It was possible to quantitatively assay HIV-1 burden in intraocular fluids using polymerase chain reaction analysis. In general, patients with plasma viral loads less than 250,000 copies/ml had undetectable (<200 copies/ml) HIV-1 in their aqueous and vitreous. CONCLUSIONS: It is likely that intraocular viral levels have several determinants in addition to plasma viral loads, with which they only partially correlate.

Color Doppler imaging discloses reduced ocular blood flow velocities in nonexudative age-related macular degeneration.

PURPOSE: To study ocular perfusion defects in age-related macular degeneration. METHODS: Twenty-five subjects with nonexudative age-related macular degeneration were compared with 25 age-matched control subjects in studies of flow velocities in several retrobulbar vessels. Color Doppler imaging, which was performed by an examiner who was masked to the subjects' assignment to the control or age-related macular degeneration group, measured peak systolic and end diastolic velocity in the ophthalmic, central retinal, and nasal and temporal posterior ciliary arteries of one eye. A resistive index was calculated from the peak systolic and end diastolic velocity. RESULTS: Subjects with nonexudative age-related macular degeneration showed a consistent trend toward lower peak systolic and end-diastolic velocities in the posterior ciliary arteries. For example, in the nasal posterior ciliary artery, the mean end diastolic velocity measured 1.45 +/- 0.34 cm per sec in the age-related macular degeneration group compared with 1.96 +/- 0.66 cm per sec in the control group, yielding a 26% decrease in the age-related macular degeneration group, which represented the largest difference and was highly statistically significant (P = .0012). The resistive index was not significantly altered in the nasal or temporal posterior ciliary artery. Subjects with nonexudative age-related macular degeneration did not differ from control subjects in peak systolic velocity, end diastolic velocity, or resistive index in the ophthalmic artery. In the central retinal artery, the end diastolic velocity was lower (1.37 +/- 1.95 cm per sec vs 1.95 +/- 0.66 cm per sec), whereas the resistive index was higher (0.83 +/- 0.05 vs 0.76 +/- 0.06 cm per sec), in the age-related macular degeneration group; these results were highly statistically significant (P = .0007 and P < .0001, respectively). CONCLUSIONS: Retrobulbar vascular changes in nonexudative age-related macular degeneration subjects include reduced flow velocities in the nasal and temporal posterior ciliary arteries. The reduced peak systolic velocity, combined with the reduced end diastolic velocity at a constant resistive index, seen in nonexudative age-related macular degeneration, is consistent with reduced bulk flow in these vessels, suggesting that choroidal perfusion is abnormal in this form of age-related macular degeneration. The changes in the central retinal artery suggest there may be a more generalized perfusion abnormality beyond the choroid in patients with age-related macular degeneration or that the central retinal artery exhibits a secondary autoregulatory response to a primary change elsewhere.

Intravitreal triamcinolone in subfoveal recurrence of choroidal neovascularisation after laser treatment in macular degeneration.

BACKGROUND: Laser treatment of extrafoveal well delineated choroidal neovascularisation in exudative age related macular degeneration has a high rate of failure with subsequent severe vision loss from subfoveal involvement. Laser treatment may limit scotoma size, but is unpalatable because of early persistent vision loss. Intravitreal triamacinolone injection may be an acceptable alternative therapy in such disparate cases. METHODS: 14 consecutive patients with recurrent neovascularisation were treated with a single 4.0 mg injection of triamacinolone and followed for up to 1 year. Visual results were compared with published data from the Macular Photocoagulation Study of recurrent neovascularisation. RESULTS: Mean visual acuity remained stable at about 20/200 throughout the study period in the treated patients. This is comparable to the outcomes in the Macular Photocoagulation Study for laser retreated patients, and better than the observation group. CONCLUSIONS: Intravitreal triamcinolone may be an acceptable treatment of subfoveal recurrent neovascularisation while avoiding early persistent vision loss from laser retreatment.

Intravitreal triamcinolone with photodynamic therapy for subfoveal choroidal neovascularisation in age related macular degeneration.

AIMS: To report the effects of intravitreal triamcinolone acetonide (iTAAC) injections as an adjunctive treatment to photodynamic therapy (PDT) with verteporfin for new subfoveal choroidal neovascularisation (CNV) in age related macular degeneration (AMD). METHODS: We retrospectively reviewed the records of all AMD patients who had iTAAC within 6 weeks of their first PDT and had a follow up of one year or longer. The proportion of eyes after one year follow up that lost or gained >or=15 and >or=30 ETDRS letters, baseline and one year lesion greatest linear dimension (GLD), number of PDTs, and side effects were assessed. RESULTS: Fourteen patients were evaluated. Eleven received one initial combined treatment and three received an additional combined treatment after 6 months. Median follow up was 18 months (range 12 to 25 months). Overall, 7% gained >or=30 letters, 50% maintained stable vision, 14% lost 15-29 letters, and 29% lost >or=30 letters. Overall, mean GLD increased from 2580 (SD 1088) microm to 3946 (SD 1503) micro m (p = 0.01). The mean number of PDTs during the first year was 2.57. Side effects were mild intraocular pressure elevation in 28.5% and cataract progression in 50% of phakic eyes. CONCLUSIONS: iTAAC with PDT in AMD was found to be relatively safe and had reasonable results for lesions with some classic component.

Altered retrobulbar vascular reactivity in early diabetic retinopathy.

AIM/BACKGROUND: In diabetic eye disease the factors leading to compromised circulation and the resulting loss of visual function are poorly understood. Although retinal circulation has been widely investigated, it accounts for only a fraction of total eye blood flow. Blood flow was investigated in the larger vessels feeding the eye in patients with early diabetic retinopathy. METHODS: Eleven patients with early diabetes with minimal or no retinopathy and 11 healthy controls were evaluated for retrobulbar blood flow velocity using colour Doppler imaging for the ophthalmic and central retinal arteries. Patients and subjects were tested while breathing room air and again under conditions of isocapnic hyperoxia. RESULTS: Hyperoxia induced a significant change in the central retinal artery end diastolic velocity (EDV) (p = 0.008) and resistance index (RI) (p = 0.032) in normal subjects, but not in diabetic patients. Consequently, during hyperoxia, the diabetic patients were significantly higher for EDV (p = 0.006) and significantly lower for RI (p = 0.002) compared with normal controls. Hyperoxia caused no significant change in either group in the ophthalmic artery; nevertheless, under isocapnic hyperoxia conditions the diabetic patients had lower peak systolic velocity (p = 0.05) and lower RI (p = 0.05) than normal subjects. CONCLUSIONS: Imposition of isocapnic hyperoxia produces significant differences in the ophthalmic and central retinal artery blood flow velocities in diabetic patients with early disease when compared with normal subjects. These results demonstrate that diabetic patients with minimal or no retinopathy suffer from irregular ocular vascular function in the major vessels feeding the eye.

Hyperoxia improves contrast sensitivity in early diabetic retinopathy.

AIM: The cause of vascular and visual pathology in diabetic retinopathy remains unknown. If retinal hypoxia plays a role, then early in the course of diabetes 100% oxygen breathing should normalise both contrast sensitivity and retinal blood flow. METHODS: This hypothesis was tested in 12 diabetic patients with minimal retinopathy who, none the less, exhibited reduced contrast sensitivity (p = 0.003 versus 12 age and sex-matched controls) and prolonged retinal arteriovenous dye transit (p = 0.0001 versus controls). RESULTS: Isocapnic hyperoxia failed to alter contrast sensitivity in controls, while it significantly improved contrast sensitivity in patients (at 12 cpd; p = 0.042) to levels indistinguishable from normal. Individual improvement in contrast sensitivity correlated positively with the severity of the initial defect (r = +0.84, p = 0.0008). Hyperoxia also had haemodynamic effects; it slowed retinal arteriovenous passage of fluorescein dye in controls, but did not further slow this transit time in patients. CONCLUSIONS: These results demonstrate the reversibility of early contrast sensitivity deficits in diabetes mellitus, and support the hypothesis that factors linked to tissue hypoxia initiate both visual and vascular dysfunction in diabetic retinopathy.

Choroidal neovascular membrane inhibition in a laser treated rat model with intraocular sustained release triamcinolone acetonide microimplants.

AIM: To determine if intravitreal microimplants containing triamcinolone acetonide (TAAC) inhibit experimental fibrovascular proliferation (FVP) induced by laser trauma in a rat as a model of choroidal neovascular membranes (CNVMs). METHODS: 20 anaesthetised male Brown Norway rats received a series of eight krypton red laser lesions per eye (647 nm, 0.05 s, 50 micro m, 150 mW). Three types of sterilised TAAC microimplant designs were evaluated: implant A consisting of 8.62% TAAC/20% polyvinyl alcohol (PVA) matrix (by dry weight); implant B consisting of 3.62% TAAC/20% PVA matrix; and implant C consisting of a dual 8.62% TAAC/20% PVA matrix design combined with a central core (0.5 mm) of compressed TAAC to extend the implant release time. For each animal studied, one eye received one of the three aforementioned TAAC implant designs, while the fellow eye received a control implant consisting of PVA but without TAAC. The animals were sacrificed at day 35 and ocular tissues were processed for histological analysis. Serial histological specimens were methodically assessed in a masked fashion to analyse each laser lesion for the presence or absence of FVP; maximum FVP thickness for each lesion was measured from the choriocapillaris. RESULTS: All three types of TAAC implants inhibited FVP relative to controls in a statistically significant fashion. In the eyes that received implant A (n = 8), the mean thickness of the recovered lesions (n = 36) measured 32 (SD 22) micro m, compared to 52 (30) micro m (p <0.005) for the recovered lesions (n = 40) from the fellow control eyes. In the eyes that received implant B (n = 6), the mean thickness of the recovered lesions (n = 31) measured 28 (15) micro m, compared to 50 (29) micro m (p <0.001) for the lesions (n = 19) recovered from the fellow control eyes. In the eyes that received implant C (n = 6), the mean thickness of the recovered lesions (n = 21) measured 39 (24) micro m, compared to 65 (30) micro m (p <0.001) for the lesions (n = 39) recovered from the fellow control eyes. CONCLUSIONS: All three of the tested TAAC microimplant designs produced potent inhibition of FVP in a rat model of CNVMs. There were no differences in inhibition of FVP between the three different types of implants evaluated. This study provides evidence that: (1) corroborates previous investigations that propose TAAC as a potential treatment for CNVMs in humans, and (2) demonstrates TAAC can be effectively delivered via long acting sustained release intraocular microimplants. It should be noted, however, that the FVP observed in this rat laser trauma may not reflect the CNVM observed in human with exudative age related macular degeneration (AMD).

Changing therapeutic paradigms in CMV retinitis in AIDS.

Cytomegalovirus (CMV) retinitis is a common ocular complication of immunosuppression. The management of CMV retinitis has been continuously evolving over the last decade. The mainstay of therapy remains ganciclovir and foscarnet. However, increasing resistance and ongoing toxicities to these agents remain a challenge. Additional frequently utilised agents include cidofovir and fomivirsen. The advent of highly active antiretroviral therapy (HAART) has allowed the restoration of immunocompetency to many patients previously challenged by CMV infection. In some circumstances, HAART has even eliminated the need for ongoing antiviral therapy. This paper reviews the current treatment modalities, including their toxicities and dosing recommendations.

Potential therapeutic application of antisense oligonucleotides in the treatment of ocular diseases.

Antisense oligonucleotides are a class of compounds being developed as therapeutic agents for many types of diseases. Although still relatively early in the clinical characterisation, the power of this technology lies in the ability to utilise genetic information and the known molecular mechanisms of disease to foster efficient and rational drug design. Consideration of novel approaches to treating ocular diseases is of interest because there are many ocular diseases with no satisfactory treatments. The recent availability of animal models of many ocular diseases provides the opportunity to use antisense oligonucleotides to understand the mechanisms of disease pathology and to potentially intervene therapeutically in ocular disease. There are already a number of examples where antisense oligonucleotides have been applied to the study of ocular physiology and disease and there is an antisense oligonucleotide approved for the treatment of cytomegalovirus (CMV) retinitis. We summarise current research in this area and highlight the properties of these compounds that are favourable for use as ocular therapeutics.