Five-year follow-up of fundus autofluorescence and retinal sensitivity in the fellow eye in exudative age-related macular degeneration in Japan.

PURPOSE: To assess the 5-year change in abnormal fundus autofluorescence (FAF) patterns and retinal sensitivity in the fellow eye of Japanese patients with unilateral exudative age-related macular degeneration (AMD). METHODS: Patients with unilateral exudative AMD who developed abnormal FAF in the fellow eyes were enrolled. FAF imaging and microperimetry were performed at baseline and follow-ups. FAF findings were classified into 8 patterns based on the International Fundus Autofluorescence Classification Group to assess retinal sensitivity. Forty-five points covering the central 12 degrees on microperimetry were superimposed onto the FAF images. Each point was classified depending on the distance from the abnormal FAF. "Close" was defined as the portion within 1 degree from the border of any abnormal FAF, and "Distant" was defined as the portion over 1 degree from the border of abnormal FAF. To investigate the association between the retinal sensitivity and distance from the abnormal FAF, hierarchical linear mixed-effect models were used with the distance, time and time squared from baseline (months), and angle (degrees) as fixed effects. Differences among patients, eyes, and test point locations were considered successively nested random effects. RESULTS: We studied 66 fellow eyes with abnormal FAF. Twenty-seven eyes were followed-up during the 5 years. In the 13 of 27 eyes (48%), the abnormal FAF patterns had changed during the 5 years. We found retinal sensitivity was associated significantly with the distance from the abnormal FAF ("Distant": p<0.001, time2 from baseline: p<0.001, angle: p<0.001). The mean retinal sensitivity of the "Close" tended to deteriorate after the third year and eventually showed the similar sensitivity as the portion within the abnormal FAF. CONCLUSION: FAF patterns can change about half during the 5 years and the retinal sensitivity near abnormal FAF tends to deteriorate after the third year.

Fundus autofluorescence and retinal sensitivity in fellow eyes of age-related macular degeneration in Japan.

PURPOSE: Abnormal fundus autofluorescence (FAF) potentially precedes onset of late age-related macular degeneration (AMD) in Caucasian patients. Many differences exist between Asian and Caucasian patients regarding AMD types and severity, gender, and genetic backgrounds. We investigated the characteristics of abnormal FAF and retinal sensitivity in the fellow eyes of Japanese patients with unilateral neovascular AMD. METHODS: Sixty-six patients with unilateral neovascular AMD and abnormal FAF in the fellow eye were enrolled in this multicenter, prospective, observational study. The best-corrected visual acuity, fundus photographs, FAF images, and retinal sensitivity on microperimetry were measured periodically for 12 months. The FAF images were classified into eight patterns based on the International Fundus Autofluorescence Classification Group. The points measured by microperimetry were superimposed onto the FAF images and fundus photographs and classified as "within," "close," and "distant," based on the distance from the abnormal FAF and other findings. The relationship between the location of the baseline abnormal FAF and retinal sensitivity was investigated. RESULTS: In Japanese patients, patchy (33.3%) and focally increased (30.3%) patterns predominated in the abnormal FAF. Intermediate-to-large drusen was associated predominantly with hyperfluorescence and hypofluorescence. Neovascular AMD developed within 1 year in six (9.1%) eyes, the mean baseline retinal sensitivity of which was 12.8 ± 4.7 dB, significantly (p<0.002) lower than the other eyes. In 44 of the other 60 eyes, microperimetry was measurable at baseline and month 12 and the mean retinal sensitivity improved significantly from 13.5 ± 4.4 to 13.9 ± 4.8 dB (p<0.001), possibly associated with lifestyle changes (e.g., smoking cessation, antioxidant and zinc supplementation). The mean retinal sensitivities of points within and close to the abnormal FAF were 9.9 and 11.7 dB, respectively, which were significantly lower than the 14.0 dB of the points distant from the abnormal FAF. CONCLUSION: In Japanese patients, patchy and focally increased patterns predominated in the abnormal FAF. The retinal sensitivity was lower close to/within the abnormal FAF. FAF and microperimetry are useful to assess macular function before development of neovascular AMD or geographic atrophy.

Degeneration of retinal on bipolar cells induced by serum including autoantibody against TRPM1 in mouse model of paraneoplastic retinopathy.

The paraneoplastic retinopathies (PRs) are a group of eye diseases characterized by a sudden and progressive dysfunction of the retina caused by an antibody against a protein in a neoplasm. Evidence has been obtained that the transient receptor potential melastatin 1 (TRPM1) protein was one of the antigens for the autoantibody against the ON bipolar cells in PR patients. However, it has not been determined how the autoantibody causes the dysfunction of the ON bipolar cells. We hypothesized that the antibody against TRPM1 in the serum of patients with PR causes a degeneration of retinal ON bipolar cells. To test this hypothesis, we injected the serum from the PR patient, previously shown to contain anti-TRPM1 antibodies by westerblot, intravitreally into mice and examined the effects on the retina. We found that the electroretinograms (ERGs) of the mice were altered acutely after the injection, and the shape of the ERGs resembled that of the patient with PR. Immunohistochemical analysis of the eyes injected with the serum showed immunoreactivity against bipolar cells only in wild-type animals and not in TRPM1 knockout mice,consistent with the serum containing anti-TRPM1 antibodies. Histology also showed that some of the bipolar cells were apoptotic by 5 hours after the injection in wild type mice, but no bipolar cell death was found in TRPM1 knockout mice, . At 3 months, the inner nuclear layer was thinner and the amplitudes of the ERGs were still reduced. These results indicate that the serum of a patient with PR contained an antibody against TRPM1 caused an acute death of retinal ON bipolar cells of mice.

Serum concentrations of bevacizumab (avastin) and vascular endothelial growth factor in infants with retinopathy of prematurity.

PURPOSE: To determine the serum concentrations of bevacizumab and vascular endothelial growth factor (VEGF) in infants with retinopathy of prematurity (ROP) who received intravitreal bevacizumab; and to determine whether the changes in the serum concentration of bevacizumab were significantly correlated with the serum concentration of VEGF after intravitreal bevacizumab. DESIGN: Case series. METHODS: Eleven infants (4 girls and 7 boys) with ROP were studied. They received 0.25 mg or 0.5 mg of intravitreal bevacizumab to either 1 eye (unilateral cases) or both eyes (bilateral cases) with vascularly active ROP. Serum samples were collected before and 1 day, 1 week, and 2 weeks after the intravitreal bevacizumab. The serum concentrations of bevacizumab and VEGF were measured by enzyme-linked immunosorbent assay, and the correlation in the serum levels between the 2 was determined. RESULTS: The serum concentration of bevacizumab before and 1 day, 1week, and 2 weeks after a total of 0.5 mg of intravitreal bevacizumab was 0 ng/mL, 195 ± 324 ng/mL, 946 ± 680 ng/mL, and 1214 ± 351 ng/mL, respectively. The serum bevacizumab level before and 1 day and 1 week after a total 1.0 mg of intravitreal bevacizumab was 0 ng/mL, 248 ± 174 ng/mL, and 548 ± 89 ng/mL, respectively. The serum concentration of VEGF before and 1 day, 1 week, and 2 weeks after a total of 0.5 mg intravitreal bevacizumab was 1628 ± 929 pg/mL, 427 ± 140 pg/mL, 246 ± 110 pg/mL, and 269 ± 157 pg/mL, respectively. There was a significant negative correlation (r = -0.575, P = .0125) between the serum concentration of bevacizumab and VEGF when a total of 0.25 mg or 0.5 mg of bevacizumab was injected. CONCLUSIONS: These results indicate that bevacizumab can escape from the eye into the systemic circulation and reduce the serum level of VEGF in infants with ROP. Continued extensive evaluations of infants are warranted for possible effects after intravitreal bevacizumab in ROP patients.

Photoreceptor rescue of pigment epithelium-derived factor-impregnated nanoparticles in Royal College of Surgeons rats.

PURPOSE: To investigate the protective effect of intravitreal injection of pigment epithelium-derived factor-impregnated nanoparticles (PEDF-NPs) against photoreceptor degeneration in Royal College of Surgeons (RCS) rats. METHODS: Three-week-old RCS rats received an intravitreal injection of PBS, blank NPs, PEDF (2.5 µg), or PEDF-NPs (2.5 µg). Eyes were assessed with morphological, immunohistochemical, and physiologic analysis over the following 8 weeks. Cell death was examined using the terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end labeling (TUNEL) assay. RESULTS: In RCS rats, the a- and b-wave amplitudes on electroretinograms in eyes treated with PEDF-NPs were greater than those in retinas receiving other treatment. Immunocytochemistry showed consistently greater opsin preservation in eyes treated with PEDF-NPs. A significantly higher number of photoreceptors and significantly fewer TUNEL-positive cells were present after treatment with PEDF-NPs, compared to PEDF-treated eyes. CONCLUSIONS: The results suggest that intravitreally injected PEDF-NPs delayed photoreceptor degeneration by inhibiting apoptosis in the RCS rat retina due to targeting and sustained release of PEDF.

Dry age-related macular degeneration: recent progress of therapeutic approaches.

Age-related macular degeneration (AMD) is a progressive retinal degenerative disease and a common cause of blindness. In AMD, there are two phenotypes; "atrophic (dry)" and "neovascular (wet)". The former is characterized by the geographic atrophy due to death of retinal pigment epithelium, and the latter is developed due to choroidal neovascularization. While wet AMD can be treated by the inhibition of vascular endothelial growth factor or photodynamic therapy, so far there are no available treatments for dry AMD. Fortunately, understanding of pathogenesis in dry AMD has significantly been progressed and many candidates for the treatment of dry AMD have been introduced in clinical trials as well as preclinical stages. In this article, the progress of therapeutic approaches for dry AMD is reviewed.

Biodegradable intraocular therapies for retinal disorders: progress to date.

In general, it is difficult to achieve effective levels of drugs in the vitreous and the retina via topical and/or systemic administration. Intraocular drug delivery systems that achieve longer duration of pharmacological effect with lower administration frequency are urgently needed. Intraocular sustained drug release via implantable devices or injectable particles has been investigated for the treatment of various vitreoretinal disorders. Several non-biodegradable implants are available in clinical practice or in the late developmental phase: Vitrasert (ganciclovir intravitreal implant) for cytomegalovirus retinitis, Retisert (fluocinolone acetonide intravitreal implant) for non-infectious uveitis, Iluvien (fluocinolone acetonide intravitreal implant) for diabetic macular oedema, and NT-501 (a polymer implant containing human retinal epithelial cells genetically modified to secrete ciliary neurotrophic factor) for non-neovascular (dry) age-related macular degeneration and/or retinitis pigmentosa. Many biodegradable formulations, including different shapes of rods, nail-like plugs, discs, or micro- or nanoparticles, have also been investigated, but are not available as yet for the treatment of vitreoretinal disorders. The most developed biodegradable device, Ozurdex (dexamethasone intravitreal implant), is approved as first-line therapy for the treatment of macular oedema following branch retinal vein occlusion or central retinal vein occlusion. In this article, we review the progress of major biodegradable drug delivery systems currently in clinical trials or in experimental stages for the treatment of vitreoretinal disorders.

Pharmacokinetics of bevacizumab after topical, subconjunctival, and intravitreal administration in rabbits.

PURPOSE: To investigate the pharmacokinetics of bevacizumab in rabbits for three different routes of administrations: intravitreal injection, subconjunctival injection, and eye drops. METHODS: Pigmented rabbits received bevacizumab in one eye by topical eye drops (1.25 mg/0.05 mL six times daily for the first 7 days), single subconjunctival injection (1.25 mg/0.05 mL), or single intravitreal injection (1.25 mg/0.05 mL). Bevacizumab concentrations in plasma and ocular tissues in the treated and fellow eyes were determined by sandwich enzyme-linked immunosorbent assay at 1, 2, 4, and 12 weeks after administration. RESULTS: After intravitreal injection in the treated eye, the mean maximum concentrations (C(max)) of bevacizumab in the iris/ciliary body and retina/choroid were 109,192.6, and 93,990.0 ng/g, respectively, whereas after subconjunctival injection, the C(max) was 1418.7 and 295.8 ng/g, respectively. In the fellow eyes, when the drug was administered by intravitreal injection, the C(max) was 753.6 ng/g in the iris/ciliary body and 224.2 ng/g in the retina/choroid and by subconjunctival injection was 1192.9 and 187.0 ng/g, respectively. With eye drops, only a small level of bevacizumab was detected in the iris/ciliary body and retina/choroid. Systemic exposure to bevacizumab was at the same level when administered by intravitreal or subconjunctival injection. CONCLUSIONS: Intravitreal injection of bevacizumab was the most effective route of administration for intraocular tissue. Also, bevacizumab injected subconjunctivally was transported into the intraocular tissues of the treated eyes at an effective level. Both intravitreal and subconjunctival injections of bevacizumab resulted in high plasma concentrations. Bevacizumab was distributed into the intraocular tissues in fellow eyes via the systemic circulation. This treatment may be effective for blocking vascular endothelial growth factor activity.

Prolonged protective effect of basic fibroblast growth factor-impregnated nanoparticles in royal college of surgeons rats.

PURPOSE: To investigate the protective effect of intravitreal injection of basic fibroblast growth factor-impregnated nanoparticles (bFGF-NPs) against photoreceptor degeneration in Royal College of Surgeons (RCS) rats. METHODS: Three-week-old RCS rats received intravitreal injection of PBS, blank NPs, bFGF (2.5 microg), or bFGF-NPs (2.5 microg). Eyes were assessed by morphologic, immunohistochemical, and physiological analyses for the following 8 weeks. Cell death was examined using the TUNEL assay, and bFGF protein levels in the retina were measured by Western blot analysis. Rhodamine (Rh)-labeled bFGF-NPs were injected intravitreally and visualized by confocal microscopy to determine the localization of the nanoparticles in the retina. RESULTS: Intravitreally injected Rh-labeled bFGF-NPs were found in the outer nuclear layer 6 and 8 weeks after injection. ERG a- and b-wave amplitudes in bFGF-NP-treated retinas were greater than amplitudes in retinas receiving other treatment. Immunocytochemical analysis showed consistently greater opsin preservation in bFGF-NP-treated retinas, and a significantly higher number of photoreceptors and significantly fewer TUNEL-positive cells were present after bFGF-NP treatment than after bFGF treatment. Western blot analysis showed a significant increase in the bFGF level in bFGF-NP-treated retinas. CONCLUSIONS: The results suggest that intravitreally injected bFGF-NPs prevent photoreceptor degeneration by inhibiting apoptosis in the RCS rat retina because of targeting and sustained release of bFGF. This novel drug delivery system for bFGF may serve as a potential short-term treatment for photoreceptor degeneration in humans.