Macular Degeneration: Otani A

Otani A, Sasahara M, Yodoi Y, Kameda T, Tsujikawa A, Yoshimura N. · Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Japan. · Nippon Ganka Gakkai Zasshi. · Pubmed #19606806 No free full text.

Abstract: PURPOSE: The current study was designed to investigate the role of circulating bone marrow (BM)-derived stem cells in the pathogenesis of polypoidal choroidal vasculopathy (PCV), a distinct type of neovascular age-related macular degeneration (AMD). METHODS: Thirty one clinically documented PCV patients were enrolled. Circulating BM-derived stem cells were collected from the patients' peripheral blood and cultured. Colony forming capacity (Hill assay) and migration activity (Boyden chamber system) were examined and analyzed. RESULTS: Colony forming units (CFU-Hill) were significantly fewer in bilateral PCV patients than in unilateral PCV patients. CFU-Hill was impaired in patients with larger (> 5000 microm) PCV lesions compared with patients with smaller PCV lesions. Migration activity of BM-derived stem cells was also reduced significantly in the bilateral PCV patients than in the unilateral PCV patients. CONCLUSIONS: Similar to CNV associated with AMD, impaired functional activity of circulating BM-derived stem cells was observed in PCV patients with bilateral or larger lesions. Circulating BM-derived stem cells may have a role in the pathogenesis of PCV.

Hayashi H, Yamashiro K, Tsujikawa A, Ota M, Otani A, Yoshimura N. · Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Sakyo, Kyoto, Japan. · Am J Ophthalmol. · Pubmed #19327745 No free full text.

Abstract: PURPOSE: To evaluate the correlation between visual outcome and foveal photoreceptor integrity after successful treatment of eyes with neovascular age-related macular degeneration (AMD). DESIGN: Retrospective chart review. METHODS: We retrospectively studied the medical records of 51 eyes of 51 patients with neovascular AMD who were treated successfully with photodynamic therapy (PDT). All eyes were followed-up for more than 24 months after the initial treatment. Using spectral-domain optical coherence tomography, the status of the inner segment and outer segment (IS/OS) photoreceptor junction was assessed as a hallmark of the integrity of the foveal photoreceptor layer. RESULTS: At the final visit, no eyes showed an exudative change. A complete or discontinuous IS/OS line was detected beneath the fovea in 8 (15.7%) and 25 (29.4%) eyes, respectively, whereas 28 (54.9%) had no IS/OS line. Eyes with a continuous or discontinuous IS/OS line beneath the fovea had better final visual acuity (VA) than did eyes without an IS/OS line (P < .001, respectively). Of the 51 eyes, 36 showed polypoidal choroidal vasculopathy (PCV), whereas 15 were diagnosed as having typical AMD without PCV. Visual outcome was significantly better in eyes with PCV (P = .026). Most eyes (13/15; 86.7%) with typical AMD had no IS/OS line at the final visit, whereas only 13 (36.1%) of the 36 eyes with PCV had no IS/OS line beneath the fovea. CONCLUSIONS: Integrity of the photoreceptor layer beneath the fovea is associated with the final VA in neovascular AMD after successful PDT.

Tsujikawa A, Nakanishi H, Ojima Y, Iwama D, Tamura H, Otani A, Yoshimura N. · Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan. · Clin Experiment Ophthalmol. · Pubmed #19278475 No free full text.

Abstract: PURPOSE: To report cases of the macular type of polypoidal choroidal vasculopathy with a remote lesion. METHODS: We report six patients (seven eyes) with polypoidal choroidal vasculopathy who had macular and remote lesions. These eyes were examined with angiography and tomography. RESULTS: All seven eyes showed an exudative macular lesion beneath the fovea. In addition, all eyes showed remote polypoidal lesions that were not connected to the macular lesions; the remote lesion was detected outside of the vascular arcade in five eyes, superotemporally beside the optic disc in one eye and on the nasal side of the optic disc in one eye. Indocyanine green angiography, fluorescein angiography and optical coherence tomography failed to reveal any sign of a branching vascular network or choroidal neovascularization that connected the macular lesion with the more remote lesion. At the initial visit, visual acuity in the seven eyes ranged from 6/150 to 6/9 (median, 6/15). Four eyes underwent photodynamic therapy to the exudative macular lesion. During 27.6 +/- 14.3 months of follow up, no worsening was detected in any of the remote lesions. Median visual acuity was 6/60 at the final visit. CONCLUSIONS: Some patients with macular polypoidal choroidal vasculopathy also have a remote lesion, although the remote lesion seems to have only a minor effect on visual outcome.

Gotoh N, Nakanishi H, Hayashi H, Yamada R, Otani A, Tsujikawa A, Yamashiro K, Tamura H, Saito M, Saito K, Iida T, Matsuda F, Yoshimura N. · Department of Ophthalmology, Kyoto University Graduate School of Medicine, Kyoto, Japan. · Am J Ophthalmol. · Pubmed #19268887 No free full text.

Abstract: PURPOSE: To determine the characteristics of the polymorphisms in the ARMS2 gene in Japanese patients with age-related macular degeneration (AMD) and those with polypoidal choroidal vasculopathy (PCV) and in healthy controls, and also to show possible associations of the polymorphisms with the disease. DESIGN: Case-control association study. METHODS: Fifty-six unrelated Japanese individuals with AMD, 55 with PCV, and 77 controls were studied. The most common polymorphism in the ARMS2 gene on chromosome 10 was resequenced. Association tests were performed for inferred haplotypes. RESULTS: A total of 22 polymorphisms were identified, and 13 were shared with those in White persons with AMD. The sequence of the deletion-and-insertion polymorphism, de1443ins54, a functional polymorphism causing an instability of the messenger ribonucleic acid of ARMS2 in the Japanese, did not differ from that in White persons. Among the polymorphisms seen in the White population, rs10490923 (R3H) as well as 7 other polymorphisms were not observed in the Japanese. One haplotype, which contained the T allele of the rs10490924 (A69S) and the variant of de1443ins54 polymorphism, had an odds ratio of 3.14 (P = 7.8 x 10(-6)) for AMD and 2.00 (P = .0058) for PCV. Among the 9 polymorphisms that were unique to the Japanese population, 2 had a minor allelic frequency of more than 0.05, and these 2 polymorphism were included as nonrisk haplotypes. CONCLUSIONS: The de1443ins54 polymorphism is a common variant between White and Japanese populations. It is strongly associated not only with AMD but also with PCV.

Sasahara M, Otani A, Yodoi Y, Yoshimura N. · Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan. · Invest Ophthalmol Vis Sci. · Pubmed #18806291 No free full text.

Abstract: PURPOSE: In a prior study, the correlation was investigated between circulating hematopoietic stem cells (HSCs) and the activity or severity of choroidal neovascularization (CNV) in patients with age-related macular degeneration (AMD). The present study was designed to explore the role of circulating HSCs in the pathogenesis of CNV in patients with idiopathic (i)CNV. METHODS: Thirteen patients with clinically documented iCNV and 10 age-sex matched patients without iCNV or systemic disease were enrolled in a case-control study. Circulating HSCs were collected from the patients' peripheral blood and cultured. Colony-forming capacity, migration activity, and invasion activity of HSCs were experimentally analyzed. RESULTS: Colony-forming units by Hill's assay (CFU-Hill) were markedly lower (P<0.001) in patients with iCNV (12.8+/-3.2) than in healthy patients (67.6+/-12.6). Invasion activities of HSCs were reduced significantly in patients with iCNV. CFU-Hill was impaired in the patients (4.0+/-1.2) with CNV more than 1500 microm compared with the patients (20.3+/-4.0) with CNV less than 1500 microm (P=0.006). CONCLUSIONS: Similar to the previous finding of CNV associated with AMD, impaired functional activities of circulating HSCs were observed in patients with iCNV, which correlated with the size of iCNV. These results in young patients provide evidence to support the role of circulating HSCs in the pathogenesis of CNV.

Iwama D, Otani A, Sasahara M, Yodoi Y, Gotoh N, Tamura H, Tsujikawa A, Yoshimura N. · Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan. · Br J Ophthalmol. · Pubmed #18662914 No free full text.

Abstract: AIM: To examine the effects of photodynamic therapy (PDT) with verteporfin combined with low-dose intravitreal triamcinolone acetonide (IVTA) for exudative age-related macular degeneration (AMD) that is resistant to PDT alone. DESIGN: Retrospective case series. METHODS: A retrospective review was performed, using the medical records of 22 eyes of 21 patients who consecutively received combined PDT and 2 mg of IVTA for exudative AMD with a suspected chorioretinal anastomosis or for AMD that was resistant to prior PDT alone. Only those patients who could be followed up for more than 12 months after this combined therapy were enrolled in the study. Best corrected visual acuity and intraocular pressure measurements were taken during each examination. Colour photography, fluorescein/indocyanine green angiography and optical coherence tomography were carried out at baseline and every 3 months thereafter. Need for retreatment was based on dye leakage and the presence of serous retinal detachement (SRD) seen by optical coherence tomography. RESULTS: Visual acuity improved or was maintained in the majority of patients, with the mean change between baseline and the last visit being an improvement of 0.94 lines (p = 0.45). Seventeen (77%) of the 22 eyes showed improved or maintained visual acuity after 12 months of follow-up. Eight (36%) of the 22 eyes continued to show an SRD at the 12-month follow-up; this corresponded to unchanged or even decreased leakage of dye. The mean number of retreatments was 1.36, but the incidence of side effects accompanying treatment was not as high as that reported previously for combined therapy that utilised higher-dose IVTA. CONCLUSIONS: PDT combined with low-dose IVTA for exudative AMD seems to be as effective and safe as combined therapy with the higher-dose IVTA that was reported previously.

Kurashige Y, Otani A, Sasahara M, Yodoi Y, Tamura H, Tsujikawa A, Yoshimura N. · Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan. · Am J Ophthalmol. · Pubmed #18614133 No free full text.

Abstract: PURPOSE: To report on the two-year visual outcomes of indocyanine green angiography-guided photodynamic therapy (PDT) for polypoidal choroidal vasculopathy (PCV) patients. DESIGN: Retrospective case study. METHODS: A retrospective analysis that examined the clinical and angiographic data related to 41 eyes of 38 PCV patients (25 males, 13 females; average age +/- standard deviation [SD], 72.9 +/- 7.4 years) with follow-up periods of 24 months or more. RESULTS: The average number of PDT treatments was 1.65. After the 12-month follow-up, 12 eyes required retreatment. Although the mean visual acuity (VA) +/- SD before PDT (0.55 +/- 0.38 logarithm of the minimum angle of resolution units) improved to 0.46 +/- 0.41 at 12 months after the initial PDT, at 24 months, it declined significantly to 0.59 +/- 0.44 (P = .0018). Although only seven of 41 eyes exhibited VA deterioration at the 12-month follow-up examination, a decreased VA was noted in 18 eyes during the period starting from the 12-month follow-up until the final examination. The cases were bilateral in 11 (61.1%) of the 18 eyes. At the final examination, the mean VA of the bilateral cases but not the unilateral cases was significantly lower than that observed for the initial VA. CONCLUSIONS: PDT is an effective treatment against PCV over the short-term for both unilateral and bilateral cases. However, the VA prognosis may not the same after 12 months, especially for those PCV patients who have exudative age-related macular degeneration in contralateral eye.

Yodoi Y, Sasahara M, Kameda T, Yoshimura N, Otani A. · Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan. · Invest Ophthalmol Vis Sci. · Pubmed #18055794 links to  free full text

Abstract: PURPOSE: Circulating hematopoietic stem cells (HSCs) appear to have roles in the formation of choroidal neovascularization (CNV) in age-related macular degeneration (AMD). This study was conducted to investigate whether the number or function of HSCs plays a role in neovascular AMD. METHODS: Eighty-one patients with neovascular AMD who underwent comprehensive fundus examinations every 3 months were included. The number of CD34(+) HSCs isolated from peripheral blood was counted by flow cytometry. Serum cytokine levels were assessed by enzyme-linked immunosorbent assay. To examine the function of circulating HSCs, mononuclear cells were cultured and then colony forming unit (CFU-EC) and migration were measured. RESULTS: The number of circulating CD34(+) HSCs was significantly increased in the patients with active CNV without major systemic diseases (stable: 3.8 +/- 0.3 cells/microL, active: 5.5 +/- 0.7 cells/microL, stable versus active: P < 0.05). The number of HSCs correlated positively with the erythropoietin serum level (r = 0.47, P = 0.002). Although there was no significant difference in the CFU-EC between the patients with CNV and the control subjects, a significant decrease of CFU-EC was observed in the patients with bilateral or larger CNV. CONCLUSIONS: The findings suggest that CD34(+) HSCs may be recruited from bone marrow through a signal from active CNV. Furthermore, HSCs may play a role in the severity of CNV.

Sasahara M, Tsujikawa A, Musashi K, Gotoh N, Otani A, Mandai M, Yoshimura N. · Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan. · Am J Ophthalmol. · Pubmed #17011852 No free full text.

Abstract: PURPOSE: To describe the incidence and clinical characteristics of polypoidal choroidal vasculopathy (PCV) associated with choroidal vascular hyperpermeability. DESIGN: Retrospective observational case series. METHODS: We reviewed the medical records of 122 consecutive eyes with PCV and 106 consecutive eyes with exudative age-related macular degeneration (AMD). Fluorescein angiography and indocyanine green (ICG) angiography were performed using a confocal scanning laser system. In the midphase of ICG angiography, we evaluated choroidal vascular hyperpermeability, which is recognized as one of the characteristic findings in central serous chorioretinopathy (CSC). Choroidal vascular hyperpermeability appeared as multifocal patchy areas of hyperfluorescence with blurred margins within the choroid that increased in intensity with time after injection of the dye. RESULTS: Of 122 eyes with PCV, 12 (9.8%) eyes of 10 patients exhibited multifocal choroidal hyperfluorescence in the midphase of ICG angiography, whereas two (1.9%) of 106 eyes with exudative AMD showed a similar appearance (P = .013). Of the 12 eyes in 10 patients with PCV that demonstrated multifocal choroidal hyperfluorescence, we also noted that the early phase of ICG angiography showed choroidal filling delay in seven eyes (58%) and venous dilation in 12 eyes (100%). Four of these 12 eyes (33%) had a medical history of CSC, and nine (90%) of the 10 patients revealed multifocal choroidal hyperfluorescence bilaterally. CONCLUSIONS: Multifocal choroidal hyperfluorescence seen by ICG angiography occurs more frequently in eyes with PCV than in those with AMD. Choroidal vascular hyperpermeability, reportedly a characteristic finding in CSC, might be one of the risk factors of PCV.

Gotoh N, Yamada R, Hiratani H, Renault V, Kuroiwa S, Monet M, Toyoda S, Chida S, Mandai M, Otani A, Yoshimura N, Matsuda F. · Department of Ophthalmology, Kyoto University Graduate School of Medicine, Kyoto, Japan. · Hum Genet. · Pubmed #16710702 No free full text.

Abstract: Age-related macular degeneration (ARMD) is the leading cause of blindness in the elderly population not only Western but also Asian industrial countries. In Caucasian, a polymorphism of the complement factor H gene (CFH), the C allele of rs1061170 (Y402H), was established as the first strong genetic factor for excursively exudative type of ARMD. In this study, we performed an extensive sequencing of the 22 exons in the CFH gene by recruiting 146 exudative ARMD patients and 105 normal controls of Japanese origin and identified 61 polymorphisms. We found that the frequency of the C allele of rs1061170 (Y402H) is much lower (0.04) in Japanese controls than in Caucasians (0.45). No case disease susceptibility to exudative ARMD was noted for rs1061170 (Y402H) (chi (2) = 3.19, P (corr) = 0.423), or other 12 single nucleotide polymorphisms (SNPs) whose frequency is greater than 0.05. When haplotypes were inferred for 13 SNPs (these 12 SNPs with a frequency greater than 0.05 and rs1061170), three haplotypes whose pattern was similar to those in Caucasians were identified but with substantial difference in frequency. Again we failed to identify genetic association between Japanese exudative ARMD and any of the haplotypes including the J1 haplotype which was shown to be susceptible to ARMD in Caucasians (chi (2 )=( )3.92, P (corr) = 0.157). CFH does not appear to be a primary hereditary contributor to ARMD in Japanese. The absence of CFH contribution to ARMD in Japanese may correlate with the findings in ethnic differences of ARMD phenotypes.

Otani A, Takagi H, Oh H, Koyama S, Sugita G, Ogura Y. · Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan. · Retina. · Pubmed #12824844 No free full text.

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Otani A, Takagi H, Oh H, Koyama S, Ogura Y, Matumura M, Honda Y. · Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto 606, Japan. · Microvasc Res. · Pubmed #12074642 No free full text.

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Otani A, Takagi H, Oh H, Koyama S, Matsumura M, Honda Y. · Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Japan. · Invest Ophthalmol Vis Sci. · Pubmed #10440243 links to  free full text

Abstract: PURPOSE: To elucidate the potential role of angiopoietins and the Tie2 system in choroidal neovascularization. METHODS: Surgically excised choroidal neovascular membranes (CNVMs) were obtained at vitrectomy from five eyes with age-related macular degeneration, three eyes with idiopathic neovascular maculopathy, and two eyes had degenerative myopia and two eyes had angioid streaks. Light microscopic immunohistochemistry was performed to detect cytokines such as vascular endothelial growth factor (VEGF), Ang1, and Ang2 and cellular components such as retinal pigment epithelial (RPE) cells, macrophages, and endothelial cells. Immunofluorescent double staining using confocal microscopy was performed to identify the cell types that secrete specific cytokines. RESULTS: Ang1 and Ang2 were positive in all surgically excised CNVMs, regardless of the primary disease. Double staining revealed that many of the cytokeratin, CD68 and factor VIII positive cells also had Ang1 and Ang2 immunoreactivities. In contrast to Ang1, Ang2 immunoreactivity tends to be higher in the highly vascularized regions of many CNVMs, and the localization was very similar to that of VEGF staining. Almost all vascular structures had prominent immunoreactivity for Tie2, which was confirmed by double staining for Tie2 and factor VIII. Tie2 immunoreactivity was also observed in the RPE monolayer and in pigmented, polygonal, and fibroblast-like cells in the stroma. CONCLUSIONS: Present findings that Ang2 and VEGF are co-upregulated and that Tie2 is expressed in a variety of cell types in CNVMs further support a crucial role of the interaction between VEGF and Ang2 in pathologic angiogenesis of CNVM formation.