Publications by authors named "Noriyasu Hashida"

53 Publications

Rubicon regulates A2E-induced autophagy impairment in the retinal pigment epithelium implicated in the pathology of age-related macular degeneration.

Biochem Biophys Res Commun 2021 Apr 16;551:148-154. Epub 2021 Mar 16.

Department of Ocular Immunology and Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Suita, Osaka, Japan. Electronic address:

Waste product deposition and light stress in the retinal pigment epithelium (RPE) are crucial factors in the pathogenesis of various retinal degenerative diseases, including age-related macular degeneration (AMD), a leading cause of vision loss in elderly individuals worldwide. Given that autophagy in the RPE suppresses waste accumulation, determining the molecular mechanism by which autophagy is compromised in degeneration is necessary. Using polarized human RPE sheets, we found that bis-retinoid N-retinyl-N-retinylidene ethanolamine (A2E), a major toxic fluorophore of lipofuscin, causes significant impairment of autophagy and the simultaneous upregulation of Rubicon, a negative regulator of autophagy. Importantly, this impairment was reversed in Rubicon-specific siRNA-treated RPE sheets. In a retinal functional analysis using electroretinograms (ERGs), mice with the RPE-specific deletion of Rubicon showed no significant differences from control cre-expressing mice but presented partially but significantly enhanced amplitudes compared with Atg7 knockout mice. We also found that an inflammatory reaction in the retina in response to chronic blue light irradiation was alleviated in mice with the RPE-specific deletion of Rubicon. In summary, we propose that upregulating basal autophagy by targeting Rubicon is beneficial for protecting the RPE from functional damage with ageing and the inflammatory reaction caused by light-induced cellular stress.
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http://dx.doi.org/10.1016/j.bbrc.2021.02.148DOI Listing
April 2021

The generation of fluorometholone nanocrystal eye drops, their metabolization to dihydrofluorometholone and penetration into rabbit eyes.

Int J Pharm 2021 Jan 13;592:120067. Epub 2020 Nov 13.

Department of Ophthalmology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.

Fluorometholone is a widely used anti-inflammatory ophthalmic formulation, which elicits a lower ocular hypertensive response than other glucocorticoid medications. This serves to mitigate against the risk of steroid-induced glaucoma. Based on the hypothesis that an improved corneal permeability can increase the bioavailability of a drug, we sought to obtain fluorometholone in suspension with a small particle size. Accordingly, we describe the formulation of fluorometholone nanocrystal eye drops, which have a mean particle size of 201.2 ± 14.1 nm (standard deviation (s.d.)) when measured by dynamic light scattering. Scanning electron microscopy further indicates that fluorometholone nanocrystals are predominantly rectangular in shape. Fluorometholone microcrystals, on the other hand, with a mean particle size of 9.24 ± 4.51 µm (s.d.), tend to have a rod-like morphology. Powder x-ray diffraction revealed that fluorometholone microcrystal and nanocrystal formulations have the same crystal structure, with the main diffraction peaks at 2θ = 10.4 and 15.3°. The nanocrystal formulation was found to be stable, long-term, when stored at 10 °C for up to 6-months. High pressure liquid chromatography (HPLC) of the aqueous humor of rabbit eyes 15-240 mins after the in vivo application of fluorometholone eye drops to the ocular surface revealed that the molecule had been converted to 20α-dihydrofluorometholone (with no evidence of a 20β-dihydrofluorometholone fraction), and that penetration was 2-6 fold higher and longer lasting with the nanocrystal, rather than the microcrystal, formulation. In current study we show how newly generated fluorometholone nanocrystals when administered as eye drops enter the anterior chamber of the eye and become metabolized to dihydrofluorometholone.
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http://dx.doi.org/10.1016/j.ijpharm.2020.120067DOI Listing
January 2021

Complete Visual Recovery From Severe Outer Retinitis After Tonsillitis.

J Neuroophthalmol 2020 Sep 11. Epub 2020 Sep 11.

Department of Ophthalmology (RK, KM, NH, KN), Osaka University Graduate School of Medicine, Osaka, Japan; Department of Ophthalmology (KK), Kindai University Faculty of Medicine, Osaka-Sayama City, Japan; Osaka University Graduate School of Frontier Biosciences (TF), Osaka, Japan; and Integrated Frontier Research for Medical Science Division (KN), Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan.

Background: To report a case of severe acute bilateral outer retinitis after tonsillitis and rapid morphologic and functional recovery after steroid treatment.

Methods: Observational case report.

Results: A 26-year-old woman with acute bilateral blurred vision that developed after tonsillitis underwent spectral-domain optical coherence tomography (SD-OCT) that showed photoreceptor outer segment damage. Full-field electroretinography (ERG) and multifocal ERG were nonrecordable. The patient had a remarkable anatomic and functional recovery in response to steroid treatment; however, partial damage remained around the macula on SD-OCT, and an adaptive optics imaging system showed damaged cone photoreceptors.

Conclusions: Prednisolone is an effective treatment for a disease that is believed to be due to suspicious involvement of the autoimmune system. Even severe outer retinitis can recover completely with rapid diagnosis and treatment.
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http://dx.doi.org/10.1097/WNO.0000000000001073DOI Listing
September 2020

Identification of as a susceptibility gene for neovascular age-related macular degeneration and polypoidal choroidal vasculopathy.

Br J Ophthalmol 2020 Mar 9. Epub 2020 Mar 9.

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China

Purpose: The endothelial and cell-specific angiopoietin-Tie pathway plays an important regulatory role in angiogenesis. In this study, we investigated the associations of the () gene with neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV), using haplotype-tagging single-nucleotide polymorphisms (SNPs) analysis.

Methods: This study involved totally 2343 subjects, including a Hong Kong Chinese cohort (214 nAMD patients, 236 PCV patients and 433 control subjects), a Shantou Chinese cohort (189 nAMD patients, 187 PCV patients and 531 control subjects) and an Osaka Japanese cohort (192 nAMD patients, 204 PCV patients and 157 control subjects). Thirty haplotype-tagging SNPs in were genotyped in the Hong Kong cohort using TaqMan technology. Two SNPs (rs625767 and rs2273717) showing association in the Hong Kong cohort were genotyped in the Shantou and Osaka cohorts. The SNP-disease association of individual and pooled cohorts were analysed.

Results: Two SNPs (rs625767 and rs2273717) showed suggestive association with both nAMD and PCV in the Hong Kong cohort. In the meta-analysis involving all the three cohorts, rs625767 showed significant associations with nAMD (p=0.01; OR=0.82, 95% CI 0.70 to 0.96; I=0%), PCV (p=0.02; OR=0.83, 95% CI 0.71 to 0.97; I=27%) and pooled nAMD and PCV (p=0.002; OR=0.82, 95% CI 0.72 to 0.93; I=0%), with low inter-cohort heterogeneities.

Conclusion: This study revealed as a novel susceptibility gene for nAMD and PCV in Japanese and Chinese. Further studies in other populations are warranted to confirm its role.
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http://dx.doi.org/10.1136/bjophthalmol-2019-315746DOI Listing
March 2020

Chronological Observations of Iris Flocculi in a Japanese Family with Thoracic Aortic Aneurysm and Dissections.

Case Rep Ophthalmol 2019 Sep-Dec;10(3):397-402. Epub 2019 Nov 26.

Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan.

Iris flocculi, a type of hereditary iris pigment epithelial cyst, have been reported in association with smooth muscle α-2 actin (ACTA2) gene as the causative gene of familial thoracic aortic aneurysm and dissections (FTAAD). The purpose of the report was to examine morphological changes in the shape of flocculi and iris features over time by comparing infants to adults with FTAAD combined with iris flocculi. A Japanese family with FTAAD and bilateral iris flocculi and the Arg149Cys gene mutation was included. A slit-lamp photograph and anterior segment optical coherence tomography (AS-OCT) were used to evaluate the structure and location of iris flocculi. AS-OCT was also used to measure the internal shape and iris thickness of the dilated pupil muscle. A morphological change in the cyst was confirmed to be existent in the youngest cases. Pigment discoloration and iris atrophy of the iris body were observed in all cases. Besides, a decrease in iris thickness was observed with AS-OCT measurement. Changes across generations in iris flocculi occurred in a Japanese family with TAAD. ACTA2 gene abnormalities may cause iris atrophy and decrease thickness in addition to iris flocculi in early life. The prognosis is poor when FTAAD is combined with iris flocculi, and prevention of cardiovascular disease is necessary based on earlier findings of its emergence.
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http://dx.doi.org/10.1159/000504432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940443PMC
November 2019

Bilateral serous retinal detachment associated with subretinal fibrin-like material in a case of pregnancy-induced hypertension.

Am J Ophthalmol Case Rep 2019 Dec 9;16:100572. Epub 2019 Nov 9.

Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.

Purpose: To describe a case of bilateral serous retinal detachment (SRD) associated with subretinal fibrin-like material (SRFM) in pregnancy-induced hypertension (PIH).

Observations: Angiography of a 31-year-old primigravida with PIH who developed acute bilateral SRD with SRFM after caesarean section showed choroidal hypoperfusion and dye leakage. Optical coherence tomography revealed irregularity of the ellipsoid zone and retinal pigment epithelium. The patient's visual acuity was hand motion in the both eyes at the initial examination. After 30 days, SRD and SRFM spontaneously disappeared. Moreover, the EZ returned and the visual acuity significantly improved to 20/25 in the right and 20/20 in the left eye.

Conclusions And Importance: Although there are reports on central serous chorioretinopathy or Vogt-Koyanagi-Harada disease, there have been no studies on SRFM complications in patients with PIH. In the current case, we speculated that SRFM was associated with acute intense choroidal ischemia and inflammation secondary to this ischemic condition. Distinguishing whether inflammation necessitating treatment is involved in SRFM may be difficult. Short observation intervals and frequent examinations are important to ensure that treatment timings are not missed.
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http://dx.doi.org/10.1016/j.ajoc.2019.100572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880124PMC
December 2019

Cornea Findings of Spectral Domain Anterior Segment Optical Coherence Tomography in Uveitic Eyes of Various Etiologies.

Cornea 2019 Oct;38(10):1299-1304

Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan.

Purpose: To evaluate the morphologic appearance of keratic precipitates (KPs) with spectral domain anterior segment optical coherence tomography (AS-OCT) for the diagnosis of uveitic eyes of various etiologies.

Methods: In all, 153 eyes of 153 patients with different types of uveitis were examined to investigate the morphologic appearance of KPs. The study included 63 eyes with herpetic iridocyclitis/endotheliitis, 58 eyes with ocular sarcoidosis, 5 eyes with Fuchs heterochromic iridocyclitis, and 27 eyes with masquerade syndrome with primary intraocular lymphoma (PIOL). AS-OCT was used to analyze the different KP types among various uveitic groups.

Results: KPs were observed in 30 eyes (51.7%) from the ocular sarcoidosis group and in 15 eyes (55.6%) from the PIOL group. In the herpetic iridocyclitis/endotheliitis group, all cases showed KPs (16 cases were positive for herpes simplex virus, 22 cases for varicella zoster virus, and 27 cases for cytomegalovirus). The reflectivity and morphology of the KPs in the AS-OCT images demonstrated different patterns depending on the causative virus. Hemispheric and relatively large KPs were observed in ocular sarcoidosis cases. KPs with Fuchs heterochromic iridocyclitis appeared as small dots. By contrast, relatively high-intensity and dense KPs were observed in PIOL cases. The morphologic features of the KPs in different types of uveitis also showed other patterns such as hemispheric and rectangular-shaped KPs protruding from the retrocornea.

Conclusions: AS-OCT images showed characteristic and specific morphological patterns. AS-OCT examination is a noninvasive and repeatable method for the diagnosis of uveitis by evaluating the morphologies of KPs and treatment effectiveness.
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http://dx.doi.org/10.1097/ICO.0000000000002065DOI Listing
October 2019

Conjunctival dysbiosis in mucosa-associated lymphoid tissue lymphoma.

Sci Rep 2019 06 10;9(1):8424. Epub 2019 Jun 10.

Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka University, Osaka, Japan.

To investigate the conjunctival microbiota and the association between the development of conjunctival mucosa-associated lymphoid tissue (MALT) lymphoma and dysbiosis, DNA samples were collected from 25 conjunctival MALT lymphoma patients and 25 healthy controls. To compare the microbiota, samples were collected from the following four body locations: conjunctiva, meibomian gland, periocular skin and hand. Extracted DNA was analyzed by 16S rRNA sequences, and libraries were sequenced on an Illumina MiSeq sequencer. The differences in bacteria were characterized by using principal coordinate analysis of metagenomics data, and the differences in bacterial compositions were evaluated by linear discriminant analysis effect size. The conjunctival microbiota of MALT lymphoma patients was compositionally different from that of healthy controls. For the conjunctival MALT lymphoma patients, alterations in the microbial composition were detected, and a remarkable change was detected at the conjunctiva. Detailed analysis showed that a specific population of the microbiota, the genus Delftia, was significantly more abundant in conjunctival MALT lymphoma patients, and the genera Bacteroides and Clostridium were less abundant in the MALT lymphoma patients. A specific microbiota on the ocular surface in conjunctival MALT lymphoma patients was detected, and dysbiosis may play an important role in the pathophysiology of conjunctival MALT lymphoma.
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http://dx.doi.org/10.1038/s41598-019-44861-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557838PMC
June 2019

Rare Histological Type of Adenoma of the Nonpigmented Ciliary Epithelium.

Case Rep Ophthalmol 2019 Jan-Apr;10(1):75-80. Epub 2019 Feb 20.

Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan.

We report the rare case of an adenoma of the nonpigmented ciliary epithelium (NPCE). A 67-year-old healthy man presented with a regularly shaped and nonpigmented mass at the iris root of his right eye. His best-corrected visual acuity was 1.5 with normal intraocular pressure. During observation, the size of the tumor remained stable for 1.5 years but then rapidly grew, extending through the iris, and gradually enlarged to the point of compressing the iris. Ultimately, an iridocyclectomy with scleral resection under a lamellar scleral flap was performed. The histopathologic features of the resected tissue were consistent with adenoma of the NPCE. Histopathological analysis showed that the tumor consisted of both tubular and solid components. There were solid lesions inside of the ciliary epithelium and tubular lesions outside. We observed positive immunoreactivity to vimentin and cytokeratin CK (AE1/AE3) and negative reactivity to S-100 and CD68, both rarely associated with adenoma of NPCE. During 1 year of follow-up after the iridocyclectomy, no signs of tumor recurrence were observed.
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http://dx.doi.org/10.1159/000497033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6489088PMC
February 2019

Diagnostic evaluation of optical coherence tomography angiography and fundus autofluorescence in bilateral diffuse uveal melanocytic proliferation.

Am J Ophthalmol Case Rep 2018 Sep 21;11:32-34. Epub 2018 Apr 21.

Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan.

Purpose: To demonstrate the utility of optical coherence tomography angiography (OCTA) in visualizing the choroidal vasculature in bilateral diffuse uveal melanocytic proliferation (BDUMP), so as to elucidate pathophysiology and also aid in diagnosis. Additionally, to recommend autofluorescence (AF) over traditional angiography for purposes of noninvasive diagnosis.

Observations: Three BDUMP cases are examined using AF, and two are examined using OCTA. Additionally, the cases vary in etiology and include a case with iris cysts, which we believe to have only been recorded once before in scientific literature, steroids were successfully used to treat two cases and anti-tumor drugs were used to treat the third case. OCTA revealed altered choroidal vasculature in the two cases tested, and AF was successfully used to diagnose all three cases regardless of etiology.

Conclusions And Importance: We believe the OCTA findings are potentially elucidative regarding the pathophysiology at the choroidal layer, where BDUMP lesions primarily exist. Given the limited number of recorded BDUMP cases and relatively unknown pathophysiology, OCTA may prove to be invaluable in visualizing disease progression. Also we were able to use AF to diagnose all three cases ranging from extremely rare iris cysts to a more conventional presentation, indicating its utility regardless of etiology.
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http://dx.doi.org/10.1016/j.ajoc.2018.04.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097180PMC
September 2018

Atypical indocyanine green angiography findings after indocyanine green-assisted internal limiting membrane peeling.

Can J Ophthalmol 2018 08 11;53(4):e158-e162. Epub 2017 Dec 11.

Osaka University Graduate School of Medicine, Osaka, Japan.

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http://dx.doi.org/10.1016/j.jcjo.2017.10.025DOI Listing
August 2018

Adalimumab in Active and Inactive, Non-Infectious Uveitis: Global Results from the VISUAL I and VISUAL II Trials.

Ocul Immunol Inflamm 2019 17;27(1):40-50. Epub 2018 Jul 17.

c Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine , Hokkaido University , Sapporo , Japan.

Purpose: Report global adalimumab safety and efficacy outcomes in patients with non-infectious uveitis.

Methods: Adults with non-infectious intermediate, posterior, or panuveitis were randomized 1:1 to receive placebo or adalimumab in the VISUAL I (active uveitis) or VISUAL II (inactive uveitis) trials. Integrated global and Japan substudy results are reported. The primary endpoint was time to treatment failure (TF).

Results: In the integrated studies, TF risk was significantly reduced (hazard ratio [95% CI]) with adalimumab versus placebo (VISUAL I: HR = 0.56 [0.40-0.76], p < 0.001; VISUAL II: HR = 0.52 [0.37-0.74], p < 0.001). In Japan substudies, no consistent trends were observed between groups (VISUAL I: HR = 1.20 [0.41-3.54]; VISUAL II: HR = 0.45 [0.20-1.03]). Adverse event rates were similar between treatment groups in both studies (854 to 1063 events/100 participant-years).

Conclusions: Adalimumab lowered time to TF versus placebo in the integrated population; no consistent trends were observed in Japan substudies. Safety results were consistent between studies.
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http://dx.doi.org/10.1080/09273948.2018.1491605DOI Listing
November 2019

Corneal infiltration and xanthoma formation in mycosis fungoides.

Am J Ophthalmol Case Rep 2018 Sep 20;11:95-97. Epub 2018 Jun 20.

Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan.

Purpose: To report a case of corneal infiltration and xanthoma formation in mycosis fungoides (cutaneous T-cell lymphoma).

Observations: A middle aged Japanese man with mycosis fungoides (MF) involving the face was referred to Ophthalmology for evaluation of unilateral, painless conjunctival injection. Biopsy of the conjunctiva revealed a malignant T cell population consistent with MF tumor invasion. Years later, he returned following several episodes of infectious keratitis with a painless, yellow, rapidly forming mass in the left eye over two weeks. Corneal biopsy showed foamy histiocytes and positive staining for CD68, and a diagnosis of corneal xanthoma was made.

Conclusions And Importance: Severe ocular surface disease can rarely occur in MF by direct invasion of tumor cells. Corneal infiltration and xanthoma development may be avoidable by careful monitoring for infectious keratitis in patients with conjunctival involvement, as in our case.
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http://dx.doi.org/10.1016/j.ajoc.2018.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040233PMC
September 2018

Chronic Retinal Necrosis Severely Complicated by Neovascular Glaucoma: A Case Report.

Case Rep Ophthalmol 2017 Sep-Dec;8(3):489-495. Epub 2017 Oct 26.

Department of Ophthalmology Osaka University Graduate School of Medicine, Suita, Japan.

Background: Chronic retinal necrosis (CRN) is a rare chronic granular necrotizing retinitis that was first described in 2013. CRN is characterized by intraocular inflammation accompanied by occlusive vasculitis, granular retinitis, and slowly progressing necrosis around the retina in a host with partial immune dysfunction. Cytomegalovirus (CMV) is reported to be a causative agent. There are several ocular complications such as retinal detachment and neovascular glaucoma; however, there has been no description of a clinical manifestation of neovascular glaucoma in CRN. We herein present a case of severe neovascular glaucoma in association with CRN.

Case Presentation: An 80-year-old man was referred to our hospital with poor control of inflammation and intraocular pressure (IOP). The IOP in his left eye was 29 mm Hg. Anterior chamber cells (2+) and keratic precipitates were observed. In the peripheral retina, vitreous opacities and granular necrotizing retinitis were noticed. Fluorescein angiography revealed extensive retinal nonperfusion area from the macula lesion to the periphery. PCR analysis of aqueous humor showed the presence of CMV. A diagnosis of CRN was made soon afterwards. Antiviral drug and systemic corticosteroid were administered. The treatment temporally resolved the symptom; however, panretinal photocoagulation and intravitreal injection of bevacizumab were performed to treat iris neovascularization. During the follow-up, trabeculectomy was performed because of poor IOP control. At the final visit, severe uncontrolled neovascular glaucoma caused hyphema, and his left eye lost light perception.

Conclusion: The prognosis of CRN is poor because of severe neovascular glaucoma and careful observation and active treatments are necessary.
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http://dx.doi.org/10.1159/000480724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731101PMC
October 2017

Hemorrhagic hypopyon as presenting feature of intravascular lymphoma, a case report.

BMC Ophthalmol 2017 Oct 25;17(1):195. Epub 2017 Oct 25.

Department of Ophthalmology, Osaka University Medical School, E7, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Background: Herpes uveitis has been previously reported to present with hyphema, but hemorrhagic hypopyon is rarely reported as a herpetic uveitis manifestation. We report a case of herpes simplex virus (HSV) presenting with hemorrhagic hypopyon, and speculate on the underlying pathophysiology with relation to an intravascular lymphoma which was subsequently diagnosed as a result.

Case Presentation: We present a case wherein a 62-year-old Japanese rheumatoid arthritis woman, with HSV uveitis, presented with hemorrhagic hypopyon in the anterior chamber and a fever with photophobia. Patient was treated with antiviral drugs which improved the hyphema and corneal lesions, but lesions recurred 3 months later. This rare presentation of HSV induced uveitis, and its subsequent recurrence, aroused suspicion of an additional hypopyon-inducing pathology. On account of previous history of lung opacities and elevated LDH, intravascular lymphoma was eventually diagnosed via lung biopsy. She was treated for the lymphoma which also completely resolved all ocular symptoms without any recurrence as of 1.5 years later.

Conclusion: The exceedingly rare presentation of hemorrhagic hypopyon may have been enabled by an interaction of the HSV with the intravascular lymphoma. HSV involvement was indicated by the dendritic lesions, IgG assay, and response to anti-viral drugs. The ocular involvement of the intravascular lymphoma seems to be indicated by virtue of the anti-tumor drugs completely resolving all ocular symptoms.
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http://dx.doi.org/10.1186/s12886-017-0591-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5657083PMC
October 2017

Identification of ANGPT2 as a New Gene for Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy in the Chinese and Japanese Populations.

Invest Ophthalmol Vis Sci 2017 02;58(2):1076-1083

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China 3Shantou University/The Chinese University of Hong Kong Joint Shantou International Eye Center, Shantou, China 4Prince of Wales Hospital Eye Centre, Hong Kong, China.

Purpose: We determine the angiopoietin 2 (ANGPT2) gene as a new susceptibility gene for neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV).

Methods: A total of 34 haplotype-tagging single-nucleotide polymorphisms (SNPs) were first genotyped in an exploratory Hong Kong Chinese cohort. Suggestive SNPs were replicated in a Shantou Chinese cohort and an Osaka Japanese cohort, with a total of 2343 subjects. The SNP rs800292 in the complement factor H (CFH) gene was genotyped in all the subjects. Genetic association and gene-gene interaction were analyzed.

Results: In the Hong Kong cohort, four SNPs in ANGPT2 (rs13255574, rs4455855, rs13269021, and rs11775442) were nominally associated with nAMD and PCV. The four ANGPT2 SNPs showed the same trends of association in the Shantou and Osaka cohorts. Combining the data from the 3 study cohorts revealed that SNPs rs4455855 and rs13269021 achieved study-wise significance (P < 0.0016), conferring an approximately 1.3-fold of increased risk for nAMD and PCV. Interaction analysis revealed the CFH SNP rs800292 has a highly significant interaction with the ANGPT2 SNP rs13269021 in nAMD and PCV in the combined analysis. Subsequent stratification analysis confirmed the interaction.

Conclusions: This study reveals ANGPT2 as a new susceptibility gene for nAMD and PCV, and it may affect disease susceptibility in association with CFH. Thus, this report provides new insights into the genetic architecture of nAMD and PCV.
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http://dx.doi.org/10.1167/iovs.16-20575DOI Listing
February 2017

Clinical Findings of Anterior Segment Spectral Domain Optical Coherence Tomography Images in Cytomegalovirus Corneal Endotheliitis.

Cornea 2017 Apr;36(4):411-414

Department of Ophthalmology, Graduate School of Medicine, Osaka University, Osaka, Japan.

Purpose: To evaluate the morphological characteristics of posterior corneal regions including keratic precipitates in eyes with cytomegalovirus (CMV) corneal endotheliitis using anterior segment spectral domain optical coherence tomography (SD-OCT).

Methods: Thirteen eyes of 13 patients with polymerase chain reaction-proven CMV corneal endotheliitis were included in this study. Slit-lamp images and anterior segment SD-OCT images of the posterior cornea were obtained to analyze the clinical characteristics of corneal structures and keratic precipitates. Morphological changes in the posterior cornea throughout the course of an antiviral treatment were also investigated.

Results: Anterior SD-OCT images showed protruding structures at the posterior cornea. These protruding structures exhibited dendritic, dome-shaped, quadrangular, or saw-tooth appearance, and reflectivity of these structures was high. Reflectivity of posterior corneal images including the endothelium and deep stromal corneal regions were also high (76.9%). Because corneal inflammation and corneal edema improved, the protruding structures and high-intensity regions of posterior corneal images were resolved after a course of antiviral treatment.

Conclusions: The anterior segment SD-OCT examination represents a useful noninvasive alternative to diagnose and monitor CMV corneal endotheliitis.
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http://dx.doi.org/10.1097/ICO.0000000000001103DOI Listing
April 2017

Feasibility study of a non-invasive eye fixation and monitoring device using a right-angle prism mirror for intensity-modulated radiotherapy for choroidal melanoma.

J Radiat Res 2017 May;58(3):386-396

Department of Ophthalmology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.

We aimed to describe the feasibility and efficacy of a novel non-invasive fixation and monitoring (F-M) device for the eyeballs (which uses a right-angle prism mirror as the optic axis guide) in three consecutive patients with choroidal melanoma who were treated with intensity-modulated radiotherapy (IMRT). The device consists of an immobilization shell, a right-angle prism mirror, a high magnification optical zoom video camera, a guide lamp, a digital voice recorder, a personal computer, and a National Television System Committee standard analog video cable. Using the right-angle prism mirror, the antero-posterior axis was determined coincident with the optic axis connecting the centers of the cornea and pupil. The axis was then connected to the guide light and video camera installed on the couch top on the distal side. Repositioning accuracy improved using this method. Furthermore, the positional error of the lens was markedly reduced from ±1.16, ±1.68 and ±1.11 mm to ±0.23, ±0.58 and ±0.26 mm in the horizontal direction, and from ±1.50, ±1.03 and ±0.48 mm to ±0.29, ±0.30 and ±0.24 mm in the vertical direction (Patient #1, #2 and #3, respectively). Accordingly, the F-M device method decreased the planning target volume size and improved the dose-volume histogram parameters of the organ-at-risk via IMRT inverse planning. Importantly, the treatment method was well tolerated.
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http://dx.doi.org/10.1093/jrr/rrw104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440859PMC
May 2017

Association of ABCG1 With Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy in Chinese and Japanese.

Invest Ophthalmol Vis Sci 2016 Oct;57(13):5758-5763

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China 4Joint Shantou International Eye Center, Shantou, China 5Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong, China.

Purpose: We investigated the association of the ATP-binding cassette, subfamily G, member 1 (ABCG1) gene with polypoidal choroidal vasculopathy (PCV) and neovascular age-related macular degeneration (nAMD) in independent Chinese and Japanese cohorts.

Methods: A total of 12 haplotype-tagging single-nucleotide polymorphisms (SNPs) and the SNP rs57137919 in the ABCG1 gene were first analyzed in a Hong Kong Chinese cohort of 235 nAMD, 236 PCV, and 365 controls, using TaqMan genotyping assays. Two SNPs (rs57137919 and rs225396) that showed a disease-association were genotyped in a Shantou Chinese cohort of 189 nAMD, 187 PCV, and 670 controls, and an Osaka Japanese cohort of 192 nAMD, 204 PCV, and 157 controls, totaling 2435 subjects. Association analysis was performed in individual cohorts, followed by a pooled analysis of the data from all three cohorts.

Results: In the Hong Kong cohort, SNP rs57137919 was associated with PCV (odds ratio [OR] = 1.35). A tagging SNP rs225396 was associated with nAMD (OR = 1.28) and PCV (OR = 1.32). In the Osaka cohort, SNP rs225396 was associated with nAMD (OR = 1.42) and PCV (OR = 1.74). In the pooled analysis involving the 3 study cohorts, rs225396 showed an enhanced association with nAMD (P = 0.01, OR = 1.21, I2 = 14%) and PCV (P = 0.0001, OR = 1.35, I2 = 46%).

Conclusions: In this study, we have newly identified a haplotype-tagging SNP, rs225396, in ABCG1 to be associated with PCV and nAMD in Chinese and Japanese cohorts. This provides new evidence to support ABCG1 as a susceptibility gene for PCV and nAMD. Further replication in other populations should be warranted.
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http://dx.doi.org/10.1167/iovs.16-20175DOI Listing
October 2016

Recurrent pseudohypopyon in association with primary vitreoretinal lymphoma: a case report.

BMC Ophthalmol 2016 Jul 8;16:103. Epub 2016 Jul 8.

Department of Ophthalmology, Osaka University Graduate School of Medicine, E7, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Background: Primary vitreoretinal lymphoma (PVRL) is a rare and fatal ocular malignancy that is mostly classified as diffuse large B cell lymphoma (DLBCL). PVRL is often fatal because of its association with the central nervous system (CNS). PVRL frequently masquerades as uveitis and sometimes recurs in clinical findings as keratic precipitates (KPs) and subretinal lesions. Pseudohypopyon is one of the clinical findings of the local recurrence of PVRL and is treated with radiotherapy; however, the effectiveness of local control with an intravitreal injection of methotrexate (MTX) has not yet been determined. We herein present a case of recurrent vitreoretinal lymphoma that repeatedly developed pseudohypopyon and treated with intravitreal MTX.

Case Presentation: A 64-year-old woman was diagnosed with PVRL involving primary central nervous system lymphoma (PCNSL). She received radiotherapy to the whole brain and a local ocular treatment, which resulted in temporary remission of the disease. Pseudohypopyon was detected during the follow-up. It was 2-mm high, viscous, and swollen in the center. Anterior chamber biopsy revealed the presence of atypical lymphocytes, indicating the recurrence of DLBCL. Pseudohypopyon was treated with intravitreal methotrexate and completely disappeared. Pseudohypopyon has since repeatedly appeared and been treated with intravitreal MTX each time. The recurrence of PVRL with KPs and subretinal invasion was treated with intravitreal MTX each time. Recurrence with pseudohypopyon was not simultaneous with KPs or subretinal invasion. No CNS involvement was detected during the observation period.

Conclusions: Pseudohypopyon is one of the signs of recurrent vitreoretinal lymphoma. Although pseudohypopyon was temporarily controlled with intravitreal MTX, this treatment did not completely induce its remission.
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http://dx.doi.org/10.1186/s12886-016-0279-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939057PMC
July 2016

Ethnic specific association of the CAV1/CAV2 locus with primary open-angle glaucoma.

Sci Rep 2016 06 14;6:27837. Epub 2016 Jun 14.

Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong, Hong Kong, China.

A single-nucleotide polymorphism (SNP) rs4236601 at the CAV1/CAV2 locus is associated with primary open-angle glaucoma (POAG). Rs4236601 is common in Caucasians but rare in East Asians. Here we conducted a haplotype-tagging SNP analysis followed by replication in a total of 848 POAG cases and 1574 controls drawn from 3 cities in China and 1 city in Japan. Two SNPs, rs4236601 (odds ratio [OR] = 6.25; P = 0.0086) and a tagging-SNP rs3801994 (OR = 1.32; P = 0.042), were associated with POAG in the Hong Kong Chinese cohort after age and gender adjustments. Rs4236601 was associated with POAG also in Shantou (OR = 6.09; P = 0.0037) and Beijing (OR = 3.92; P = 0.030) cohorts after age and gender adjustment, with a pooled-OR of 5.26 (P = 9.0 × 10(-6)) in Chinese; but it is non-polymorphic in the Osaka cohort. SNP rs3801994 showed a similar trend of effect in the Shantou and Beijing cohorts, with a pooled-OR of 1.23 (P = 0.022) and 1.20 (P = 0.063) in Chinese, prior to and after age and gender adjustment, respectively; but it showed a reverse effect in the Osaka cohort (OR = 0.58; P = 0.033) after the adjustments. We have thus confirmed the association of rs4236601 with POAG in different Chinese cohorts. Also, we found a common SNP rs3801994 of diverse associations with POAG between Chinese and Japanese.
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http://dx.doi.org/10.1038/srep27837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906515PMC
June 2016

Optical coherence tomography manifestations of primary vitreoretinal lymphoma.

Graefes Arch Clin Exp Ophthalmol 2016 Dec 1;254(12):2319-2326. Epub 2016 Jun 1.

Department of Ophthalmology, Osaka University Medical School, 2-2 Yamadaoka E7, Suita, Osaka, 565-0871, Japan.

Background: Primary vitreoretinal lymphoma (PVRL), a subset of primary central nervous system lymphoma (PCNSL), is a high-grade malignant tumor that shows various chorioretinal findings. Optical coherence tomography (OCT) is useful for detecting these lesions, and various abnormalities on OCT images have been reported. The purpose of this report was to investigate retrospectively the OCT manifestations of various disease stages and compare the manifestations of pretreatment, recurrent, and chronic cases.

Methods: We reviewed the medical charts and OCT images of 38 consecutive cases with PVRL. When abnormalities were detected on OCT images, the patients were classified based on the treatment of the primary disease: pretreatment if not treated, recurrent if treated previously, and chronic when chronic changes.

Results: Twenty-six eyes (20 cases) had abnormalities in the post-pole OCT images, i.e., 16 eyes (12 cases) were in the pretreatment group, seven eyes (five cases) were in the recurrent group, and five eyes (five cases) were in the chronic group. Two eyes (two cases) had abnormalities on OCT in the pretreatment and recurrent or chronic stages. The pretreatment and recurrent groups had subretinal or retinal pigment epithelium (RPE) level abnormalities more often than intraretinal changes. Twelve of 16 pretreated eyes and all seven eyes with recurrent disease had subretinal or RPE level abnormalities. One pretreatment case and three recurrent cases had atypical OCT manifestations of intraretinal (round lesions) or epiretinal changes (villous-shaped lesions).

Conclusions: Although pretreatment cases and recurrent cases showed similar OCT abnormalities and the specific changes in the various disease stages were unclarified, collecting OCT data from various disease stages will facilitate detection of typical OCT changes of PVRL and lead to early diagnosis and treatment.
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http://dx.doi.org/10.1007/s00417-016-3395-xDOI Listing
December 2016

Rare Association of Perivascular Granulomatous Lesions in a Patient with Acute Retinal Necrosis.

Case Rep Ophthalmol 2015 Sep-Dec;6(3):373-9. Epub 2015 Nov 21.

Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan.

Purpose: The aim of this study was to examine sequential changes in perivascular granulomatous lesions with acute retinal necrosis (ARN).

Methods: A healthy 46-year-old Japanese woman, who developed floaters and pain in her left eye, underwent optical coherence tomography (OCT), fluorescein angiography, and routine ophthalmological examinations. Treatment-associated changes in perivascular granulomatous lesions were monitored using spectral-domain (SD)-OCT.

Results: The patient had no previous ophthalmic history, and her general condition was good. A slit-lamp examination revealed keratic precipitates and aqueous cells (2+) in the left eye. A fundus examination showed yellow-white patches of necrotizing retinal lesions in the temporal upper area, retinal arteritis, retinal hemorrhage, and vitreous opacities. The patient was diagnosed with ARN according to diagnostic criteria. SD-OCT images confirmed high-intensity and uniform granulomatous deposits in the perivascular area and fovea. Systemic corticosteroids and antiviral therapy were initiated, resulting in the gradual resolution of granulomatous lesions. The patient continues to be followed untreated without evidence of recurrence, retinal detachment, or active inflammation.

Conclusions: This is the first report of perivascular granulomatous lesions in a patient with ARN. Our results showed that the formation of granulomas may be induced in the retina of ARN patients without fulminant inflammation.
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http://dx.doi.org/10.1159/000442084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4677696PMC
December 2015

Incidence and clinical features of recurrent Vogt-Koyanagi-Harada disease in Japanese individuals.

Jpn J Ophthalmol 2015 May 26;59(3):157-63. Epub 2015 Mar 26.

Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan.

Purpose: Our aim was to determine the recurrence rate of inflammation in Vogt-Koyanagi-Harada (VKH) disease and to describe its clinical features.

Methods: We retrospectively evaluated patients diagnosed as having VKH disease with exudative retinal detachment at the Osaka University Hospital or the Japanese Community Healthcare Organization, Osaka Hospital, between 1998 and 2012. All patients received high-dose corticosteroid therapy as the initial treatment and were followed for at least 6 months. Demographic data, including age, sex, visual acuity (VA) levels at initial presentation and at 1 year after initial therapy, treatment received, and recurrent episodes were reviewed.

Results: Fifty-five consecutive patients with VKH disease were identified (36 women; mean age 38.6 ± 10.4 years). Fourteen patients (25.5 %) had recurrent inflammation, which manifested as posterior uveitis in eight and as anterior uveitis in six of the patients. Recurrent posterior segment inflammation was more likely to develop in patients whose VA at initial presentation was poor (P = 0.039) and in whom orally administered corticosteroid was tapered rapidly (to 30 mg within 3 weeks or less, to 20 mg within 2 months or less, and to 10 mg within 3 months or less) (P = 0.006, P = 0.066, and P = 0.041, respectively).

Conclusions: About 25 % of patients with VKH disease had recurrent inflammation. Poor initial VA and rapid tapering of the corticosteroid were associated with posterior recurrence.
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http://dx.doi.org/10.1007/s10384-015-0377-1DOI Listing
May 2015

[Diagnostic evaluation of sarcoid choroidal granuloma using high-penetration optical coherence tomography].

Nippon Ganka Gakkai Zasshi 2014 Dec;118(12):1013-9

Objectives: We report a case of sarcoidosis that manifested as choroidal granuloma. We followed the treatment-associated changes in the granulomatous lesion by serial examinations using high-penetration optical coherence tomography (HP-OCT).

Case: A 77-year-old woman, who was referred to our clinic with granulomatous uveitis, presented initially with a yellowish-white subretinal granuloma formation surrounding the left optic disk. On presentation, diffuse keratic precipitates, anterior chamber inflammation and snowball-like vitreous opacity were observed. The HP-OCT image of subretinal lesion showed a low density choroidal space-occupying lesion. Due to the presence of bilateral hilar lymphadenopathy based on a close inspection of the entire body and abnormal cardiac/mediastinal uptake with positron emission tomography in combination with computed tomography (PET-CT), the definite clinical diagnosis group of sarcoidosis was made. Sub-Tenon injection of triamcinolone acetonide (STTA) was administered. In response to the treatment, HP-OCT showed that the choroidal granuloma had disappeared. Six months after treatment, the lesion recurred, however, this choroidal lesion resolved on OCT within the following 6 months in response to an STTA injection. As a complete atrioventricular block was observed during the follow-up, a pacemaker was implanted.

Discussion: The findings and clinical course strongly suggested choroidal granuloma of ocular sarcoidosis. HP-OCT allowed a detailed observation of the space-occupying lesion and helped make a diagnosis and observe the course of treatment.
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December 2014

Choroidal nevus in an eye with polypoidal choroidal vasculopathy.

Case Rep Ophthalmol 2014 Sep-Dec;5(3):463-7. Epub 2014 Dec 13.

Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan.

Purpose: To report an eye with polypoidal choroidal vasculopathy (PCV) and a choroidal nevus.

Methods: This is an observational case report.

Results: A healthy 69-year-old woman was referred to the Osaka University Hospital with a diagnosis of a macular tumor. She complained of having distorted vision in her left eye. The medical history of the patient was unremarkable. At the initial examination, her best-corrected visual acuity (BCVA) was 20/20 in both eyes, and the intraocular pressure was 18 mm Hg in both eyes. A slit-lamp examination showed no abnormalities in the anterior segment of both eyes and a fundus examination of the left eye showed a slightly elevated juxtafoveal chorioretinal lesion and polyp-like reddish-orange lesions. The juxtafoveal choroidal lesion was located beneath a choroidal neovascularization (CNV). An optical coherence tomography confirmed CNV with pigment epithelial detachment (PED). Fluorescein angiography showed juxtafoveal hyperfluorescence due to CNV. Indocyanine green angiography demonstrated a branching choroidal vascular network that resembled polypoidal lesions. A fundus autofluorescence showed a mosaic pattern and a slight hyperautofluorescence at the CNV. We diagnosed the patient as having PCV. Aflibercept was injected intravitreally because of her PED. After the injection, PED improved and her visual acuity remained stable during the 12-month follow-up period.

Conclusions: In cases of PCV, FAF images are helpful in determining the status of the posterior pole. Intravitreal injections of aflibercept can improve PED associated with CNV, and the BCVA will remain stable for at least 12 months.
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http://dx.doi.org/10.1159/000370044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4296248PMC
January 2015

Choroidal excavation in vogt-koyanagi-harada disease.

Case Rep Ophthalmol 2014 May 16;5(2):222-5. Epub 2014 Jul 16.

Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan.

Purpose: To report a case of choroidal excavation accompanied by Vogt-Koyanagi-Harada disease (VKH).

Methods: A 54-year-old Japanese woman who was complaining of bilateral blurring of vision associated with headache underwent optical coherence tomography (OCT), fluorescein angiography, and indocyanine green angiography as well as a routine ophthalmological examination.

Results: Fundoscopy showed papilloedema and serous retinal detachment in both eyes. Fluorescein angiography detected bilateral multifocal leakage with pooling of dye in the subretinal space. Indocyanine green angiography showed patches of hyperfluorescence and hypofluorescent spots bilaterally. A diagnosis of VKH was reached soon afterwards. OCT of the left eye revealed the presence of a unilateral choroidal excavation under the fovea and subretinal fibrin over the site of the excavation. Treatment successfully resolved VKH symptoms with gradual resolution of subretinal fibrin and fluid; however, the choroidal excavation remained.

Conclusions: This case is the first report of choroidal excavation associated with VKH. Our results suggest that choroidal excavation can be induced by choroidal inflammation caused by VKH.
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http://dx.doi.org/10.1159/000365441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4152928PMC
May 2014

Adaptive replanning intensity-modulated radiotherapy for choroidal metastasis of breast cancer using optical coherence tomography.

J Radiat Res 2014 May 4;55(3):502-8. Epub 2014 Apr 4.

Miyakojima IGRT Clinic, 1-16-22 Miyakojima-ku, Osaka, 534-0021, Japan.

Swept source optical coherence tomography (SS-OCT) is a convenient method for precise, early-stage detection of choroidal metastatic lesions, involving assessment of tumor response, and for regular follow-up studies. Using information obtained with SS-OCT, we performed intensity-modulated radiotherapy (IMRT) for a patient with choroidal metastasis from breast cancer with more accuracy than had been previously possible. We made replanning adaptive radiotherapy (ART) three times based on the rapid tumor shrinkage detected by weekly assessments with SS-OCT. Accordingly, the planning target volume (PTV) decreased from 1.6 cm(3) to 0.61 cm(3) (38%), with 0.95 cm(3) (59%) and 0.75 cm(3) (46%) as intermediate values during the treatment course. The D0.1 cm3 of the right optic nerve was also reduced from 1.70 Gy/fraction to 0.69 Gy/faction, with 1.41 Gy/fraction and 1.29 Gy/fraction as intermediate values. Adaptive replanning IMRT made it possible to perform locally curative treatment of the metastatic choroidal lesion with a higher dose for the PTV, and a lower dose for organs at risk (OARs).
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http://dx.doi.org/10.1093/jrr/rru023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014173PMC
May 2014

Diagnostic evaluation of ocular toxocariasis using high-penetration optical coherence tomography.

Case Rep Ophthalmol 2014 Jan 8;5(1):16-21. Epub 2014 Jan 8.

Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan.

Purpose: To study a case with intraretinal Toxocara larvae in a granuloma using high-penetration optical coherence tomography (HP-OCT).

Methods: A 50-year-old man, who was referred to our clinic with ocular toxocariasis, initially presented with granuloma formation in the retina. We followed the treatment-associated changes in the toxocariasis lesion by a series of examinations using HP-OCT before and after a systemic corticosteroid and anthelmintic therapy.

Results: The posterior pole granuloma initially appeared as a yellowish-white intraretinal lesion with an exudative focus and dye leakage seen on angiography. After therapy, the lesion was no longer exudative. During treatment-free periods, an intraretinal lesion was seen protruding from the retinal surface into the vitreous cavity. HP-OCT confirmed the elevated lesion protruding from the retinal surface into the vitreous cavity. With treatment, the protruding focus flattened during the following 8 months, but the lesion recurred after the treatment stopped.

Conclusions: The findings and clinical course strongly suggested ocular toxocariasis. The protruding retinal lesion may have been an ocular manifestation of toxocariasis. HP-OCT was useful in the follow-up and diagnosis.
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http://dx.doi.org/10.1159/000358191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3934803PMC
January 2014

Association between ocular findings and preventive therapy with onset of central nervous system involvement in patients with primary vitreoretinal lymphoma.

Graefes Arch Clin Exp Ophthalmol 2014 Apr 19;252(4):687-93. Epub 2014 Feb 19.

Department of Ophthalmology, Osaka University Graduate School of Medicine, E7, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan,

Purpose: To investigate if the site of ocular lesions and prophylactic treatment in patients with primary vitreoretinal lymphoma (PVRL) are associated with the time to onset of central nervous system (CNS) involvement.

Methods: We retrospectively studied 26 patients (seven men, 19 women; mean age, 67.0 ± 11.1 years) with a diagnosis of PVRL at our hospital between January 2001 and October 2011 and a minimum 2-year follow-up after treatment. We classified the PVRL lesions as: (1) the vitreous opacity type, vitreous opacity of 2+ or higher without retinal lesions, (2) the retina type, vitreous opacity of 1+ or less with retinal lesions only, or (3) the concomitant type, with both. We also evaluated whether prophylactic treatment of systemic chemotherapy such as high-dose methotrexate (HD-MTX) and intrathecal MTX (IT-MTX), or topical ocular treatments such as intravitreal injections of MTX and rituximab, inhibited the onset of CNS involvement in patients with PVRL without cerebral involvement.

Results: During a mean follow-up of 44.0 ± 18.7 months, CNS involvement began in 14 patients (53.8 %), i.e., three (60 %) of five patients with retina-type lesions, five (41.7 %) of 12 patients with vitreous opacity-type lesions, and six (66.7 %) of nine patients with concomitant-type lesions. There was no significant (P = 0.496) association between the site of the ocular lesions and the onset of brain lesions. In addition, CNS involvement occurred in eight of 11 patients receiving CNS prophylactic chemotherapy and six of 15 patients receiving no prophylaxis; the difference between the two did not reach significance (P = 0.131). The time to onset of cerebral involvement in the CNS prophylactic chemotherapy group (42.8 ± 13.8 months) was significantly (P = 0.0005) longer than in the group that did not receive prophylaxis (10.2 ± 2.0 months). Preventive systemic chemotherapy, especially HD-MTX, significantly prolonged the time to the onset of brain lesions compared to IT-MTX and local ocular therapy.

Conclusions: While prophylactic systemic chemotherapy did not inhibit the onset of CNS involvement in most of patients with PVRL, it significantly prolonged the time to cerebral involvement.
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http://dx.doi.org/10.1007/s00417-014-2584-8DOI Listing
April 2014