Publications by authors named "Yoshihiko Usui"

144 Publications

Intraocular surgery under adalimumab therapy in patients with refractory uveitis: a single center study of 23 eyes.

Jpn J Ophthalmol 2021 Sep 7. Epub 2021 Sep 7.

Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, Japan.

Purpose: We assessed the efficacy and safety of performing intraocular surgery for refractory uveitis under adalimumab (ADA) therapy.

Study Design: Single-center cohort study between 2016 and 2019.

Methods: In uveitis patients undergoing intraocular surgery under ADA treatment, we collected clinical data before surgery, and at the first visit, 6 months and last visit after surgery (follow-up 19.3 ± 8.1 months). Primary outcomes were visual acuity (VA) improvement in patients after cataract surgery, intraocular pressure (IOP) in patients after trabeculectomy and intraocular inflammation in all patients. Secondary outcomes were activated inflammation, vitreous opacity (OCV), uveitic macula edema (UME) and infection.

Results: Of 81 patients (161 eyes) initiated ADA therapy for uveitis, 19 patients (23 eyes) underwent intraocular surgery and were analyzed. Twelve of 18 eyes (66.6%) that underwent cataract surgery or vitrectomy with/without cataract surgery had improved VA at the last visit compared to before surgery. All 5 eyes that underwent trabeculectomy showed controlled IOP 6 months after surgery. Intraocular inflammation was resolved in 22 of 23 eyes at the first postoperative visit. Postoperative intraocular inflammation recurred in 3 eyes; 2 with UME, 1 with OCV. No eyes developed infection postoperatively. Preoperative ADA therapy duration was unrelated to relapse of intraocular inflammation.

Conclusion: Surgery for refractory uveitis under ADA treatment is safe and achieves good visual outcome and uveitis control if inflammation exists before surgery. ADA does not increase the risk of infections. Intraoperative findings of UME at surgery requires attention for postoperative relapse.
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http://dx.doi.org/10.1007/s10384-021-00871-3DOI Listing
September 2021

Clinico-epidemiological analysis of 1000 cases of orbital tumors.

Jpn J Ophthalmol 2021 Sep 27;65(5):704-723. Epub 2021 Jul 27.

Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.

Purpose: To clarify the incidence, demography and clinical features of orbital tumors diagnosed in a single institute in Japan.

Study Design: Retrospective, observational case series.

Methods: Patients with primary orbital tumors including tumor-like lesions diagnosed clinically or histopathologically at Tokyo Medical University Hospital between 1995 and 2019 were analyzed. Incidence of all orbital tumors, demographic profile and clinical features of major benign and malignant tumors were reviewed retrospectively.

Results: Totally 1000 cases of primary orbital tumor were diagnosed clinically or histopathologically during the study period. Benign tumors accounted for 72% and malignant tumors 28%. 55% of benign tumors and 99% of malignant tumors were proven histopathologically. The most common benign orbital tumor was idiopathic orbital inflammation (27%), followed by IgG4-related ophthalmic disease (17%), cavernous venous malformation (13%) and pleomorphic adenoma (9%). The most common malignant tumor was lymphoma (70%), followed by adenoid cystic carcinoma (7%) and solitary fibrous tumor (5%).

Conclusions: Epidemiology of orbital tumors has changed by the improvement of imaging techniques, establishment of novel clinical and histopathological criteria, and changes in population age structure associated with the aging society. Currently, lymphoproliferative diseases including lymphoma and IgG4-related ophthalmic diseases form the major orbital tumors in Japan.
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http://dx.doi.org/10.1007/s10384-021-00857-1DOI Listing
September 2021

Iris metastasis as the initial presentation of metastatic esophageal cancer diagnosed by fine needle aspiration biopsy: A case report.

Medicine (Baltimore) 2021 Jun;100(22):e26232

Department of Ophthalmology, Keio University School of Medicine.

Rationale: Metastasis of neoplasms to the eye is quite uncommon. In this case report, we describe a patient where primary esophageal cancer was diagnosed by fine needle aspiration biopsy (FNAB) of an iris tumor.

Patient Concerns: A 70-year-old male complained of redness and discomfort in the right eye.

Diagnosis And Interventions: The patient's right eye was diagnosed as idiopathic uveitis, and a topical steroid was administered. As vitreous opacities were observed even after topical therapy, oral prednisolone was administered. On slit-lamp examination of the right eye, an iris mass with neovascularization was seen in the anterior chamber. A metastatic tumor was suspected, and FNAB was performed. Histology revealed squamous cell carcinoma. Systemic workup revealed esophageal cancer with several metastases. Best-corrected visual acuity decreased to 20/400, and intraocular pressure was 40 mmHg in the right eye. Two iris tumors with neovascularization were present extending into the anterior chamber with posterior iris synechiae and 360 degree peripheral anterior synechiae. Intraocular pressure in the right eye was medically managed with hypotensive eye drops and oral acetazolamide. Iris metastases were treated with 40 Gray of radiation therapy and concurrent chemotherapy.

Outcomes: The tumor regressed, but intraocular pressure was refractory to treatment because of 360 degree goniosynechial closure. The right eye lost light perception six months after treatment commenced, and the patient died 9 months after the onset of therapy due to multiple systemic metastases.

Lessons: This is a rare case of masquerade syndrome without systemic symptoms in which FNAB of an iris tumor led to a diagnosis of metastatic esophageal squamous cell carcinoma. Although the patient lost his sight due to uncontrollable ocular hypertension, systemic chemotherapy, and radiation therapy were initially effective in the treatment of the metastatic iris tumor. As the prognosis of patients with metastatic iris tumors is poor, it is important for ophthalmologists to consider such diagnoses and conduct systemic investigations when necessary.
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http://dx.doi.org/10.1097/MD.0000000000026232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183745PMC
June 2021

Programmed Cell Death-1 Pathway Deficiency Enhances Autoimmunity Leading to Dacryoadenitis of Mice.

Am J Pathol 2021 06 8;191(6):1077-1093. Epub 2021 Mar 8.

Department of Developmental Anatomy and Regenerative Biology, National Defense Medical College, Saitama, Japan. Electronic address:

Programmed cell death protein (PD)-1 is a coinhibitory molecule that suppresses immune response and maintains immune homeostasis. Moreover, the PD-1 pathway blocks cancers from being attacked by immune cells. Anti-PD-1 antibody therapy such as nivolumab improves survival in cancer patients. However, the occurrence of autoimmune inflammatory disorders in various organs has been increasingly reported as an adverse effect of nivolumab. Of the disorders associated with nivolumab, Sicca syndrome occurs in 3% to 11% of cases and has unknown pathologic mechanisms. Whether the absence of the PD-1 pathway causes functional and morphologic disorders in lacrimal glands was determined by analyzing PD-1 gene-knockout (Pdcd1) mice. Histopathologic analysis showed that Pdcd1 mice developed dacryoadenitis beginning at 3 to 4 months of age, and deteriorated with age. Flow-cytometric analysis confirmed that cells infiltrating the affected lacrimal glands consisted mainly of CD3 T cells and only a small proportion of CD19 B cells. Among infiltrating T cells, the CD4 Th-cell subset consisted of Th1 cells producing interferon-γ in an early stage of dacryoadenitis in Pdcd1 mice. Experiments of lymphocyte transfer from Pdcd1 into irradiated wild-type mice confirmed that CD4 T cells from Pdcd1 mice induced dacryoadenitis. These results indicate that PD-1 plays an important role in the prevention of autoimmune inflammatory disorders in lacrimal glands caused by activated CD4 Th1 cells.
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http://dx.doi.org/10.1016/j.ajpath.2021.02.014DOI Listing
June 2021

Optical coherence tomography angiography for the diagnosis of granulomatosis with polyangiitis with serous retinal detachment: A case report.

Medicine (Baltimore) 2021 Feb;100(7):e24789

Department of Ophthalmology, Nagoya University Graduate School of Medicine.

Rationale: Granulomatosis with polyangiitis (GPA) is a rare systemic autoimmune disease of unknown etiology. GPA affects multiple ocular tissues, most commonly the orbit, conjunctiva, cornea, and sclera. Retinal and choroidal manifestations are rare in GPA, but they often include choroidal neovascularization (CNV).

Patient Concerns: A 36-year-old man was diagnosed with GPA. He had been taking oral steroid treatment for 8 years. He experienced disease recurrence and the dose of oral prednisolone was increased after steroid pulse therapy. Fundus examination showed small retinal pigment epithelial detachment and serous retinal detachment (SRD). Optical coherence tomography (OCT) revealed a protruded lesion inside the SRD. Fluorescein angiography (FA) showed a small, dot-shaped fluorescein leakage in the SRD, and indocyanine green fluorescein fundus angiography showed choroidal vascular hyperpermeability that was consistent with the hyperfluorescence seen with FA. We had to determine whether the protruded lesion inside the SRD was CNV secondary to the inflammation due to GPA or whether it was central serous chorioretinopathy (CSC)-like condition caused by high-dose steroid treatment.

Diagnoses: We confirmed that the SRD was due to CSC but not CNV because the protruded lesion examined by B-scan OCT angiography (OCTA) showed no blood flow.

Interventions: We decided to reduce the dose of steroid.

Outcomes: Since the reduction of steroids, no sign of worsening in the protruded lesions with SRD has been observed.

Lessons: We therefore propose the effectiveness of this advanced function of OCTA for the examination of blood flow signal images to detect CNV.
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http://dx.doi.org/10.1097/MD.0000000000024789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899876PMC
February 2021

Clinicopathologic analysis of 32 ciliary body tumors.

Jpn J Ophthalmol 2021 Mar 19;65(2):237-249. Epub 2021 Feb 19.

Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.

Purpose: To describe the demographic profile, clinical and histopathologic features, and treatment of ciliary body tumors.

Study Design: Retrospective, observational case series.

Methods: Thirty-two patients (32 eyes) with ciliary body tumors diagnosed histopathologically at Tokyo Medical University Hospital between 1994 and 2017 were retrospectively reviewed.

Results: The patients' mean age at diagnosis was 45.4 ± 17.0 (range, 14-87) years. Ten of the patients were male, and 22, female. Twenty-four cases (75%) were benign tumors, comprising 9 melanocytomas, 7 adenomas, 4 mesectodermal leiomyomas, 2 leiomyomas, and 2 other tumors; and 8 cases (25%) were malignant tumors, comprising 6 melanomas and 2 low-grade adenocarcinomas. Local resection of the tumor was performed in 20 patients, including 3 cases of melanoma and 2 cases of adenocarcinoma. Enucleation was initially performed in 3 cases of melanoma, 1 case of melanocytoma with iris melanoma, and 2 cases of benign tumors difficult to differentiate clinically from melanoma. In the 17 patients who underwent local resection and were followed for at least 3 years, the outcome was best-corrected visual acuity better than 0.1 logMAR in 8 patients (47%), but hand motions in 2 patients (12%).

Conclusions: Melanocytoma and adenoma of the ciliary epithelium were the major ciliary body tumors found in this study. Management of ciliary body tumors with accurate clinical diagnosis remains challenging because of the anatomic characteristics and clinical similarities to melanoma in the majority of the cases.
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http://dx.doi.org/10.1007/s10384-021-00814-yDOI Listing
March 2021

Machine Learning Approach for Intraocular Disease Prediction Based on Aqueous Humor Immune Mediator Profiles.

Ophthalmology 2021 Aug 21;128(8):1197-1208. Epub 2021 Jan 21.

Department of Ophthalmology, Tokyo Medical University Hospital, Tokyo, Japan.

Purpose: Various immune mediators have crucial roles in the pathogenesis of intraocular diseases. Machine learning can be used to automatically select and weigh various predictors to develop models maximizing predictive power. However, these techniques have not yet been applied extensively in studies focused on intraocular diseases. We evaluated whether 5 machine learning algorithms applied to the data of immune-mediator levels in aqueous humor can predict the actual diagnoses of 17 selected intraocular diseases and identified which immune mediators drive the predictive power of a machine learning model.

Design: Cross-sectional study.

Participants: Five hundred twelve eyes with diagnoses from among 17 intraocular diseases.

Methods: Aqueous humor samples were collected, and the concentrations of 28 immune mediators were determined using a cytometric bead array. Each immune mediator was ranked according to its importance using 5 machine learning algorithms. Stratified k-fold cross-validation was used in evaluation of algorithms with the dataset divided into training and test datasets.

Main Outcome Measures: The algorithms were evaluated in terms of precision, recall, accuracy, F-score, area under the receiver operating characteristic curve, area under the precision-recall curve, and mean decrease in Gini index.

Results: Among the 5 machine learning models, random forest (RF) yielded the highest classification accuracy in multiclass differentiation of 17 intraocular diseases. The RF prediction models for vitreoretinal lymphoma, acute retinal necrosis, endophthalmitis, rhegmatogenous retinal detachment, and primary open-angle glaucoma achieved the highest classification accuracy, precision, and recall. Random forest recognized vitreoretinal lymphoma, acute retinal necrosis, endophthalmitis, rhegmatogenous retinal detachment, and primary open-angle glaucoma with the top 5 F-scores. The 3 highest-ranking relevant immune mediators were interleukin (IL)-10, interferon-γ-inducible protein (IP)-10, and angiogenin for prediction of vitreoretinal lymphoma; monokine induced by interferon γ, interferon γ, and IP-10 for acute retinal necrosis; and IL-6, granulocyte colony-stimulating factor, and IL-8 for endophthalmitis.

Conclusions: Random forest algorithms based on 28 immune mediators in aqueous humor successfully predicted the diagnosis of vitreoretinal lymphoma, acute retinal necrosis, and endophthalmitis. Overall, the findings of the present study contribute to increased knowledge on new biomarkers that potentially can facilitate diagnosis of intraocular diseases in the future.
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http://dx.doi.org/10.1016/j.ophtha.2021.01.019DOI Listing
August 2021

Differential Tissue Metabolic Signatures in IgG4-Related Ophthalmic Disease and Orbital Mucosa-Associated Lymphoid Tissue Lymphoma.

Invest Ophthalmol Vis Sci 2021 01;62(1):15

Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.

Purpose: To identify tissue metabolomic profiles in biopsy specimens with IgG4-related ophthalmic disease (IgG4-ROD) and mucosa-associated lymphoid tissue (MALT) lymphoma and investigate their potential implication in the disease pathogenesis and biomarkers.

Methods: We conducted a comprehensive analysis of the metabolomes and lipidomes of biopsy-proven IgG4-ROD (n = 22) and orbital MALT lymphoma (n = 21) specimens and matched adjacent microscopically normal adipose tissues using liquid chromatography time-of-flight mass spectrometry. The altered metabolomic profiles were visualized by heat map and principal component analysis. Metabolic pathway analysis was performed by Metabo Analyst 4.0 using differentially expressed metabolites. The diagnostic performance of the metabolic markers was evaluated using receiver operating characteristic curves. Machine learning algorithms were implemented by random forest using the R environment. Finally, an independent set of 18 IgG4-ROD and 17 orbital MALT lymphoma specimens were used to validate the identified biomarkers.

Results: The principal component analysis showed a significant difference of both IgG4-ROD and orbital MALT lymphoma for biopsy specimens and controls. Interestingly, lesions in IgG4-ROD were uniquely enriched in arachidonic metabolism, whereas those in orbital MALT lymphoma were enriched in tricarboxylic acid cycle metabolism. We identified spermine as the best discriminator between IgG4-ROD and orbital MALT lymphoma, and the area under the receiver operating characteristic curve of the spermine to discriminate between the two diseases was 0.89 (95% confidence interval, 0.803-0.984). A random forest model incorporating a panel of five metabolites showed a high area under the receiver operating characteristic curve value of 0.983 (95% confidence interval, 0.981-0.984). The results of validation revealed that four tissue metabolites: N1,N12-diacetylspermine, spermine, malate, and glycolate, had statistically significant differences between IgG4-ROD and orbital MALT lymphoma with receiver operating characteristic values from 0.708 to 0.863.

Conclusions: These data revealed the characteristic differences in metabolomic profiles between IgG4-ROD and orbital MALT lymphoma, which may be useful for developing new diagnostic biomarkers and elucidating the pathogenic mechanisms of these common orbital lymphoproliferative disorders.
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http://dx.doi.org/10.1167/iovs.62.1.15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814356PMC
January 2021

Identification of Markers Predicting Clinical Course in Patients with IgG4-Related Ophthalmic Disease by Unbiased Clustering Analysis.

J Clin Med 2020 Dec 17;9(12). Epub 2020 Dec 17.

Department of Ophthalmology, Tokyo Medical University Hospital, Tokyo 160-0023, Japan.

Purpose: To describe the clinical features of patients with immunoglobulin G4 (IgG4)-related ophthalmic disease (IgG4-ROD) grouped by unbiased cluster analysis using peripheral blood test data and to find novel biomarkers for predicting clinical features.

Methods: One hundred and seven patients diagnosed with IgG4-ROD were divided into four groups by unsupervised hierarchical cluster analysis using peripheral blood test data. The clinical features of the four groups were compared and novel markers for prediction of clinical course were explored.

Results: Unbiased cluster analysis divided patients into four groups. Group B had a significantly higher frequency of extraocular muscle enlargement ( < 0.001). The frequency of patients with decreased best corrected visual acuity (BCVA) was significantly higher in group D ( = 0.002). Receiver operating characteristic (ROC) curves for the prediction of extraocular muscle enlargement and worsened BCVA using a panel consisting of important blood test data identified by machine learning yielded areas under the curve of 0.78 and 0.86, respectively. Clinical features were compared between patients divided into two groups by the cutoff serum IgE or IgG4 level obtained from ROC curves. Patients with serum IgE above 425 IU/mL had a higher frequency of extraocular muscle enlargement (25% versus 6%, = 0.004). Patients with serum IgG4 above 712 mg/dL had a higher frequency of decreased BCVA (37% versus 5%, ≤ 0.001).

Conclusion: Unsupervised hierarchical clustering analysis using routine blood test data differentiates four distinct clinical phenotypes of IgG4-ROD, which suggest differences in pathophysiologic mechanisms. High serum IgG4 is a potential predictor of worsened BCVA, and high serum IgE is a potential predictor of extraocular muscle enlargement in IgG4-ROD patients.
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http://dx.doi.org/10.3390/jcm9124084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766793PMC
December 2020

Serum Metabolomic Profiling of Patients with Non-Infectious Uveitis.

J Clin Med 2020 Dec 6;9(12). Epub 2020 Dec 6.

Department of Ophthalmology, Tokyo Medical University, Tokyo 160-0023, Japan.

The activities of various metabolic pathways can influence the pathogeneses of autoimmune diseases, and intrinsic metabolites can potentially be used to diagnose diseases. However, the metabolomic analysis of patients with uveitis has not yet been conducted. Here, we profiled the serum metabolomes of patients with three major forms of uveitis (Behҫet's disease (BD), sarcoidosis, and Vogt-Koyanagi-Harada disease (VKH)) to identify potential biomarkers. This study included 19 BD, 20 sarcoidosis, and 15 VKH patients alongside 16 healthy control subjects. The metabolite concentrations in their sera were quantified using liquid chromatography with time-of-flight mass spectrometry. The discriminative abilities of quantified metabolites were evaluated by four comparisons: control vs. three diseases, and each disease vs. the other two diseases (such as sarcoidosis vs. BD + VKH). Among 78 quantified metabolites, 24 kinds of metabolites showed significant differences in these comparisons. Four multiple logistic regression models were developed and validated. The area under the receiver operating characteristic (ROC) curve (AUC) in the model to discriminate disease groups from control was 0.72. The AUC of the other models to discriminate sarcoidosis, BD, and VKH from the other two diseases were 0.84, 0.83, and 0.73, respectively. This study provides potential diagnostic abilities of sarcoidosis, BD, and VKH using routinely available serum samples that can be collected with minimal invasiveness.
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http://dx.doi.org/10.3390/jcm9123955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762156PMC
December 2020

Elucidation of Pathophysiology and Novel Treatment for Diabetic Macular Edema Derived from the Concept of Neurovascular Unit.

Authors:
Yoshihiko Usui

JMA J 2020 Jul 7;3(3):201-207. Epub 2020 Jul 7.

Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.

The retina transmits light signals to the brain via a complex structure composed of photoreceptor cells, neurons including ganglion cells, glial cells such as astrocytes and Mueller cells, as well as retinal blood vessels that feed the retina. The retina performs such high-level physiological function and maintains homeostasis effectively through interactions among the cells that form the neurovascular units (NVUs). Furthermore, as a component of the blood‒retinal barrier (BRB), the vascular structure of the retina is functionally based on the NVUs, in which the nervous system and the vascular tissues collaborate in a mutually supportive relationship. Retinal neurons such as ganglion cells and amacrine cells are traditionally considered to be involved only in visual function, but multiple functionality of neurons attracted attention lately, and retinal neurons play an important role in the formation and function of retinal blood vessels. In other words, damage to neurons indirectly affects retinal blood vessels. Diabetic macular edema is the leading cause of vision loss in diabetic retinopathy, and this type of edema results in neurological and vascular disorders. In this article, the regulatory mechanism of retinal capillaries in diabetic macular edema is reviewed from the viewpoint of NVU.
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http://dx.doi.org/10.31662/jmaj.2020-0022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590397PMC
July 2020

Comprehensive Gene Analysis of IgG4-Related Ophthalmic Disease Using RNA Sequencing.

J Clin Med 2020 Oct 27;9(11). Epub 2020 Oct 27.

Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.

High-throughput RNA sequencing (RNA-seq) uses massive parallel sequencing technology, allowing the unbiased analysis of genome-wide transcription levels and tumor mutation status. Immunoglobulin G4-related ophthalmic disease (IgG4-ROD) is a fibroinflammatory disease characterized by the enlargement of the ocular adnexal tissues. We analyzed RNA expression levels via RNA-seq in the biopsy specimens of three patients diagnosed with IgG4-ROD. Mucosa-associated lymphoid tissue (MALT) lymphoma, reactive lymphoid hyperplasia (RLH), normal lacrimal gland tissue, and adjacent adipose tissue were used as the controls ( = 3 each). RNA-seq was performed using the NextSeq 500 system, and genes with |fold change| ≥ 2 and < 0.05 relative to the controls were defined as differentially expressed genes (DEGs) in IgG4-ROD. To validate the results of RNA-seq, real-time polymerase chain reaction (PCR) was performed in 30 IgG4-ROD and 30 orbital MALT lymphoma tissue samples. RNA-seq identified 35 up-regulated genes, including matrix metallopeptidase 12 (MMP12) and secreted phosphoprotein 1 (SPP1), in IgG4-ROD tissues when compared to all the controls. Many pathways related to the immune system were included when compared to all the controls. Expressions of MMP12 and SPP1 in IgG4-ROD tissues were confirmed by real-time PCR and immunohistochemistry. In conclusion, we identified novel DEGs, including those associated with extracellular matrix degradation, fibrosis, and inflammation, in IgG4-ROD biopsy specimens. These data provide new insights into molecular pathogenetic mechanisms and may contribute to the development of new biomarkers for diagnosis and molecular targeted drugs.
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http://dx.doi.org/10.3390/jcm9113458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693346PMC
October 2020

Vitreous metabolomics profiling of proliferative diabetic retinopathy.

Diabetologia 2021 01 25;64(1):70-82. Epub 2020 Oct 25.

Department of Ophthalmology, Tokyo Medical University Hospital, Tokyo, Japan.

Aims/hypothesis: Proliferative diabetic retinopathy (PDR) with retinal neovascularisation (NV) is a leading cause of vision loss. This study identified a set of metabolites that were altered in the vitreous humour of PDR patients compared with non-diabetic control participants. We corroborated changes in vitreous metabolites identified in prior studies and identified novel dysregulated metabolites that may lead to treatment strategies for PDR.

Methods: We analysed metabolites in vitreous samples from 43 PDR patients and 21 non-diabetic epiretinal membrane control patients from Japan (age 27-80 years) via ultra-high-performance liquid chromatography-mass spectrometry. We then investigated the association of a novel metabolite (creatine) with retinal NV in mouse oxygen-induced retinopathy (OIR). Creatine or vehicle was administered from postnatal day (P)12 to P16 (during induced NV) via oral gavage. P17 retinas were quantified for NV and vaso-obliteration.

Results: We identified 158 metabolites in vitreous samples that were altered in PDR patients vs control participants. We corroborated increases in pyruvate, lactate, proline and allantoin in PDR, which were identified in prior studies. We also found changes in metabolites not previously identified, including creatine. In human vitreous humour, creatine levels were decreased in PDR patients compared with epiretinal membrane control participants (false-discovery rate <0.001). We validated that lower creatine levels were associated with vascular proliferation in mouse retina in the OIR model (p = 0.027) using retinal metabolomics. Oral creatine supplementation reduced NV compared with vehicle (P12 to P16) in OIR (p = 0.0024).

Conclusions/interpretation: These results suggest that metabolites from vitreous humour may reflect changes in metabolism that can be used to find pathways influencing retinopathy. Creatine supplementation could be useful to suppress NV in PDR. Graphical abstract.
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http://dx.doi.org/10.1007/s00125-020-05309-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718434PMC
January 2021

Comprehensive miRNA Analysis Using Serum From Patients With Noninfectious Uveitis.

Invest Ophthalmol Vis Sci 2020 09;61(11)

Department of Ophthalmology, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan.

Purpose: MicroRNAs (miRNAs) are noncoding RNAs and have attracted attention as a biomarker in a variety of diseases. However, extensive unbiased miRNAs analysis in patients with uveitis has not been completely explored. In the present study, we comprehensively analyzed the deregulated miRNAs in three major forms of uveitis (Behҫet's disease [BD], sarcoidosis and Vogt-Koyanagi-Harada disease [VKH]) to search for potential biomarkers.

Methods: This study included 10 patients with BD, 17 patients with sarcoidosis, and 13 patients with VKH. Eleven healthy subjects were used as controls. The miRNAs expression levels were studied by microarray using serum samples from patients with uveitis and healthy controls.

Results: A total of 281 upregulated miRNAs and 137 downregulated miRNAs were detected in patients with BD, 35 upregulated miRNAs and 86 downregulated miRNAs in patients with sarcoidosis, and 153 upregulated miRNAs and 35 downregulated miRNAs in patients with VKH. Some deregulated miRNAs were involved in the mitogen-activated protein kinase signaling pathway and inflammatory cytokine pathways. Furthermore, we identified miR-4708-3p, miR-4323, and let-7g-3p as the best predictor miRNAs for BD, sarcoidosis, and VKH, respectively. Panels of miRNAs with diagnostic potential for the three diseases were generated using machine learning.

Conclusions: In this study, comprehensive miRNA analysis identified deregulated miRNAs in three major forms of noninfectious uveitis. This study provides new insights into molecular pathogenetic mechanisms and useful information toward developing novel diagnostic biomarkers and therapeutic targets for BD, sarcoidosis, and VKH.
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http://dx.doi.org/10.1167/iovs.61.11.4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476662PMC
September 2020

Anti-TNF-α Therapy for Refractory Uveitis Associated with Behçet's Syndrome and Sarcoidosis: A Single Center Study of 131 Patients.

Ocul Immunol Inflamm 2020 Aug 20:1-8. Epub 2020 Aug 20.

Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.

Purpose: The efficacy of infliximab (IFX) and adalimumab (ADA) for treating Behçet's syndrome (BS) and sarcoidosis has not been compared adequately.

Methods: We reviewed the medical records of patients with uveitis diagnosed at Tokyo Medical University Hospital and compared the efficacy of IFX and ADA for BS and the efficacy of ADA for sarcoidosis and BS.

Results: 68 patients in IFX group and 63 patients in ADA group were analyzed. In BS patients, IFX and ADA were both effective in improving uveitic macular edema (UME). ADA improved UME in BS but not in sarcoidosis patients. The efficacy of ADA in reducing doses of corticosteroids and glaucoma medications was better in sarcoidosis than in the BS group.

Conclusion: Both IFX and ADA are efficacious in improving UME in BS patients. The reason that ADA improves UME better in BS than in sarcoidosis may be due to the difference in pathogenesis between these diseases.
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http://dx.doi.org/10.1080/09273948.2020.1791346DOI Listing
August 2020

Blockade of costimulatory CD27/CD70 pathway promotes corneal allograft survival.

Exp Eye Res 2020 10 14;199:108190. Epub 2020 Aug 14.

Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.

Purpose: To determine whether the CD27/CD70 pathway plays a significant role in corneal allograft rejection by investigating the effect of blocking the CD27/CD70 pathway by anti-CD70 antibody on corneal allograft survival.

Methods: Orthotopic penetrating keratoplasty was performed using C57BL/6 donor grafts and BALB/c recipients. Expression of CD27 and CD70 on rejected cornea was examined by immunohistochemistry. Corneal transplant recipients received intraperitoneal injection of anti-CD70 antibody (FR70) or control rat IgG. Alloreactivity was measured by mixed lymphoid reaction (MLR) in recipients administered control rat IgG and those administered anti-CD70 antibody. Corneal expression of IFN-γ and IL-12 was also examined in both groups. Graft opacity was assessed over an 8-week period and graft survival was evaluated using Kaplan-Meier survival curves. Proportion of CD4CD44 memory T cells in lymph nodes was measured by flow cytometry.

Results: CD4CD27 cells and CD11cCD70 cells were present in rejected cornea. Anti-CD70 antibody administration suppressed alloreactivity in corneal allograft recipients, and inhibited IFN-γ expression in recipient cornea (p < 0.05). Anti-CD70 antibody suppressed opacity score of recipient cornea and prolonged corneal allograft survival (p < 0.05). Proportion of CD4CD44 memory T cells in recipient lymph nodes was reduced by anti-CD70 antibody treatment.

Conclusion: The CD27/CD70 pathway plays a significant role in corneal allograft rejection by initiating alloreactive Th1 cells and preserving memory T cells. Anti-CD70 antibody administration prolongs corneal allograft survival indicating the potential therapeutic effect of CD27/CD70 pathway blockade on corneal allograft rejection.
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http://dx.doi.org/10.1016/j.exer.2020.108190DOI Listing
October 2020

Distinctive Tissue and Serum MicroRNA Profile of IgG4-Related Ophthalmic Disease and MALT Lymphoma.

J Clin Med 2020 Aug 5;9(8). Epub 2020 Aug 5.

Department of Ophthalmology, Tokyo Medical University, Tokyo 160-0023, Japan.

The molecular pathogenesis of orbital lymphoproliferative disorders, such as immunoglobulin G4-related ophthalmic disease (IgG4-ROD) and orbital mucosa-associated lymphoid tissue (MALT) lymphoma, remains essentially unknown. Differentiation between the two disorders, which is important since the work-up and treatment can vary greatly, is often challenging due to the lack of specific biomarkers. Although miRNAs play an important role in the regulation of carcinogenesis and inflammation, the relationship between miRNA and orbital lymphoproliferative diseases remains unknown. We performed a comprehensive analysis of 2565 miRNAs from biopsy and serum specimens of 17 cases with IgG4-ROD, where 21 cases with orbital MALT lymphoma were performed. We identified specific miRNA signatures and their miRNA target pathways, as well as the network analysis for IgG4-ROD and orbital MALT lymphoma. Machine-learning analysis identified miR-202-3p and miR-7112-3p as the best discriminators of IgG4-ROD and orbital MALT lymphoma, respectively. Enrichment analyses of biological pathways showed that the longevity-regulating pathway in IgG4-ROD and the mitogen-activated protein kinase (MAPK) signaling pathway in orbital MALT lymphoma was most enriched by target genes of downregulated miRNAs. This is the first evidence of miRNA profiles of biopsy and serum specimens of patients with IgG4-ROD and orbital MALT lymphoma. These data will be useful for developing diagnostic and therapeutic interventions, as well as elucidating the pathogenesis of these disorders.
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http://dx.doi.org/10.3390/jcm9082530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464164PMC
August 2020

Identification of Prognostic Markers in Patients with Primary Vitreoretinal Lymphoma by Clustering Analysis Using Clinical Data.

J Clin Med 2020 Jul 20;9(7). Epub 2020 Jul 20.

Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.

(1) Purpose: Primary vitreoretinal lymphoma (PVRL) is associated with poor prognosis because most of the patients with PVRL develop central nerve system lymphoma. The prognostic biomarker of PVRL is largely unknown. Cluster analysis has been used to identify phenotypic groups within various diseases. In this study, we aimed to describe clinical features of patients with PVRL grouped by clustering analysis and to identify biomarkers for predicting survival prognosis in patients with PVRL. (2) Materials and Methods: Forty patients with PVRL were divided into two groups by clustering analysis using clinical data. Clinical features of the two groups were compared. (3) Result: Clustering analysis classified patients into groups A and B. The survival rate during the follow-up period was significantly lower in group B than in group A ( = 0.03). Serum IgG, serum IgA, vitreous IL-10 and vitreous IL-10 to IL-6 ratio were significantly different between groups A and B ( = 0.03, 0.005, 0.008 and 0.03, respectively). Receiver operating characteristic (ROC) curves generated for the four variables indicated that serum IgA was most suitable for the prediction of prognosis. Patients with serum IgA below 184 mg/dL obtained from the ROC curve had a lower three-year survival rate ( = 0.03) and more episodes of recurrence of lymphoma (3.2 times versus 1.8 times, = 0.02) compared with patients with serum IgA above 184 mg/dL. (4) Conclusion: The survival rate was significantly different in PVRL patients classified into two groups by clustering analysis. Patients with lower serum IgA had more recurrences and poorer survival than patients with higher IgA.
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http://dx.doi.org/10.3390/jcm9072298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409000PMC
July 2020

Clinical features and prognosis of sebaceous carcinoma arising in the eyelid or conjunctiva.

Jpn J Ophthalmol 2020 Sep 8;64(5):549-554. Epub 2020 Jul 8.

Department of Plastic Surgery, Tokyo Medical University, Tokyo, Japan.

Purpose: The aim of this study was to clarify the demographics, clinical features, and outcomes of Japanese patients with sebaceous carcinoma of the eyelid or conjunctiva.

Study Design: Retrospective study.

Methods: One hundred twenty-five patients with sebaceous carcinoma of the eyelid or conjunctiva diagnosed at Tokyo Medical University Hospital between 1994 and 2017 were reviewed. The outcomes of the 116 patients who were treated and followed for at least 24 months at our hospital were investigated.

Results: The patients reviewed comprised 52 men and 74 women. The average age at diagnosis was 70.6 ± 13.8 (range 31-96) years. The main lesion was located in the upper eyelid in 51% of the patients; in the lower eyelid in 38% of the patients; and in other regions in 11% of the patients. Treatments included surgical resection with or without eyelid reconstruction in 108 cases (93%), orbital exenteration in 5 cases (4%), and radiation therapy in 3 cases (3%). Local recurrence was detected in 11 cases (9%). Metastasis to the regional lymph nodes was confirmed in 10 cases (9%). Four patients (3%) died because of direct intracranial invasion of the tumor. Risk of local recurrence and metastasis was significantly related to larger tumor size.

Conclusion: Proper diagnosis and treatment at the optimal timing is critical to improve the outcome of sebaceous carcinoma of the eyelid or conjunctiva. Long-term follow-up is required because local recurrence and metastasis may occur several years after treatment.
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http://dx.doi.org/10.1007/s10384-020-00756-xDOI Listing
September 2020

High-Throughput MicroRNA Profiling of Vitreoretinal Lymphoma: Vitreous and Serum MicroRNA Profiles Distinct from Uveitis.

J Clin Med 2020 Jun 12;9(6). Epub 2020 Jun 12.

Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.

Purpose: Vitreoretinal lymphoma (VRL) is a non-Hodgkin lymphoma of the diffuse large B cell type (DLBCL), which is an aggressive cancer causing central nervous system related mortality. The pathogenesis of VRL is largely unknown. The role of microRNAs (miRNAs) has recently acquired remarkable importance in the pathogenesis of many diseases including cancers. Furthermore, miRNAs have shown promise as diagnostic and prognostic markers of cancers. In this study, we aimed to identify differentially expressed miRNAs and pathways in the vitreous and serum of patients with VRL and to investigate the pathogenesis of the disease.

Materials And Methods: Vitreous and serum samples were obtained from 14 patients with VRL and from controls comprising 40 patients with uveitis, 12 with macular hole, 14 with epiretinal membrane, 12 healthy individuals. The expression levels of 2565 miRNAs in serum and vitreous samples were analyzed.

Results: Expression of the miRNAs correlated significantly with the extracellular matrix (ECM) ‒receptor interaction pathway in VRL. Analyses showed that miR-326 was a key driver of B-cell proliferation, and miR-6513-3p could discriminate VRL from uveitis. MiR-1236-3p correlated with vitreous interleukin (IL)-10 concentrations. Machine learning analysis identified miR-361-3p expression as a discriminator between VRL and uveitis.

Conclusions: Our findings demonstrate that aberrant microRNA expression in VRL may affect the expression of genes in a variety of cancer-related pathways. The altered serum miRNAs may discriminate VRL from uveitis, and serum miR-6513-3p has the potential to serve as an auxiliary tool for the diagnosis of VRL.
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http://dx.doi.org/10.3390/jcm9061844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356511PMC
June 2020

Retinal microglia are critical for subretinal neovascular formation.

JCI Insight 2020 06 18;5(12). Epub 2020 Jun 18.

Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA.

Abnormal subretinal neovascularization is a characteristic of vision-threatening retinal diseases, including macular telangiectasia (MacTel) and retinal angiomatous proliferation (RAP). Subretinal neovascular tufts and photoreceptor dysfunction are observed in very-low-density lipoprotein receptor (Vldlr-/-) mutant mice. These changes mirror those observed in patients with MacTel and RAP, but the pathogenesis is largely unknown. In this study, we show that retinal microglia were closely associated with retinal neovascular tufts in Vldlr-/- mice and retinal tissue from patients with MacTel; ablation of microglia/macrophages dramatically prevented formation of retinal neovascular tufts and improved neuronal function, as assessed by electroretinography. Vldlr-/- mice with retinal pigmented epithelium-specific (RPE-specific) Vegfa had greatly reduced subretinal infiltration of microglia/macrophages, subsequently reducing neovascular tufts. These findings highlight the contribution of microglia/macrophages to the pathogenesis of neovascularization, provide valuable clues regarding potential causative cellular mechanisms for subretinal neovascularization in patients with MacTel and RAP and suggest that targeting microglia activation may be a therapeutic option in these diseases.
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http://dx.doi.org/10.1172/jci.insight.137317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406258PMC
June 2020

Changes in Etiology of Uveitis in a Single Center in Japan.

Ocul Immunol Inflamm 2020 Feb 18:1-6. Epub 2020 Feb 18.

Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.

: We investigated the changes in etiology of uveitis at the Uveitis Clinic of Tokyo Medical University Hospital in recent years.: Medical records of patients with uveitis diagnosed between 2011 and 2017 (Group A) and between 2001 and 2007 (Group B) were reviewed.: 1,587 patients in group A and 1,507 patients in group B were analyzed. For noninfectious uveitis, frequencies of Vogt-Koyanagi-Harada disease, intraocular lymphoma (IOL) and iridocyclitis in young girls increased, while those of sarcoidosis and Behçet's disease decreased in the recent era. For infectious uveitis, herpetic iridocyclitis, ocular toxoplasmosis, ocular syphilis, and bacterial endophthalmitis increased, while acute retinal necrosis and ocular toxocariasis decreased. Unclassified uveitis decreased, whereas infectious uveitis and IOL increased due to the availability of new diagnostic tests.: Etiologies of uveitis have changed over the years. Further development of novel tests and diagnostic criteria would increase definitive diagnosis for unclassified uveitis. (147/150 words).
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http://dx.doi.org/10.1080/09273948.2019.1709649DOI Listing
February 2020

Evaluation of Retinal Pigment Epithelium Layer Change in Vogt-Koyanagi-Harada Disease With Multicontrast Optical Coherence Tomography.

Invest Ophthalmol Vis Sci 2019 08;60(10):3352-3362

Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.

Purpose: Clinical evaluation of retinal pigment epithelium (RPE) change is important for the therapeutic management of chronic Vogt-Koyanagi-Harada (VKH) disease. We evaluated long-term change in the RPE layer in VKH disease, using near-infrared (NIR; 817 nm) images and autofluorescence images at 488 nm (short-wavelength [SW]-AF) and 785 nm (NIR-AF), and compared those images with images from multicontrast optical coherence tomography (MC-OCT). MC-OCT is capable of simultaneous measurement of OCT angiography, polarization-sensitive OCT, and standard OCT.

Methods: We evaluated 24 eyes of 12 patients with chronic VKH disease. RPE changes were assessed using NIR, NIR-AF, SW-AF, and MC-OCT imaging performed from 6 to 48 months after disease onset. RPE-melanin-specific contrast OCT images were calculated using the dataset from MC-OCT.

Results: Granular hyper NIR-AF lesions were observed in 8 of 24 eyes (33%). Eyes with granular hyper NIR-AF lesions showed a sunset glow fundus appearance significantly more frequently than did eyes without such lesions (P < 0.0001). MC-OCT imaging confirmed that there was melanin accumulation at the RPE-Bruch's membrane band at the location of granular hyper NIR-AF lesions. Granular hyper NIR-AF lesions were unclear in SW-AF and color fundus images, but clearly detectable in NIR images. Areas of hyper NIR-AF lesions gradually decreased over time.

Conclusions: Melanin accumulation in the RPE layer at the location of granular hyper NIR-AF lesions was confirmed with MC-OCT imaging. Long-term follow-up showed the reversible nature of this accumulation. MC-OCT is useful for the evaluation of change at the RPE layer in chronic VKH disease.
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http://dx.doi.org/10.1167/iovs.19-27378DOI Listing
August 2019

Primary Intraocular Methotrexate-related Lymphoproliferative Disorder in a Patient with Rheumatoid Arthritis Undergoing Long-term Methotrexate Therapy.

Ocul Immunol Inflamm 2021 Apr 28;29(3):456-459. Epub 2019 Oct 28.

Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.

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http://dx.doi.org/10.1080/09273948.2019.1668428DOI Listing
April 2021

An unusual case of Behcet disease with posterior scleritis: A case report.

Medicine (Baltimore) 2019 Aug;98(35):e16886

Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.

Rationale: Posterior scleritis is an ocular inflammatory disorder that can be associated with both infectious and non-infectious immune reactions. Behcet disease is a chronic, relapsing, multisystemic inflammatory disorder with uveitis. There are no reported cases of posterior scleritis with Bechet disease.

Patient Concerns: A 50-year-old man previously diagnosed with systemic Behcet disease presented with ocular pain and decreased vision in the left eye.

Diagnosis: Posterior scleritis associated with Behcet disease was diagnosed based on optical coherence tomography showing choroidal folds, as well as contrast computed tomography and ultrasound sonography demonstrating thickening of the posterior sclera.

Interventions: Treatment with systemic corticosteroids was initiated. Since inflammation relapsed during steroid tapering, anti-tumor necrosis factor-alpha (TNF-α) therapy was used in combination, and tapering of steroids was possible without recurrence of inflammation for 12 months.

Outcomes: Posterior scleritis was resolved and visual acuity improved. With the continuation of TNF-α therapy, oral prednisolone was successfully tapered and discontinued. No relapse of inflammation was observed at follow-up 1 year after discontinuation of prednisolone.

Lessons: Ophthalmologists should be aware of the possibility of rare manifestation of posterior scleritis in patients with Behcet disease, and that combined use of systemic steroids and anti-TNF-α therapy may resolve the scleritis without recurrence of inflammation.
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http://dx.doi.org/10.1097/MD.0000000000016886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736338PMC
August 2019

Effectiveness of prophylactic intravitreal bevacizumab injection to proliferative diabetic retinopathy patients with elevated preoperative intraocular VEGF in preventing complications after vitrectomy.

Clin Ophthalmol 2019 28;13:1063-1070. Epub 2019 Jun 28.

Department of Ophthalmology, Tokyo Medical University Hospital, Tokyo, Japan.

Purpose: This study aimed to elucidate the effects of intravitreal bevacizumab (IVB) injections for the prevention of post-vitrectomy complications in proliferative diabetic retinopathy (PDR) patients with elevated vitreous vascular endothelial growth factor (VEGF) concentration.

Design: Prospective case series.

Methods: Thirty-three patients (42 eyes) with PDR who underwent primary vitrectomy in the Department of Ophthalmology, Tokyo Medical University Hospital were studied. We measured VEGF concentrations in vitreous humor collected at the time of vitrectomy using ELISA. IVB injections were performed after vitrectomy in patients with vitreous VEGF levels exceeding 1,000 pg/mL. New bleeding occurring within 1 month of vitrectomy was defined as early vitreous hemorrhage (VH).

Main Outcome Measure: The incidence of complications after vitrectomy including postoperative early VH.

Results: IVB injections were administered to 11 eyes (26%) with vitreous VEGF concentrations exceeding 1,000 pg/mL. None of the 11 eyes that received an IVB injection developed early VH. Among 31 eyes (74%) with vitreous VEGF concentrations lower than 1,000 pg/mL, two eyes (6%) developed early VH after vitrectomy.

Conclusions: Prophylactic IVB injections administered to patients with elevated preoperative intraocular VEGF concentrations were effective in preventing post-vitrectomy early VH.
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http://dx.doi.org/10.2147/OPTH.S203921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605036PMC
June 2019

Successful Treatment of Necrotizing Retinitis with Epstein-Barr Virus-Positive Ocular Fluid by Intravitreal Methotrexate Injection.

Ocul Immunol Inflamm 2020 May 3;28(4):552-555. Epub 2019 Jul 3.

Department of Ophthalmology, Tokyo Medical University , Tokyo, Japan.

Purpose: To present a case of necrotizing retinitis with Epstein-Barr virus (EBV)-positive ocular fluid in a patient with sudden unilateral vision loss, which was successfully treated with intravitreal methotrexate (MTX) injections.

Methods: Retrospective case report.

Results: An 83-year-old female who had been on methylprednisolone for 20 years due to interstitial pneumonia developed vitreous opacity and extensive necrotizing retinitis with retinal hemorrhage sparing the posterior pole in the left eye. Multiplex polymerase chain reaction (PCR) for viral DNA using vitreous sample was positive for EBV but negative for herpes simplex virus, varicella-zoster virus, and cytomegalovirus. Real-time PCR detected EBV-DNA in aqueous humor but not in peripheral blood sample. Serologic testing was negative for , syphilis, and HIV. The patient did not respond to systemic ganciclovir or acyclovir. Subsequent treatment with intravitreal MTX resulted in immediate clinical improvement correlating with a decrease in copy number of EBV-DNA.

Conclusion: Intravitreal MTX may be an effective treatment option for patients with necrotizing retinitis and EBV-positive ocular fluid not responding to conventional antiviral therapy.
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http://dx.doi.org/10.1080/09273948.2019.1609047DOI Listing
May 2020

Granuloma-like formation in deeper retinal plexus in ocular sarcoidosis.

Clin Ophthalmol 2019 27;13:895-896. Epub 2019 May 27.

Department of Ophthalmology, Tokyo Medical University, Tokyo 160-0023, Japan.

Sarcoidosis is a multi-system disease characterized by the presence of non-caseating epithelioid granulomas in affected tissues and the most frequent cause of noninfectious uveitis in Japan. Ocular manifestations of sarcoid uveitis vary enormously and commonly characterized by granulomatous anterior uveitis, intermediate uveitis, and posterior uveitis such as retinal periphlebitis, choroiditis, optic nerve granuloma and papillitis. However, case reports of multiple granuloma formation related to sarcoid uveitis is uncommon. This report describes the use of optical coherence tomography angiography to visualize changes occurring in granuloma formation in deeper retinal plexus before and after systemic corticosteroid treatment.
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http://dx.doi.org/10.2147/OPTH.S200519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549785PMC
May 2019

The long dystrophin gene product Dp427 modulates retinal function and vascular morphology in response to age and retinal ischemia.

Neurochem Int 2019 10 11;129:104489. Epub 2019 Jun 11.

Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA. Electronic address:

Mutations in dystrophin are the major cause of muscular dystrophies. Continuous muscular degeneration and late stage complications, including cardiomyopathy and respiratory insufficiency, dominate the clinical phenotype. Gene expression and regulation of the dystrophin gene outside of muscular tissue is far more complex. Multiple tissue-specific dystrophin gene products are widely expressed throughout the body, including the central nervous system and eye, predisposing affected patients to secondary complications in non-muscular tissues. In this study, we evaluated the impact of the full-length dystrophin gene product, Dp427, on retinal homeostasis and angiogenesis. Based on the clinical case of a Duchenne muscular dystrophy (DMD) patient who developed severe fibrovascular changes in the retina in response to hypoxic stress, we hypothesized that defects in Dp427 make the retina more susceptible to stresses such as ageing and ischemia. To further study this, a mouse strain lacking Dp427 expression (Mdx) was studied during retinal development, ageing and in the oxygen-induced retinopathy (OIR) model. While retinal vascular morphology was normal during development and ageing, retinal function measured by electroretinography (ERG) was slightly reduced in young adult Mdx mice and deteriorated with age. Mdx mice also had increased retinal neovascularization in response to OIR and more pronounced long-term deterioration in retinal function following OIR. Based on these results, we suggest that DMD patients with a mutation in Dp427 may experience disturbed retinal homeostasis with increasing age and therefore be prone to develop excessive retinal neovascular changes in response to hypoxic stress. DMD patients in late disease stages should, thus, be regularly examined to detect asymptomatic retinal abnormalities and prevent visual impairment.
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http://dx.doi.org/10.1016/j.neuint.2019.104489DOI Listing
October 2019
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