Patterns of anti-vascular endothelial growth factor treatment for chorioretinal vascular diseases: Analysis of a nationwide claims database in Japan.

BACKGROUND: Although intravitreal anti-vascular endothelial growth factor therapy is currently considered the first-line treatment for chorioretinal vascular diseases in Japan, information regarding its treatment pattern is scarce. This study investigated the patterns of anti-vascular endothelial growth factor treatment for chorioretinal vascular diseases. METHODS: A health insurance claims database from acute care hospitals was used to estimate treatment intervals and continuation and drop-out rates regarding the anti-vascular endothelial growth factor. Patients aged ≥50 years diagnosed with neovascular age-related macular degeneration or aged ≥18 years diagnosed with diabetic macular edema or retinal vein occlusion were analyzed. RESULTS: Data were included for 76,535, 49,704, and 37,681 patients with neovascular age-related macular degeneration, diabetic macular edema, and retinal vein occlusion, respectively; exactly 8,111, 2,283, and 6,896 received the treatment, respectively. The mean and median interval ranges during the maintenance phase by treatment initiation year were 94-100 and 73-80, 111-120 and 98-102, and 97-103 and 87-93 days for neovascular age-related macular degeneration, diabetic macular edema, and retinal vein occlusion, respectively, without any trend over time. A tendency to increase the treatment continuation rate was indicated in later years by Kaplan-Meier curves. The drop-out rate in the treatment initiation year (2016) was 32% from 63% (2009), 53% from 69% (2014), and 36% from 47% (2013) for neovascular age-related macular degeneration, diabetic macular edema, and retinal vein occlusion, respectively. CONCLUSIONS: For all these diseases, the treatment intervals did not change remarkably, and a tendency toward improved treatment continuation was suggested.

Efficacy, Durability, and Safety of Faricimab in Patients From Asian Countries With Diabetic Macular Edema: 1-Year Subgroup Analysis of the Phase III YOSEMITE and RHINE Trials.

PURPOSE: To assess the 1-year efficacy, durability, and safety of faricimab in patients with diabetic macular edema from Asian and non-Asian countries. DESIGN: Global, multicenter, randomized, double-masked, active comparator-controlled, phase III trials. METHODS: Subgroup analysis of patients from Asian (N=144) and non-Asian (N=1747) countries randomized to faricimab 6.0 mg every 8 weeks (Q8W), faricimab per personalized treatment interval (PTI), or aflibercept 2.0 mg Q8W in the YOSEMITE/RHINE (NCT03622580/NCT03622593) trials. Primary endpoint: best-corrected visual acuity (BCVA) changes from baseline at 1 year, averaged over weeks 48, 52, and 56. RESULTS: Mean BCVA change from baseline at 1 year in the Asian country subgroup was similar between arms: faricimab Q8W (n=50), +10.9 (95% CI: 8.6-13.2); faricimab PTI (n=48) +10.0 (7.7-12.4) letters; aflibercept Q8W (n=46) +9.0 (6.6-11.4) letters. BCVA gains in the non-Asian country subgroup (n=582, 584, 581) were +11.3 (10.5-12.1), +11.2 (10.5-12.0), and +10.7 (9.9-11.5) letters, respectively. At 1 year, 49% of Asian country patients in the faricimab PTI arm achieved Q16W dosing (vs. 52% non-Asian) and 78% achieved ≥Q12W dosing (vs. 72% non-Asian). Anatomic improvementswere generally greater with faricimab versus aflibercept and similar between the Asian and non-Asian country subgroups. Faricimab was well tolerated, with no new safety signals. CONCLUSIONS: Vision, durability, anatomic, and safety outcomes were generally similar between the Asian and non-Asian country subgroups, suggesting that global YOSEMITE/RHINE results may be generalized to the Asian population. These data support the benefit-risk profile of faricimab for treating Asian patients with diabetic macular edema.

Long-Term Prognosis of Patients with Polypoidal Choroidal Vasculopathy Treated with Photodynamic Therapy.

We evaluated the long-term prognosis of the eyes of patients with polypoidal choroidal vasculopathy (PCV) treated with photodynamic therapy (PDT). In total, 60 eyes of 57 patients diagnosed with PCV and treated with PDT were reviewed retrospectively in real-world settings. The best-corrected visual acuity (BCVA), central retinal thickness (CRT), anatomical findings (vision-threatening findings), and treatment history were assessed. In total, 38 eyes underwent PDT as the initial treatment (initial PDT group) and 22 eyes underwent PDT as a rescue treatment (rescue PDT group). In the initial PDT group, 11 eyes (29%) did not require additional therapy throughout the observation period and maintained good BCVA. A total of 27 eyes (71%) underwent additional treatments and the mean BCVA was only stabilized for 2 years; thereafter, decreased vision occurred even with additional treatments. In the rescue PDT group, 22 eyes (95%) required additional treatment. Hard exudate, serous pigment epithelial detachment, and the total vision-threatening score were related to worse BCVA. Initial PDT may be effective in about 30% of cases with preservation of good vision and no need for additional treatment. However, patients with received rescue PDT needed additional treatment in most cases and the vision decreased in many cases.

Polypoidal Choroidal Vasculopathy: Updates on Risk Factors, Diagnosis, and Treatments.

There have been recent advances in basic research and clinical studies in polypoidal choroidal vasculopathy (PCV). A recent, large-scale, population-based study found systemic factors, such as male gender and smoking, were associated with PCV, and a recent systematic review reported plasma C-reactive protein, a systemic biomarker, was associated with PCV. Growing evidence points to an association between pachydrusen, recently proposed extracellular deposits associated with the thick choroid, and the risk of development of PCV. Many recent studies on diagnosis of PCV have focused on applying criteria from noninvasive multimodal retinal imaging without requirement of indocyanine green angiography. There have been attempts to develop deep learning models, a recent subset of artificial intelligence, for detecting PCV from different types of retinal imaging modality. Some of these deep learning models were found to have high performance when they were trained and tested on color retinal images with corresponding images from optical coherence tomography. The treatment of PCV is either a combination therapy using verteporfin photodynamic therapy and anti-vascular endothelial growth factor (VEGF), or anti-VEGF monotherapy, often used with a treat-and-extend regimen. New anti-VEGF agents may provide more durable treatment with similar efficacy, compared with existing anti-VEGF agents. It is not known if they can induce greater closure of polypoidal lesions, in which case, combination therapy may still be a mainstay. Recent evidence supports long-term follow-up of patients with PCV after treatment for early detection of recurrence, particularly in patients with incomplete closure of polypoidal lesions.

AUTOLOGOUS POSTERIOR CAPSULE FLAP TRANSPLANTATION IN THE MANAGEMENT OF REFRACTORY MACULAR HOLE IN A PSEUDOPHAKIC EYE.

PURPOSE: To report a case of refractory macular hole (MH) in pseudophakic eye treated with autologous posterior capsule flaps transplantation. METHODS: Case report. RESULTS: A 48-year-old man visited our hospital with visual loss in the right eye because of unclosed MH. The patient had undergone two previous surgeries in another hospital, that is, the first included a cataract surgery, vitrectomy, and internal limiting membrane peeling with sulfur hexafluoride (SF 6 ) gas tamponade, and the second included an ineffective autologous internal limiting membrane flap technique and massaging the edges of the MH with a soft-tipped flute needle followed by the same gas, but the MH remained open. In our hospital, posterior capsule flaps were acquired from the same eye, inserted into the MH, and the same gas tamponade was performed, which was about four months after the disease onset (3 months after the prior second surgery). The patient kept face-down position for a week after the surgery and the MH was closed, which remained for over 12 months. The visual acuity improved from 20/250 to 20/60, and the retinal sensitivities around the MH gradually improved. CONCLUSION: An autologous posterior capsule flaps transplantation was effective in the management of refractory MH to not only close the MH but also improve the visual outcomes.

Recommendations for OCT Angiography Reporting in Retinal Vascular Disease: A Delphi Approach by International Experts.

PURPOSE: To develop a consensus nomenclature for reporting OCT angiography (OCTA) findings in retinal vascular disease (e.g., diabetic retinopathy, retinal vein occlusion) by international experts. DESIGN: Delphi-based survey. SUBJECTS, PARTICIPANTS, AND/OR CONTROLS: Twenty-five retinal vascular disease and OCTA imaging experts. METHODS, INTERVENTION, OR TESTING: A Delphi method of consensus development was used, comprising 2 rounds of online questionnaires, followed by a face-to-face meeting conducted virtually. Twenty-five experts in retinal vascular disease and retinal OCTA imaging were selected to constitute the OCTA Nomenclature in Delphi Study Group for retinal vascular disease. The 4 main areas of consensus were: definition of the parameters of "wide-field (WF)" OCTA, measurement of decreased vascular flow on conventional and WF-OCTA, nomenclature of OCTA findings, and OCTA in retinal vascular disease management and staging. The study end point was defined by the degree of consensus for each question: "strong consensus" was defined as ≥85% agreement, "consensus" as 80% to 84%, and "near consensus" as 70% to 79%. MAIN OUTCOME MEASURES: Consensus and near consensus on OCTA nomenclature in retinal vascular disease. RESULTS: A consensus was reached that a meaningful change in percentage of flow on WF-OCTA imaging should be an increase or decrease ≥30% of the absolute imaged area of flow signal and that a "large area" of WF-OCTA reduced flow signal should also be defined as ≥30% of the absolute imaged area. The presence of new vessels and intraretinal microvascular abnormalities, the foveal avascular zone parameters, the presence and amount of "no-flow areas," and the assessment of vessel density in various retinal layers should be added for the staging and classification of diabetic retinopathy. Decreased flow ≥30% of the absolute imaged area should define an ischemic central retinal vein occlusion. Several other items did not meet consensus requirements or were rejected in the final discussion round. CONCLUSIONS: This study provides international consensus recommendations for reporting OCTA findings in retinal vascular disease, which may help to improve the interpretability and description in clinic and clinical trials. Further validation in these settings is warranted and ongoing. Efforts are continuing to address unresolved questions.

Progression of age-related macular degeneration in eyes with abnormal fundus autofluorescence in a Japanese population: JFAM study report 3.

PURPOSE: To evaluate the progression of early age-related macular degeneration to neovascular age-related macular degeneration (nAMD), and identify the abnormal fundus autofluorescence (FAF) patterns and markers of choroidal neovascularization (CNV) in fellow eyes of patients with unilateral nAMD. METHODS: Sixty-six patients with unilateral nAMD who developed abnormal FAF in the fellow eyes were enrolled in this multicenter, prospective, observational study, and followed-up for 5 years. FAF images on Heidelberg Retina Angiogram Digital Angiography System (HRA) or HRA2 were classified into eight patterns based on the International Fundus Autofluorescence Classification Group system. The patients in which the fellow eyes progressed to advanced nAMD, including those who did not develop nAMD, were assessed based on the following factors: baseline FAF patterns, age, sex, visual acuity, drusen, retinal pigmentation, baseline retinal sensitivity, family history, smoking, supplement intake, hypertension, body mass index, and hematological parameters. RESULTS: Of the 66 patients, 20 dropped out of the study. Of the remaining 46 patients, 14 (30.42%, male: 9, female: 5) progressed to nAMD during the 5-year follow-up. The most common (50% eyes) FAF pattern in the fellow eyes was the patchy pattern. According to the univariate analysis, CNV development was significantly associated with age, supplement intake, and low-density lipoprotein levels (p<0.05). Multivariable analysis revealed that patients who showed non-compliance with the supplement intake were more likely to develop nAMD (p<0.05). No significant association was found between the patchy pattern and CNV development (p = 0.86). CONCLUSION: The fellow eyes (with abnormal FAF) of patients with unilateral nAMD may progress from early to advanced nAMD. However, no FAF pattern was found that predicted progression in nAMD.

Mental Status and Feasibility of an Intravitreal Ranibizumab Treat-and-Extend Regimen in Patients with Neovascular Age-Related Macular Degeneration.

INTRODUCTION: Anti-vascular endothelial growth factor (VEGF) therapy is the first-choice treatment for neovascular age-related macular degeneration (nvAMD); however, patients often are burdened physically, financially, and mentally. We investigated the relationship between mental status and feasibility of an intravitreal ranibizumab treat-and-extend (TAE) regimen for nvAMD. METHODS: In this prospective, multicenter study, 75 patients with nvAMD received ranibizumab intravitreally in a TAE regimen. After two monthly injections, the injection intervals were extended step-by-step to 6, 8, 12, and 16 weeks in eyes with dry maculas on optical coherence tomography (OCT) and, if exudation persisted or relapsed, shortened by one step. The best corrected visual acuity (BCVA) measurement and OCT were performed at baseline and on the same days of the scheduled injections. At baseline, all patients completed a survey, the Hospital Anxiety and Depression Scale (HADS), regarding mental burden. At week 52, patients on the TAE regimen for 1 year completed the HADS and a questionnaire designated to assess treatment-associated mental status. RESULTS: Fifty-one patients (68%) completed the 1-year TAE regimen; 24 eyes (32%) discontinued the TAE regimen because of the rescue treatment, difficulty in completing clinical visits, or financial burden. In 51 eyes on the TAE regimen for 1 year, the mean BCVAs improved from 64.3 letters at baseline to 71.6 letters at week 52. The mean anxiety and depression scores on HADS decreased significantly (p < 0.01) after the 1-year treatment. Women tended to have higher anxiety scores, possibly associated with fear of injection and recurrence, while some men had higher depression scores potentially associated with financial burden, difficulty in completing clinical visits, and subsequent interruption of the TAE regimen especially in eyes with low treatment efficacy. CONCLUSIONS: A TAE regimen of intravitreal ranibizumab injections preserves vision in eyes with nvAMD and reduces mental burden associated with disease relapse. TRIAL REGISTRATION: This clinical study was registered retrospectively on December 22, 2014 with the ClinicalTrials.gov identifier NCT02321839.

A case of Nd:YAG laser-induced traumatic macular hole with good visual prognosis after vitrectomy with inverted internal limiting membrane technique.

PURPOSE: To report an accidental case of traumatic macular hole caused by Nd:YAG laser in a dermatology clinic. OBSERVATIONS: A 24-year-old woman sustained a laser injury to her right eye while practicing a dermatologic treatment using a Nd:YAG laser without wearing protective goggles. She noticed sudden-onset and progressing visual loss in her right eye and consulted an ophthalmologist 2 days after injury. The best-corrected visual acuity (BCVA) of her right eye decreased to 20/133. Fundus examination showed white parafoveal flecks with a central retinal hemorrhage and underlying serous retinal detachment. The retinal sensitivity in this lesion deteriorated. Two weeks later, a full-thickness macular hole (FTMH) developed in the affected eye. She was referred to Nagoya City University Hospital where the laser damage described was observed. The BCVA was 20/67. She underwent pars plana vitrectomy performed using the inverted internal limiting membrane (ILM) flap technique and gas tamponade. One week postoperatively, the FTMH closed, the BCVA in her right eye improved to 20/50, and the retinal sensitivity in the macular area mostly improved. The BCVA gradually improved and reached 20/25 9 months after the injury. CONCLUSIONS AND IMPORTANCE: Protective goggles must be worn when using an Nd:YAG laser in the laboratory or clinical setting. In the unfortunate event of a FTMH, early vitrectomy with an inverted ILM flap technique can be helpful to achieve a good visual prognosis.

Impact on visual acuity and psychological outcomes of ranibizumab and subsequent treatment for diabetic macular oedema in Japan (MERCURY).

PURPOSE: The MERCURY study aimed to evaluate the effects on visual acuity and psychological symptoms, and safety, of ranibizumab and subsequent treatment in patients with diabetic macular oedema (DME) and impaired visual acuity (VA). We report data from the prespecified 12-month interim analysis. METHODS: This was a 24-month, phase 4, open-label, single-arm, prospective, observational study conducted at 20 specialised retinal centres in Japan. Participants were 209 patients with DME and impaired VA, not previously treated with either intravitreal or systemic anti-vascular endothelial growth factor (anti-VEGF) agents, who initiated ranibizumab 0.5 mg per investigator discretion. Following ranibizumab administration, patients were treated per routine clinical practice. Other treatments were allowed. The main outcome measure was the mean change in best-corrected VA (BCVA) in logarithmic minimum angle of resolution (logMAR) from baseline to month 12. An exploratory objective was to assess patients' psychological status using the Hospital Anxiety and Depression Scale (HADS). RESULTS: The mean ± standard deviation BCVA at baseline was 0.43 ± 0.39 logMAR. The mean number of injections of ranibizumab and anti-VEGF agents from baseline to month 11 was 3.2 ± 2.0 and 3.6 ± 2.4, respectively. The BCVA change from baseline to 12 months was - 0.08 ± 0.34 logMAR (p = 0.011), showing a significant improvement; the HADS-anxiety score also decreased significantly (p = 0.001) and the depression score decreased numerically (p = 0.080). CONCLUSION: MERCURY study data confirm the effectiveness of real-world treatment initiated with ranibizumab in Japanese patients with DME. In addition, treatment was able to positively influence anxiety via VA improvement.

Efficacy and safety of brolucizumab versus aflibercept in eyes with polypoidal choroidal vasculopathy in Japanese participants of HAWK.

PURPOSE: To compare the efficacy and safety of brolucizumab versus aflibercept in eyes with polypoidal choroidal vasculopathy (PCV) over 96 weeks in the HAWK study. DESIGN: HAWK was a global, 2-year, randomised, double-masked, multicentre phase III trial in participants with neovascular age-related macular degeneration. METHODS: Of the Japanese participants with PCV, 39 received brolucizumab 6 mg and 30 received aflibercept 2 mg. After 3 monthly loading doses, brolucizumab-treated eyes received an injection every 12 weeks (q12w) but were adjusted to q8w if disease activity was detected. Aflibercept-treated eyes received fixed q8w dosing. Mean change in best-corrected visual acuity (BCVA), the proportion of participants on q12w, retinal thickness, retinal fluid changes and safety were assessed to Week 96. RESULTS: Mean change in BCVA (early treatment diabetic retinopathy study (ETDRS) letters) from baseline to week 48/week 96 was+10.4/+11.4 for brolucizumab and +11.6/+11.1 for aflibercept. For brolucizumab-treated eyes, the probability of only q12w dosing after loading through week 48 was 76%, and 68% through week 96. Fluid resolution was greater with brolucizumab than aflibercept: respective proportions of eyes with intraretinal fluid and/or subretinal fluid were 7.7% and 30% at week 48% and 12.8% and 16.7% at week 96. Brolucizumab exhibited an overall well-tolerated safety profile despite a higher rate of intraocular inflammation compared with aflibercept. CONCLUSION: In Japanese eyes with PCV, brolucizumab q12w/q8w monotherapy resulted in robust and consistent BCVA gains that were comparable to q8w aflibercept dosing. Anatomical outcomes favoured brolucizumab over aflibercept, with 76% of brolucizumab participants maintained on q12w dosing after loading to week 48.

A case series from a single family of familial retinal arteriolar tortuosity with common history of sudden visual loss.

PURPOSE: To report family members with familial retinal arteriolar tortuosity (FRAT) identified after sudden visual loss. OBSERVATIONS: A 15-year-old boy had sudden visual loss in his left eye while playing on a horizontal bar. He was referred to Nagoya City University Hospital from an eye clinic. The ophthalmologic examination showed retinal hemorrhage bilaterally. His best-corrected visual acuity (BCVA) was 20/17 in the right eye and 20/67 in the left eye. Bilateral retinal arteriolar tortuosity as well as retinal hemorrhage was seen. Since his mother with 54 years of age also had a history of retinal hemorrhage that improved spontaneously, fundus examination was performed, revealing tortuosity of the retinal arterioles. Consequently, the patient and his mother were diagnosed as FRAT. He was followed without intervention. Retinal hemorrhage gradually decreased and resolved after 3 months. The BCVA of his left eye gradually improved and reached 20/20 after 1 year. CONCLUSIONS AND IMPORTANCE: In this case, the family history was very useful for early diagnosis. Immediate and accurate diagnosis allowed the patient to be followed without intervention and achieve subsequent resolution of retinal hemorrhage and improved vision. FRAT should be considered in cases of sub-internal limiting membrane hemorrhages in young patients even in the presence of discrete retinal arteriolar tortuosity.

Alu complementary DNA is enriched in atrophic macular degeneration and triggers retinal pigmented epithelium toxicity via cytosolic innate immunity.

Long interspersed nuclear element-1 (L1)­mediated reverse transcription (RT) of Alu RNA into cytoplasmic Alu complementary DNA (cDNA) has been implicated in retinal pigmented epithelium (RPE) degeneration. The mechanism of Alu cDNA­induced cytotoxicity and its relevance to human disease are unknown. Here we report that Alu cDNA is highly enriched in the RPE of human eyes with geographic atrophy, an untreatable form of age-related macular degeneration. We demonstrate that the DNA sensor cGAS engages Alu cDNA to induce cytosolic mitochondrial DNA escape, which amplifies cGAS activation, triggering RPE degeneration via the inflammasome. The L1-extinct rice rat was resistant to Alu RNA­induced Alu cDNA synthesis and RPE degeneration, which were enabled upon L1-RT overexpression. Nucleoside RT inhibitors (NRTIs), which inhibit both L1-RT and inflammasome activity, and NRTI derivatives (Kamuvudines) that inhibit inflammasome, but not RT, both block Alu cDNA toxicity, identifying inflammasome activation as the terminal effector of RPE degeneration.

Remote screening of diabetic retinopathy using ultra-widefield retinal imaging.

AIMS: To study the possibility of constructing a remote interpretation system for retinal images. METHODS: An ultra-widefield (UWF) retinal imaging device was installed in the internal medicine department specializing in diabetes to obtain fundus images of patients with diabetes. Remote interpretation was conducted at Nagoya City University using a cloud server. The medical data, severity of retinopathy, and frequency of ophthalmologic visits were analyzed. RESULTS: Four hundred ninety-nine patients (mean age, 62.5 ± 13.4 years) were included. The duration of diabetes in 240 (48.1%) patients was less than 10 years and 433 (86.7%) patients had a hemoglobin (Hb) A1c below 8%. Regarding the retinopathy severity, 360 (72.1%) patients had no diabetic retinopathy (NDR), 63 (12.6%) mild nonproliferative retinopathy (NPDR), 38 (7.64%) moderate NPDR, 13 (2.6%) severe NPDR, and 25 (5.0%) PDR. Two hundred forty-one (48.3%) patients had an ophthalmologic consultation within 1 year, 104 (20.8%) had no history of an ophthalmologic consultation. DR was not present in 86 (82.7%) patients who had never had an ophthalmologic examination, 30 (78.9%) patients with severe NPDR or PDR had had an ophthalmologic visit within 1 year. The frequency of ophthalmic visits was correlated negatively with age, diabetes duration, HbA1c, and severity of retinopathy. CONCLUSION: Remote interpretation of DR using UWF retinal imaging was useful for retinopathy screening. During the COVID-19 pandemic, a remote screening system that can ensure compulsory social distancing and reduce the number of ophthalmic visits can be a safe system for patients and clinicians.

Non-ICGA treatment criteria for Suboptimal Anti-VEGF Response for Polypoidal Choroidal Vasculopathy: APOIS PCV Workgroup Report 2.

PURPOSE: To develop and validate OCT and color fundus photography (CFP) criteria in differentiating polypoidal choroidal vasculopathy (PCV) from typical neovascular age-related macular degeneration (nAMD) in eyes with suboptimal response to anti-vascular endothelial growth factor (VEGF) monotherapy and to determine whether OCT alone can be used to guide photodynamic therapy (PDT) treatment. DESIGN: Clinical study evaluating diagnostic accuracy. PARTICIPANTS: Patients with nAMD who received 3-month anti-VEGF monotherapy but had persistent activity defined as subretinal fluid or intraretinal fluid at month 3 assessments. METHODS: In phase 1, international retina experts evaluated OCT and CFP of eyes with nAMD to identify the presence or absence of features due to PCV. The performance of individual and combinations of these features were compared with ICGA. In phase 2, these criteria were applied to an independent image set to assess generalizability. In a separate exercise, retinal experts drew proposed PDT treatment spots using only OCT and near-infrared (NIR) images in eyes with PCV and persistent activity. The location and size of proposed spot were compared with ICGA to determine the extent of coverage of polypoidal lesions (PLs) and branching neovascular network (BNN). MAIN OUTCOME MEASURES: Sensitivity and specificity of CFP and OCT criteria to differentiate PCV from nAMD and accuracy of coverage of OCT-guided PDT compared with ICGA. RESULTS: In eyes with persistent activity, the combination of 3 non-ICGA-based criteria (sharp-peaked pigment epithelial detachment [PED], subretinal pigment epithelium [RPE] ring-like lesion, and orange nodule) to detect PCV showed good agreement compared with ICGA, with an area under the receiver operating characteristic curve of 0.85. Validation using both an independent image set and assessors achieved an accuracy of 0.77. Compared with ICGA, the OCT-guided PDT treatment spot covered 100% of PL and 90% of the BNN. CONCLUSIONS: In nAMD eyes with persistent activity, OCT and CFP can differentiate PCV from typical nAMD, which may allow the option of adjunct PDT treatment. Furthermore, OCT alone can be used to plan adjunct PDT treatment without the need for ICGA, with consistent and complete coverage of PL.

Twenty-Four Month Results of Intravitreal Ranibizumab for Macular Edema after Branch Retinal Vein Occlusion: Visual Outcomes and Resolution of Macular Edema.

Purpose: To report 24-month results after one intravitreal ranibizumab (IVR) injection followed by pro re nata (PRN) dosing for macular edema (ME) after branch retinal vein occlusion (BRVO).Methods: Eyes with BRVO met the followings were included: 77 letters or less best-corrected visual acuity (BCVA) (Early Treatment Diabetic Retinopathy Study [ETDRS] score) and central retinal thickness (CRT) of 250 µm or more. IVR injection was performed followed by a PRN regimen. The retreatment criteria included visual loss of five or more ETDRS letters compared with the previous visit, 250 µm or more of CRT, or presence of residual or recurrent ME including the parafoveal lesions. The primary outcome measures were the BCVA changes at month 12 and month 24 from baseline, and the secondary outcomes were changes in CRT, resolution of ME, the number of IVR injections, and changes of nonperfused areas (NPAs).Results: Twenty eyes of 20 patients (5 men, 15 women; mean age, 68.2 years) were enrolled. The mean BCVAs (ETDRS letters) at baseline, month 12, and month 24 were 62.0, 80.2, and 80.9, respectively. The mean ETDRS letters gains were 18.3 and 19.0 at month 12 and month 24, respectively. The percentages of patients with Snellen equivalent BCVAs of 20/20 or better at month 12 and month 24 were 75% and 70%, respectively. The mean CRTs at baseline, month 12, and month 24 were 480, 252, and 272 µm, respectively. Forty percent of all eyes had complete resolution of ME. The mean number of IVR injections was 8.3 times, which gradually decreased over time. The NPA change in either Zone 1 or Zone 2 was not significant during the follow-up. No adverse side effects were observed.Conclusion: IVR injection followed by a PRN regimen provided pretty good visual outcomes at month 24.

Cytoplasmic synthesis of endogenous Alu complementary DNA via reverse transcription and implications in age-related macular degeneration.

Alu retroelements propagate via retrotransposition by hijacking long interspersed nuclear element-1 (L1) reverse transcriptase (RT) and endonuclease activities. Reverse transcription of Alu RNA into complementary DNA (cDNA) is presumed to occur exclusively in the nucleus at the genomic integration site. Whether Alu cDNA is synthesized independently of genomic integration is unknown. Alu RNA promotes retinal pigmented epithelium (RPE) death in geographic atrophy, an untreatable type of age-related macular degeneration. We report that Alu RNA-induced RPE degeneration is mediated via cytoplasmic L1-reverse-transcribed Alu cDNA independently of retrotransposition. Alu RNA did not induce cDNA production or RPE degeneration in L1-inhibited animals or human cells. Alu reverse transcription can be initiated in the cytoplasm via self-priming of Alu RNA. In four health insurance databases, use of nucleoside RT inhibitors was associated with reduced risk of developing atrophic macular degeneration (pooled adjusted hazard ratio, 0.616; 95% confidence interval, 0.493-0.770), thus identifying inhibitors of this Alu replication cycle shunt as potential therapies for a major cause of blindness.

Multimodal Imaging of Microvascular Abnormalities in Retinal Vein Occlusion.

The technologies of ocular imaging modalities such as optical coherence tomography (OCT) and OCT angiography (OCTA) have progressed remarkably. Of these in vivo imaging modalities, recently advanced OCT technology provides high-resolution images, e.g., histologic imaging, enabling anatomical analysis of each retinal layer, including the photoreceptor layers. Recently developed OCTA also visualizes the vascular networks three-dimensionally, which provides better understanding of the retinal deep capillary layer. In addition, ex vivo analysis using autologous aqueous or vitreous humor shows that inflammatory cytokine levels including vascular endothelial growth factor (VEGF) are elevated and correlated with the severity of macular edema (ME) in eyes with retinal vein occlusion (RVO). Furthermore, a combination of multiple modalities enables deeper understanding of the pathology. Regarding therapy, intravitreal injection of anti-VEGF drugs provides rapid resolution of ME and much better visual improvements than conventional treatments in eyes with RVO. Thus, the technologies of examination and treatment for managing eyes with RVO have progressed rapidly. In this paper, we review the multimodal imaging and therapeutic strategies for eyes with RVO with the hope that it provides better understanding of the pathology and leads to the development of new therapies.

Efficacy and safety of intravitreal aflibercept for polypoidal choroidal vasculopathy: 96-week outcomes in the Japanese subgroup of the PLANET study.

PURPOSE: To evaluate the efficacy and safety of intravitreal aflibercept (IVT-AFL) versus IVT-AFL plus rescue photodynamic therapy (IVT-AFL + rPDT) in the subgroup of Japanese patients with polypoidal choroidal vasculopathy (PCV) enrolled in the PLANET study. STUDY DESIGN: A 96-week, double-masked, sham-controlled phase-3b/4 randomized clinical trial conducted at multiple centers from May 2014 to August 2016. PATIENTS AND METHODS: Patients with PCV (BCVA 73-24 ETDRS letters [20/40-20/320 Snellen]) received 3 initial monthly doses of IVT-AFL 2 mg. At week 12, the patients were randomly assigned 1:1 to IVT-AFL + sham PDT or IVT-AFL + rPDT. Patients not requiring rescue received IVT-AFL every 8 weeks; those requiring rescue received IVT-AFL monthly plus sham/active PDT. Following week 52, the treatment intervals could be extended > 8 weeks. RESULTS: The baseline demographics for the 159 Japanese patients were balanced. At week 96, the mean BCVA change was + 9.7 (IVT-AFL) versus + 9.5 letters (IVT-AFL + rPDT) (least-squares mean difference of - 0.3; 95% CI, - 3.7 to 3.1); the mean central subfield thickness reduction was - 148.0 µm versus - 145.9 µm. Overall, 17.1% of the patients required rescue PDT. At week 96, 25.0% (IVT-AFL) and 37.9% (IVT-AFL + rPDT) of the patients had complete polyp regression; 84.1% (IVT-AFL) and 88.4% (IVT-AFL + rPDT) of the patients had no evidence of active polyps. The mean number of injections (weeks 52-96) were 4.6 (IVT-AFL) and 4.5 (IVT-AFL + rPDT). Overall, 36.0% (IVT-AFL) and 33.8% (IVT-AFL + rPDT) of the patients experienced ocular treatment-emergent adverse events. CONCLUSION: IVT-AFL monotherapy was efficacious for the treatment of Japanese patients with PCV, and the addition of rescue PDT did not show additional benefits.

Treatment patterns for retinal diseases in patients newly-treated with anti-VEGF agents: A retrospective analysis of claims data from the Japan Medical Data Center database.

PURPOSE: To describe treatment patterns in patients diagnosed with neovascular age-related macular degeneration (nAMD), retinal vein occlusion (RVO), or diabetic macular edema (DME), newly-treated with anti-vascular endothelial growth factor (anti-VEGF) agents as recorded in the Japanese Medical Data Center (JMDC) database. STUDY DESIGN: This non-interventional, descriptive, retrospective, observational cohort study included insured Japanese patients aged ≥ 21 and ≤ 75 years at index date (anti-VEGF treatment initiation). METHODS: Patients with minimum one claim in JMDC database with a diagnosis code for nAMD, RVO, or DME between October 2007-May 2015 and with minimum of one claim for anti-VEGF agents on or after the date of diagnosis were included. Frequency and proportion of claims submitted for anti-VEGF injections were assessed during 12 months post-index date. RESULTS: The median (interquartile range) number of claims for anti-VEGF injections during 12 months post-index date were 3 (1, 4) for nAMD (n = 255), 2 (1, 3) for RVO (n = 223) and 2 (1, 4) for DME (n = 125) patients. Frequencies of nAMD, RVO and DME patients with one or more claims for a retinal disease treatment other than an anti-VEGF agent were 4 (1.57%), 59 (26.46%) and 68 (54.40%) during the 12 months pre-index date and 21 (8.24%), 85 (38.12%) and 62 (49.60%) in the 12 months post-index date, respectively. CONCLUSIONS: The median number of anti-VEGF injections per patient was lower than those reported in clinical trials. Although various pre- and concomitant treatments were used in RVO and DME, anti-VEGF monotherapy was the first-line treatment in > 90% of nAMD patients.