Central retinal artery occlusion after intravitreal brolucizumab injection for treatment-naïve neovascular age-related macular degeneration; a case report.

BACKGROUND: To report a case of central retinal artery occlusion (CRAO) after intravitreal injection of brolucizumab for a treatment-naïve neovascular age-related macular degeneration (nAMD) patient without comorbid cardiovascular disease history. CASE PRESENTATION: A 79-year-old Asian male without a cardiovascular disease history such as diabetes or hypertension underwent three times of monthly consecutive intravitreal brolucizumab injections for treatment of progressed nAMD in his left eye. Two days after the third injection, the patient presented with acute painless visual loss. Typical retinal whitening with a cherry red spot was observed on the fundus photograph, and retinal swelling with hyper-reflectivity was also identified on the optical coherence tomography (OCT) scan. On the fundus fluorescein angiography, arm-to-retina time and arteriovenous transit time were remarkedly delayed, but clinical findings suggesting an intraocular inflammation (IOI) were not observed. Therefore, CRAO was diagnosed, and anterior chamber paracentesis was administrated immediately. However, there had been no improvement in visual acuity during the follow-up period of three months, despite prolonged oral steroid and anti-platelet agent medication. CONCLUSIONS: In rare cases, patients without cardiovascular comorbidities can develop CRAO after intravitreal brolucizumab injection without gross evidence of IOI. Therefore, CRAO should always be in consideration and careful observation is required after intravitreal brolucizumab injection for nAMD patients with old age, even if the patient does not have any other cardiovascular disease history.

Influence of Vitreoretinal Surgery on Ocular Surface Dynamics Using Keratograph 5M.

PURPOSE: To evaluate changes of ocular surface dynamics using Keratograph 5M for 3 months after vitreoretinal surgery. METHODS: Eighty-three patients were divided into three groups: phacoemulsification group, vitrectomy group, and combined group. Keratograph 5M was performed for all patients at 1 week, 1 month, and 3 months after the surgery. Ocular surface dynamics parameters measured by Keratograph 5M, including noninvasive keratograph first tear film breakup time (NifBUT), noninvasive keratograph average tear film breakup time (NiaBUT), and tear meniscus height (TMH) were compared among the three groups over time. RESULTS: The mean age of all patients (46 men and 37 women) was 62.2 ± 8.4 years. NifBUT and NiaBUT were significantly decreased at 1 week after surgery compared to those at baseline in all three groups (all p < 0.001). NifBUT and NiaBUT in the phacoemulsification group almost recovered to the preoperative level, while those in the vitrectomy group and the combined group were still significantly less than those at baseline. NifBUT and NiaBUT in the phacoemulsification group were significantly longer than those in the vitrectomy group and the combined group at 3 months. After 1 week, TMHs were significantly higher in the vitrectomy group (p = 0.001) and the combined group (p = 0.022) than in the phacoemulsification group, while TMHs were significantly less in the vitrectomy group (p = 0.010) and the combined group (p < 0.001) than in the phacoemulsification group at 3 months after surgery. CONCLUSIONS: These results suggest that vitreoretinal surgery could induce alteration of ocular surface dynamics for 3 months. The vitrectomy group and the combined group showed tear film instability compared to the cataract surgery alone group. Patients who underwent vitreoretinal surgery experienced more severe dry eye syndrome symptoms than those who underwent cataract surgery. Thus, managing dry eye syndrome after vitreoretinal surgery should be considered important for patients.

Short-term Efficacy and Safety of Intravitreal Brolucizumab Injection for Treatment-Naive Exudate Age-related Macular Degeneration: A Multicenter Study.

PURPOSE: To compare short-term efficacy and safety of intravitreal brolucizumab injection with aflibercept in treatment-naive neovascular age-related macular degeneration (nAMD) patients. METHODS: A total of 59 eyes from 59 treatment-naive nAMD patients in three hospitals were retrospectively reviewed. Of which, 27 patients underwent intravitreal brolucizumab injections and 32 received aflibercept. After monthly consecutive three injections, best-corrected visual acuity (BCVA; in logarithm of minimal angle of resolution [logMAR]), central macular thickness (CMT), dry macula achievement rate, and intraocular inflammation (IOI) incidence were compared. RESULTS: After loading-phase treatment, BCVA was significantly increased from 0.48 ± 0.30 logMAR at baseline to 0.33 ± 0.21 logMAR at 3 months in the brolucizumab group (p = 0.002) and 0.40 ± 0.39 logMAR at baseline to 0.33 ± 0.36 logMAR at 3 months in the aflibercept group (p = 0.007). But there was no significant difference in BCVA improvement at 3 months between the two groups. CMT significantly decreased from 429.67 ± 250.59 µm at baseline to 210.67 ± 93.53 µm at 3 months in the brolucizumab group and from 346.69 ± 159.09 µm to 234.52 ± 83.42 µm in the aflibercept group (both p < 0.001). The amount of CMT reduction was significantly greater in the brolucizumab group after 3 months (p = 0.036). In typical AMD eyes, brolucizumab showed similar BCVA improvement but better CMT reduction at 3 months (p = 0.018). Dry macula achievement rate was not significantly different between the two groups. One IOI was observed in the brolucizumab group. CONCLUSIONS: Intravitreal injections of brolucizumab and aflibercept showed similar anatomical and functional outcomes. But CMT reduction was greater in the brolucizumab group. One IOI was identified, which was tolerable for topical agents. These results suggest that brolucizumab could be a novel first line treatment option for treating naive nAMD patients.

An interpretable and interactive deep learning algorithm for a clinically applicable retinal fundus diagnosis system by modelling finding-disease relationship.

The identification of abnormal findings manifested in retinal fundus images and diagnosis of ophthalmic diseases are essential to the management of potentially vision-threatening eye conditions. Recently, deep learning-based computer-aided diagnosis systems (CADs) have demonstrated their potential to reduce reading time and discrepancy amongst readers. However, the obscure reasoning of deep neural networks (DNNs) has been the leading cause to reluctance in its clinical use as CAD systems. Here, we present a novel architectural and algorithmic design of DNNs to comprehensively identify 15 abnormal retinal findings and diagnose 8 major ophthalmic diseases from macula-centered fundus images with the accuracy comparable to experts. We then define a notion of counterfactual attribution ratio (CAR) which luminates the system's diagnostic reasoning, representing how each abnormal finding contributed to its diagnostic prediction. By using CAR, we show that both quantitative and qualitative interpretation and interactive adjustment of the CAD result can be achieved. A comparison of the model's CAR with experts' finding-disease diagnosis correlation confirms that the proposed model identifies the relationship between findings and diseases similarly as ophthalmologists do.

Vogt-Koyanagi-Harada syndrome-like uveitis after nivolumab administration as a treatment for ovarian cancer.

PURPOSE: To report a case of Vogt-Koyanagi-Harada (VKH) syndrome-like posterior uveitis after nivolumab administration to treat an ovarian cancer with an electrophysiological finding. A 61-year-old woman with ovarian cancer (stage 3A) and salpingo-oophorectomy surgery history visited the clinic complaining of blurred vision in both eyes. She had been enrolled a clinical trial using nivolumab in patients with ovarian cancer. She received four cycles of nivolumab administration and experienced blurred vision one week before the initial visit. There was no remarkable finding in the anterior segment and the vitreous body. Multiple subretinal fluid accumulations and serous retinal detachment were identified on the posterior pole. Subretinal fluid with choroidal folding was noted in optical coherence tomography, and multiple leakage points were also observed in wide-field fundus fluorescein angiography. Therefore, intravenous high-dose steroid pulse therapy was applied under the diagnosis of VKH syndrome-like posterior uveitis induced by an immunotherapy agent. After steroid therapy, the subretinal fluid was absorbed completely, and the patient's visual acuity was recovered to the normal range. The amplitudes in the multifocal electroretinogram were also restored after the treatment. CONCLUSION: Nivolumab is a human IgG4 monoclonal antibody and an immune checkpoint inhibitor. It is associated with the upregulation of T-cell activity by interfering with the interaction between the programmed death-1 (PD-1) receptor and the PD-ligand. Targeted therapy using immunotherapy agents has been widely used for malignant melanoma, lung cancer, renal cell carcinoma, and other cancers. However, immunotherapy agents such as nivolumab can induce autoimmune-related adverse events including uveitis. This report suggests that VKH syndrome-like posterior uveitis could be induced by nivolumab administration for an ovarian cancer treatment, which was resolved by steroid pulse therapy.

Surgical Outcomes of Vitrectomy for Macular Hole-induced Retinal Detachment According To Various Surgical Methods: A Multicenter Retrospective Study.

PURPOSE: To investigate the surgical outcomes of vitrectomy for macular hole-induced retinal detachment(MHRD), with respect to the surgical adjunctive method used. METHOD: We performed retrospective multicenter study of patients who underwent vitrectomy for MHRD. The visual/anatomical outcomes after vitrectomy were analyzed. We also analyzed these outcomes according to surgical method and the presence of persistent macular hole after the vitrectomy. RESULT: Thirty-four patients (34 eyes) from 6 hospitals were included in this study. The mean age of the patients was 64.56 ± 12.23 years; 31 patients (91.2%) were female. The mean LogMAR best-corrected visual acuity (BCVA) significantly improved 6 months after vitrectomy (p < .001). Retinal detachment completely improved in 32 eyes (94.1%). The visual prognoses and macular hole closure rates were not different depending on subretinal fluid drainage site. The presence or absence of a persistent macular hole after vitrectomy did not affect the visual outcomes. However, the recurrence of MHRD was significantly higher in eyes with persistent macular holes(p = .015). CONCLUSION: The surgeries to treat MHRD differed in terms of the procedure depending on the surgeons, but the visual outcomes did not differ depending on the surgical adjunctive method employed. There were no differences in the visual prognoses, regardless of whether there was a persistent macular hole; however, recurrence was significantly higher in eyes with persistent macular holes. Therefore, further surgical treatment might be considered for eyes with persistent macular holes after MHRD surgery.

Correlations among metamorphopsia test scores, optical coherence tomography findings and multifocal electroretinogram responses in epiretinal membrane patients.

PURPOSE: To quantify metamorphopsia with a novel objective method in patients with epiretinal membrane (ERM) and to compare the relationships among metamorphopsia scores, spectral-domain optical coherence tomography (OCT) findings, and multifocal electroretinogram (mfERG) results. METHODS: This study included 52 eyes of 52 patients with idiopathic ERM who underwent comprehensive ophthalmologic examinations, including measurement of best-corrected visual acuity (BCVA), OCT, and mfERG. The degree of metamorphopsia was quantified using MonPack One® (Metrovision, Perenchies, France). On the topographic map of the early treatment diabetic retinopathy (ETDRS) grid, retinal thickness in the central, superior, inferior, nasal, and temporal subfields were measured, and metamorphopsia scores for each corresponding subfield were also obtained. The amplitudes and implicit times of mERG were elicited from each subfield. Then, the correlations among metamorphopsia scores, OCT findings, and mfERG responses were analyzed. RESULTS: The mean age of the patients was 65.3 ± 18.5 y, and the average metamorphopsia score of the individual subfields was 2.03 ± 1.18. Initial BCVA was 0.50 ± 0.12 logMAR, but there was no significant correlation between metamorphopsia scores and BCVA. The metamorphopsia scores from the central subfields showed significant correlations with central retinal thickness (CRT) (p = 0.001). The mean metamorphopsia scores in the central subfield showed a significant relationship with the mean N1 and P1 amplitudes (p = 0.001, p = 0.048, respectively), while no relationship was observed between metamorphopsia scores and mfERG amplitudes in other subfields. CONCLUSIONS: The degree of metamorphopsia in patients with ERM could be objectively quantified in each subfield using a novel metamorphopsia test. The metamorphopsia scores were significantly correlated with retinal thickness, especially at the central subfields, and the scores in the central subfields were significantly correlated with the N1 and P1 amplitudes of mfERG. Thus, the metamorphopsia test can be a useful method to evaluate metamorphopsia symptoms for patients with ERM.

Leber hereditary optic neuropathy following head trauma and ocular trauma on contralateral eye: a case report.

PURPOSE: To present a case of activation of Leber hereditary optic neuropathy (LHON) following head and ocular trauma of the fellow eye in the patient with no remarkable symptoms and normal visual acuity prior to trauma. A 31-year-old healthy man was referred to our hospital after a traffic accident. He had blowout fractures of medial and inferior orbital wall of the left eye, subcutaneous hematoma of the left forehead, and bony fragment that compressed the left optic nerve. Initially, best-corrected visual acuity (BCVA) was 20/20 in the right and 20/1000 in the left eyes. Relative afferent pupillary defect of the left eye was apparent, and fundus examination revealed choroidal rupture circumferentially crossing the macular area. Nine months later, the patient complained with gradual vision loss in the right eye, which was the contralateral eye of the ocular trauma. BCVA was 20/200, and perimetry revealed cecocentral scotoma in the right eye. BCVA in both eyes reduced to 20/2000 1 year post-trauma. Visual evoked potentials revealed markedly decreased in amplitudes and elongated latencies for both eyes. Mitochondrial DNA analysis revealed a G11778A mutation; therefore, a diagnosis of activation of LHON followed by trauma was made for the previously unaffected carrier. CONCLUSIONS: This is a case in which activation of LHON occurred in a healthy carrier following head and ocular trauma of the fellow eye. This observation suggests the possibility that LHON activation in healthy carriers may occur in patients who experience head or ocular trauma even in the fellow eye.

Development and Validation of Deep Learning Models for Screening Multiple Abnormal Findings in Retinal Fundus Images.

PURPOSE: To develop and evaluate deep learning models that screen multiple abnormal findings in retinal fundus images. DESIGN: Cross-sectional study. PARTICIPANTS: For the development and testing of deep learning models, 309 786 readings from 103 262 images were used. Two additional external datasets (the Indian Diabetic Retinopathy Image Dataset and e-ophtha) were used for testing. A third external dataset (Messidor) was used for comparison of the models with human experts. METHODS: Macula-centered retinal fundus images from the Seoul National University Bundang Hospital Retina Image Archive, obtained at the health screening center and ophthalmology outpatient clinic at Seoul National University Bundang Hospital, were assessed for 12 major findings (hemorrhage, hard exudate, cotton-wool patch, drusen, membrane, macular hole, myelinated nerve fiber, chorioretinal atrophy or scar, any vascular abnormality, retinal nerve fiber layer defect, glaucomatous disc change, and nonglaucomatous disc change) with their regional information using deep learning algorithms. MAIN OUTCOME MEASURES: Area under the receiver operating characteristic curve and sensitivity and specificity of the deep learning algorithms at the highest harmonic mean were evaluated and compared with the performance of retina specialists, and visualization of the lesions was qualitatively analyzed. RESULTS: Areas under the receiver operating characteristic curves for all findings were high at 96.2% to 99.9% when tested in the in-house dataset. Lesion heatmaps highlight salient regions effectively in various findings. Areas under the receiver operating characteristic curves for diabetic retinopathy-related findings tested in the Indian Diabetic Retinopathy Image Dataset and e-ophtha dataset were 94.7% to 98.0%. The model demonstrated a performance that rivaled that of human experts, especially in the detection of hemorrhage, hard exudate, membrane, macular hole, myelinated nerve fiber, and glaucomatous disc change. CONCLUSIONS: Our deep learning algorithms with region guidance showed reliable performance for detection of multiple findings in macula-centered retinal fundus images. These interpretable, as well as reliable, classification outputs open the possibility for clinical use as an automated screening system for retinal fundus images.

Complete occlusion of anterior capsulorhexis after uneventful cataract surgery, treated with YAG laser capsulotomy.

BACKGROUND: Capsular contraction syndrome (CCS) has been reported as an uncommon complication after an cataract extraction surgery with intact anterior capsulorhexis. This report is written to present a case of complete occlusion of the anterior capsulorhexis opening after an uneventful cataract surgery, which was treated with non-invasive treatment. CASE PRESENTATION: A 69-year-old woman complained of decreased visual acuity in her right eye, which had started 2 months ago. She underwent phacoemulsification with an uneventful anterior capsulorhexis before 3 months. A total occlusion of the anterior capsulorhexis opening with capsular phimosis was identified on slit-lamp biomicroscopy, and a circular anterior capsulotomy using neodymium-doped yttrium aluminum garnet (Nd:YAG) laser was performed immediately. The capsulotomy site remained clear after a couple of years. CONCLUSIONS: It is supposed that proliferation of fibrotic tissue was relatively prominent in this case, rather than the appearance of capsular phimosis. This case can be an uncommon showing a total occlusion of the anterior capsulorhexis opening with prominent fibrotic proliferation pattern after an uneventful cataract surgery. Additionally, the occlusion could be removed with a non-invasive procedure, and was maintained clearly for several years.

En face optical coherence tomography findings in a case of Alport syndrome.

Alport syndrome is a rare hereditary disease that is associated with retinal abnormalities such as dot-and-fleck retinopathy and temporal macular thinning. The main pathophysiological process of Alport syndrome is loss of the collagen network in the basement membrane. However, the alterations in each retinal layer have not been fully evaluated. In the case presented here, we evaluated the retina of a patient with Alport syndrome using en face optical coherence tomography (OCT). The findings suggested that the primary alterations occur in the internal limiting membrane and the retinal pigment epithelium basement membrane which is a part of the Bruch's membrane. The adjacent retinal layers are damaged subsequently. In conclusion, en face OCT could be useful in evaluating retinal abnormalities and understanding their underlying pathophysiology in Alport syndrome.

Retinal Pigment Epithelium Responses to Selective Retina Therapy in Mouse Eyes.

PURPOSE: To investigate the characteristics of retinal pigment epithelium (RPE) and retinal damage induced by selective retina therapy (SRT) in mice, and to elucidate longitudinal changes in RPE cells. METHODS: C57BL/6J mice received SRT and continuous-wave laser photocoagulation (cwPC). The cell death pattern was evaluated using TUNEL assay, and proliferative potential of the RPE cells was evaluated using 5-ethynyl-2'-dexoyuridine (EdU) assay. To investigate the cell-cell integrity of RPE cells, ß-catenin staining was performed. The number and hexagonality of RPE cells in the SRT-treated area were estimated using a Voronoi diagram with time periods of 3 hours to 14 days. Antibodies to microphthalmia-associated transcription factor (MiTF) and orthodenticle homeobox 2 (Otx2) were used to confirm the specific characteristics of RPE cells in the SRT-treated area. RESULTS: The number of TUNEL-positive cells located in the neural retina was significantly lower in lesions treated with SRT compared to those treated with cwPC. EdU-positive RPE cells were first detected 3 to 12 hours after SRT, and increased until 3 to 7 days after SRT. ß-catenin staining showed that hexagonality was compromised and subsequently, RPE cells expanded in size within the targeted location. The number of RPE cells in SRT lesions decreased gradually until 12 hours after SRT and recovered by 14 days. Upregulated expression of MiTF and Otx2 was observed for 2 weeks in the SRT lesions. CONCLUSIONS: Selective retina therapy seems to induce selective RPE damage without collateral thermal injury in the neural retina. Furthermore, SRT-treated lesions recovered by proliferation of RPE cells that were present in the treated lesions and by expansion of adjacent RPE cells.

The effect of cilostazol on electrophysiologic changes in non-proliferative diabetic retinopathy patients.

PURPOSE: To evaluate the effects of cilostazol, an antiplatelet and vasodilation agent, on the retinal function of patients with non-proliferative diabetic retinopathy (NPDR) using a full-field electroretinogram (ffERG). METHODS: A total of 20 eyes from 20 patients were enrolled as the cilostazol-treated group, and 16 eyes from 16 patients were enrolled as the control group to assess the functional effects of cilostazol. Ophthalmologic examinations including fundus fluorescein angiography (FFA), fundus color photography, optical coherence tomography (OCT), and ffERG responses were recorded at baseline and after 1 year of cilostazol treatment. The number of microaneurysms on FFA, the number of exudates on fundus photographs, and central macular thickness (CMT) on OCT were compared between the two groups. Recording of ffERG was also performed at baseline and repeated after 1 year of treatment. The mean implicit times and amplitudes of a- and b-waves in each ffERG response were analyzed to evaluate the retinal function. RESULTS: CMT and the numbers of microaneurysms and exudates showed no significant change in the cilostazol-treated group. There was no significant change in ffERG parameters between baseline and 1 year after the treatment in each group. The mean changes in implicit times from the cilostazol-treated group were significantly less than in the control group in b-waves from dark-adapted 3 ERG (p = 0.017) and 10 ERG responses (p = 0.047). On the other hand, the mean changes in amplitudes were not significant after 1 year of cilostazol treatment, but there were slight increases in amplitudes of dark-adapted 0.01 ERG and 10 ERG in the cilostazol-treated group. CONCLUSIONS: These results suggest that cilostazol administration could reduce the implicit times of ffERG in patients with NPDR. It may be beneficial to preserve the retinal function in the diabetic retina, and additional research with larger populations and extended duration are needed to clarify the efficacy and safety of cilostazol for these patients.

Time-Dependent Changes of Cell Proliferation After Laser Photocoagulation in Mouse Chorioretinal Tissue.

PURPOSE: This study investigated the time course of cell proliferation after laser photocoagulation and analyzed the cell types of proliferating cells. METHODS: C57BL/6J mice received unilateral laser photocoagulation. Intraperitoneal bromodeoxyuridine (BrdU) injection was performed, and mice were divided into two groups according to the injection paradigm: group 1 with continuous injection and group 2 with periodic injection. Each group was again divided into four subgroups according to injection period: 0 to 3 days (n = 11), 0 to 7 days (n = 14), 0 to 14 days (n = 6), and 0 to 28 days (n = 6) after laser photocoagulation for group 1; and 0 to 3 days (n = 11), 4 to 7 days (n = 6), 8 to 14 days (n = 6), and 15 to 28 days (n = 6) after laser photocoagulation for group 2. The eyes were examined with immunohistochemistry using anti-BrdU antibody and other various antibodies for identification of proliferating cells. Manual cell counting and flow cytometry were performed for quantification. RESULTS: In group 1, the number of BrdU+ cells showed marked increase during the first 3 days of laser lesioning, reaching its maximum after 7 days (P < 0.05). Group 2 also demonstrated peak proliferation during the first 3 days, but a significantly reduced number of BrdU+ cells were detected during 4 to 7 days, 8 to 14 days, and 15 to 28 days of laser treatment (P < 0.05). BrdU+ cells colocalized with CD11b, F4/80, iba1, RPE65, CD31, and glial fibrillary acidic protein (GFAP) labeling, and CD11b+, F4/80+, and iba1+ cells constituted the main fraction of BrdU+ cells. CONCLUSIONS: Laser photocoagulation induced cell proliferation mostly during the first 3 days, and many proliferating cells were identified as inflammatory cells, RPE cells, endothelial cells, and Müller cells.

Functional evaluation using multifocal electroretinogram after selective retina therapy with a microsecond-pulsed laser.

PURPOSE: To evaluate the changes of retinal function with multifocal electroretinogram (mfERG), and estimate the association between functional and structural changes after selective retina therapy (SRT) with microsecond-pulsed laser in comparison to continuous wave laser photocoagulation (cwPC). METHODS: Selective retina therapy and cwPC were applied with 10 × 10 shots and 1/2 lesion-width on the retina in the right and left eyes of 20 healthy Chinchilla Bastard rabbits, respectively. Optical coherence tomography (OCT), fundus fluorescein angiography (FFA), and mfERG were performed before, and on days 1, 7, and 30 after both laser treatments. The mean ratios of amplitudes and implicit times of N1 and P1 from eight hexagons covering laser-treated retinal lesions/total retina were measured. Histology was obtained after killing three rabbits at each time period to observe the anatomic changes after both laser treatments. RESULTS: The mean ratios of amplitudes of N1 and P1 in SRT lesions did not change significantly for 30 days after laser treatment. Only subtle reductions of the mean ratios of N1 and P1 amplitudes on day 1, thereafter the amplitudes showed the trend to recover toward baseline values. Histology and OCT revealed temporary and reversible morphologic changes after SRT, which restored to normal within 1 month. However, the mean ratios of N1 amplitudes on days 7 and 30 (P = 0.010, P < 0.001, respectively), and P1 amplitudes on days 7 and 30 (P < 0.001, P < 0.001, respectively) declined significantly in cwPC lesions compared with baseline. Disorganization and atrophic changes were identified on histology and OCT after cwPC. CONCLUSIONS: The results suggest that SRT preserved retinal function as well as anatomical structure after treatment.