Hiroko Terasaki

Intravitreal aflibercept for diabetic macular edema: 100-week results from the VISTA and VIVID studies

PURPOSE To compare efficacy and safety of 2 dosing regimens of intravitreal aflibercept injection (IAI) with macular laser photocoagulation for diabetic macular edema (DME). DESIGN Two similarly designed, randomized, phase 3 trials, VISTA(DME) and VIVID(DME). PARTICIPANTS Patients (eyes; n=872) with type 1 or 2 diabetes mellitus who had DME with central involvement. METHODS Eyes received IAI 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 monthly doses (2q8), or laser control. MAIN OUTCOME MEASURES The primary end point was mean change from baseline in best-corrected visual acuity (BCVA) at week 52. This report presents the 100-week results including mean change from baseline in BCVA, proportion of eyes that gained ≥15 letters, and proportion of eyes with a ≥2-step improvement in the Diabetic Retinopathy Severity Scale (DRSS) score. RESULTS Mean BCVA gain from baseline to week 100 with IAI 2q4, IAI 2q8, and laser control was 11.5, 11.1, and 0.9 letters (P < 0.0001) in VISTA and 11.4, 9.4, and 0.7 letters (P < 0.0001) in VIVID, respectively. The proportion of eyes that gained ≥15 letters from baseline at week 100 was 38.3%, 33.1%, and 13.0% (P < 0.0001) in VISTA and 38.2%, 31.1%, and 12.1% (P ≤ 0.0001) in VIVID. The proportion of eyes that lost ≥15 letters at week 100 was 3.2%, 0.7%, and 9.7% (P ≤ 0.0220) in VISTA and 2.2%, 1.5%, and 12.9% (P ≤ 0.0008) in VIVID. Significantly more eyes in the IAI 2q4 and 2q8 groups versus those in the laser control group had a ≥2 step improvement in the DRSS score in both VISTA (37.0% and 37.1% vs. 15.6%; P < 0.0001) and VIVID (29.3% and 32.6% vs. 8.2%; P ≤ 0.0004). In an integrated safety analysis, the most frequent serious ocular adverse event was cataract (2.4%, 1.0%, and 0.3% for 2q4, 2q8, and control). CONCLUSIONS In both VISTA and VIVID, the 52-week visual and anatomic superiority of IAI over laser control was sustained through week 100, with similar efficacy in the 2q4 and 2q8 groups. Safety in these studies was consistent with the known safety profile of IAI.

Polypoidal choroidal vasculopathy treated with macular translocation: clinical pathological correlation

Aims: To report the histopathology of two specimens of polypoidal choroidal vasculopathy (PCV) obtained from two eyes of Japanese patients. Methods: Specimens were obtained under direct visualisation during macular translocation surgery with 360 degree retinotomy. The clinical findings were correlated with the light microscopic findings of the two specimens. Results: One specimen from a 77 year old man was the central portion of the lesion that lay under the sensory retina on the retinal pigment epithelium (RPE). The specimen was made up mainly of fibrous tissue with small, thin walled vessels. Indocyanine green angiography after surgery revealed that active leaking polypoidal element remained under the RPE. Another specimen obtained from a 62 year old man was made up of a fibrovascular membrane situated within Bruchs membrane. The part of this specimen inferior to the foveal region included a collection of dilated, thin walled blood vessels without pericytes, surrounded by macrophages that stained positive for CD68. The dilated vessels appeared to be correlated with the orange coloured polyps observed by ophthalmoscopy, the polypoidal structure seen in indocyanine green angiograms, and the pyramidal elevation with intermediate reflectivity by optical coherence tomography. Conclusion: Polypoidal structures are located within Bruchs space. They are composed of clusters of dilated, thin walled blood vessels surrounded by macrophages and fibrin material. The positive immunohistochemical staining for vascular endothelial growth factor in the RPE and the vascular endothelial cells suggests that this fibrovascular complex is a subretinal choroidal neovascularisation.

New classification of capsular block syndrome

Purpose: To propose a new classification of capsular block syndrome (CBS) to improve understanding of the etiology and provide effective treatment. Setting: Shohzankai Medical Foundation, Miyake Eye Hospital, Nagoya, and Japanese Red Cross Society, Wakayama Medical Center, Wakayama, Japan. Methods: Three groups of eyes with CBS were reviewed: eyes originally reported and diagnosed as having CBS; eyes experiencing CBS after hydrodissection and luxation of the lens nucleus; and eyes with CBS accompanying liquefied aftercataract or capsulorhexis‐related lacteocrumenasia. Results: In all 3 groups, the CBS occurred in eyes with a ‐continuous curvilinear capsulorhexis (CCC). It was characterized by accumulation of a liquefied substance within a closed chamber inside the capsular bag, formed because the lens nucleus or the posterior chamber intraocular lens (IOL) optic occluded the anterior capsular opening created by the CCC. Depending on the time of onset, CBS can be classified as intraoperative (CBS seen at the time of lens luxation following hydrodissection), early postoperative (original CBS), and late postoperative (CBS with liquefied aftercataract or lacteocrumenasia). The etiology of the accumulated substance and the method of treatment are different in each type. Conclusion: Capsular block syndrome is a complication of cataract/10L surgery that can occur during and after surgery. Correctly identifying the type of CBS is crucial to understanding the nature and effective treatment of this disorder.

Occult macular dystrophy

PURPOSE Occult macular dystrophy is a hereditary macular dystrophy without any visible abnormality of the fundus or abnormality indicated by fluorescein angiography even when visual acuity is decreased. Normal full-field electroretinogram in both cone and rod components with abnormal focal macular cone electroretinogram is the key to diagnosing this disorder. The purpose of this study was to identify the function of the macular rods and to provide detailed clinical findings in occult macular dystrophy. METHODS Thirteen patients from eight families were examined. The fundi of 12 patients were essentially normal (occult macular dystrophy), and the oldest patient in one family disclosed bulls eye maculopathy. In the 12 patients, including the patient with bulls eye maculopathy, the profiles of cone and rod absolute thresholds were performed across the 60-degree horizontal meridian of the posterior pole. RESULTS All 12 patients showed cone sensitivity loss only in the macular area. Six relatively young patients revealed normal rod sensitivity, whereas six older patients showed borderline rod sensitivity or abnormal rod sensitivity in the macular area. CONCLUSIONS The pathology of occult dystrophy involves either only the macular cone system or macular cone and rod systems without any visible abnormality. This difference of the pathology suggests a different clinical entity or a different stage of occult macular dystrophy.

Ocular Adnexal IgG4-Related Lymphoplasmacytic Infiltrative Disorder

OBJECTIVE To determine the clinicopathological characteristics of patients with infiltration of IgG4-positive plasma cells into the ocular adnexa. METHODS We designed a prospective study to evaluate 24 patients with ocular adnexal lymphoplasmacytic infiltrative lesions, including sclerosing inflammation and reactive lymphoid hyperplasia. We analyzed peripheral blood and biopsy specimens from all patients. The classification criteria for placement in the IgG4-related group included having both an elevated serum level of IgG4 of 135 mg/dL or greater and an IgG4:IgG ratio of infiltrating plasma cells of 30% or greater. RESULTS Ten patients met the classification criteria (IgG4-related group), 9 patients did not meet the criteria (IgG4-unrelated group), and 5 patients met 1 but not both criteria (indeterminate group). Patients in the IgG4-related group had significantly higher bilateral involvement (P = .02), a higher number of allergic diseases (P = .01), and elevated IgE serum levels (P = .01). Of the 10 patients in the IgG4-related group, 3 also had polyclonal hypergammaglobulinemia, 6 had systemic lymphadenopathy or salivary gland enlargement, and 1 developed autoimmune pancreatitis. Patients in the IgG4-unrelated group did not have these serum and/or systemic abnormalities. CONCLUSION The IgG4-related and IgG4-unrelated groups have different patterns of tissue involvement and systemic disease associations and possibly different prognoses.

Whole genome sequencing in patients with retinitis pigmentosa reveals pathogenic DNA structural changes and NEK2 as a new disease gene

Significance Retinitis pigmentosa (RP) is a genetic disease that causes progressive blindness and that is caused by mutations in more than 50 genes. Conventional methods for identification of both RP mutations and novel RP genes involve the screening of DNA sequences spanning coding exons. In our work, we conversely test the use of whole genome sequencing, a technique that takes into account all variants from both the coding and noncoding regions of the human genome. In our approach, we identify a number of unique RP mutations, a previously undescribed disease gene, as well as pathogenic structural DNA rearrangements originating in introns. We performed whole genome sequencing in 16 unrelated patients with autosomal recessive retinitis pigmentosa (ARRP), a disease characterized by progressive retinal degeneration and caused by mutations in over 50 genes, in search of pathogenic DNA variants. Eight patients were from North America, whereas eight were Japanese, a population for which ARRP seems to have different genetic drivers. Using a specific workflow, we assessed both the coding and noncoding regions of the human genome, including the evaluation of highly polymorphic SNPs, structural and copy number variations, as well as 69 control genomes sequenced by the same procedures. We detected homozygous or compound heterozygous mutations in 7 genes associated with ARRP (USH2A, RDH12, CNGB1, EYS, PDE6B, DFNB31, and CERKL) in eight patients, three Japanese and five Americans. Fourteen of the 16 mutant alleles identified were previously unknown. Among these, there was a 2.3-kb deletion in USH2A and an inverted duplication of ∼446 kb in EYS, which would have likely escaped conventional screening techniques or exome sequencing. Moreover, in another Japanese patient, we identified a homozygous frameshift (p.L206fs), absent in more than 2,500 chromosomes from ethnically matched controls, in the ciliary gene NEK2, encoding a serine/threonine-protein kinase. Inactivation of this gene in zebrafish induced retinal photoreceptor defects that were rescued by human NEK2 mRNA. In addition to identifying a previously undescribed ARRP gene, our study highlights the importance of rare structural DNA variations in Mendelian diseases and advocates the need for screening approaches that transcend the analysis of the coding sequences of the human genome.

Characteristics of Bone Marrow–Derived Microglia in the Normal and Injured Retina

PURPOSE To compare the distribution and immunologic characteristics of bone marrow (BM)-derived and resident microglia in the retina. METHODS Mice were irradiated and injected with enhanced green fluorescent protein-positive (EGFP(+)) BM cells. One month to 12 months after BM transplantation, eyes were analyzed histologically for the expression of EGFP and various monocyte/microglia/macrophage markers (Iba-1, F4/80, GS-1, major histocompatibility complex [MHC] class II). N-methyl-N-nitrosourea (MNU) was injected or retinal detachment was created to induce retinal damage. RESULTS Many BM-derived EGFP(+) cells were found in the ciliary body and choroid and around the optic nerve in the uninjured eyes. Within the retina, few such cells existed at the retinal margin and juxtapapillary area at 3 to 12 months after BM transplantation. However, after MNU injection, many EGFP(+) cells were found in the retina adjacent to the retinal vessels, optic nerve, and ciliary body that rapidly spread throughout the retina. Most of them showed morphologic and immunohistochemical features of microglia. By 7 days after MNU injection, EGFP(+) BM-derived cells occupied approximately 15% of the total Iba-1(+) retinal microglia. Meanwhile, the proportion of MHC class II(+) cells was larger among BM-derived (EGFP(+)/Iba-1(+)) than resident (EGFP(-)/Iba-1(+)) microglia. In the eyes with retinal detachment, EGFP(+)/F4/80(+) cells engrafted exclusively around the detached retina. CONCLUSIONS In response to retinal damage, numerous BM-derived cells migrated to the retina from the ciliary body, optic nerve, and retinal vessels and differentiated into microglia. The higher rate of immunologic activation and the increased specificity to the damaged site appeared to be the characteristic features of BM-derived microglia.

Transplantation of human embryonic stem cell-derived retinal tissue in two primate models of retinal degeneration

Significance We first confirmed the ability of human embryonic stem cell-derived retina (hESC-retina) to form structured mature photoreceptor layers after transplantation into nude rats. We then developed two monkey models of retinal degeneration and evaluated their utility as host models for transplantation studies. Finally, we performed a pilot study of hESC-retina transplantation in the developed models and conducted in vivo monitoring studies using clinical devices and subsequently confirmed structured graft maturation and the potential formation of synaptic contacts between graft and host cells. This study demonstrates the competency of hESC-retina as a graft source and the eligibility of two newly developed monkey models that may be useful in future, long-term, functional studies of retinal transplantation. Retinal transplantation therapy for retinitis pigmentosa is increasingly of interest due to accumulating evidence of transplantation efficacy from animal studies and development of techniques for the differentiation of human embryonic stem cells (hESCs) and induced pluripotent stem cells into retinal tissues or cells. In this study, we aimed to assess the potential clinical utility of hESC-derived retinal tissues (hESC-retina) using newly developed primate models of retinal degeneration to obtain preparatory information regarding the potential clinical utility of these hESC-retinas in transplantation therapy. hESC-retinas were first transplanted subretinally into nude rats with or without retinal degeneration to confirm their competency as a graft to mature to form highly specified outer segment structure and to integrate after transplantation. Two focal selective photoreceptor degeneration models were then developed in monkeys by subretinal injection of cobalt chloride or 577-nm optically pumped semiconductor laser photocoagulation. The utility of the developed models and a practicality of visual acuity test developed for monkeys were evaluated. Finally, feasibility of hESC-retina transplantation was assessed in the developed monkey models under practical surgical procedure and postoperational examinations. Grafted hESC-retina was observed differentiating into a range of retinal cell types, including rod and cone photoreceptors that developed structured outer nuclear layers after transplantation. Further, immunohistochemical analyses suggested the formation of host–graft synaptic connections. The findings of this study demonstrate the clinical feasibility of hESC-retina transplantation and provide the practical tools for the optimization of transplantation strategies for future clinical applications.

Intravitreal injection of bevacizumab for macular edema secondary to branch retinal vein occlusion:results after 12 months and multiple regression analysis.

Purpose: To evaluate the 12-month follow-up results of intravitreal bevacizumab therapy for macular edema secondary to branch retinal vein occlusion and to identify the pretreatment factors that were associated with an improvement of the final visual outcome. Methods: Fifty eyes of 50 patients with macular edema secondary to branch retinal vein occlusion received an injection of 1.25 mg/0.05 mL bevacizumab. Additional injections were done when recurrence of macular edema occurred or the treatment was not effective. The best-corrected visual acuity and foveal thickness were measured. Stepwise multiple regression analyses were also performed. Results: The mean logarithm of the minimum angle of resolution visual acuity improved significantly from 0.53 to 0.26, and the mean foveal thickness decreased significantly from 523 to 305 &mgr;m during the 12-month follow-up period. The mean number of injections was 2.0 (range, 1–4). Stepwise multiple regression analyses showed that younger patients had both better visual acuity at 12 months and greater improvement of visual acuity during 12 months. In addition, better pretreatment visual acuity was associated with better visual acuity at 12 months but with less improvement of the visual acuity. Conclusion: Intravitreal bevacizumab therapy can be a long-term effective treatment for macular edema secondary to branch retinal vein occlusion.

Intravitreal Aflibercept for Macular Edema Secondary to Central Retinal Vein Occlusion: 18-Month Results of the Phase 3 GALILEO Study

PURPOSE To evaluate intravitreal aflibercept for treatment of macular edema secondary to central retinal vein occlusion (CRVO). DESIGN Randomized, double-masked, phase 3 study. METHODS A total of 177 patients with macular edema secondary to CRVO were randomized to receive 2 mg intravitreal aflibercept (n = 106) or sham (n = 71) every 4 weeks for 20 weeks. From weeks 24 to 48, patients were monitored every 4 weeks; the former group received intravitreal aflibercept as needed (PRN), and the sham group received sham. From weeks 52 to 76, patients were monitored every 8 weeks, and both groups received intravitreal aflibercept PRN. The primary endpoint (proportion of patients who gained ≥15 letters) was at week 24. This study reports exploratory outcomes at week 76. RESULTS The proportion of patients who gained ≥15 letters in the intravitreal aflibercept and sham groups was 60.2% vs 22.1% at week 24 (patients discontinued before week 24 were considered nonresponders; P < .0001), 60.2% vs 32.4% at week 52 (last observation carried forward, P < .001), and 57.3% vs 29.4% at week 76 (last observation carried forward; P < .001). Mean μm change from baseline central retinal thickness was -448.6 vs -169.3 at week 24 (P < .0001), -423.5 vs -219.3 at week 52 (P < .0001), and -389.4 vs -306.4 at week 76 (P = .1122). Over 76 weeks, the most common ocular serious adverse event in the intravitreal aflibercept group was macular edema (3.8%). CONCLUSIONS The visual and anatomic improvements seen after fixed, monthly dosing at week 24 were largely maintained when treatment intervals were extended. Patients with macular edema following CRVO benefited from early treatment with intravitreal aflibercept.