Oral Hypoxia-Inducible Factor 2α Inhibitor Belzutifan in Ocular von Hippel-Lindau Disease: Subgroup Analysis of the Single-Arm Phase 2 LITESPARK-004 Study.

PURPOSE: To report the efficacy of the oral hypoxia-inducible factor 2α inhibitor belzutifan in participants with von Hippel-Lindau disease-associated retinal hemangioblastomas in the LITESPARK-004 study. DESIGN: Subgroup analysis of the phase 2, single-arm, open-label LITESPARK-004 study. PARTICIPANTS: Adults with 1 or more von Hippel-Lindau disease-associated measurable renal cell carcinoma tumors not requiring immediate surgical intervention were eligible. METHODS: Participants received oral belzutifan 120 mg once daily until disease progression or unacceptable treatment-related toxicity. MAIN OUTCOME MEASURES: Efficacy of belzutifan in retinal hemangioblastomas was a secondary end point, measured as response (improved, stable, or progressed) by independent reading center-certified graders based on color fundus imaging performed every 12 weeks using the investigator's preferred imaging standards. Additional assessments, where available, included OCT and ultra-widefield fluorescein angiography. RESULTS: Among 61 participants in LITESPARK-004, 12 had 1 or more evaluable active retinal hemangioblastomas in 16 eyes at baseline per independent reading center. As of April 1, 2022, the median follow-up for participants with ocular von Hippel-Lindau disease at baseline was 37.3 months. All 16 eyes were graded as improved, with a response rate of 100.0% (95% confidence interval, 79.4%-100%). No new retinal hemangioblastomas or ocular disease progression were reported as of data cutoff date. Eight participants underwent additional multimodal eye assessments performed at the National Institutes of Health study site. Among this subgroup, 10 of 24 hemangioblastomas in 8 eyes of 6 participants measured 500 µm or more in greatest linear dimension at baseline and were analyzed further. All 10 hemangioblastomas had a mean area reduction of 15% or more by month 12 and of 30% or more by month 24. CONCLUSIONS: Belzutifan showed promising activity against ocular von Hippel-Lindau disease, including capacity to control retinal hemangioblastomas, with effects sustained for more than 2 years while treatment is ongoing. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Correlation of Ocular Plane-Wave Doppler With Optical Coherence Tomography Angiography in Preeclampsia.

OBJECTIVES: Preeclampsia (PE) is a severe complication of pregnancy characterized by hypertension, proteinuria and compromised fetal blood supply. The eye, like other end organs, is affected by this systemic condition, but unlike in other organs, ocular media transparency allows high-resolution optical visualization of the vascular structure of the retina. Our aim was to assess how ultrasound-determined ocular blood-flow correlates with vascular structure of the retina and choriocapillaris determined by optical coherence tomography angiography (OCTA). METHODS: Plane-wave ultrasound and OCTA were performed on both eyes of 40 consecutive subjects consisting of normal controls (n = 11), mild PE (n = 5), severe PE (n = 17) and chronic or gestational hypertension (n = 7) within 72 hours following delivery. From ultrasound, we measured pulsatile flow velocity and resistance indices in the central retinal artery (CRA) and vein, the short posterior ciliary arteries (SPCAs) and choroid. From OCTA, we measured vascular density (VD) in the superficial, deep retina and choriocapillaris. We determined differences in Doppler and OCTA parameters among groups and correlations between ultrasound and OCTA. RESULTS: In severe PE, flow resistance was reduced with respect to controls. Flow velocity and resistance in the and SPCA were moderately correlated with VD in the choriocapillaris and peripapillary retina, but VD in PE did not differ significantly from controls. CONCLUSIONS: Although OCTA parameters were moderately correlated with Doppler ultrasound, OCTA did not demonstrate significant differences between PE and controls postpartum.

Evaluation of the age-related eye disease study clinical lens grading system AREDS report No. 31.

PURPOSE: To examine the grading (interrater) reliability of the Age-Related Eye Disease Study (AREDS) Clinical Lens Grading System (ARLNS). DESIGN: Evaluation of diagnostic test or technology. PARTICIPANTS: One hundred fifty volunteers (284 eyes). METHODS: Participants with lens opacities of varying severity were independently graded at the slit lamp for cataract severity by 2 examiners (retinal or anterior segment specialists) using the ARLNS, which employs 3 standard photographs of increasing severity for classifying each of the 3 major types of opacity. Lens photographs were taken and graded at a reading center using the more detailed AREDS System for Classifying Cataracts from photographs. MAIN OUTCOME MEASURES: The Pearson correlation, weighted-kappa, and limits-of-agreement statistics were used to assess the interrater agreement of the gradings. RESULTS: Examinations were performed on 284 lenses (150 participants). Tests of interrater reliability between pairs of clinicians showed substantial agreement between clinicians for cortical and posterior subcapsular opacities and moderate agreement for nuclear opacities. A similar pattern and strength of agreement was present when comparing scores of retinal versus anterior segment specialists. Interrater agreement between clinical and reading center gradings was not as great as inter-clinician agreement. CONCLUSIONS: Interrater agreements were in the moderate to substantial range for the clinical assessment of lens opacities. Inherent differences in cataract classification systems that rely on slit lamp vs photographic assessments of lens opacities may explain some of the disagreement noted between slit lamp and photographic gradings. Given the interrater reliability statistics for clinicians and the simplicity of the grading procedure, ARLNS is presented for use in studies requiring a simple, inexpensive method for detecting the presence and severity of the major types of lens opacities. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article.

Preliminary assessment of celecoxib and microdiode pulse laser treatment of diabetic macular edema.

PURPOSE: Inflammation may play an important role in the pathogenesis of diabetic macular edema, a major cause of vision loss in persons with diabetes. The purpose of this study was to evaluate combined antiinflammatory therapy and laser approaches for treating patients with diabetic macular edema. METHODS: In this prospective, factorial, randomized, multicenter trial, we compared cyclo-oxygenase-2 inhibitor (celecoxib) with placebo and diode grid laser with standard Early Treatment Diabetic Retinopathy Study focal laser treatment in 86 participants with diabetic macular edema. The primary outcome is change in visual acuity of > or = 15 letters from baseline, and the secondary outcomes include a 50% reduction in the retinal thickening of diabetic macular edema measured by optical coherence tomography and a 50% reduction in leakage severity on fluorescein angiography. RESULTS: Visual acuity and retinal thickening data from >2 years of follow-up did not show evidence of differences between the medical and laser treatments. However, participants assigned to the celecoxib group were more likely to have a reduction in fluorescein leakage when compared with the placebo group (odds ratio = 3.6; P < 0.01). CONCLUSION: This short-term study did not find large visual function benefits of treatment with celecoxib or diode laser compared with those of standard laser treatment. A suggestive effect of celecoxib in reducing fluorescein leakage was observed.

Age-related macular degeneration.

Age-related macular degeneration is the leading cause of blindness in elderly populations of European descent. The most consistent risk factors associated with this ocular condition are increasing age and cigarette smoking. Genetic investigations have shown that complement factor H, a regulator of the alternative complement pathway, and LOC387715/HtrA1 are the most consistent genetic risk factors for age-related macular degeneration. Although the pathogenesis of this disease is unknown, oxidative stress might have an important role. Treatment with antioxidant vitamins and zinc can reduce the risk of developing advanced age-related macular degeneration by about a quarter in those at least at moderate risk. Intravitreal injections of ranibizumab, a monoclonal antibody that inhibits all forms of vascular endothelial growth factor, have been shown to stabilise loss of vision and, in some cases, improve vision in individuals with neovascular age-related macular degeneration. These findings, combined with assessments of possible environmental and genetic interactions and new approaches to modulate inflammatory pathways, will hopefully further expand our ability to understand and treat age-related macular degeneration.

Intravitreal ranibizumab therapy for retinal capillary hemangioblastoma related to von Hippel-Lindau disease.

PURPOSE: To evaluate the effect of intravitreal ranibizumab on retinal capillary hemangioblastomas (RCHs) associated with von Hippel-Lindau (VHL) disease that are not amenable or responsive to standard therapy. DESIGN: Prospective, noncomparative, interventional case series. PARTICIPANTS: Five patients with VHL-associated RCH with exudative changes and visual loss. METHODS: Monthly intravitreal injections of ranibizumab (0.5 mg) were given over a course of 6 months for a total of 7 injections, with additional injections considered until week 52. The final study visit was designated as 8 weeks after the final study injection. MAIN OUTCOME MEASURES: The primary outcome was the change in best-corrected visual acuity (BCVA) of >/=15 letters at the final visit compared with baseline. Secondary outcomes included change in lesion size, exudation as assessed clinically and by fluorescein angiography, change in retinal thickness as evaluated by optical coherence tomography, and adverse event assessments. RESULTS: Patients received an average of 10.0+/-3.1 injections over an average period of 47+/-14 weeks, including follow-up. Mean change in BCVA was a decrease of 9+/-20 letters, with 1 patient gaining >/=15 letters, and 2 patients losing >/=15 letters. Changes in both lesion size and exudation were variable. CONCLUSIONS: Intravitreal ranibizumab, delivered as monotherapy every 4 weeks, had minimal beneficial effects on most VHL-related RCHs. Possible treatment efficacy was demonstrated in the patient with the smallest lesion with less exudation. Future prospective studies are needed to determine the potential role of an antiangiogenic agent, possibly in combination with other therapies for the treatment of such advanced ocular tumors associated with VHL.

Retinal vascular proliferation as an ocular manifestation of von Hippel-Lindau disease.

OBJECTIVES: To describe the features, natural history, and management of an unusual manifestation of ocular von Hippel-Lindau disease in the form of fine vascular proliferation. METHODS: Case series of 14 patients with definite or presumed von Hippel-Lindau disease. RESULTS: Retinal vascular proliferation consisting of fine superficial vessels was found in 16 eyes of 14 patients with von Hippel-Lindau disease. The lesion was often found in a juxtapapillary location and associated with a fibrovascular component and/or a macular epiretinal membrane. In cases with follow-up (12 patients; mean [SD] follow-up, 10.9 [7.5] years), the lesion was stable in 7 of 13 eyes but showed growth and progression resulting in vision loss in the remainder. In 5 eyes, surgical intervention with pars plana vitrectomy, membrane peel, and excision of the fibrovascular lesion resulted in visual improvement in all of the cases. CONCLUSIONS: Ocular von Hippel-Lindau disease can uncommonly manifest as vascular proliferation that consists of fine, superficial, juxtapapillary vessels that are often associated with fibrovascular proliferation and epiretinal membrane formation. The natural history of this lesion is variable and can result in vision loss from tractional effects in progressive cases. Vision-threatening cases may be successfully managed by surgical excision.

Oral supplementation of lutein/zeaxanthin and omega-3 long chain polyunsaturated fatty acids in persons aged 60 years or older, with or without AMD.

PURPOSE: Increased dietary intake of lutein/zeaxanthin and omega-long-chain polyunsaturated fatty acids (omega-3 LCPUFA) was found to be associated with reduced risk of advanced age-related macular degeneration (AMD). The purpose of the study was to examine the effect of oral supplementation of omega-3 LCPUFA on changes in serum levels of lutein/zeaxanthin during supplementation in persons 60 years of age and older, with or without AMD. METHODS: Forty participants with AMD of various degrees of severity received lutein (10 mg) and zeaxanthin (2 mg) daily and were equally randomized to receive omega-3 LCPUFA (350 mg docosahexaenoic acid [DHA] and 650 mg eicosapentaenoic acid [EPA]) or placebo for 6 months. Serum levels of lutein, zeaxanthin, and omega-3 LCPUFAs and macular pigment optical densities were measured at baseline, 1 week, and 1, 3, 6, and 9 months. RESULTS: By month 6, the median serum levels of lutein/zeaxanthin increased by two- to threefold compared with baseline. Increases in serum levels of lutein/zeaxanthin did not differ by omega-3 LCPUFA treatment (P > 0.5). After 1 month, in the omega-3 LCPUFA-treated group, the median levels of DHA and EPA increased and the placebo group had no changes. At month 6, participants with AMD had a lower increase in serum lutein concentration than did those without AMD (P < 0.05). CONCLUSIONS: The addition of omega-3 LCPUFA to oral supplementation of lutein/zeaxanthin did not change the serum levels of lutein and zeaxanthin. A long-term large clinical trial is necessary to investigate the benefits and adverse effects of these factors for the treatment of AMD.

Clinical characterization of retinal capillary hemangioblastomas in a large population of patients with von Hippel-Lindau disease.

OBJECTIVE: To report the epidemiology and ocular phenotype of retinal capillary hemangioblastomas associated with von Hippel-Lindau (VHL) disease in a large cohort of patients and to correlate patient and ocular characteristics to visual morbidity in this population. DESIGN: Cross-sectional study. PARTICIPANTS: In 220 unrelated pedigrees, 335 patients affected with VHL disease and retinal capillary hemangioblastomas (RCHs) in at least 1 eye. METHODS: Demographics of the patient population were recorded and the ocular phenotype of each patient was obtained with a comprehensive ocular examination. MAIN OUTCOME MEASURES: The patient population was characterized and the ocular phenotype described in relationship to tumor location, number, and extent of retinal involvement. Correlations between patient demographics, ocular phenotype, and visual function were analyzed. RESULTS: We detected RCHs unilaterally in 42.1% and bilaterally in 57.9% of patients. No correlation was detected between the age, gender, or laterality of involvement. Of involved eyes, 86.6% had tumors that could be individually visualized; of these, tumors were commonly found in the peripheral retina (84.7%) only, and less commonly in the juxtapapillary area (15.3%). The tumor count in the periphery averaged 2.5+/-1.8 per eye, with 25.2% of eyes having >1 quadrant of retinal involvement. Of involved eyes, 13.4% were enucleated or prephthsical; approximately 1 in 5 patients had > or =1 eyes so affected. Severe visual impairment (visual acuity < or =20/160) in affected eyes were more likely to be associated with increasing age, the presence of juxtapapillary lesions, and an increasing number and extent of peripheral lesions. CONCLUSIONS: This large cohort of VHL patients with RCHs has enabled a systematic and quantitative characterization of the demographics, ocular features, and visual function in VHL disease. Clinical correlations between the visual morbidity and ocular features of the disease were also performed, producing measures that can help clinicians to estimate visual prognoses better based on the ocular phenotype of the disease.

Genotype-phenotype correlation in von Hippel-Lindau disease with retinal angiomatosis.

OBJECTIVES: To characterize the germline mutations found in a large population of persons having von Hippel-Lindau (VHL) disease mutations with the clinical characteristics of associated retinal capillary hemangioblastomas (RCHs), to measure the prevalence of RCHs among patients with VHL disease generally and specifically for each genotype category, to establish genotype-phenotype correlations between genotype category and phenotypic features of ocular VHL disease, and to establish genotype-phenotype correlations between genotype category and visual function. METHODS: Cross-sectional and molecular genetic study. Of 890 patients with VHL disease, 335 had ocular involvement in the form of RCHs. Statistical analysis was used to correlate the structure of the mutated VHL protein with the ocular phenotype. RESULTS: Three genotype categories (amino acid substitutions, protein-truncating mutations, and complete deletions of VHL protein) were defined in all patients. The prevalence of RCHs was lowest (14.5%) among patients with complete deletions; the overall prevalence of retinal angiomatosis was 37.2%. Genotype category had no correlation with the unilaterality or bilaterality of ocular disease or with the number or extent of peripheral RCHs. The prevalence of RCHs at the juxtapapillary location was lower among patients with protein-truncating mutations compared with those with amino acid substitutions. Complete deletions were associated with the highest mean visual acuity compared with the other 2 genotype categories. CONCLUSION: Patients with complete deletions of VHL protein have the lowest prevalence of ocular disease and the most favorable visual outcome. CLINICAL RELEVANCE: The VHL mutation genotype may be used to predict the prevalence and outcome of ocular VHL disease and to guide ophthalmic follow-up.

Ciliary neurotrophic factor (CNTF) for human retinal degeneration: phase I trial of CNTF delivered by encapsulated cell intraocular implants.

Neurotrophic factors are agents with a promising ability to retard progression of neurodegenerative diseases and are effective in slowing photoreceptor degeneration in animal models of retinitis pigmentosa. Here we report a human clinical trial of a neurotrophic factor for retinal neurodegeneration. In this Phase I safety trial, human ciliary neurotrophic factor (CNTF) was delivered by cells transfected with the human CNTF gene and sequestered within capsules that were surgically implanted into the vitreous of the eye. The outer membrane of the encapsulated cell implant is semipermeable to allow CNTF to reach the retina. Ten participants received CNTF implants in one eye. When the implants were removed after 6 months, they contained viable cells with minimal cell loss and gave CNTF output at levels previously shown to be therapeutic for retinal degeneration in rcd1 dogs. Although the trial was not powered to form a judgment as to clinical efficacy, of seven eyes for which visual acuity could be tracked by conventional reading charts, three eyes reached and maintained improved acuities of 10-15 letters, equivalent to two- to three-line improvement on standard Snellen acuity charts. A surgically related choroidal detachment in one eye resulted in a transient acuity decrease that resolved with conservative management. This Phase I trial indicated that CNTF is safe for the human retina even with severely compromised photoreceptors. The approach to delivering therapeutic proteins to degenerating retinas using encapsulated cell implants may have application beyond disease caused by genetic mutations.