Analysis of dose to the macula, optic disc, and lens in relation to vision toxicities - A retrospective study using COMS eye plaques.

PURPOSE: The aim of this study was to relate common toxicity endpoints with dose to the macula, optic disc, and lens for uveal melanoma patients treated with Iodine-125 Collaborative Ocular Melanoma Study (COMS) eye plaque brachytherapy. METHODS: A cohort of 52 patients treated at a single institution between 2005 and 2019 were retrospectively reviewed. Demographics, dosimetry, and clinical outcomes were recorded. Univariate, relative risk, and Kaplan-Meier analyses were performed to relate dose to toxicity endpoints including retinopathy, vision decline, and cataracts. RESULTS: By the end of follow up (Median = 3.6 years, Range = 0.4 - 13.5 years), 65 % of eyes sustained radiation retinopathy, 40 % demonstrated moderate vision decline (>5 Snellen lines lost), and 56 % developed cataracts. Significant (p < 0.05) risk estimates exist for retinopathy and VA decline for doses >52 Gy to the macula and >42 Gy to the optic disc. Moreover, dose to the lens > 16 Gy showed a significant risk for cataract formation. Kaplan-Meier analysis demonstrated significantly different incidence of radiation retinopathy for > 52 Gy to the macula and > 42 Gy to the optic disc. In addition, the Kaplan-Meier analysis showed significantly different incidence of cataract formation for patients with lens dose > 16 Gy. CONCLUSIONS: Dose-effect relationships exist for the macula and optic disc with respect to the loss of visual acuity and the development of retinopathy. To better preserve vision after treatment, further research is needed to reduce macula, optic disc, and lens doses while maintaining tumor control.

Dose-Response and Normal Tissue Complication Probabilities after Proton Therapy for Choroidal Melanoma.

PURPOSE: Normal tissue complication probability (NTCP) models could aid the understanding of dose dependence of radiation-induced toxicities after eye-preserving radiotherapy of choroidal melanomas. We performed NTCP-modeling and established dose-response relationships for visual acuity (VA) deterioration and common late complications after treatments with proton therapy (PT). DESIGN: Retrospective study from single, large referral center. PARTICIPANTS: We considered patients from Nice, France, diagnosed with choroidal melanoma and treated primarily with hypofractionated PT (52 Gy physical dose in 4 fractions). Complete VA deterioration information was available for 1020 patients, and complete information on late complications was available for 991 patients. METHODS: Treatment details, dose-volume histograms (DVHs) for relevant anatomic structures, and patient and tumor characteristics were available from a dedicated ocular database. Least absolute shrinkage and selection operator (LASSO) variable selection was used to identify variables with the strongest impact on each end point, followed by multivariate Cox regressions and logistic regressions to analyze the relationships among dose, clinical characteristics, and clinical outcomes. MAIN OUTCOME MEASURES: Dose-response relationship for VA deterioration and late complications. RESULTS: Dose metrics for several structures (i.e., optic disc, macula, retina, globe, lens, ciliary body) correlated with clinical outcome. The near-maximum dose to the macula showed the strongest correlation with VA deterioration. The near-maximum dose to the retina was the only variable with clear impact on the risk of maculopathy, the dose to 20% of the optic disc had the largest impact on optic neuropathy, dose to 20% of cornea had the largest impact on neovascular glaucoma, and dose to 20% of the ciliary body had the largest impact on ocular hypertension. The volume of the ciliary body receiving 26 Gy was the only variable associated with the risk of cataract, and the volume of retina receiving 52 Gy was associated with the risk of retinal detachment. Optic disc-to-tumor distance was the only variable associated with dry eye syndrome in the absence of DVH for the lachrymal gland. CONCLUSIONS: VA deterioration and specific late complications demonstrated dependence on dose delivered to normal structures in the eye after PT for choroidal melanoma. VA deterioration depended on dose to a range of structures, whereas more specific complications were related to dose metrics for specific structures.

Ocular hypertension suppresses homeostatic gene expression in optic nerve head microglia of DBA/2 J mice.

Glaucoma is the leading cause of irreversible vision loss. Ocular hypertension is a major risk factor for glaucoma and recent work has demonstrated critical early neuroinflammatory insults occur in the optic nerve head following ocular hypertension. Microglia and infiltrating monocytes are likely candidates to drive these neuroinflammatory insults. However, the exact molecular identity / transcriptomic profile of microglia following ocular hypertensive insults is unknown. To elucidate the molecular identity of microglia after long-term exposure to ocular hypertension, we used a mouse model of glaucoma (DBA/2 J). We performed RNA-sequencing of microglia mRNA from the optic nerve head at a time point following ocular hypertensive insults, but preceding detectable neurodegeneration (with microglia identified as being CD45lo/CD11b+/CD11c-). Furthermore, RNA-sequencing was performed on optic nerve head microglia from mice treated with radiation therapy, a potent therapy preventing neuroinflammatory insults. Transcriptomic profiling of optic nerve head microglia mRNA identifies metabolic priming with marked changes in mitochondrial gene expression, and changes to phagocytosis, inflammatory, and sensome pathways. The data predict that many functions of microglia that help maintain tissue homeostasis are affected. Comparative analysis of these data with data from previously published whole optic nerve head tissue or monocyte-only samples from DBA/2 J mice demonstrate that many of the neuroinflammatory signatures in these data sets arise from infiltrating monocytes and not reactive microglia. Finally, our data demonstrate that prophylactic radiation therapy of DBA/2 J mice potently abolishes these microglia metabolic transcriptomic changes at the same time points. Together, our data provide a unique resource for the community to help drive further hypothesis generation and testing in glaucoma.

OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY DETECTS SUBCLINICAL RADIAL PERIPAPILLARY CAPILLARY DENSITY REDUCTION AFTER PLAQUE RADIOTHERAPY FOR CHOROIDAL MELANOMA.

PURPOSE: To evaluate radial peripapillary capillary density (RPCD) in irradiated eyes without radiation papillopathy clinically. METHODS: Patients treated with plaque radiotherapy for unilateral choroidal melanoma without radiation papillopathy clinically received optical coherence tomography and optical coherence tomography angiography imaging at ∼12- to 24-month follow-up. Comparison of RPCD globally and meridian closest to plaque and meridian farthest to plaque of irradiated versus nonirradiated eyes was performed. RESULTS: Mean age was 55 years (n = 10). Mean largest basal diameter and thickness were 10.1 and 4.4 mm, respectively. Mean radiation dose to the optic nerve head and foveola was 41.7 and 66.2 Gy, respectively. No radiation papillopathy was detected by ophthalmoscopy throughout follow-up (mean:14 months). Radial peripapillary capillary density was significantly reduced globally (all P < 0.02). Meridian closest to plaque RPCD was significantly reduced (P < 0.01), but not meridian farthest to plaque RPCD (P = 0.07). Circumpapillary retinal nerve fiber layer thickness was not significantly reduced (P > 0.26). Radiation dose to the optic nerve head was correlated with meridian closest to plaque RPCD reduction (r = 0.76; P < 0.01). Mean radiation dose to the optic nerve head for <5% and ≥5% RPCD reductions was 35.9 ± 12.2 and 55.2 ± 6.4 Gy, respectively. CONCLUSION: Radial peripapillary capillary density reduction was found in irradiated eyes before clinical evidence of radiation papillopathy and circumpapillary retinal nerve fiber layer thickness reduction. Radial peripapillary capillary density reduction is correlated to plaque location and radiation dose to the optic nerve head.

Survival of Alpha and Intrinsically Photosensitive Retinal Ganglion Cells in NMDA-Induced Neurotoxicity and a Mouse Model of Normal Tension Glaucoma.

Purpose: We assess if α retinal ganglion cells (αRGCs) and intrinsically photosensitive retinal ganglion cells (ipRGCs) survive in mouse models of glaucoma. Methods: Two microliters of N-methyl-D-aspartate (NMDA; 1 mM) or PBS were injected intraocularly 7 days before sacrifice. Immunohistochemical analyses of the retina were performed using antibodies against RNA-binding protein with multiple splicing (RBPMS), osteopontin, and melanopsin. Immunohistochemical analyses also were performed in adult mice with glutamate/aspartate transporter (GLAST) deletion (GLAST knockout [KO] mice), a mouse model of normal tension glaucoma. Results: NMDA-induced loss of RBPMS-positive total RGCs was 58.4% ± 0.4% compared to PBS-treated controls, whereas the loss of osteopontin-positive αRGCs was 5.0% ± 0.6% and that of melanopsin-positive ipRGCs was 7.6% ± 1.6%. In GLAST KO mice, the loss of total RGCs was 48.4% ± 0.9% compared to wild-type mice, whereas the loss of αRGCs and ipRGCs was 3.9% ± 0.4% and 9.3% ± 0.5%, respectively. The distribution of survived total RGCs, αRGCs, and ipRGCs was similar regardless of the location of the retina. Conclusions: These results suggest that αRGC and ipRGC are highly tolerant to NMDA-induced neurotoxicity and NTG-like neurodegeneration in GLAST KO mice.

A practical approach to estimating optic disc dose and macula dose without treatment planning in ocular brachytherapy using 125I COMS plaques.

BACKGROUND: It has been reported that proximity of the tumor to the optic disc and macula, and radiation dose to the critical structures are substantial risk factors for vision loss following plaque brachytherapy. However, there is little dosimetry data published on this. In this study, therefore, the relationship between distance from tumor margin and radiation dose to the optic disc and macula in ocular brachytherapy using 125I Collaborative Ocular Melanoma Study (COMS) plaques was comprehensively investigated. From the information, this study aimed to allow for estimation of optic disc dose and macula dose without treatment planning. METHODS: An in-house brachytherapy dose calculation program utilizing the American Association of Physicists in Medicine Task Group-43 U1 formalism with a line source approximation in a homogenous water phantom was developed and validated against three commercial treatment planning systems (TPS). Then optic disc dose and macula dose were calculated as a function of distance from tumor margin for various tumor basal dimensions for seven COMS plaques (from 10 mm to 22 mm in 2 mm increments) loaded with commercially available 125I seeds models (IAI-125A, 2301 and I25.S16). A prescribed dose of 85 Gy for an irradiation time of 168 h was normalized to a central-axis depth of 5 mm. Dose conversion factors for each seed model were obtained by taking ratios of total reference air kerma per seed at various prescription depths (from 1 mm to 10 mm in 1 mm intervals) to that at 5 mm. RESULTS: The in-house program demonstrated relatively similar accuracy to commercial TPS. Optic disc dose and macula dose decreased as distance from tumor margin and tumor basal dimension increased. Dose conversion factors increased with increasing prescription depth. There existed dose variations (<8%) among three 125I seed models. Optic disc dose and macula dose for each COMS plaque and for each seed model are presented in a figure format. Dose conversion factors for each seed model are presented in a tabular format. CONCLUSIONS: The data provided in this study would enable clinicians in any clinic using 125I COMS plaques to estimate optic disc dose and macula dose without dose calculations.

Peripapillary vascular changes in radiation optic neuropathy: an optical coherence tomography angiography grading.

AIMS: To investigate peripapillary vascular changes secondary to radiation optic neuropathy (RON) using optical coherence tomography angiography (OCT-A) and to propose a clinical grading of RON based on OCT-A findings. METHODS: Thirty-four patients affected by RON were consecutively included. Each patient underwent best corrected visual acuity measurement (ETDRS score) and OCT-A (Nidek RS-3000 Advance device, Nidek, Gamagori, Japan). The radial peripapillary capillary plexus (RPCP) and the entire peripapillary capillary bed (EPCB) were analysed. Quantitative analysis of the OCT-A images was performed using open-source available ImageJ software (National Institutes of Health, Bethesda, Maryland, USA). Qualitative analysis based on the proposed clinical grading (Grades 0-4) was also performed by two masked graders. RESULTS: RON clinical (qualitative) classification based on RPCP correlated with the quantitative RPCP perfusion analysis (P=0.0001). RON clinical classification based on RPCP statistically correlated with ETDRS score (P=0.001). RON clinical classification based on EPCB also correlated with the quantitative EPCB perfusion analysis and ETDRS score (P=0.02 and P=0.01, respectively). Compared with the clinical classification based on EPCB, the qualitative classification based on RPCP reached a higher intergrader agreement (0.96 and 0.86, respectively). CONCLUSION: OCT-A can be used to detect RPCP abnormalities and to clinically classify RON with a high interexaminer agreement. The proposed clinical classification is supported by the quantitative analysis based on the use of specific images elaboration techniques and correlates with visual acuity of the examined eyes.

Efficacy and Safety of Low-Dose Iodine Plaque Brachytherapy for Juxtapapillary Choroidal Melanoma.

PURPOSE: To evaluate low- vs high-dose plaque brachytherapy for juxtapapillary choroidal melanoma. DESIGN: Retrospective interventional case series. METHODS: Setting: Single institution. STUDY POPULATION: Forty-seven patients with juxtapapillary choroidal melanoma. INTERVENTION: Iodine-125 plaque brachytherapy. Eyes were divided into apex low-dose (LD) and high-dose (HD) groups (≤ or > median apex dose 84.35 Gy). Main outcome measures were time to distant failure, local failure, death, enucleation, radiation retinopathy, optic neuropathy, and best-corrected visual acuity (BCVA). RESULTS: Freedom from distant failure rates were 96% and 95% in apex LD and HD groups at 5 years and 77% and 95% at 10 years, respectively (P = .84). Freedom from local failure rates were 90% in the apex LD group vs 89% in the HD group at 5 and 10 years (P = .96). Apex LD and HD groups did not differ for time to death or enucleation. Five- and 10-year freedom from radiation retinopathy and optic neuropathy rates were higher in the apex LD than HD group. Loss of ≥3 BCVA lines, final BCVA 20/40 or better, and final BCVA 20/200 or worse were more favorable in the 5 mm LD compared to HD group. Visual acuity outcomes did not differ between apex LD and HD groups. CONCLUSIONS: Low-dose iodine-125 plaque brachytherapy (67.5-81 Gy at tumor apex) provides safe and effective tumor control for juxtapapillary choroidal melanoma and may be associated with reduced radiation toxicity. Larger trials are needed to determine the optimal therapeutic dose for juxtapapillary choroidal melanoma.

Visual Outcomes of Parapapillary Uveal Melanomas Following Proton Beam Therapy.

PURPOSE: In parapapillary melanoma patients, radiation-induced optic complications are frequent and visual acuity is often compromised. We investigated dose-effect relationships for the optic nerve with respect to visual acuity after proton therapy. METHODS AND MATERIALS: Of 5205 patients treated between 1991 and 2014, those treated using computed tomography (CT)-based planning to 52 Gy (prescribed dose, not accounting for relative biologic effectiveness correction of 1.1) in 4 fractions, with minimal 6-month follow-up and documented initial and last visual acuity, were included. Deterioration of ≥0.3 logMAR between initial and last visual acuity results was reported. RESULTS: A total of 865 consecutive patients were included. Median follow-up was 69 months, mean age was 61.7 years, tumor abutted the papilla in 35.1% of patients, and tumor-to-fovea distance was ≤3 mm in 74.2% of patients. Five-year relapse-free survival rate was 92.7%. Visual acuity was ≥20/200 in 72.6% of patients initially and 47.2% at last follow-up. A wedge filter was used in 47.8% of the patients, with a positive impact on vision and no impact on relapse. Glaucoma, radiation-induced optic neuropathy, maculopathy were reported in 17.9%, 47.5%, and 33.6% of patients, respectively. On multivariate analysis, age, diabetes, thickness, initial visual acuity and percentage of macula receiving 26 Gy were predictive of visual acuity. Furthermore, patients irradiated to ≥80% of their papilla had better visual acuity when limiting the 50% (30-Gy) and 20% (12-Gy) isodoses to ≤2 mm and 6 mm of optic nerve length, respectively. CONCLUSIONS: A personalized proton therapy plan with optic nerve and macular sparing can be used efficiently with good oncological and functional results in parapapillary melanoma patients.

Feasibility of Proton Beam Therapy for Ocular Melanoma Using a Novel 3D Treatment Planning Technique.

PURPOSE: We evaluated sparing of normal structures using 3-dimensional (3D) treatment planning for proton therapy of ocular melanomas. METHODS AND MATERIALS: We evaluated 26 consecutive patients with choroidal melanomas on a prospective registry. Ophthalmologic work-up included fundoscopic photographs, fluorescein angiography, ultrasonographic evaluation of tumor dimensions, and magnetic resonance imaging of orbits. Three tantalum clips were placed as fiducial markers to confirm eye position for treatment. Macula, fovea, optic disc, optic nerve, ciliary body, lacrimal gland, lens, and gross tumor volume were contoured on treatment planning compute tomography scans. 3D treatment planning was performed using noncoplanar field arrangements. Patients were typically treated with 3 fields, with at least 95% of planning target volume receiving 50 GyRBE in 5 fractions. RESULTS: Tumor stage was T1a in 10 patients, T2a in 10 patients, T2b in 1 patient, T3a in 2 patients, T3b in 1 patient, and T4a in 2 patients. Acute toxicity was mild. All patients completed treatment as planned. Mean optic nerve dose was 10.1 Gy relative biological effectiveness (RBE). Ciliary body doses were higher for nasal (mean: 11.4 GyRBE) than temporal tumors (5.8 GyRBE). Median follow-up was 31 months (range: 18-40 months). Six patients developed changes which required intraocular bevacizumab or corticosteroid therapy, but only 1 patient developed neovascular glaucoma. Five patients have since died: 1 from metastatic disease and 4 from other causes. Two patients have since required enucleation: 1 due to tumor and 1 due to neovascular glaucoma. CONCLUSIONS: 3D treatment planning can be used to obtain appropriate coverage of choroidal melanomas. This technique is feasible with relatively low doses to anterior structures, and appears to have acceptable rates of local control with low risk of enucleation. Further evaluation and follow-up is needed to determine optimal dose-volume relationships for organs at risk to decrease complications rates.

Assessment of Macular Function during Vitrectomy: New Approach Using Intraoperative Focal Macular Electroretinograms.

PURPOSE: To describe a new technique to record focal macular electroretinograms (FMERGs) during vitrectomy to assess macular function. METHODS: Intraoperative FMERGs (iFMERGs) were recorded in ten patients (10 eyes) who undergo vitrectomy. iFMERGs were elicited by focal macular stimulation. The stimulus light was directed to the macular area through a 25 gauge (25G) glass fiber optic bundle. Background light was delivered through a dual chandelier-type light fiber probe. Focal macular responses elicited with combinations of stimulus and background luminances were analyzed. RESULTS: A stimulus luminance that was approximately 1.75 log units brighter than the background light was able to elicit focal macular responses that were not contaminated by stray light responses. Thus, a stimulus luminance of 160 cd/m2 delivered on a background of 3 cd/m2 elicited iFMEGs from only the stimulated area. This combination of stimulus and background luminances did not elicit a response when the stimulus was projected onto the optic nerve head. The iFMERGs elicited by a 10° stimulus with a duration of 100 ms and an interstimulus interval of 150 ms consisted of an a-, b-, and d-waves, the oscillatory potentials, and the photopic negative response (PhNR). CONCLUSIONS: Focal ERGs with all components can be recorded from the macula and other retinal areas during vitreous surgery. This new technique will allow surgeons to assess the function of focal areas of the retina intraoperatively.

Pupillary light reflex to light inside the natural blind spot.

When a light stimulus covers the human natural blind spot (BS), perceptual filling-in corrects for the missing information inside the BS. Here, we examined whether a filled-in surface of light perceived inside the BS affects the size of the short-latency pupillary light reflex (PLR), a pupil response mediated by a subcortical pathway for unconscious vision. The PLR was not induced by a red surface that was physically absent but perceptually filled-in inside the BS in the presence of a red ring surrounding it. However, a white large disk covering the BS unexpectedly induced a larger PLR than a white ring surrounding the BS border did, even though these two stimuli must be equivalent for the visual system, and trial-by-trial percepts did not predict PLR size. These results suggest that some physiological mechanism, presumably the retinal cells containing the photopigment melanopsin, receives the light projected inside the BS and enhances PLR.

Proton beam therapy of parapapillary choroidal melanoma.

PURPOSE: To analyze the functional outcome with regard to the development of visual acuity and radiation-induced optic neuropathy of patients with parapapillary choroidal melanoma treated with proton beam therapy. DESIGN: Clinical case series, retrospective study. METHODS: We evaluated 147 consecutive patients with parapapillary choroidal melanoma who received proton beam therapy as primary tumor treatment at the Helmholtz Center in Berlin from 1998 to 2005. A cumulative dose of 60 Cobalt Gray Equivalents (CGE) was delivered to the tumor and the optic disc received a minimum of 50 CGE. Kaplan-Meier analysis was used to assess ocular outcome and survival rates. For trend analysis of functional development, Wilcoxon-Mann-Whitney U test was used to compare the medians of 2 groups and Kruskal-Wallis test was used in the case of more than 2 groups. RESULTS: The mean follow-up time was 6.5 years (range 0.3-11.7 years). The most common side effects were radiation-induced optic neuropathy, retinopathy, and cataract. The median visual acuity before and within the first year after therapy was 0.4 logMAR (20/50), lapsing to 1.3 logMAR (20/400) after 3 years and 1.4 logMAR (20/500) after 5 years. During follow-up, no light perception developed in 17 cases (11.6%), mostly attributed to radiation-induced retinopathy, optic neuropathy, and secondary glaucoma. Enucleation was carried out in 14 patients (9.5%) because of local recurrence or severe side effects. CONCLUSION: Radiation-induced optic neuropathy is an expected issue after proton beam therapy of parapapillary choroidal melanoma, and visual impairment is common during long-term follow-up, but some useful vision can be preserved in a considerable number of patients.

[Ocular manifestations of acute T-cell lymphoblastic leukemia in hematological remission--a case report]. / Objawy oczne ostrej bialaczki limfoblastycznej T-komórkowej w stadium remisji hematologicznej--opis przypadku.

The paper presents a case of a 60 year-old female referred to the Department of Ophthalmology and Ocular Oncology, Medical College, Jagiellonian University in Krakow with the sudden severe vision deterioration in both eyes. The patient was treated for T-cell acute lymphoblastic leukemia at the local Department of Hematology, at that time she was considered to be in hematological remission. Based on findings of clinical examination and additional tests, the patient was diagnosed with leukemic infiltration of the retina and optic nerve with secondary retinal detachment. Systemic and intrathecal chemotherapy as well as local radiotherapy to both eyes were administered. Ocular manifestations of T-cell acute lymphoblastic leukemia may develop in patients in hematological remission. Standard management of leukemic infiltrates involving the retina, choroid and optic nerve includes the intrathecal chemotherapy and lo- cal radiotherapy. Such therapy caused regression and cicatrization of the ocular infiltrates, but did not improve visual acuity in the described patient.

Dosimetric and late radiation toxicity comparison between iodine-125 brachytherapy and stereotactic radiation therapy for juxtapapillary choroidal melanoma.

PURPOSE: To compare the dose distributions and late radiation toxicities for (125)I brachytherapy (IBT) and stereotactic radiation therapy (SRT) in the treatment of juxtapapillary choroidal melanoma. METHODS: Ninety-four consecutive patients with juxtapapillary melanoma were reviewed: 30 have been treated with IBT and 64 with SRT. Iodine-125 brachytherapy cases were modeled with plaque simulator software for dosimetric analysis. The SRT dosimetric data were obtained from the Radionics XKnife RT3 software. Mean doses at predetermined intraocular points were calculated. Kaplan-Meier estimates determined the actuarial rates of late toxicities, and the log-rank test compared the estimates. RESULTS: The median follow-up was 46 months in both cohorts. The 2 cohorts were balanced with respect to pretreatment clinical and tumor characteristics. Comparisons of radiation toxicity rates between the IBT and SRT cohorts yielded actuarial rates at 50 months for cataracts of 62% and 75% (P=.1), for neovascular glaucoma 8% and 47% (P=.002), for radiation retinopathy 59% and 89% (P=.0001), and for radiation papillopathy 39% and 74% (P=.003), respectively. Dosimetric comparisons between the IBT and SRT cohorts yielded mean doses of 12.8 and 14.1 Gy (P=.56) for the lens center, 17.6 and 19.7 Gy (P=.44) for the lens posterior pole, 13.9 and 10.8 Gy (P=.30) for the ciliary body, 61.9 and 69.7 Gy (P=.03) for optic disc center, and 48.9 and 60.1 Gy (P<.0001) for retina at 5-mm distance from tumor margin, respectively. CONCLUSIONS: Late radiation-induced toxicities were greater with SRT, which is secondary to the high-dose exposure inherent to the technique as compared with IBT. When technically feasible, IBT is preferred to treat juxtapapillary choroidal melanoma.

Induction of amyloid-ß(1-42) in the retina and optic nerve head of chronic ocular hypertensive monkeys.

PURPOSE: Recent studies have indicated that accumulation of amyloid ß(1-42) (Aß(1-42)), which is associated with the progression of Alzheimer disease, may also be responsible for retinal ganglion cell death in glaucoma. The purpose of this study was to investigate the expression and localization of Aß(1-42) in the retina and the optic nerve head (ONH) of monkeys with experimental glaucoma. METHODS: Five cynomolgus monkeys with a glaucomatous left eye at 4, 9, 11, 15, and 24 weeks after laser photocoagulation treatment were studied by immunohistochemical methods. Another two cynomolgus monkeys with a glaucomatous left eye at 133 weeks after laser photocoagulation treatment were used to measure Aß(1-42) concentrations in the retina by enzyme-linked immunosorbent assay. RESULTS: At 11 to 24 weeks after the laser photocoagulation treatment, Aß(1-42) was upregulated in the nerve fiber layer (NFL) and the ganglion cell layer (GCL) of the retina and the ONH, but the expression of amyloid precursor protein decreased in the NFL and ONH from levels at 9 weeks. The localizations of Aß(1-42) were merged in glial fibrillary acidic protein-positive astroglial cells but not phosphorylated neurofilament heavy- or nonphosphorylated neurofilament heavy-positive axons in the retina and the ONH. Likewise, Aß(1-42) concentrations in the retina of monkeys increased in the chronic stage of glaucoma. CONCLUSIONS: These findings indicate that the upregulation of Aß(1-42) after an intraocular pressure elevation could apply to monkeys since the structure of the ONH is more similar to humans than that of rodents.

Dosimetric benefit of a new ophthalmic radiation plaque.

PURPOSE: To determine whether the computed dosimetry of a new ophthalmic plaque, EP917, when compared with the standard Collaborative Ocular Melanoma Study (COMS) plaques, could reduce radiation exposure to vision critical structures of the eye. METHODS AND MATERIALS: One hundred consecutive patients with uveal melanoma treated with COMS radiation plaques between 2007 and 2010 were included in this study. These treatment plans were generated with the use of Bebig Plaque Simulator treatment-planning software, both for COMS plaques and for EP917 plaques using I-125. Dose distributions were calculated for a prescription of 85 Gy to the tumor apex. Doses to the optic disc, opposite retina, lens, and macula were obtained, and differences between the 2 groups were analyzed by standard parametric methods. RESULTS: When compared with the COMS plaques, the EP917 plaques used fewer radiation seeds by an average difference of 1.94 (P<.001; 95% confidence interval [CI], -2.8 to -1.06) and required less total strength of radiation sources by an average of 17.74 U (air kerma units) (P<.001; 95% CI, -20.16 to -15.32). The total radiation doses delivered to the optic disc, opposite retina, and macula were significantly less by 4.57 Gy, 0.50 Gy, and 11.18 Gy, respectively, with the EP917 plaques vs the COMS plaques. CONCLUSION: EP917 plaques deliver less overall radiation exposure to critical vision structures than COMS treatment plaques while still delivering the same total therapeutic dose to the tumor.

Radiation treatment inhibits monocyte entry into the optic nerve head and prevents neuronal damage in a mouse model of glaucoma.

Glaucoma is a common ocular disorder that is a leading cause of blindness worldwide. It is characterized by the dysfunction and loss of retinal ganglion cells (RGCs). Although many studies have implicated various molecules in glaucoma, no mechanism has been shown to be responsible for the earliest detectable damage to RGCs and their axons in the optic nerve. Here, we show that the leukocyte transendothelial migration pathway is activated in the optic nerve head at the earliest stages of disease in an inherited mouse model of glaucoma. This resulted in proinflammatory monocytes entering the optic nerve prior to detectable neuronal damage. A 1-time x-ray treatment prevented monocyte entry and subsequent glaucomatous damage. A single x-ray treatment of an individual eye in young mice provided that eye with long-term protection from glaucoma but had no effect on the contralateral eye. Localized radiation treatment prevented detectable neuronal damage and dysfunction in treated eyes, despite the continued presence of other glaucomatous stresses and signaling pathways. Injection of endothelin-2, a damaging mediator produced by the monocytes, into irradiated eyes, combined with the other glaucomatous stresses, restored neural damage with a topography characteristic of glaucoma. Together, these data support a model of glaucomatous damage involving monocyte entry into the optic nerve.