Local delivery of corticosteroids in clinical ophthalmology: A review.

Locally administered steroids have a long history in ophthalmology for the treatment of inflammatory conditions. Anterior segment conditions tend to be treated with topical steroids whilst posterior segment conditions generally require periocular, intravitreal or systemic administration for penetration. Over recent decades, the clinical applications of periocular steroid delivery have expanded to a wide range of conditions including macular oedema from retino-vascular conditions. Formulations have been developed with the aim to provide practical, targeted, longer-term and more efficacious therapy whilst minimizing side effects. Herein, we provide a comprehensive overview of the types of periocular steroid delivery, their clinical applications in ophthalmology and their side effects.

Vascular Safety of Ranibizumab in Patients With Diabetic Macular Edema: A Pooled Analysis of Patient-Level Data From Randomized Clinical Trials.

Importance: Patients with diabetic macular edema (DME) are at high risk of vascular complications, including stroke and myocardial infarction (MI). Concerns have been raised that intravitreal dosing of vascular endothelial growth factor inhibitors in DME could be associated with an increase in cardiovascular and cerebrovascular adverse events. Objective: To evaluate the cardiovascular and cerebrovascular safety of ranibizumab, 0.5 mg and 0.3 mg, compared with sham with and without laser in DME. Data Sources: Patient-level data from 6 randomized, double-masked, sham- and laser-controlled clinical trials. Study Selection: Company-sponsored (Genentech or Novartis) studies in DME completed as of December 31, 2013. Data Extraction and Synthesis: Pairwise comparisons (ranibizumab, 0.5 mg, vs sham and laser; ranibizumab, 0.3 mg, vs sham) were performed using Cox proportional hazard regression (hazard ratios, 95% CIs) and rates per 100 person-years. Data analysis was conducted from June 1 to July 15, 2015. Main Outcomes and Measures: Standardized Medical Dictionary for Regulatory Activities queries and extended searches were prospectively defined to identify relevant safety end points, including arterial thromboembolic events, MI, stroke or transient ischemic attack, vascular deaths, and major vascular events as defined by the Antiplatelet Trialists' Collaboration (APTC). Results: Overall, 936 patients were treated with ranibizumab, 0.5 mg; 250 patients with ranibizumab, 0.3 mg; and 581 patients with sham/laser. The hazard ratios associated with all pairwise comparisons included 1 for all key cardiovascular and cerebrovascular safety end points. For ranibizumab, 0.5 mg, vs sham/laser and ranibizumab, 0.3 mg, vs sham, the hazard ratios were, respectively, arterial thromboembolic events, 1.05 (95% CI, 0.66-1.68) and 0.78 (95% CI, 0.43-1.40); MI, 0.84 (95% CI, 0.41-1.72) and 0.94 (95% CI, 0.43-2.06); stroke or transient ischemic attack, 0.94 (95% CI, 0.44-1.99) and 0.53 (95% CI, 0.19-1.42); stroke (excluding transient ischemic attack), 1.63 (95% CI, 0.65-4.07) and 0.59 (95% CI, 0.14-2.46); vascular death, 2.17 (95% CI, 0.57-8.29) and 2.51 (95% CI, 0.49-12.94); and APTC-defined events, 1.09 (95% CI, 0.63-1.88) and 1.00 (95% CI, 0.51-1.96). Conclusions and Relevance: This pooled analysis includes 1 of the largest patient-level data sets on treatment of DME with ranibizumab. Although still underpowered to detect small differences for infrequent events, such as stroke, the findings suggest that intravitreous ranibizumab does not increase the risk of systemic vascular events. However, uncertainty remains for patients with DME who are at high risk for vascular disease and were not included in these trials.

The effect of intensive education on concordance with the Age-Related Eye Disease Study (AREDS) recommendations in a tertiary referral practice.

BACKGROUND/AIMS: The Age-Related Eye Disease Study (AREDS) showed that supplementation with their formula led to a significant decrease in progression of age-related macular degeneration (AMD). This study aims to assess the effect of different education protocols on concordance with the trial recommendations in two retinal clinics. METHODS: A prospective controlled survey of concordance with the AREDS recommendations in two retinal clinics was administered to 330 patients with AREDS category 3 or 4 AMD. The results were evaluated to assess the effect of differing levels of patient education. In clinic 1, there was a formal policy of giving the patient both verbal and written instructions and verbal repetition of these instructions from each staff member on each patient visit; in clinic 2, there was no specific education policy. RESULTS: Clinic 1 had a concordance rate of 81.6% and clinic 2 of 44.1%. There were no significant differences in the patient demographics between the two clinics. CONCLUSION: A high concordance rate can be achieved in clinical practice with rigorous patient education that includes a policy of having continual repetition of instructions.

Depressive symptoms and quality of life in people with age- related macular degeneration.

PURPOSE: To examine quality of life and associated factors in people with Age-Related Macular Degeneration (AMD). METHODS: One hundred and forty-five AMD participants (mean age 78.0 ± 7.7 years) and 104 age- and gender- matched controls (mean age 78.1 ± 5.8 years) comprised the study populations for this case-control study. Depressive symptoms were measured with the Goldberg Anxiety and Depression (GAD) scale; general health and daily functioning was assessed with the Medical Outcomes Study Short Form 36 (SF-36) and questions relating to assistance required for daily living activities. RESULTS: People with AMD performed more poorly than controls on the GAD depression scale, and physical functioning subscale of SF-36. 44.4% of people with AMD had clinically significant depressive symptoms compared to 17.5% of controls (p < 0.001). Multiple regression analysis revealed that AMD was independently associated with depressive symptoms and a path model indicated that AMD led to depressive symptoms both directly and indirectly via reduced general health and social functioning. CONCLUSION: Psychological and functional outcome measures are reduced in people with AMD. Earlier recognition and treatment of depressive symptoms in people with AMD may be crucial to maintaining quality of life in this group.

Australian Angiogram Review Panel--monitoring the use of photodynamic therapy with verteporfin.

BACKGROUND: Photodynamic therapy with verteporfin for choroidal neovascularization (CNV) secondary to macular disease received an Australian government grant in 2002 to fund treatment for 3 years. Funding was restricted to subfoveal predominantly classic CNV where visual acuity was at least 6/60. Access to this funding was via review of angiograms by an expert panel, the Angiogram Review Panel (ARP), managed by the Royal Australian and New Zealand College of Ophthalmologists. METHODS: De-identified data from the ARP were obtained for the period June 2002 to April 2005 inclusive and the panel's outcomes were analysed. Health Insurance Commission and Department of Veteran Affairs data for photodynamic therapy for the same interval were also retrieved. RESULTS: A total of 7198 submissions to the ARP were received for 5867 individuals in this period. Overall 86.6% eyes submitted were accepted for initial funding (treatments 2-4). There was no change over time in the percentage rejected during this period. The first reviewer accepted 77.2%. And the second reviewer accepted a further 7.7%. An additional 1.6% were accepted on appeal. It was estimated that 29.2% of this initial cohort received five or more treatments. CONCLUSIONS: The ARP data indicate an incidence of subfoveal predominantly classic CNV secondary to macular disease in Australia of about 2000 eyes per annum. Only one quarter of patients received five or more treatments. The panel provided a unique opportunity to estimate the 'whole of nation' incidence of predominantly classic subfoveal CNV secondary to macular disease and thus provides a firm foundation upon which to plan public health spending as new treatments become available.

Lesion morphology in age-related macular degeneration and its therapeutic significance.

OBJECTIVES: To quantify and categorize the lesions of neovascular age-related macular degeneration on the basis of fluorescein angiographic morphology. METHODS: We retrospectively reviewed 3580 consecutive cases of neovascular age-related macular degeneration. The lesions were graded in terms of the location, size, and composition and categorized according to the lesion components. RESULTS: A comprehensive schema for lesion description and categorization is presented. There were 2642 subfoveal (73.8%), 658 juxtafoveal (18.4%), and 276 extrafoveal (7.7%) lesions. After disciform lesions were excluded, 1337 subfoveal (72.3%), 580 juxtafoveal (88.1%), and 242 extrafoveal lesions (87.7%) consisted of at least 50% choroidal neovascularization, most of which included a classic or an occult component but not both. Subfoveal lesions (mean size, 2.82 Macular Photocoagulation Study disc areas) were significantly larger than juxtafoveal (mean size, 0.89 Macular Photocoagulation Study disc areas) or extrafoveal lesions (mean size, 1.04 Macular Photocoagulation Study disc areas) (Kruskal-Wallis, P<.001), but overall the lesions were substantially smaller than those found in the major trials. It is estimated that photodynamic therapy or photocoagulation may be offered to one half to two thirds of all patients with nondisciform neovascular age-related macular degeneration. CONCLUSION: The smaller lesion size and low proportion of mixed choroidal neovascularization lesions suggest that treatment benefit and eligibility may be greater in the clinical setting than previously thought.

Visual outcomes following vitrectomy and peeling of epiretinal membrane.

BACKGROUND: Visual outcomes of patients following vitrectomy and peeling of visually significant epiretinal membranes were assessed to determine the influence of specific perioperative factors and surgical complications on final visual acuity and functional vision. METHODS: In an unmatched, consecutive surgical series, vitrectomy and membrane peeling were performed on 125 eyes of 123 patients with visually significant macular epiretinal membranes. Patients were followed for 6-36 months. Visual outcome measures included postoperative logMAR visual acuity, change in visual acuity and functional vision tasks evaluated by questionnaire. Perioperative factors including duration of symptoms, preoperative visual acuity, aetiology, membrane type and leakage on fundal fluorescein angiogram were correlated with final visual outcomes. RESULTS: Visual acuity improved by a mean of 0.31 A+/- 0.21 units (three lines of vision). In 104 cases (83%), visual acuity improved in patients by two lines or more, with 20 cases (16%) having unchanged acuity and one case (1%) having worse acuity. Ninety-three per cent of interviewed cases reported improvement in functional vision, especially reduction of distortion. Cataract was observed in 52 cases (52% of phakic eyes) postoperatively compared with 19 cases (19%) preoperatively. Postoperative visual acuity correlated with preoperative visual acuity. Patients with worse preoperative vision recorded greater visual improvement following surgery. No other perioperative factors were found to have a prognostic value in this study. CONCLUSION: Epiretinal membrane peeling improves vision in the majority of patients with significant symptoms, even if preoperative visual acuity is not substantially reduced. Surgery improves functional vision including metamorphopsia not measurable by visual acuity, and thus assessment of functional vision should be included in surgical case planning.

Dynamic atypical optic nerve coloboma associated with transient macular detachment.

PURPOSE: Macular schisis or detachment is frequently observed in eyes with optic pits or colobomas. Although spontaneous resolution of the maculopathy has been reported, concurrent changes in the optic nerve coloboma have not. We report three cases of atypical optic nerve colobomas in which dynamic optic nerve changes coincide with the development and subsequent resolution of the associated maculopathy. METHODS: We reviewed the records of three patients with dynamic optic nerve changes associated with maculopathy. All patients were observed for at least 6 months. Fundus photography and fluorescein angiography were used to document the optic nerve and macular changes. RESULTS: Three patients were noted to have macular detachments without apparent optic nerve excavation. With observation, the maculopathy spontaneously resolved in each case. We documented concurrent optic nerve changes whereby atypical optic nerve colobomas became apparent over several months in all cases. In one case, we noted the simultaneous development of maculopathy in association with obscuration of a prior disc anomaly. None of the eyes had a posterior vitreous detachment. We could not identify any associated systemic conditions or reproduce the findings with external stimulation. Initial Snellen acuity ranged from 20/60 to 20/200. Final Snellen acuity ranged from 20/20 to 20/40. CONCLUSIONS: Fluctuating optic nerve changes may occur in the setting of atypical optic nerve coloboma and associated maculopathy. In cases of macular schisis or detachment where an optic nerve coloboma is not readily apparent, and no other causes are identified, consideration of a period of observation prior to therapeutic intervention seems appropriate.

Sympathetic ophthalmia following ciliary body laser cyclophotocoagulation for rubeotic glaucoma.

A 60-year-old Asian man presented with left rubeotic glaucoma secondary to a central retinal vein occlusion. He was successfully treated with laser diode cyclophotocoagulation of the ciliary body. Nine months later he developed right progressive visual loss, headache, corneal oedema, anterior chamber cells, flare, mutton fat keratic precipitates, a swollen disc, and a minimal inferior visual field defect. A diagnosis of sympathetic ophthalmia was made, which was confirmed by characteristic findings seen on fluorescein and indocyanine green angiography.

Light rise of the human electroretinogram is normal in retinitis pigmentosa.

AIM: To determine if the electroretinogram (ERG) light rise is reduced below normal in patients with retinitis pigmentosa (RP) and whether it is greater in patients with smaller ERG. METHODS: Both eyes of 31 normal subjects and 59 subjects with RP had photopic ERGs on ISCEV standard and brighter backgrounds, before and after dark adaptation. Recordings <2.5 micro V were excluded. RESULTS: Ratios of amplitudes before and after dark adaptation varied little. The b-wave averaged 1.88 (SD 0.41) in normal subjects and 1.66 (SD 0.62) in RP subjects, and a-waves averaged 1.44 (SD 0.42) and 1.31 (SD 0.73), respectively. None of eight t-tests were significant (<2.4). There was a positive (not negative) correlation between RP subjects' initial b-wave amplitude and light rise but not for a-waves. A-wave light rises were smaller. CONCLUSION: Retinitis pigmentosa does not reduce the light rise of recordable ERG. The light rise of the ERG is larger in those RP subjects with larger initial b-waves. This confirms previous findings. The difference between a- and b-waves in RP suggests post-receptoral processes are involved.

Case series outcomes at 1 week following verteporfin photodynamic therapy.

PURPOSE: To examine the choroidal neovascularization (CNV) fluorescein angiographic perfusion and visual acuity 1 week after photodynamic therapy (PDT) with verteporfin (Visudyne, Novartis AG, Switzerland) on predominantly classic, subfoveal lesions in age-related macular degeneration (AMD). METHOD: A retrospective case series study was conducted on the 1-week outcome of PDT treatment of 76 of 79 consecutive patients with the subfoveal, predominantly classic CNV form of AMD. Leakage from CNV was assessed by fluorescein angiography and best-corrected visual acuity determined on projected Snellen charts using a standardized protocol. RESULTS: One week after PDT treatment, absence of fluorescein leakage from CNV was observed in 100% of the 76 patients. Visual acuity improved (at least a three-line gain) in 11 patients (15%), remained unchanged (less than a three-line gain or loss) in 64 patients (84%), and deteriorated (at least a three-line loss) in only one patient (1%). CONCLUSION: The absence of fluorescein leakage from classic CNV at 1 week in all cases was consistent with the published outcome of the clinical Phase I and II PDT trials. Further, vision loss 1 week after PDT for predominantly classic CNV was very uncommon. Therefore 1-week post-PDT angiography is unnecessary for predominantly classic CNV in patients with AMD.