Off-Label Use of 0.19 mg Fluocinolone Acetonide Intravitreal Implant: A Systematic Review.

Corticosteroids are used in a variety of ophthalmological diseases. One challenge faced by ophthalmologists is to deliver corticosteroids to the posterior segment of the eye with efficacy and safety. Sustained-release corticosteroid implants may be the answer to this problem. The 0.19 mg fluocinolone acetonide (FAc) implant (Iluvien®) releases FAc for 36 months, and it is approved for the treatment of diabetic macular edema (DME) and noninfectious uveitis. We decided to do a systematic review to acknowledge in which other diseases FAc implant is being used off-label. A literature search was performed in the following three electronic databases: PubMed, Scopus, and Web of Science (from January 1st, 2000, to September 20th, 2020), using the following query: ("Fluocinolone Acetonide" OR Iluvien®) AND ("eye" OR "ocular" OR "intravitreal)." A total of 11 papers were included, and the use of FAc implant was analyzed in the following diseases: radiation-induced maculopathy (RM); paraneoplastic visual syndromes (melanoma-associated retinopathy (MAR) and cancer-associated retinopathy (CAR)); Sjogren's syndrome-related keratopathy; retinal vein occlusion (RVO); cystoid macular edema (CME); diabetic retinal neurodegeneration (DRN); and retinitis pigmentosa (RP). FAc implant may be a potential treatment for these diseases; however, the level of scientific evidence of the included studies in this review is limited. Further studies with larger cohorts and longer follow-ups are needed to validate this data.

Switch to Aflibercept in the Treatment of Neovascular AMD: Long-Term Results.

PURPOSE: To report the long-term clinical outcomes after switching from intravitreal bevacizumab or ranibizumab to aflibercept therapy in eyes with AMD. METHODS: Retrospective analysis of changes in BCVA, SD-OCT image, and frequency of injections after 1, 2, and 3 years of follow-up. RESULTS: 164 eyes were analyzed, 101 eyes switched from bevacizumab (group 1) and 63 from ranibizumab (group 2). One year after the switch, there was an overall nonsignificant mean decrease of 2 ETDRS letters in BCVA. Three years after, there was an overall mean decrease of 7 ETDRS letters, which was statistically significant. A significant improvement in the mean CRT was found at 1, 2, and 3 years. There was a significant decrease in the mean number of injections per year (7.8 to 6.5, p < 0.005) between the first and third year. CONCLUSION: Aflibercept can be useful in the management of refractory neovascular AMD, with a good morphological response. However, in the long-term, BCVA stabilization was not achieved.

Treatment of Neovascular Age-Related Macular Degeneration with Anti-VEGF Agents: Predictive Factors of Long-Term Visual Outcomes.

PURPOSE: To evaluate the predictive factors of long-term visual outcomes in neovascular age-related macular degeneration (nAMD) treated with antivascular endothelial growth factor (anti-VEGF) agents. METHODS: Unicentric retrospective review of patients with nAMD treated with anti-VEGF agents. Visual outcomes, 12 and 60 months after diagnosis, were evaluated. In an attempt to identify predictive factors of visual outcomes, multiple variables (demographic and epidemiological characteristics, angiographic and tomographic features) were analyzed, at baseline and during follow-up. RESULTS: One hundred and seventeen patients were included. In multivariate analysis, baseline best-corrected visual acuity was associated with all visual endpoints at 12 and 60 months. Additionally, age, gender, number of injections, and development of subretinal fibrosis during follow-up were also significant predictors of visual outcomes at 60 months. CONCLUSIONS: Several factors can be useful in clinical practice as predictors of visual outcomes in response to anti-VEGF treatment of nAMD.

CHOROIDAL THICKNESS IN MULTISYSTEMIC AUTOIMMUNE DISEASES WITHOUT OPHTHALMOLOGIC MANIFESTATIONS.

PURPOSE: To evaluate choroidal morphology and thickness at the posterior pole of individuals affected by multisystemic autoimmune diseases and without known ophthalmologic manifestations. METHODS: Retrospective cross-sectional study including 75 patients with autoimmune diseases (divided according to their specific disease) and 80 healthy controls. A spectral-domain optical coherence tomography using enhanced depth imaging was performed and choroidal thickness was measured in the center of fovea and at 500 µm intervals along a horizontal section. RESULTS: Lupus patients presented a thicker subfoveal choroid than controls (408.624 vs. 356.536, P < 0.001) and in all the other measurements (P < 0.001 to P = 0.003). Rheumatoid arthritis and other autoimmune diseases had an overall thinner choroid than controls (297.867 vs. 356.536 subfoveally, P = 0.004; P = 0.005-0.019 in other measurements). Results were adjusted for the covariates age (P = 0.007), spherical equivalent (P < 0.001), and systemic steroids dose (P = 0.004). Hypertension (P = 0.102), diabetes mellitus (P = 0.672), time since the beginning of therapy with hydroxychloroquine (P = 0.104) and its cumulative dose (P = 0.307), or use of other immunosuppressives (P = 0.281) had no influence on the mean choroidal thickness. No morphologic abnormalities were found. CONCLUSION: The choroid may be subclinically involved in autoimmune diseases. However, the choroidal response seems to differ depending on the autoimmune disease. Infiltrative mechanisms specific for lupus may justify the thickened choroid found in these patients.

Long-Term Effect of Anti-VEGF Agents on Intraocular Pressure in Age-Related Macular Degeneration.

PURPOSE: To analyze the effect of anti-vascular endothelial growth factor (VEGF) agents on intraocular pressure (IOP) in patients with neovascular age-related macular degeneration (AMD). Materials andMethods: This is a retrospective study that included 72 patients treated unilaterally with anti-VEGF agents according to a pro re nata regimen. Fellow noninjected eyes (n = 72) were used as controls. IOP variation and the development of sustained ocular hypertension (OHT) were assessed both in the injected and in the fellow eyes. RESULTS: While the final IOP was not significantly different between the 2 groups, sustained OHT developed in 4.2% of the injected eyes and 1.4% of the controls. In the study group, no significant IOP variation was noted during follow-up in patients receiving ≤20 injections, but there was a significant increase in IOP with time in more frequently treated patients (p = 0.041). Comparison of both subgroups demonstrated that patients receiving >20 injections suffered significantly greater IOP variation (p = 0.034) during follow-up, and that these patients tended to require IOP-lowering treatment more frequently (p = 0.090). CONCLUSION: Multiple anti-VEGF injections lead to an increase in IOP, although this variation is not sufficient to cause development of OHT in the majority of patients.

Treatment of neovascular age-related macular degeneration with anti-VEGF agents: retrospective analysis of 5-year outcomes.

PURPOSE: To evaluate the 5-year results obtained in clinical practice in the treatment of neovascular age-related macular degeneration (nAMD) with anti-VEGF agents. MATERIALS AND METHODS: We retrospectively analyzed all patients with nAMD who initiated anti-VEGF treatment before October 2009. We collected data regarding visual and anatomical outcomes. RESULTS: A total of 278 patients met the selection criteria. The mean number of intravitreal injections was 5.7 in the first year and 3.7 in the fifth year. A positive mean visual acuity variation of +3.7 Early Treatment Diabetic Retinopathy Study letters occurred in the first year, but no significant differences relative to baseline were observed thereafter. The majority of patients (71%) maintained stable visual acuity throughout follow-up. At 5 years, mean central macular thickness remained substantially inferior to baseline (-96.6 µm), and 56% of patients maintained dry retinas. CONCLUSION: Anti-VEGF therapy leads to long-term visual stabilization in the great majority of patients.

Switch to Aflibercept in the Treatment of Neovascular AMD: One-Year Results in Clinical Practice.

PURPOSE: To report the clinical outcomes of intravitreal aflibercept therapy in eyes with refractory and recurrent neovascular age-related macular degeneration (AMD) switched from intravitreal bevacizumab or ranibizumab. METHODS: This is a retrospective review of eyes with neovascular AMD switched to intravitreal aflibercept with at least 1 year of follow-up after the switch. All patients had had a minimum of 3 injections of bevacizumab or ranibizumab before the switch. Aflibercept was used in patients considered refractory to bevacizumab (group 1) and in recurrent patients on therapy with ranibizumab due to an institutional policy decision (group 2). Changes in best-corrected visual acuity, fluid on optical coherence tomography (OCT), central retinal thickness (CRT) and the frequency of injections were compared. RESULTS: Eighty-five eyes of 69 patients were analyzed, 39 eyes in group 1 and 46 in group 2. The mean follow-up time was 31.6 months prior to the switch and 14.7 months on treatment with aflibercept. One year after the switch, there was a nonsignificant mean decrease of 2 letters in visual acuity in both groups (group 1: from 58.2 to 55.8 letters, p = 0.086; group 2: from 56.4 to 54.5 letters, p = 0.168), but the mean number of injections per month was significantly lower (from 0.76 to 0.57, p < 0.001). With the switch, 90.6% of the patients showed anatomic improvement with a reduction of fluid on OCT, and both groups presented significant improvement in CRT (group 1: 65.3 µm, p = 0.051; group 2: 91.0 µm, p < 0.001). CONCLUSION: Aflibercept appears to be a valuable tool for the management of patients with poor responses to other anti-vascular endothelial growth factor drugs. These patients could have anatomic improvement, and the injection intervals could be extended.

Optical coherence tomography study of peripapillary retinal nerve fiber layer and choroidal thickness in eyes with tilted optic disc.

PURPOSE: The tilted optic disc is associated with peripapillary choroidal and retinal nerve fiber layer (RNFL) changes as well as visual field defects, often leading to diagnostic difficulties due to similarities with glaucomatous discs. We studied the peripapillary RNFL of the tilted optic disc by comparing values obtained with spectral-domain (SD) and time-domain (TD) optical coherence tomography (OCT) in order to identify characteristic RNFL patterns verified by both OCT devices, and also to determine whether SD-OCT offers any diagnostic advantage over TD-OCT. METHODS: Prospective case-control study of 16 individuals with tilted optic discs (27 eyes) and an age-matched control group (10 individuals, 20 eyes). Each case was subjected to ophthalmological examination and automated perimetry. Tilt orientation was classified based on observation of optic disc photographs, and angle of disc torsion was calculated with image processing software. RNFL measurements were obtained with TD-OCT and SD-OCT. Peripapillary choroid thickness was measured with SD-OCT. The findings were related with optic disc morphology and automated perimetry results. RESULTS: Stratus OCT results showed significantly lower superior RNFL (P<0.001) on the tilted group, whereas Spectralis indicated significantly lower superotemporal (P<0.001), superonasal (P=0.001), temporal (P=0.01), and global (P=0.01) RNFL on the tilted disc group. A significant correspondence was found between elevated disc rim and location of RNFL defect on the Spectralis (P=0.004). On the tilted group, peripapillary choroidal thickness was significantly thicker adjacent to the elevated rim (P<0.001). No correspondence was found between tilt orientation, peripapillary RNFL, or choroidal thickness and location of perimetric defects. CONCLUSIONS: Our results provide a clinical characterization of the main tilted disc morphologies and are valuable for correctly differentiating a tilted disc from a myopic glaucomatous disc. RNFL assessment by Spectralis OCT seems to be more susceptible to altered disc morphologies. The peripapillary RNFL changes found on titled disc cases could not predict the location of visual field defects.

Switch from intravitreal ranibizumab to bevacizumab for the treatment of neovascular age-related macular degeneration: clinical comparison.

OBJECTIVE: To compare outcomes after switching from intravitreal ranibizumab to bevacizumab in neovascular age-related macular degeneration (AMD). METHODS: A retrospective review of 110 eyes treated in a 1+PRN (pro re nata) clinical setting with ranibizumab that were switched to bevacizumab. Patients analyzed had at least 3 ranibizumab injections followed by at least 3 bevacizumab injections. Changes in best-corrected visual acuity (BCVA), retinal thickness and frequency of injections were compared. RESULTS: The mean duration of ranibizumab treatment was 18.1 months, followed by 12.2 months of bevacizumab. Mean injection rates per month were similar (0.54 and 0.56 respectively, p = 0.230). There were no significant differences between BCVA at baseline and at the time of the switch (52.4 and 54.8 letters, p = 0.059). After the switch, there was a statistically significant decrease in BCVA to 51.7 letters (p < 0.001). CONCLUSION: Switching patients to bevacizumab may have a minor negative effect on the initial gain obtained with ranibizumab; however the degenerative history of wet AMD could explain this small variation in visual acuity.

Open-globe injuries at an emergency department in Porto, Portugal: clinical features and prognostic factors.

PURPOSE: To describe the epidemiology, characteristics, surgical management, functional outcome, and prognostic factors of open-globe injuries requiring surgical treatment. METHODS: A retrospective review of 180 patients who underwent surgical repair of an open-globe injury at the ophthalmology emergency department of the Hospital S. João (Porto-Portugal) was performed. Prognostic factors for no light perception and for poor vision (visual acuity <3/10) in patients who retained vision after surgical treatment were determined. RESULTS: We observed a different age distribution between male and female ocular trauma (143 patients were men, with a mean age of 46.4 years, while the mean age for women was 70.9 years). Domestic accidents were the most frequent context of trauma (44.4%). However, work accidents constituted the principal context of trauma among men. Initial visual acuity, concomitant adnexa lesion, associated nonocular trauma, and intentionally caused trauma were predictors of no vision at the end of the follow-up. Older age, lens damage, and retinal detachment were predictors of poor vision in patients with retained visual acuity. Vitreous hemorrhage, posterior segment lesion, and simultaneous lesion of anterior and posterior segment anticipated both no vision and poor vision. Isolated anterior segment lesion was associated with vision survival and good vision (≥3/10). CONCLUSIONS: The prognostic factors identified in this study may aid the process of decision-making in 2 crucial moments: at the initial approach and during the follow-up of patients with vision survival after open-globe injuries.

Choroidal and macular thickness changes induced by cataract surgery.

BACKGROUND: The aim of this study was to evaluate the effect of uneventful phacoemulsification on the morphology and thickness of the macula, the submacular choroid, and the peripapillary choroid. METHODS: In 14 eyes from 14 patients, retinal macular thickness, choroidal submacular thickness, and choroidal peripapillary thickness were measured preoperatively and at one week and one month after phacoemulsification using enhanced depth imaging spectral domain optical coherence tomography. Changes in thickness of the different ocular tissues were evaluated. RESULTS: There was a statistically significant increase in mean retinal macular thickness at one month. In horizontal scans, the mean increase was +8.67±6.75 µm (P<0.001), and in vertical scans, the mean increase was +8.80±7.07 µm (P=0.001). However, there were no significant changes in choroidal morphology in the submacular and peripapillary areas one month after surgery. In vertical scans, there was a nonsignificant increase in choroidal thickness (+4.21±20.2 µm; P=0.47) whilst in horizontal scans a nonsignificant decrease was recorded (-9.11±39.59 µm; P=0.41). In peripapillary scans, a nonsignificant increase in mean choroidal thickness was registered (+3.25±11.80 µm; P=0.36). CONCLUSION: Uncomplicated phacoemulsification induces nonpathologic increases in retinal macular thickness probably due to the inflammatory insult of the surgery; however these changes are not accompanied by significant changes in choroidal thickness. In the posterior segment, the morphologic response to the inflammatory insult of phacoemulsification is mainly observed at the retinal level, and seems to be independent of choroidal thickness changes.

Comparative study of 1+PRN ranibizumab versus bevacizumab in the clinical setting.

PURPOSE: We compared the efficacy of intravitreal ranibizumab and bevacizumab for treating neovascular age-related macular degeneration using an on-demand regimen. METHODS: A total of 186 wet age-related macular degeneration eyes of 186 treatment-naïve patients were compared retrospectively (67 eyes treated with ranibizumab with 91 treated with bevacizumab). At baseline, mean age, best corrected visual acuity, and angiographic lesion types were similar in both groups. Best corrected visual acuity and ocular coherence tomography were evaluated. RESULTS: Sixty eyes treated with ranibizumab and 85 eyes treated with bevacizumab completed a 12-month evaluation. At 12 months, mean best corrected visual acuity increased by +6.65 letters with ranibizumab treatment and by +5.59 with bevacizumab treatment (P = 0.64). Visual acuity improved by ≥15 letters in 15 eyes treated with ranibizumab and in 21 eyes treated with bevacizumab (P = 0.75). An overall reduction in ocular coherence tomography central thickness occurred for all time points. The mean number of injections per eye was 5.97 with ranibizumab and 5.92 with bevacizumab (P = 0.90). CONCLUSION: Intravitreal therapies with ranibizumab or bevacizumab have similar visual and anatomical results. These results confirm those of comparison of Age-Related Macular Degeneration Treatment Trials in as-needed cohorts in clinical practice. Randomized long-term clinical trials are necessary to examine the systemic safety of these treatments.

Vascular endothelial growth factor plasma levels before and after treatment of neovascular age-related macular degeneration with bevacizumab or ranibizumab.

PURPOSE: To evaluate the changes of vascular endothelial growth factor (VEGF) plasma levels after intravitreal injections of ranibizumab or bevacizumab in patients with exudative age-related macular degeneration (AMD). METHODS: Forty-three patients with exudative AMD and 19 age- and sex-matched control patients without chorioretinal diseases were studied. Nineteen patients were treated with intravitreal ranibizumab 0.5 mg, 24 with intravitreal bevacizumab 1.25 mg. Blood samples were collected just before the first injection, and 28 days after three initial consecutive injections performed in 4-weekly intervals (loading dose). Concentration of VEGF in the plasma was measured by ELISA. RESULTS: At baseline, the median VEGF concentrations in controls were 180.97 pg/ml, in the bevacizumab group 189.72 pg/ml and in the ranibizumab group 191.36 pg/ml. VEGF plasma concentrations in patients with wet AMD were comparable to controls (p = 0.225). Twenty-eight days after the third injection, a significant reduction of 42% in the median VEGF plasma levels was found in bevacizumab-treated patients (109.97 pg/ml; p = 0.0002) but not in ranibizumab-treated patients (189.97 pg/ml; p = 0.198) where a reduction of 0.7% in the median value was found. CONCLUSIONS: Intravitreal bevacizumab significantly reduced VEGF plasma levels until 28 days after intravitreal injection in patients with exudative AMD. Ranibizumab did not achieve a significant plasma VEGF reduction at the same time-point. These findings alert to the potential systemic safety differences between the two drugs after intravitreal administration.

A clear cell renal cell carcinoma inhibiting the response to intravitreal antivascular endothelial growth factor therapy in wet age-related macular disease.

PURPOSE: Wet age-related macular degeneration (AMD) is an ocular disorder that can be successfully treated with intravitreal antivascular endothelial growth factor (VEGF) therapy. We report a case of incomplete response to intravitreal therapy associated with a clear cell renal cell carcinoma (ccRCC). METHODS: A 72-year-old male with wet AMD responded poorly to intravitreal bevacizumab and ranibizumab injections. The removal of a ccRCC led to the spontaneous stabilization of the choroidal neovascular lesion. The renal carcinoma was examined for Von Hippel-Lindau (VHL) gene alterations. Immunohistochemical profiling of the hypoxia-inducible factor (HIF) pathway addressing the marker HIF-1α and its downstream targets VEGF, glucose transporter 1 and carbonic anhydrase IX was performed. RESULTS: Genotyping of the ccRCC revealed the presence of a truncating VHL mutation (p.E134fs*25). Immunohistochemistry displayed HIF pathway target activation and VEGF expression in the ccRCC tumour cells. Following tumour removal, the neovascular lesion remained stable for 6 months without any further anti-VEGF therapy. CONCLUSION: The somatic VHL mutation correlates with persistent high levels of HIF-1α pathway targets and VEGF expression in the ccRCC. We postulate that this increased VEGF in the tumour and subsequently in the plasma levels could have caused the incomplete response to intravitreal anti-VEGF therapy. Stabilization of the wet AMD following tumour removal indicates that the angiogenic secreting tumour (ccRCC) abrogates the response to VEGF inhibitor therapy. Thus, in cases of poor response to intravitreal anti-VEGF therapy, systemic evaluation including plasma levels of VEGF and/or systemic screening for VEGF-producing tumours should be considered.

Arterial thromboembolic events in patients with exudative age-related macular degeneration treated with intravitreal bevacizumab or ranibizumab.

BACKGROUND/AIMS: To compare retrospectively the incidence of arterial thromboembolic events (ATEs) in patients treated with bevacizumab or ranibizumab for exudative age-related macular degeneration. METHODS: Charts of 378 patients treated with at least 1 intravitreal injection of ranibizumab or bevacizumab were reviewed to calculate the incidence of ATEs. Only patients under monotherapy were analyzed. RESULTS: ATEs occurred in 15 patients: 12 (12/97) with bevacizumab (12.4%) and 3 (3/219) with ranibizumab (1.4%) - odds ratio 10.16; 95% confidence interval 2.80-36.93; p < 0.0001. ATEs in the bevacizumab and ranibizumab cohorts included stroke, myocardial infarction, angina pectoris, peripheral thromboembolic disease, transient ischemic attack, sudden death and lethal stroke. CONCLUSION: In this series, bevacizumab raised the risk of ATEs when compared to ranibizumab. In an elderly population with multiple cardiovascular risk factors, the new ATEs may not be attributed exclusively to the intravitreal bevacizumab administration. These findings raise an issue that must be confirmed in randomized clinical trials.

Ranibizumab treatment for choroidal neovascularization from causes other than age-related macular degeneration and pathological myopia.

AIM: Evaluation of safety and efficacy of intravitreal ranibizumab in the treatment of choroidal neovascularization (CNV) secondary to causes other than age-related macular degeneration (AMD) or pathological myopia (PM). METHODS: Retrospective and multicentric analysis of 21 eyes with CNV. Nine eyes had angioid streaks, 5 inflammatory chorioretinal diseases, 3 central serous chorioretinopathy and 4 idiopathic CNV. Follow-ups lasted ≥3 months. Best-corrected visual acuity (BCVA), ocular coherence tomography (OCT) and fundus examination were assessed monthly. RESULTS: Sixteen eyes (76%) completed 180 days of follow-up. Overall BCVA increased by +9.8 letters with treatment (p = 0.015). Visual acuity improvements ≥15 letters occurred in 43%. A significant reduction in OCT central thickness was observed. No cases of severe visual acuity loss, systemic or ocular side effects were registered. CONCLUSION: Short-term results of intravitreal ranibizumab for CNV unrelated to AMD or PM are encouraging. This treatment may constitute the only option for some of these patients.

Intravitreal bevacizumab for neovascular age-related macular degeneration with or without prior treatment with photodynamic therapy: one-year results.

PURPOSE: The purpose of this study was to elucidate the effect of prior photodynamic therapy (PDT) on the efficacy of intravitreal bevacizumab for the treatment of neovascular age-related macular degeneration. METHODS: One hundred and nine eyes of 102 patients with neovascular age-related macular degeneration were evaluated-80 eyes without prior treatment (group 1) and 29 with prior PDT (group 2). Best-corrected visual acuity, ocular coherence tomography, and funduscopy were assessed monthly. Results were evaluated at 1, 3, 6, and 12 months. RESULTS: One hundred and one eyes completed a 12-month evaluation. At 12 months, best-corrected visual acuity increased 5.6 letters with treatment (P = 0.001): +5.7 letters in group 1 and +5.4 in group 2 (P = 0.92). Overall, visual acuity improved > or =15 letters in 22.5% of eyes: 24.0% of naive eyes versus 18.5% with prior PDT (P = 0.56). Best-corrected visual acuity loss > or =15 letters occurred in 6 eyes, 5 with naive lesions. An overall reduction in ocular coherence tomography central retinal thickness was observed at all time points. Mean number of injections per eye per year was 5.6, 6.13 in group 1 versus 4.22 in group 2 (P = 0.01). Two retinal pigment epithelial tears, one subretinal macular hemorrhage, and two strokes occurred in naive lesions. CONCLUSION: The authors showed similar efficacy for intravitreal bevacizumab independently of prior PDT treatment. Eyes with prior PDT needed a statistically significantly lower number of injections to control their lesions.