Purpose:To assess changes in retinal vascular calibre following intravitreal ranibizumab treatment in patients with diabetic macular oedema (DMO). Methods:A post hoc analysis of data from a prospective clinical study assessing patients treated with ranibizumab for DMO was conducted. 76 eyes of 67 treatment naive patients were recruited. Patients received three, monthly, ranibizumab injections. From months 3 to 12, ranibizumab injections were administered PRN. Retinal vascular calibre was measured from digital fundus photographs with a semiautomated computer programme (SIVA) and summarised as central retinal artery (CRAE) and vein (CRVE) equivalent. Artery to vein ratio (AVR) was derived from CRAE/CRVE. The primary and secondary outcomes were change in CRAE, CRVE, AVR, CMT and BCVA from baseline to month 2 and 12, respectively. Results:BCVA improved significantly from 60.71 ± 8.24 letters by 6.76 ± 6.40 (P < 0.001) at month 2 and 10.12 ± 10.86 (P < .001) at 12. CMT, 470.58 μm ± 106.91 μm, significantly reduced by 81.41 μm ± 99.73 μm (P  < 0.001) at month 2 and 132.48 ± 141.79 μm (P < 0.001) at month 12. There was a statistically significant CRVE decrease by -8.44 μm ± 11.27 μm (P < 0.0001) at month 2 and -4.68 ± 12.41 μm (P = 0.03) at month 12, whilst AVR increased by +0.02 μm ± 0.04 μm (P = 0.02) at month 2 and +0.02 μm ± 0.04 μm (P = 0.01) at month 12. Conclusion:Ranibizumab treatment was associated with a significant reduction in CRVE and increase in AVR. It is possible that the positive effect of ranibizumab therapy on improvements in BCVA and CMT may be related to reduction of retinal venous calibre and hydrostatic pressure.

Introduction:Fluorescein angiography (FA) is a useful investigation in the diagnosis and treatment of retinal and choroidal disease. FA has well-reported adverse effects, most being mild. Very few cases have reported cutaneous venous staining following FA. Case Presentation:Two cases are reported. Case 1 was a 90-year-old female with bilateral neovascular age-related macular degeneration. In the few minutes following her routine FA, she developed cutaneous fluorescein staining ascending along the superficial forearm veins proximal to the cannula in situ at the dorsal wrist. Case 2 was a 50-year-old male with diabetic macular oedema. In the minutes following his FA, he developed cutaneous fluorescein staining descending along the dorsal forearm veins distal to the cannula in situ at the cubital fossa. Both patients were managed conservatively with the stain resolving in the next few days. Conclusion:Cutaneous fluorescein staining around superficial vasculature is a rare phenomenon. Despite this, it seems to be self-limiting and does not require any treatment.

Purpose: To determine the effectiveness of anti-vascular endothelial growth factor (VEGF) therapy in the setting of optic disc edema secondary to hematologic malignancies. Observations: The report features two patients (one male, one female) in their 70's with biopsy proven hematologic malignancies who subsequently developed optic disc edema. The patients were commenced on a trial of successive intravitreal Aflibercept 2mg/0.05mL therapy. The best corrected visual acuity for patient 1 improved from 20/50 oculus dexter (OD) and 20/80 oculus sinister (OS), to 20/20 OD (4 lines Early Treatment of Diabetic Retinopathy Study (ETDRS)) and 20/32 OS (4 lines ETDRS). Similarly, patient 2's best corrected visual acuity improved from 20/100 OU to 20/50 OD (3 lines ETDRS) and 20/40 OS (4 lines ETDRS) following initiation of treatment. In addition, optical coherence tomography imaging obtained before and after therapy demonstrated an improvement in both patient's optic disc edema and cystoid macular edema. Conclusions and importance: The findings of this report suggest that in patients with a known hematologic malignancy, optic disc edema and cystoid macular edema may be amenable to anti-VEGF treatment, especially if there are clinical and angiographic features of vascular endothelial growth factor overexpression.

BACKGROUND:Intravitreal ranibizumab for diabetic macular oedema (DMO) has been recently shown to modulate levels of aqueous cytokines. This study investigates the associations between changes in aqueous cytokine levels following intravitreal ranibizumab therapy and the corresponding anatomical and functional changes in the eye. METHODS:Twenty-five patients comprising 30 eyes diagnosed with DMO were prospectively recruited. All eyes received three loading dose ranibizumab injections at baseline, week 4 and week 8, followed by pro re nata treatment based on best-corrected visual acuity (BCVA) and central macular thickness (CMT) up to week 48. Prior to ranibizumab administration, aqueous samples were collected from all eyes, and subsequent sampling was performed at week 8. Levels of 32 cytokines were assessed at baseline and at week 8. RESULTS:At baseline, higher aqueous TNF-α levels were associated with poorer BCVA (p = 0.033), greater macular volume (p = 0.017) and worse diabetic retinopathy (p = 0.047). Higher levels of IL-7 were associated with poorer BCVA and greater macular volume (MV). Following treatment with ranibizumab there was a significant correlation with reduction of aqueous TNF-α and improvements in BCVA and MV, both at 6 months (BCVA [r = -0.558, p = 0.001], MV [r = 0.410, p = 0.024]) and 12-months (BCVA [r = -0.413, p = 0.023], MV [r = 0.482, p = 0.008]). The change in VEGF concentration following ranibizumab treatment did not correlate with either BCVA or MV improvements (p > 0.05). CONCLUSIONS:Higher levels of aqueous TNF-α and IL-7 correlated with worse DMO, both anatomically and functionally. Reductions in levels of aqueous TNF-α, but not VEGF, post ranibizumab treatment were associated with improvement in BCVA and MV.

Background: To examine whether the clinical performance of predicting late age-related macular degeneration (AMD) development is improved through using multimodal imaging (MMI) compared to using colour fundus photography (CFP) alone, and how this compares with a basic prediction model using well-established AMD risk factors. Methods: Individuals with AMD in this study underwent MMI, including optical coherence tomography (OCT), fundus autofluorescence, near-infrared reflectance and CFP at baseline, and then at 6-monthly intervals for 3-years to determine MMI-defined late AMD development. Four retinal specialists independently assessed the likelihood that each eye at baseline would progress to MMI-defined late AMD over 3-years with CFP, and then with MMI. Predictive performance with CFP and MMI were compared to each other, and to a basic prediction model using age, presence of pigmentary abnormalities, and OCT-based drusen volume. Results: The predictive performance of the clinicians using CFP [AUC = 0.75; 95% confidence interval (CI) = 0.68-0.82] improved when using MMI (AUC = 0.79; 95% CI = 0.72-0.85; p = 0.034). However, a basic prediction model outperformed clinicians using either CFP or MMI (AUC = 0.85; 95% CI = 0.78-91; p <= 0.002). Conclusions: Clinical performance for predicting late AMD development was improved by using MMI compared to CFP. However, a basic prediction model using well-established AMD risk factors outperformed retinal specialists, suggesting that such a model could further improve personalised counselling and monitoring of individuals with the early stages of AMD in clinical practice.

Objective We tested the hypothesis that targeted retinal laser photocoagulation (TPRP) to peripheral retinal ischaemia reduces the overall burden of aflibercept injections when treating diabetic macular oedema (DMO) over a 24-month period. Methods Prospective, double-masked, multicentre, randomised controlled trial in Australia comparing aflibercept monotherapy, following a treat-and-extend protocol, or combination therapy of aflibercept and TPRP for DMO. The aflibercept monotherapy group received placebo laser. The primary outcome measure was the mean number of intravitreal aflibercept injections for each group at 24 months. Secondary outcome included: mean change in central macular thickness (CMT) and vision at trial completion, the proportion of eyes whose DMO resolved and the mean injection treatment interval. Ocular and systemic adverse events were recorded. Results We enrolled 48 eyes of 47 patients; 27 eyes were randomised to combination therapy (aflibercept and TPRP) and 21 to aflibercept monotherapy. Thirty-two eyes (67%) completed the 2-year study. The number of intravitreal treatments given were similar for combination therapy (10.5 (SD 5.8) and monotherapy (11.8 (SD5.6)) ( P = 0.44). The mean visual improvement (+4.0 (−1.8, 9.8) and +7.8 (2.6, 12.9) letters, P = 0.32), mean decrease in CMT (−154 (−222,−87) µm and −152 (−218,−86) µm, P = 0.96), proportion of eyes with CMT < 300 µm (48% and 67%; P = 0.50) and safety outcomes were similar in both the combination and monotherapy treatment groups (respectively). Conclusions Laser to areas of ischaemic peripheral retina does not reduce the burden of intravitreal aflibercept injections when treating diabetic macular oedema.

The number of people living with diabetes is expected to rise to 578 million by 2030 and to 700 million by 2045, exacting a severe socioeconomic burden on healthcare systems around the globe. This is also reflected in the increasing numbers of people with ocular complications of diabetes (namely, diabetic macular oedema (DMO) and diabetic retinopathy (DR)). In one study examining the global prevalence of DR, 35% of people with diabetes had some form of DR, 7% had PDR, 7% had DMO, and 10% were affected by these vision-threatening stages. In many regions of the world (Australia included), DR is one of the top three leading causes of vision loss amongst working age adults (20-74 years). In the management of DMO, the landmark ETDRS study demonstrated that moderate visual loss, defined as doubling of the visual angle, can be reduced by 50% or more by focal/grid laser photocoagulation. However, over the last 20 years, antivascular endothelial growth factor (VEGF) and corticosteroid therapies have emerged as alternative options for the management of DMO and provided patients with choices that have higher chances of improving vision than laser alone. In Australia, since the 2008 NHMRC guidelines, there have been significant developments in both the treatment options and treatment schedules for DMO. This working group was therefore assembled to review and address the current management options available in Australia.

Purpose: This study aimed to assess the association between cytokine expression and optical coherence tomography (OCT) features of diabetic macular edema (DME).Methods: This is a post-hoc analysis of the baseline data of a prospective study designed to evaluate the effect of intravit-real ranibizumab injections on aqueous humor cytokine levels in patients with center-involved DME. OCT images were evaluated for baseline imaging features of DME, including central macular thickness (CMT), macular volume (MV), subretinal fluid (SRF) height, morphological pattern of DME, intraretinal cyst (IRC) size, status of the ellipsoid zone/ external limiting membrane (EZ/ELM), presence of disorganization of retinal inner layers (DRIL), number of hyper-reflective foci (HRF), and the presence of epiretinal membrane (ERM) or vitreomacular traction (VMT). Hierarchical cluster analysis (HCA) was used to identify two groups (clusters) of subjects that shared similar cytokine characteristics (low and high expression profiles), and differences in OCT imaging parameters across clusters were compared using multivariable logistic regression models.Results: Aqueous cytokine concentrations and OCT images were obtained from 30 eyes of 25 patients recruited. The HCA demonstrated that eyes in the low-concentration cytokine profile group were associated with better BCVA (OR = 0.90, [95% CI 0.81-0.99], p = 0.05), thinner CMT (OR = 1.08, [95% CI 1.01-1.17], p = 0.03), and lower MV (OR = 2.08, [95% CI 1.10-3.90], p = 0.02). Reduced BCVA, greater CMT, and larger MV were individually correlated with multiple cytokines, including IL-7, IL-9, MIP-1 alpha, and TNF-alpha. Increased SRF was significantly associated with IL-15 (r = 0.40, p = 0.03) and eotaxin (r = 0.47, p = 0.008). Increased levels of IL-6 (H = 39, p = 0.04), IL-13 (H = 44, p = 0.02), and sVEGFR-1 (H = 25.5, p = 0.05) were associated with the presence of DRIL, whereas GM-CSF was protective (H = 131, p = 0.01).Conclusions: These findings associate higher cytokine expression with worse BCVA, CMT, and MV. Although it is likely that multiple cytokines are associated with the functional and anatomic features of DME, we identified specific cytokines that may drive the process, such as TNF-alpha, IL-6, IL-7, and IL-9.

BACKGROUND:The BEVORDEX trial compared outcomes of eyes with diabetic macular oedema (DMO) randomised to receive either intravitreal dexamethasone (DEX-) implant or bevacizumab over 2 years. We assessed long-term efficacy and safety outcomes 5 years from enrolment.METHODS:Patients received standard clinical care after they finished the study. Their files were reviewed for visual and anatomical outcomes, post-trial treatments and complications.RESULTS:Three-year and five-year data were available for 82% and 59% of eyes enrolled in the BEVORDEX study, respectively. Visual acuity gains at end of trial were generally lost by both treatment groups at 5 years but the macular thickness did not change from end of trial to 5 years. A similar proportion of eyes from each treatment group gained ≥10 letters at 5 years from enrolment in the BEVORDEX trial.Eyes that were initially randomised to the DEX-implant group had significantly fewer treatments but were more likely to develop proliferative diabetic retinopathy (PDR) over the 5-year period compared with eyes initially randomised to bevacizumab. The proportion of eyes that had cataract surgery by 5 years was similar between initial treatment groups.CONCLUSIONS:Eyes in the BEVORDEX trial had similar 5-year rates of cataract surgery, however, more eyes converted to PDR in the group initially treated with DEX-implant. Eyes that were initially treated for 2 years with either intravitreal DEX-implant of bevacizumab followed by standard of care had similar visual and anatomical outcomes at 5 years.

To evaluate the acute effects of caffeine and glucose intake on retinal vascular calibre of healthy adults. This prospective crossover study was conducted at the Centre for Eye Research Australia (Melbourne, Australia). Standardized doses of 300 mg caffeine (approximately 3 cups coffee), 30 g glucose or 300 ml of water, were each given to 19 healthy subjects on separate days. Retinal photographs and blood pressure measurements were taken at baseline, 30-, 60- and 120-min after ingestion of each solution. Central retinal artery and vein equivalents (CRAE, CRVE) and the arterio-venule ratio were measured using computer-assisted software. The mean retinal vascular calibre measurements were compared between pre- and post-ingestion images. After caffeine intake, significant reductions were observed in mean CRAE of − 9.3 μm, − 10.4 μm and − 8.5 μm and CRVE of − 16.9 μm, − 18.7 μm and − 16.1 μm at 30-, 60- and 120-min after intake when compared with baseline (p ≤ 0.002 for all; paired t test). No significant changes were observed in mean retinal vascular calibre measurements after intake of either glucose or water when compared to baseline (p ≥ 0.072 for all). When controlling for baseline characteristics and blood pressure measurements, only caffeine intake had a significant effect on reducing both CRAE and CRVE at all time points post ingestion (p ≤ 0.003 for all, multiple linear regression model). Caffeine is associated with an acute vasoconstrictive effect on retinal arterioles and venules in healthy subjects. Factors other than blood pressure-induced autoregulation play a significant role in caffeine-associated retinal vasoconstriction.

Clinical & Experimental OphthalmologyVolume 48, Issue 5 p. 711-713 LETTER TO THE EDITOR Intravitreal injection does not change anterior chamber morphology on anterior segment optical coherence tomography Alp Atik FRANZCO, Corresponding Author Alp Atik FRANZCO alp.atik@mail.harvard.edu orcid.org/0000-0001-6754-6380 Department of Ophthalmology, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia Correspondence Dr Alp Atik, Department of Ophthalmology, Royal Victorian Eye and Ear Hospital, 32, Gisborne Street, East Melbourne,VIC 3002. Email: alp.atik@mail.harvard.eduSearch for more papers by this authorSanjeewa S. Wickremasinghe FRANZCO, Sanjeewa S. Wickremasinghe FRANZCO Department of Ophthalmology, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, AustraliaSearch for more papers by this authorSukhpal S. Sandhu FRANZCO, Sukhpal S. Sandhu FRANZCO Department of Ophthalmology, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, AustraliaSearch for more papers by this authorGhee S. Ang FRANZCO, Ghee S. Ang FRANZCO Department of Ophthalmology, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, AustraliaSearch for more papers by this author Alp Atik FRANZCO, Corresponding Author Alp Atik FRANZCO alp.atik@mail.harvard.edu orcid.org/0000-0001-6754-6380 Department of Ophthalmology, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia Correspondence Dr Alp Atik, Department of Ophthalmology, Royal Victorian Eye and Ear Hospital, 32, Gisborne Street, East Melbourne,VIC 3002. Email: alp.atik@mail.harvard.eduSearch for more papers by this authorSanjeewa S. Wickremasinghe FRANZCO, Sanjeewa S. Wickremasinghe FRANZCO Department of Ophthalmology, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, AustraliaSearch for more papers by this authorSukhpal S. Sandhu FRANZCO, Sukhpal S. Sandhu FRANZCO Department of Ophthalmology, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, AustraliaSearch for more papers by this authorGhee S. Ang FRANZCO, Ghee S. Ang FRANZCO Department of Ophthalmology, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, AustraliaSearch for more papers by this author First published: 17 March 2020 https://doi.org/10.1111/ceo.13752Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume48, Issue5July 2020Pages 711-713 RelatedInformation

Aim:To investigate the association between intravitreal ranibizumab therapy and serum cytokine concentrations in patients with diabetic macular edema (DME).Methods:Twenty-five patients with center-involved DME were recruited prospectively. Serum samples were collected from the patients before and 4 weeks after two ranibizumab injections. The levels of 32 cytokines at these two time points were assessed using a multiplex array assay.Results:Following two ranibizumab injections, there was a statistically significant decrease in the median [interquartile range] levels of Interleukin 1-1beta (IL-1β) from 5.56 [3.6, 8.75] to 2.33 [1.51, 2.89], Interleukin 13 (IL-13) from 4.30 [1.84, 18.55] to 0.38 [0.38, 0.78], granulocyte-colony stimulating factor (G-CSF) from 64.65 [42.9, 108] to 37.8 [27.3, 46.37], Interferon gamma (IFN-γ) from 241 [103.33, 753.4] to 94.4626 [42.04, 118.58], Interferon gamma-induced protein 10 (IP-10) from 234.68 [144.16, 285.98] to 158.73 [94.71, 198.64], Macrophage Inflammatory Protein-1 alpha (MIP-1α) from 3.65 [2.62, 11.02] to 1.41 [0.94, 1.88], and Tumor necrosis factor- alpha (TNF-α) from 131.09 [100.68,28 240.27] to 45.19 [24.04, 68.55]. There was a statistically significant increase in the levels of Interleukin 9 (IL-9) from 0.76 [0.76, 7.03] to 19.67 [5.36 27.76], Macrophage Inflammatory Protein-1 beta (MIP-1β) from 0.28 [0.28, 30 0.28] to 6.79 [I3.74, 14.16], Vascular endothelial growth factor (VEGF) from 2.55 [2.55, 2.55] to 25.24 [14.51, 41.73], and soluble vascular endothelial growth factor -1 (sVEGFR-1) from 333.92 [204.99, 440.43] to 500.12 [38.7, 786.91]. A Bonferroni-corrected p value of 0.00156 was considered statistically significant.Conclusions:In patients with DME, intravitreal ranibizumab therapy appears to influence the serum levels of a range of cytokines. After two injections, intravitreal ranibizumab therapy appears to be associated with a significant decrease in inflammatory mediators and a rise in VEGF and sVEGFR1.

IMPORTANCE Diabetic retinopathy (DR) may progress following cataract surgery due to surgery-induced inflammation. The effect of intravitreal bevacizumab (BVB) and triamcinolone acetonide (TCA), which have differing anti-inflammatory properties, on DR progression following cataract surgery has not been reported. BACKGROUND To report the progression of DR in diabetic patients undergoing cataract extraction treated with intravitreal BVB or TCA during the surgery. DESIGN Post-hoc analysis of 6 month data from a prospective, randomized, double-masked clinical trial PARTICIPANTS: Diabetic patients with clinically significant cataract and fovea involving diabetic macular oedema (DME), or a recent history of DME. METHODS Participants were randomly allocated 1:1 to receive intravitreal BVB 1.25 mg or TCA 4 mg during and post cataract surgery as needed. The rate of DR progression between groups was compared. MAIN OUTCOME MEASURE(S) DR progression RESULTS: There were 61 eyes included. Patients receiving BVB were older than those receiving TCA (70.2 vs 64.3 years; P < 0.05). Three participants (10.7%) in the BVB and three (9.09%) in the TCA group had a 1-step progression, while none in BVB and only one (3%) in the TCA group demonstrated 2-step DR progression. In the majority of these patients, DR progression was from mild to moderate NPDR. CONCLUSION AND RELEVANCE In this study, BVB and TCA groups had a similar, and lower rate of DR progression compared to previous studies where no adjunctive treatment was administered, suggesting that patients with DME may benefit from either intra-operative intravitreous BVB or TCA injection to reduce the risk of DR progression following cataract surgery. This article is protected by copyright. All rights reserved.

ABSTRACTImportanceDiabetic retinopathy (DR) may progress following cataract surgery due to surgery‐induced inflammation. The effect of intravitreal bevacizumab (BVB) and triamcinolone acetonide (TCA), which have differing anti‐inflammatory properties, on DR progression following cataract surgery has not been reported.BackgroundTo report the progression of DR in diabetic patients undergoing cataract extraction treated with intravitreal BVB or TCA during the surgery.DesignPost hoc analysis of 6‐month data from a prospective, randomized, double‐masked clinical trial.ParticipantsDiabetic patients with clinically significant cataract and fovea involving diabetic macular oedema (DME), or a recent history of DME.MethodsParticipants were randomly allocated 1:1 to receive intravitreal BVB 1.25 mg or TCA 4 mg during and post‐cataract surgery as needed. The rate of DR progression between groups was compared.Main Outcome MeasuresDR progression.ResultsThere were 61 eyes included. Patients receiving BVB were older than those receiving TCA (70.2 vs 64.3 years; P < .05). Three participants (10.7%) in the BVB and three (9.09%) in the TCA group had a one‐step progression, while none in BVB and only one (3%) in the TCA group demonstrated two‐step DR progression. In the majority of these patients, DR progression was from mild to moderate non‐proliferative diabetic retinopathy.Conclusion and RelevanceIn this study, BVB and TCA groups had a similar, and lower rate of DR progression compared to previous studies where no adjunctive treatment was administered, suggesting that patients with DME may benefit from either intraoperative intravitreous BVB or TCA injection to reduce the risk of DR progression following cataract surgery.

Background To evaluate the safety and efficacy of a treat-and-extend protocol of aflibercept for cystoid macular oedema (CMO) secondary to central retinal vein occlusion (CRVO). Methods Twenty patients with CMO secondary to CRVO were included in this prospective cohort study. After 3 loading 4-weekly injections, treatment intervals were increased by 2 weeks if there was no clinical activity, to a maximum of 12 weeks. If clinical activity recurred or persisted, the interval between injections was shortened by 2 weeks, to a minimum of 4 weeks. Main outcome measures were change in visual acuity and the proportion of patients gaining 15 or more Early Treatment of Diabetic Retinopathy Study (ETDRS) letters from baseline at 6, 12 and 18 months. Results Mean BCVA gain from baseline was 19.7 ± 13.8, 22.2 ± 13.9 and 21.9 ± 15.8 ETDRS letters at 6, 12 and 18 months, respectively. Sixty-five percent of patients gained 15 or more ETDRS letters at 6 months, increasing to 70.6% at 12 and 18 months. Patients received 5.0 [4.0 to 6.0], 8.5 [8.0 to 10.3] and 11.0 [9.0 to 12.5] injections by 6, 12 and 18 months, respectively. Conclusions The visual outcomes achieved with a treat-and-extend protocol in this study were similar to the pivotal trials of aflibercept for CMO secondary to CRVO, which used monthly and then as-needed protocols. Trial registration Australian and New Zealand Clinical Trials Registry, registration number ACTR N12615000417583 , 01/05/2015.

Clinicians adopt varying strategies for antisepsis with PI, which to this day remains efficient, economical and effective. Clinicians should prudently consider effective PI application, and we thank Koerner and Grzybowski for encouraging debate and raising the profile of this issue.