Intravitreal anti-vascular endothelial growth factor therapy in the treatment of vision loss associated with hematologic malignancy.

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.

Fluorescein Angiogram Causing Cutaneous Venous Staining: A Rare Self-Resolving Phenomenon.

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.

Elevated aqueous TNF-α levels are associated with more severe functional and anatomic findings in eyes with diabetic macular oedema.

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.

Clinical performance of predicting late age-related macular degeneration development using multimodal imaging.

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.

Five-year outcomes of eyes initially enrolled in the 2-year BEVORDEX trial of bevacizumab or dexamethasone implants for diabetic macular oedema.

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.

Acute effects of caffeine and glucose intake on retinal vessel calibres in healthy volunteers.

PURPOSE: To evaluate the acute effects of caffeine and glucose intake on retinal vascular calibre of healthy adults. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Diabetic retinopathy progression 6 months post-cataract surgery with intravitreous bevacizumab vs triamcinolone: A secondary analysis of the DiMECAT trial.

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 MEASURES: DR progression. RESULTS: There 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 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 intraoperative intravitreous BVB or TCA injection to reduce the risk of DR progression following cataract surgery.

The association between intravitreal ranibizumab therapy and serum cytokine concentrations in patients with diabetic macular edema.

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-1ß) 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-1ß) 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.

A treat and extend protocol with Aflibercept for cystoid macular oedema secondary to central retinal vein occlusion - an 18-month prospective cohort study.

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 ACTRN12615000417583, 01/05/2015.

Secondary and Exploratory Outcomes of the Subthreshold Nanosecond Laser Intervention Randomized Trial in Age-Related Macular Degeneration: A LEAD Study Report.

PURPOSE: To evaluate the secondary and exploratory outcomes of the Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study, a 36-month trial of a subthreshold nanosecond laser (SNL) treatment for slowing the progression to late age-related macular degeneration (AMD) in its early stages. DESIGN: Multicenter, randomized, sham-controlled trial. PARTICIPANTS: Two-hundred ninety-two patients with bilateral large drusen. METHODS: Participants were randomly assigned to receive SNL or sham treatment to the study eye at 6-month intervals. MAIN OUTCOME MEASURES: The secondary outcome measure of the LEAD study was the time to development of late AMD, defined by multimodal imaging in the non-study eye. The exploratory outcome measures were the rate of change in best-corrected visual acuity (BCVA), low-luminance visual acuity, microperimetric mean sensitivity, drusen volume in the study and non-study eyes, and participant-reported outcomes based on the Night Vision Questionnaire and Impact of Vision Impairment questionnaire. RESULTS: Progression to late AMD in the non-study eye was not significantly delayed with SNL treatment (hazard ratio, 0.83; 95% confidence interval, 0.40-1.71; P = 0.611). There was no evidence of effect modification based on the coexistence of reticular pseudodrusen; interaction P = 0.065). There was no significant difference between study groups in the rate of change of low-luminance visual acuity, microperimetric mean sensitivity, and drusen volume in the study or non-study eyes, and Night Vision Questionnaire and Impact of Vision Impairment questionnaire scores (all P ≥ 0.167). The rate of BCVA decline was slightly higher for participants in the SNL group compared with the sham treatment group in the study eye (-0.54 and 0.23 letters/year, respectively; P < 0.001) but not the non-study eye (-0.48 and -0.56 letters/year, respectively; P = 0.628). CONCLUSIONS: Subthreshold nanosecond laser treatment of one eye did not have an effect on delaying progression to late AMD in the fellow eye and did not, in general, have an impact on the exploratory structural, functional, and participant-reported outcomes.

Prospective randomised clinical trial of intravitreal bevacizumab versus triamcinolone in eyes with diabetic macular oedema undergoing cataract surgery: 6-month results.

AIM: To report the 6-month results of a clinical trial that compared intravitreous bevacizumab (BVB) 1.25 mg versus triamcinolone acetonide (TA) 4 mg when administered as an adjunct during cataract surgery to patients with diabetic macular oedema (DMO). METHODS: Prospective, double-masked, single-centre (Royal Victorian Eye and Ear Hospital, Melbourne) clinical trial. Patients with visually significant cataract and centre-involving DMO (either current or prior) were randomised (1: 1) to receive either intravitreous BVB 1.25 mg or TA 4 mg at the time of cataract surgery and if required at review. Main outcome measures were changes in best-corrected visual acuity (BCVA) and central macular thickness (CMT) from baseline to the 6-month time point of this 12-month study. RESULTS: 61 eyes of 58 patients were enrolled. At baseline, both groups were similar in terms of BCVA and CMT (p>0.2). At 6 months, there was no significant difference in vision between the groups, with mean letter gain of +21.4 (95% CI +14.5 to +28.4) in the TA group and +17.3 (95% CI +12.1 to +22.6) in the BVB group (p=0.35). The TA group had a significant sustained anatomical improvement at 6 months, with a reduction in CMT (-51.4 µm; 95% CI -98.2 to -4.7) compared with thickening in the BVB group (+15.6 µm; 95% CI -26.4 to +57.7, p=0.04). CONCLUSIONS: When given as an adjunct to cataract surgery, both TA and BVB improved visual outcomes at 6 months postoperatively. However, only TA resulted in sustained improvement in CMT, with the majority not requiring any further treatment postoperatively.

Subthreshold Nanosecond Laser Intervention in Age-Related Macular Degeneration: The LEAD Randomized Controlled Clinical Trial.

PURPOSE: There is an urgent need for a more effective intervention to slow or prevent progression of age-related macular degeneration (AMD) from its early stages to vision-threatening late complications. Subthreshold nanosecond laser (SNL) treatment has shown promise in preclinical studies and a pilot study in intermediate AMD (iAMD) as a potential treatment. We aimed to evaluate the safety of SNL treatment in iAMD and its efficacy for slowing progression to late AMD. DESIGN: The Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study is a 36-month, multicenter, randomized, sham-controlled trial. PARTICIPANTS: Two hundred ninety-two participants with bilateral large drusen and without OCT signs of atrophy. METHODS: Participants were assigned randomly to receive Retinal Rejuvenation Therapy (2RT®; Ellex Pty Ltd, Adelaide, Australia) SNL or sham treatment to the study eye at 6-monthly intervals. MAIN OUTCOME MEASURES: The primary efficacy outcome was the time to development of late AMD defined by multimodal imaging (MMI). Safety was assessed by adverse events. RESULTS: Overall, progression to late AMD was not slowed significantly with SNL treatment compared with sham treatment (adjusted hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.33-1.14; P = 0.122). However, a post hoc analysis showed evidence of effect modification based on the coexistence of reticular pseudodrusen (RPD; adjusted interaction P = 0.002), where progression was slowed for the 222 participants (76.0%) without coexistent RPD at baseline (adjusted HR, 0.23; 95% CI, 0.09-0.59; P = 0.002), whereas an increased progression rate (adjusted HR, 2.56; 95% CI, 0.80-8.18; P = 0.112) was observed for the 70 participants (24.0%) with RPD with SNL treatment. Differences between the groups in serious adverse events were not significant. CONCLUSIONS: In participants with iAMD without MMI-detected signs of late AMD, no significant difference in the overall progression rate to late AMD between those receiving SNL and sham treatment were observed. However, SNL treatment may have a role in slowing progression for those without coexistent RPD and may be inappropriate in those with RPD, warranting caution when considering treatment in clinical phenotypes with RPD. Our findings provide compelling evidence for further trials of the 2RT® laser, but they should not be extrapolated to other short-pulse lasers.

Diabetic retinopathy: a complex pathophysiology requiring novel therapeutic strategies.

INTRODUCTION: Diabetic retinopathy (DR) is the leading cause of vision loss in the working age population of the developed world. DR encompasses a complex pathology, and one that is reflected in the variety of currently available treatments, which include laser photocoagulation, glucocorticoids, vitrectomy and agents which neutralize vascular endothelial growth factor (VEGF). Whilst these options demonstrate modest clinical benefits, none is yet to fully attenuate clinical progression or reverse damage to the retina. This has led to an interest in developing novel therapies for the condition, such as mediators of angiopoietin signaling axes, immunosuppressants, nonsteroidal anti-inflammatory drugs (NSAIDs), oxidative stress inhibitors and vitriol viscosity inhibitors. Further, preclinical research suggests that gene therapy treatment for DR could provide significant benefits over existing treatments options. AREAS COVERED: Here we review the pathophysiology of DR and provide an overview of currently available treatments. We then outline recent advances made towards improved patient outcomes and highlight the potential of the gene therapy paradigm to revolutionize DR management. EXPERT OPINION: Whilst significant progress has been made towards our understanding of DR, further research is required to enable the development of a detailed spatiotemporal model of the disease. In addition, we hope that improvements in our knowledge of the condition facilitate therapeutic innovations that continue to address unmet medical need and improve patient outcomes, with a focus on the development of targeted medicines.

The Influence of Intravitreal Ranibizumab on Inflammation-associated Cytokine Concentrations in Eyes With Diabetic Macular Edema.

Purpose: To evaluate the effect of intravitreal ranibizumab injections on aqueous concentrations of angiogenic or inflammatory cytokines in patients with diabetic macular edema (DME). Methods: Thirty eyes of 25 patients with center-involved DME were recruited to the study. All had a central macular thickness (CMT) of >300 µm and best-corrected visual acuity (BCVA) between 28 and 70 logMAR letters (Snellen equivalent 20/320-20/40). At baseline, all eyes had 0.1 mL of aqueous collected before ranibizumab treatment. At week 4, a second ranibizumab injection was administered and at week 8, aqueous sampling was repeated before a third ranibizumab injection. From week 12, all eyes were followed at 4-weekly intervals and the need for ranibizumab treatment was determined by BCVA and CMT measurements. Levels of 32 cytokines were assessed at baseline and at week 8 using a multiplex array assay. Results: Following two consecutive ranibizumab injections, there was a statistically significant reduction in VEGF (P < 0.00001), as well as IL-1ß (P = 0.00006), IL-7 (P = 0.00002), IL-8 (P = 0.00023), IL-10 (P < 0.00001), IL-12 (P < 0.00001), IL-17 (P = 0.00024), MCP-1 (P = 0.00023), and TNF-α (P < 0.00001). There was also an upregulation of soluble VEGF receptor-2 (P = 0.00004). A P < 0.0015 was considered significant in this study. Conclusions: Ranibizumab treatment influences various inflammatory cytokine concentrations in addition to reducing aqueous VEGF concentrations in patients with DME. This may contribute to its therapeutic effect in patients with DME.

New Treatment Modalities for Geographic Atrophy.

Age­related macular degeneration (AMD) is a significant cause of global visual morbidity and is projected to affect 288 million people by the year 2040. The advent of treatment with anti‒vascular endothelial growth factor (anti­VEGF) drugs has revolutionized the treatment of neovascular AMD (nAMD) but there have been no similar breakthroughs for the treatment of geographic atrophy (GA) to retard its progression. The advancements in imaging and new understanding of disease mechanisms, based on molecular and genetic models, have paved the way for the development of novel experimental treatment options for GA that aim to cater to a thus far largely unmet need. This review paper focuses on the recent clinical trials of new treatment options for slowing GA progression rates with emphasis on the agents that are currently undergoing, or have already undergone, significant clinical trial testing. Several new groups of drugs, including those targeting the complement cascade and agents considered as neuroprotective, have shown some promising results and could potentially pave the way forward in the treatment of this devastating disease.