MAIA microperimeter for short-duration fixation stability measurements in central vision loss: Repeatability and comparison with the Nidek MP1.

PURPOSE: This study reports the repeatability of 20 s-duration fixation stability measurements recorded with the Macular Integrity Assessment (MAIA) microperimeter in patients with central vision loss, in contrast to the Nidek MP1 microperimeter. METHODS: Fixation stability was recorded in 39 eyes of 25 patients with macular disease using MAIA and the MP1 for 20 s intervals, twice for each eye, with each instrument. Twenty eyes were identified as the better eye (BE) and 19 eyes as the worse eye (WE). Fixation stability was quantified with the 95% bivariate contour ellipse area (BCEA), logarithmically transformed. Bland-Altman plots were used to determine the 95% limits of agreement. RESULTS: For MAIA, the 95% limits of agreement were ±0.84 log deg2 for the BE and ±0.66 log deg2 for the WE. Similarly, for the MP1 these limits were ±0.48 log deg2 for the BE and ±0.72 log deg2 for the WE. Inter-device repeatability was modest, ±1.09 log deg2 for the BE and ±1.01 log deg2 for the WE, and a proportional bias was detected. Occasionally, MAIA did not register all the expected number of data points, and included far outliers in the BCEA calculation; the inter-device repeatability did not improve when these outliers were removed. CONCLUSIONS: Repeatability of 20 s-duration fixation stability examination in patients with central vision loss is specific to the instrument used. We recommend that only data from same type of microperimeter with the same fixation duration should be compared when using fixation stability as an outcome measure to monitor disease progression, effect of treatment or in clinical trials.

A DOUBLE-MASKED, RANDOMIZED, SHAM-CONTROLLED, SINGLE-CENTER STUDY WITH PHOTOBIOMODULATION FOR THE TREATMENT OF DRY AGE-RELATED MACULAR DEGENERATION.

PURPOSE: The LIGHTSITE I study investigated the efficacy and safety of photobiomodulation (PBM) treatment in subjects with dry age-related macular degeneration. METHODS: Thirty subjects (46 eyes) were treated with the Valeda Light Delivery System, wherein subjects underwent two series of treatments (3× per week for 3-4 weeks) over 1 year. Outcome measures included best-corrected visual acuity, contrast sensitivity, microperimetry, central drusen volume and drusen thickness, and quality of life assessments. RESULTS: Photobiomodulation-treated subjects showed a best-corrected visual acuity mean letter score gain of 4 letters immediately after each treatment series at Month 1 (M1) and Month 7 (M7). Approximately 50% of PBM-treated subjects showed improvement of ≥5 letters versus 13.6% in sham-treated subjects at M1. High responding subjects (≥5-letter improvement) in the PBM-treated group showed a gain of 8 letters after initial treatment (P < 0.01) and exhibited earlier stages of age-related macular degeneration disease. Statistically significant improvements in contrast sensitivity, central drusen volume, central drusen thickness, and quality of life were observed (P < 0.05). No device-related adverse events were reported. CONCLUSION: Photobiomodulation treatment statistically improved clinical and anatomical outcomes with more robust benefits observed in subjects with earlier stages of dry age-related macular degeneration. Repeated PBM treatments are necessary to maintain benefits. These pilot findings support previous reports and suggest the utility of PBM as a safe and effective therapy in subjects with dry age-related macular degeneration.

ADVERSE EVENTS OF THE ARGUS II RETINAL PROSTHESIS: Incidence, Causes, and Best Practices for Managing and Preventing Conjunctival Erosion.

PURPOSE: To analyze and provide an overview of the incidence, management, and prevention of conjunctival erosion in Argus II clinical trial subjects and postapproval patients. METHODS: This retrospective analysis followed the results of 274 patients treated with the Argus II Retinal Prosthesis System between June 2007 and November 2017, including 30 subjects from the US and European clinical trials, and 244 patients in the postapproval phase. Results were gathered for incidence of a serious adverse event, incidence of conjunctival erosion, occurrence sites, rates of erosion, and erosion timing. RESULTS: Overall, 60% of subjects in the clinical trial subjects versus 83% of patients in the postapproval phase did not experience device- or surgery-related serious adverse events. In the postapproval phase, conjunctival erosion had an incidence rate of 6.2% over 5 years and 11 months. In 55% of conjunctival erosion cases, erosion occurred in the inferotemporal quadrant, 25% in the superotemporal quadrant, and 20% in both. Sixty percent of the erosion events occurred in the first 15 months after implantation, and 85% within the first 2.5 years. CONCLUSION: Reducing occurrence of conjunctival erosion in patients with the Argus II Retinal Prosthesis requires identification and minimization of risk factors before and during implantation. Implementing inverted sutures at the implant tabs, use of graft material at these locations as well as Mersilene rather than nylon sutures, and accurate Tenon's and conjunctiva closure are recommended for consideration in all patients.

Reading with central vision loss: binocular summation and inhibition.

PURPOSE: There are conflicting reports as to whether there is a binocular advantage or disadvantage when reading with central vision loss. This study examined binocular reading summation in patients with macular degeneration. METHODS: Seventy-one patients with bilateral central vision loss [mean age: 63 (S.D. = 21) years] participated. Reading performances during binocular and monocular viewing with the better eye (i.e., the eye with the best monocular visual acuity) were evaluated using different versions of the Italian MNREAD reading chart (www.precision-vision.com). Fixation stability and preferred retinal loci (PRLs) were recorded monocularly for each eye. The overall sample was split into inhibition, equality, and summation groups based on the binocular ratio (i.e., binocular/monocular) of the maximum reading speed. RESULTS: 41% of patients experienced binocular inhibition, 42% summation, and 17% equality. Binocular reading speed of the inhibition group was approximately 30 words per minute slower than those of the equality and summation groups, although the inhibition group had the best visual acuity. These patients generally had monocular PRLs in non-corresponding locations temporal or nasal to the scotoma, had the largest interocular acuity difference and lacked residual stereopsis. The three groups did not differ in fixational control, contrast sensitivity or critical print size. CONCLUSIONS: Equal proportions of patients with central vision loss show binocular reading summation and inhibition. Patients with binocular reading inhibition have poorer reading performance and different clinical characteristics than those with binocular reading summation and equality.

RETINAL DETACHMENT AND RETROBULBAR CYSTS IN A LARGE COHORT OF OPTIC NERVE COLOBOMA.

PURPOSE: To examine the relationship between retinal detachment and retrobulbar cysts in patients with optic nerve coloboma (ONC) and Morning Glory syndrome (MGS). METHODS: Patients diagnosed with either ONC or MGS were identified through a search of the Sick Kids database. Seventy-one patients either agreed to come in for a B-scan or had an incidental orbital B-scan or magnetic resonance imaging or both. Eyes with orbital B-scan ultrasound and/or magnetic resonance imaging images were assessed independently by two ophthalmologists and a radiologist for the presence of retrobulbar cysts. Retinal detachment was identified clinically with either indirect ophthalmoscopy or from fundus photographs. RESULTS: Forty-five of 71 (63%) and 26/71 (37%) patients had ONC and MGS, respectively. Retinal detachment occurred significantly more often in eyes with MGS than with ONC (9/17 [53%] vs. 5/45 [11%], P = 0.03, respectively). Retrobulbar cysts were not detected more often in MGS than in ONC (11/45 [24%] vs. 7/26 [27%]; P = 1.0). Eyes with retrobulbar cysts were significantly more likely to be associated with retinal detachment than those without (7/18 [39%] vs. 7/53 [13%]; P = 0.04). CONCLUSION: Retinal detachment occurs more frequently in MGS than in ONC in a cohort of patients referred to a specialist children's retinal service. Eyes with retrobulbar cysts are more likely to be associated with retinal detachment.

Worldwide Argus II implantation: recommendations to optimize patient outcomes.

BACKGROUND: A position paper based on the collective experiences of Argus II Retinal Prosthesis System investigators to review strategies to optimize outcomes in patients with retinitis pigmentosa undergoing retinal prosthesis implantation. METHODS: Retinal surgeons, device programmers, and rehabilitation specialists from Europe, Canada, Middle East, and the United States were convened to the first international Argus II Investigator Meeting held in Ann Arbor, MI in March 2015. The recommendations from the collective experiences were collected. Factors associated with successful outcomes were determined. RESULTS: Factors leading to successful outcomes begin with appropriate patient selection, expectation counseling, and preoperative retinal assessment. Challenges to surgical implantation include presence of staphyloma and inadequate Tenon's capsule or conjunctiva. Modified surgical technique may reduce risks of complications such as hypotony and conjunctival erosion. Rehabilitation efforts and correlation with validated outcome measures following implantation are critical. CONCLUSIONS: Bringing together Argus II investigators allowed the identification of strategies to optimize patient outcomes. Establishing an on-line collaborative network will foster coordinated research efforts to advance outcome assessment and rehabilitation strategies.

Genetic Risk Evaluation in Wet Age-Related Macular Degeneration Treatment Response.

OBJECTIVE: To evaluate the pharmacogenetic relationship between CFH haplotypes and single nucleotide polymorphisms (SNPs) with response to ranibizumab treatment for neovascular age-related macular degeneration (nAMD). PATIENTS AND METHODS: This was a prospective cohort study involving 70 treatment-naive nAMD patients. Patients were genotyped for CFH haplotypes and SNPs in the C3, ARMS2, and mtDNA genes. Visual acuity and central macular thickness were assessed at baseline and during 6 monthly follow-up visits. Multivariate logistic regression was used to determine the association between genotypes and a gain of ≥15 letters at the 6-month endpoint after adjusting for potential confounders. RESULTS: CFH haplotypes were associated with a gain of ≥15 letters at the 6-month endpoint (p = 0.046). Patients expressing protective haplotypes were more likely to achieve a gain of ≥15 letters relative to the greatly increased risk haplotypes [OR 6.58 (95% CI: 1.37, 31.59)]. CONCLUSION: CFH is implicated in nAMD patient treatment response to ranibizumab.

TREAT-AND-EXTEND REGIMENS WITH ANTI-VEGF AGENTS IN RETINAL DISEASES: A Literature Review and Consensus Recommendations.

PURPOSE: A review of treat-and-extend regimens (TERs) with intravitreal anti-vascular endothelial growth factor agents in retinal diseases. METHODS: There is a lack of consensus on the definition and optimal application of TER in clinical practice. This article describes the supporting evidence and subsequent development of a generic algorithm for TER dosing with anti-vascular endothelial growth factor agents, considering factors such as criteria for extension. RESULTS: A TER algorithm was developed; TER is defined as an individualized proactive dosing regimen usually initiated by monthly injections until a maximal clinical response is observed (frequently determined by optical coherence tomography), followed by increasing intervals between injections (and evaluations) depending on disease activity. The TER regimen has emerged as an effective approach to tailoring the dosing regimen and for reducing treatment burden (visits and injections) compared with fixed monthly dosing or monthly visits with optical coherence tomography-guided regimens (as-needed or pro re nata). It is also considered a suitable approach in many retinal diseases managed with intravitreal anti-vascular endothelial growth factor therapy, given that all eyes differ in the need for repeat injections. CONCLUSION: It is hoped that this practical review and TER algorithm will be of benefit to health care professionals interested in the management of retinal diseases.

Bilateral Panuveitis Associated with Morvan Syndrome: A Case Report and Review of the Literature.

PURPOSE: Morvan syndrome (MoS) is a neurologic disorder belonging to a spectrum of autoimmune encephalitis, Contactin-associated protein-like 2 (Caspr2) antibody syndrome. We report a case of bilateral panuveitis associated with MoS. METHODS: Case report and review of the literature. RESULTS: A 57-year-old male with Morvan syndrome presented with painless vision loss and floaters. Initial visual acuities were 20/50 and 20/60. Hallmarks of this uveitis included persistently active vitritis, and nonhemorrhagic retinitis with nonperfusion and neovascularization. Uveitis consistently flared with attempted immunosuppressive tapers. Vision deteriorated to count fingers (2 ft) OU over 2.5 years despite corticosteroids, mycophenolate mofetil, intravenous immunoglobulin, adalimumab, and rituximab. Explanations for reduced final visual acuity included macular atrophy, disruption of retinal architecture, epiretinal membrane, vitritis, and cataract. CONCLUSIONS: This case constitutes the first report of uveitis associated with MoS and Caspr2 antibody syndrome, raising the question of autoimmunity targeting the retinal inner and/or outer plexiform layers.

Incidence of endophthalmitis and use of antibiotic prophylaxis after intravitreal injections.

PURPOSE: To report the incidence of endophthalmitis in association with different antibiotic prophylaxis strategies after intravitreal injections of anti-vascular endothelial growth factors and triamcinolone acetonide. DESIGN: Retrospective, comparative case series. PARTICIPANTS: Fifteen thousand eight hundred ninety-five intravitreal injections (9453 ranibizumab, 5386 bevacizumab, 935 triamcinolone acetonide, 121 pegaptanib sodium) were reviewed for 2465 patients between January 5, 2005, and August 31, 2010. The number of injections was determined from billing code and patient records. METHODS: The indications for injection included age-related macular degeneration, diabetic macular edema, central and branch retinal vein occlusion, and miscellaneous causes. Three strategies of topical antibiotic prophylaxis were used by the respective surgeons: (1) antibiotics given for 5 days after each injection, (2) antibiotics given immediately after each injection, and (3) no antibiotics given. MAIN OUTCOME MEASURES: The primary outcome measures were the incidence of culture-positive endophthalmitis and culture-negative cases of suspected endophthalmitis. RESULTS: Nine eyes of 9 patients with suspected endophthalmitis after injection were identified. Three of the 9 cases had culture-positive results. The overall incidence of endophthalmitis was 9 in 15 895. The incidence of culture-negative cases of suspected endophthalmitis and culture-proven endophthalmitis after injection was 6 in 15 895 and 3 in 15 895, respectively. Taking into account both culture-positive endophthalmitis and culture-negative cases of suspected endophthalmitis, the incidence per injection was 5 in 8259 for patients who were given antibiotics for 5 days after injection, 2 in 2370 for those who received antibiotics immediately after each injection, and 2 in 5266 who received no antibiotics. However, if considering culture-proven endophthalmitis alone, the use of topical antibiotics, given immediately or for 5 days after injection, showed lower rates of endophthalmitis compared with those without postinjection antibiotics. The risk of endophthalmitis after intravitreal injection varied among agents that were used. Among the 9 cases of clinically suspected endophthalmitis, regardless of prophylactic strategies used, the incidence of endophthalmitis per injection was 2 in 935 for triamcinolone acetonide, 3 in 9453 for ranibizumab, and 4 in 5386 for bevacizumab. CONCLUSIONS: The overall rate of intravitreal injection-related endophthalmitis is greater with the use of topical antibiotics, given immediately or for 5 days after the injection, compared with no antibiotics.

A prospective randomized clinical trial comparing nepafenac, intravitreal triamcinolone and no adjuvant therapy for epiretinal membrane.

PURPOSE: To compare the efficacy of topical nepafenac 0.1% versus intravitreal triamcinolone acetonide (IVTA) at the conclusion of vitrectomy surgery versus no adjuvant therapy (NAT) in improving macular morphology post-operatively in patients undergoing vitrectomy for epiretinal membrane (ERM), as measured by optical coherence tomography (OCT) imaging and best-corrected visual acuity (BCVA). METHODS: Design: Prospective randomized clinical trial Setting: Multi-centre 80 patients scheduled to undergo vitrectomy surgery for idiopathic ERM were randomized to receive either IVTA (4 mg/0.1 cc) at the end of surgery, topical nepafenac sodium 0.1% TID for 1 month post-operation or no adjuvant treatment (NAT). Optical coherence tomography (OCT) imaging, best-corrected visual acuity and intraocular pressure (IOP) were measured before surgery, and 1 and 2 months post-operation. RESULTS: Although all three groups showed reduction in macular thickness post-operation, the NAT group showed the most improvement, with a reduction of 136.18 ± 29.84 µm at two months. There was no statistically significant difference in macular thickness between the groups at each time point, p = 0.158. The NAT group also had the best recovery in BCVA with an improvement of 0.207 logMAR (10.35 letters) at two months post-operation. There was no statistically significant difference in BCVA between the groups, p = 0.606. There was statistically significant difference in the IOP between the three groups, p = 0.04 only at 1-month visit. The IVTA group had the highest rise in average IOP at both 1 and 2 months post-operation (2.72 and 1.58 mmHg, respectively). CONCLUSION: Our study data suggest there was no advantage in the use of topical nepafenac or IVTA for post-vitrectomy ERM surgery.

Stable oxime-crosslinked hyaluronan-based hydrogel as a biomimetic vitreous substitute.

Vitreous substitutes are clinically used to maintain retinal apposition and preserve retinal function; yet the most used substitutes are gases and oils which have disadvantages including strict face-down positioning post-surgery and the need for subsequent surgical removal, respectively. We have engineered a vitreous substitute comprised of a novel hyaluronan-oxime crosslinked hydrogel. Hyaluronan, which is naturally abundant in the vitreous of the eye, is chemically modified to crosslink with poly(ethylene glycol)-tetraoxyamine via oxime chemistry to produce a vitreous substitute that has similar physical properties to the native vitreous including refractive index, density and transparency. The oxime hydrogel is cytocompatible in vitro with photoreceptors from mouse retinal explants and biocompatible in rabbit eyes as determined by histology of the inner nuclear layer and photoreceptors in the outer nuclear layer. The ocular pressure in the rabbit eyes was consistent over 56 d, demonstrating limited to no swelling. Our vitreous substitute was stable in vivo over 28 d after which it began to degrade, with approximately 50% loss by day 56. We confirmed that the implanted hydrogel did not impact retina function using electroretinography over 90 days versus eyes injected with balanced saline solution. This new oxime hydrogel provides a significant improvement over the status quo as a vitreous substitute.

Risk factors for acute endophthalmitis after cataract surgery: a population-based study.

OBJECTIVE: To identify risk factors for suspected acute endophthalmitis after cataract surgery. DESIGN: Population-based retrospective cohort. PARTICIPANTS: Administrative data from more than 440,000 consecutive cataract surgeries in Ontario, Canada, from April 1, 2002, to March 31, 2006. METHODS: Consecutive physician billing claims for cataract surgery and specific intraoperative and postoperative procedures related to complications of cataract surgery were identified. Acute endophthalmitis was defined using surrogate markers for intraocular infection, including vitrectomy, vitreous injection, or aspiration procedures not in combination with air/fluid exchange or dislocated lens extraction, performed 1 to 14 days after cataract surgery. Anterior vitrectomy performed on the day of surgery was used as a surrogate marker for capsular rupture. MAIN OUTCOME MEASURES: Overall rates of endophthalmitis were calculated and grouped by patient demographics, surgical facility, season, year, and association with capsular rupture. RESULTS: There were 617 suspected acute endophthalmitis cases of 442,177 cataract surgeries over the 4 years. The overall unadjusted and adjusted rates of suspected acute endophthalmitis were both 1.4 per 1000 cataract surgeries. Men had higher rates than women (1.70 vs. 1.19/1000 surgeries, P<0.0001) with an adjusted odds ratio of 1.40 (95% confidence interval, 1.19-1.64).The oldest age group (>or= 85 years) had the highest rate (2.18/1000), and the youngest group (20-64) had the second highest rate (1.76/1000). The endophthalmitis rates for these age groups were significantly different from those aged 65 to 84 years. The endophthalmitis rate was approximately 10-fold higher in those with capsular rupture compared with those without (13.11 vs. 1.34/1000, P<0.0001), with an adjusted odds ratio of 9.56 (95% confidence interval, 6.43-14.2). CONCLUSIONS: The overall rates of suspected acute endophthalmitis are low but significantly higher in certain patient groups. Our population-based analysis can be used as a benchmark for quality-improvement initiatives and can assist clinicians in educating their patients regarding the risks associated with cataract surgery. Future work is required to address the higher rate of endophthalmitis in men, those with capsular rupture, and the oldest patients undergoing cataract surgery.

Retinal arteriolar hemodynamic response to a combined isocapnic hyperoxia and glucose provocation in early sight-threatening diabetic retinopathy.

PURPOSE: To quantify the magnitude of change of retinal arteriolar hemodynamics induced by a combined isocapnic hyperoxia and glucose provocation in diabetic patients with early sight-threatening diabetic retinopathy (DR) and in age-matched control subjects and to compare the response to that of an isocapnic hyperoxia provocation alone. The study hypothesis was that hyperglycemia reduces the retinal vascular reactivity response to a hyperoxic stimulus. METHODS: The sample comprised 17 control subjects (group 1), 15 patients with no clinically visible DR (group 2), 16 patients with mild-to-moderate nonproliferative DR (group 3), and 15 patients with diabetic macular edema (group 4). Retinal hemodynamic measurements were acquired in the subjects, at baseline and 1 hour after consuming a standardized oral glucose load drink while breathing oxygen isocapnic with baseline. RESULTS: Retinal blood velocity and flow significantly decreased in all groups (P < or = 0.001 and P < or = 0.0002, respectively) in response to a combined isocapnic hyperoxia and glucose provocation. The maximum-to-minimum velocity ratio significantly increased (P < or = 0.005), and wall shear rate (WSR) significantly decreased (P < or = 0.0002), in groups 1, 2, and 3, but not in group 4. The vascular reactivity response was not significantly different across the groups. The control group demonstrated a reduced change in flow (P = 0.009) and WSR (P = 0.010) to the combined isocapnic hyperoxia and glucose provocation compared with that of hyperoxia alone. CONCLUSIONS: The vascular reactivity response to a combined isocapnic hyperoxia and glucose provocation produced a pronounced reduction in blood flow. Unlike the response to hyperoxia alone, the vascular reactivity response was not significantly different across the groups. Hyperglycemia reduced the retinal vascular reactivity response to hyperoxia in age-matched control subjects.

Rehabilitation of lost functional vision with the Argus II retinal prosthesis.

The Argus II retinal prosthesis is the first commercially available device for restoration of vision in patients with Retinitis Pigmentosa or with similar retinal pathology who still have minimal residual native vision. The technology is able to restore vision with production of artificial visual percepts which usually are given adequate useful interpretation by the visual system in most implanted patients. The technology usually produces visual perception at the level of shape identification or better in some cases enabling in many less dependence on vision substitution devices and skills. There is no consensus among vision rehabilitation practitioners on single methods for assessments, outcome measures and training, yet there is constant progress in these areas of concern. Hence the current vision rehabilitation practice related to the implantation of the Argus II retinal prosthesis is a work in progress with many learning opportunities for all involved. All agree that implementation of this technology in clinical practice requires the combined work of a multi-disciplinary team which includes a specialized surgical team as well as a specialized rehabilitation team in order to obtain optimal results. Our own experience is presented in this paper and indicates so far that the Argus II technology is beneficial to patients and that it could be successfully managed within the Canadian heath care system.

The Toronto experience with the Argus II retinal prosthesis: new technology, new hope for patients.

Surgical restoration of vision with retinal prostheses is a new and developing technology currently available in a select group of countries, Canada among them. The Argus II retinal prosthesis is the first commercially available device for restoration of vision in patients with Retinitis Pigmentosa or with similar retinal pathology who still have minimal residual native vision. The surgery is complex and requires training however it is within the abilities of any experienced retina surgeon. Surgical experience builds up with each case and in our patients length of surgery constantly went down. Complications occurred however we experienced no catastrophic events. Most notable is that in our implanted cases the Argus II technology proved to be beneficial to most patients. In order to obtain optimal results with this surgical intervention it is absolutely required that the surgical work is complemented simultaneously with the work of a specialized rehabilitation team. A review of the technology, of our experience, comments and concerns is presented in this paper.

Retinal hemodynamics in early diabetic macular edema.

The objective of this study was to establish the baseline retinal hemodynamic characteristics of stratified groups of diabetic patients at increasing risk for the development of diabetic macular edema (DME). Group 1 had 50 control subjects, group 2 had 56 diabetic patients without clinically visible retinopathy, group 3 had 54 diabetic patients with microaneurysms and/or hard exudates within two disc diameters of the fovea in the absence of clinically manifest DME, and group 4 had 40 patients with clinically manifest DME. Retinal hemodynamics (diameter, velocity, maximum-to-minimum velocity ratio, and flow) were assessed. Intraocular pressure, blood pressure, and relevant systemic markers of diabetes control and complications were also undertaken. The maximum-to-minimum velocity ratio was elevated with increasing risk of clinically significant DME (P < 0.0001). No significant differences were found between the groups with respect to diameter, velocity, or flow. The maximum-to-minimum velocity ratio was correlated to age, duration of diabetes, blood pressure, pulse rate, intraocular pressure, and serum potassium levels. In conclusion, the maximum-to-minimum velocity ratio was significantly increased with increasing risk of development of DME. Retinal arteriolar hemodynamics were positively correlated to age, duration of diabetes, and blood pressure. These findings suggest a reduction in the compliance (i.e., an increase of vascular rigidity) of the arteriolar circulation with increasing risk of DME.