All posts in Updated Retinal Bulletin

Topical Dorzolamide-Timolol With Intravitreous Anti–Vascular Endothelial Growth Factor for Neovascular Age-Related Macular Degeneration

Importance

There is a subset of eyes with neovascular age-related macular degeneration (AMD) that have persistent exudation despite fixed-interval intravitreous anti–vascular endothelial growth factor (VEGF) injections.

Objective

To evaluate the effect of topical dorzolamide hydrochloride–timolol maleate on anatomic and functional outcomes in eyes with neovascular AMD and incomplete response to anti-VEGF therapy.

Design, Setting, and Participants

An exploratory, prospective single-arm interventional study at a tertiary referral academic private practice. Patients with neovascular AMD and persistent macular edema despite fixed-interval intravitreous anti-VEGF therapy were enrolled. Baseline spectral-domain optical coherence tomography and clinical data, including visual acuity and intraocular pressure, were obtained at enrollment and from one visit before enrollment. The study was performed at the Retina Service of Wills Eye Hospital and the offices of Mid Atlantic Retina from February 1, 2015, through September 30, 2015. Patients were followed up for at least 2 visits after enrollment. Central subfield thickness, maximum subretinal fluid height, and maximum pigment epithelial detachment height from spectral-domain optical coherence tomography were recorded at each visit. INTERVENTIONS Enrolled eyes received a regimen of topical dorzolamide-timolol twice daily and continued to receive the same intravitreous anti-VEGF therapy at the same interval as received before enrollment for the duration of the study.

Main Outcomes and Measures

Change in central subfield thicknesswas the primary outcome measure. Changes in maximum subretinal fluid height, maximum pigment epithelial detachment height, and visual acuity were the secondary outcome measures.

Results

Ten patients (10 eyes) completed the study. The mean age of the patients was 78.2 years (age range, 65-91 years), and 6 were male. Eight eyes received intravitreous aflibercept, and 2 eyes received intravitreous ranibizumab. All study eyes had been receiving long-term anti-VEGF therapy with the same medication before study enrollment for a mean of 21.9 injections. The mean central subfield thickness decreased from 419.7 μmat enrollment to 334.1 μm at the final visit (P = .01). The mean maximum subretinal fluid height decreased from 126.6 μmat enrollment to 49.5 μm at the final visit (P = .02). The mean maximum pigment epithelial detachment height decreased from 277.4 μmat enrollment to 239.9 μmat the final visit (P = .12). The mean logMAR visual acuity were 0.54 at enrollment and 0.48 at the final visit (P = .60).

Conclusions and Relevance

These data suggest that topical dorzolamide-timolol may reduce central subfield thickness and subretinal fluid in eyes with persistent exudation despite consistent, fixed-interval intravitreous anti-VEGF treatment for neovascular AMD.

Full Paper: Topical Dorzolamide-Timolol With Intravitreous Anti–Vascular Endothelial Growth Factor for Neovascular Age-Related Macular Degeneration
(371K PDF)

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Conversion to Aflibercept After Prior Anti-VEGF Therapy for Persistent Diabetic Macular Edema

Diabetic Macular Edema (DME) is the leading cause of visual impairment in patients with diabetic retinopathy.1 In 2010, approximately 20.6 million out of a projected 92.6 million adults with diabetic retinopathy worldwide were estimated to have concurrent DME.2 This global healthcare burden will likely continue to increase at alarming rates, as some models estimate the number of diabetics will double by the year 2030.3

With the Early Treatment Diabetic Retinopathy Study (ETDRS) in the 1980s,4 macular laser photocoagulation became the mainstay of DME management, and it remained the standard of care in the decades that followed. The advent of intravitreal pharmacotherapy agents, primarily driven by the class of vascular endothelial growth factor (VEGF) inhibitors, has since revolutionized how this condition is treated. Validated through the RISE and RIDE phase 3 clinical trials,5 ranibizumab (Lucentis; Genentech, South San Francisco, California, USA) became the first VEGF inhibitor approved by the Food & Drug Administration (FDA) for this indication in 2012.

While off-label, bevacizumab (Avastin; Genentech) has been evaluated through smaller trials, such as the BOLT study.6 Most recently, aflibercept (Eylea; Regeneron, Tarrytown, New York) gained FDA approval to treat DME in July 2014 with the VIVID and VISTA phase 3 clinical trials.7,8

While there is ample evidence supporting the safety and efficacy of the 3 anti-VEGF agents in the management of DME, a head-to-head comparison only recently became available when the Diabetic Retinopathy Clinical Research Network (DRCR) published the 1-year outcomes of its Comparative Effectiveness Study of Intravitreal Aflibercept, Bevacizumab, and Ranibizumab for DME (Protocol T).9 The results demonstrated that when baseline visual acuity (VA) loss was mild (›20/ 40), there was no clinical difference between the 3 medications. However, when the initial acuity loss was more severe (‹20/50), a greater visual benefit was derived from aflibercept.9

Since the FDA approval of aflibercept for DME, and in light of Protocol T’s findings, many retinal specialists are converting eyes from ranibizumab or bevacizumab to aflibercept with the goal of optimizing treatment outcomes, particularly in cases of refractory DME. In the current study, we evaluated the short-term functional and anatomic responses of patients with persistent DME after multiple previous anti-VEGF injections that were converted to aflibercept therapy.

Full Paper: Conversion to Aflibercept After Prior Anti-VEGF Therapy for Persistent Diabetic Macular Edema
(1.78M PDF)

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Lamellar Macular Hole: Two Distinct Clinical Entities?

Purpose

To investigate whether lamellar macular holes can be divided into different subgroups.

Design

Retrospective observational case series.

Methods

In this institutional study, clinical charts and spectral-domain optical coherence tomography (OCT) images of 102 eyes of 90 consecutive patients diagnosed with lamellar macular hole were reviewed. In OCT imaging, the presence of lamellar macular hole was defined according to the following findings: presence of irregular foveal contour, separation of the layers of the neurosensory retina, and the absence of full-thickness macular defect. Mean outcome was the morphologic and functional characterization of different subtypes of macular hole.

Results

Two different subtypes of lamellar macular hole were identified: tractional and degenerative. The first type, tractional, was diagnosed in 43 eyes, and was characterized by the schitic separation of neurosensory retina between outer plexiform and outer nuclear layers. It often presented with an intact ellipsoid layer and was associated with tractional epiretinal membranes and/or vitreomacular traction. The second type, degenerative, was diagnosed in 48 eyes, and its distinctive traits included the presence of intraretinal cavitation that could affect all retinal layers. It was often associated with nontractional epiretinal proliferation and a retinal “bump.” Moreover, it often presented with early ellipsoidal zone defect and its pathogenesis, although chronic and progressive, remains poorly understood. Eleven eyes shared common features with both tractional and degenerative lamellar macular holes and were classified as mixed lesions.

Conclusions

Degenerative and tractional lamellar macular holes may be 2 distinct clinical entities. A revision of the current concept of lamellar macular holes is needed.

Full Paper: Lamellar Macular Hole: Two Distinct Clinical Entities?
(3.56M PDF)

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Association Between Oral Fluoroquinolone Use and Retinal Detachment

Importance

Several studies have focused on the current use of oral fluoroquinolones and the risk for retinal detachment (RD), but the existence of this association is under debate. Given the widespread fluoroquinolone use, investigation of this association is essential.

Objective

To assess the association between oral fluoroquinolone use and the risk for RD, including the rhegmatogenous and exudative types.

Design, Setting, and Participants

This case-crossover study included 27 540 adults with RD from French health care databases from July 1, 2010, through December 31, 2013. Patients with a history of RD or retinal break, endophthalmitis, intravitreal injection, choroidal retinal vitreal biopsy, and human immunodeficiency virus infection or those hospitalized within 6 months of RD were excluded. The risk period of primary interest was current use, defined as exposure to fluoroquinolones within 10 days immediately before RD surgery, according to previous findings. Oral fluoroquinolone use was assumed to start on the day the prescription was dispensed.

Main Outcomes and Measures

Exposure to fluoroquinolones during the risk period (1-10 days) compared with the control period (61-180 days). The association was also assessed regarding use in the recent (11-30 days) and past (31-60 days) intermediate risk period, type of fluoroquinolone, and type of RD.

Results

Of the 27 540 eligible patients (57%men; mean [SD] age, 61.5 [13.6] years), 663 patients with RD were exposed to fluoroquinolones during the observation period, corresponding to 80 cases exposed during the 10-day risk period (10 days before RD) and 583 cases exposed during the control period (61-180 days).We found a significant increased risk for RD during the 10-day period after the dispensing of oral fluoroquinolones, with an adjusted odds ratio of 1.46 (95%CI, 1.15-1.87). The risk was significantly increased for rhegmatogenous and exudative RD, with adjusted odds ratios of 1.41 (95%CI, 1.04-1.92) and 2.57 (95%CI, 1.46-4.53), respectively. Recent and past use of fluoroquinolones were not associated with a higher risk for RD, with adjusted odds ratios of 0.94 (95%CI, 0.78-1.14) and 1.06 (95%CI, 0.91-1.24), respectively.

Conclusions and Relevance

Current oral fluoroquinolone use was associated with an increased risk for RD, including the rhegmatogenous and exudative types. These findings, along with the available literature, suggest an association between fluoroquinolone use and the risk for RD. The nature of this association should be further investigated in future studies.

Full Paper: Association Between Oral Fluoroquinolone Use and Retinal Detachment
(365K PDF)

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Ocular Complications in Children with Diabetes Mellitus

Diabetes mellitus (DM) is a well-known cause of multiple ophthalmic problems in adults, including diabetic retinopathy (DR), macular edema, cataract, refractive change, and microvascular paralytic strabismus. Diabetic retinopathy and macular edema progress to the ultimate ocular complication of blindness in 12 000 to 24 000 new patients each year in the United States, making DM the leading cause of blindness among American adults aged 20 to 74 years.1 The Early Treatment of Diabetic Retinopathy Study and the Diabetic Retinopathy Study demonstrated that early recognition and treatment of diabetic macular edema and proliferative DR (PDR) in patients with DM reduced the risk of moderate and severe vision loss.2,3 Therefore, there has been a fervent public health effort to establish ophthalmic screening regimens for those with DM, beginning at an early age. For a screening program to be worthwhile, it must identify a disease that is asymptomatic and has a cost-effective treatment, conditions that generally are met by DR.

Current guidelines by the American Academy of Ophthalmology encourage annual screening examinations for all patients with type 1 DM to begin 5 years after diagnosis of DM.4 However, the age at diagnosis and prevalence of DR among children are not well established, with varied reports in the literature, and there is a paucity of information about the onset and prevalence of other diabetic ocular complications among children because the majority of studies have focused on DR. Some data are available with regard to modifiable risk factors to prevent the development of ophthalmic complications of DM, but not particularly in the very young. Findings from the Diabetes Control and Complications Trial (DCCT) demonstrated that intensive glucose control in children aged 13 to 17 years with type 1 DM reduced the risk of development of DR by 53%.5,6 The risk of DR seems to increase with increased duration of DM,7-9 but 1 study of DM in young children suggested that development of type 1 DM at a very young age (i.e., ‹5 years) might protect against the development of DR.10 Even less is known about DR risk and incidence among children with type 2 DM, which is an increasingly important population to study given the growing prevalence of children with this disease. In light of our limited knowledge of the age at onset and prevalence of these ocular complications, the clinical effectiveness of annual diabetic eye examinations in children is unclear. We sought to determine the prevalence and onset of ocular pathology among children with DM, including DR, cataract, high refractive error, and strabismus. We also sought to identify potential risk factors for ocular disease and to recommend an updated ophthalmic screening regimen for asymptomatic children with DM on the basis of our study results and a review of the literature.

Full Paper: Ocular Complications in Children with Diabetes Mellitus
(365K PDF)

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Early Vitrectomy for Spontaneous Fundus-Obscuring Vitreous Hemorrhage

Acute, Spontaneous Posterior Vitreous Detachment (PVD) has been associated with a reported 10%–15% incidence of retinal tears.1 However, when acute PVD is associated with vitreous hemorrhage, the incidence of retinal tears rises to reported rates of 54%–91%.2–8

In the setting of a dense fundus-obscuring vitreous hemorrhage, the clinical examination is made more difficult by an inability to visualize the fundus. In these cases, B-scan ophthalmic ultrasonography is used to rule out an underlying retinal tear or detachment. Studies looking at the accuracy of ultrasonography in determining the presence of retinal tears have demonstrated variable results.9,10

Given the high risk of underlying retinal pathology, an important consideration becomes whether early surgical intervention with pars plana vitrectomy (PPV) results in improved visual and anatomic outcomes as compared to careful monitoring. The decision to intervene must balance the risks of vitrectomy vs the risk of missing an underlying tear and not responding in a timely fashion.11–13

Several noncomparative studies have looked at the question of appropriate patient management in patients with an acute dense vitreous hemorrhage in the setting of PVD. One retrospective observational case series concluded that the incidence of underlying pathology is high but close observation is appropriate in many cases, except in those individuals who have a history of retinal detachment in the contralateral eye.14 Two studies analyzed patients treated with early vitrectomy and concluded that surgical management is both safe and effective.15,16 A gap in the literature has been a study comparing 2 management approaches in a similar setting. We set out to design a comparative analysis to determine whether, in patients presenting with a dense, fundus-obscuring vitreous hemorrhage from presumed PVD, early surgical intervention results in improved patient outcomes.

Full Paper: Early Vitrectomy for Spontaneous Fundus-Obscuring Vitreous Hemorrhage
(406K PDF)

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The Effects of Cataract Surgery on Patients With Wet Macular Degeneration

Age-related Macular Degeneration (AMD) and cataract are common causes of vision loss in our aging population. Recent advances in the treatment of wet AMD have succeeded to either stabilize or improve vision in a large proportion of cases.1–4 It is therefore not uncommon for wet AMD patients to develop visually significant cataracts. However, there is concern about proceeding with cataract surgery in patients with wet AMD, as there may be a risk of exacerbating choroidal neovascularization (CNV) or progressing geographic atrophy.

There is little evidence in the current literature to aid the decision to proceed with cataract surgery in patients undergoing active treatment for wet AMD. Concern exists that intraocular pressure fluctuations and increased inflammatory mediators associated with uncomplicated cataract surgery may disrupt or further stimulate delicate neovascular vessels. Adverse events related to worsening wet AMD may lead to poorer visual outcome or increased AMD treatment demands, requiring further cost and clinic visits for the patient.

Our study aims to evaluate the visual outcomes and possible complications of cataract surgery in patients with wet AMD. This is the first study to include a control arm and an examination of specific optical coherence tomography (OCT) features.

Full Paper: The Effects of Cataract Surgery on Patients With Wet Macular Degeneration
(464K PDF)

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Phenotypic Characterization of Complement Factor H R1210C Rare Genetic Variant in Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is a complex disorder triggered by a wide range of environmental and genetic risk factors.1-3 Numerous common variants are known markers of AMD including several complement pathway genes: complement factor H (CFH),4-8 complement factor I,9 complement component 2, complement factor B,7,10 and complement 3.11

We previously reported the association of a rare CFH variant with AMD, R1210C, which is the strongest genetic risk factor to date, with an odds ratio (OR) of 20.12,13 The R1210C variant is also known to be associated with inherited forms of atypical hemolytic uremic syndrome and primary glomerulonephritis.14-21 In addition to linking 2 clinically unrelated conditions, such as AMD and atypical hemolytic uremic syndrome,the R1210C finding suggests that compromised function of the factorH protein is involved in AMD pathogenesis as a causal factor and not merely as an associated factor.12

In that initial report, the R1210C rare variant was associated with an earlier age at diagnosis of advanced AMD.12 This variant is also significantly associated with progression from early or intermediate AMD to advanced stages in a multigene prediction model.22,23 However, the fundus phenotype typically related to the variant is still to be determined. This knowledge is needed to better understand the manifestations of this rare CFH mutation and to help detect and characterize this phenotype in clinical practice. Identification of such high-risk individuals will be important for screening, potential new therapeutic strategies, and personalized medicine. Therefore, the objective of this study, conducted from 2012 to 2014, was to determine specific fundus features of a white population carrying the CFH R1210C rare variant.

Full Paper: Phenotypic Characterization of Complement Factor H R1210C Rare Genetic Variant in Age-Related Macular Degeneration
(461K PDF)

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Progressive Atrophy in AMD Even With Treatment

Anti-VEGF therapies in many patients with wet age-related macular degeneration go on to develop atrophy. The speculation for causes of this are:

  1. Natural progression of underlying age-related macular degeneration driving the atrophy.
  2. Atrophy is associated with choroidal neovascularization.
  3. Atrophy is associated with anti-VEGF therapy independent of choroidal neovascularization.

No answers to these theories are yet available, so we should not change how we treat patients. We should, however, advise patients that treating wet age-related macular degeneration may not stop the progression of their underlying dry age-related macular degeneration.

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