Archive for 2015

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)


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)


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)


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)


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.


Incidence, Progression, and Associated Risk Factors of Medium Drusen in Age-Related Macular Degeneration

Findings From the 15-Year Follow-up of an Australian Cohort

Early age-related macular degeneration (AMD) is characterized by the presence of drusen and retinal pigmentary abnormalities.1,2 Drusen vary in size (diameter range, ≤63 to ≥250 μm) and type (hard, soft, distinct, and indistinct). Pigmentary abnormalities include clusters of pigment granules within the sensory retina (increased pigmentation) and sharply demarcated areas of retinal pigment epithelium (RPE) depigmentation.

The international classification and grading system for AMD categorizes medium drusen as intermediate soft drusen, defined as drusen with a maximum diameter of 63 to less than 125 μm, larger than the maximum diameter of hard drusen (‹63 μm) but smaller than the minimum diameter of large soft drusen (≥ 125 μm).1 A similar definition of this drusen type was used by the Age-Related Eye Disease Study2 and clinical classification system,3 categorized as medium drusen. urthermore, the Wisconsin Age-Related Maculopathy Grading System4 defines medium drusen by the maximum diameter, although the categorization of medium drusen is not used. In this study, we describe this type of drusen as medium drusen.

Despite recent interest in medium drusen and their inclusion in AMD incidence studies,5,6 knowledge of the associated risk factors and the progression of medium drusen is limited. Medium drusen have been underrepresented in studies3,7-9 compared with large drusen, soft drusen, and pigmentary lesions. In this study, we aimed to assess the 15-year incidence and progression of medium drusen in an older Australian cohort, as well as associations between common AMD risk factors and the development and progression of medium drusen.

Full Paper: Incidence, Progression, and Associated Risk Factors of Medium Drusen in Age-Related Macular Degeneration
(200K PDF)


Influence of the Vitreomacular Interface on Treatment Outcomes in the Comparison of Age-Related Macular Degeneration Treatments Trials

The role of the vitreomacular interface (VMI) in the pathophysiologic features and treatment of neovascular age-related macular degeneration (AMD) has generated much recent interest. In retrospective and prospective observational case series, a higher prevalence of vitreomacular adhesion (VMA) has been reported in eyes with neovascular AMD compared with eyes with nonneovascular AMD.1-3 In a paired eye study, VMA was observed more frequently in eyes with neovascular AMD compared with the fellow nonneovascular AMD eye that served as a control.4 Some investigators also have observed that VMA occurs at the vitreoretinal interface overlying the choroidal neovascularization (CNV).1,2,4 Vitreomacular adhesion also influences treatment and outcomes in neovascular AMD; the absence of VMA has been associated with slightly better visual acuity (VA),5,6 and eyes with VMA may require more frequent dosing compared with neovascular AMD eyes without VMA.5,6 This combined body of evidence suggests thatVMA may have a role in the pathogenesis and management of CNV.

The purpose of our study was to assess the relationship of the VMI to treatment frequency in neovascular AMD, as well as to VA and anatomic outcomes in the Comparison of AMD Treatments Trials (CATT),7 one of the largest prospective treatment trials for neovascular AMD conducted to date.

Full Paper: Influence of the Vitreomacular Interface on Treatment Outcomes in the Comparison of Age-Related Macular Degeneration Treatments Trials
(319K PDF)


Prevalence of Intermediate-Stage Age-Related Macular Degeneration in Patients With Acquired Immunodeficiency Syndrome

AGE-RELATED MACULAR DEGENERATION (AMD) IS the leading cause of late-onset visual impairment and blindness in persons over 65 years of age.1,2 Age-related macular degeneration is staged as early, intermediate, or late. Small drusen are the hallmark of earlystage AMD; intermediate-stage AMD consists of extensive medium-size drusen or any large drusen, with or without pigment changes. Late-stage AMD is defined by either choroidal neovascularization or geographic atrophy.3–6 In the United States, it is estimated that ~1.2 million persons have neovascular AMD; 970,000 have geographic atrophy; and 8 million have intermediate-stage AMD.1

Antiretroviral-treated, immune-restored, human immunodeficiency virus (HIV)-infected persons have a marked reduction in opportunistic infections and a substantially increased lifespan compared to those from the era before modern combination antiretroviral therapy.7–10 However, despite the improved immune function and increased lifespan, antiretroviral therapy does not fully restore health. Compared to similarly-aged, non-HIV-infected peers, antiretroviral-treated, immune-restored, HIV-infected persons have a substantially shortened lifespan, largely owing to an increased risk of non–acquired immunodeficiency syndrome (AIDS) diseases associated with aging.11–14 These diseases include cardiovascular disease, non-AIDS cancers, metabolic diseases, and neurocognitive decline, and collectively suggest that antiretroviral-treated, immune-restored HIV infection is associated with an “accelerated/accentuated aging” phenotype.11 Therefore, we undertook to evaluate whether persons with AIDS had an increased prevalence of AMD, using retinal photographs taken at enrollment in the Longitudinal Study of the Ocular Complications of AIDS (LSOCA) cohort.

Full Paper: Prevalence of Intermediate-Stage Age-Related Macular Degeneration in Patients With Acquired Immunodeficiency Syndrome
(340K PDF)


Genetic Testing for Age-Related Macular Degeneration Not Indicated Now

Age-related macular degeneration is a very common condition that is caused by a complex interplay of genetic and environmental factors. It is likely that, in the future, genetic testing will allow physicians to achieve better clinical outcomes by administering specific treatments to patients based on their genotypes. However, improved outcomes for genotyped patients have not yet been demonstrated in a prospective clinical trial, and as a result, the costs and risks of routine genetic testing currently outweigh the benefits for patients with age-related macular degeneration.

Full Paper: Genetic Testing for Age-Related Macular Degeneration Not Indicated Now
(197K PDF)


Repeated Intravitreous Ranibizumab Injections for Diabetic Macular Edema and the Risk of Sustained Elevation of Intraocular Pressure or the Need for Ocular Hypotensive Treatment


For the management of retinal disease, the use of intravitreous injections of anti–vascular endothelial growth factor has increased. Recent reports have suggested that this therapymay cause sustained elevation of intraocular pressure (IOP) and may potentially increase the risk of glaucoma for patients with retinal disease. OBJECTIVE To assess the risk of sustained IOP elevation or the need for IOP-lowering treatments for eyes with diabetic macular edema following repeated intravitreous injections of ranibizumab.

Design, Setting, and Participants

An exploratory analysiswas conducted within a Diabetic Retinopathy Clinical Research Network randomized clinical trial. Study enrollment dates were from March 20, 2007, to December 17, 2008. Of 582 eyes (of 486 participants) with center-involved diabetic macular edema and no preexisting open-angle glaucoma, 260 were randomly assigned to receive a sham injection plus focal/grid laser treatment, and 322 were randomly assigned to receive ranibizumab plus deferred or prompt focal/grid laser treatment.

Main Outcomes and Measures

The cumulative probability of sustained IOP elevation, defined as IOP of at least 22mmHg and an increase of at least 6mmHg from baseline at 2 consecutive visits, or the initiation or augmentation of ocular hypotensive therapy, through 3 years of follow-up.


The mean (SD) baseline IOP in both treatment groups was 16 (3)mmHg (range, 5-24mmHg). The cumulative probability of sustained IOP elevation or of initiation or augmentation of ocular hypotensive therapy by 3 years, after repeated ranibizumab injections, was 9.5%for the participants who received ranibizumab plus prompt or deferred focal/grid laser treatment vs 3.4%for the participants who received a sham injection plus focal/grid laser treatment (difference, 6.1%[99%CI, −0.2%to 12.3%]; hazard ratio, 2.9 [99% CI, 1.0-7.9]; P = .01). The distribution of IOP and the change in IOP from baseline at each visit through 3 years were similar in each group.

Conclusions and Relevance

In eyes with center-involved diabetic macular edema and no prior open-angle glaucoma, repeated intravitreous injections of ranibizumab may increase the risk of sustained IOP elevation or the need for ocular hypotensive treatment. Clinicians should be aware of this risk and should consider this information when following up with patients who have received intravitreous injections of anti–vascular endothelial growth factor for the treatment of diabetic macular edema.

Full Paper: Repeated Intravitreous Ranibizumab Injections
(231K PDF)