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
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
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
AUTOSOMAL RECESSIVE STARGARDT DISEASE (STGD1) is the most common inherited juvenile macular degeneration.1 Most patients develop bilateral loss of vision in childhood or early adulthood. This subtype of Stargardt disease is caused by mutations in the ABCA4 gene, which encodes a retina-specific transporter protein (ABCR) in the rims of rod and cone photoreceptor outer segment discs.2–4 Retinal degeneration in ABCA4-linked Stargardt disease is believed to result from the toxic effects of lipofuscin that accumulates in the retinal pigment epithelium (RPE) and the subsequent degeneration of photoreceptors.5
Light can induce photochemical injury at the ocular fundus. Depending on the level and duration of the irradiance, the primary site of damage can be either the photoreceptors or the RPE.6 In ABCA4-linked retinopathies, products generated by the visual cycle accumulate and contribute to retinal damage via both direct toxic effects and increased photosensitivity. A major fluorophore of lipofuscin, bis-retinoid N-retinylidene-N-retinyl-ethanolamine (A2E), accumulates with other, currently unidentified lipofuscin constituents within the RPE.7–9 Thus, an excessive accumulation of A2E has been observed in both Abca4-/- mice and patients with Stargardt disease.5,10 Lipofuscins (and A2E in particular) are potent photosensitizers11–14 that can induce oxidative damage, thereby accelerating light-induced retinal damage and RPE atrophy.14–16 This oxidative damage may affect the rate of disease progression in patients with Stargardt disease…
Full Paper: The Effect of Light Deprivation in Patients With Stargardt Disease
It is the intent of this Update to provide you with information that is practical and useful in answering your patient’s questions in your clinical practice. To that end, we present new and emerging data regarding the studies being done with antiangiogenic agents, combination therapies, pharmacological and surgical management of age-related macular degeneration. We will also include review of gene testing and gene therapy, vitamin therapy for age-related macular degeneration, emerging developments in ocular imaging, artificial vision, diabetic retinopathy update, and an induced pluripotent stem cell update.
In addition to cutting edge research information, clinical findings that are important signs to recognize when following up on patients who have had retinal detachment surgery, treatments for age-related macular degeneration, retinal vein occlusions, and other retinal diseases will be discussed. Emphasis will be placed on clinical signs that are important for re-referral to a retina subspecialist.
Practical application to your daily practices will be our focus so we can all provide the most up-to-date information and care to our patients. Additionally, distilling the research frontiers with the greatest potential for clinical applicability will enable us to give hope to our patients with severe debilitating diseases.
We encourage feedback on ways we can improve our effort to meet your educational and practice needs.
Update [March 2014]
Dr. Radtke’s current newsletter to patients and colleagues.
Development of OCT (optic coherence tomography) has help clinicians gain a better understanding of the critical role played by the vitreous in macular and retinal vascular diseases.
With early-stage PVD (posterior vitreous detachment), fibrocellular organization of vitreous remnants left on the retinal surface during vitreoretinal separation is the most likely cause of idiopathic epiretinal membrane.
There has been a longstanding interest in developing pharmacologic methods for nonsurgical induction of PVD, a technique known as pharmacologic vitreolysis. Pharmacologic agents are candidates for vitreolysis if they have the ability to induce vitreous liquefaction, weakening the vitreoretinal adhesion or both. A variety of agents have been studies to date, including:
- Tissue plasminogen activator
- Vitreosolve (Vitreoretinal Technologies, Inc., Irvin, CA)
- Arginine-glycerine-aspartate peptide.
- Ocriplasmin (formally microcplasmin)
Recently, two, Phase-3 clinical trials of ocriplasmin in patients with symptomatic vitreomacular adhesions were completed.
Vitreomacular adhesion (VMA) at the macula causes metamorphopsia or visual distortion. Ocriplasmin by ThromboGenics is the only agent that induces both liquefaction and separation of the vitreous from the retinal interface.
VMA = VMT
- Pharmacologic resolution of VMA at 28 days was 26.5%.
- Placebo group (p‹0.001) was 10.1%.
- If patients with epiretinal membranes were excluded, 34.5% versus 14.3%.
There were 7.7% who had unexplained visual loss, which resolved within six months. Other side effects included:
- Floaters – 13%
- Eye pain – 10.5%
- Photopsia – 10%
- Blurred vision – 6.5%
Less than robust results of the ocriplasmin trials point to the complexity of pharmacologic vitreolysis and suggest that the ideal vitreolytic agent, or combination of agents, has yet to be identified. Other options would include:
- Intravitreal gas injection (pneumatic vitreolysis)
- Vitreous surgery
Vitreous surgery currently remains the gold standard for treating significant vitreomacular disorders and likely will continue to be the preferred treatment for some time.
The perfect vitreolytic drug capable of inducing PVDs consistently with a clear retinal surface and no toxicity concerns would be the preferred treatment.
Papers of particular interest, published within the annual period of review, have been highlighted as:
*of special interest
**of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 226).
Radtke ND, Aramant RB, Petry HM, et al. Vision improvement in retinal degeneration patients by implantation of retina together with retinal pigment epithelium. Am J Ophthalmol 2008; 146:172-182.
This study demonstrates the safety and clinical benefit of retina RPE grafts in human subjects with retinal degeneration. Visual improvement was observed in seven of ten patients (three retinitis pigmentosa and four AMD).
Radtke ND, Aramant RB, Seiler MJ, et al. Vision change after sheet transplant of fetal retina with retinal pigment epithelium to a patient with retinitis pigmentosa. Arch Ophthalmol 2004; 122:1159-1165.
We were honored that our work received such recognition from these esteemed professors.
TruSopt (dorzolamide) reduces cystoid macular edema in patients with Retinitis Pigmentosa.
Gerald Fishman, M.D., University of Illinois at Chicago, demonstrated that all patients in his study showed a significant reduction in swelling in at least one eye after using TruSopt three times a day for one to two months. Results of the study were published in the January 10, 2007, issue of the British Journal of Ophthalmology.