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
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
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.
Two recent articles published in the Archives of Ophthalmology expose the risks of Ocriplasmin injection into the vitreous:
1. Acute Panretinal Structural and Functional Abnormalities After Intravitreous Ocriplasmin Injection — JAMA Ophthalmol. 2014;132(4):484-486.
Conclusion: Retinal dysfunction associated with intravitreous ocriplasmin injection is not limited to the macular region and seems to involve the entire retina. Enzymatic cleavage of intraretinal laminin is a biologically plausible mechanism for acute ocriplasmin retinal toxic effects.
2. Vision Loss After Intravitreal Ocriplasmin: Correlation of Spectral-Domain Optical Coherence Tomography and Electroretinography — JAMA Ophthalmol. 2014;132(4):487-490.
Conclusion: On the basis of these findings, it is possible that ocriplasmin may have a diffuse enzymatic effect on photoreceptors or the retinal pigment epithelium that is not limited to areas of vitreomacular adhesion. The rod photoreceptors may be more susceptible than cone photoreceptors to the effects of ocriplasmin. Further work is needed to understand mechanisms of visual impairment after ocriplasmin.
Robert E. MacLaren from Oxford, England has published an article in The Lancet, January 2014, describing the results of six patients who received gene therapy for choroideremia.
The initial results of the retinal gene therapy showed improved rod and cone function. In all patients over six months, there was an increase in retinal sensitivity in the treated eyes that correlated with the vector dose of the gene therapy.
The study assessed the effects of an adeno-associated virus (AAV) vector encoding REP1 (AAV.REP1) in patients with choroideremia. Choroideremia is an x-linked recessive disease that causes blindness due to mutations in the CHM gene, which encodes the Rab escort protein 1 (REP1).
The findings warrant further assessment of gene therapy in choroideremia, age-related macular degeneration, retinitis pigmentosa, and Stargardt’s disease.
A Japanese government panel Wednesday June 25, 2013 approved the world’s first clinical research using iPS cells. Massayo Takahoshi, M.D., Ph.d will serve as head of the clinical study in Kobe Japan.
Six patients with wet AMD will have skin cells taken and genetically reprogrammed to become iPS cells. These cells will be modulated to grow into RPE cells which will take 10 months. The sheets of the RPE cells will then be transplanted into the eyes under the retina of patients who have had abnormal blood vessels removed.
These patients will then be monitored over the next four years to determine how well the implants have performed and whether the body has accepted them.
We will all benefit from the information obtained about minimizing tumorigensis from the induced genetic mutations and possible viral contamination regardless of what level of efficacy is attained.
A patient who you are following that has had a retinal detachment repair or a vitrectomy for any reason is doing well. If the patient then develops any of the following signs or symptoms, it may justify a re-referral to a retinal subspecialist:
- An intraocular pressure of below 6 mmHg.
- An injected conjunctiva with associated pain.
- A hazy cornea.
- White, round-like deposits on the corneal endothelium.
- Rubeosis on the iris.
- Patient complains of seeing flashes of light or gnats in their eyes.
- Vessel in-growth in the limbal area.
- Patient complaining of seeing a shade or blurring in their field of vision.
- Patient having difficulty seeing.
- Intraocular pressure elevation above 30 mmHg.
- Band keratopathy in eye with Silicone oil.
- Patient complains of feeling like they have a lash in their eye.
A phone call to the retinal subspecialist may suffice or he/she may feel examining the patient is in order.
We were acknowledged by the Foundation for Fighting Blindness for our effort in one of six emerging retinal therapies receiving foundation funding as part of its Translational Research Acceleration Program (TRAP). The emerging treatments included those using stem cells, gene therapies, and pharmaceuticals.
Multilayered Cell Replacement Therapy
Many retinal diseases, including Stargardt disease, dry age-related macular degeneration, and choroideremia, lead to loss of photoreceptors and a supportive layer of cells called retina pigment epithelium (RPE). Dr. David Gamm of the University of Wisconsin is using induced pluripotent stem cells (iPSC) to develop a two-layered cell replacement therapy.
To minimize rejection of this and other treatments, he is also developing lines of iPSC from “super donors,” individuals from across the United States whose immune profiles favorably math those of the country’s general population. For these efforts, Dr. Gamm is collaborating with scientists from: University of California, Santa Barbara; University of Pennsylvania; Cellular Dynamics International; and Retina Vitreous Resource Center in Louisville, Kentucky.