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New Risk Calculator for Advanced AMD
A funny thing happened on the way to creating a risk calculator for advanced age-related macular degeneration (AMD). A team of researchers, headed by Michael L. Klein, MD, had assumed that genetics would be a powerful and essential component of the model. But the phenotype classification, based upon the macula’s appearance during a routine eye exam, trumped genetics as well as the other variables in the model.
The result is a risk calculator that can yield predictive information for clinical practice, either with or without knowing the patient’s genotype.1 The calculator predicts the likelihood of an individual’s developing advanced disease—either geographic atrophy or neovascular AMD—at yearly time points over a 10-year period.
The validated predictive model for AMD was developed using longitudinal data from 2,846 white participants in the Age-Related Eye Disease Study (AREDS).2 (White participants were used in order to suppress racial and ethnic variation in AMD susceptibility genes.) The AREDS enrolled individuals 55 to 80 years old, without advanced AMD in either eye or with advanced AMD in only one eye, and followed them for approximately 10 years.
The risk calculator includes the following variables: age, smoking, family history of AMD (first-degree relatives) and phenotypic features based on a simple scale of 0 to 4 points. This scale uses two retinal abnormalities at baseline: one or more drusen of at least 125 µm in the smallest diameter, and any definite hyper- or hypopigmentation. Two other variables augment the baseline severity scale: drusen of at least 250 µm in the smallest diameter in one or both eyes, and advanced AMD in one eye.
An optional genetic component incorporates genotypes of the most common variants associated with AMD, CFH Y402H and ARMS2 A69S, providing a more refined prediction in certain individual cases. “Other genetic variables were evaluated but did not add to the predictive value,” said Dr. Klein, professor of ophthalmology and director, Macular Degeneration Center, Oregon Health & Science University, Portland.
This isn’t the first AMD risk calculator, and not even the first using the AREDS data. Most other predictive models, which can yield an accurate estimate of lifetime risk of AMD, rely primarily upon an individual’s genotype. However, because genetic testing may be costly, it is more practical in many circumstances to have an eye examination, including evaluation of the macula, Dr. Klein said. An eye exam would assess the risk of AMD as well as other potentially serious eye diseases, he added.
The value of knowing an approximate risk might influence whether a physician follows a patient more closely; advises home monitoring of central vision; or recommends preventive measures, such as dietary changes or nutritional supplements, Dr. Klein said.
“In the future, risk assessment will become more important in clinical practice with the discovery of new and more effective methods of prevention and early treatment,” Dr. Klein said. At the same time, “Risk calculation will become more accurate through new and better methods of assessing the macula, as well as increasing knowledge of the role of environmental factors and genetics in AMD.”
1 The risk calculator is available at www.ohsucasey.com/amdcalculator
2 Klein ML et al. Arch Ophthalmol.
Dr. Klein reports no related financial interests.
Ocular Surface Morbidity
Sunken Globe May Affect Corneal Health
More than a simple matter of aesthetics, age-related sunken globe may be an important contributor to ocular surface morbidity. Researchers at the Ocular Surface Center in Miami, Fla., drew this conclusion after comparing records of 38 patients with varying degrees of sunken upper lids to 26 patients without this change.1
With the added support of photographs—taken as a long-term, routine practice at the center—the researchers were able to spot patterns in patients, seeing connections between this aesthetic change and the sight-threatening problem of corneal epithelial breakdown. Corneal complications, in fact, correlated well with severity of sunken upper eyelids.
Among the symptoms assessed were incomplete blinking and closure, abnormal Bell phenomenon, lid/punctum ectropion, and delayed tear clearance—all of which were more common in the study group.
Although there was less ocular irritation or pain in the study group than in controls, tearing and mucous buildup were more prominent in those with sunken eyelids, particularly first thing in the morning.
This is largely a nighttime issue, said study coauthor, Scheffer C. G. Tseng, MD, PhD. With shrinkage of orbital fat, the globe sinks toward the optic nerve when the patient is supine and separates from the eyelid surface, leaving an air space between the eyelid and cornea. In a patient whose sensory nerves are intact, this will cause discomfort upon awakening—a classic complaint of recurrent corneal erosion syndrome, he said.
But the cornea will dry out and decompensate in patients who have poor ocular sensitivity because they will be unaware that changes are occurring, said Dr. Tseng. Once corneal complications develop, a physician will sit up and take note but may not understand what caused them, he added.
Declining neurotrophic status in some patients is linked to aging and may be aggravated by other factors, such as diseases affecting the trigeminal nerve, including herpes and diabetes, said Dr. Tseng. He noted that this was borne out by the study’s findings.
This paper is especially important in light of recent reports about prostaglandin- associated periorbitopathy (PAP), said Dr. Tseng, who became aware of this glaucoma medication side effect after his paper’s publication. (For more about PAP, see the March EyeNet.)
1 Liang L et al. Ophthalmology.
Dr. Tseng reports no related financial interests.
Trends in Practice
Frequency of Gonioscopy
How routinely do you perform gonioscopy? This was a question posed to comprehensive ophthalmologists in a recent Academy survey. For some respondents, the answer might have been somewhat aspirational, said Dale K. Heuer, MD, glaucoma specialist and professor and chairman of ophthalmology and director of Froedtert and Medical College of Wisconsin Eye Institute in Milwaukee.
Among those surveyed, approximately 20 percent said they perform gonioscopy on all glaucoma patients and suspects at least once a year, and another 20 percent reported doing so less often than every three years. About 40 percent said they perform gonioscopy every one to three years. And nearly 20 percent report that they do so only on those with anatomically narrow angles.
“If they are doing this, it might be even more than is needed in some cases,” said Dr. Heuer, referring to the ever-present challenge of separating those who need extra glaucoma monitoring and intervention from those who don’t.
“At one end of the spectrum are patients who start with relatively narrow angles and may need the exam every year or two,” said Dr. Heuer. Also, pseudoexfoliation patients are prone to angle narrowing over time, and their lenses may shift forward more than is typical, so they may need similarly frequent exams.
“At the other end of the spectrum are people who are pseudophakic and in whom you’ve confirmed that the angle is widely open,” he said. “I don’t see any value in doing gonioscopy again because the angle anatomy shouldn’t change.” Individuals with a widely open angle also don’t need annual gonioscopy, said Dr. Heuer. Depending upon the width of the angle, every three to five years will do.
A 2003 chart review of patterns of care found that fewer than half of clinicians performed gonioscopy during initial evaluations for primary open-angle glaucoma.1 Has the “needle” moved much since this report was written? Dr. Heuer is doubtful.
1 Fremont A. Arch Ophthalmol.
Dr. Heuer is a consultant for Alcon and Allergan and is the data and safety monitoring board chairman for Lux Biosciences.
CLINICAL PREFERENCES. To better understand current practices on a number of topics, the Academy surveyed comprehensive ophthalmologists about how they would handle various clinical situations. Each month, EyeNet will feature one question—this month about how frequently gonioscopy is repeated—and ask an expert to provide perspective on the responses.
Gene Tx for X-Linked RP
A common, inherited form of retinitis pigmentosa (RP) can be prevented or reversed in dogs by gene therapy, according to a recent study.1 The technique is expected to be applied to humans in the near future; that is the prediction of two lead researchers in the dog study.
The impact on protecting the canine retina was “dramatic,” said Gustavo Aguirre, VMD, PhD, professor of medical genetics and ophthalmology at the University of Pennsylvania School of Veterinary Medicine. “The evidence from the dogs is ‘one treatment fits all,’” he said, noting that severe and early visual loss in humans and animals with RP results from photoreceptor failure caused by mutations in the X-linked retinitis pigmentosa GTPase-regulator (RPGR) gene. Injection of a viral vector that carries the normal form of the RPGR gene rescues the photoreceptors, he said. Imaging studies showed that the approach preserved photoreceptor nuclei and other cellular segments of rods and cones that are critical to normal photoreceptor function, providing evidence that the intervention was effective.
The investigators tested this gene-therapy approach both before disease onset and shortly after photoreceptor degeneration, and they achieved a successful outcome in both settings. Several versions of the virus and gene were tried. The selected therapeutic virus was effective in all four dogs treated, and restoration of rods and cones was seen on histologic examination, compared with a control group, Dr. Aguirre noted.
“What happens at the border of the treatment area over time? We don’t really know yet,” said William Beltran, DVM, PhD, assistant professor of ophthalmology at Penn’s School of Veterinary Medicine. However, it appears that “rescue” occurs in enough of the cells to ensure vision is protected.
1 Beltran WA et al. Proc Natl Acad Sci USA.
Drs. Aguirre and Beltran report no financial interests related to the research.