Future research may lead to development of polygenic risk score that will enable clinicians to accurately predict myopia in children, obviating the need for cycloplegic autorefraction.

Clinicians may soon be able to use genetic information alone to determine the risk of myopia in very young children, according to researchers.

“A personalized medicine approach to detecting children at risk of myopia is now feasible, although currently the accuracy of polygenic risk scores (PRSs) is not yet good enough to warrant their use in clinical practice,” write Neema Ghorbani Mojarrad and colleagues at the University of Bradford in Bradford, UK. 

Genetics analysis may predict myopia in children

Today, the best predictor of children at risk of myopia is a low hyperopic refractive error at an age before myopia typically manifests, so clinicians seeking to evaluate risks of myopia in young children typically rely on a screening regimen of cycloplegic autorefraction.

Successfully predicting risks of myopia in children can help clinicians recommend lifestyle changes such as more time outdoors, which can help mitigate or prevent the development of myopia.

However, the use of cycloplegic autorefraction is time- and resource-intensive, so Mojarrad and his team wanted to see if they could develop a PRS for evaluating risk based purely on genetic information.

To develop their PRS, the researchers conducted three genome-wide association studies (GWASs). Data used for the GWASs included 287,448 UK Biobank participants who had not undergone autorefraction, and 95,619 UK Biobank participants who had undergone noncycloplegic autorefraction.

In addition, researchers collected data on 328,917 individuals whose information had originally been compiled to study the relationship between genes and years of educational attainment and was downloaded from the Social Science Genetic Association Consortium (SSGAC) website.

The researchers then combined their data in a meta-analysis in order to increase the effective sample size. They generated a PRS for each participant using genotypes for 1.1 million variants.

Researchers validated their PRS by using it to predict rates of myopia in 1,516 women whose genome data and known rates of myopia were obtained from the Avon Longitudinal Study of Parents and Children (ALSPAC).
	
	

 Effects of atropine for controlling myopia progession in children

The PRS derived from the SSGAC GWAS provided limited predictive accuracy (R

= 100% would be a completely accurate prediction). The autorefraction and non-autorefraction GWASs were also relatively inaccurate (R

The researchers were able to improve the accuracy of the PRS by combining sets of traits. The best result came from combining the autorefraction and non-autorefraction GWASs (R

 = 10.8%). Combining all three traits yielded even greater accuracy (R

The GWAS was unable to produce a PRS that was as accurate as the results obtainable using cycloplegic autorefraction. Measured in terms of the under the receiver operating characteristic (AUROC), where 0.5 is a useless model and 1.0 is a perfect model, the PRS had an AUROC of 0.67 while the cycloplegic autorefraction had an AUC of 0.87.

While they were unable to develop a suitably accurate alternative to cycloplegic autorefraction for predicting rates of myopia, Mojarrad and his team were able to conclude from their study that children can be categorized into three groups based on the risk of developing myopia. Those with a PRS in the top 25% were at 3-fold to 5-fold higher risk of myopia, and those in the top 10% were at 3.5-fold to 6-fold increased risk, whereas those in the top 5% were at 4.5-fold to 6.5-fold higher risk.

Researchers are hopeful that this information will aid clinicians in recommending lifestyle interventions or prescribing orthokeratologic or atropine treatment

Mojarrad and his team are encouraged by the results of their study, and predict that future research may lead to the development of a PRS that will enable clinicians to accurately predict myopia in children, obviating the need for cycloplegic autorefraction.
	
	

Mojarrad has no financial disclosures related to this content.

Articles

Genetic analysis could predict myopia in children

Residual refractive errors may be preoperative culprits.

This article was reviewed by Scott M. Macrae, MD


	
	Refractive surgeons have a number of options from which to choose when considering presbyopia-correcting IOLs.

Trifocal IOLs continue to gain in popularity in Europe. One has been approved in the United States, the 

 is that surgeons must be attuned to the presence of residual refractive errors, which seems to be the issue associated with this technology. Those refractive errors can constitute a make or break for patients.
	
	

Trifocal IOL a key for premium cataract surgery practice

According to Scott M. MacRae, MD, it is mandatory to correct any residual refractive errors before attacking the presbyopia. 

 implantation, when a patient is 20/happy, they see well at all distances; if they are 20/unhappy, I evaluate the residual refractive errors and, if found, try to refine them,” said Dr. MacRae, professor ophthalmology and visual sciences, Flaum Eye Institute University of Rochester, Rochester, NY.

Sometimes there is no residual refractive error, and the unhappiness may result from the presence of retinal issues, such as cystoid macular edema, epiretinal membranes, cystoid macular edema; posterior capsular opacification; irregular astigmatism resulting from anterior basement macular dystrophy or dry eye; or unrealistic expectations. 

“However, the one that we can treat the best is the residual refractive error,” he noted.

Dr. MacRae credited Richard Lindstrom, MD, with raising the consciousness about the importance of the residual refractive error when he pointed out that between one and three months postoperatively, over 57% of eyes with premium IOLs may not have achieved the full benefit of the implants because of the bugaboo, the residual refractive error. 

The multifocal IOLs are particularly sensitive to residual refractive errors, in that 10.8% to 25% of eyes treated with a multifocal IOL required a re-treatment such as a lens exchange, LASIK, or PRK (Potvin et al. 

 2008;24:243-50. doi: 10.3928/1081597X-20080301-05). Dr. MacRae  pointed out.
	
	

Finding an option with presbyopia-correcting IOLs


	Dr. MacRae pointed out that he could not overemphasize the understanding of the patient’s optics. One factor in the optics is the corneal topography. He recounted the case of a patient with anterior basement membrane dystrophy causing irregular astigmatism, who had undergone implantation of a multifocal IOL. 

The patient was unhappy with her outcome and required a superficial keratectomy and PTK to improve her vision. Another patient had had contact lens-induced corneal distortion and, he noted, likely should not have received a multifocal IOL. 

Some success was achieved with partial correction of the regular astigmatism. 

“However, cases such as this are difficult to correct, and multifocal IOLs are best avoided,” Dr. MacRae said.

Another factor is measurement of the postoperative manifest refraction. In Dr. MacRae’s practice, the technicians dig deep to identify as little as 0.75 D of hyperopia or 0.50 D of myopia. If this is uncovered, that amount of refractive error is put into a trial lens frame to allow the patient to test the impact of the refraction in the real world. 

A positive evaluation after that with a near card then determines if the refractive error correction solves the problem. If it is, a PRK or LASIK can be performed. If the patient is unsure, he or she uses a soft contact lens or spectacles containing the refractive error for a few weeks before a determination is made, he explained.
	
	

Presbyopia-correcting IOLs enhance customization

In addition to the multifocal IOLs, diffractive and extended-depth-of-focus IOLs also are particularly impacted by small amounts of residual refractive errors, especially astigmatism. 

As noted, 0.75 D of astigmatism can wreak havoc with visual quality and performance, but when combined with subtle irregular astigmatism or posterior capsular opacification, large angle kappa, dry eye, and anterior basement membrane dystrophy, there is an additive effect that reduces image quality, he said. 
	
	

Physicians on quest to end dysphotopsias in premium IOLs

“Surgeons should be very aware of this,” he advised.

Dr. MacRae and colleagues performed a study at the University of Rochester in which they compared three multifocal IOLs (ReSTOR3D, ReSTOR3D; Micro F diffractive trifocal, FineVision; and Mplus refractive bifocal IOL, Oculentis) to the AcrySof monofocal IOL. 

The investigators corrected the refractive errors and added increasing amounts of astigmatism to determine the through-focus image quality of the IOLs. 

“We found that 0.75 D and 1 D of astigmatism dramatically reduced the image quality compared to the monofocal IOL,” he said. “Therefore, correcting even that small degree of astigmatism is important for these patients if they are symptomatic.”
	
	

Changing focus of accommodating IOLs now reaching a new level


	What’s the best way? LASIK, PRK, and relaxing incisions are all good methods depending on the need.

Dr. MacRae performs LASIK in health eyes, and even older patients experience rapid visual recovery. PRK is useful to correct residual refractive errors in post-LASIK eyes. He noted that he likes to perform a mini-PRK for refinement, in which the epithelium with a 7-mm diameter is removed instead of removal of epithelium with a diameter of 8.5 mm, a 30% decrease. This approach allows quicker recovery by one day, less risk of an epithelial defect, and less patient discomfort. 

Limbal relaxing incisions are effective in cases with mixed astigmatism of less than 1.25 D. In these cases, he advised against going too centrally (8 mm or less) on the cornea because of the potential for development of coma and less efficient wound healing. 
	 


	Dr. MacRae summed up his pearls. First, rule out and correct any accompanying issues such as posterior capsular opacification and retinal problems as well as the refractive error. 

“Most importantly, inform the patient preoperatively that the possibility of IOL refinements may be necessary postoperatively,” he concluded. “Rather than considering this a treatment failure, consider it as an anticipated refinement.”
	
	

Dr. Macrae has no financial interest in the topic of this report.

Avoiding IOL refinements after presbyopia-correction surgery

Mineralized calcium in tooth enamel may be linked to drusen deposits. 

This article was reviewed by Dinusha Rajapakse, PhD


	
	A team of investigators at the National Eye Institute (NEI) has determined that a protein associated with deposition of mineralized calcium in tooth enamel may be related to drusen deposits in patients with dry 

“The protein is amelotin, which seems to be specific to dry AMD, and may potentially prove to be a therapeutic target in the disease,” said Dinusha Rajapakse, PhD, the first author of the study and a visiting research fellow at the NEI, in Bethesda, MD, working in the laboratory of Graeme Wistow, PhD, chief of the NEI Section on Molecular Structure and Functional Genomics and senior investigator of the study cited in 

 Risuteganib: Exploring novel dry AMD treatment

This finding may ultimately prove to be a boon for patients with dry AMD because, unlike wet AMD, there is currently no treatment available for the dry form of the disease.

Hydroxyapatite is a component of bone and tooth enamel. In their study, the investigators corroborated that hydroxyapatite, a calcium-rich mineral compound previously associated with AMD progression, is deposited in dry AMD.
	
	Small spherules of hydroxyapatite filled with cholesterol were identified in drusen from patients with dry AMD. 

In the study, when the retinal pigment epithelium (RPE) cells were starved of serum for 9 days, the investigators saw formation of amelotin deposits.

Dr. Rajapakse and colleagues reported that amelotin “was strongly upregulated after extended starvation and is responsible for the mineralization of [hydroxyapatite] in their cell culture model. Blocking this pathway in the RPE cell line also blocked the production of these drusen-like deposits.”
	
	

DARP in molecule reducing wet AMD treatment burden for patients 

The team also examined human cadaver eyes with dry AMD, wet AMD, or no AMD. Amelotin was only found in eyes with dry AMD. In these eyes, amelotin was sometimes found in areas of the RPE without drusen, but it was primarily present in soft drusen with large deposits of hydroxyapatite.

“Before this study, nobody really knew how hydroxyapatite was accumulating in dry AMD drusen,” said Dr. Rajapakse. “Finding this tooth-specific protein in the eye-the protein that is linked to hydroxyapatite deposition, that was really unexpected.” 

Study targets subretinal option for AMD treatment

The reason for hydroxyapatite deposition remains unknown, but Dr. Wistow speculated that it may be the result of a “protective mechanism gone awry.” 

“It’s possible that these protein, lipid, and mineral deposits may help damaged RPE cells block blood vessels from growing into the retina, a problem that is one of the key features of wet AMD,” he said. “But when the mineral deposits get too extensive, they may also block nutrient flow to the RPE and photoreceptors, leading to retinal cell death.” 

According to Dr. Wistow, mechanistically, amelotin looks like a key player for the formation of these very specific hydroxyapatite spherules. 

“That’s what it does in the teeth, and here it is in the back of the eye,” he said.
	
	

He pointed out that this underscores the need to develop drugs that can specifically block the function of amelotin in the eye, which may delay disease progression. 

“But we won’t know until we try it,” Dr. Wistow said.

However, this cannot be done until animal models are developed to test new therapies for dry AMD. Dr. Wistow’s laboratory is currently in the process of developing a new murine model for dry AMD.
	
	He also believes that the cell culture model, which mimics features of dry AMD, could potentially be useful for high throughput drug screening to find molecules that slow or prevent the development of soft drusen.
	
	

Ophthalmology Times: May 2020

Genetic analysis could predict myopia in children

Avoiding IOL refinements after presbyopia-correction surgery

Discovery of protein in eye link to therapeutic options for dry AMD