Laird Harrison

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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

The use of confocal microscopy establishes methodology to count the keratocytes in the corneal stroma, and measure the density of the ADAScs in the implanted tissue, as well as in the corneal stroma. 

This article was reviewed by Monal El Zarif, OD, Msc


	
	New evidence with confocal microscopy shows that adipose-derived adult stem cells (ADAScs) injected into the stromal pocket of patients with keratoconus can transform into keratocytes, according to Mona El Zarif, OD, Msc.

The use of confocal microscopy to monitor and evaluate the evolution of the stem cells over time is novel, said Dr. El Zarif, a doctoral student at Miguel HernÃ¡ndez University in Alicante, Spain, at the European Society of Cataract and Refractive Surgeons (ESCRS) annual meeting. 

“It allowed a qualitative and quantitative assessment of the cells,” she explained. 

The technique establishes a new methodology to count the keratocytes in the corneal stroma, and measure the density of the ADAScs in the implanted tissue, as well in the corneal stroma she said.
	
	

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	The researchers compared three groups of adult patients with keratoconus in an experimental, interventional, prospective, consecutive case series. In the first group, five patients were implanted with ADAScs alone without scaffold.

In the second group, five patients were implanted with decellularized human corneal stroma, essentially a scaffold without ADAScs. 

“We decellularize the lamina from the donor human cornea stroma,” Dr. El Zarif noted.
	
	

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	The third group was implanted with ADAScs embedded onto a scaffold made from a decellularized lamina.

“We observed that the automatic count of cells done by the software of the confocal microscopy was not accurate,” said Dr. El Zarif. “That’s why we proceeded with a manual count of cells. We proceeded choosing a good image, a good number of keratocytes and good contrast and quality of illumination.” 

For anyone wanting to try this approach, she recommends starting the count of cells with 50% illumination and contrast determining a fixed area.

In this study, Dr. El Zarif analyzed an area of about 0.1 mm and counted the most illuminated and most refringent cells with well-defined edges. 

“The dark gray cells are not counted in our study because they don’t belong to the plan of observation,” she said.

When the researchers could not find any defined structure similar to keratocytes, they considered the tissue in question to be acellular. 
	
	

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By this definition, the decellularized lamina in this study remained acellular a month after implantation.

By contrast, cells in the recellularized lamina after one month had structures similar to normal keratocytes Fand these cells become more similar to keratocytes six to 12 months postoperation.

The researchers used software in the confocal microscope to calculate the density of the cells. They defined cell density as the number of cells multiplied by 10 (cell/mm

The results were promising. In the first group, those implanted with ADAScs but no scaffold, the ADASc appeared round in shape, and more luminous, refringent, and voluminous. The shape of ADASc changed after 6 months from round to fusiform until after 12 months the morphology of these cells looked like a normal cornea.

In the second group, those patients implanted with decellularized lamina only, the lamina remained acellular for the first month after implantation. 
	
	


	After three months, it became recellularized by the patients’ own keratocytes.

“There was a migration of keratocytes from the host stroma toward the lamina,” said Dr. Zarif. The posterior surface of the lamina recellularized before the anterior surface. After a year, the keratocytes populated the lamina in a similar way to a normal cornea stroma.

The third group, implanted with recellularized lamina, showed structures like normal keratocytes after one month. These were more voluminous in the posterior surface of the lamina. With some patients they had dendritic shape after one year of implantation.

In all three groups, 12 months after the surgery the researcher noted gradual and significant increase in the cellularity of the anterior and posterior stromas of the patients in comparison to the preoperative density, with a 

 value for this difference of less than 0.001 in the anterior and posterior stroma.
	
	

Color-LED topography measures corneas consistently in analysis 


	As the study progressed, the research team continued to make new discoveries in each of the groups.

In the first group, the researchers noted a gradual but significant increase of the cellularity of the mid corneal stroma (

In groups 2 and 3, one year after surgery, the researchers observed a significant increase (

  <  0.001) in cellularity in the anterior and posterior surfaces and within the lamina.

Compound eye as treatment for neurotrophic keratitis 


	They found that cell density was significantly higher in patients implanted with recellularized laminas than in those implanted with decellularized laminas, both on the anterior surface and within the lamina (

 =0.011), and on the posterior surface of the lamina (

After making its initial findings on cell density, the research team continued to follow up on this measurement. 

After one year, group 3 had greater cell density than either group 2 or group 1 in the anterior stroma. It had greater cell density than group 2 in the anterior stroma, the anterior surface of the lamina, the mid stroma of the lamina and the posterior surface of the lamina.
	
	

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	In conclusion, Dr. El Zarif said, confocal microscopy is an essential tool for the evaluation and monitoring “in vivo” of the ADASC.

“It allowed a qualitative and quantitative assessment of the cells through the experiment,” she said. “And it allowed monitoring of the progressive morphological changes that occurred in the implanted tissue in decellularized and recellularized laminas.”

Dr. El Zarif added that the technique assisted in determining the change in the cells’ densities in the grafted tissue as well as in all the posterior and anterior corneal stroma. 

Dr. El Zarif has no financial disclosures.

Microscopy study suggests stem cell success in keratoconus 

David P. PiÃ±ero, PhD, and colleagues set out to evaluate the intrasession repeatability of anterior aberrometric measurements obtained by the Cassini and to compare it with those obtained by the Pentacam in healthy eyes. 

This article was reviewed by David P. PiÃ±ero, PhD

Color light-emitting diode (LED) technology can consistently measure anterior topography, aberrometry, and total corneal astigmatism, according to David P. PiÃ±ero, PhD.
	
	But these measurements cannot be used interchangeably with those obtained through Scheimpflug imaging (Pentacam, Oculus), said Dr. PiÃ±ero of the University of Alicante, in Alicante, Spain.
	
	One technology (Cassini Total Corneal Astigmatism) is a multispot (up to 700), multicolor (red, yellow, and green) LED tear film-reflection topography imaging system designed to avoid source mismatch and decrease artifacts caused by shadows.
	
	

Research shows small-aperture IOL is bringing stability into focus 


	
	The system uses ray tracing to process every three spots identified by the software and to define the relevant local elevation. Employing the reflection of seven infrared LEDs for second Pukinje imaging, it measures the center of the posterior corneal surface.
	
	“This Cassini technology has shown its usefulness to measure the shape of the anterior corneal surface in different types of eye including keratoconus and scarred corneas,” Dr. PiÃ±ero said. Several studies have evaluated the intrasession repeatability of some measurements the device provides. “But I haven’t found any paper evaluating the intrasession repeatability of corneal asphericity or corneal high order aberrations provided by this device,” he said.
	
	And he noted that papers by other authors, showed clinically relevant differences in keratometry and other parameters between the Cassini and other devices.
	
	


	Dr. PiÃ±ero and colleagues set out to evaluate the intrasession repeatability of anterior corneal topographic and aberrometric measurements obtained by the Cassini and to compare it with those obtained by the Pentacam in healthy eyes.
	
	They made this comparison in 35 healthy eyes of 35 patients, with an age range of 16 to 66 years at the, University of Alicante. They obtained three consecutive measurements in each patient to assess the intrasession repeatability. Then they obtained one measurement in each patient with the Pentacam system. They found that the within-subject standard deviation for keratometric readings were 0.02 mm with intraclass correlation coefficient readings of at least 0.992.
	
	In addition, they found the intrasession repeatability for anterior astigmatic measurements was 0.16D, and for total astigmatic measurements it was 0.05D. The intraclass coefficient readings were 0.930-0.978. They found a standard deviation of 0.06 mm for asphericity and 0.03 mm for corneal diameter, “which can also be considered as a good level of intrasession repeatability,” Dr. PiÃ±ero said.
	
	

Latest tonometry devices all have their pluses and minuses 


	
	When analyzing aberrometry repeatability, however, researchers found “something curious,” he said. “We obtained very good correlation coefficients and intraclass correlation coefficients, and within subject standard deviations, for all this Zernike terms for the second order to the fourth order,” he said. “But when we analyzed one component of the secondary astigmatism and one component of the quadrafoil, we obtained a limited intrasession repeatability.”
	
	He attributed this discrepancy to the very small amount of aberration; even a slight difference in a very small difference can appear to be a statistically significant variation, he said. “This is probably the reason, but we have to investigate more.”
	
	On the other hand, the differences between the readings of the Cassini and Pentacam devices were statistically significant for keratometry, total astigmatism, asphericity, and in some Zernike terms.
	
	“If we analyze the ranges of agreement between these two devices, we find, that for keratometry it was more than 0.06 mm which can be considered clinically relevant because this can have an impact, for example, in higher power calculation of more than 0.5 D,” he said.
	
	There were differences in astigmatic corneal components of more than 0.69D, in asphericity of more than 0.35 mm. There was a trend for the Cassini of obtaining steeper values of curvature, as well as higher values of total corneal astigmatism.
	
	In Zernike terms, there were differences of 0.2 Î¼m for the second order, 0.13 Î¼m for the third order, and 0.01 Î¼m for the fourth order. 

This article was adapted from Dr. PiÃ±ero's presentation at the 2019 congress of the European Soceity of Cataract and Refractive Surgeons. He did not indicate any proprietary interests relevant to the subject matter. 

Color-LED topography measures corneas consistently in analysis 

New offering is extending patients' depth of focus with minimal drawbacks 

 remains stable after two years, extending patients’ depth of focus with few dysphotopsias, researchers say. Subjects implanted with the AcuFocus IC-8 IOL, which works on the principle of pinhole optics, maintained mean monocular logMAR far visual acuity of 0.11 ± 0.13, intermediate visual acuity of 0.08 ± 0.15 and near visual acuity of 0.20 ± 0.15 at a mean follow-up of 29.9 months.

“The drawbacks are minimal,” said John Vukich, MD, who practices at Davis Duehr Dean in Madison, WI. “Patient satisfaction has been extraordinary.” Dr. Vukich presented the two-year results of aEuropean post-market study along with highlights of the advantages of the IC-8 over toric 

The IC-8 is a one-piece hydrophobic acrylic posterior chamber 

with an optic that contains an embedded mask with a 1.36-mm central aperture. The dimensions of the mask and aperture contained within the optic are based on the AcuFocus Kamra corneal inlay, with a smaller diameter and flatter radius of curvature to account for its more posterior placement within the eye.

It is CE Marked and currently available in some European and Asia Pacific markets. Phase III clinical trials are nearing completion in the United States.

To evaluate the long-term effectiveness of the IC-8, Dr. Vukich and colleagues reviewed the charts of 64 patients presenting at a single visit after implantation of the IC-8 in one eye and an aspheric monofocal

 in the other. The target refractions were -0.75 D in the IC-8 eye and plano in the monofocal eye.

The patients achieved mean binocular logMAR far visual acuity of -0.01 ± 0.10, intermediate visual acuity of 0.04 ± 0.14 and near visual acuity of 0.18 ± 0.15. That compared with -0.04 ± 0.11, 0.05 ± 0.13 and 0.17 ± 0.14 at six months.

“These results were immediate in their optical benefit and durable; there seemed to be no significant drop off,” said Dr. Vukich, adding the small-aperture lens offers advantages in correcting corneal astigmatism.
	
	

Why remove an IOL? Survey brings key trends into focus 

Fewer than 5% of patients opt for toric IOLs, even though 52.6% present with more than 0.75 D of cylinder prior to 

Dr. Vukich also noted that axis shifts can induce misalignment, and misalignment and postimplantation rotation reduces the effectiveness of toric lenses. He cited reports that every degree of rotation reduces effectiveness by 3.3%.

By contrast, Dr. Vukich said, the IC-8 remains 100% effective, even with 30 degrees of rotation. It can tolerate up to 1.50 D of corneal astigmatism. The small-aperture design is symmetrical, eliminating the need for axis alignment.

In the post-market study, patients with less than 0.75 D of astigmatism achieved mean logMAR far visual acuity of 0.00, intermediate visual acuity of 0.05 and near visual acuity of 0.18.

Those with 0.76 D to 1.50 D achieved -0.01 for distance, 0.05 for intermediate and 0.22 for near. For those with greater than 1.50 D, those number were 0.06, 0.27 and 0.42 respectively.

The IC-8 can also compensate for many corneal irregularities from injury or previous corneal surgery, he said.

“This is a lens that is forgiving,” said Dr. Vukich. “You do not have to worry about small amounts of astigmatism causing problems. It gives you a large landing zone, a large range where you get a good distance outcome for quality of vision.”
	
	The IC-8 will compete against multifocal lenses that also offer a solution for patients who would like to address their presbyopia at the same time as their cataracts.
	
	

Toric, presbyopia-correcting IOLs good ptions for glaucoma patients 


	
	The multifocal lenses now on the market provide good functional vision, but with the drawbacks of reduced contrast, visual disturbances and noncontinuous range of vision. The IC-8 offers advantages over these lenses because the aperture itself creates the depth of focus, said Dr. Vukich.
	
	“From that standpoint it is a very smooth transition,” he said. “It’s a seamless change in depth of focus from far to near.”
	
	

This article is adapted from Dr. Vukich's presentations at American Society of Cataract and Refractive Surgery 2019. Dr. Vukich is a consultant to AcuFocus, Avedro, Clerio, Vision, Johnson & Johnson, STAAR Surgical, and Zeiss. 

Author | Laird Harrison

Articles

Genetic analysis could predict myopia in children

Microscopy study suggests stem cell success in keratoconus

Color-LED topography measures corneas consistently in analysis

Research shows small-aperture IOL is bringing stability into focus