The quest to treat presbyopia

For cataract-refractive surgeons, novel treatments could be their “Holy Grail.”

Presbyopia has a multitude of corneal-based and lens-based options for treatment, yet it still remains the anterior segment surgeon’s “Holy Grail.” There are no pharmacologic treatments, and (to date) no methods to prevent its onset. But that may change in the near future, experts say. Let’s hope so: By 2030, as many as 2.1 billion people may be affected by presbyopia worldwide, according to a 2018 study in Ophthalmology by Fricke, Tahhan, Resnikoff, et al.

Presbyopia is likely multifactorial, “otherwise everyone would become presbyopic at the same time,” says Sumitra Khandelwal, MD, Baylor College of Medicine, Houston, Texas. The gamut of patients presenting with presbyopia can range in ages from late 30s to a pseudophakic person in his 70s, notes Karl Stonecipher, MD, director of Southeastern Eye Laser and Refractive Center in Greensboro, N.C.

“We now have wonderful ways to address this ubiquitous disorder, even at different substages of life,” adds George O. Waring IV, MD, FACS, Waring Vision Institute, Mount Pleasant, S.C.; these options are predominantly lens-based.

The AAO Focal Points on “dysfunctional lens syndrome” (the term describes the natural changes in the crystalline lens after approximately age 42) characterized and staged the natural aging changes of the crystalline lens. Based on these stages, presbyopia is the second stage of ocular maturity, Dr. Waring says.

Here are the current and near-future options for that second stage.


“It would be great to have a technology, a tool, a device, a drug … something that actually prevents even the onset of presbyopia from the very beginning,” Dr. Khandelwal says. Barring that, an IOL technology with “a perfect accommodative lens that provides great quality optics and gives our patients a full range of vision without compromising night vision or contrast sensitivity” is the Holy Grail, says Alice Epitropoulos, MD, FACS, Cataract & Refractive Center of Ohio in Columbus. While she’s “pretty confident” those may be on the horizon, “we still have a way to go.”

Dr. Waring thinks about safety first, then optics, lifestyle and cost, “and we let all of our patients know that.” Those four variables are what makes a “one-stop solution” unrealistic for now.

Until there is an IOL that mimics the ability to see multiple focal points like a natural lens that we are born with, the ideal situation will remain out of reach, Dr. Khandelwal says.

“I’ve not heard of a lens that has been able to save distance, intermediate and near vision without the concomitant glare and halos,” she says. “That’s our challenge.”


Breaking down the categories

Current options include lens-, corneal- and scleral-based options; for hyperopic presbyopes the lens choice may provide great vision, but that is unlikely for the myopic presbyope. Still, lens-based options “tend to be more predictable than some of the other options available to treat astigmatism, and possibly even presbyopia,” says Dr. Epitropoulos. She points out that some surgeons feel that lens-based options are less invasive, while others maintain that scleral options are less invasive since this procedure does not directly affect the visual axis.

In the first stage of dysfunctional lens syndrome, Dr. Waring explains, patients typically do best with a corneal-based solution and “presently we have options ranging from blended vision, with laser vision correction, to presbyopia corneal inlays, one of which is currently FDA approved.”

However, Dr. Khandelwal says the issue for inlays is it’s “refractive surgery on the cornea. You’re trying to compensate for the lens by doing surgery on the cornea.” Still, corneal inlays “may be an ideal option” for the presbyope who wants a reading option, according to Dr. Stonecipher. He notes that the Presbia Flexivue Microlens is undergoing review with the FDA. Should it be approved, it and the Kamra (CorneaGen) will be two inlay options available in the United States.

Refractive lensectomy is becoming an option for a larger sector of the population because of recent improvement with lenses and the safety of the procedure, according to a 15-year retrospective study Dr. Stonecipher coauthored in 2015. He says that he is among those who “have offered this as a presbyopic solution for quite some time,” and that “most patients have excellent visual acuity outcomes following refractive lensectomy.”

After refractive surgery

For the pre-cataract, post-refractive surgery patient, Dr. Stonecipher believes the extended depth of focus (EDoF) lenses can be used “with great success.” In his hands, with between 500-600 cases to date, “the EDoF lenses are pretty much on target; our enhancement rate is 1.3% for the myopic presbyope.” Hyperopic post-LASIK patients are more likely to benefit from modified monovision, or blended vision, he said, because they have more prolate corneas.

“That’s the one exception to the rule — I’m not as comfortable placing a multifocal or EDoF lens in an eye with an already steep cornea,” Dr. Stonecipher says.

The presbyopic, post-RK patients can be more challenging, he explains. “They’ll come in with vision around 20/30 or 20/40. Surprisingly, patients with four RK incisions do well with blended vision as well, as long as the corneas aren’t too dramatically interrupted.”

High “opes” and the old standby

For Dr. Waring, the higher the hyperopia, the lower the threshold to do a lens-based procedure for presbyopia. Conversely, the higher the myopia, the higher the threshold to do a lens-based procedure “due to the relative risk for retinal detachment in this subgroup,” he explains.

Monovision or modified monovision contact lenses, of course, can often be a successful stop-gap measure until cataract surgery is warranted. Dr. Stonecipher says that “somewhere around 30% to 35% of the population can tolerate a true monovision.” For now, however, surgeons must determine if the lenses are bad enough to warrant cataract surgery, and, if not, if the patient might benefit from refractive lensectomy.


Lasers and lenses

“Accommodation is complex and multifactorial in nature,” Dr. Epitropoulos says. “That’s why the first-generation Crystalens (Bausch + Lomb), a single vaulting optic, usually works well for distance and intermediate vision but is not as predictable as we’d like it to be. We’re getting close with trifocal lenses to a better lens-based solution.”

Modifiable IOLs, trifocal and quadrifocal diffractive lenses are in the pipeline, along with new generation EDoF technologies, Dr. Waring says. “There is some early promising work on direct femtosecond laser on the human crystalline lens to treat presbyopia.”

The AcrySof IQ PanOptix (Alcon), likely the next lens to be approved, is a trifocal IOL that “has given us better distance, intermediate and near with less dysphotopsias,” Dr. Stonecipher says. Other trifocal IOLs in development include the AT Lisa (Carl Zeiss Meditec) and FineVision (PhysIOL).

For post-RK patients with 8+ incisions, the IC-8 (AcuFocus) is a small aperture IOL that allows for near-vision in a non-dominant eye, using a monovision concept. “This is really going to be a game changer for patients who have higher-order aberrations, because the IC-8 essentially creates a miotic pupil,” Dr. Epitropoulos says. “It’s going to be very good for particular cases, such as PRK or LASIK patients who have corneal injuries, patients who have suffered from higher-order aberrations. Those are very challenging patients we really don’t have any technology for now.”

Dr. Stonecipher believes the IC-8 or an IOL under investigation from the German company Morcher may be a viable option, as he is “very impressed with the latest data coming from trials outside the United States.”

Technologies that allow surgeons to adjust the optical power or provide them with the ability to customize implanted IOLs are “an appealing alternative, and there are several future technologies that may allow this possibility: modular lenses, light-adjustable lenses and refractive index shaping,” Dr. Epitropoulos says. “IOL customization may become the standard for cataract surgery in the future.”

Dr. Stonecipher believes that the current lenticular technology will produce a truly accommodative lens in the near future to add to current treatments.

Drugs: The new frontier

A pharmacologic agent “that could maintain vision would be excellent for that group as a start,” Dr. Khandelwal says. “Obviously if you could then keep them from becoming presbyopic at all, that would be even better, certainly as a stop-gap,” adding that we should have a majority of these in the marketplace by 2020. Several topical treatments are currently being evaluated.

Presbyopia Therapies is investigating PRX-100, which incorporates both aceclidine as a muscarinic antagonist to create a strong pinhole effect and the short-acting low-dose tropicamide. This reversible treatment provides restored accommodation of at least four to seven hours, according to the company.

Novartis is investigating EV06, which uses lipoic acid choline ester to weaken the oxidation-induced disulfide bond formation between crystalline proteins in the human lens; it “un-crosslinks” collagen fibers to restore accommodation.

FOV Tears, a binocular presbyopia-correcting drop, is a combination of parasympathetic, alpha agonists 1 and 2, an anti-cholinesterase and an NSAID.

Also in the pipeline

Avedro is developing a non-invasive refractive cross-linking treatment for presbyopia, which the company refers to as PiXL. Avedro plans to initiate a Phase 2 clinical trial with PiXL in the first half of 2019.

Scleral-based procedures may be more viable in the future than is currently the case, Dr. Waring predicts.

“We’ve worked with both scleral spacing bands and also with scleral laser procedures,” he says. “The scleral laser procedure, in particular, is showing very impressive early results, in a minimally invasive fashion. While it’s not a zonular treatment directly, it’s targeting the zonular complex.”


Dr. Khandelwal is not particular about which treatment may be the Holy Grail.

“It’s always interesting when you have an opportunity to find treatment for something that affects pretty much everybody in their lifetime,” she says. “There are very few diseases out there where that happens; presbyopia is one. If we can address and reverse this disease, that would be fantastic.” OM

Disclosures: Dr. Epitropoulos reports financial relationships with Alcon, Bausch + Lomb and Johnson & Johnson Vision. Dr. Khandelwal reports financial relationships with Alcon, Bausch + Lomb and Zeiss. Dr. Stonecipher reports financial relationships with AcuFocus, Alcon, Allergan, Bausch + Lomb, Johnson & Johnson Vision, Presbia and Refocus Group. Dr. Waring reports financial relationships with Alcon, Bausch + Lomb, Johnson & Johnson Vision and Perfect Lens.