New Pathways in Keratoconus Treatment

ARVO presentations show that interest is heating up.

By Jerry Helzner, Senior Editor

Many ophthalmologists and vision researchers have characterized the last decade as a “golden age” in the specialty. This claim can be substantiated by the significantly improved patient care and treatment options achieved through such advances as anti-VEGF therapy for retinal disease, presbyopia-correcting IOLs and the femtosecond laser for multiple uses in LASIK, corneal transplant and, most recently, cataract surgery.

One of the best ways to ascertain that researchers are making progress against a significant eye disease or condition is to count the number of ARVO presentations relating to that disease or condition in any given year. This year, there were a total of 129 posters, presentations, lectures or panel discussions that had keratoconus as a primary or secondary focus.

While such traditional keratoconus (and post-LASIK ectasia) treatments as rigid gas permeable contact lenses, Intacs corneal inserts and corneal transplantation received their share of researchers' attention in the presentations, the real interest at ARVO was on the progress being made on many fronts in corneal collagen crosslinking, a therapy that is of major interest because it can help patients (with minimum corneal thickness of 400 µm and no other contraindications such as prior herpetic infection or corneal scarring) who otherwise would have to undergo a corneal transplant procedure.

Developed in Germany in the 1990s and used routinely in Europe for the past decade as a way to strengthen the cornea and actually reverse the visual deficits caused by keratoconus and post-LASIK ectasia, collagen crosslinking is estimated by authoritative researchers to still be about two years away from FDA approval in this country. Currently, numerous studies are taking place in an attempt to determine the best approaches and techniques for achieving the most positive outcomes with this highly innovative therapy, which essentially involves saturating the cornea with riboflavin and then exposing it to a beam of ultraviolet light for a specific time period.

The “epi-off” method of collagen corneal cross-linking that is illustrated above first saturates the cornea with riboflavin. ILLUSTRATIONS COURTESY OF AVEDRO CORP.

Here, I will examine several of the most noteworthy presentations on corneal collagen crosslinking recently presented at this year's ARVO meeting, while also touching on research relating to the more traditional treatments for keratoconus.

Epi-off or Epi-on

One of the biggest debates now going on among top researchers in corneal collagen crosslinking is whether the procedure should be performed with the epithelium off or with the epithelium on.

Corneal specialist Yaron Rabinowitz, MD, of Beverly Hills, has received National Eye Institute funding for his research on keratoconus continuously since 1993, the largest single grant for the study of keratoconus and potential treatment options. Dr. Rabinowitz is almost fierce in his belief that crosslinking should only be performed with the epithelium removed.

“Epi-off is the only methodology that has been laboratory tested and has been shown to be safe in the treatment of humans,” he contends. “Epi-on is advocated only by a handful of doctors, the vast minority doing this procedure.”

At this year's ARVO meeting, Dr. Rabinowitz and his co-author, Ronald Gaster, MD, reported on a study they had conducted involving 32 patients who had undergone “epi-off ” cross linking. The purpose of the study was to compare the outcomes of 26 patients who had experienced mechanical debridement of the epithelium against six patients who had the epithelium removed by a laser. The mean age of both patient cohorts was similar at 22.5 years for the laser group and 23.5 years for the mechanical debridement group.

At six months, the researchers found that, in the laser group, mean uncorrected visual acuity improved by 3.1 lines while the mechanical group improved by only 1.5 lines.

No patients in the laser group lost any lines of vision but 30% of the patients in the mechanical group lost one or more lines.

Drs. Rabinowitz and Gaster concluded that the “early results suggest that laser crosslinking gives better early visual outcomes than standard crosslinking using the epi-off technique. Uncorrected acuity using this technique is superior to any published data on epi-on studies.” The authors noted that “larger sample sizes need to be studied to determine if laser crosslinking should become the preferred technique for removing the epithelium during crosslinking.”

An interesting contrast to the epi-off study is an epi-on ARVO presentation by researchers led by Roy Rubinfeld, MD, of Chevy Chase, Md.

In this 181-eye study, outcomes were followed from a minimum of three months to 18.7 months maximum, with mean follow-up time of 10 months. Measures such as cornea hysteresis, corneal resistance factor and astigmatism all showed marked improvement.

In terms of best spectacle-corrected visual acuity (BSCVA), 46.4% of eyes gained one or more lines, 38.5% experienced no change and 30.2 % had a loss of one or more lines of vision. Average PSCVA was 20/145 preoperatively and 20/114 postop.

The researchers concluded that epi-on crosslinking “appears to be a safe and effective treatment for patients with corneal ectatic disease.”

Longer-Term Outcomes in Crosslinking

In an interesting ARVO presentation following the clinical time course of 85 eyes that underwent crosslinking for either keratoconus or ectasia, researchers led by Peter Hersh, MD, of Teaneck, NJ, performed a battery of comprehensive functional and structural tests on patients at baseline, one month, three months, six months and one year.

The researchers found what they called “a generally definable time course,” with worsening of the relevant metrics at one month, returning to baseline at three months, improvement at six and 12-months, and stabilization beyond one year.

The improvements at one year postop were significant and seen in BSCVA, night driving, reading, diplopia, glare, halo and starbursts.

A precisely timed beam of ultraviolet-A light is used in crosslinking to strengthen mechanical properties of the cornea.

A longer-term, three-year study of crosslinking outcomes in 97 eyes was conducted by researchers led by Dan Epstein, MD, of Zurich. BSCVA, refraction, topography, tomography and aberrations were all documented periodically.

At 36 months, 61% of eyes had gained two or more lines of BSCVA and all other measures of corneal health had shown marked improvement. The researchers noted that improvement was across all age groups.

“Improvement in BSCVA is likely due to the significant reduction of corneal asymmetry and wavefront aberrations,” the researchers concluded.

Another longer-term study, this one conducted by researchers in Bern, Switzerland, involved 29 eyes of 23 children and adolescents (mean age 14.8 years) who had progressive keratoconus and were treated with corneal cross linking. The patients were examined preoperatively and at one, four, 12, 24 and 36 months, with a mean follow-up period of 20.7 months.

The researchers reported that BSCVA was either unchanged or improved in every treated eye, while other relevant metrics either improved or remained stable through-out the follow-up period.

The researchers concluded that corneal crosslinking is effective in arresting keratoconus progression in children and adolescents.

Presentations on Corneal Transplant

Though the major buzz at ARVO centered on new advances and techniques in corneal crosslinking, traditional treatments for keratoconus were not ignored.

An interesting presentation by researchers Anna Djougarian and Gerald Zaidman, MD, of Valhalla, NY, followed 37 eyes of 21 children and adolescents. Of these, 26 eyes had corneal transplant surgery for keratoconus between 2000 and 2008 and 11 (most with lesser visual deficits) did not. The patients were followed through 2011. Six eyes presented preoperatively with hydrops and were not recorded for BCVA.

Of the remaining 20 eyes that underwent corneal transplant, six eyes had preoperative BCVA of 20/30 to 20/50, 6 had BCVA of 20/70 to 20/100, seven had BCVA of 20/150 to 20/400 and one eye was counting fingers. Twenty-five of the 26 eyes operated on had clear grafts, though 13 eyes experienced graft rejection episodes. Twelve of those 13 eyes cleared after treatment and one graft failed due to graft rejection. No eyes developed cataracts.

At the most recent follow-up, 22 of the 25 eyes with clear grafts had BCVA greater than 20/40, with 10 of those 22 eyes at 20/25 or better. One eye was 20/60, one was counting fingers and one was 20/100 due to a wound dehiscence after blunt corneal trauma.

The researchers concluded that 85% of the pediatric patients followed did well following corneal transplant surgery with excellent visual recovery. Though there was a 50% incidence of graft rejection, nearly all cleared with medical therapy.

Another corneal transplant study, conducted by researchers in London, evaluated outcomes in which femtosecond-laser assisted mushroom configuration PK or DALK was performed in 11 eyes of 11 patients (mean age 31) with advanced keratoconus. Four patients underwent PK and seven DALK (two of these converted to PK intraoperatively due to Descemet's membrane perforations). Preoperative risk factors included four eyes with previous hydrops and one eye that had undergone LASIK.

Mean follow-up was 10.7 months.

Noting that they had taken on cases of advanced keratoconus with pre-existing high-risk characteristics, the researchers concluded that the femto-assisted treatment technique provided good wound approximation and wound healing while producing visual results comparable to patients with less severe disease.

A Three-Month Study of Intacs

Another study conducted by Dr. Hersh sought to determine the value of Intacs corneal segments in improving UCVA and BCVA over a three-month period. Placement of Intacs inserts can improve tolerance for hard contact lenses and delay the need for corneal transplant.

The study was a single-center retrospective review of patients who received Intacs for treatment of keratoconus or corneal ectasia. There were 31 eyes of 30 patients with a mean age of 43 years. Patients were divided into subgroups based on the Intacs segment size they received. Mean UCVA preoperatively was 20/230 while mean BCVA preoperatively was 20/54.

At three months postop, mean UCVA had improved to 20/142 and mean BCVA to 20/48.

Other relevant measures such as mean refractive spherical equivalent and corneal astigmatism also were significantly improved. UCVA improved significantly only in the subgroup with symmetric 350 µm segments, while corneal astigmatism improved significantly only for the subgroup that received asymmetric segments.

The researchers concluded that Intacs can be a beneficial treatment for keratoconus and corneal ectasia.

Other ARVO presentations

► Researchers in London found that scleral contact lenses can be a useful tool in the management of keratoconus and in improving visual acuity.

► Japanese researchers suggested that keratoconus patients who wear rigid gas-permeable contact lenses should be examined often because frequent prescription changes are common in these patients. Most frequent types of changes found by these researchers were lens power, base curves, lens designs and lens sizes.

► Finally, researchers in Mexico conducted a random review of 500 patient charts for adolescents and found that 1.8% of the patients had been treated for keratoconus. In the United States, it is estimated that the incidence of keratoconus is approximately one in 2,000 individuals. OM