research digest

Study Explores Drug's Potential Neuroprotective Effect in Humans

Stefano Gandolfi, M.D., recently studied whether there is a neuroprotective effect associated with brimonidine (Alphagan) -- unrelated to its known effect on IOP -- in patients with glaucoma. He evaluated this novel, but not yet proven, concept prospectively in a randomized trial of 52 eyes.

"This study is the first that has offered some evidence of a drug effect unrelated to IOP in visual field deterioration in human glaucoma. The results of this study must be confirmed by other trials in order to reach a reliable level-of-evidence," Dr. Gandolfi noted.

Researchers assigned 27 eyes to treatment with brimonidine and 25 eyes to receive argon laser trabeculoplasty (ALT). To be eligible for the study, patients were required to have proven glaucomatous visual field defect; an IOP of less than 20 mmHg and treatment with at least two drugs; open-angle, glaucomatous optic neuropathy; a clear lens; a BCVA better than 0.2 LogMAR; no AMD; and no neurological diseases.

In an 18-month run-in period, ongoing therapy was administered and patients' visual fields and IOP were continually assessed. Patients had visual acuity and optic disc evaluated every 3 to 4 months, with a total of five or six visual fields performed on each eye.

After the run-in period, patients were randomized to treatment with 0.2% brimonidine twice a day or a 360° ALT procedure. Patients who had a less than 10% drop in their IOP were crossed over to the other treatment. During the 18 months of follow-up, the same assessments were performed as described above for the run-in period.

After the eyes that failed the original treatment were crossed over to the other arm, 29 brimonidine eyes qualified for follow-up as did 21 ALT eyes. A total of 41 eyes completed follow-up: 22 brimonidine and 19 ALT.

The data showed:

► Among eyes in the brimonidine group, the average mean slope preoperatively was -1.37 dB/yr
vs. -0.99 dB/yr for those in the ALT arm (p=.488).

► Among eyes in the brimonidine group, the average mean slope postoperatively was +0.85 db/yr vs. -0.77 db/yr for in the ALT group (p=.0009).

► The average pre-op IOP among eyes in the brimonidine group was 18.51 mmHg vs. 18.67 for those in the ALT group (p=.49).

► The average post-op IOP was 15.7 mmHg for brimonidine-treated eyes vs. 14.6 mmHg for ALT- treated eyes (p=.004).

Dr. Gandolfi concluded that brimonidine treatment had a significant effect on mean slope (power = 90%, alpha probability = 5%). Eyes of patients taking brimonidine had a slower field progression compared with the ALT eyes (power = 85% and alpha probability = 10%).

Even though brimonidine was poorer at controlling IOP than ALT, it was more effective for reducing field deterioration in patients with progressive glaucoma.

[Dr. Gandolfi has no financial interest in Allergan or brimonidine. He is an investigator for a current Allergan-sponsored multicenter randomized clinical trial and a member of the speakers' bureau.]

Comparing Fourier Analysis with Zernike Polynomials

Stephen D. Klyce, Ph.D., said recently that while Zernike polynomials are useful for decomposing and measuring lower-order aberrations of the eye, in order to fully understand and quantitate all aberrations, a 2-D Fourier analysis is superior.

"In performing custom ablations, the goal is not only to correct sphere and cylinder, but to converge light rays through an aberrated eye onto the posterior part of the globe," Dr. Klyce said. This becomes a big challenge when eyes have severe aberrations.

Because Zernikes perform what is basically a smoothing function, there is room for error when this technique is applied to a wavefront from an eye with a complex cornea. In a clinical trial involving more than 500 patients, Dr. Klyce and his colleague Michael K. Smolek, Ph.D., looked at patients with keratoconus following penetrating keratoplasty and after hyperopic corrections. They correlated the vision of those patients with the wavefront RMS as fit with Zernike polynomials. There was a good correlation between the patients' vision and their eyes' aberrations as expressed by the Zernike terms. However, there was an equally strong correlation between the patients' vision and the Zernike fit error, as the researchers found in a subgroup of 88 patients.

This means that the Zernike polynomials do not really fit all of the aberrations that need to be corrected by a customized procedure. In corneas that have more complex shapes and aberrations, a better describing function is needed to correlate wavefront with visual acuity, Dr. Klyce said.

So, he investigated the results of using the wavefront information to directly calculate the point spread function in an eye. The two-dimensional Fourier transform of the pupil function is used to calculate the point spread function.

Performing the calculation results in a raw point spread function with a significant amount of distortion. The noise of the measurement can also be calculated and removed to produce a clean image that should be the actual point spread function produced in that eye.

"To date, most of the customized treatments have corrected vision in fairly normal ammetropic eyes with clinically insignificant amounts of higher-order aberrations," Dr. Klyce said.

"For this purpose, the Zernike polynomial decomposition method has been adequate. However, as laser sculpting moves into the arena of correcting vision in aberrated eyes, this mathematical approach will not be adequate to capture all the aberrations significant to good visual acuity. Better methods, such as 2-D Fourier transforms, more accurately capture higher-order aberrations."

[This work was supported by a research grant from the National Eye Institute; Dr. Klyce received no financial support from any source.]

Latest Phaco Technology Promotes Safer Procedure

Phacoemulsification performed with the AMO Sovereign system and WhiteStar software resulted in fewer torn posterior capsules and vitrectomies. To evaluate the relative safety of this technology, William J. Fishkind, M.D., studied vitrectomy rates for surgeries performed in his ambulatory surgery center.

Dr. Fishkind performed a retrospective analysis of the vitrectomy rates among 1,361 eyes. From 1989 to 1998 he used the Alcon 10,000 and the AMO Prestige machines to perform phaco. In 1999 he used only the Prestige machine for phaco and from January 2000 to May 2001 he used the standard AMO Sovereign machine.

The AMO Sovereign machine combined with the WhiteStar software was introduced in his practice in June 2001. For the purpose of this study, he evaluated cases performed up until November 2003.

The vitrectomy rate in Dr. Fishkind's ASC from 1989 to 1998 was 1.19%. That rate increased to 2.5% for 1999, but then dropped again to 0.43% from January 2000 to May 2001. From June 2001 to 2003, Dr. Fishkind reported a vitrectomy rate of 0.66%.

"Although there are many factors which influence vitrectomy rates during phaco," Dr. Fishkind said. "The WhiteStar's new technology allows more anterior and safer phaco, as demonstrated by the decreased incidence of vitrectomy."

[Dr. Fishkind is a consultant for AMO.]

Once-a-Day Allergy Drop Shown to be Safe, Effective

A new 0.2% formulation of olopatadine HCl ophthalmic solution (Patanol), dosed once a day, was safe and effective for the treatment of symptoms in patients with seasonal allergic conjunctivitis or rhinoconjunctivitis. This new formulation of an existing product is currently awaiting FDA approval for once-a-day dosing.

Mark Abelson, M.D., recently presented results from a double-masked, randomized, placebo- controlled study of the 0.2% formulation. In this hybrid environmental study, 260 allergic patients were assigned to receive either olopatadine 0.2% or placebo, once daily for 10 weeks. The investigators asked patients to evaluate and report the frequency of their signs and symptoms on a weekly basis.

At each study location, a daily grass pollen count was recorded. To compare treatment differences in the slopes for ocular signs and symptoms as a function of pollen count, repeated measures of analysis of variance were used. Key findings:

► Patients in the olopatadine group had significantly less ocular itching and redness due to pollen when compared with patients receiving placebo. The p-values for itching and redness were .0382 and .0220, respectively.

► Investigators compared the slopes of the lines predicting pollen effects on ocular itching and redness and found a significantly lower slope among the olopatadine group vs. the placebo patients.

► In the treatment group, the slopes were 0.008260 for ocular itching and .006032 for redness vs. 0.010746 and 0.008569, respectively, in controls.

When patients' mean scores for itching and redness upon each visit were compared, olopatadine was statistically superior to placebo. There were no patient discontinuations or serious adverse events.

"Olopatadine 0.2% ophthalmic solution is safe, well-tolerated, and effective when dosed once daily for the treatment of the ocular signs and symptoms of allergic conjunctivitis," Dr. Abelson concluded.

[Dr. Abelson was unavailable to confirm his financial interest status or lack thereof.]

LASIK, Phakic IOLs or Lensectomy for Which Myopic Patients?

Richard Lindstrom, M.D., recently conducted a literature review of several thousand patients in order to help surgeons evaluate the appropriate roles for LASIK, phakic IOLs and refractive lensectomy for managing myopic patients.

"The surgical armamentarium is rich and these procedures provide good visual outcomes among patients with any degree of myopia," Dr. Lindstrom said. "This review attempts to help surgeons select the right approach for the patient, based on the evidence available."

According to this review, which also included outcomes from the Minnesota Eye Consultants, the best procedure for patients with low to moderate myopia (-1D to -6D) is custom LASIK.

Dr. Lindstrom reported that there were equal outcomes with each of the three approaches in patients with high myopia (­6D to ­10D), so the choice lies with the surgeon and the patient. However, if the patient has a thick cornea or a shallow anterior chamber, LASIK is the favored procedure.

On the other hand, patients who have thin corneas and normal-depth anterior chambers appear to do better with phakic IOLs. Patients with presbyopia and cataracts should opt for refractive lensectomy for the treatment of high myopia.

Phakic IOL or a refractive lensectomy is indicated by the evidence for patients with extreme high myopia (greater than -10D). Usually, younger patients who have a clear lens should opt for phakic IOL for treatment of extreme high myopia. Evidence favors refractive lensectomy in older patients who are in the presbyopic age group or have cataracts.

Presbyopic patients with +1D to +6D corrections should receive refractive lensectomy with multifocal or accommodating IOL.

"Surgeons should select the best procedure for each patient based on objective outcomes," Dr. Lindstrom said.

[Dr. Lindstrom is a consultant for Bausch & Lomb, AMO, Santen, TLC Vision, Eyeonics and STAAR.]

1-Year Results for Uveitis Implant Reported

A fluocinolone acetonide implant was effective for controlling inflammation and improving visual acuity among patients with uveitis. Bausch & Lomb is developing the system and it plans to file with the FDA this year for a uveitis indication.

During a recent meeting, Glenn Jaffe, M.D., reported 1-year results of the multicenter, randomized, dose-masked trial, which was designed to evaluate a sustained-release fluocinolone acetonide intravitreal implant in patients suffering from posterior segment uveitis. One eye of the 278 patients in the trial was randomized to either a 0.5-mg or 2.0-mg implant; the fellow control eye had no implant.

Investigators measured recurrence rate, visual acuity, and adjunctive therapy use. The 1-year results showed that the combined recurrence rate for the two implant doses was 4.3% vs. 56.3% for the nonimplanted fellow eyes (p<.0001).

A significantly higher proportion of eyes with the fluocinolone acetonide implant compared with nonimplanted eyes had a three or more line visual acuity improvement at 34 weeks (26.2% vs. 6.2%).

The eyes with the fluocinolone acetonide implant also required significantly less treatment with adjunctive therapy. While at baseline 59.0% of patients used systemic corticosteroid and/or immunosuppressive therapy, at 1-year following implant only 12% of patients were using these additional treatments (p<.0001).

About 70% of the treated eyes received sub-Tenon injections in the 12 months before implantation of the sustained-release fluocinolone acetonide vs. just 4% following implantation (p<.0001). The rate of topical steroid usage also declined (p<.0001).

Serious adverse events most commonly reported were a 25.9% rate of cataract extraction and a 11.9% instance of filtering procedures.

"It is important to note that IOP and lens clarity must be closely monitored in patients with uveitis," Dr. Jaffe said.

[Dr. Jaffe has a financial interest in Control Delivery Systems.]