NIH chief sees shift toward prevention in research

FORT LAUDERDALE, Fla. — A shift in research focus from disease treatment to disease prevention, now under way at the National Institutes of Health, is creating “much excitement for advancement in the field of vision research,” said Elias A. Zerhouni, MD, director of the NIH.

Dr. Zerhouni addressed this change in focus at the NIH in a keynote speech here at the annual meeting of the Association for Research in Vision and Ophthalmology.

“As a strategy in science, you want to minimize the health burden and maximize the health benefits,” Dr. Zerhouni told attendees.

The traditional approach to medical treatment has been to intervene when a disease becomes intolerable and the health burden is great, Dr. Zerhouni said. Patients may have reinforced this treatment mentality with the belief that the value of medicine is greater once a disease has become more serious, he added.

One of the new goals of the NIH is to delay the onset of debility from disease, Dr. Zerhouni said. Medicine has already been able to do this with chronic diseases such as cystic fibrosis and HIV/AIDS, he noted. While science has not yet been able to cure or prevent those diseases, patients are living longer and better with treatment, he said.

“Over the past 30 years, there has been a paradigm shift from [treating] acute to chronic conditions,” Dr. Zerhouni told attendees.

As the population ages, chronic eye diseases such as age-related macular degeneration and glaucoma will be among the vision disorders that are most disabling to society, he said.

The large aging population, health disparities among the public, emerging diseases and the need for biodefense will be important areas of research in the 21st century, Dr. Zerhouni said. All these factors will have an effect on the state of the public health, he said.

The new NIH research goals will encourage clinicians to pursue studies to understand the biological network of molecules, Dr. Zerhouni said. Nanomedicine is an area that needs further exploration, including a greater understanding of the role of RNA-interference technology in vision, he said.

“[We want to] stimulate the creation of academic entities dedicated to translational science, [to] be the link between basic and clinical science,” he said.

Nobel winner speaks

Peter Agre, MD, a 2003 Nobel Prize award recipient in chemistry, spoke about his research on aquaporins, proteins that carry water throughout the body. Image: Johns Hopkins University and The Nobel Organization

The man who first identified aquaporins described how they function in the eye to ARVO attendees.

Peter Agre, MD, a 2003 Nobel Prize award recipient in chemistry, spoke about his research in understanding the mechanism of aquaporins, proteins responsible for carrying water throughout the body.

“Water is a major component of our cells and tissues, including our eyes,” Dr. Agre said. “A fundamental problem is the movement of water among biological components, [such as] what happens in the eye with aqueous humor.”

Before he and his colleagues undertook the challenge of identifying, isolating and cloning a water channel, “the issue of water transport was thought of as a diffusion problem,” he said.

In the eye, there are aquaporins in the lens and the corneal endothelium, as well as in the ciliary body, the iris and the trabecular meshwork, he said. Aquaporin mutation may be responsible for conditions such as cataract, he said.

“The structure understood at the anatomic level is implicated in multiple disorders,” Dr. Agre said.

Molecular medicine is the field that will be challenged with understanding the cellular and subcellular components where aquaporins are expressed, Dr. Agre said. More research must be done to understand how aquaporins work in the body on a systemic level, he noted.

Dr. Agre shared the Nobel Prize in chemistry in 2003 with Roderick MacKinnon, who was awarded the prize for his research on the passage of salts among cell membranes.

Factor H, AMD development

A variation of the gene called factor H may have a role in triggering the onset of AMD, according to several speakers.

A study appearing in May in the Proceedings of the National Academy of Sciences, led by Rando Allikmets, PhD, of Columbia University Medical Center, found that a gene variant of the polymorphism complement factor H (CFH) — an immune protein that regulates infection in the retinal pigment epithelium — may inhibit the suppression of inflammation. Patients with this gene variant are more likely to develop AMD later in life, according to a press release from Columbia.

“This is an exciting new development,” C. Thomas Caskey, MD, said in a presentation. “The discovery of factor H provides a very significant lead to AMD research because it confirms what many researchers have thought all along – AMD may be an inflammatory disease.”

“We now understand the genetic variation that is behind AMD and are beginning to target the trigger that sets the process in motion,” Dr. Allikmets said in the press release. “By targeting the molecules involved in inflammation and its regulation we believe we can begin to develop therapies and diagnostic tools that could help countless people keep their sight.”

Dean Bok, PhD, acknowledged the importance of the findings of Dr. Allikmets and colleagues during his presentation. Dr. Bok described the molecular structure of CFH: “CFH is a plasma protein that regulates compliment activation in the amino acid sequence. When a non-silent variant CFH is present, changes are produced in the sequence.”

Dr. Caskey explained further, “[This sequence change] could mean a decrease in function relating to structure, specifically inflammatory response.” He said that this genetic finding appears to “open a plethora of therapeutic options” for AMD patients, but he cautioned that CFH research still has many hurdles to overcome.

“More research is needed to confirm the mechanism behind factor H and the implications for AMD treatment and prevention,” Dr. Caskey added.

Lucentis extension study

Ranibizumab was well tolerated in patients with AMD who received a reduced dosage of the drug for more than a year after an initial clinical trial, according to a poster presentation.

“Subjects receiving Lucentis [ranibizumab, Genentech] had stable visual acuity and stable lesion characteristics despite a reduced frequency of injections,” Jeffrey S. Heier, MD, and colleagues reported.

Patients from phases 1 and 2 of the Lucentis clinical trials who lost less than 15 letters of vision during the trials (94%) were eligible for the extension study. A total of 70 patients enrolled in the extension. Due to a study protocol amendment, the initial dose of 0.3 mg was increased to 0.5 mg per injection. Injection frequency was reduced from one injection every 4 weeks to a flexible dosing interval that relied on visual acuity and lesion characteristics to determine the treatment schedule, Dr. Heier said.

By the final follow-up visit (mean 415 days), patients had averaged 0.22 injections every 4 weeks. The study authors said “ranibizumab continued to be well tolerated” and visual acuity remained stable.

Adverse events included conjunctival hemorrhage, increased IOP, blurred vision, iris and uveal tract inflammation. These side effects were mild or moderate in all patients, Dr. Heier said.

Squalamine with PDT

Yachts line the port of Fort Lauderdale, where the Fort Lauderdale Convention Center, the site of ARVO, is located. Image: N Nader

The angiogenic inhibitor squalamine was found to be safe and well tolerated in conjunction with photodynamic therapy in patients with subfoveal neovascularization, according to results from a phase 2 clinical trial.

“The drug was safe, tolerated and showed a trend toward visual stability and improvement,” Thomas A. Ciulla, MD, said. While a trend in improved visual acuity was noted, he said, the visual benefit was not statistically significant when compared to visual outcomes with PDT and placebo.

“The trend toward visual improvement was not significant in this small early study. But we expect to see further benefit in a larger multicenter trial,” Dr. Ciulla noted. Phase 3 of the squalamine trial is currently in the planning stages, and study sites are being selected.

Squalamine will be marketed as Evizon by Genaera Corp. in the United States if it earns regulatory approval, Dr. Ciulla said.

In the phase 2 trial, 45 patients with subfoveal neovascularization marked by minimally classic, predominately classic or occult lesions were enrolled. Patients were randomized to either squalamine injections of 10 mg, 20 mg or 40 mg concomitant with Visudyne (verteporfin for injection, QLT/Novartis) or to verteporfin PDT and placebo.

“Patients randomized to squalamine and PDT tended to have stable visual acuity over time and shared an average gain of 1.3 lines of visual acuity,” Dr. Ciulla said. Patients who underwent PDT and placebo tended to have decreased visual acuity, with an average loss of one line of vision.

TTT follow-up data

Transpupillary thermotherapy was associated with a significant clinical benefit in a subgroup of patients with wet AMD in a clinical trial comparing the laser treatment to sham treatment, according to Elias Reichel, MD.

Preliminary results of the trial in 60 patients were released in February, Dr. Reichel said. He updated the results to include 305 patients who have reached the 18-month follow-up point in the trial. These confirm the earlier results, Dr. Reichel said.

The TTT4CNV Clinical Trial compared treatment with transpupillary thermotherapy (TTT) with a sham placebo treatment. As in the earlier results, a subgroup of patients in the TTT4CNV trial with a baseline visual acuity of 20/100 or worse demonstrated a benefited from TTT compared with placebo. About 41% of the patients enrolled in the trial had a baseline visual acuity of 20/100 or worse, according to a press release from Iridex, the sponsor of the trial.

At 12 months after treatment, 23% of the eyes treated with TTT in this subgroup showed improvement of vision by one or more lines, and 14% of eyes treated with TTT showed improvement of vision by three or more lines. No eyes in the placebo group showed improvement.

At the 18 month follow-up, there was a two-line benefit in preserving vision in this subgroup compared with the placebo-treated eyes, according to Iridex. On average, eyes treated with TTT lost two lines of visual acuity while those on placebo lost four lines.

These differences were statistically significant, according to the company.

“These less-than-or-equal-to-20/100 subgroup findings indicated that TTT is beneficial compared to natural history in eyes with subfoveal occult choroidal neovascularization and best-corrected visual acuity of 20/100 or worse,” Dr. Reichel said in the press release.

Blue Mountains Study

The risk of retinopathy development in a senior Australian population without diabetes was found to be 9.7%, according to a study.

Sudha Cugati, MD, presented the 5-year follow-up data on a cohort of 1,725 non-diabetic participants in the Blue Mountains Eye Study regarding the development of retinopathy lesions. “Findings from this older population [age 49 years and greater] confirm that retinopathy lesions develop relatively frequently in older persons without diabetes,” Dr. Cugati said.

At 5-year follow-up, retinopathy lesions were evident in 10.6% of study participants. “This incidence was positively correlated with an increasing age,” Dr. Cugati noted.

Newly isolated microaneurysms were found in 3.6% of subjects, 5.5% of subjects developed hemorrhages, and 1.6% of participants developed multiple lesions. An increased risk of these symptoms was noted in women, patients with elevated glucose levels and stage 1 or 2 hypertension. Dr. Cugati said the differences associated with these variables were not statistically significant.

Macular retinoblastoma

Aggressive management with chemotherapy and repeated laser applications resulted in tumor control in a large percentage of patients with macular retinoblastoma, according to a study.

“Retinoblastoma patients were treated successfully with aggressive chemotherapy and repetitive focal laser treatment applied directly to the fovea,” said Amy C. Schefler, MD. A retrospective study at the Bascom Palmer Eye Institute in Miami of 45 eyes of 34 patients with macular retinoblastoma found that tumor control and avoidance of enucleation was achieved in 87% of eyes treated with the aggressive regimen.

Patients classified by the Reese-Ellsworth system as having stages 1 to 4 retinoblastoma (group 1) received four to nine cycles of systemic chemotherapy with vincristine, etoposide and carboplatin (standard treatment for cancer patients). Patients with stage 5 disease (group 2), received six to 10 cycles of the chemotherapy, with or without cyclosporine. All patients underwent focal laser treatment with a diode laser at every visit until symptoms resolved or tumors became inactive.

With a median follow-up of 42 months, Dr. Schefler said, all patients in group 1 with mild to moderate disease avoided external beam radiation or enucleation. Six patients in group 2 required enucleation, but no patient in the study needed external radiation, she said. Additionally, no patients developed metastatic retinoblastoma or a second malignancy, and none died within the study interval.

Complications included iris atrophy (64%), peripheral focal lens opacity (13%), peripheral anterior synechiae (4%) and foveal neovascular membrane (2%).

Retisert for uveitis

Patients who received a sustained-release fluocinolone acetonide implant had a significantly lower rate of uveitis after implantation than in the year before implantation, according to Glenn J. Jaffe, MD. The need for adjunctive therapy was also reduced in treated eyes, he said.

Dr. Jaffe presented results of a 2-year phase 2b/3 study of the device. Retisert (fluocinolone acetonide intravitreal implant, Bausch & Lomb) is an extended-release implant, designed to deliver the corticosteroid to the back of the eye over a period of approximately 2.5 years. The device was approved for treatment of posterior uveitis by the Food and Drug Administration in April.

Glenn J. Jaffe

“There was a low rate of recurrence of uveitis,” Dr. Jaffe said during a press briefing at the meeting. “The use of systemic steroids, immunosuppressant or periocular injections was also reduced significantly in patients implanted with the device.”

In the study, 278 patients with uveitis were randomized to implantation in one eye with either a 0.58 mg or 2.1 mg formulation of Retisert. The uveitis recurrence rate before implantation in the treated eye and the rate in the untreated fellow eye were used as controls.

The recurrence rate in treated eyes declined from 59.7% before implantation to 5.4% after implantation at 1 year postop. By 2 years, the eyes implanted with the Retisert device had a recurrence rate of 11.2%, compared with more than a 50% recurrence rate in the untreated fellow eyes. This difference was statistically significant, Dr. Jaffe said.

“The recurrence rate dropped dramatically in the study eye, whereas in the fellow eye it actually increased dramatically from 25.4% at baseline,” he noted.

The need for adjunctive therapy with steroids or immunosuppressant in the study eyes was reduced by 2 years postop, from 52.5% to 12.5%, and the need for periocular injection of steroids was reduced from 68% to 9.7%, Dr. Jaffe said. In the fellow eyes, the need for adjunctive therapy increased from 30.4% before study enrollment to 45.3% after study enrollment.

The Retisert implant is expected to become available this summer, according to Bausch & Lomb.

Retinal stem cell research

The field of retinal stem cell research has seen great advances in the past decade, but work still lies ahead, according to researchers.

“There has been spectacular progress in this field, but there are still great challenges,” said Ruben R. Adler, MD. He discussed his current efforts in stem cell research, in which he seeks to replace degenerated photoreceptor cells with healthy cells.

“When photoreceptors die, they don’t come back,” Dr. Adler explained. “We are trying to replace these dead cells with healthy stem cells to prevent blindness.”

One problem with culturing stem cells, he said, is that, at present, there is “no magic bullet” to turn progenitor cells into mature synaptically connected photoreceptors.

“What we need is a growth factor that would speed up the transformation,” Dr. Adler noted.

In a separate presentation, Derek van der Kooy, MD, explained that stem cells used in retinal research are often taken from the ciliary marginal zone of the retina. He said the advantage of stem cells is their “multipotentiality” and “self-renewal,” which makes them ideal tools for ocular tissue regeneration.

“In culture, one human stem cell can proliferate to 10,000 stem cells in just a week,” he said. At the University of Toronto, Dr. van der Kooy has been cloning human retinal stem cells and studying their response to implantation in living animals.

“We are trying to put human receptor stem cells in mouse eyes to see if the cells integrate well,” he said.

Cell integration and biocompatibility are crucial to success whether dealing with stem cells or with implanted artificial tissue, said Raymond Lezzi, MD, in another presentation. Speaking about retinal prostheses, he said improving the “interface” of foreign material implanted in diseased or degenerative tissue may be achieved through therapeutic adjuncts.

“Drug delivery may be helpful in fighting off rejection of retinal prostheses and will improve the biocompatibility of the prosthesis,” Dr. Lezzi said.

Shigeru Kinoshita, MD, PhD, another presenter at the session, who has developed corneal epithelial stem cell sheets for use in patients with corneal degeneration, agreed that tissue integration is vital. He said the rejection rate declines significantly when patients implanted with his corneal graft material are managed with immunosuppressant therapy.

Selective retinal therapy

Selective retinal therapy was found to be a safe and effective treatment for focal diabetic maculopathy, according to a poster presentation.

Study author Hanno Elsner, MD, and colleagues reported that selective retinal therapy (SRT) is safer than conventional argon laser therapy because SRT selectively targets degenerative retinal pigment epithelial cells without damaging the surrounding retinal structures.

“It offers the potential for earlier treatment and the possibility of treating closer to the fovea without the side effects associated with conventional [treatment],” the study authors said in their poster. In a study of 60 patients, with 6 months’ follow-up, SRT reduced retinal thickness and lesion leakage, preserving or improving visual acuity in 88.7% of patients.

Patients underwent SRT treatment with a frequency-doubled, Q-switched Nd:YLF laser, which emitted 30 pulses at a repetition rate of 100 Hz. At 3- and 6-month follow-ups, retinal thickness decreased from 244 µm to 230 µm in the fovea and 351 µm to 330 µm in the edematous macular area. Lesion leakage was reduced in 31.1% of patients, remained stable in 52.1% of patients and increased in 15.8% of patients.

Imaging retinal abnormalities

A non-mydriatic optical imager from Optos detected a high prevalence of retinal abnormalities in a population with little or no known eye disease, according to a poster presentation.

“The Panoramic 200A facilitates an effective means of screening for retinal abnormalities in subjects who might otherwise be reluctant or disinclined to present for dilated funduscopic examinations,” J. King, MD, and colleagues reported.

In the study, 512 eyes of 269 participants were voluntarily screened for retinal abnormalities in an exhibit hall setting. Only 26% of eyes were considered to be within “normal” physiological limits, the authors said.

Retinal images were obtained and reviewed by an ophthalmologist who found drusen in 19.1% of participants, macular drusen in 11.3% of participants and “suspicious” optic nerves with apparent thinning of the neural rim in 9.2% of participants. Nearly 44% of eyes had peripapillary pigment atrophy, 16.1% had peripheral pigmentary changes, and choroidal nevi were apparent in 6.9% of eyes.

Study authors noted that few subjects were aware of their existing eye disease. In a company press release, Optos officials said that the instrument “appears to offer distinct advantages over standard 30° fluorescein angiography, particularly with respect to diabetic retinopathy.”

Optos added that the imager may be an option for evaluation and treatment of ocular oncologic pathology.

OCT and LASIK patients

Optical coherence tomography is a useful tool in monitoring corneal healing in LASIK patients, according to a poster presentation.

Sameena Haque, BScOptom, MCOptom, and colleagues investigated OCT images to “assess how light backscatter profiles change after LASIK, expecting to see the intensity of the flap interface reduce with time.”

In the study, both eyes of 27 LASIK patients were monitored. Central corneal OCT measurements were taken preoperatively and at 1 day, 1 week and 6 months after surgery.

At 1 day postoperatively, the flap interface could be clearly seen on the OCT image, the researchers said. Preoperative intensity was greater than post-incision intensity, and this remained true throughout the 6 months of follow-up. The researchers said that scatter intensity did not increase to baseline levels, and it was “still significantly different at 6 months.”

The researchers said the interface was not always easily visualized in the OCT images.

They concluded that “the intensity and width of interface scatter decreases with time, suggesting a reduced area of healing at 6 months.”

Epithelial re-growth

A patient who had wavefront-guided photorefractive keratectomy showed epithelial re-growth in less than 2 weeks, according to a case study.

Charles E. Campbell, PhD, and colleagues studied day-to-day surface changes after PRK in two eyes of the same patient throughout the course of 1 year. They reported the results in a poster.

Carmen A. Puliafito, MD, MBA, told attendees at a symposium that researchers and clinicians have recognized that vascular endothelial growth factor (VEGF) is a crucial element in the successful treatment of acute neovascularization.

The PRK was performed with the Visx CustomVue wavefront system for the Visx Star S4 excimer laser. Corneal topography measurements were taken almost daily, the researchers said, beginning on the fourth day after surgery, immediately after a bandage contact lens was removed, for 1 month and then at wider intervals to 1 year postop.

The authors noted that the bandage lens was removed on the fourth day after surgery, and by the fifth day the epithelium had remodeled sufficiently.

Tests, wavefront results

A variety of tests, including those that measure vision, sensory information, refraction, contrast sensitivity and ocular comfort, are all important in identifying the results of wavefront-guided refractive surgery, according to a study.

Nancy Keir and colleagues set out to determine “whether fundamental factors exist to account for the relationships between the variables for a CustomCornea clinical trial.” CustomCornea is the wavefront-guided ablation system used on the Alcon LADARVision laser. The study results were presented in a poster.

In the study, LASIK was performed in 163 myopic eyes with or without astigmatism with Alcon’s LADARVision laser with the LADARWave device. A number of factors were measured. Factor 1 included high-luminance vision (visual acuity measured under dim lighting conditions). Factor 2 included sensory ratings, such as light sensitivity, glare and haloes. Other factors measured included spherical ametropia (factor 3), contrast sensitivity (factor 4) and ocular discomfort (factor 5).

The researchers found that high-luminance vision showed the most variability (25%). Sensory ratings showed the second-most variability (17%), “with questions regarding glare and haloes providing the most information on this factor,” according to the poster. Sphere and spherical equivalent refraction were the most significant variables describing factor 3, and low spatial frequency photopic contributed the most to factor 4. Burning, tearing and dryness were the key variables regarding ocular comfort for factor 5, the researchers said.

Laser makes stable keratoplasty

Penetrating keratoplasty performed with the IntraLase femtosecond laser induces less astigmatism than conventional PK and may be able to provide patients with more stable structural results, according to Roger F. Steinert, MD.

Dr. Steinert and colleagues at the University of California, Irvine, performed a study in which they randomized eight corneoscleral rims to receive either traditional blade-trephination PK or a modified IntraLase “top-hat shaped keratoplasty.” Dr. Steinert discussed their results at the meeting.

In the IntraLase version, a 9-mm cylindrical cut is made from the posterior surface of the cornea into the stroma, stopping at about two-thirds of corneal depth. The laser then performs a horizontal lamellar dissection at two-thirds corneal depth from a 9-mm diameter to a 7-mm diameter, followed by a 7-mm cylindrical cut from the lamellar plane to the anterior corneal surface, Dr. Steinert said. Wound integrity was evaluated by measuring IOP to determine the level at which leakage occurred.

Both techniques induced similar steepening of the corneal curvature after the placement of the running suture, indicating similarity of the suture tension in the specimens. The IntraLase group showed a mean change in average curvature of +3.43 D, while the traditional PK group showed a mean change in average curvature of +3.21 D. Corneas that underwent the procedure with IntraLase tended to show less induced astigmatism when compared with the traditional PK group, he said.

After the laser-based transplant, suture removal may be performed as early as 3 months, and the strength of the repaired area can be nearly 10 times that of conventional transplants, according to a press release from the university.

Clinical trials of the technique are expected to begin this summer at Irvine, the university said in the press release.

Intacs for marginal degeneration

Intrastromal corneal ring segments were helpful in treating contact lens-intolerant patients with pellucid marginal degeneration, according to a study.

L. DiSilvestre, MD, and colleagues studied the stromal healing response after treatment with Intacs (Addition Technologies) intrastromal corneal ring segments in patients with pellucid marginal degeneration.

Before surgery, researchers noted that tomography and confocal microscopy “found normal morphologic features in the central cornea, whereas in peripheral sections, irregular and elongated epithelial cells with altered arrangement of keratocytes were observed.”

Eight eyes of eight contact lens-intolerant patients were implanted with Intacs segments. Two inserts were placed, one in the superior cornea and one in the inferior cornea. After implantation, researchers said, “the stroma in the superior and inferior cornea showed signs of activation (highly reflective nuclei with visible processes) in some of the patients. Around the [segment], moderate fibrosis was detected.”

The authors concluded that the procedure “resulted in efficacy and safety in all patients and provided fast visual rehabilitation.”

Cyclosporine, ocular rosacea

Patients with ocular rosacea who did not respond to other treatments responded well to treatment with topical cyclosporine, according to Henry D. Perry, MD, and colleagues.

The researchers presented results of a retrospective chart review of 55 ocular rosacea patients who were unresponsive to other treatments, including oral tetracycline. The treatment period with topical cyclosporine was 6 to 17 months.

The authors noted in a poster presentation that 18% of patients who were unresponsive to other treatments showed “complete resolution when treated with cyclosporine.” They said 31% of patients showed significant improvement, and 31% experienced mild to moderate relief of symptoms and improved clinical signs.

The authors noted that 4% of patients had recurrence of symptoms while on treatment despite initial improvement, and 30% of patients showed poor response to the treatment and withdrew from treatment after 6 months.

Furthermore, 5% of patients who responded to cyclosporine were able to discontinue all medications withoutrecurrence of rosacea.

“Topical cyclosporine was sufficient to control ocular rosacea in 68% of responsive patients at last follow-up; they required no additional medications,” the study authors said.

In 27% of patients, low-dose tetracycline was continued along with the topical cyclosporine.

Corneal sensitivity, iris pigmentation

As iris pigmentation increases, corneal sensitivity decreases, according to the results of a study.

Anna M. Ntola and colleagues set out to assess the effect of iris pigmentation and ethnicity on corneal and skin sensitivity, tear film breakup time and blink rate. They presented their results in a poster.

For the study, 200 subjects were divided into four ethnic groups: white (100 patients), Asian (40 patients), Chinese (40 patients) and African (20 patients). Patients were classified according to iris color. Researchers said all measurements were made on the right eye only, and they were made after 12 noon. “to avoid any diurnal bias.”

The authors said that skin sensitivity was assessed at the upper closed eyelid; tear film breakup time was assessed after the instillation of 0.7 µL of fluorescein; and blink rate was video recorded for 5 minutes and digitally analyzed.

The researchers concluded that corneal sensitivity is affected by iris color and ethnicity and that whites have a progressive decrease in sensitivity with increasing iris pigmentation.

They added that “tear film stability is not affected by iris color, although a significant difference was found between measurements.” The researchers suggested that dark-brown eyes tended to maintain a more stable tear film. Additionally, they said, tear film stability “is not affected by ethnic group.”

Finally, no significant difference was found in blink rate between the different iris color grades or ethnic groups. The authors said that only a “weak relationship” was found between corneal sensitivity and blink rate for all patients studied; however, patients with lower-than-average corneal sensitivity blinked more often than subjects with higher-than-average corneal sensitivity. They also found that blink rate decreased as corneal sensitivity decreased.

Conjunctival sensitivity/dry eye

Conjunctival sensitivity is an important risk factor in the development of symptoms of dry eye disease, a study found.

Ping Situ and colleagues compared corneal and conjunctival sensitivity to cooling stimuli in 97 non-contact-lens-wearing patients.

They studied subjects both with and without symptoms of ocular dryness. The subjects were grouped by age and gender. The researchers measured corneal and conjunctival sensitivity at room temperature with a pneumatic esthesiometer.

Results showed that “corneal and conjunctival sensitivity to cooling stimuli were higher in the subjects who have dry eye symptoms than those who are asymptomatic,” the study authors said. Additionally, they noted that “this corneal and conjunctival hypersensitivity may indicate the alteration of sensory processing in the symptomatic patients.”

They also noted that conjunctival sensitivity was higher than corneal sensitivity in the dry eye group, and conjunctival sensitivity was higher in women than men in the dry eye group.

Evaluating dry eye

The symptoms that are most bothersome to patients with dry eye are not necessarily their most common symptoms, according to A. Schaberg and colleagues. Because the way patients with dry eye perceive their symptoms does not always align with the way researchers measure their symptoms, more useful ways of evaluating dry eye symptoms are needed, the researchers said in a poster presentation. They also noted that these discrepancies may affect researchers’ ability to measure the effects of treatment in dry eye trials.

Dr. Schaberg and colleagues set out to identify the usefulness of standard symptom assessments in identifying and measuring dry eye. They studied patients who were participating in a multicenter trial evaluating a dry eye treatment. At the baseline of the study and at each clinic visit, patients defined and then rated the severity of the most bothersome or worst symptom of their dry eye disease on a scale of 0 to 4. Their responses were classified into a number of defined categories, such as “affects vision,” “dryness,” “cosmetic,” and so on. Corneal and conjunctival staining and the ocular surface disease index (OSDI) were also assessed at each visit.

The “worst” symptoms reported most often among 443 patients were discomfort/pain/irritation (71%), dryness (9%), abnormal rheology (8%) and affects vision (7%).

“The mean OSDI symptom score was higher (27.4) for subjects whose worst symptom was coded as discomfort/pain/irritation or dryness than for subjects with other symptoms (23.7),” the researchers reported. “The mean OSDI visual function score was significantly greater … for the subjects whose worst symptom was coded as ‘affects vision’ compared to all others.”

Determining cost-effectiveness

Treatment of people who have an annual risk of developing primary open-angle glaucoma of at least 2% is likely to be cost-effective, and a management strategy of delaying treatment of people with ocular hypertension until POAG develops may be unnecessarily conservative, one physician said.

Steve M. Kymes, MD, investigated the cost-effectiveness of treating patients with ocular hypertension as opposed to observing them.

Dr. Kymes considered a variety of questions, including what patients want and how they view their quality of life with ocular hypertension and with the possibility of developing glaucoma. He considered the effectiveness of treating no one with ocular hypertension, treating patients with greater than 5% risk of developing POAG, treating those with greater than 2% of developing POAG and treating all patients with ocular hypertension.

“Eighty percent of the time, treating would be the best option,” he said.

The decision to treat, however, also depends on the patient’s attitude toward the risk of developing glaucoma and blindness, he said.

Anti-VEGF therapies represent ‘revolution’ in molecular therapy

Carmen A. Puliafito FORT LAUDERDALE, Fla. – The identification of vascular endothelial growth factor as a target for therapy has created a paradigm shift in the treatment of age-related macular degeneration, said Carmen A. Puliafito, MD, MBA, at a symposium held here during the ARVO meeting. Researchers and clinicians have recognized that vascular endothelial growth factor (VEGF) is crucial for the successful treatment of acute neovascularization, Dr. Puliafito told attendees at a symposium on anti-VEGF therapies. The symposium, Anti-VEGF Therapies in the Management of Choroidal Neovascularization, was a continuing medical educational activity sponsored by SLACK Incorporated and supported by an unrestricted educational grant from Genentech. Macugen (pegaptanib sodium, Eyetech Pharmaceuticals), an anti-VEGF drug that was recently approved for use in the United States, is administered every 6 weeks. Lucentis (ranibizumab, Genentech), which is still in phase 3 trials and has not yet been approved for marketing in the United States, is administered every 4 weeks. Avastin (bevacizumab, Genentech), a systemic drug used in treatment of metastasized colorectal cancer, is still in preliminary trials for use in AMD, he said. Results suggest that Lucentis delivers a durable treatment effect, Dr. Puliafito said. Patients have achieved good visual acuity up to 22 months after stopping the 10-dose treatment regimen. At this early stage, limitations of the anti-VEGF therapies exist, Dr. Puliafito said. One problem is that clinicians have yet to determine whether the treatment regimen of injections administered every 4 to 6 weeks will over the long term be the most appropriate therapy, he said. “More important, what do our patients want?” Dr. Puliafito asked. Systemic drug At the same symposium, Philip J. Rosenfeld, MD, PhD, discussed the preliminary results with the systemic drug Avastin in retarding retinal neovascularization. Avastin works by “marinating” the tissue where VEGF is expressed, Dr. Rosenfeld said. Philip J. Rosenfeld The drug was developed for the treatment of colorectal cancer, Dr. Rosenfeld said. As an anti-VEGF drug, it works similarly to Lucentis, he said. “We were encouraged about the possibility of Avastin having similar efficacy,” he said. Avastin, administered systemically, works as an antibody that binds to VEGF. The drug’s effect lasts for a long time without repeat treatment, but the VEGF returns once the effect of Avastin fades, Dr. Rosenfeld explained. He said a trial called the Systemic Avastin for Neovascularization AMD (SANA) Study is under way. Patients in the study receive 5 mg/kg of Avastin in two or three doses given 2 weeks apart. Treatment is continued only if leakage from choroidal neovascularization is observed. In cancer patients, thromboembolic events have occurred as a result of Avastin use, and the drug now has a warning that its use may result in the development of gastrointestinal perforation and wound dehiscence. In the SANA Study, which to date includes 19 patients with 3-month follow-up, researchers have noted an increase in blood pressure levels, which later return to normal. Physicians will likely have to monitor patient blood pressure levels during the 6-month study as a result, Dr. Rosenfeld said. “We still don’t know the risk of thromboembolic events with more doses,” he said.