At Press Time

Glaucoma: A Degenerative Nerve Disease?

By Leslie Goldberg, Associate Editor

Comparisons Are Made to Alzheimer's and Parkinson's.

■ A new paradigm for understanding glaucoma has emerged, according to a New York Times article published in July. Some respected researchers are now saying that glaucoma isn't simply an eye disease, but a degenerative nerve disorder, not unlike Alzheimer's or Parkinson's disease.

Ophthalmology Management asked glaucoma experts Malik Kahook, MD, of Denver and Andrew Rabinowitz, MD, based in Phoenix, what the thinking is among other glaucoma specialists.

Dr. Kahook says that this idea remains in the fringes of thought among general ophthalmologists and glaucoma specialists.

“While most eye doctors now realize that glaucoma is more than just an eye pressure problem, the idea that there might be an active degenerative problem intrinsic to the nervous system remains poorly understood and rarely discussed outside of small group of researchers,” he says.

Dr. Rabinowitz says that glaucoma specialists have long felt that glaucoma was in part, a vasculopathy and that it was more likely to occur at higher IOPs than at lower. “Now we can begin to compare glaucoma to other central nervous system disorders which are chronic in nature,” says Dr. Rabinowitz.

He says that the reason a person develops Alzheimers is not readily clear and that with the exception of head trauma, the same can be said for Parkinson's disease.

“The reason a person develops a progressive optic neuropathy in the absence of elevated intraocular pressure remains equally enigmatic. Clearly we continue to probe deeply into the causes of glaucomatous damage in patients with IOPs in the normal range,” says Dr. Rabinowitz.

He says perhaps there is some unifying etiology that can explain all three progressive disorders, such as a previous sub-clinical viral illness in a genetically predisposed individual. He adds that while this theory has no current scientific basis or backing, certainly the fact that medications in the antiviral family such as memantine have been applied to this disease model warrants further study.

When asked why IOP has been removed from the definition of glaucoma, Dr. Kahook explains that studies have shown that many patients with so-called normal IOP can still develop glaucoma and that patients still have progressive visual field loss despite what appears to be a significant reduction in IOP with medications, laser and/or surgery.

“Therefore, using IOP as a criteria for disease was removed and new research continues to explore other likely causative factors such as poor perfusion pressure, autoimmune dysregulation and oxidative stressors which are all likely to play a role in some, if not all patients,” he says. “It is important to keep in mind that simple answers are rarely found to complex diseases.”

Dr. Kahook says it would be a stretch to think that currently marketed medications will be beneficial enough to show a measurable difference in visual field defect progression. This is due to limitations in metrics used to measure disease progression, as well as to the length and complexity of studies needed to document such findings. He does, however, believe that neuroprotective medications will be discovered for glaucoma.

“There are several candidate molecules currently being investigated that hold promise in both in vitro studies as well as animal-based studies using various models of glaucoma. Experience has shown that the true effectiveness of a medication is not known until human studies are done, and these studies will have many hurdles to cross in order to be successful,” says Dr. Kahook.

Dr. Kahook says that significant developments in imaging devices will be required to help validate and quantify the effectiveness of neuroprotective agents for treating glaucoma.

“The article in the New York Times was probing and provocative. It called upon all readers who are within reach of answering these questions to try a bit harder as the baby boomers march forward in time,” concludes Dr. Rabinowitz.

IN MEMORIUM

Jeffrey Gilbard, Developer of TheraTears

By Jerry Helzner, Senior Editor

■ Jeffrey P. Gilbard, MD, who spent years researching dry eye before forming a company whose products combat that condition, has died as a result of a bicycling accident. He was 55.

Dr. Gilbard transitioned from researcher to entrepreneur in 1995 by forming Advanced Vision Research (AVR) after being unable to license TheraTears to an established pharmaceutical company. Spurred by Dr. Gilbard's creative marketing and distribution strategies, TheraTears soon gained a wide following as an effective, scientifically formulated over-the-counter treatment for dry eye.

In more recent years, AVR has expanded to 11 products, some of which are nutritional supplements designed to prevent retinal disease and foster overall ocular health.

Dr. Gilbard had originally intended to pursue a career in business, but while in high school he began reading the textbook that was going to be used in the freshman economics course.

“I enjoyed the first 100 pages, but then I hit the accounting appendix, Dr. Gilbard told Ophthalmology Management in a 2004 interview. “I withdrew the application to Penn's Wharton School and went to Brown instead. I started doing molecular biology research as an undergraduate and became an ophthalmologist.”

In medical school at Columbia's College of Physicians and Surgeons, Dr. Gilbard submitted a summer research project designed to develop a method for measuring the osmolarity of tear microvolumes in patients with dry eye, which could then be used as a diagnostic test. Though he didn't receive a grant at that time, a medical school faculty member sponsored his continued research.

That summer, young Dr. Gilbard developed the first technique to collect tear sample microvolumes without getting reflex tearing or sample evaporation. One day, while reading in the library, it dawned on him that elevated tear-film osmolarity could explain all the pathological changes on the ocular surface in dry eye and that artificial tear solutions ought to be hypotonic.

From those beginnings, the idea for TheraTears was born. A 1978 grant from the National Eye Institute set the wheels in motion.

AVR, which is based in Woburn, Mass., said it will now be led by Chief Operating Officer Leigh Reynolds.

Thom Zimmerman, Glaucoma Pioneer

■ Thom J. Zimmerman, MD, PhD, 66, the principal developer of the glaucoma medication timolol maleate (Timoptic), has died after a brief illness. He is remembered by his closest colleague as an original thinker, a colorful personality and a standout athlete.

“Thom was the kind of guy who made life interesting,” says Christopher Paterson, PhD, who teamed with Dr. Zimmerman to help build the University of Louisville department of ophthalmology into a national leader. “He was given to pink and green Versace suits, sported a purple Mohawk haircut in middle age and was one of the great out-of-the-box thinkers. In fact, Thom wouldn't even recognize that any ‘box’ existed.”

Dr. Zimmerman had a reputation as a generous and kind colleague, willing to share his prodigious knowledge with other ophthalmologists.

Timoptic, a beta blocker introduced by Merck in 1978, was the leading glaucoma medication for two decades before being replaced as the market leader by latanoprost.

Dr. Zimmerman served for many years as the chairman of the department of ophthalmology at the University of Louisville. He gave up that position in 1999 to become global medical adviser for ophthalmic drugs to Pharmacia-Upjohn, the developer of latanoprost. After his stint in the corporate world, Dr. Zimmerman returned to the University of Louisville.

Dr. Zimmerman served on the editorial boards of numerous ophthalmic journals, gave many lectures and wrote several books that have achieved the status of being among the most widely cited references in ophthalmology.

He received both his undergraduate and MD degrees from the University of Illinois and his PhD degree from the department of pharmacology, University of Florida School of Medicine, in 1976.

Dr. Zimmerman was a star athlete, earning scholarships to the University of Illinois in both football and tennis.

The University of Louisville department of ophthalmology intends to celebrate Dr. Zimmerman's achievements by holding a Dr. Thom Zimmerman Glaucoma Symposium on Oct. 10. The University hopes to make the Zimmerman Symposium an annual event.

Major Progress on Combating Trachoma

Three More Countries Wage Successful Campaigns.

■ Trachoma — the blinding disease that has been the scourge of hot, dry and poor third-world countries — is being systematically eliminated as a public health threat, thanks to an all-out effort spearheaded by the World Health organization, the International Trachoma Initiative, the Carter Center and pharmaceutical giant Pfizer.

The good news is that Ghana, Mexico and Saudi Arabia were recently added to the list of countries that have been successful in overcoming trachoma, an infection of the eyelids carried by flies. These three countries join Oman, Morocco and Iran, which in 2006 announced that they had eliminated trachoma as a public health threat.

Efforts to fight trachoma involve a strategy whose acronym is SAFE. The strategy encompasses Surgery, Antibiotics, Facial cleanliness and Environmental improvements. A key to implementing the strategy has been the contribution of Pfizer in providing the drug Zithromax to control the infection. In the last decade, Pfizer has provided more than $1 billion in pharmaceutical and financial donations. The company recently renewed its commitment to continue to provide resources to eliminate the disease.

The organizations committed to fighting trachoma have set a goal of eliminating the disease by 2020. It is estimated that about 40 million people in 56 countries are still at risk for the disease, with more than eight million people still in need of eyelid surgery to avoid blindness.

Research Digest

New & Noteworthy Journal Articles

Compiled by Andrew E. Mathis, PhD, Medical Editor

► Prostaglandins test well for glaucoma. Two studies in the July 2009 issues of the British Journal of Ophthalmology and Ophthalmology found that latanoprost and bimatoprost are particularly effective in lowering IOP in both normal-tension and primary angle-closure glaucoma.

The Ophthalmology study was a metaanalysis of 15 clinical trials of frequency prescribed glaucoma drugs. Of the pros taglandins included, latanoprost and bimatoprost were the most effective, though both were outperformed in IOP lowering by brimonidine, an alpha-2 agonist that lowered IOP by 24%. The pros taglandins reduced IOP by 12%, as did the beta blockers timolol and betaxolol and the carbonic anhydrase inhibitors dorzolamide and brinzolamide.

The BJO article was an observer-masked study of 54 patients receiving either latanoprost or bimatoprost. The mean IOP-lowering effect of the drugs was similar (8.4 mm Hg with latanoprost vs. 8.9 mm Hg with bimatoprost). The slightly higher effectiveness of bimatoprost may be offset by its higher side-effect profile, the authors note.

► New non-contact biometry device. Scientists in Birmingham, England, have published the results of a recent study in the July 2009 issue of the British Journal of Ophthalmology, demonstrating the validity and repeatability of measurements taken with the LenStar non-contact low-coherence reflectometry device.

The team measured pupil size, white-to-white, two types of corneal curvature, corneal thickness, anterior-chamber depth, crystalline lens thickness and axial length in 112 patients between the ages of 41 and 96 who had undergone cataract surgery. The patients had several ocular measurements taken with the LenStar, which were compared to measurements taken with the IOLMaster. Twenty-one of the original 112 patients also underwent A-scan ultrasonography. The LenStar's measurements were similar to the IOLMaster without having to make corneal contact to take them. Variability in readings was ≤2% of average value, indicating a high degree of repeatability.

The LenStar was only recently approved in the United Kingdom. It is not yet available in the United States.

► Long-term PRK results published. A team of Italian surgeons conducted a 14-year follow-up of patients who underwent myopic PRK between 1991 and 1993. The study, published in the June 2009 issue of the Journal of Refractive Surgery, followed 49 eyes in 31 patients who had PRK performed with the Summit UV200 excimer laser. While follow-up every two years consisted of refractive exam, VA measurement, IOP and corneal status, at the 14-year follow-up, corneal topography and endothelial cell count were also performed.

At the 14-year mark, BCVA was at least equal to preoperative BCVA in most eyes examined. Furthermore, increases in IOP were seen in only four eyes, and in all cases these increases were temporary. Three patients reported difficulty in night vision.

All patients completed a quality-of-life questionnaire, and 74% of high myopic patients and 84% of low myopic patients reported satisfaction with the outcomes. High myopia was defined for this study as ≥6 D preoperatively. The authors of the study suggest that this retrospective study's results suggest that myopic PRK is safe and reliable.

► Large retrospective LASIK study. A refractive surgeon in Amman, Jordan has published in the August 2009 issue of the Journal of Refractive Surgery the results of a retrospective study of 77,124 eyes in 46,384 patients, which he measured for refractive error following LASIK. Fouad N. Sayegh, MD, PhD, distributed the patients into four groups: emmetropia, hyperopia, low-to-moderate myopia and high (>6 D) hyperopia. Dr. Sayegh then correlated axial length to corneal power as a function of age for his analysis.

Dr. Sayegh found that 23.8% of LASIK patients were myopic, with another 3.8% having high myopia. Furthermore, 17.5% of patients whose cases were examined had hyperopia. He also found that refractive error in hyperopic patients tended to increase between the ages of 30 and 50.

Based on his observations, Dr. Sayegh recommends that the likelihood of progression of either myopia or hyperopia be assessed before LASIK is undertaken and discussed with patients. His data offer some guidelines on how to predict when and to what extent refractive error will occur.

► Cancer of the eyelid. Ocular oncologists and pathologists from the Wills Eye Institute and Thomas Jefferson University, both in Philadelphia, caution ophthalmologists to screen patients with cancer for malignancies of the eyelid. In an article published in the August 2009 issue of Archives of Ophthalmology, the team conducted a retrospective review of 20 patients who developed cancers on the eyelid.

Study subjects included patients whose primary cancers had emerged in the skin, breast, kidney, lung and salivary glands, as well as elsewhere in the eye. Twelve of the 20 patients presented with a solitary nodule and half had concomitant ocular metastasis. Treatments and survival rates are also discussed in the article.

While prognosis for cancers of the eyelid remains poor, the authors write, it is important to screen patients presenting with the symptoms mentioned in order to diagnosis cancer earlier and in its more treatable phases. Earlier treatment almost always correlates with a higher success rate. OM