Understanding of glaucoma is incomplete but still potent

Although the root causes of glaucoma remain elusive, a rational approach to sight-preserving treatment is still possible.

Ophthalmologists today have access to the most advanced glaucoma diagnostic hardware and software, the most potent drugs to reduce intraocular pressure and the most advanced and least invasive surgical devices and techniques ever devised. Still, the disease persists as a leading cause of blindness.

Are we advancing on a cure for glaucoma? Will we see a cure in our lifetimes? Is medicine anywhere near to finding the root cause of glaucoma?

In answer to these questions, leading glaucoma researcher George L. Spaeth, MD, simply answered, “Medicine is not close to finding out the ‘root cause for glaucoma,’ because there is no single root cause for glaucoma.

“An analogy may help,” Dr. Spaeth continued. “There are, for example, many types of cancer. That fact means that there may never be a cure for ‘cancer’ in the generic sense. But as you know well, there are already cures for several types of cancer.”

Dr. Spaeth noted that not long ago leukemia was universally fatal. Now many types of leukemia can be treated with medicine, and individuals can be cured. He said even in a subcategory like “skin cancer,” some skin cancers such as basal cell carcinoma can be easily cured with surgery, whereas others such as a melanoma frequently cannot be cured even with the most extensive surgery.

“There is no ‘cure for cancer,’ but there are cures for certain types of cancers. The analogy applies to glaucoma. The fact that there are several types of glaucoma does not hinder diagnosis and treatment of glaucoma. It makes it more complex, but that is true of any condition in the body,” Dr. Spaeth said.

Dr. Spaeth and other glaucoma experts interviewed for this article said that although our understanding of glaucoma is as yet incomplete, physicians can still make intelligent choices in caring for their glaucoma patients over years and decades. The glaucoma armamentarium may lack the ability to cure, but thoughtful physicians can care for their patients with better tools than ever before, both medical and surgical.

In this article, three well-known glaucomatologists survey the current state of glaucoma research and patient care. They outline ways to make the best treatment choices given the knowledge we currently possess, and they examine what must be done next to further the ability of physicians to control progression of the disease and to press toward a cure.

Not one disease

Dr, Spaeth noted that no one will ever find “one root cause of the disease” because glaucoma is not one disease.

“Consider one subdivision of glaucoma, specifically, angle-closure glaucoma,” he said. “Angle-closure glaucoma is a disease that can be cured in most white patients if a peripheral iridotomy is performed prior to the development of peripheral anterior synechiae. This is one of the few glaucomatous conditions that can really be cured. It is an exciting treatment, and people who have peripheral iridotomies before they develop peripheral anterior synechiae probably have no greater chance of developing glaucomatous nerve damage than anyone else in the general population. However, angle-closure glaucoma in Chinese patients behaves differently. Even if a peripheral iridotomy is done successfully, there is a great likelihood that Chinese individuals with primary angle-closure glaucoma will go on to develop elevated pressure and optic nerve damage.”

Dr. Spaeth said this type of finding is one of the reasons continued research is necessary, to understand why these two types of glaucomas that seem superficially similar are not the same entity.

Eve Higginbotham, MD, agreed with Dr. Spaeth that glaucoma is regionalized and has genetic properties that go beyond simple explanations.

“A lot of it stems from the fact that glaucoma has so many soft variables. Visual field variability makes it difficult to determine in many patients when a new defect occurs,” she said. “It is also often difficult to determine subtle changes in the optic nerve. As a profession, we have made significant strides in defining glaucoma. Instead of IOP we are at least focused on the optic nerve and its function.”

“However we’re limited by our ability within our current technology to determine how the disease starts and is progressing,” she said.

Treatment options, algorithm

Richard A. Lewis, MD, said there is no “golden rule” for treating glaucoma.

“Deciding on a treatment is really influenced by training, by the patient and by marketing. There is no consensus. We all want maximum pressure relief and total compliance. However, because patients have no physical sense of the disease, compliance is tough. Patients don’t feel the presence of the disease and, therefore, stop taking the drugs when they’re supposed to.”

Dr. Lewis said he typically treats patients medically with a prostaglandin first, followed if necessary by a beta-blocker. He looks to surgery if nothing seems to work pharmaceutically. He makes decisions regarding what surgical approach to use based on patient characteristics.

However, Dr. Lewis pointed out, no matter what a physician does, the patient will still gradually continue to lose sight. There is currently no way to stop the clinical deterioration of the eyesight of a patient with glaucoma, only to slow it.

Dr. Spaeth said he prefers to use an algorithm such as the following in making treatment decisions: 1) Does this person have glaucomatous damage? 2) Does the person have progressing glaucomatous damage? 3) How rapidly is the glaucomatous damage progressing? 4) How long will the person continue to get worse? 5) What is the mechanism of the glaucomatous damage?

He gave some examples to illustrate how he applies the algorithm.

If a patient does not have glaucomatous damage, it is not likely that treatment is necessary unless the person possesses risk factors that indicate a high likelihood of developing damage in the future.

Another patient may have no damage but may have an IOP of 50 mm Hg. If that person is going to live more than several months, then it is likely that the person will experience glaucomatous damage in the eye with elevated pressure. If one wants to prevent that damage, then treatment is appropriate, Dr. Spaeth said.

By comparison, another patient may have no glaucomatous damage but a pressure of 30 mm Hg. If that patient is expected to live perhaps only 6 months, in that person no treatment is necessary because within that 6 months it is unlikely that the elevated IOP will cause a problem. On the other hand, a person with the same findings, but with a life expectancy of 50 years, may need treatment in order to prevent glaucomatous damage from occurring or slow the progression of glaucoma.

“Finally, consider the person who has a pressure of 30 mm Hg but who has severe damage in the eye. That person’s eyesight is already damaged, and if it can be shown that the damage is progressing, then the likelihood that that damage will cause severe functional loss is great. Thus, in such an individual it is clear that vigorous treatment is urgently necessary,” Dr. Spaeth said.

He explained that there are differences of opinion regarding how vigorously to treat, because patients differ in what they want and physicians differ in what they think is best for patients. He said some ophthalmologists think it is appropriate to try to prevent patients from having any damage from glaucoma.

“I do not share that belief,” Dr. Spaeth said. “I think it is acceptable to let a patient develop some damage, as long as that damage is not going to interfere with the person’s function and is not likely to progress to more damage in the future. It is not that the other doctor is wrong and I’m right, nor is it that the other doctor is right and I’m wrong. These are philosophical differences that have nothing to do with glaucoma but rather with how different physicians believe patients should be treated.”

Assessing risk

Dr. Higginbotham said that checking a patient for glaucoma begins on the first visit, no matter what his or her associated risk factors are.

For instance, a 25-year-old white patient with no family history of the disease still needs a careful assessment of the optic nerve, as much as a 65-year-old black patient with two other family members suffering with the disease.

“There may be a chance of early traumatic glaucoma that can be treated sooner if found sooner,” Dr. Higginbotham said.

When glaucoma is detected, she said, the first step is to educate the patient at the first exam and continue from there.

“Patient education is the primary factor in increasing compliance,” Dr. Higginbotham said. In her experience, as well as documented in the literature, she said, as many as two-thirds of patients may fail to comply with their medication regimens.

Dr. Higginbotham said that sometimes it really is best to simply observe depending upon the circumstances of the patient and the presence of certain risk factors. She said early in her career that was one of the hardest decisions to make.

“It’s a decision that must be made on an individual basis,” she said.

A clinical trial in Sweden is currently addressing this subject, she said. Glaucoma patients in the study are being randomized into groups receiving treatment or nontreatment.

Importance of genetics

According to Dr. Lewis, the real answers to glaucoma will be found in the field of genetic research.

“Differentiating the various forms of glaucoma is difficult,” he said. “We’ve never been able to universally classify glaucoma. We can treat with medicine and laser surgery, but we can’t cure till we find the genetic cause. Glaucoma certainly runs in families, so we know there’s a genetic factor. Family history often leads to the discovery of systemic problems.”

Dr. Higginbotham said understanding genetics is the next big step for glaucoma specialists. She said diagnosis of glaucoma has in the past relied on the risk factors of race, family history, age and the principal ophthalmic risk factor, elevated IOP. But in the future a patient’s genetic profile may replace race as an important risk factor.

She pointed out that blacks are the population most susceptible to glaucoma in the United States. In contrast, aborigines in Australia, who phenotypically resemble individuals of African descent in this country, have a primary open-angle glaucoma rate of almost 0%.

“Specific genetic profiles are the key. Unless we start talking about it in terms of genetics, nothing will change. Race is simply a placeholder,” Dr. Higginbotham said.

While not ruling out gene therapy on a whole, Dr. Spaeth said he believes that there is much less hope that gene therapy will create effective treatments in the near future. “My hunch is that it is going to be a long, long time before gene therapy is effective and safe gene therapy.”

Dr. Spaeth said he believes understanding the genetic basis of glaucoma will make a major difference in how patients with glaucoma are diagnosed and managed. He said he doubts genetics will be the final answer to the disease, but it will certainly be one of the next steps in understanding it.

“In the immediate future I believe that studying the microbiological nature of patients will be extremely important in diagnosing glaucoma, and in finding out what clinical subtype of glaucoma the person has. This will allow us to get a much better sense about who is going to get worse and how rapidly a person is going to get worse,” Dr. Spaeth said.

He said it will not be too long before the molecular biological nature of an individual gives physicians important guidelines regarding treatment options.

“For example, we will know that certain patients will respond to certain types of drops and other similar patients will not respond to those same types of drops. In addition, we’ll probably have a pretty good idea of how patients will respond to surgery, so that we can use the appropriate medicinal and surgical treatment more rationally,” Dr. Spaeth said.

Lack of focus?

To outsiders it may appear that glaucoma research lacks the focus associated with the refractive and cataract fields. Dr. Lewis explained that the nature of glaucoma research is different from those other fields.

“With glaucoma we’re trying to find and stop the cause,” he said. “The other fields are simply fixing the effects of changes to the eye.”

However, he said, because there is no consensus on what causes glaucoma, and indeed seemingly no single cause, there is by nature no consensus on how to treat it and therefore many different approaches to treatment.

Dr. Higginbotham pointed out that one of the few points on which all agree, and a major front that needs continued work, is patient compliance.

In terms of making glaucoma drug regimens easier for patients to comply with, she said the focus needs to be on lengthening the time between doses of medicine. This has been improved in recent years. Drug regimens that required multiple administrations of multiple drugs have been reduced in many patients to daily administration of one drug.

Dr. Higginbotham said if that interval could be stretched to a week or a month patients might be more complaint.

There might even be the possibility of an intravitreal implant for sustained release of glaucoma medication as an effective mode of treatment, she posited. However, the surgery to implant such a device could risk loss of vision.

No lack of focus

Dr. Spaeth takes the position that glaucoma research does not lack focus. It simply must take place in many areas simultaneously.

“There are many different areas being investigated because there are many different areas that needs to be investigated. For example, it is appropriate to try to figure out what regulates the flow of aqueous through the trabecular meshwork. Beautiful research is being done on that,” he said.

Compliance is an important issue in his view as well.

“The understanding that comes from that research will probably not give us any help whatsoever in understanding another important question about glaucoma, specifically, why it is that somewhere around one-third of our patients do not use their medications,” Dr. Spaeth said.

Furthermore, he said, “Research into what controls the flow of aqueous through the trabecular meshwork probably will not give us a good idea of whether a person is predisposed to developing glaucomatous optic nerve damage because of a certain abnormality of the blood vessels of the optic nerve.”

Dr. Spaeth said all these areas — the posterior trabecular meshwork, socioeconomic considerations and blood flow — need to be studied, as well as others.

“It is easy with all this work being done to see just the trees and not the forest. I think that can be a problem. It is easy to forget that the goal of our understanding and the goal of our treatment are to try to keep people healthy. That is the ultimate goal, and the goal towards which all of the research is directed,” he said.

Using the knowledge we have

Dr. Spaeth noted that although we do not understand the mechanism that accounts for IOP abnormality in glaucoma patients, we still have important knowledge that can be used intelligently.

“While we do not know the ultimate cause for intraocular pressure abnormality, we also do not know the ultimate cause why somebody gets diabetes or heart disease or any other condition,” he said. “Consider the most common cause for visual loss around the world: cataract. We don’t understand how to prevent cataracts, but that doesn’t mean that we can’t treat cataracts very well. Not knowing the cause for something doesn’t mean that there is not a good treatment for it.”

Dr. Spaeth used the London cholera epidemic nearly 500 years ago as an example: “It was noted that the people who got cholera lived in certain areas of London, and a smart ‘epidemiologist’ reasoned that it was related to the water the people were drinking. There was no understanding that cholera was caused by an organism. Simply recognizing that the people who were drinking water from one water supply were more likely to get cholera than those who were drinking water from another water supply led to changing the water supply, with the result that there was a drastic improvement in the health of the people in London.”

Dr. Spaeth continued, “Although we do not know everything that regulates the level of intraocular pressure when the anterior chamber angle is open, we do know that when the anterior chamber angle is open, certain drops are more likely to work than when the angle is closed. Understanding that mechanism is extremely important and leads to a rational approach to the management of glaucoma. Can it get better? Yes. Is it in a shambles? No. The treatment for glaucoma is already extremely rational.”

Looking to the future, Dr. Higginbotham said that curing glaucoma will eventually depend on gene therapy, a treatment that she does not expect to see within our lifetimes.

“In the past 5 years, from my perspective, there’s been nothing new in glaucoma. All the clinical trials are giving us is information about the drugs we already have, but nothing new,” said Dr. Higginbotham. She noted a variety of studies comparing drugs to surgery or to combination treatments.

A bit more optimistic was Dr. Lewis: “It seems difficult to believe that in another 20 years we’ll be having this discussion. It’s likely that another young doctor could come up with a completely new and creative way of looking at the disease and find the missing links.”

And while Dr. Lewis said he hopes that in a few decades this disease will be a faded memory, when asked what kind of a timeline he foresaw for its end, he could not give an answer.

For Your Information:

• George L. Spaeth, MD, can be reached at Wills Eye Hospital, 900 Walnut St., Philadelphia, PA 19107-5598; (215) 928-0166; fax: (215) 928-0166; kparker@hslc.org.
• Richard A. Lewis, MD, can be reached at 3939 J Street, Suite 102, Sacramento, CA 95819; (916) 455-9938; fax: (916) 451-1953; e-mail: rlewismd@pacbell.net.
• Eve Higginbotham, MD, can be reached at 419 West Redwood, Suite 58D, Baltimore, MD 21201; (410) 328-5929; fax: (410) 328-6346; e-mail: FCWEJH6786@aol.com.