September 01, 2006
4 min read
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Did you ever wonder about … why we don’t know what causes glaucoma?

The causes of IOP elevation are unknown because it is unclear how IOP is controlled.

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From the Lab to the Clinic [logo]

The question arises for nearly every glaucoma patient – “Doctor, what causes glaucoma?” It is likely that the pathophysiology of primary open-angle glaucoma is an elevated IOP combined with some altered sensitivity of the optic nerve to damage from that pressure. We do not know what causes the IOP elevation because we truly do not know how IOP is controlled.

What do we know? The major anatomic pathways of aqueous drainage have been located, and there are some well-supported theories about how resistance is regulated within these pathways. In cases of high IOP, the defect is reduced aqueous drainage caused by an abnormal resistance to outflow. Patients with primary open-angle glaucoma produce the same amount of aqueous as normal people the same age.

Some of the IOP-dependent agents in the development pipeline lower IOP by affecting aqueous drainage; thus, it will be helpful for us to briefly review our current understanding of aqueous drainage.

Major anatomic pathways of aqueous drainage

Aqueous leaves the anterior chamber primarily through two pathways: 1) through the conventional pathway, which is through the trabecular meshwork into Schlemm’s canal, then onto the collecting channels and finally through the episcleral veins, and 2) through the uveoscleral pathway, which is through the ciliary body face and into the choriocapillaris. Some components then diffuse through the sclera while others exit via the vortex veins.

In older adults, the majority of aqueous drains through the conventional pathway. In younger adults (less than 30 years), a larger amount of aqueous may drain through the uveoscleral pathway.

What controls the resistance to outflow in these pathways?

Douglas J. Rhee, MD [photo]
Douglas J. Rhee

In the conventional pathway, the majority of resistance is believed to be located within the trabecular meshwork – specifically the juxtacanalicular area, which is the part of the trabecular meshwork immediately adjacent to Schlemm’s canal. The juxtacanalicular area is not a static structure. It is amorphous and dynamic. There are three mechanisms that potentially regulate IOP: the formation of openings (termed “B pores”) between Schlemm’s canal inner wall cells (also known as the “paracellular pathway”); the formation of openings (termed “I pores”) within cells (also known as the “transcellular pathway”); and the turnover of extracellular matrix, which surrounds the cells and is at the openings of the pores.

I asked some glaucoma subspecialists to comment on research that is being done on the conventional outflow pathway.

Douglas H. Johnson, MD, said that in recent work, Mark Johnson found fewer pores in glaucomatous eyes than in eyes without glaucoma.

“This difference could be enough to account for the outflow resistance in glaucoma,” Dr. Douglas Johnson said.

Some compounds now under investigation may work by creating more space in between cells.

Paul L. Kaufman, MD, said he has been investigating compounds that work “by disturbing the actin cytoskeleton and actomyosin contractility in the JCT and inner wall cells.”

“There is relaxation of the cells, thus making the entire outer meshwork more expansive and porous,” Dr. Kaufman said.

David L. Epstein, MD, said that a novel outflow drug might have to be administered only once or twice per year. This is the focus of his own research in drug discovery, which is the legacy of his previous studies of ethacrynic acid. Although there are no trabecular meshwork outflow drugs in use, there is the potential for restoration of normal outflow function by drugs that can “normalize” the outflow resistance in glaucoma.

“The nature of the outflow resistance barrier likely involves the interaction of trabecular meshwork and Schlemm’s canal cells and their respective extracellular matrices,” Dr. Epstein said.

Recently, there has been some biochemical and ultrastructural evidence that prostaglandin analogues may have an effect on trabecular meshwork by increasing extracellular matrix turnover in a similar manner to the effect on the uveoscleral pathway – by altering matrix metalloproteinase activity. Dr. Kaufman said he believes that the prostaglandin analogues’ effect on trabecular meshwork “would constitute a small component of their ocular hypotensive action.”

Dr. Johnson said, “If this finding is verified, it gives insight into the mechanism of IOP control and opens up new targets for drug and future gene therapy.”

In the uveoscleral pathway, the resistance is controlled by altering the extracellular matrix turnover and the muscular tone of the ciliary body. Prostaglandin analogues lower IOP primarily by increasing extracellular matrix turnover in the uveoscleral pathway. Miotic agents cause constriction of ciliary body smooth muscle cells, leading to increased resistance (ie, less drainage) through the uveoscleral tract. Conversely, cycloplegic agents will sometimes lower IOP by relaxing the ciliary body smooth muscle cells and allowing greater uveoscleral drainage.


Figure of juxtacanalicular region of the trabecular meshwork. Possible mechanisms of regulation of aqueous drainage in the juxtacanalicular region include formation of I pores, formation of B pores and turnover of extracellular matrix.

Image: adapated from Rhee DJ

The future

What we currently call primary open-angle glaucoma is likely a group of many disorders. These disorders combine alterations that cause problems in outflow drainage with altered sensitivity of ganglion cells and/or the optic nerve. Although we cannot yet definitively explain the defect or defects that cause high IOP, we are getting closer.

According to Robert N. Weinreb, MD, the future seems bright.

“The introduction of cutting-edge and powerful research technologies to the study of the outflow pathways has led to a reawakening of outflow research, as well as enhancing our understanding of aqueous outflow biology. To translate the emerging information into clinical practice, however, it will be critical to develop relevant models of outflow in humans and practical methods to readily assess aqueous humor dynamics,” Dr. Weinreb said.

For more information:
  • Douglas J. Rhee, MD, is an assistant professor of ophthalmology at Harvard Medical School and on the faculty of the Massachusetts Eye and Ear Infirmary. He can be reached at 243 Charles St., Boston, MA 02144; 617-573-3670; fax: 617-573-3707; e-mail: dougrhee@aol.com.
  • David L. Epstein, MD, can be reached at Duke University Eye Center, DUMC Box 3802, Durham, NC 27710; 919-684-5846.
  • Douglas H. Johnson, MD, can be reached at Mayo Clinic, 200 First St. SW, Rochester, MN 55905; 507-284-2787.
  • Paul L. Kaufman, MD, can be reached at University of Wisconsin, Ophthalmology & Visual Sciences, Room 102, 2870 University Ave., Madison, WI 53705; 608-263-6074.
  • Robert N. Weinreb, MD, can be reached at University of California, San Diego, 9415 Campus Point Drive, La Jolla, CA 92093; 858-534-6290.