EyeNet Magazine

Mechanisms and Monitoring: New Thinking on Glaucoma
By Marianne Doran, Contributing Writer

Measuring intraocular pressures alone may be less useful in some glaucoma suspects than evaluating their sensitivity to any pressure. As this notion grows stronger, the technologies for monitoring optic disc changes are gathering more attention.

Imaging technologies that can assess glaucomatous changes in the optic nerve have been available for 15 years. But as evidence of the instruments’ predictive powers continues to emerge, the new technologies are finding a home in the day-to-day practice of glaucoma management, as well as playing a role in the management of other optic neuropathies.

“A reasonable literature review now shows that instruments that image the retinal nerve fiber layer or optic disc can provide predictive data on which patients with high pressures will develop glaucoma and perhaps which patients with suspected glaucoma under the threshold of detection will go on to develop clinical disease,” said Christopher A. Girkin, MD, professor of ophthalmology and director of the glaucoma service at the University of Alabama at Birmingham.

The currently available instruments’ value in following progression of optic nerve damage over time is less clear. “These technologies are good at separating healthy eyes from eyes that are unhealthy and may have glaucoma,” said Robert N. Weinreb, MD, professor of ophthalmology and director of the Hamilton Glaucoma Center at the University of California, San Diego. “The challenge for all of them is to demonstrate and have validated their use in clinical practice for detecting progression.”

Progression software has been developed and validated for confocal scanning laser tomography (Heidelberg Retina Tomograph, or HRT) and is under development for scanning laser polarimetry with variable corneal compensation (GDx VCC) and optical coherence tomography (OCT).

Imaging for Today and Tomorrow

Joel S. Schuman, MD, professor and chairman of ophthalmology at the University of Pittsburgh, noted that the available devices measure different aspects of the ocular tissue but perform in a similar fashion. Each has high reproducibility.

  • HRT images the optic nerve head. It takes coronal slices of tissue at various depths and reassembles them to produce a 3-D surface topography map. The technology provides information such as cup surface area and volume, rim volume, and cup-to-disc ratio. Dr. Schuman noted that HRT (HRT3, Heidelberg Engineering) has the most mature progression detection software and has been validated both for measuring the optic nerve at a single point in time and for measuring changes over time.
  • GDxVCC images the retinal nerve fiber layer (RNFL) using polarized light that is directed into the eye and reflected back to a detector. Birefringent tissue, including the RNFL, cornea and lens, changes the phase of the polarized light. The phase shift is measured to determine the amount of birefringent tissue in the eye. With the instrument’s compensator, GDxVCC (Carl Zeiss Meditec) primarily assesses the thickness of the RNFL, and it has been validated for its ability to discriminate normal from glaucomatous eyes.
  • OCT has been commercially available since 1996, but entered wide use after the introduction of an improved version of the technology in 2002. It functions much like B-mode ultrasonography, except that it relies on light instead of sound. Using low-coherence interferometry, OCT (Carl Zeiss Meditec) produces a cross-sectional image of ocular structures. Often likened to an optical biopsy, OCT creates slices of tissue that can be used to measure RNFL thickness. The technology also provides information on the topography of the optic nerve head. Dr. Schuman noted that longitudinal studies suggest that OCT is able to detect progression.

Value beyond glaucoma. “I have access to all three instruments, and I longitudinally follow patients with forms of optic neuropathy other than glaucoma. I personally have found OCT to be quite a useful adjunct to the clinical exam and visual field testing,” said Larry P. Frohman, MD, professor of ophthalmology and neurosciences at the University of Medicine & Dentistry of New Jersey. “I have a sense that when we are following people over time it is fairly reproducible. It seems to be correlating with what we expect to see in terms of functional deficits in the patients. We are using it in conditions such as demyelinating disease, and compressive tumors such as meningiomas and pituitary adenomas,” Dr. Frohman added. “I think it might be a particularly helpful adjunct in cases of intrinsic optic nerve tumors that we need to follow over long periods, such as the optic nerve glioma—pilocytic astrocytoma—of neurofibromatosis I, using visual fields as our marker of early disease progression. We would like to see if this technology might point out progressive nerve fiber layer loss, which might make us consider instituting therapy before field loss is seen. And it is a useful technology for following optic neuropathy in those who cannot reliably peform visual fields,” said Dr. Frohman.

The next big thing. Ultrahigh-resolution OCT (UHR-OCT) is expected to be a significant advance in monitoring glaucoma progression. The instrument measures the wavelengths of light that are reflected back to the detector. This enables UHR-OCT to measure the tissue much more quickly—about 60 times faster—than conventional OCT. The high speed allows more data to be acquired much more quickly.

“This technology will allow us to create 3-D data sets, and that will enable us to know exactly where a particular OCT image is taken in the fundus,” Dr. Schuman said. “We’ll be able to precisely register the OCT from one visit to the next. We expect that this will improve our reproducibility and sensitivity and specificity of measurement, but that remains to be proven.”

For now, UHR-OCT is being used in only a few academic research centers, Dr. Weinreb noted, adding that he believes the technology offers “tremendous promise in diagnosing glaucoma as well as in detecting progression.”

Impact on Clinical Practice

The commercially available imaging technologies are being used primarily in a predictive fashion. The mounting evidence supporting their value in this regard appears to be bolstering physicians’ comfort level with the technology.

According to Dr. Girkin, the instruments are helping to redefine glaucoma suspects and ocular hypertensives. “In the Zangwill study1 using OHTS baseline data, there was a much higher chance that a patient with a glaucomatous-appearing HRT using Moorfields Regression Analysis would develop visual field defects,” Dr. Girkin said. “The study showed a really strong negative predictive value, and as the data go out longer, it should just get better. It’s becoming more and more valid to add HRT into the calculation of risk in ocular hypertensives.”

Dr. Girkin remarked that even a year ago he just used photos and relied very little on imaging instruments. “The instruments have been out for more than 10 years, but there have been no data on them,” he said. “It’s only in the last few years that enough predictive data have emerged that will allow you to know what a finding means. So that’s actually a big change.”

Finding the right tool for the job. With a glaucoma suspect, he takes simultaneous stereophotos and obtains SITA (Swedish interacting thresholding algorithm) standard visual fields if the photos are normal. Depending on his level of suspicion, he may order one of the specialized functional tests like short wavelength automated perimetry (SWAP). “If the nerve fiber layer is really crisp and visible, and the patient has cupping and a larger disc, I just leave it at a visual field test,” Dr. Girkin said. “But if I can’t see the nerve fiber layer well, I might get an OCT or GDx or both. It depends on the patient and what I can’t see in that patient.”

Does having these quantitative tests change the threshold for treatment? Dr. Schuman said the imaging technologies do help guide therapy, and they can help the clinician cinch a diagnosis without having to repeat the visual function tests multiple times. “If I see a very subtle abnormality on a visual field test––maybe even one that isn’t outside normal limits—and I find a correspondence with the ocular structure, such as thinning of the neural retinal rim or thinning of the retinal nerve fiber layer, I will often treat that patient.”

Researchers are tackling the mechanisms of glaucoma from several new angles.

Tinkering With Optic Nerve Biomechanics

Claude F. Burgoyne, MD, and Crawford Downs, PhD, of the Devers Eye Institute in Portland, Ore., are working to understand the engineering of the optic nerve head as a biological structure. Their research uses an engineering technique called finite element modeling to predict the behavior of optic nerve head connective tissues under varying degrees of load. “Our group, along with Ross Ethier’s group in Toronto, is beginning to generate data that suggest which parts of the connective tissue structure might importantly contribute to the susceptibility of a given eye to a given level of eye pressure,” said Dr. Burgoyne, senior scientist and research director of the Optic Nerve Head Research Laboratory at Devers.

These characteristics are not yet clinically measurable, he noted. “But we think that engineering of the optic nerve head is going to create new targets for imaging that one day will allow clinicians to have a sense of how strong or weak a particular optic nerve head is. This will contribute to their setting of a target intraocular pressure for a given patient’s eye.” The engineering research might one day drive optic nerve imaging in a new direction—from looking primarily for the presence of glaucomatous damage to determining a patient’s susceptibility to such damage. “One new concept that might come from optic nerve head biomechanics is that we should use imaging when we first meet a patient in order to characterize the architecture of their connective tissue,” Dr. Burgoyne said. “I think within the next few years we will be able to put numbers to what we think is important.”

In related work, Dr. Burgoyne and his collaborators are using new histomorphometric imaging technologies to follow the development of very early experimental glaucoma in monkeys. At the first signs of tissue damage, the animals are sacrificed, and the researchers are then able to build precise histologic reconstructions of their optic nerve tissue. According to Dr. Burgoyne, this research has revealed some remarkable changes in the thickness of the prelaminar neural tissue and in the thickness of the underlying lamina cribrosa. “Early in the neuropathy these tissues thicken rather than thin. We think these changes occur early and probably precede or coincide with detectable changes on the surface of or in the thickness of the nerve fiber layer. The potential is there to image in a different way and with a different target to detect early changes that would signal that a particular nerve is not happy with the level of pressure it is experiencing.” Dr. Burgoyne thinks the next generation of OCT may be able to detect these changes.

All the Way to the Visual Cortex

Experimental data from primate and human glaucoma have shown that degenerative changes in the optic nerve extend well into the vision structures of the brain. Neeru Gupta, MD, PhD, and colleagues have mapped glaucoma-induced damage from retinal ganglion cell axons to the lateral geniculate nucleus and also to the visual cortex in human glaucoma. Dr. Gupta is associate professor of ophthalmology and vision sciences, and director of the glaucoma and nerve protection unit at St. Michael’s Hospital, University of Toronto.

Related research has recently detected cortical changes using functional imaging in glaucoma patients. “Glaucoma behaves much like a neurodegenerative disease,” Dr. Gupta said. “The loss of a specific population of neurons, the spread of damage from sick neurons to connected healthy neurons, and injury from oxidative stress and glutamate excitotoxicity seen in glaucoma are also hallmarks of many neurodegenerative diseases, including Alzheimer’s.”

It is possible that neuroprotective agents might become adjunctive therapy in glaucoma management. A trial of memantine (Namenda) has been completed in glaucoma patients and is currently under analysis. “Combining pressure-lowering therapies that protect retinal ganglion cells in the eye with neuroprotective agents that cross the blood-brain barrier and perhaps protect visual neurons in the central nervous system might be a better way to prevent damage from disease,” said Dr. Gupta.

She added that the changes in the optic nerve may be just the tip of the iceberg. Future studies, she said, may involve visual function or neuroimaging methods that take into account some of the brain changes in glaucoma.

Immunologic Intrigue in Neurodegeneration

Gülgün Tezel, MD, and her colleagues are continuing to explore the role of the immune system in glaucoma. It’s not clear whether immune system activity plays a primary role in glaucoma, but evidence strongly supports a secondary role in promoting progression.

“There is evidence that initially the immune system may be protective, but in the presence of glaucomatous tissue stress, glial cells are activated,” said Dr. Tezel, associate professor in the departments of ophthalmology and visual sciences, and anatomical sciences and neurobiology at the University of Louisville. “These cells may facilitate the activation of T cells and the generation of autoantibodies against retinal protein. This may contribute to retinal ganglion cell death.” Dr. Tezel noted that many glaucoma patients have increased titers of serum antibodies. Immune complexes have been detected in glaucomatous human retinas, and glaucomatous human eyes show evidence of complement activation. “In vivo studies and in vitro studies using retinal ganglion cell cultures, glial cell cultures and T-cell cultures all support immune system involvement,” she said. Elevated IOP, hypoxia and oxidative stress in the optic nerve and retina may tip the balance of the immune system, pushing it from a quiescent state to one in which antigen-presenting cells are activated.

Dr. Tezel’s group recently found that oxidative stress activates the antigen-presenting capability of glial cells, thereby establishing communication between glial cells and T cells.

Quality Matters

Like all instrumentation, these monitoring devices are only as good as the individuals who perform and interpret the tests. Drs. Schuman and Weinreb pointed out several potential pitfalls. “It’s not unusual to see patients who were referred to us because they have had a change in one of the instrument-based measures, but their clinical exam has not changed,” Dr. Weinreb said. “In some cases, the instruments are detecting disease or progression of disease at an earlier stage than is possible with the clinical exam. But more often the interpretation of the measurements is incorrect, or errors were made in acquiring the images.”

Artifact in, artifact out. These errors can lead to untimely treatment. “When you obtain an imaging study on a patient, you need to be certain that the quality of that study is adequate to be analyzed and that the analysis is performed properly before drawing any clinical conclusions,” Dr. Schuman said. “The user has to evaluate the test, and there are a variety of quality indices for the different tests.” On HRT, he said, the standard deviation should be less than 30. GDx has a quality number, which should be 8 or greater. With OCT, it’s signal strength, which should be 6 or higher.

“Look at the images,” Dr. Schuman continued. “If the GDx is an atypical scan, the data should not be accepted. If an HRT shows movement artifact, for example, don’t trust the data on that scan. In an OCT image that shows areas of signal dropout or regions where the analysis algorithm has failed, the images should not be trusted.” Dr. Schuman and colleagues recently published a handbook called Everyday OCT,2 which educates the user on how to obtain high-quality images and how to evaluate the images for clinical use.

Still no match for clinical skill. It’s easy to become enamored of technology, but clinical skill and low-tech exams remain important. “At the current time, I use the imaging technologies as an adjunct to my clinical examination of the optic nerve,” Dr. Weinreb said.

According to Dr. Schuman, “Physicians should always use the technology to bring them back to the patient. If the imaging test reveals an area of abnormality, I encourage physicians to go back to the clinical exam and try to see the indicated abnormality in the patient’s eye. You can almost always see it once it has been pointed out on the test. The imaging findings should never be accepted in a vacuum. The physician should use the imaging information together with the functional testing results to evaluate structure-function correspondence, which is also important.”

1 Zangwill, L. M. Arch Ophthalmol 2005;123:1188–1197.
2 Schuman, J. S. et al. Everyday OCT: A Handbook for Clinicians and Technicians (Thorofare, N.J.: Slack Inc., 2007).


Claude F. Burgoyne, MD
Senior scientist and research director, Optic Nerve Head Research Laboratory, Devers Eye Institute, Portland, Ore. Financial disclosure: Heidelberg Engineering provides an HRT instrument for lab.

Larry P. Frohman, MD
Professor of ophthalmology and neurosciences, University of Medicine & Dentistry of New Jersey, Newark. Financial disclosure: None.

Christopher A. Girkin, MD
Professor of ophthalmology and director of the glaucoma service, University of Alabama, Birmingham. Financial disclosure: Consultant for Heidelberg Engineering and Carl Zeiss Meditec.

Neeru Gupta, MD, PHD
Associate professor of ophthalmology and vision sciences, director of the glaucoma and nerve protection unit, St. Michael’s Hospital, University of Toronto. Financial disclosure: Consultant to Allergan and investigator in the memantine trial.

Joel S. Schuman, MD
Professor and chairman of ophthalmology, and director of the Eye Center, University of Pittsburgh; professor of bioengineering, Eye and Ear Institute, Pittsburgh. Financial disclosure: Receives research support from Heidelberg Engineering and Carl Zeiss Meditec, and, as one of the inventors of optical coherence tomography, receives royalties for intellectual property as licensed by Massachusetts Institute of Technology to Carl Zeiss Meditec.

Gülgün Tezel, MD
Associate professor of ophthalmology and visual sciences, and anatomical sciences and neurobiology, University of Louisville. Financial disclosure: Research support from the NEI and Research to Prevent Blindness.

Robert N. Weinreb, MD
Professor of ophthalmology, and director, Hamilton Glaucoma Center, University of California, San Diego. Financial disclosure: Research instruments from Carl Zeiss Meditec and Heidelberg Engineering.

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