Glaucoma:The Latest Diagnostic Tools
Today's technologies are faster, more accurate and able to detect glaucoma much earlier. Here's an overview of what's available.
By Mireille P. Hamparian, M.D., Encino, Calif., and Alan L. Robin, M.D., Baltimore, Md.

Recent advances in technology have done a great deal to enhance our ability to detect and treat glaucoma in its earliest stages. And increasing numbers of eyecare professionals are taking advantage of the new technologies.

For example, hundreds of disc imaging systems have been sold during the past decade. More have been sold at the Academy and ASCRS meetings in the past 2 years than in the previous 8 years combined. Not only are the instruments and software better, but reimbursement for related procedures has become much more reasonable.

A major step forward

Previous technologies, which primarily monitored changes in intraocular pressure (IOP), loss of visual function and grossly visible structural changes in the disc, made diagnosing and monitoring glaucoma difficult at best:

• The sensitivity and specificity of disc changes and IOP as evidence of glaucoma are less than 50%. (Many patients who present with IOPs greater than 21 mm Hg or large cupping and cup-to-disc asymmetry don't have glaucoma.)
• As an indicator of glaucoma, the nerve fiber layer is much more sensitive and specific. However, it's hard to see in vivo, and until recently we've had to rely on qualitative assessments -- sketches and photos of the optic nerve -- to monitor glaucomatous structural damage and progression. In addition, nerve fiber layer photos are difficult to read when the patient is elderly or African-American, and these are the patients most likely to have glaucoma.

In contrast, the new modalities can more reliably measure change in disc size and shape, as well as focal thinning in the nerve fiber layer. This allows us to intervene at an earlier stage of glaucoma progression and monitor those patients who present with elevated IOPs or large cup-to-disc ratios but still have normal perimetry.

Perhaps the most compelling reason to use the new imaging technology is that clinically detectable structural changes in the nerve fiber layer and optic disc can occur years before functional measurements of the optic nerve (such as standard automated perimetry) are able to detect a problem. In fact, a patient may lose half of his optic nerve head axons before perimetric defects become obvious. (Also, visual fields have inter-test variability; you need at least two or three of them to confirm a defect.)

Each of the new technologies has its strong and weak points. For example, some of the new modalities are primarily designed to screen for potential glaucoma, although they can also be used to follow progression of the disease. (Our ability to use these modalities effectively for the latter purpose will increase as we gain more experience with them.)

This article will help you choose which instrument or modality makes the most sense for your practice by reviewing some of the most relevant attributes of the options available.

Perimetry: Frequency Doubling Technology (FDT)

Zeiss Humphrey's FDT is a portable visual field analyzing device that's demonstrated relatively high sensitivity and specificity for detecting visual field loss in eyes with moderately advanced glaucoma. The patient observes a series of alternating light and dark bars, which rapidly switch between black and white. This causes most patients with healthy visual function to perceive twice as many bars as are actually there. (The level of contrast is set so that 99% of normal subjects observe the same effect.)

This frequency-doubling stimulus is presented randomly to a total of 17 different visual field locations within the central visual field.

How it works: We believe the stimulus is detected primarily by a subset of magnocellular retinal ganglion cells that have nonlinear response properties. These magnocellular ganglion cells may be among the first casualties of glaucoma. Hence, inability to experience the doubling phenomena indicates early glaucomatous damage.

Results of an FDT screening are considered abnormal when the following are present:

• any defect in the central five locations
• two mild or moderate defects in the outer 12 spots
• one severe defect in the outer 12 spots.

Results are also considered abnormal if total test time for each eye is greater than 90 seconds.

When any of these criteria are present, the FDT is considered "positive." When you obtain a positive result, you can either quickly repeat the test or perform conventional threshold perimetry.

Advantages of the FDT. These include:

• The FDT is very easy for a technician to use; it requires only a few minutes of instruction. The menu is simple, and operation leaves little room for error.
• It features a screening mode and a full threshold mode. (The screening algorithm is a quick and accurate tool for glaucoma detection.)
• The machine isn't at all intimidating for the patient. It has no perimetric "bowl," so the patient can feel comfortable without claustrophobia.
• The FDT tolerates up to 6 diopters of blur, so the technician usually doesn't have to worry about proper spectacle correction.
• The test requires no eye drops; it's unaffected by pupil sizes as small as 2 mm.
• The test can be performed under normal lighting conditions.
• The procedure takes only 45 to 70 seconds per eye to perform.
• The FDT has a unique pre-test capability to help you determine which threshold perimetry algorithm (if any) would be best to use.
• The instrument is relatively portable. (It weighs about 15 pounds).

Other points to consider. These include:

• The test is subjective; it depends on the patient's response.
• Because structural loss of retinal nerve fibers may precede functional loss, this technology has limited usefulness for early detection of glaucoma.
• Determining which results are normal and which indicate early glaucoma can be difficult.
• The FDT may not be useful for long-term follow-up and detection of change.
• The FDT printout looks different from the printouts produced by other instruments, which most of us are used to. It requires a little practice to interpret.

Perimetry: The Swedish Interactive Thresholding Algorithm (SITA)

SITA algorithms (used by the Humphrey automated visual field perimeter) have done a lot to revolutionize perimetry. SITA algorithms are designed to perform visual fields similar to those that use the full threshold algorithm, but with one important advantage: SITA algorithms don't depend on the conventional staircase method. For that reason they significantly decrease test times, while still maintaining the integrity of the test results.

How it works: Instead of using the usual staircase methods, which test each area in the visual field once, SITA returns to check a second time -- but only if nearby areas show a suspicious result. (This helps keep the test time short.) As the test proceeds, these functions are updated.

SITA fast. SITA fast differs from SITA standard in the number of crossings, the step size and perhaps most important, the amount of allowable error in the threshold estimate. If a given test result is reliable (based on the patient performance indices the device provides), it can dependably detect scotomas along with their relative depths and help quantify the level of glaucoma damage.

For patients who still can't perform a reliable test with the SITA full threshold because of problems with attention span or rapid fatigue, the SITA fast test can often be quite useful.

Advantages of the SITA algorithm. These include:

• Patients and technicians are happier with the shortened test time.
• Quicker testing allows you to perform almost 30% more examinations in a given time period. This, in turn, allows you to recoup the cost of the perimeter much more quickly -- and make more efficient use of your technicians' time.
• This test has a slightly higher mean sensitivity than tests using earlier algorithms, perhaps because of the shorter testing time and reduced patient fatigue.
• Both inter- and intra-test variability of the SITA is comparable to conventional full threshold perimetry. In fact, it displays a little less variability between repeated tests, probably also as a result of reduced fatigue, which allows for earlier and more reliable detection of visual field deterioration.

Other points to consider. These include:

• The test is subjective.
• It doesn't detect nerve fiber loss at its earliest stage, and therefore doesn't detect glaucoma at its earliest stages.
• SITA can't calculate short-term fluctuation or corrected pattern standard deviation.
• One of the remarkable things about SITA fast is that it operates most of the time right at threshold. However, this characteristic can limit its utility in a screening situation because its high speed is less tolerant of patient errors than SITA standard.

Note: Some doctors who have worked with this algorithm have concluded that the relative sensitivity of the tests depends on how far the disease has progressed:

• SITA standard is much more sensitive than either SITA fast or full threshold in early field loss.
• SITA standard and full threshold are comparably sensitive in moderate loss.
• In advanced disease, they show minimal difference in sensitivity.

Perimetry: Portability and design advantages

A new perimeter, the Oculus Easyfield, uses familiar technology, but offers practical advantages because of its size and cost. It's the first portable and relatively inexpensive device that can both screen patients for glaucomatous damage and quantify results (making it possible to monitor progression and accurately follow these patients).

Despite its relatively small size and cost, the Oculus Easyfield is a capable glaucoma detection device. Preliminary comparative studies suggest the Easyfield may be more sensitive and specific to moderate and severe glaucoma damage than the FDT test. (Evaluations are currently under way comparing full-threshold perimetry testing by the Easyfield and Humphrey instruments.)

How it works: The technology is similar to conventional computerized static perimetry.

Advantages. These include:

• The small size and relatively low cost may increase the cost-efficiency of glaucoma detection.
• Unlike most conventional perimeters, the Easyfield
  doesn't require the patient to put his head inside a bowl, which some patients find claustrophobic.
• If you screen for glaucoma and results are positive, threshold determinations can be made with the same instrument.

Other points to consider. These include:

• The Easyfield doesn't provide a large normative database for statistical comparison.
• The Easyfield lacks statistical packages for longitudinal follow-up.

The Easyfield and Humphrey FDT are similar in size and price (about $7,000), but the FDT instrument weighs 19 pounds, compared to the Easyfield's 13 pounds.

Scanning laser ophthalmoscopy

The Heidelberg Retina Tomograph II (HRT II) uses confocal scanning laser imaging technology to create a detailed, 3-D topographic map of the optic nerve head. The measurements permit analysis of rim and cup volume, cup shape, and indirect analysis of retinal surface height and other topographic parameters. The HRT II also indirectly calculates the thickness of the nerve fiber layer (NFL). It includes a normative database for comparison, and graphically displays deviation from that database. (It can perform a similar comparison to previous visits by the same patient.)

How it works: The HRT II uses CAT-scan-like technology to record three sequences of cross-sectional images during a 4-second period, and then assembles the resulting data into a 3-D topographic map. First-time measurements are analyzed using regression techniques developed by Moorfields Eye Hospital in London, which evaluate the relationship between neuroretinal rim area and optic disc area.

The instrument also divides the optic nerve and surrounding region into six sectors and evaluates each sector separately. An on-screen color map indicates whether each section falls within normal, borderline or abnormal parameters.

Advantages of scanning laser ophthalmoscopy. These include:

• Images may be obtained through undilated pupils and early cataracts.
• Low level light is used.
• Minimal operator training is required. The HRT II features single-button operation.
• The color-coded maps are relatively easy to read and interpret.
• The HRT II automatically rejects images that are blurred by poor focus or patient movement. It provides a standard deviation figure for each image that tells you how accurate that measurement was.

(Heidelberg has also recently enhanced the capabilities of the HRT II with an optional macular edema module. This module provides a way to measure macular thickness changes over time using topographic retinal thickness measurements and macular mapping techniques.)

Other points to consider. These include:

• Image resolution depends on the optics of the human eye. Cataracts may impede the quality of the image.
• Variations in topography can be caused by blood vessels in the cup and fluctuations in IOP, and the optic nerve head.

Scanning laser polarimetry

The GDx and GDx Access nerve fiber analyzers (from Laser Diagnostic Technologies Inc.) measure the retinal nerve fiber layer (RNFL) thickness with a scanning laser polarimeter based on the birefringent properties of the RNFL. Measurements are obtained from a band 1.75 disc diameters concentric to the disc.

How it works: This technology uses a polarized near infrared (780 nm) laser beam to scan across the fundus at the optic nerve head and peripapillary retina. The birefringence causes a change in the state of polarization of the reflected light, known as retardation. The amount of retardation that occurs is linearly related to the thickness of the RNFL.

In vitro measurements in an animal model show excellent correlation between retardation and RNFL thickness, with resolution of measurements at about 13 microns. The GDx displays higher retardation values in the superior and inferior regions of the disc, corresponding to greater RNFL thickness in these areas. The scan also shows reduced retardation over blood vessels, corresponding with the observation that vessels embedded within the RNFL reduce the thickness on top of the vessels.

Advantages of scanning laser polarimetry. These include:

• Clinical measurements are highly reproducible.
• Readings can be done very quickly.
• Operation is straightforward. The technician doesn't need to mark the optic nerve, just center a circle within the optic nerve region.
• This technology has a higher sensitivity than the Glaucoma Hemifield test.
• Using this technology doesn't require pupil dilation.
• Results are independent of the optical resolution of the eye.
• This technology is specifically designed to measure the critical retinal nerve fiber layer, where glaucomatous damage can be seen first.
• A Both GDx instruments feature an age- and race-related normative database for valuable first visit comparison.

Other points to consider. These include:

• Polarizing structures of the eye other than the RNFL may interfere with the retardation values; the cornea (and to a much lesser degree the lens) are also birefringent. (Both instruments include a compensator unit to correct for retardation arising in the lens and cornea.)
• Peripapillary atrophy and chorioretinal scars may increase retardation values, although these artifacts are apparent on the image.

Note: Even though retardation values of structures of the eye other than the RNFL can interfere with the accuracy of these measurements, values are constant for any given individual. Consequently, serial scans may be used to follow a patient over time and determine progression of disease.

• RNFL thickness values in normal and glaucomatous eyes show considerable overlap because of large variability in the number of axons among normal subjects. Accordingly, the mean retardation values of the GDx vary considerably among normal subjects.

However, retardation ratios of the superior or inferior region compared to the temporal area have good correlation with visual field mean deviation for both normal patients and those with glaucoma. (Sensitivity and specificity can be as high as 96% and 93% respectively.)

The two formats. Differences between the GDx Nerve Fiber Analyzer and the GDx Access include:

• The GDx Nerve Fiber Analyzer captures the image with four times more pixels than the GDx Access.
• The Access unit is a smaller, more portable unit available for lease only, with a fee-per-exam program. (In contrast, the Nerve Fiber Analyzer must be purchased.) The GDx Access includes software upgrades and services.

The GDx is better suited for a large volume practice with a sizeable glaucoma population. The GDx Access is better suited for a smaller glaucoma population.

Optical coherence tomography

Optical coherence tomography (OCT) is similar to ultrasonography, but it makes its measurements using light instead of sound. For that reason, it has much higher resolution in both axial and lateral dimensions. (The OCT instruments from Zeiss Humphrey have a resolution of 10 microns axially and 20 microns for transverse.)

Because this technology has obvious potential for glaucoma detection, Zeiss Humphrey has recently produced a new version of the instrument -- the OCT2 -- with added features specifically designed to increase the instrument's usefulness in glaucoma detection. The OCT2 lets you monitor three relevant variables: the optic disc, the RNFL, and macular thickness and structure.

How it works: Optical coherence tomography uses low-coherence interferometry to measure the echo time delay of light, which is backscattered from different layers in the retina. (The OCT uses a super luminescent diode with a bandwidth of 30 nm as its light source; the OCT2 uses a broad band of wavelengths.)

The instrument then uses the time delay of the backscattered light to calculate the distance between reflecting surfaces, based on the refractive index of the medium. A constant value of 1.36 is assumed for retinal tissues.

By scanning the beam across the retina, the OCT2 creates a two-dimensional cross-section of the area being scanned. This makes it possible to "see" the structural condition of the internal tissues, including photoreceptors, retinal pigment epithelium and choroid.

The instrument can measure retinal changes directly using nerve fiber analysis or monitor progression using volumetric analysis and checking cup-to-disc ratios. OCT measurements of the RNFL correlate well with the functional status of the eye as measured by automated visual fields.

Advantages of OCT technology. These include:

• Unlike ultrasonography instruments, OCT instruments are noncontact.
• The OCT2 includes a limited age-related normative database.
• The OCT 2 can compare current scans to previous scans of the same patient.
• The OCT2 can scan in a straight line, or in a circle (which is particularly useful for scanning the optic disc). In addition, it can scan a series of concentric circles and create a donut-shaped retinal nerve fiber layer thickness map, or make a series of straight-line scans through a single point and use the information to analyze disc structure.
• In most cases, the performance of the OCT isn't affected by the refractive state of the eye, minimal nuclear sclerosis or media opacities.
• In addition to optic nerve measurements for detection of glaucoma, the OCT can be used for diagnosing diseases of the retina, as well as the anterior segment and cornea.

Other points to consider. These include:

• It requires pupil dilation.
• Posterior subcapsular and cortical cataracts can significantly impair the quality of measurements.
• The normative database is still small.
• Although the depth values of the scan are independent of the optical dimensions of the eye, the length of a scan across the fundus does depend on the optical dimensions of the individual eye.
• The assumption of a constant value for magnification results in a small error in standard deviation.
• Although significant differences in RNFL thickness between groups of normal and glaucomatous subjects have been demonstrated, considerable overlap of individual measurements between the groups exists because of variability of RNFL thickness in normal subjects (as discussed earlier).

Everybody wins

This new generation of technology makes it possible to do a much better job of catching glaucoma early and monitoring its progression. In addition to quantifying various aspects of optic nerve topography and retinal nerve fiber structure that were previously very difficult to assess, the technologies offer our practices a host of benefits:

• The simpler, more user-friendly nature of the new technologies means that a less-trained technician (requiring less salary) can operate them. This also allows for better utilization of manpower.
• The need for less training means less trauma when a technician leaves your practice. (In contrast, performing fundus photography requires great skill, so replacing a good technician can be a real problem.)
• We can evaluate our patients more profitably because tests take less time.

Future advances in technology and design will no doubt offer even greater benefits for patients and practices alike. But in the meantime, today's options have plenty to offer, and both your practice and your patients stand to benefit. If you've been considering purchasing some new instrumentation to help bring your practice into the 21st century, there's no time like the present.

Dr. Robin is a world-recognized leader in the diagnosis, medical management and surgical treatment of glaucoma. He's clinical professor of ophthalmology at the University of Maryland, an associate professor at the Wilmer Institute of the Johns Hopkins School of Medicine and adjunct clinical professor for the Department of Veteran Affairs in the Maryland healthcare system. He has published and lectured extensively, and is a member of the editorial board of Graefe's Archives of Ophthalmology.
Dr. Hamparian is a glaucoma specialist in Enrico, Calif.