Structural, functional testing both essential for glaucoma diagnosis

Murray Fingeret

As clinicians examine patients at risk for glaucoma, watching for signs that the condition is developing, several questions arise. One common question is: “Does structural damage always precede functional loss?” When discussing structural damage, you may ask: “Does retinal nerve fiber layer (RNFL) loss always precede optic nerve damage?” With regard to functional testing, several new visual field tests such as short-wavelength automated perimetry (SWAP) and frequency doubling technology (FDT) perimetry are now commonly used. However, you may ask: “Do they always reveal loss before that seen on standard automated perimetry (SAP)”?

One reason why these questions are confusing is that the companies marketing these tests and instruments highlight only their strengths. A sales pitch that is repeated often enough may soon become perceived as fact, and it becomes the educator’s role to clarify how each test fits into the clinical picture.

The companies do not intentionally aim to deceive, but rather they use the best information available at the time to develop their marketing campaigns. When the data shifts, a lag exists before marketing campaigns are adjusted. Further confusing these issues, no consensus exists even among experts about the role for each of the new glaucoma diagnostic tests.

Recognizing pre-perimetric glaucoma

Open-angle glaucoma, early in its development, tends to be bilateral and asymmetric. One question is whether a person with progressive glaucoma may have optic nerve damage without visual field loss. Many practitioners have observed this scenario clinically.

The recognition of “pre-perimetric glaucoma” depends upon several factors, including:

• at what disease stage the patient is observed
• the size of the optic disc (damage is more difficult to observe in small optic nerves)
• the practitioner skill in optic nerve evaluation
• the criteria applied in deciding whether glaucoma is present (some clinicians erroneously require optic nerve and visual field loss to be present before labeling the condition as glaucoma)

The window of time during which only structural damage may be observed varies individual to individual. In some, the window may span years, while in others, weeks or months. Still, the condition named “pre-perimetric” or “early” glaucoma is not the usual point at which most clinicians diagnose glaucoma. Rather, the diagnosis is usually established when both optic nerve and visual field loss are present.

Visual field loss seen first in some OHTS patients

To further confuse the situation, visual field loss and not optic nerve/RNFL damage is the presenting sign of glaucomatous damage in some. This has been observed clinically in high-risk patients with elevated IOP and apparently healthy optic nerves and was reported in the Ocular Hypertension Treatment Study (OHTS).

In OHTS, individuals at risk for developing glaucoma due to elevated intraocular pressure (IOP) were carefully followed with direct ophthalmoscopy (undilated) and threshold perimetry twice a year and a dilated optic nerve evaluation with stereo fundus photography annually.

In the observation group, the majority showed optic nerve loss first (57.3%), but almost a third (32.6%) had visual field loss as their presenting sign, with 10.1% showing concurrent field and nerve damage. This can be interpreted several different ways. If dilated optic nerve examinations had been done twice a year, similar to the rate at which perimetry was performed, a greater number of cases with nerve damage would have been discovered, lowering the rate at which field loss was detected first.

On the other hand, detecting subtle optic nerve loss is difficult even among “experts,” and it is worth noting that world-class experts at a central reading center interpreted the fundus photography. Therefore, it seems unlikely that this high level of detection of optic nerve loss could be maintained in everyday clinical practice.

It is possible that the “field-first” cases had difficult-to-detect optic nerve changes. Finding several black spots on a sheet of paper (the field) that was previously clean is a more easily identifiable end point.

OHTS ancillary study results concur

The OHTS Baseline Topographic Optic Disc Measurement Ancillary Study, performed using the Heidelberg Retina Tomograph (Heidelberg Engineering, Vista, Calif.), revealed some interesting results that appear to support these points. This paper discussed the predictive power of imaging, because several topographic optic disc measurements performed at the time of study entry were associated with the development of observable disc or field damage.

However, I would add an additional interpretation: in some individuals, subtle optic nerve changes may have been present at the time of entry into the study, and only the optic nerve imaging instrument detected them. This may explain why some individuals developed field loss with apparently healthy optic nerves.

Do new perimeters detect loss sooner?

Recently, I attended a lecture on the diagnosis of early glaucoma. The speaker used several examples to illustrate how new visual field technologies (in this case, SWAP) detected functional loss while the standard field remained full. After displaying several cases, the perception was that visual field loss was always detected first on the newer tests. The “Glaucoma Continuum” has been described illustrating this principle with optic nerve/RNFL damage occurring first, followed by SWAP/FDT damage, and the last changes developing on SAP. Indeed, I have described this principle many times in my lectures.

I started thinking about this paradigm, now widely accepted, when an instrument company asked me to participate in a roundtable discussion that addressed new technologies in glaucoma. Each of the expert panelists was asked to bring a case that illustrated the concept of early glaucomatous damage with changes present in the optic nerve along with a normal standard field and loss on either FDT or SWAP. While each of us was able to present such a case, we all struggled in getting them.

During the discussion, we each remarked how few of these early glaucoma cases we had. This struck me as contradictory. If FDT or SWAP routinely occurred as a mid-point in the cycle, between initial structural loss and loss seen on SAP, why is it that we rarely observe it? Is it that the window of time is very short, and if it is so short, is it a matter of practical clinical importance?

Early glaucoma manifestation still being studied

I believe the concept of how early glaucoma manifests is evolving. Rather than individuals showing SWAP or FDT field loss initially, initial functional loss may be detected in one of several ways.

Bengtsson and Heijl recently published a paper in which they performed full threshold SWAP, SITA SWAP and SITA Fast SAP on 101 individuals with ocular hypertension (OHTN) or early-manifest glaucoma. Conventional wisdom would lead one to expect that among this high-risk group, more individuals would have SWAP loss than SITA loss.

Surprisingly, the authors found no significant difference in the number of depressed test points among the three tests. SAP was as good at detecting early visual field loss as the SWAP tests. Some individuals showed loss initially on one test and some on another, probably based upon the mechanism by which the glaucoma was developing.

Overlap existed among those positive on one or more tests. Forty-six individuals were flagged on all three tests; SWAP and SITA SWAP each detected six individuals who were normal on the other two tests, while SITA Fast identified 10 individuals who were normal on the SWAP tests. Four individuals had clusters flagged only on full threshold SWAP and SITA Fast, five only on SITA Fast and SITA SWAP, and 10 only on full threshold SWAP and SITA SWAP.

The authors’ conclusion was that conventional perimetry detected as many individuals with early glaucoma as either SITA SWAP or SWAP. This study reinforces the concept that in individuals developing glaucoma, different mechanisms may be involved with loss first observed on different tests. Rather than striking a blow against emerging new field technologies, these findings reinforce the notion that the different field tests are complementary. Using more than one type of visual field test may help detect loss in individuals suspected of developing glaucoma.

Does RNFL loss occur first?

The last question is whether RNFL loss always precedes optic nerve damage when glaucoma is in its infancy. Burgoyne and Downs have addressed this issue in their monkey model, in which the IOP was elevated while the optic nerve/RNFL was observed for developing damage. Their results showed that in some eyes the RNFL changes first, while in others the damage is seen within the optic nerve.

Most clinicians report that structural loss is usually detected through optic nerve damage. RNFL loss is not commonly observed clinically due to the technical difficulty in examining the RNFL as well as observable loss being masked if cataracts or a lightly pigmented fundus are present.

Technological development will help detection

New instrumentation such as the GDx VCC (Carl Zeiss Meditec, Dublin, Calif.) or OCT Stratus (Carl Zeiss Meditec) may help detect RNFL loss. These technologies have also led to the concept of “instrument-driven” glaucoma being present. In this situation, noted in high-risk individuals, RNFL loss is observed on one of the instruments while the visual field is clean and the optic nerve appears healthy.

Could the instrument be so sensitive that it can detect RNFL loss before it is observed clinically or manifested with perimetry? This issue requires further study, but presently, when the instruments were used in individuals with early glaucoma, their sensitivity and specificity rates varied from 75% to 95%, depending upon the interpretation criteria applied and the study cited.

While the instruments perform admirably, they are not ready to be used alone. Instead, results from these devices must be considered along with all other findings obtained during clinical examination, just as we do with more standard observations such as intraocular pressure. Given that even the best instruments have false positive rates of 5%, as is implied by a specificity of 95%, we must expect that in individuals with healthy optic nerves and clean visual fields with positive RNFL/optic nerve imaging results, some of the positives will represent false positives and are not due to true disease.

When this scenario presents itself, I would recommend identifying the individual as a glaucoma suspect and monitoring carefully. When damage is confirmed with a second test such as visible optic nerve/RNFL damage or visual field loss of any form, then glaucoma is confirmed.

Perhaps in the future I will devote a column to how the diagnosis of glaucoma has evolved such that damage present only on RNFL/optic nerve imaging tests represents true damage. However, for now, this is not the case.

In summary, the way we diagnose glaucoma is evolving quickly. Learning how each of the new tests fits into the clinical spectrum is important. Presently, we need to include both structural and functional assessment as we grapple with detecting early glaucomatous damage.

For more information:

• Murray Fingeret, OD, is chief of the optometry section at the Department of Veterans’ Affairs Medical Center in Brooklyn and Saint Albans, N.Y., and a professor at SUNY College of Optometry. He is also a member of the Primary Care Optometry News Editorial Board. He may be contacted at St. Albans VA Hospital, Linden Blvd. and 179th St., St. Albans, NY 11425; (718) 298-8498; fax: (516) 569-3566; e-mail: murrayf@optonline.net. Dr. Fingeret has no direct financial interest in the products mentioned in this article. He is a paid consultant for Carl Zeiss Meditec.

Suggested reading:

• Bagga H, Feuer WJ, Greenfield DS. Detection of psychophysical and structural injury in eyes with glaucomatous optic neuropathy and normal standard automated perimetry. Arch Ophthalmol. 2006;124(2): 169-176.
• Bagga H, Greenfield DS, Feuer W, Knighton RW. Scanning laser polarimetry with variable corneal compensation and optical coherence tomography in normal and glaucomatous eyes. Am J Ophthalmol. 2003;135(4):521-529.
• Bengtsson B, Heijl A. Diagnostic sensitivity of fast blue-yellow and standard automated perimetry in early glaucoma. Ophthalmology. 2006;113:1092-1097.
• Burgoyne CF, Downs JC, Bellezza AJ, Hart RT. Three-dimensional reconstruction of normal and early glaucoma monkey optic nerve head connective tissues. Invest Ophthalm Vis Sci. 2004;45(12):4388-4399.
• Hoh ST, Greenfield DS, Mistlberger A, et al. Optical coherence tomography and scanning laser polarimetry in normal, ocular hypertensive, and glaucomatous eyes. Am J Ophthalmol. 2000;129:129-135.
• Johnson CA, Adams AJ, Casson EJ, Brandt JD. Blue-on-yellow perimetry can predict the development of glaucomatous visual field loss. Arch Ophthalmol. 1993;115:225-233.
• Johnson CA, Sample PA, Cioffi GA, et al. Structure and function evaluation (SAFE): I. Criteria for glaucomatous field loss using standard automated perimetry (SAP) and short-wavelength automated perimetry (SWAP). Am J Ophthalmol. 2002;34:177-185.
• Johnson CA, Sample PA, Zangwill LM, et al. Structure and function evalution (SAFE): II. Comparison of optic disk and visual field characteristics. Am J Ophthalmol. 2003;35:148-154.
• Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Study. A randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open angle glaucoma. Arch Ophthalmol. 2002;120:701-713.
• Sample PA, Weinreb RN. Progressive color visual field loss in glaucoma. Invest Ophthalmol Vis Sci. 1992;33:2068-2071.
• Zangwill LM, Weinreb RN, Beiser JA, et al. Baseline topographic optic disc measurments with the development of primary open-angle glaucoma. Arch Ophthalmol. 2005;1223:1188-1197.