Ординатура / Офтальмология / Английские материалы / Mechanisms of the Glaucomas_Shields, Tombran-Tink, Barnstable_2008

to elimination of IOP from the definition of glaucoma. IOP does, however, remain a strong risk factor, and its importance increases with higher values as shown by Kass and co-workers (12). In 1974, Ehlers and Kruse-Hansen found that there was a normal variation in the thickness of the cornea and that thinner corneas resulted in lower IOP measurements on Goldman applanation tonometry (13). Glaucomatologists did, however, not pay much attention to this finding until in the late 1990s and early this century (14).

The definition and diagnostic criteria of glaucoma have been changed and today only include structural criteria, that is, structural changes in the optic nerve on the one hand and functional criteria, that is, mostly various forms of visual field defects on the other hand. Prevalence surveys using previous definitions of glaucoma including IOP, in some instances history of glaucoma and even only use of glaucoma medication lead to inclusion in the “glaucoma group” of a considerable proportion of persons who do not have glaucoma and people who do have glaucoma, mostly normal tension glaucoma, are not diagnosed and therefore do not receive treatment (15).

MATERIAL AND METHODS

The Reykjavik Eye Study is population-based survey. Appropriate ethical approvals were obtained from the Data Protection Commission and the Hospital Ethics Committee following the guidelines of the Helsinki Declaration. The participants were citizens of Reykjavik, 50 years and older who were randomly sampled using the national population census. The examination took place in 1996. Of those 1635 randomly sampled, 1379 could be contacted and were eligible. Of these 1045 elected to participate, 461 men and 584 women, a response rate of 75.8%. All were Caucasians. They were examined in the University Eye Department in Reykjavik. All participants were required to answer a questionnaire regarding lifestyle, such as outdoor exposure, alcohol and smoking habits, health, disease, previous surgery, and medication including eye medication, and they were specifically asked whether they had been diagnosed with glaucoma and what medication or treatment they were receiving or had received because of glaucoma.

EXAMINATION

All participants were examined utilizing the standard examination protocol including kertorefractometry (Nidek ARK 900), air puff tonometry (Nidek NT 2000, average of three successful measurements), scheimpflug photography of the anterior segment (Nidek EAS 1000) including central corneal thickness measurements (16), slit-lamp examination of the anterior segment, biomicroscopy of fundi with 78D lens, and simultaneous stereo fundus photography one centred on the optic disc, the other on the centre of the macula (Nidek 3Dx/NM). Pseudoexfoliation (PEX) was specifically looked for on the slit-lamp after maximal dilatation of pupils with Tropicamide 1% and Phenylephrine 10% eye drops, and each eye was examined by two

experienced ophthalmologists. Only those participants with a central shield and/or peripheral band on the anterior lens capsule were considered to have definite PEX, and if they also had glaucoma, they were considered to have pseudoexfoliative glaucoma (6).

A subgroup of 85 people (8.1%) were recalled at approximately 3 and 12 months for full threshold visual field assessment (Octopus G1X) and gonioscopy (Goldman single-mirror lens) at 3 months. These included all 45 persons with history of glaucoma (one each with angle closure and neovascular glaucoma and 43 with history of OAG) as well as further 40 persons considered to have an optic disc suspect for glaucoma. The visual fields were evaluated in a masked fashion by two glaucoma specialists, and the grading of the optic disc was done by one experienced glaucoma specialist in all instances, also in a masked fashion and using the simultaneous stereo fundus photographs centred on the optic disc. The horizontal and vertical disc diameters as well as cup-to-disc ratios were determined following the Beaver Dam Eye Study protocol (9,10). This is done by using a plastic template with circles of increasing size. The circles are superimposed over the discs and cups measuring the largest cup-to-disc ratio within 20° of the horizontal and vertical midline. We also did measurements in millimeters of disc morphology using the Nidek 3D Station (17).

DEFINITIONS

In keeping with Wolfs et al. (8) and Foster et al. (18) for the diagnosis of glaucoma in cross-sectional prevalence surveys we used the optic nerve head of those not with glaucoma to establish the 97.5th and 99.5th percentiles. Definitions for OAG, categories 1–2, and the glaucoma suspects (GSs) are provided in Table 1. Selection of vertical cup-to-disc ratio (VCDR) >0.7 and 0.8 was based on the 97.5th and 99.5th percentiles, respectively. Also included are cup-to-disc ratio (C/D) asymmetry of 97.5th percentile (>0.2) and 99.5th percentile (≥0.3) as well as focal glaucomatous disc changes. The 97.5th percentiles are used for patients with glaucoma where glaucomatous visual field defects (GVFDs) are also established and the stricter structural definition of 99.5th percentiles (category 2) is used for those where visual field loss has not been shown possibly associated with poor performance of the participant or he/she was too frail to do a visual field test.

In healthy eyes, 97.5th percentile cut-off for IOP was about 23 mmHg. This was therefore considered abnormal and utilized as a part of our definition of GS. Eyes where IOP had been affected by medication, laser, or other surgery were disregarded for this purpose. IOP was not a part of the definition of glaucoma.

We treated the right and left eyes separately for statistical purposes as the two eyes of a person are not independent variables. Statistical analysis was done using SPSS 13.0 for Windows (SPSS, Chicago, IL) and included descriptive statistics, t-test, linear regression, binary and multinominal logistic regression, and ANOVA with post hoc testing.

Table 1

Classification Criteria Used for Open-Angle Glaucoma and Glaucoma Suspect

Diagnostic criteria for open-angle glaucoma (modified from (17))

One of the following:

1.Category 1 diagnosis (structural and functional evidence): 2/3 of the following criteria with a glaucomatous visual field defect (GVFD):

a.Vertical cup to disc ratio ≥97.5th percentile (>0.7)

b.Focal glaucomatous disc change (disc hemorrhage, notch of the neuroretinal rim, marked sloping of rim tissue, narrowest remaining rim of 0.1 disc diameter or less)

c.C/D asymmetry ≥97.5th percentile (>0.2)

2.Category 2 diagnosis (structural evidence only with unproved field loss): 2/3 of the following criteria:

a.Vertical cup to disc ratio ≥99.5th percentile (>0.8)

b.Focal glaucomatous disc change (disc hemorrhage, notch of the neuroretinal rim, marked sloping of rim tissue, narrowest remaining rim of 0.1 disc diameter or less)

c.C/D asymmetry ≥99.5th percentile (≥0.3)

Diagnostic criteria for open-angle glaucoma suspect (GS)

One of the following:

1.IOP ≥23 mmHg

2.IOP ≥23 mmHg with 1/3 of the following criteria for glaucomatous optic neuropathy (GON):

a.Vertical cup to disc ratio ≥99.5th percentile

b.Focal glaucomatous disc change (disc hemorrhage, notch of the neuroretinal rim, marked sloping of rim tissue, narrowest remaining rim of 0.1 disc diameter or less)

c.C/D asymmetry ≥99.5th percentile

3.IOP ≥23 mmHg with GVFD

4.+GVFD only

5.1/3 criterion for glaucomatous optic neuropathy (GON) listed in (2) above

Criteria for GVFD included the following:

1.Asymmetry across the horizontal midline (in early/moderate cases)

2.Located in the mid-periphery (in early/moderate cases)

3.Clustered in neighboring test points

4.Not explained by any other disease

5.Considered a valid representation of the subject’s functional status (based on performance indices such as false-positive rate)

RESULTS

Figure 1 shows the distribution of IOP in healthy right eyes. We found a big overlap of IOP in OAG and non-OAG eyes. Analyzing IOP for healthy right eyes, we established a 97.5% cut-off that was about 23 mmHg, and IOP ≥23 mmHg was used as a part of our definition for GSs though not included in the diagnosis of OAG. The quality of photographs was also assessed and those with too poor quality were disregarded. Of the 1045 persons, 1026 had gradable stereo photographs for at least

Intraocular Pressure (mmHg)

Fig. 1. Distribution of intraocular pressure, right eyes (n = 940). There was a big overlap of IOP in OAG and non-OAG eyes.

one eye and 1015 had gradable photograph for the right eye and 1014 for the left eye. The mean VCDR in our population is 0.4 “SD 0.23,” mode 0.5, range 0.0–1.0 (6).

Table 2 shows age-specific prevalence (%) of OAG and 95% confidence intervals of the 1045 persons who elected to participate. Table 3 shows the age-specific prevalence of pseudoexfoliation in the Reykjavik Eye Study. According to our definition, the diagnosis of OAG was established in 42 persons (Table 2). Seventeen persons were diagnosed with both GVFD, and on structural criteria (category 1), 25 persons were diagnosed on structural criteria only (99.5 percentile, category 2), that is without definite visual field defect or without visual field measurement but on stricter structural criteria.

It is of interest that 43 persons had history of OAG and had received pressurelowering treatment. Only 17 of these persons (39.6%) were deemed to have OAG

Table 2

Age-Specific Prevalence of OAG in the RES (31% PEX)

(29,30) that is similar to our results. Great normal variability in optic disc, rim, and cup size may also be a diagnostic problem though we have recognized that large optic discs usually have large rim and cup.

It is of utmost importance to use visual field measurements in prevalence studies though this is difficult because of the fact that one visual field per person leads to high proportion of false-positive and false negative results. Thus, in the Rotterdam Eye Study, 18.4% of the participants failed the initial visual field screening, whereby 1.1% were eventually deemed to have glaucoma on visual field criteria (31). Foster and co-workers considering visual field testing in prevalence surveys suggested that around 33% false-negative rate was not uncommonly found with 95% CI = 13–53% (18).

We did not only find a proportion of undiagnosed glaucoma in our survey but also that a proportion of those treated for glaucoma did not have glaucoma according to our definition. This has also been found in other surveys and may include cases with ocular hypertension that have not yet converted to glaucoma with optic disc and visual field changes. In some instances, treatment may have prevented such a conversion (12). In the Blue Mountains Eye Study (11), 108 persons had glaucoma according to their definition, 53 persons (49%) had previously been diagnosed as glaucoma and 55 persons (51%) were previously undiagnosed. Additionally, 37 participants gave history of glaucoma and pressure-lowering treatment without qualifying as glaucoma according to their definition. Thus in the Blue Mountains Eye Study in Australia, 90 persons presented with history of glaucoma and glaucoma treatment whereof 37 (41.1%) did not have criteria necessary for the diagnosis of glaucoma. In the RES, 43 persons had history of glaucoma and had received treatment, 17 thereof (40%) qualified on optic disc and visual field criteria indeed all having GVFD, 16 (37%) were considered to be glaucoma, suspect some of them had ocular hypertension and pseudoexfoliation and were therefore at increased risk of converting to glaucoma.

Corresponding with the treating ophthalmologists in Reykjavik confirmed these indications for treatment. Persons with ocular hypertension may be likely to convert to glaucoma within few years, and some may have been likely to do so without medication, in particular those with pseudoexfoliation (12,32,33). Ten patients on treatment did, however, not have proven ocular hypertension, pseudoexfoliation nor any disc or visual field changes though it seems likely that they were treated for ocular hypertensive episodes or apparent disc changes over time. It is also possible that some cases are due to false-positive visual field results. The above suggests that approximately 25% of the persons on glaucoma treatment did not require glaucoma treatment and this proportion may have been somewhat higher as not all of the GSs are likely to convert to glaucoma. To be told that one has glaucoma and to be put on treatment may have severe implications for the patients. Not only may it affect the conjunctiva, in some cases causing allergy and even cataract formation, but may also have serious psychological effect (34).

Pseudoexfolation is a risk factor for glaucoma and ocular hypertension (33). In our study, 108 persons, 10.7%, had pseudoexfoliation as compared to 2.2% in the Blue Mountain Eye Study (11) and 1.3% in a study from Western Ireland (25).

Our results are, however, similar to some Scandinavian studies (35,36). The proportion of people with pseudoexfoliation who also have glaucoma varies in the literature from 7 to 30% (37). In the Reykjavik Eye Study, 12% of PEX eyes also had glaucoma, whereas 31% of glaucomatous eyes also had definite PEX.

Like many other studies in the western world, the Reykjavik Eye Study found that some considerable proportion of persons treated for glaucoma may not require treatment whereas similar proportion of persons with glaucoma have not been diagnosed and therefore not received glaucoma treatment. The main reason for putting these persons without glaucoma on treatment seems to be ocular hypertension and a proportion of these persons have thicker than average central cornea leading to falsely elevated IOP measurements. Increased awareness of this and consequent increased frequency of measurements of central corneal thickness (CCT) in recent years may have reduced these numbers. Elevated IOP together with PEX increases the likelihood of both being put on pressure-lowering treatment and converting to glaucoma. Disc size varies and affects cup size and rim size. Other conditions also cause diagnostic problems as we found for instance similar appearance of optic disc in a myopic patient with advanced OAG and another one who had had temporal arteritis, maintaining some central vision. Single visual field tests result in rather many false-positive and falsenegative cases. Longitudinal data including repeated optic disc photography and visual field measurements are important when attempting to get glaucoma treatment to those who have glaucoma and to avoid treating non-glaucomatous eyes.

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