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

glaucoma cases, and to test the usefulness of laser imaging techniques in the screening of glaucoma.

At first it should be mentioned that no research related to the prevalence of glaucoma has been carried out in Poland up to now. It is enormously important to prevent the disability caused by glaucoma by the early detection of the disease. Imaging techniques can potentially play a role in detecting glaucoma. However, the usefulness of these methods in the screening has not been established yet. In this cross-sectional study, we employed imaging methods with polarimetry (GDx) and confocal laser scanning [Heidelberg retina tomography (HRT)] as well as established diagnostic procedures.

Participants and Methods

Population

The study was performed in a well-defined geographic area in Wroclaw, a city of about 600,000 population in the South-West of Poland.

A randomly selected sample, representative for Wroclaw population, was examined to determine the prevalence of glaucoma. The selection of subjects entering the study was based on a database provided by local Registry Office and the Office for Population Evidence. This database includes, among other things, such details as a birth date and a permanent residency address of each citizen. Based on this data, the Main Department of Statistics generated sampling frames for a 10-year stratum (between 40 and 79 years) separately for each gender and drew a simple random sample based on the above-mentioned registry according to the previously designed algorithm of selection.

We randomly selected and invited 6000 inhabitants on the basis of the following assumptions: a prevalence of 2%, a maximum tolerable random sampling error of 0.4%, and a response rate of 80%. To obtain statistically significant level of the test (0.05), a sample of at least 4633 subjects needed to be examined (45). In every case, the participants were invited by letter, informing them of the aims and procedures of the research, and the informed consent was signed. The study was approved by the local Committee of Medical Ethics.

Procedures

The study conducted in Wroclaw was preceded by a pilot study to assess the response rate and the accuracy of applied methods.

The design of the study included two stages: the first stage dealt with screening and was aimed to find the subjects suspected of glaucoma, who entered the second stage of the study, where we established a definitive diagnosis.

After the complete diagnostic examinations, the subjects were classified as “healthy,” “suspected,” or “definite glaucoma.” According to the schedule applied in the second stage of the study, the follow up examinations, if needed, were performed after 3, 6, and 12 months to determine the final diagnosis.

During the first visit, all participants were asked to fill in a detailed questionnaire concerning demographic data, medications, family history, and general medical history. Next, an ophthalmologic examination was performed including the following tests: slit-lamp examination of the anterior segment to estimate the peripheral depth of the anterior chamber by means of the Van Herrick method, evaluation of the optic nerve

head by means of handheld 78-D lens, IOP measurement using a pneumatic noncontact tonometry or Goldmann tonometer, and one of the scanning laser-based imaging techniques: HRT or GDx. All these tests were conducted without pharmacological mydriasis.

Measurements of IOP were performed by means of a non-contact tonometer and repeated three times consecutively. When the mean value of the three measurements was more than 18 mmHg, a Goldmann applanation tonometry was applied.

Optic nerve configuration was studied using the HRT. A mean topographic image of three 10° field-of-view scans, judged to be of acceptable quality, was obtained for each tested eye. While viewing stereoscopic photographs of the optic disc, a trained technician outlined the optic disc margin on this image.

In our study, we investigated the following topographical parameters: mean cup depth, maximum cup depth, height variation in contour, mean height contour, cup shape, disc area, cup area, cup–disc area ratio, cup volume below surface, rim area, rim volume above reference plane, rim disc ratio, RNFL thickness, RNFL crosssection, and reference height. We also examined values from the discriminant analysis formula of Mikelberg et al. (43) (the HRT classification in current HRT software version 2.01; Heidelberg Engineering, Heidelberg, Germany) and one developed by Bathija et al. (46).

The presumed thickness of the RNFL was measured with a scanning laser polarimeter by means of an instrument with a fixed corneal polarization compensator. All measurements in our study were obtained from a mean of three 15° images, centred in the ONH. The standard 10 pixel wide band was concentrically located with the optic disc margin at 1.75 disc diameters. All analyses atone location were performed by the same operator.

All subjects with glaucoma and 1 out of 10 suspected were examined by two independent glaucoma specialists. The inter-operation variation represented the percentage agreement between the observations made by two observers.

To enter the second stage of the study, all subjects had to fulfill at least one of the following criteria:

1.IOP level more than 21 mmHg.

2.The value of discriminant analysis formula of Weinreb > 0.501 (32) or the Number value > 25 (47) in GDx examination.

3.The value of discriminant analysis formula of Mikelberg > 0.5 (43) and HRT examination.

4.Ophthalmoscopy findings:

a.Narrowing of the neuroretinal rim expressed by a rim/disc ratio of <0.1 anywhere

b.rim/disc (R/D) ratio ≥0.1 and ≥0.4, for a circumferential extent of more than 90° of disc

c.ovality of the cup with a difference in vertical to horizontal cup/disc ratio (c/d) ≥0.2

d.asymmetrical disc excavation with a difference in c/d >0.2 between the two eyes

e.disc hemorrhage crossing the rim

5.Anterior chamber angle width (Van Herrick method) less than 1/4 corneal thickness.

6.Whenever it was not possible to perform one or more of the screening methods.

7.Previously diagnosed glaucoma.

In the second stage of the study, the following tests were performed:

1.measurement of the visual acuity with a chart displaying Snellen’s E at 6 m

2.slit-lamp examination with pharmacological mydriasis, with particular attention to the pseudoexfoliative material

3.dynamic indentation gonioscopy by 4-mirror Zeiss-type lenses—results graded according to Spaeth’s grading system (48)

4.multiple measurement of IOP with applanation tonometry during 24-h period, at the hours: 6.00 a.m., 9.00 a.m., 12.00, 3.00 p.m., 6.00 p.m., and 9.00 p.m.

5.static perimetry with OCTOPUS 101 (INTERZEAG) with the application of the two first phases of dG2

6.corneal pachymetry with “POCKET” device (Quantal Medical)—in all patients with ocular hypertension (OH) or glaucoma

Diagnostic Criteria

Glaucoma was diagnosed if at least two of the following three criteria were met:

1.one of the above-mentioned morphological abnormalities of the optic nerve head

2.glaucomatous visual field defined in case of at least three contiguous points of reduced sensitivity at p < 5% and at least one of them with probability of p < 1% or corrected loss variance (CLV) < 5% that could not be explained on the basis of other ocular or neurological causes and confirmed in at least two subsequent examinations

3.IOP > 21 mmHg measured by applanation tonometry at the turn of at least two independent measurements

Depending on the level of IOP and the configuration of the chamber angle, the various forms of glaucoma were diagnosed. POAG was diagnosed at the presence of the above described disc or field abnormalities and an IOP > 21 mmHg, with a chamber angle considered not occludable and devoid of goniosynechiae and vascular anomalies. If the IOP measurement did not show the increase above 21 mmHg, then normal pressure glaucoma (NPG) was defined. At the presence of chamber angle abnormalities such as

1.complete closure (defined as the evidence of significant obstruction of the functional trabecular meshwork by the peripheral iris in all the quarters of the angle circumference in the primary position with intention)

2.partial closure of the chamber angle (defined as an angle where the pigment trabecular meshwork was not visible throughout less than three quarters of the angle circumference in the primary position without manipulation or intention)

3.configuration of the drainage angle potentially prone to temporary occlusion (suspected on the basis of signs of previous IOP rise)

4.evidence of the previous episodes of IOP rise, atrophy of the iris, irregular pupil, gray-white subcapsular cataract in the pupil area, and non-reactive mydriasis without accompanying signs of secondary angle closure, the PACG was defined.

The prevalence of the pseudoexfoliation syndrome (PEX) was 1.4%. Twelve subjects of this group (63%) were diagnosed with glaucoma (16% of all detected OAG cases).

Table 4 shows the results of screening tests sensitivity and specificity. The highest sensitivity (85%) was associated with the Number value (GDx), and the measurement of IOP was characterized by the highest sensitivity.

Among imaging examinations, the biggest ROC area was shown by the discrimination function according to Mikelberg et al., in HRT examination (0.79), the following was the Weinreb discrimination function in GDx (0.77) and the Number value (0.73). There were no statistically significant differences observed between ROC curve area for these parameters.

Discussion

In our study, the mean level of IOP in examined population was 15.2 mmHg. Comparable results were obtained in some other studies such as Beaver Dam Study (USA), 15.2 mmHg (7); Egna–Neumarkt Study (Italy), 15.1 mmHg (11); Baltimore Study (USA), 17.4 mmHg (9); and Blue Mountains Study (Australia), 16.1 mmHg (10); and was higher than reported among Asian populations [Taiwan, 13.4 mmHg (49); Mongolia, 12.4 mmHg (50); and Japan, 13.3 mmHg (51)]. In the study performed in Mongolia, a mean IOP lower than 9 mmHg was noted in 7% of the population, while in Wroclaw, this was 1% of the population.

The IOP values were distributed as a Gaussian curve skewed to the right. The noted progressive increase in the mean IOP in subsequent age groups corresponds with the results of most published population studies. There was no significant difference of mean IOP between genders.

The differences in demographic characteristics of the studied groups, diagnostic methods employed, and the applied diagnostic criteria for glaucoma should be considered while comparing the prevalence of glaucoma in various population studies. The majority of reported glaucoma epidemiology studies do not cover the subjects under the age of 40, that is justified by the sporadic cases of glaucoma in younger age group.

Possible differences in the lower age limit of subjects included in the study have no major influence on overall results. However, the age and the percentage of the oldest participants in the study may change radically its final results, because the prevalence

Table 4

Sensitivities and Specificities of the Screening Tests

of glaucoma increases significantly with age. Without considering those differences, no valuable comparison of various population is possible.

Diagnostic procedure and methods employed in different studies have unquestionable influence on the population assessment. It seems particularly important to define precisely the glaucomatous optic nerve disc lesions. The lack of defined and widely accepted criteria makes it difficult to interpret the examination results. Similar difficulties are associated with the assessment of visual field abnormalities. Hence, the method used and the way the examination is performed is the additional factor influencing the results. Visual field examination in earlier studies was carried out with the use of the ancient kinetic techniques and are often not comparable with the results of current computerized static methods, characterized by higher sensitivity in the detection of pathological changes (52).

In some earlier population studies, elevated IOP over 21 mmHg was considered the precondition for glaucoma diagnosis (12,19,29). The IOP level above this value is considered to be the most important risk factor for glaucoma, but its diurnal fluctuation and more importantly the possibility of glaucoma development without IOP rises (as it is in normal tension glaucoma) do not allow to include the IOP criterion as absolute in glaucoma diagnosis. Therefore, in our study, visual field changes and morphological optic disc changes were considered sufficient for glaucoma diagnosis.

Other important difficulty in comparative evaluation of various population studies is posed by the employment of different classification of glaucoma. According to some authors (10,18), the term open-angle glaucoma (OAG) includes cases of POAG with elevated IOP, cases of NPG, and cases of glaucoma in the course of pseudoexfoliation syndrome (capsular glaucoma, CG); however, the others classify each of these as a separate entity (7,10).

According to our study, the prevalence of glaucoma was 1.6% (95% CI = 1.3–2) and its separate types, respectively, are as follows: POAG, 1.01% and NPG, 0.27%, glaucoma in the course of PEX, 0.25%; PACG, 0.06%; and OAG as defined above, 1.53%. It is considerably more than found and described by Leske in 1983, based on her earlier studies (53). She estimated the prevalence of OAG in white populations over 40 years of age slightly higher than 0.5%. Such a low estimated result was probably due to the use of older, less sensitive visual field examination techniques with Goldmann kinetic perymetry. The evaluation of optic disc morphology by the authors of the studies mentioned above was based first of all on the assessment of the size of disc excavation and the presence of ischaemic peridiscal atrophy, disregarding such features as the condition of neuroretinal rim (local deficits and hemorrhages).

More recent studies of glaucoma prevalence reveal higher OAG prevalence rate. In European populations it reached the following values: 2% (Egna–Neumarkt Study, Northern Italy) (11), 1.1% (Rotterdam Study, The Netherlands) (12), 1.3% (Baltimore Study, USA) (9), and in Australia, 2.4% (Blue Mountains Eye Study) (10). While comparing these results, slight differences in age groups, particularly including the subjects over 80 years of age, should be considered. With reference to these differences it can be stated that the prevalence of glaucoma according to the studies cited for the population between 40 and 79 years of age was 1.8% (Egna–Neumarkt Study), 1.7%

(Roscoman Study), 1.1% (Rotterdam Study), 1.6% (Beaver Dam Study), and 1.7% (Blue Mountains Study).

The study performed in Wroclaw population showed a significant rise in OAG prevalence with 4.6% in the oldest age group. This trend is observed in other population studies as well. For example, in the age group between 70 and 79 years, the glaucoma prevalence in Europe was 6.5% (Egna–Neumarkt Study) (11), 3.1% (Rotterdam Study) (12), and in white populations of Northern America, 2.9 (Baltimore Study) (9), 2.1% (Beaver Dam Study) (7), and 4.7% (Blue Mountains Study) (10). Lower prevalence shown in Baltimore and Rotterdam Study may be due to the use of other methods of visual field examination. In those studies, visual field was examined with the Goldmann kinetic perimetry method; however, it was found that computerized static perimetry is more sensitive in the detection of glaucomatous visual field defects and consequently allows earlier detection of pathological changes.

Comparing population studies the prevalence of OAG in black communities was higher (4.6%). In the age group of 40–79 years, the prevalence rate was as follows: 5.6% according to Barbados Study (15) and 8.9% according to Santa Lucia Study (13). Among the oldest groups, aged between 70 and 79, that difference was even higher: 14.8% in Barbados Study (15) and 17.4% in Santa Lucia Study (13).

The prevalence of NPG in Wroclaw population was 0.27%. This was 27% of all POAG cases. This is considerably less than reported by authors of other population studies dated from 1960 to 1980, where subjects with NPG constituted more than half cases of POAG. This result differs significantly from the results of Wroclaw study. The results of Beaver Dam Study (32%) (7) and Egna–Neumarkt Study (29%) (11) showed similar to ours share of NPG in the cases of POAG. None of the previous studies are comparable in this aspect with Japanese study. Shiose et al. (51) reported threefold higher prevalence of NPG in relation to POAG, which is the unique observation.

The unquestionable difficulty in comparing various population studies is due to differences in measurement methods and diagnostic criteria for NPG. In many studies, IOP was measured only once (8,10,29) and only some carried out 24-h IOP monitoring (11). If the qualification of patients to the NPG group was based on a single screening IOP result, every second patient with POAG would be wrongly classified as NPG case. That is a possible explanation for significant differences between the results of different studies performed in white populations.

Our study revealed a relatively high percentage of glaucoma cases diagnosed for the first time. That was 71% of all glaucoma cases. This number is higher than reported by other authors of population studies in white communities: 53% in Rotterdam Study (12), 50% in Baltimore Study (9), 51% in Blue Mountains Study (10), and 62% in LatinAmerican population of the USA (18). Similar percentage of cases with previously undiagnosed glaucoma was reported in rural Wales communities, 70% (29) and in Northern Italy 78% (11).

Taking into account, that in over half of glaucoma patients a single result of IOP measurement can be sufficient to rise the suspicion of the disease, the fact of not having diagnosed approximately 70% of glaucoma cases seems astonishing. It is possible that elevated IOP is a stronger predictive value for glaucoma detection than suggested by many authors in the last few decades.

The percentage of subjects with OH detected in Wroclaw population was 1.9%. The number of OH cases was almost twice as high as POAG cases.

It is significantly less when compared to the results of older studies from northern Europe, where the OH prevalence observed was much higher: 8.6% in Sweden (54), 9.1% in Wales (29) as well as higher relation between POAG and OH, 1:12 and 1:30, respectively. The latter observation is among others because of the low prevalence of POAG detected in those studies (0.85 and 0.49%, respectively), which can be at least partly associated with the visual field examination methods employed (Goldmann kinetic perimetry).

The results of Wroclaw study are similar to the newer study of Egna–Neumarkt (Italy), where OH was diagnosed in 2.1% of subjects (11) and even to the results of Santa Lucia Study (13), which included the subjects from black population.

Significant differences in the estimation of OH prevalence can be due to the use of different examination methods but may reveal the existing differences between populations as well.

Both OH and NPG prevalence allow the conclusion that in the population studied, there is a strong correlation between OH and POAG. Glaucoma was diagnosed in almost half of the patients, who had the OH elevation over 21 mmHg on at least two separate measurements in diagnostic examinations. However, only in every fourth patient diagnosed with POAG we did not observe IOP over 21 mmHg. These results confirm the unquestionable meaning of IOP level in the estimation of glaucoma risk. On the basis of the results of epidemiological studies dated from 1970s to 1980s, the usefulness of tonometric tests could seem lower due to the fact that every diagnosed case of glaucoma was matched with 12–30 cases of OH and the half of all glaucoma patients with IOP lower than 21 mmHg. This relation might have been caused by the insufficient sensitivity of the methods detecting glaucomatous neuropathy.

Among different techniques potentially used as screening for glaucoma, the highest sensitivity (85%) was found for number parameter (GDx), slighty lower (78%) for the Mikelberg discriminant function (HRT) and Weinreb discriminant function (GDx).

The specificity of these tests was relatively low and was 52, 73, and 63%. The highest specificity was reached by the test based on the IOP measurement (98%), its sensitivity, however, was only 53%.Therefore, employing IOP measurement as the only screening test would identify slightly more than a half of all patients with glaucoma (with a cut-off value 21 mmHg). Stereoscopic ONH assessment showed to be highly specific (92%) and at the same time relatively sensitive (73%).

While assessing the possibility of employment of those examination techniques on the large scale, one should keep in mind the low PPV of these tests of about 7%. It means that among fifteen subjects with the positive result of the screening test which needs time-consuming and expensive verifying examination, only one suffers from glaucoma. Considering also high equipment cost, it is difficult to justify extending these screening methods to the whole population.

There is a need for the further improving of the screening methods or trying to find such a combination of them, which would yield the best results.

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