The prevalence of glaucoma in a 70‐year‐old Swedish population in the city area of Gothenburg

To determine the prevalence of and risk factors for open‐angle glaucoma in a population of 70‐year‐olds in Gothenburg, Sweden and to compare the visual function between the glaucoma population and the non‐glaucoma population.


| I N T RODUC T ION
Glaucoma is the second most common cause of blindness globally and its prevalence increases with age (Rudnicka et al., 2006;Tham et al., 2014).In the terminology and guidelines for glaucoma, the risk factors for open-angle glaucoma are described being older age, elevated intraocular pressure (IOP), non-white ethnicity, a family history of glaucoma, pseudoexfoliations (PEX), disc haemorrhage and myopia (European Glaucoma Society, 2020; Klein et al., 1992).In the EMGT study from 1999, low diastolic blood pressure and thinner central cornea thickness (CCT) likewise were found to be risk factors of glaucoma progression (Leske et al., 1999).The progression of glaucoma is difficult to predict, but it has been suggested to progress from full vision to blindness in 15-70 years (Hattenhauer et al., 1998;Heijl et al., 2009;Öhnell et al., 2019;Oliver et al., 2002).Several population-based studies have reported that large proportions of glaucoma are undiagnosed (McCann et al., 2020;Nizankowska & Kaczmarek, 2005;Varma et al., 2004).
Visual field defects (VFDs) may appear in different locations and for different reasons.In neurological diseases, such as stroke or brain tumour, VFD manifestation is not rare (Sand et al., 2018;Wang et al., 2021).Some ophthalmic diseases lead to general low vision, while age-related macular degeneration causes central vision loss (Acton et al., 2012;Prins et al., 2016).Glaucoma leads to characteristic paracentral VFDs (Williams et al., 2020).
The aims of this study were to determine the prevalence of glaucoma in a population of 70-year-olds in Gothenburg, Sweden, to investigate the possible risk factors for open-angle glaucoma and to determine the visual function in the population of glaucoma patients versus the non-glaucomatous group.

| Participants
The project is part of the Gothenburg H70 Birth Cohort Studies.The H70 Studies are multidisciplinary population studies examining birth cohorts of older populations in Gothenburg, systematically recruited via the Swedish Population Register (Swedish Tax Agency, 2007).The full study protocol has been described elsewhere (Rydberg Sterner et al., 2019).This study includes a cohort born in 1944 that was examined in 2014-2016 at the age of 70 years (n = 1203), see Figure 1.The participants were asked to complete a questionnaire about self-reported ocular morbidity and family history of glaucoma.Of the entire cohort, 1182 participants (98,3%) responded the questionnaires.The question about glaucoma was: 'Are you currently being or have you previously been treated for glaucoma?' and the question of a family history of glaucoma was 'Did your mother, father or siblings have a diagnosis of glaucoma?'All participants (n = 1203) were subjected to blood pressure measurements and diabetes tests.The participants born on dates ending in 0 or 5 were offered an ophthalmic examination at the Department of Ophthalmology, Sahlgrenska University Hospital and 560 participants were examined, 47% of the entire cohort.

| Ethics
The study was performed in accordance with the tenets of the Declaration of Helsinki as well as the General Data Protection Regulation.The Regional Ethical Review Board in Gothenburg, Sweden (Dnr 127-14) gave approval to the project.Written and informed consent was given from all the participants.

| Ophthalmic examination
The 560 participants underwent an ophthalmic examination covering the best-corrected visual acuity (BCVA), near visual acuity (VA) and IOP.The IOP was measured twice using the AT 900 Goldmann Applanation Tonometer (Haag-Streit Group).CCT was determined with the SP-100 Pachymeter (Tomey Technology and Vision), and contrast sensitivity (CS) measurements using Mars contrast sensitivity testing (Mars Perceptrix Corporation).The ophthalmic examination also included a visual field examination, tested monocularly using the C-20-5 perimetry screening test with frequency-doubling technology (FDT) (Carl Zeiss Meditec Inc.).For participants with VFDs detected using FDT, in whom no previously known diagnosis was evident, additional visual field testing was performed using the Humphrey Field Analyser (HFA) 2 with the SITA-Fast 24-2 test (Carl Zeiss Meditec Inc.).To analyse the visual field tests of HFA, the visual field index (VFI) of the HFA was used, with a VFI of >98% being considered to indicate a normal visual field.The test had to be reliable, and the participant had to perform the test correctly, for example, having good fixation and adequate responses.
To evaluate the posterior segment of the eye, photographs of the fundus were taken and optical coherence tomography (OCT) was performed using the 3D OCT 2000 fundus camera (Topcon).Photos of the optic nerve head, retinal nerve fibre layer (RNFL), and macula were taken after pupil dilation using the Nonmyd 7, 10-megabyte fundus camera (Kowa).Although OCT F I G U R E 1 Flowchart of the study population and cohort of participants undergoing ophthalmic examination with monocular perimetry.provides a low level of evidence for glaucoma, it was used as a complement to analyse various ophthalmic ailments in VFD cases.The lens and the possible presence of PEX were photographed using the Canon EOS 7D slit-lamp camera (Haag-Streit Group).
All ophthalmic data and eye imaging results were evaluated on two different occasions by first a senior ophthalmologist and then by a glaucoma specialist and the two reviewers discussed until a consensus was reached on the diagnosis.The physicians did not meet the participants but inspected the fundus photos, OCT images and visual field test results of all 560 participants.If the ophthalmologists could exclude glaucoma from looking at photos, OCT images and patient reports, further perimetry was unnecessary.

| Definition of ocular hypertension and glaucoma
For participants who reported having glaucoma or ocular hypertension (OHT), the diagnoses were distinguished based on whether or not the participants had an optic nerve rim loss and/or RNFL defects, as viewed primarily on colour-free fundus images but also verified on OCT in images of the optic nerve head.The ophthalmologists also looked for corresponding VFD not explainable by other causes.Both an optic nerve rim loss or/and RNFL defects plus a VFD constituted a diagnosis of glaucoma.High IOP in the absence of VFD was diagnosed as OHT, even if the subject had classified him/herself as having glaucoma.An IOP of >21 mmHg, measured on repeated occasions and obtained either from medical records or through examination, and the absence of any optic nerve rim loss and/or RNFL defects were required for diagnosis of OHT.
Eyes without a previous diagnosis of glaucoma but who met the optic nerve loss or/and RNFL defect and VFD criteria were eyes having probable glaucoma.A definite glaucoma diagnosis would have required repeated monitoring demonstrating glaucoma progression over time, but since this was a cross-sectional study, the diagnosis of probable glaucoma was determined from a single examination.Participants without glaucoma, that is without optic nerve and/or RNFL defects and VFDs, were considered the non-glaucomatous group; therefore, participants with OHT were part of the nonglaucomatous group.

| Statistical analysis
Comparison regarding gender differences between the entire cohort (self-reported IOP-lowering treatment) and the cohort whose members also had an ophthalmic examination was done using Fisher's exact chi-square test.P-values < 0.05 were considered statistically significant.To compare means, Student's t-test was used.Categorical data are presented as numbers and proportions (%), while continuous parameters such as blood pressure, presence of diabetes, IOP and CCT are presented as means ± standard deviations.For prevalence numbers, 95% confidence intervals (CIs) were given.To analyse the possible risk factors for glaucoma in this population, binary logistic regression was used.The covariates were entered in a stepwise backward conditional manner, and adjusted odds ratios and 95% CIs are given.
Significant differences in functional BCVA, that is BCVA of the best eye, between the non-glaucomatous group and participants with glaucoma were analysed using the Pearson chi-square test.The eye with better BCVA could be either normal or a glaucomatous eye.BCVA was also calculated for glaucomatous eyes using analysis of variance (anova) and Dunnett's post hoc testing.Calculations were conducted between the nonglaucomatous group and the glaucoma groups, between the non-glaucomatous group and previously unknown glaucoma group, and between the non-glaucomatous group and OHT group.For analysis of BCVA in glaucomatous eyes, the right eye was chosen in all cases except those with unilateral glaucoma in which only the left eye was affected.For the presentation of BCVA, the mean logarithm of the minimum angle of resolution (LogMAR), the median (decimal VA) and the geometric mean (decimal VA) are shown.Binocular CS was dichotomously analysed using a cut-off of ≥1.52 (the agenormal value) and the Pearson chi-square test.All statistical analyses were performed using version 25.0 of IBM SPSS Statistics for Macintosh (IBM Corp).

| Prevalence of self-reported glaucoma
The prevalence of persons with self-reported IOPlowering treatment was 4.1% (95% CI 3.0%-5.2%)in the entire cohort, and 3.4% (95% CI 1.9%-4.9%)among those who underwent ophthalmic examination (p = 0.31), data not shown.The proportion answering 'yes' to the question 'Are you currently being or have you previously been treated for glaucoma?' did not differ significantly between participants who had been ophthalmologically examined (n = 560) and those who had not (n = 643).In addition, we found no gender difference between the examined and unexamined cohorts (Fisher's exact test, p = 0.72).Among participants self-reporting glaucoma in the entire population (n = 915), 53.7% were females compared to 50% in the ophthalmologically examined group.

| Prevalence of glaucoma among ophthalmologically examined participants
At the ophthalmic examination, we could ascertain the real number of glaucoma cases (Table 1).In all, 12 participants (2.1%) had known glaucoma (self-reported and confirmed upon ophthalmic examination) and 15 (2.7%) had previously unknown glaucoma (discovered upon ophthalmic examination).Most people had glaucoma in one eye only, whereas 22% were bilaterally affected.The prevalence of glaucoma in the total examined population was consequently 4.8% (95% CI 3.0%-6.6%).The proportion of undiagnosed cases was 56% among the glaucoma population.None of the glaucoma eyes had a VFI of <50%.
In the examined population, there were 18 persons in total with IOP-lowering treatment.33% of them had OHT and not glaucoma.

| Risk factors among ophthalmic examined participants
A significant larger proportion of participants with than without glaucoma had a family history of glaucoma (Table 1).The proportion of participants with diastolic blood pressure >90 mmHg was greater in the non-glaucomatous group than the glaucoma group ( p < 0.001); no significant differences were seen regarding diabetes, myopia, PEX, or CCT.Participants with glaucoma had significantly higher IOPs than did members of the non-glaucomatous group (Table 1).Mean IOP among the non-glaucomatous group was 16 mmHg.Those with glaucoma and receiving IOPlowering treatment had a mean IOP of 17 mmHg, while the previously undiagnosed and untreated glaucoma cases had a mean IOP of 21 mmHg.Although IOP was higher in the group of participants with newly detected glaucoma than in participants with previously known glaucoma, 67% of the members in the previously unknown glaucoma group had normal IOPs (i.e.≤21 mmHg).
In a binary logistic regression model (Table 2), a family history of glaucoma and an IOP >21 mmHg were confirmed as risk factors for open-angle glaucoma.

| VA and CS
Regarding distance VA, there was no significant difference in the BCVA of the best eye between the nonglaucomatous group and the group of participants with glaucoma or OHT (Table 3).Neither was there any significant difference in near VA between the groups: 8.5% of glaucoma cases versus 6.0% of the nonglaucomatous group (p = 0.53) could not read <6-point text (data not shown).However, analysis of BCVA of the right eye (glaucomatous eyes only) showed that persons in the group of glaucoma, detected at the examination, had lower VA than did the non-glaucomatous group (Table 3).All persons with glaucoma or OHT had normal CS.

| Prevalence of VFDs among ophthalmic examined participants
Of the examined participants (N = 560), 91 (16%) had some type and degree of VFD (Figure 1).The most common VFD aetiology was glaucoma (30%), either selfreported and confirmed or discovered upon examination (Table 4).After glaucoma, the most common reasons for an exhibited defect according to FDT were cataract and macular disorders.In the group of examined participants, 2.1% had a previous diagnosis of glaucoma and 2.7% were previously undiagnosed cases.The total prevalence of glaucoma in the present cohort was 4.8%.The global prevalence is 3.54% in the 40-to 80-year age range, and according to Tham et al., the prevalence of glaucoma is greater in urban than rural areas (Tham et al., 2014).The populations of Africa and Asia have a greater prevalence of glaucoma than is found in Europe.The incidence of glaucoma in Europe, in the population over 40 years old, is over 2% (Karvonen et al., 2019;Quigley & Broman, 2006); this prevalence will increase with age to over 4% (Keel et al., 2019;Rudnicka et al., 2006).About risk factors for glaucoma, the participant age was not included as a parameter in this study, as all participants were the same age; also, as all participants were of Caucasian origin, ethnicity was not a relevant parameter.However, higher IOP and a family history of glaucoma were identified as risk factors for glaucoma, but not PEX or myopia.In earlier Swedish studies, PEX was found to be a substantial risk factor for progressive glaucoma (Aström et al., 2007;Ekström, 2012;Heijl et al., 2009).Participants with glaucoma had lower diastolic blood pressure than did the non-glaucomatous group, supporting the findings of the European Glaucoma Society and the recently presented findings of Lee et al. that low blood pressure is associated with increased risk of glaucoma (Lee et al., 2021).The exact relationship between blood pressure and glaucoma is unclear, and contradictory results have been obtained in population-based studies (Cantor et al., 2018;Wang et al., 2021;Zhao et al., 2014).The participants in our study had no other significant blood pressure differences (high systolic BP or real low diastolic BP), see Table 1.
The BCVA in glaucomatous eyes was significantly lower in the persons in the group of glaucoma detected at the examination than the non-glaucomatous group; in contrast, there was no difference in BCVA measured in the best eye, which is more relevant for binocular VA. b Binary logistic regression.A p-value of <0.05 was considered statistically significant.
T A B L E 3 Best-corrected visual acuity (BCVA) and contrast sensitivity in a 70-year-old Swedish cohort with glaucoma or ocular hypertension (N = 560).d BCVA in the right eye for both glaucoma and the non-glaucomatous group, except for glaucoma patients; when the right eye was non-glaucomatous the left eye was chosen instead.e p-Value for post hoc test (Dunnett) between controls and previously unknown glaucoma.A p-value < 0.05 was considered significant.

Characteristics
All participants with either glaucoma or OHT had normal CS.In summary, there seems to be no difference in functional vision between participants with and without glaucoma.
In this study, 56% of glaucoma cases were previously undiagnosed.In an earlier Swedish study, a prevalence of 1.2% of previously undetected glaucoma was found at ages >55 years (Heijl et al., 2013).Among the probable glaucoma cases in this study, the majority (67%) had normal IOP.This corroborates the findings from previous studies that persons with normal-tension glaucoma are overlooked in reality and therefore at risk of not being diagnosed (Grodum et al., 2002).The question of screening the older population for glaucoma truly entails both ethical and cost-effectiveness considerations.Burr et al show that surveying general population is not cost-effective (Burr et al., 2007).Instead, maybe persons with risk factors such as older age and a family history of glaucoma may benefit from screening.The researchers hope for advanced technology to be effective making the first assessment.
Examinations for screening purposes must be efficient to ensure a high degree of cost-effectiveness, suggesting that FDT, which is a quick way of measuring the visual field, may be suitable in a screening context.However, the present results indicate that, while perimetry with FDT will find VFDs, in twothirds of the cases the aetiology of the VFD will be other than glaucoma (Figure 1, Table 4).Previous research also show that a substantial number of patients are overdiagnosed with glaucoma (Founti et al., 2018), with patients receiving a diagnosis and/or treatment of glaucoma without actually fulfilling the structural or functional for the diagnosis.Also, the finding in this study that there was no significant difference in BCVA of the best eye when comparing the glaucoma group and non-glaucomatous group, thus suggesting no relevant difference in functional vision, raises the question of whether the participants with newly detected glaucoma in our study will ever experience impaired vision or whether they will simply worry unnecessarily of the obtained diagnosis.On the other hand, it is important to identify glaucoma with a high progression rate to slow down the disease as untreated glaucoma will always progress faster (Heijl et al., 2009).

| Strengths and limitations
This is the first study identifying the prevalence of glaucoma in a 70-year-old Swedish population in the city area of Gothenburg.The cohort was large enough to give a good overview of visual function in a normal population.The small number of people with glaucoma precluded analysis of the glaucoma cohort in greater depth.In addition, although subjects were invited to participate in a strictly consecutive fashion to prevent selection bias, individuals with severe disease or physical disabilities may have found it hard to participate because of the extensive examinations and medical consultations to be performed in a hospital setting and because of difficulties accessing these research facilities.Finally, the question in the selfreporting protocol, 'Are you currently being or have you previously been treated for glaucoma?',was incorrectly answered by six persons who were receiving IOPlowering topical treatment because of OHT, but who had diagnosed themselves with glaucoma.Therefore, one should always be aware that self-reported diagnoses may not be 100% accurate as there is always a risk of misinterpretation.
In summary, this cross-sectional study investigated the prevalence of and the risk factors for open-angle glaucoma in a 70-year-old Swedish population, identifying a large number of participants with previously undiagnosed glaucoma as well as many individuals with VFDs due to other causes.A family history of glaucoma and higher IOP levels were found to be risk factors.The majority of the newly discovered glaucoma cases had normal IOP levels (i.e.≤21 mmHg) leading to a higher risk of not being diagnosed.Interestingly, visual function (i.e.BCVA in the best eye) did not differ between patients with glaucoma and Demographics and clinical characteristics in 70-yearolds (n = 560).
Abbreviations: B, Regression coefficient; CI, Confidence interval; OR, Adjusted odds ratio; SE, Standard error a Including previously known and previously unknown glaucoma cases.
Abbreviations: AMD, age-related macular degeneration; FDT, frequencydoubling technology.a Test of each eye with the screening programme.Some persons had more than one diagnosis.b Previously undiagnosed glaucoma with both visual field defect and retinal nerve fibre layer defect in fundus photo and optical coherence tomography of the optic disc outside normal limits.c Self-reported and confirmed glaucoma.d −3.0 dioptres or higher degree of myopia.e Deficient cooperation due to cognitive dysfunction.
Pearson's chi-squared test between the non-glaucomatous group and all groups with either glaucoma or previously unknown glaucoma, or ocular hypertension.
a Non-glaucomatous group = participants without glaucoma and/or ocular hypertension.bBest eye included both glaucoma eye or healthy eye.c