To assess the prevalence of pseudoexfoliation (PEX) and its associations in a Russian population.
Population-based cross-sectional study.
Setting: Ufa capital of Bashkortostan, Russia and a rural region in Bashkortostan.
the Ural Eye and Medical Study included 5,899 (80.5%) of 7,328 eligible individuals (mean age, 59.0 ± 10.7 years old; range, 40-94 years). Observation procedures: as part of an ophthalmological and general examination, presence and degree of PEX was assessed using slit-lamp biomicroscopy after medical pupillary dilation. Main outcome measurements: PEX prevalence.
After excluding pseudophakic and aphakic individuals, the study included 5,451 (92.4%) participants. PEX prevalence (3.6%; 95% confidence interval [CI]:3.1-4.1), increased from 0.5% (95% CI, 0.1-0.9) in individuals 40 to <50 years old to 10.4% (95% CI, 5.0-15.8) in individuals aged 80+ years. Higher PEX prevalence was associated (multivariate analysis) with older age (odds ratio [OR], 1.09; 95% CI, 1.07-1.11; P < 0.001), Russian ethnicity (OR, 1.50; 95% CI, 2.09-1.11; P = 0.02), higher prevalence of open-angle glaucoma (OR, 2.40; 95% CI, 1.36-4.23; P = 0.003), and higher intraocular pressure (OR, 1.06; 95% CI, 1.02-1.09; P = 0.001). PEX prevalence was not significantly associated with gender ( P = 0.49), region of habitation ( P = 0.11), body mass index ( P = 0.68), level of education ( P = 0.26), smoking ( P = 0.11), alcohol consumption ( P = 0.52), history of cardiovascular or cerebrovascular disease ( P = 0.94) and dementia ( P = 0.77), prevalence of diabetes mellitus ( P = 0.16), arterial hypertension ( P = 0.45), chronic obstructive pulmonary disease ( P = 0.73), chronic kidney disease ( P = 0.09), and hearing loss ( P = 0.31).
In this typical, ethnically mixed, population from Russia with an age of 40+ years, PEX prevalence (3.6%; 95% CI, 3.1-4.1) was associated with older age, Russian ethnicity, higher intraocular pressure and open-angle glaucoma. It was independent of any systemic parameter including diabetes, arterial hypertension, previous cardiovascular and cerebrovascular diseases and dementia.
Pseudoexfoliation of the lens (PEX), as an age-associated disorder and linked to the lysyl oxidase-like-one ( LOXL1 ) gene, is characterized by the presence of an amorphic whitish fibrillary material on the lens surface, pupillary margin, and iris surface and in the anterior chamber angle, in addition to a structural weakness of the lens fibers and elevation of intraocular pressure (IOP). In some previous investigations, the PEX material was found also in extraocular tissues, such as in extraocular muscles, heart, lung, liver, kidney, skin, and meninges. , , These studies implied that the PEX syndrome was a systemic disease with the most prominent manifestation in the anterior segment of the eye. , The ophthalmological importance of PEX has been based on its association with elevated IOP leading to secondary open-angle glaucoma, an increased risk of intraoperative complications in cataract surgery, and an elevated probability of subluxation or luxation of the lens or pseudophakos. The prevalence of PEX as assessed in previous population-based studies ranged from 0.2% to 30% in dependence of the study population examined and the detection method applied.
Despite the importance of PEX in ophthalmology and its potential involvement in diseases of internal organs, and although the PEX prevalence varied markedly in previous studies between ethnicities and world regions, information about the frequency of PEX in Russia or in East Europe and Central Asia has not been available so far. This may be remarkable as Russia is, by area and population the largest and one of the largest countries worldwide. In addition, most previous population-based studies assessed the prevalence only of a few non-ophthalmological diseases, so that potential associations of PEX with systemic disorders could not be examined. Therefore this population-based investigation was conducted to explore the prevalence of PEX in Russia and to examine potential associations of PEX with a multitude of internal medical disorders.
Subjects and Methods
The Ural Eye and Medical Study was a population-based investigation performed in an urban and rural region in the Russian republic of Bashkortostan at the southwestern end of the Ural Mountains from 2015 to 2017. , Inclusion criteria for the study were living in the study regions and an age of 40 years or older. The Ethics Committee of the Academic Council of the Ufa Eye Research Institute approved the study design, and all participants gave an informed written consent. Ufa, with a population of 1.1 million inhabitants, is the capital of the republic of Bashkortostan in Russia. The population of Ufa and the population of the whole republic of Bashkortostan with a population of 4.07 million is ethnically composed of Russians, Tatars, Bashkirs, Ukrainians, and other ethnicities. The study included 5,899 (80.5%) individuals (2,580 [43.7%] men) of 7,328 eligible individuals (mean age, 59.0 ± 10.7 years; range, 40-94 years). The non-participation of the eligible but non-participating individuals was due to the individuals’ decision not to participate. The composition of the study population with respect to gender and age corresponded to the gender and age distribution in the Russian population according to the census carried out in 2010, with no significant differences between both populations ( P = 0.25). , With respect to the ethnic composition, the percentage of the non-Russian groups was higher in the present study population than in the population of all Russia. For that reason, the statistical analysis was additionally performed separately for both groups, the Russian group and the non-Russian group. Mean body height was 164.8 ± 8.8 cm (median, 164 cm; range, 112-196 cm), mean body weight was 75.9 ± 14.6 kg (median, 75 kg; range, 31-170 kg), and mean body mass index was 27.9 ± 5.0 kg/m 2 (median, 27.4 kg/m 2 ; range: 13.96-60.96 kg/m 2 ). Illiteracy (equivalent to level 0 or pre-primary education of the International Standard Classification of Education (ISCED) was present for 17 (0.3%) individuals, 104 (1.8%) participants had passed the fifth grade (equivalent to ISCED level I; primary education or first stage of basic education), 593 (10.1%) participants the 8th grade (equivalent to ISCED level II or lower secondary education), 659 (11.2%) participants the 10th grade (equivalent to ISCED level III or upper secondary education), and 782 (13.3%) individuals the 11th grade (equivalent to ISCED level IV or post-secondary non-tertiary education). Graduates (equivalent to ISCED level V or first stage of tertiary education) were 2,052 (34.8%) individuals, and postgraduates (equivalent to ISCED level VI or second stage of tertiary education) were 52 (0.9%) study participants. A specialized secondary education had been achieved by 1,638 (27.8%) individuals. With respect to the ethnic background of the study population, there were 1,185 (20.1%) Russians, 2,439 (41.3%) Tartars, 1,061 (18.0%) Bashkirs, 587 (10%) Chuvash, 21 (0.4%) Mari, 104 (1.8%) other ethnicities, and 502 (8.5%) did not indicate their ethnic background.
All study participants underwent a series of examinations, which started with a detailed interview performed by trained social workers. The interview included more than 250 standardized questions on the socioeconomic background (level of education, monthly income, ownership of a house, second house, refrigerator, telephone, smartphone, television set, car, two-wheeler, tractor, bullock cart and computer/laptop), smoking habits and alcohol consumption, physical activity parameters, diet parameters, depression and anxiety, and known diagnosis and therapy for major diseases. The examinations further included anthropometry, blood pressure measurement, handgrip dynamometry, spirometry, and biochemical analysis of blood samples taken under fasting conditions. The Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER) statement guidelines were applied for collecting the data. According to the new guidelines of the American Heart Association, normal blood pressure was differentiated from elevated blood pressure, stage 1 and stage 2 of arterial hypertension, and a hypertensive crisis. Diagnostic criteria for diabetes mellitus were a fasting serum glucose concentration of ≥7.0 mmol/L or a self-reported history of physician-based diagnosis or therapy of diabetes mellitus. The study design was described in detail recently.
The ophthalmologic examinations included determination of uncorrected visual acuity, presenting visual acuity and best corrected visual acuity after performing an automated refractometry (Auto-2Ref/Keratometer HRK-7000A HUVITZ Co, Ltd, Gyeonggi-do, Korea), perimetry (screening test program with 82 test points and an extension of 50° in all directions; PTS 1000 Perimeter, Optopol Technology Co., Zawercie, Poland), anterior segment biometry (Pentacam HR, Typ70900, OCULUS, Optikgeräte GmbH Co., Wetzlar, Germany), slit lamp biomicroscopy of the anterior ocular segment, and non-contact tonometry (Tonometer Kowa KT-800, Kowa Company Ltd., Hamamatsu City, Japan). After inducing medical mydriasis (tropicamide 0.8% and phenylephrine 5% given twice in a 10-min interval), a second slit lamp examination was performed by a board-certified ophthalmologist to assess the presence of PEX. PEX was divided into 7 stages, ranging from “no pseudoexfoliation” (stage 0), to faint pseudoexfoliation (small dark islands in the intermediary annular region corresponding to the moving pupillary margin) (stage 1), confluent dark islands in the annular region (stage 2), visible edges of pseudoexfoliative material clearly detectable in at least one location on the lens surface (stage 3), complete circular edge of pseudoexfoliative material on the lens surface (central island or in the lens periphery) (stage 4), pseudoexfoliative dandruff on the pupil margin (stage 5), and pseudoexfoliative material on the corneal endothelium, in the anterior chamber angle, and/or lens subluxation (stage 6). This grading system had similarities to the description of PEX by Prince and associates. Applying the classifying scheme for cataract of the Age-Related Eye Disease Study, w nuclear cataract was assessed on digital photographs of the lens. Cortical lens opacities and posterior subcapsular opacities were graded using photographs taken by retroillumination (Topcon slit lamp and camera, Topcon Corp. Tokyo, Japan). The optic disc and macula were examined on digital monoscopic 60° photographs (VISUCAM 500, Carl Zeiss Meditec AG, Jena, Germany) and by spectral-domain optical coherence tomography (OCT) (RS-3000, NIDEK co., Ltd., Aichi Japan). The OCT scans were used to measure the peripapillary retinal nerve fiber layer thickness, the width and shape of the neuroretinal rim, the depth of the optic cup, and the thickness of the retina as a whole and divided into various retinal layers in the foveola and in the perifoveal region. The degree of fundus tessellation was examined on the fundus photographs centered on the macula and centered on the optic nerve head. Fundus tessellation was differentiated between grade “0” (no tessellation) and grade ”3” (marked tessellation). AMD was defined as suggested by the recent Beckman Initiative for Macular Research Classification Committee. Glaucoma was defined by morphological criteria as suggested by Foster and associates. The differentiation between open-angle glaucoma and primary angle-closure glaucoma was based on the appearance of the anterior chamber angle on the images taken with the Pentacam camera.
Inclusion criterion for the present study was the possibility of assessing the presence of PEX during the slit lamp-based biomicroscopy examination of the anterior chamber. Eyes after cataract surgery were excluded from the study. The data were statistically analyzed using SPSS version 25.0 software (SPSS, Chicago, Illinois) for Windows (Microsoft, Redmond, Washington). First, the mean prevalence of PEX was determined (expressed as mean and 95% confidence intervals [CI]), by either including only 1 randomly selected eye per study participant or, in a second step, by including the eye with higher stage of PEX per individual into the analysis. Continuous parameters were presented as mean ± standard deviations. We conducted binary univariate regression analyses of associations between the prevalence of PEX and other ocular and systemic parameters, followed by a multivariate binary regression analysis. The latter included the PEX prevalence as dependent variable and, as independent parameters, all those variables that were associated ( P ≤ 0.10) with the prevalence of PEX in the univariate analyses. In a step-by-step manner, those variables were dropped from the list of independent parameters that either showed a high collinearity or that were no longer significantly associated with the PEX prevalence. Odds ratios (OR) and their 95% CI were calculated. All P values were 2-sided and considered statistically significant when the values were less than 0.05.
Of 5,889 individuals primarily participating in the Ural Eye and Medical Study, the present investigation included 5,451 (92.4%) individuals (3,099 (56.9%) women) with assessment of PEX. Their mean age was 58.1 ± 10.2 years (median, 57 years; range, 40-94 years), and their axial length was 23.3 ± 1.1 mm (median, 23.2 mm; range, 19.8-32.9 mm). The group of individuals with assessment of PEX, compared with the group of individuals without assessment of PEX, was significantly ( P < 0.001) younger (58.1 ± 10.2 years vs 69.9 ± 10.7 years, respectively), had a significantly ( P < 0.001) shorter axial length (23.3 ± 1.1 mm vs 23.6 ± 1.4 mm, respectively), and showed a significantly ( P = 0.002) higher proportion of women (3,099 of 5,151 or 56.9% vs 220 of 248 or 49.1%, respectively).
The mean prevalence of PEX of any stage was 196 of 5,451 or 3.6% (95% CI, 3.1-4.1), if only 1 randomly selected eye per study participant was included in the statistical analysis. The prevalence of any PEX was strongly associated with older age (OR, 1.08; 95% CI, 1.07-1.10; P < 0.001) ( Table 1 ). The prevalence of PEX increased from 0.5% (95% CI, 0.1-0.9) in the age group from 40 to < 50 years to 5.6% (95% CI, 4.5-6.7) in the age group of 60 to < 70 years, and to 10.4% (95% CI, 5.0-15.8) in the age group of 80+ years ( Table 1 ). If the statistical analysis included the eye with the higher stage of PEX per individual, the mean prevalence of PEX of any stage was 269 of 5,451 or 4.9% (95% CI, 4.4-5.5) ( Table 1 ). PEX was present unilaterally in 158 individuals (158 of 269 or 58.7% of the individuals with PEX) 74 right eyes; 84 left eyes), and it occurred bilaterally in 113 individuals (111 of 269 or 41.3% of the individuals with PEX).
|Age Group, y||n||Any PEX (Randomly Selected Eye Per Individual)||Stage of PEX (Randomly Selected Eye Per Individual) a||Any PEX (Worse PEX Eye Per Individual Selected)|
|40 to <45||491||0.2% (0.0, 0.6)||0.002 ± 0.5||0.2% (0.00-0.6)|
|45 to <50||737||0.7% (0.1-1.3)||0.01 ± 0.19||1.1% (0.3-1.8)|
|50 to <55||900||1.6% (0.8-2.4)||0.05 ± 0.41||2.1% (1.2-3.1)|
|55 to <60||1,003||2.1% (1.2-3.0)||0.07 ± 0.53||3.0 (1.9-4.1)|
|60 to <65||871||4.7% (3.3-6.1)||0.16 ± 0.77||7.0 (5.3-8.7)|
|65 to <70||732||6.7% (4.9-8.5)||0.24 ± 0.91||9.0 (6.9-11.1)|
|70 to <75||288||9.0% (5.7-12.4)||0.34 ± 1.11||11.8 (8.1-15.6)|
|75 to <80||304||8.6% (5.4-11.7)||0.31 ± 1.05||11.5 (7.9-15.1)|
|80+||125||10.4% (5.0-15.8)||0.41 ± 1.24||12.0 (6.2-17.8)|
|Total||5,451||3.6 (3.1-4.1)||0.13 ± 0.68||4.9 (4.4-5.5)|
a PEX was divided into 7 stages. Stage 0 = no pseudoexfoliation; stage 1 = faint pseudoexfoliation (small dark islands in the intermediary annular region corresponding to the moving pupillary margin); stage 2 = confluent dark islands in the annular region; stage 3 = visible edges of pseudoexfoliative material clearly detectable in at least 1 location on the lens surface; stage 4 = complete circular edge of pseudoexfoliative material on the lens surface (central island or in the lens periphery); stage 5 = pseudoexfoliative dandruff on the pupil margin; stage 6 = pseudoexfoliative material on the corneal endothelium, in the anterior chamber angle, and/or lens subluxation.
Due to the association between the PEX prevalence and older age and because other factors potentially associated with PEX were also correlated with older age, the following binary regression analysis was adjusted for age when associations between the PEX prevalence and other parameters were tested. In that analysis, higher prevalence of PEX was associated ( P ≤ 0.10) with the systemic parameters of Russian ethnicity ( P = 0.008), lower body height ( P = 0.06), lower waist-to-hip circumference ratio ( P = 0.06), lower number of days of fruit consumption ( P = 0.04); higher prevalence of back pain ( P = 0.05), headache ( P < 0.001) and history of falling ( P < 0.001); lower serum concentration of urea ( P = 0.07) and creatinine ( P = 0.09); lower stage of chronic kidney disease ( P = 0.07); and higher depression score ( P = 0.009) and state-trait anxiety score ( P = 0.01); and with the ocular parameters of higher intraocular pressure (IOP) before mydriasis ( P < 0.001) and after medical mydriasis ( P < 0.001), and higher prevalence of glaucoma as a whole ( P < 0.001) and of open-angle glaucoma ( P < 0.001) and of the stage of glaucomatous optic nerve damage ( P < 0.001) ( Tables 2,3 , Supplemental Table 1 ). The PEX prevalence was not significantly associated with the systemic parameters of gender ( P = 0.38), body mass index ( P = 0.68), level of education ( P = 0.26), smoking ( P = 0.11), any alcohol consumption ( P = 0.52), history of cardiovascular and cerebrovascular disorders ( P = 0.69) and dementia ( P = 0.77), prevalence of diabetes mellitus ( P = 0.16), arterial hypertension ( P = 0.45), chronic obstructive pulmonary disease ( P = 0.73), hearing loss ( P = 0.31), and hand dynamometry ( P = 0.15).
|Parameter||OR||95% CI||P Value|
|Age, 1 y intervals||1.08||1.07-1.10||<0.001|
|Ethnicity, any other/Russian||1.53||1.12-2.10||0.008|
|Body height, cm||0.98||0.97-1.001||0.06|
|Waist/hip circumference, ratio||0.19||0.03-1.07||0.06|
|In a week how many days do you eat fruits?, no. of days||0.93||0.87-0.997||0.04|
|History of low back pain, Yes/No||1.34||0.995-1.80||0.054|
|History of headache, Yes/No||1.70||1.26-2.28||<0.001|
|History of falling, Yes/No||1.78||1.30-2.45||<0.001|
|Stage of chronic kidney disease, 0-5||0.98||0.96-1.002||0.07|
|Depression score, −4 to +15||1.05||1.01-1.09||0.009|
|State-Trait Anxiety Inventory, score −7 to 13||1.05||1.01-1.10||0.01|