Exfoliation syndrome is an age-related disease leading to ocular and systemic complications. We aimed to evaluate the prevalence of exfoliation syndrome (XFS) in Egypt and its association with cataract as one of its comorbidities.
Methods
In a retrospective, hospital-based study, 155,032 Egyptians aged over 40 years from all 27 Egyptian governorates were evaluated for the prevalence of XFS and cataract in the period between January 2015 and June 2020.
Results
A total of 2448 (1.6%) of the studied subjects had XFS. Their mean age was 71.2 ± 9.62 years which was significantly higher than those of subjects with no XFS. Men comprised 1348 (55.1%) of those diagnosed with XFS and this association was statistically significant (OR 1.57, 95% CI 1.45–1.70). Considering the ratio between subjects in our cohort from each region and its real population, the overall corrected prevalence in Egypt was 4.49% (Territorial regions 6.89%, Upper Egypt 5.51%, Lower Egypt 4.38%, and Greater Cairo 3.29%). Among all subjects with XFS, cataract was found in 2150 subjects (87.8%) and XFS represented 6.4% of all subjects diagnosed with cataract in our cohort (n = 33,610). Among subjects with no cataract (n = 121,422), 298 subjects had XFS (OR 0.04, 95% CI 0.03–0.04).
Conclusion
Egypt has a moderate XFS prevalence compared to other countries. There is a strong association between XFS and cataract, and XFS was more common in elderly males. The results can be explained by differences in diet, ethnicity, climate, and maybe other factors.
Key Summary Points
Why carry out this study?
Exfoliation syndrome (XFS) is a universal disease, but its prevalence varies from one population to another with different geographical and ethnic background.
We evaluated the prevalence of XFS in Egypt with its different regions and governorates and determined its association with cataract in the population aged over 40 years.
What was learned from the study?
Overall prevalence of XFS in Egypt was moderate (4.49%). It was more commonly found in older ages, males, those residing in territorial regions as well as those having cataract.
Identifying prevalence among different countries may help in the search for etiological factors, and results can be extrapolated to neighboring countries aiding in designing effective screening programs for the at-risk population.
Introduction
Exfoliation syndrome (XFS) is an age-related systemic disease of the extracellular matrix, characterized by the deposition of distinctive fibrillar material in many ocular and extraocular tissues [1]. It has been reported that XFS has associations with sensorineural hearing loss, hyperhomocysteinemia [2], and systemic vascular diseases such as hypertension, angina pectoris, myocardial infarction, stroke, and abdominal aortic aneurysm [3].
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Lindberg first described XFS in a Finnish population in 1917 following his observation of the presence of bluish-gray deposits on the pupillary border of 50% of his patients with chronic glaucoma [4]. Historically, XFS has been thought to affect principally North European and the Scandinavian population [5]. However, it has been proven to occur virtually in any area of the world, yet its prevalence varies among different ethnic groups and geographical regions [6].
Historically, the epidemiology of XFS is among the most controversial subjects in the literature, and many studies on the prevalence of XFS in various populations with different ethnic backgrounds exist [7]. The lowest prevalence is recorded in Eskimos and Inuits from Greenland (0%), whereas the highest prevalence is reported among Finns (22.4%) [8], Swedes (23%) [9], Icelanders (30%) [10], and Navajo Indians (38%) [11].
As the true prevalence of XFS in our country, Egypt, and its different regions, is not yet well known, we conducted this study to investigate XFS prevalence and association with cataract, as one of the most common comorbidities, in Egypt and different Egyptian governorates.
Methods
A retrospective hospital-based study was conducted in both branches of a high-volume ophthalmology hospital with a catchment area from all over Egypt—Watany Eye Hospital, Cairo, Egypt. The electronic medical records of the hospital were filtered for all subjects over the age of 40 years who had visited the hospital for comprehensive ophthalmological examination owing to any eye complaint during the period between January 2015 and June 2020.
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All the subjects underwent the routine complete undilated and dilated ophthalmological examination. Tropicamide 1% eye drops were usually used once or twice. The diagnosis of XFS was definite if at least one eye showed the following: the pupillary margin had precipitations of grayish dandruff-like material and the lens surface showed a whitish central coating whose diameter was slightly less than the normal pupillary diameter, or if the lens periphery showed a whitish coating bordered anteriorly by a darker ring-like region. This darker, ring-like region corresponded to the region of the pupillary margin movements over the lens surface [1]. The patient was considered cataractous if they had cortical, nuclear, or posterior subcapsular lens opacity in either eye. We excluded subjects with bilateral aphakia or pseudophakia on presentation as the diagnosis of XFS in such eyes is markedly less accurate. Moreover, eyes with congenital, developmental, traumatic, and complicated cataracts were also excluded. For each subject, the following data were collected: age, sex, the governorate of residence, presence of XFS, and presence of cataract. The governorates were grouped into the main four regions of Egypt: Greater Cairo, Upper Egypt, Lower Egypt, and finally the Suez Canal and territorial region (Fig. 1) [12].
Since not all the governorates were equally represented in our sample, the prevalence in each region cannot be simply calculated as the average of those of the governorates included in this region. Therefore, we opted to calculate the corrected prevalence rate among the four regions.
The XFS prevalence in subjects that presented to our hospital from each governorate equals the number of subjects found to have XFS from this governorate divided by the total number of subjects that presented from the same governorate.
The estimated number of subjects with XFS in each governorate equals the XFS prevalence in subjects that presented to our hospital from each governorate multiplied by the total number of subjects aged over 40 years living in that governorate.
The corrected XFS prevalence in each region equals the sum of estimated subjects with XFS in all the governorates of the region divided by the region population over 40 years.
The population of each governorate over 40 years was extracted from the results of the Central Agency for Public Mobilization and Statistics (CAPMAS) 2017 census which was within the study period [13].
The research protocol has been submitted to the Ethics Committee of Watany Research and Development Center (WRDC), Cairo, Egypt, and was found to agree with the tenets of the Declaration of Helsinki. The Ethics Committee of WRDC waived the ethical approval and the need to obtain patient consent because of the retrospective nature of the study.
Statistical Analysis
The statistical analysis was performed using MedCalc Statistical Software version 19.4 (MedCalc Software Ltd, Ostend, Belgium). Means, standard deviations (SDs), odds ratios (OR), and 95% confidence intervals (CI) were calculated. A p value of less than 0.05, measured by Welch’s test, indicated statistical significance.
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Results
A total of 155,032 indigenous Egyptians aged over 40 years from all the 27 Egyptian governorates were included. Of them, 2448 had XFS. The mean age of studied subjects was 59.5 years (SD 11.9) (median 59, range 40–100). The mean age of subjects with XFS was 71.2 years (SD 9.62) (median 71, range 41–100) which was significantly higher than those of subjects with no XFS, 59.3 years (SD 11.9) (median 59, range 40–99), (P < 0.0001). This was further confirmed by the increase in OR of XFS with age (Table 1).
Table 1
Prevalence and odds ratio of XFS in each age group
Age group (years)
Total number of subjects
Patients with XFS
Number
%
Odds ratio
Odds ratio 95% CI
40–49
38,898
48
0.12
0.058
0.044–0.078
50–59
38,763
221
0.57
0.293
0.256–0.337
60–69
43,174
796
1.84
1.253
1.151–1.365
70–79
26,088
896
3.43
2.919
2.686–3.173
80–89
7359
419
5.7
4.333
3.891–4.828
90–100
750
68
9.06
6.364
4.944–8.192
CI confidence interval
Although 86,840 (56.0%) of the studied patients were female, 1348 (55.1%) of those diagnosed with XFS were male. The association between XFS and male sex was statistically significant (OR 1.57, 95% CI 1.45–1.70).
Regarding the geographical distribution of the studied subjects among the main four regions in Egypt, 139,701 subjects (90.1% of the cohort) were from Greater Cairo, 10,244 (6.6%) from Upper Egypt, 2784 (1.8%) from Suez Canal and territorial areas, and 2303 (1.5%) from Lower Egypt (Table 2).
Table 2
Prevalence in the sample and corrected prevalence of different Egyptian regions
Region
Governorate
XFS cases
All studied subjects in the cohort
Estimated number of subjects with XFS
Actual population > 40 years
Corrected prevalence of XFS in each region
N
%
N
%
Greater Cairo
Cairo
1343
54.8
133,968
86.4
28,725
2,865,355
Giza
253
10.3
4091
2.6
120,522
1,948,834
Qalyubia
65
2.65
1642
1.1
52,799
1,333,785
Subtotal
1661
67.9
139,701
90.1
202,046
6,147,974
3.29%
Lower Egypt
Alexandria
11
0.44
344
0.2
47,784
1,494,325
Beheira
6
0.24
88
0.06
101,269
1,485,282
Damietta
0
Zero
74
0.05
–
386,566
Dakahlia
11
0.44
304
0.2
61,464
1,698,636
Gharbia
14
0.57
265
0.2
71,402
1,351,537
Kafr El-Sheikh
0
0
43
0.03
–
852,851
Monufia
23
0.94
413
0.3
59,149
1,062,113
Sharqia
45
1.8
772
0.5
97,741
1,676,794
Subtotal
110
4.49
2303
1.5
438,809
10,008,104
4.38%
Suez Canal and territorial areas
Ismailia
41
1.67
491
0.3
25,637
307,020
Matrouh
0
0
21
0.01
–
76,459
North Sinai
16
0.65
155
0.1
9626
93,256
Port Said
13
0.53
511
0.3
5826
229,017
Red Sea
12
0.5
618
0.4
1486
76,536
South Sinai
6
0.24
63
0.04
1957
20,552
Suez
37
1.51
906
0.6
7498
18,3591
New Valley
6
0.24
19
0.01
20,359
64,470
Subtotal
131
5.35
2784
1.8
72,389
1,050,901
6.89%
Upper Egypt
Beni Suef
30
1.22
558
0.4
35,200
654,715
Asyut
100
4.1
1428
0.9
65,617
937,017
Aswan
47
1.92
519
0.3
32,013
353,505
Faiyum
28
1.14
634
0.4
31,133
704,933
Luxor
36
1.47
499
0.3
22,486
311,685
Minya
118
4.82
2846
1.8
49,087
1,183,912
Qena
57
2.33
1671
1.1
24,207
709,635
Sohag
130
5.31
2089
1.3
65,560
1,053,493
Subtotal
546
22.3
10,244
6.6
325,303
5,908,895
5.51%
Total
2448
100
155,032
100
1,038,547
23,115,874
4.49%
In our study, Cairo governorate had the highest number of studied subjects (n = 133,968), representing 86.4% of the sample. This was follwed by Giza governorate with 4091 subjects (2.6%), then Minya governorate with 2846 (1.8%), and lastly Sohag governorate with 2089 (1.3%) (Table 2).
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The overall prevalence of XFS in our cohort was 1.6%. However, considering the ratio between subjects in the cohort from the four regions and the real population of each region, the overall corrected prevalence in Egypt was 4.49%. The corrected prevalence was highest among the inhabitants of the Suez Canal and territorial areas, accounting for 6.89%, followed by Upper Egypt with 5.51%, Lower Egypt with 4.38%, and least among subjects from Greater Cairo with 3.29% (Table 2).
Among all subjects, cataract was found in 33,610 subjects (21.7%). It was present in 2150 (87.8%) of the subjects diagnosed with XFS (n = 2448) but in only 31,460 (20.3%) of the subjects with no XFS (n = 152,584). The OR of cataract in XFS was 27.77 (95% CI 24.59–31.38).
On the other hand, XFS was found in 2150 subjects (6.4%) of those diagnosed with cataract (n = 33,610) and in 298 subjects (0.24%) of those without cataract (n = 121,422), (OR 0.04, 95% CI 0.03–0.04). This confirmed the strong association between XFS and cataract.
Regarding the other associated factors, XFS was most likely to be found in men (Table 3).
Table 3
Odds ratio and 95% CI of factors associated with XFS
Total subjects
XFS group
Non-XFS group
OR
95% CI
N = 155,032
N = 2448
N = 152,584
Cataract
Present
33,610
2150
31,460
27.78
24.59–31.38
Absent
121,422
298
121,124
Upper Egypt
Resident
10,244
546
9698
4.23
3.84–4.66
Non-resident
144,788
1902
142,886
Lower Egypt
Resident
2303
110
2193
3.52
2.89–4.29
Non-resident
152,729
2338
150,391
Territorial regions and Suez Canal
Resident
2784
131
2653
3.19
2.66–3.83
Non-resident
152,248
2317
149,931
Gender
Male
68,192
1348
66,844
1.57
1.45–1.70
Female
86,840
1100
85,740
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Discussion
The reasons speculated to be behind marked the variability in prevalence rates of XFS even within the same country or region can be multifactorial: ethnic differences, age, gender distribution, genetic predisposition of the population under study, their geographical distribution with different climatic conditions, dietary habits, the variable clinical criteria used for diagnosis, the examiner’s experience in detecting early stages of the disease on routine examination without pupillary examination, and the difficulty in detection of lenticular signs of XFS in patients with existing cataract [7]. Therefore, we opted for a large sample to dilute some individual factors and to reach a more realistic prevalence estimate.
To the best of our knowledge, the only previous estimate for XFS cases in Egypt was based on a cohort from Upper Egypt only [14]. We assumed that the prevalence may differ from one region to another; hence, we conducted this study with a much larger sample from every governorate in Egypt. However, Greater Cairo residents represented 90.1% of our sample, as it is the most populated region in Egypt as it includes the most populated governorate, Cairo; moreover, both branches of our hospital are located in Cairo. Meanwhile, subjects from the Upper Egypt region represented only 6.6%. Nevertheless, we included in our cohort more cases than those included in the Upper Egypt study.
We found the corrected prevalence of XFS to be 4.49% in Egyptians over 40 years of age. Our corrected prevalence of XFS in Upper Egypt (5.51%) was slightly higher than that estimated by Shazly et al. in a smaller cohort from Upper Egypt (4.1%) [14]. We believe that the difference in prevalence is related to climate conditions or dietary habits, with less folate intake in Upper Egypt [15]. Lower risk of XFS is associated with higher total folate intake, supporting a possible causal effect secondary to increased plasma homocysteine levels [16] which is a well-studied potential biomarker for XFS [17].
We compared our XFS prevalence to those of neighboring countries sharing similar geographical features, ethnic backgrounds, climatic conditions, diet, and lifestyle, namely the Mediterranean and Middle Eastern countries. Table 4 shows the different prevalence rates from studies involving subjects attending general ophthalmic clinics in these countries.
Table 4
Summary of studies on XFS prevalence in the Mediterranean and Middle Eastern countries in patients attending ophthalmological clinics
Among Mediterranean countries, the prevalence rate we calculated was comparable to those of Croatia (3.6%) [18], Salnés Eye Study (6.5%) [19], Central Anatolia (5.7%) [20], Eskisehir of Turkey (5.0%) [21], and Eastern Mediterranean of Turkey (7.2%) [22]. However, higher prevalence rates were detected in Greece [23, 24] with the highest reported rate of 24.3% among the northwest population of Epirus [25], northeast and northwest regions of Spain (13.2 and 18.9%, respectively) [26, 27], Tunisia (12.5%) [28], and Black Sea region of Turkey (12.2%) [29]. This could be attributed to true factors we could not account for or to the less accurate estimation by relatively small sample size. Even in the largest of them, it was about 1/28th of our cohort.
Among other Middle Eastern countries, our prevalence rate was higher than prevalence rates of northeast Iran (0.46%) [30] but it was aligned with a recent study from a tertiary eye center in Jordan (4.9%) [31] and Saudi Arabia (3.5%) [32]. Yet it was lower than those of Central Iran (13.1%) [33], Iraq (29%) [34], and Yemen (18%) [35]. This is probably related to two facts; first, the larger sample size of the studies that aligned with our results, and second, the proximity of Egypt to the aforementioned countries (Saudi Arabia and Jordan) latitude-wise, where all are more or less surrounding the 30° N. This fact is associated with almost the same hazard of solar radiation [36].
The age-dependent nature of XFS has been established beyond doubt [7]. For example, in the Reykjavik Eye Study examining the prevalence of XFS in Iceland, the prevalence increased from 2.5% in those aged 50–59 years to 40.6% in those aged 80 years or over, exhibiting a more than 16-fold rise in prevalence [37]. We found a similar trend in our study where the prevalence increased from 0.12% in those aged 40–49 years to 9.06% in those aged 90 years or over, with a marked rise in OR as shown in Table 1.
The reviewed studies reporting XFS prevalence varied in their inclusion criteria regarding age. Our study aimed to include the largest possible age group and so we included all those over 40 years of age to avoid missing such an important category of patients with significant findings and to detect XFS as it begins. We recommend including this wide age group in future studies aiming to investigate XFS prevalence rates.
Regarding gender, there is conflicting data on gender predilection for XFS in the literature. Many studies [9, 38] reported a slightly higher XFS prevalence in women, whereas others reported the opposite; mainly in southern Europe like Spain [39], Turkey [22], and Mexico [40]. Our study showed preponderance for men, which could be attributed to the currently adopted recommendation of folate intake for women in the child-bearing period in our country which was not the case in studies done years or decades ago leading to different outcomes.
In our study, we detected a prevalence rate of XFS of 6.4% among those with cataract, as opposed to only 0.24% in those without cataract. These results highlight a strong association between XFS and cataract and emphasize the need to examine cataract cases meticulously searching for XFS owing to its operative and postoperative implications. This association has been long recognized and investigated. Forsius reported variable prevalence rates of XFS among the cataract cohort ranging from 0.3% in Poland, 3.5% in France, 18% in Norway, and 33% in Finland [5]. Furthermore, among all our patients with XFS (n = 2448), cataract was found in 2150 of them (87.8%). Even though a few studies found no causal relationship [41], a proposed hypothesis for this strong association is that XFS can promote ischemia of ocular tissues as well as defective antioxidant defense mechanisms that in turn could alter iris vasculature and blood–aqueous barrier. Thereby, the lens metabolism could be negatively affected with resultant cataract formation [42].
In comparison to the other Mediterranean and Middle Eastern countries (Table 5), our result regarding the prevalence of XFS in patients with cataract (6.4%) was comparable to Turkey [43] and Jordan [44] (11% and 10.3%, respectively) but much lower than the rest of the studies which all reported rates of 20% or more. This could be attributed to significantly older populations studied than in our study, as well as smaller samples studied.
Table 5
Summary of studies on XFS prevalence in the Mediterranean and Middle Eastern countries in patients with age-related cataract
Our study avoided some defects encountered in previous studies; namely by recruiting a larger sample, including younger age group, as well as studying subjects from different regions within the same country. However, it has its limitations. First, we missed the diagnosis in cataract-operated subjects as we excluded aphakic and pseudophakic patients possibly leading to underestimation of the condition. Second, different governorates were unequally represented. Third, variable examiners’ experience could affect the detection of early cases of XFS, in which the subtle signs may be hard to discern or missed altogether.
Our understanding of predisposing factors to XFS is still limited. There is still a universal need for standardized definition and methodological assessment of XFS to allow for the comparison of prevalence studies among diverse populations.
Acknowledgements
Funding
No funding or sponsorship was received for this study or publication of this article. The Rapid Service Fee was funded by the authors.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authorship Contributions
All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Bassem F Aziz, Amr I Elawamry, Maged M Roshdy and Caroline A Tawfik. The first draft of the manuscript was written by Bassem F Riad and Caroline A Tawfik and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Disclosures
Bassem F Aziz, Amr I Elawamry, Maged M Roshdy and Caroline A Tawfik declare that they have no conflicts of interest.
Compliance with Ethics Guidelines
The research protocol has been submitted to the Ethics Committee of Watany Research and Development Center (WRDC), Cairo, Egypt, and was found to agree with the tenets of the Declaration of Helsinki. The Ethics Committee of WRDC waived the ethical approval and the need to obtain patient consent because of the retrospective nature of the study.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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