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Year : 2021  |  Volume : 28  |  Issue : 1  |  Page : 36-50  

A case–cohort study of exfoliation risk factors and literature review

1 Department of Ophthalmology, American University of Beirut; Department of Ophthalmology, Rafic Hariri University Hospital, Beirut, Lebanon
2 Department of Ophthalmology, Aristotle University, Thessaloniki, Greece
3 Department of Ophthalmology, American University of Beirut, Beirut, Lebanon
4 Department of Statistics and Research Methodology, Lebanese American University; Department of Statistics and Research Methodology, Lebanese University, Beirut, Lebanon
5 Department of Ophthalmology, Medical University of Lodz, Lodz, Poland

Date of Submission07-Aug-2020
Date of Acceptance16-Feb-2021
Date of Web Publication30-Apr-2021

Correspondence Address:
Prof. Ahmad M Mansour
Department of Ophthalmology, American University of Beirut, Beirut
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/meajo.MEAJO_358_20

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The purpose of the study is to evaluate the risk factors associated with exfoliation in a case-cohort setting and literature review. This single-center, prospective, case-cohort study was carried out from January 2010 to April 2020 on patients operated for cataract surgery by a single surgeon in Lebanon. Forty-nine consecutive patients with exfoliation syndrome (XFS) and 62 consecutive control patients were identified and further investigated for selected systemic (diabetes mellitus, systemic hypertension, asthma, or atopy) and ocular variables (baseline vision, severity of nuclear sclerosis, glaucoma, eye rubbing, history of dry eye, or allergic eye disease). The mean baseline Snellen visual acuity was 20/283 in XFS versus 20/145 in control cases (P = 0.012). XFS also demonstrated significantly denser nuclear sclerosis than controls (P = 0.00958). By univariate analysis, allergic conjunctivitis (15 [30.6%] vs. 2 [3.2%]; P < 0.001), dry eye (20 [40.8%] vs. 13 [21.0%]; P = 0.0133), and habitual rubbing of the eyes (33 [67.3%] vs. 19 [30.6%]; P < 0.001) were associated with the presence of XFS. Habitual ocular rubbing was closely associated with allergic conjunctivitis (odds ratio [OR] = 13.0; 95% confidence interval [CI]: 2.8–58.8; P = 0.032). After multivariable analysis, the following variables showed significant results: glaucoma (OR = 34.5; 95% CI: 4.4–250; P = 0.010), duration of surgery (OR = 5.6; 95% CI 2.43–12.9; P < 0.001), and habitual ocular rubbing (OR = 4.42; 95% CI: 1.97–9.90; P = 0.029). This study shows a novel potential correlation between eye rubbing and XFS in a Lebanese cohort. Chronic eye rubbing induces or may exacerbate preexistent zonular damage in subjects with XFS, hence the need to better manage concurrent ocular surface disorder in these patients.

Keywords: Allergic conjunctivitis, cataract, dry eye, exfoliation syndrome, lens zonules, ocular rubbing, phacoemulsification, pseudoexfoliation syndrome

How to cite this article:
Mansour AM, Konstas AG, Mansour HA, Charbaji AR, El Jawhari KM. A case–cohort study of exfoliation risk factors and literature review. Middle East Afr J Ophthalmol 2021;28:36-50

How to cite this URL:
Mansour AM, Konstas AG, Mansour HA, Charbaji AR, El Jawhari KM. A case–cohort study of exfoliation risk factors and literature review. Middle East Afr J Ophthalmol [serial online] 2021 [cited 2022 May 18];28:36-50. Available from: http://www.meajo.org/text.asp?2021/28/1/36/315319

   Introduction Top

Exfoliation syndrome (XFS) is currently a global disease affecting an estimated 70 million people, worldwide.[1] XFS appears to be a syndrome targeting ocular tissues with deposition of fibrillary material on the lens capsule with similar deposits in other parts of the body, such as the skin, kidneys, liver, heart, and lungs. XFS material is a mixture of several biologic components made of amyloid, laminin, elastic fibers, and collagen basement membrane.[2] The causes of XFS are not well known,[3],[4] especially with animal models lacking,[5],[6] leaving researchers with the human Tenon's capsule fibroblasts as a model system for the study of XFS.[7] Advanced age appears as a major risk factor as well as some genetic factors.[8] Some evidence exists for the association between XFS and lysyl oxidase-like 1 (LOXL1) protein gene implicated in elastin formation and maintenance and less so with the calcium channel protein gene CACNA1A, and the extracellular matrix chaperon clusterin protein. Known environmental risk factors for the disease have included solar exposure,[9] ambient temperature, living at more northern latitudes,[10] dietary factors,[9],[11] and infectious etiology.[12] The possible relationship between XFS and selected ocular and systemic factors was investigated in a Lebanese cohort.

   Methods Top

This is a prospective data registry of all patients undergoing phacoemulsification in one surgical suite by a single surgeon (AMM) from January 2010 to April 2020. All patients provided written informed consent in accordance with the Declaration of Helsinki. Institutional Review Board (Rafic Hariri University Hospital, Beirut, Lebanon) approval was obtained for this study. Data were anonymized to maintain confidentiality. Systemic factors recorded have included age, gender, hypertension, diabetes mellitus, coronary artery disease, morbid obesity, Alzheimer neurodegenerative disorder, and intake of alpha agonists for benign prostatic hypertrophy and any major disease (migraine, cancer). Recorded ocular factors were preoperative and postoperative best-corrected visual acuity (BCVA), intraocular lens power, presence of XFS, glaucoma, macular degeneration, and diabetic retinopathy. Seven hundred and fifteen patients (mean age: 74 years) were enrolled in this study, and 387 of them underwent bilateral cataract removal. Surgeries were performed on 1097 eyes (599 right eyes and 498 left eyes) and were nearly equally distributed among men (509) and women (588). A case–cohort study was designed in which cases with XFS and controls without XFS were drawn from within this large prospective study. We selected a consecutive (most recent to less recent date of surgery) control group. In addition, we conducted a survey on these two groups to collect additional ocular and systemic variables between January 2010 and April 2020 (approved by the Institutional Review Board at Rafic Hariri University Hospital). This survey was done by phone call to answer the presence of habitual ocular rubbing before glaucoma topical therapy, history of therapy for either dry eye or allergic conjunctivitis, skin atopy or asthma, erectile dysfunction, and sensorineural hearing loss. The survey was carried by a blinded operator (KAJ). The subjects who answered positively for ocular rubbing (before glaucoma therapy) were contacted a second time to fill an ocular rubbing score.

We included all patients with significant cataract and visual acuity 20/40 (6/12) or less and with any accompanying ocular morbidity (keratoconus, XFS, glaucoma, maculopathy, reduced endothelial cells [<1800 cells/mm2], and central corneal opacity) or systemic morbidity (controlled diabetes mellitus, controlled systemic hypertension, stable stroke, and controlled angina) and Alzheimer's disease or adult Down's syndrome. Exclusion criteria included refusal to sign an informed consent, recent conjunctivitis of any kind, uncontrolled systemic hypertension or diabetes mellitus, active proliferative diabetic retinopathy, active untreated neovascular macular degeneration, Marfan syndrome, homocystinuria, systemic amyloidosis, true XFS[13] (history of radiotherapy, glass blowing, excessive heat exposure from oven burning or metal welding), and eyes that require concomitant vitrectomy (for vitreous hemorrhage or retinal detachment).

Preoperatively, we carried out slit lamp examination, before and after pupillary dilatation, with one drop of tropicamide (Mydriacyl® 1%, Alcon, Fort Worth, Texas, USA), fundoscopy, tonometry, measurement of BCVA, and ocular measurement with an optical biometer (IOL Master 700; Carl Zeiss Meditec AG, Jena, Germany). Target refraction was emmetropia. In the final analysis, only the first operated eye in subjects with bilateral exfoliation was included. In the control group, the first operated eye of consecutive subjects without XFS was enrolled. BCVA was measured by the same surgeon (AMM) using Snellen visual charts. Nuclear hardness was graded after pupillary dilation on the slit lamp (Haag-Streit® slit lamp 900 [Haag-Streit AG, Koeniz, Switzerland]) by the same surgeon using the 5-level Emery-Little Classification System (soft, semi-soft, medium hard, hard, and rock-hard). Glaucoma diagnosis relied upon intraocular pressure above 21 mmHg, glaucomatous optic disc cupping >0.7, and typical glaucoma-related visual field loss. A rubbing score has been designed to assess numerically the intensity of the ocular friction [Table 1].
Table 1: Rubbing score is the sum of the items listed (all before initiation of glaucoma eye drops)

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Statistical analysis

Statistical analyses were performed using SPSS version 22 (IBM, Chicago, IL, USA), and t-test was used for testing the difference between the means of two independent samples. Multivariate analysis was carried using simple discriminant analysis when the dependent variable is categorical variable broken into yes and no using ANOVA and confirmed by cross-tabulation and Pearson's Chi-square test. Significance is set at P < 0.05.

Literature search

The databases of Medline, Embase and Google Scholar were systematically searched by one of us (AMM) for relevant articles published between 1975 and May 2020 using the search terms: exfoliation or pseudoexfoliation AND risk factors; exfoliation or pseudoexfoliation AND young age and using forward searching, checking references in major reviews (on exfoliation/pseudoexfoliation), and in all retrieved articles. Only comparative studies showing positive results with statistical significance set at P < 0.05 for the associated risk factors were included in the final tabulations.

   Results Top

The number of surveyed patients was 49 in the XFS group and 61 in the control group [Table 2] and [Table 3]. The completion rate of telephone survey approached 100% as patients or their close relatives (in case of death) completed the survey, for example, the survey in the control group was completed by 57 patients or by their mates in four deceased patients (100% response); likewise, the survey in the XFS group was completed by 45 patients or by their mates in 3 of 4 deceased patients (98% response). All enrolled subjects were Caucasians. The two groups were not different for gender, diabetes mellitus, coronary artery disease, or morbid obesity [Table 2]. XFS patients had longer follow-up because of the need to monitor for future or current glaucoma. XFS group was significantly older (by 7.4 years) than the control group. There was no significant difference for the presence of diabetes mellitus, systemic hypertension, coronary artery disease, morbid obesity, asthma or skin atopy, sensorineural hearing loss, or use of oral alpha-agonist for benign prostatic hypertrophy. Erectile dysfunction occurred in 12 of 22 XFS males (54.5%) versus 3 of 17 control males (17.6%) (P = 0.0069). Additional systemic findings in the XFS group not listed in [Table 2] included migraine in 4, rheumatoid arthritis in 3, stroke in 2, and temporal arteritis or sarcoidosis or interstitial lung fibrosis or colon cancer or lung cancer or toxic goiter or Parkinson's or sleep apnea in one case each. Additional systemic findings in the control group included breast cancer in two cases and sleep apnea or carotid stenosis or Parkinson's or migraine in one case each.
Table 2: Potential systemic risk factors for pseudoexfoliation by univariate analysis

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Table 3: Potential ocular risk factors for pseudoexfoliation by univariate analysis

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Eye-wise, the two groups were not different for baseline astigmatism, presence of posterior subcapsular cataract, baseline refraction (measured indirectly by the inserted intraocular lens power), and final BCVA [Table 3]. The two groups were different in terms of several ocular characteristics. The mean baseline spectacle-corrected Snellen visual acuity was 20/270 in the XFS versus 20/145 in the control (P = 0.032). Duration of surgery was near double in XFS than in controls (36.0 min vs. 17.4 min; P < 0.001), partly from higher grades of severity of nuclear sclerosis in the eyes with XFS (P = 0.023). Glaucoma (18 [36.7%] vs. 1 [16.1%]; P < 0.001), allergic conjunctivitis (before glaucoma therapy) (17 [34.7%] vs. 2 [3.2%]; P < 0.001), dry eye (before glaucoma therapy) (21 [42.9%] vs. 13 [21.0%]; P = 0.0074), and rubbing score of the eyes (before initiation of glaucoma medical therapy) (8.69 vs. 2.11; P < 0.001) were significantly more common in the XFS group. Other ocular findings in six patients with XFS and not listed in [Table 2] included: Sjogren's syndrome in 3, chronic anterior blepharitis in 2, severe ocular rosacea in 2, and large old herpetic corneal scar in 1, while a single patient in the control group had chronic anterior blepharitis.

A multiple regression was run to predict the potential risk factors for XFS [Table 4]. These variables significantly predicted the occurrence of XFS (F = 6.68; P < 0.001; R2 = 0.642): duration of cataract surgery (P < 0.001), glaucoma diagnosis (P = 0.004), history of local therapy for allergic conjunctivitis (P = 0.044), and ocular rubbing score (P < 0.001).
Table 4: Multiple regression analysis of risk factors for pseudoexfoliation

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For XFS patients, 48 completed the survey, 30 admitted rubbing, and 18 denied rubbing. Of note, 23 XFS patients were witnessed rubbing the eyes in the clinic (all before any potential therapy for glaucoma). Severity of rubbing: 3 severe, 10 moderate, and 17 mild; frequency of daily rubbing: more than 10 times in 6, between 5 and 10 in 1, and <5 times in 23; rubbing was throughout the year in 13, seasonal in 6, and occasional in 11. Years of rubbing: 10 reported >20 years, 8 had between 11 and 20, 8 had between 6 and 10, and 4 had <6 years. For the 61 control patients who completed the survey, 14 admitted rubbing and 47 denied rubbing. Five control patients were witnessed ocular rubbing in the clinic (all before any potential therapy for glaucoma). Severity of rubbing: 1 severe, 2 moderate, and 11 mild; frequency of daily rubbing: more than 10 times in 1 and <5 times in 13; rubbing was throughout the year in 4, seasonal in 4, and occasional in 6. Years of rubbing: 4 had >20 years, 1 had between 11 and 20, 4 had between 6 and 10, and 5 had <6 years.

Literature review of positive risk factors for XFS in general [Table 5], [Table 6], [Table 7][14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67],[68],[69],[70],[71],[72],[73],[74],[75],[76],[77],[78],[79],[80],[81] and XFS in young subjects [Table 8][82],[83],[84],[85],[86],[87],[88],[89],[90],[91],[92],[93],[94],[95],[96],[97],[98],[99] was tabulated and this information was used to synthesize the literature findings with the current study findings.
Table 5: Literature review of articles showing positive ocular risk factors in pseudoexfoliation

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Table 6: Literature review of articles showing positive systemic nonvascular risk factors in pseudoexfoliation

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Table 7: Literature review of articles showing positive systemic vascular risk factors in pseudoexfoliation

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Table 8: Systematic literature review of patients with early onset pseudoexfoliation pseudoexfoliation (<age 45 years)

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   Discussion Top

In the Lebanese cohort under investigation, XFS was associated with advanced age, glaucoma, habitual ocular rubbing, and longer time for cataract surgery. While advanced age [Table 6],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67],[68],[69],[70] glaucoma [Table 5],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38] and longer surgery duration[100] are well established risk factors for XFS [Table 5],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38] ocular rubbing has received little attention in the literature.

What are the causes of ocular rubbing in exfoliation syndrome?

A major precipitating factor in the cohort under investigation is the presence of dry eye and to a lesser extent the presence of allergic conjunctivitis. Rubbing was associated in the current study with dry eye, and dry eye is a known feature in XFS patients.[101] XFS patients have lower basal tear test scores, decreased tear breakup time, loss of goblet cell density (by impression conjunctival cytology),[101] and significant  Meibomian gland More Details dysfunction.[23] These ocular surface disorders have been attributed partly to deposition of exfoliation material in the conjunctiva.[102],[103] Possible other explanations have included: degenerative disease of the ocular surface with deposition of neurodegenerative proteins similar to that found in Alzheimer's or Parkinson, autoinflammatory disease of the conjunctiva, and vascular insufficiency [Table 9]. Allergic conjunctivitis was also associated with rubbing but to a lesser extent in the present Lebanese study with one subject having XFS and vernal catarrh. Asthma and abnormal pulmonary function tests (obstructive airway disease) have been associated with XFS [Table 6].[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67],[68],[69],[70] Batur et al.[66] in 60 patients with XFS without pulmonary disease detected a significant decline in pulmonary function tests versus 52 controls matched for age, gender, and smoking history. Similarly, in the Reykjavik Eye Study, a population-based study involving 1045 subjects (108 XFS) followed for 5 years, asthma was significantly associated with XFS (odds ratio 1.91; [95% confidence interval 1.00–3.62]) by multivariate analysis.
Table 9: Possible causes of ocular rubbing, dry eye and allergic conjunctivitis in pseudoexfoliation subjects

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What are the consequences of ocular rubbing on the eye?

Acute rubbing of the eye can cause transient astigmatism,[107],[108] elevated intraocular pressure,[109],[110] and corneal hydrops.[111] Chronic rubbing has been linked with the development of keratoconus,[112],[113] cataract,[114] optic disc cupping,[115] and retinal detachment.[116] Küchle[84] reported 2 young subjects with keratoconus necessitating penetrating keratoplasty at ages 31, 37 and 40 years with XFS detected between 4 and 6 years after surgery. Küchle attributed this temporal relationship to possible slow virus transmitted from the donor cornea. We propose that rubbing caused the concomitant keratoconus and XFS. This is further confirmed by analysis of XFS in young subjects [Table 8]:[82],[83],[84],[85],[86],[87],[88],[89],[90],[91],[92],[93],[94],[95],[96],[97],[98],[99] Half of young subjects with a reported risk for XFS had keratoconus. Out of 35 subjects with XFS under 45 years of age, detailed clinical data were available in 18:9 having some kind of corneal ectasia and 9 having had intraocular surgeries (2 after penetrating trauma and 7 had primary glaucoma). The decreased endothelial cell count in XFS[28] could be due to XFS material accumulation[30] or from eye rubbing as rubbing per say decreases endothelial cell density.[117],[118]

Zonular stretching in health, trauma, and exfoliation syndrome

The function of the zonules is mechanical with its relatively elastic fibers able to stretch up to four times their original length before breaking, but this elasticity declines markedly with age. Biochemically, a zonule consists of a microfibril backbone comprised fibrillin and a restricted set of glycoproteins (80% being FBN1 and LTBP2).[119] LOXL1, a crosslinking enzyme responsible collagen and elastin biogenesis, is detected at significant levels, and this enzyme is implicated in the pathogenesis of XFS. Assia et al.[120] tested the stretching capability of lens zonules in 40 postmortem human eyes. They found that zonules can slowly stretch up to 3.82 mm in young subjects before rupturing. That value of maximal zonular stretch tended to decrease with the age by 0.5 mm for every 5 years in normal eyes, while eyes with XFS had even more friable zonules. Similarly, Saber et al.[121] found a median mechanical zonular stretch tolerance of 3.00 mm on postmortem eyes that previously had extracapsular extraction. The zonular apparatus is involved extensively in XFS. Ultrasound biomicroscopic grading of zonular changes in XFS included uneven and disrupted zonules, followed by patchy deposits on the zonules. A more severe grade involves diffuse granulation over thickened zonules[122] with web-like structure in between zonules. The end stage is extensive loss of zonules.[123] Similarly, occult zonular defects were present on ultrasound biomicroscopy in 21 of 49 patients (42.9%) following ocular trauma.[124] XFS was detected in a study of young amateur boxers.[125] How much the eye is indented around the limbus during ocular rubbing or ocular trauma? In acute blunt trauma, the damage is one time and severe, while with severe repetitive rubbing, the damage is cumulative progressive and infinitesimal. The eyeball is deformed with shortening of anteroposterior length and distension of the equatorial region, leading to stretch of the zonules [Figure 1]a and [Figure 1]b. Delori et al.[126] demonstrated in a pig eye model that blunt trauma causes indentation of the cornea with lens–cornea touch and backward displacement of the lens together with widening of the pars plana. This causes severe zonular stretching over several milliseconds [Figure 1]b. Second, there is compression of the angle, iris, ciliary body, anterior vitreous, lens over the area rubbed, resulting in squeezing injury to the zonules [Figure 2]a and [Figure 2]b. Third, XFS material can act as cutting fulcrum when eye is rubbed or traumatized. Note that flaccid cornea, or eyes with hypotony, or have more distortion of cornea and more indentation of the globe.
Figure 1: Sketch of a cross-section of the anterior globe centered around the zonules. (a) Normal section. (b) Section during rubbing. With vigorous knuckle rubbing or blunt trauma to the central cornea, the cornea indents with retraction of the lens and stretching of the ciliary body causing sudden elongation of the zonules

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Figure 2: (a) Small section through limbus. (b) Section of limbus after ocular rubbing on the limbal area. If rubbing center on the limbus or pars plana, there is contusion of the zonules by a smashing effect

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Delori et al.[126] used the technology of high-speed cinematography and single-flash high-speed photographs to document the globe deformation in 75 pig eyes immersed in gelatin, with high impact pellet to the center of the cornea. The distance between the posterior pole of the lens to the vitreous base elongated by 28% at 0.4 ms and shrank by 13% (from baseline) at 1 ms before resuming baseline level. If we extrapolate similar changes in humans, this deformation translates to sudden distension of the zonules by around 3 mm. The same applies after vigorous rubbing, but the distension of the zonules is slower and milder as witnessed by rubbing videos by volunteer on dynamic medical imaging (Investigating Eye Rubbing with Dynamic Medical Imaging, www.defeatkeratoconus.com). The equator of the vitreous base measures around 21 mm in normal eyes and expands by 28% or near 3.0 mm on either side of the zonules over a fraction of a millisecond in pellet or rub model. Superfast distension of the zonules leads to more breakage than gradual distension; hence, the breakage distension at high speed is estimated to be around 1 mm or so.[127]

Itching from atopy or dry eye is a trigger for chronic aggressive rubbing. Other causes of ocular rubbing include several disorders associated with an obsessive- compulsive form of ocular rubbing: Tourette syndrome,[128] Leber's congenital amaurosis, retinitis pigmentosa,[129] and the extreme form of the oculo-digital reflex also known as the pop-eye phenomenon.[130] To control chronic rubbing that may be the cause of XFS, there is a need for an increased vigilance and care of the eyes in XFS patients in the form of: education, meticulous therapy of ocular surface disease (preservative free antiallergic and lubricant, therapy of meibomian gland dysfunction or blepharitis), wearing of safety glasses, psychologic consultation or need for/ pharmacotherapy. Larger studies are needed to delineate the subset of XFS that relate to environmental factors.

Based on the above data [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], we propose that ocular rubbing [Figure 3] leads in susceptible eyes to keratoconus, iridoschisis, disruption of zonules, and partial tears of anterior capsule around zonules.[113],[131],[132],[133] Following severe rubbing, the intraocular pressure can rise to 100 mmHg[109] with collapse of peripheral anterior chamber, with the zonules becoming stretched or compressed by the posterior part of the iris, leading to tearing.
Figure 3: Proposed pathophysiology of associated ocular, systemic, and biochemical factors in relation to exfoliation syndrome

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The current study suffers from the shortcoming of any survey and from the small number of participants. However, the strength of the study includes near absence of nonresponse (high nonresponse rate can result in bias of the measures of outcome) and combining the current data with data from the systematic literature review, leading to a proposed comprehensive pathophysiology of XFS. Scientific evidence has shown that XFS is a multifactorial disease involving complex interaction of possible genetic and environmental factors. Our study and review of the literature point to a new factor (ocular rubbing) implicated in the pathogenesis of XFS and hence the need to better manage concurrent ocular surface disorder in these patients. Further studies with larger numbers of patients are needed to delineate more clearly the contribution of ocular rubbing, ocular surface disease, and other ocular or systemic or genetic factors [Table 5], [Table 6], [Table 7], [Table 8] to the development of XFS.

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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]


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