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Review
What have we learned about exfoliation syndrome since its discovery by John Lindberg 100 years ago?
  1. Samir Nazarali1,
  2. Faraz Damji2,
  3. Karim F Damji3
  1. 1 Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
  2. 2 School of Kinesiology, Faculty of Education, University of British Columbia, Vancouver, British Columbia, Canada
  3. 3 Department of Ophthalmology and Visual Sciences, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
  1. Correspondence to Dr Karim F Damji, Department of Ophthalmology and Visual Sciences, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada; kdamji{at}ualberta.ca

Abstract

Exfoliation syndrome (XFS) is a systemic disease with significant ocular manifestations, including glaucoma and cataract. The disease impacts close to 70 million people globally and is now recognised as the most common identifiable cause of open-angle glaucoma. Since the discovery of XFS 100 years ago by Dr John G. Lindberg, there has been considerable advancement in understanding its pathogenesis and resulting clinical implications. The purpose of this paper is to summarise information regarding the epidemiology, pathophysiology, ocular manifestations and systemic associations of XFS with the objective of sharing clinical pearls to assist in early detection and enhanced management of patients.

  • Glaucoma
  • Exfoliation Syndrome
  • Exfoliative Glaucoma

https://doi.org/10.1136/bjophthalmol-2017-311321

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    Introduction

    This year marks the 100th anniversary since the discovery of exfoliation syndrome (XFS), an age-related, systemic, elastic microfibrillopathy initially reported by Finnish ophthalmologist John G. Lindberg in 1917.1 During his time as a student, Lindberg was interested in exploring Axenfeld’s observations regarding iris degeneration in older patients, including sometimes poor pupillary dilation. While conducting his research, Lindberg became increasingly aware of greyish fringes at the pupillary border and on the membrane of the anterior lens capsule.2 He continued to explore his findings and documented them as detailed hand drawings (figure 1). In 1917, Lindberg drafted his thesis ‘Clinical investigations on depigmentation of the pupillary border and translucency of the iris’ which was written in Swedish.3 Unfortunately, Lindberg did not receive credit for his discovery despite numerous papers published by colleagues on exfoliation following his thesis.4 5 In 1954, Dvorak-Theobald, a pathologist, suggested the term pseudoexfoliation to distinguish Lindberg’s discovery from true lens capsule delamination seen in glass blowers and individuals exposed to infrared radiation.6

    Figure 1
    Figure 1

    Hand drawings by John Lindberg showing exfoliation material on the lens capsule.2

    Remarkably, Lindberg’s descriptions and conclusions of exfoliation material on the anterior lens capsule continue to be valid a century later. Since his discovery, our understanding of XFS has evolved to include fibrillar extracellular deposits that accumulate on ocular tissues throughout the anterior segment. It is now regarded as the most common identifiable cause of open-angle glaucoma throughout the world and is associated with formation of cataract.7 8 It is also now known to be a systemic disease,9 10 related in part to genetic and environmental factors. Emerging literature suggests close associations with systemic pathology, including cardiovascular and cerebrovascular diseases.11

    Various advances in our understanding of exfoliation over the past 100 years have important clinical relevance for patient care related to glaucoma, cataract and other ocular and systemic vascular disease. The purpose of this paper is to summarise information regarding the epidemiology, pathophysiology, ocular manifestations and systemic associations of XFS with the goal of sharing clinical pearls that we hope will result in early detection and enhanced management of patients with this condition.

    Epidemiology

    Historically, XFS was regarded as a disease limited to individuals of Scandinavian origin. However, Scandinavian heritage has not been proven to be a significant risk factor for XFS.12 XFS is now considered to be a global disease affecting 60 to 70 million people worldwide13 and 0.3% to 30% of people over the age of 60 years.14 Variability in prevalence can be attributed to true population differences, study sample heterogeneity, differences in clinical criteria used to diagnose XFS and clinician-dependent factors.15 16 The prevalence varies widely from 0% in Eskimos to 40.6% in patients older than 80 years in Nordic countries.17–20

    XFS is an age-related disorder that increases dramatically in prevalence with age. In an Icelandic population, the prevalence of XFS was 17.7% in those aged 70 to 79 years and reached 40.6% in patients over 80 years.21 The disease also appears to manifest more commonly in certain ethnic groups and geographical regions within countries. Ethnic and intraregional variations are exemplified by US prevalence estimates of 1.6% in Southeastern habitants compared with 38% in Navajo Indians.22–24 XFS is highly prevalent in several African populations with an estimated 25% of all open-angle glaucoma in Ethiopia attributable to XFS, whereas prevalence estimates in patients over 40 years range from 5.1% to 7.7%.25 26 Ethnic differences were also noted in a South African study where the prevalence of XFS was 20% in black patients compared with 1.4% in white patients, whereas a study in the USA found that prevalence was 0.3% in black patients and 2% in white patients.27 28 Although not directly comparable due to heterogeneity in patient samples and study design, there are variances in XFS prevalence among Asian nations in patients over 50 years: South Korea 0.11%, China 2.38%, India 3.01%, Japan 3.4% and Pakistan 6.45%.14 29–32 Similarly, there is variation in XFS prevalence in patients over 40 years in the Middle East: Egypt 4.1%, Turkey 5% and Saudi Arabia 9.3%.33–35

    The Blue Mountain Eye Study (BMES) evaluated 3654 people aged 49 to 97 years and found that glaucoma was eight times more frequent in eyes that had XFS after adjusting for age, sex and other glaucoma risk factors. In addition, XFS was found in one or both eyes in 13.4% of patients with glaucoma compared with 1.9% of patients without glaucoma.36

    Pathophysiology

    XFS in the eye is characterised by deposition of extracellular fibrillar material on all structures bathed in aqueous humour in the anterior segment.37 With slit-lamp examination, XFS appears as fine ‘dandruff-like’ material which is typically found on the anterior lens capsule in a concentric ring pattern. Exfoliative material deposits can also be found on the trabecular meshwork, pupillary margin, lens zonules, the face of the ciliary body and on the corneal endothelium. The origin of exfoliative material is unclear; however, evidence suggests emergence from intraocular cells (trabecular and corneal endothelium, ciliary and lens epithelium and iris) and extraocular cells (fibrocytes, vascular and muscle).38

    Ocular pathology associated with XFS includes peripupillary iris depigmentation, trabecular meshwork hyperpigmentation (an early feature), secondary open-angle and/or angle-closure glaucoma, cataract, lens subluxation and corneal endothelial compromise and decompensation. Evidence has also suggested an association between XFS and central retinal vein occlusion, potentially connected through the unique vascular alterations observed in XFS.39

    Although the mechanism of intraocular pressure (IOP) elevation remains debated, a common hypothesis is increased outflow resistance primarily in the trabecular meshwork.40 Friction between the iris and the lens disrupts the iris pigment epithelium, which subsequently releases pigment into the anterior chamber.16 Aqueous outflow is disrupted as pigment and exfoliative material deposit in the trabecular spaces as well as near the endothelium of Schlemm’s canal.41 In addition, there is evidence of local production of exfoliation material by endothelial cells of the trabecular meshwork and Schlemm’s canal. Therefore, aggregation of exfoliative material may be derived from passive deposition from aqueous as well as local production within the meshwork/inner wall of Schlemm’s canal, resulting in elevation of IOP.

    The association between cataract formation and XFS has been proposed numerous times in the literature.42–44 The BMES showed a positive association between the 10-year incidence of nuclear cataract and XFS.45 It is hypothesised that XFS changes the composition of aqueous, resulting in changes in lens metabolism, subsequently leading to cataract formation. The breakdown of the blood–aqueous barrier, formed by tight junctions between various epithelial cells and between vascular endothelial cells, is another hallmark feature of XFS and contributes to the accumulation of aqueous proteinaceous material.46 Additionally, the impact of the disease on the zonular apparatus can result in surgical complications, including capsular rupture, zonular dialysis, vitreous loss and retained lens fragments.47 48 Signs of zonular weakness include phacodonesis, iridodonesis, decentration of the nucleus and vitreous prolapse in the anterior chamber. Phacodonesis and lens dislocation are related to weakness of the zonules as well as abnormal zonular attachment on the lens or ciliary body related to exfoliation material and are more likely when XFS is dense.49–51 One study found that shallow anterior chambers are associated with zonular instability, with intraoperative complications of 13.4% in eyes with anterior chamber depths less than 2.5 mm and 2.8% in eyes with anterior chamber depths of 2.5 mm or larger.52

    Zonular weakness and posterior synechiae in patients with XFS may also predispose to angle closure glaucoma.47 The increased rigidity of the iris causes aqueous pressure in the posterior chamber to build at the iris root, leading to angle-closure glaucoma.47 In addition, zonular fibres can separate from the ciliary body and lens, thereby causing an inferior displacement of the lens; decreased support of the lens can also allow it to move anteriorly with resultant pupillary block.53

    Genetics

    Variants in the lysl oxidase-like 1 (LOXL1) gene on chromosome 15q24, particularly, three single-nucleotide polymorphisms (SNPs), have been strongly associated with XFS.54 Several meta-analyses have provided evidence of the overwhelming association between LOXL1 SNPs and increased risk of XFS across various ethnic groups.55–58 In a study by Chen et al looking at Caucasian, African, Japanese, Indian and Chinese populations, SNP rs3825942 was found to be the common at-risk allele for XFS in all populations with an overall OR of 10.89.57 LOXL1 is part of a family of enzymes that are active in crosslinking collagen and elastin in the extracellular matrix, helping prevent age-related loss of tissue elasticity.59 Alterations in the coding region for this enzyme disrupt extracellular matrix metabolism, resulting in accumulation of elastic fibre components characteristic of XFS.54

    In a landmark study, LOXL1 gene variants were found in 99% of XFS cases in Scandinavian populations. Surprisingly, a large number of controls also demonstrated the gene variants, despite being unaffected.54 CACNA1A was discovered as the second locus associated with susceptibility to XFS.60 A recent study uncovered a rare variant in LOXL1, p.Tyr407Phe, that interestingly strongly protects against XFS.61 The authors suggest that the protective effect may be via stabilisation of extracellular matrix from increased elastin and fibrillin-1 deposition. In the same paper, five new loci that serve as genetic risk factors were identified and suggest new biological pathways for pathogenesis.61 The loci include POMP, TMEM136, AGPAT1, RBMS3 and SEMA6A.61 Potential pathophysiological pathways include effects on ubiquitin-conjugating enzymes (POMP), vascular endothelia (TMEM136), omega-6 polyunsaturated fatty acid levels (AGPAT1) and other yet to be discovered biological pathways.

    Other genes such as clusterin, APOE, CNTNAP2, GST and TNF-α have also been found to be associated with XFS, but are limited to certain populations, implying either weak or ethnic-specific associations.60 62 With the current understanding of inheritance, the clinical utility of genetic testing for XFS is limited; the multifactorial nature of the disease limits the specificity of such a diagnostic test.

    Environmental factors

    Numerous environmental factors, some potentially modifiable, have been suggested to increase the risk of disease in genetically predisposed individuals. In addition, an understanding of these environmental factors may provide an explanation for the current genotype–phenotype mismatch. Stein et al identified a ‘latitude effect’, which found that people with XFS tend to reside at higher latitudes in the northern hemisphere.63 This trend was also noted in the Nurses’ Health Study and Health Professionals Follow-up Study, where geographical residence in the middle or southern tiers of the USA was associated with a reduced risk of XFS compared with residence in the northern tier.12 Environmental factors such as solar irradiation and climatic variables are hypothesised to be responsible for the latitude effect.64 Ultraviolet radiation can upregulate the expression of LOXL1 as well as elastic fibre proteins found in exfoliation material.65 Studies have shown that time spent outdoors during summer months as well as ocular exposure to light from reflective surfaces, such as water or snow, is associated with an elevated risk of XFS.12 64 Colder climates including Iceland, Norway and Sweden have the highest prevalence of XFS.63 It has been proposed that cold temperatures facilitate a precipitation reaction, leading to extracellular deposits.66

    Additionally, dietary factors may also contribute to XFS. Low folate intake is related to elevated homocysteine levels, which is in turn associated with increased risk of XFS.67 Increased caffeine intake is also associated with higher homocysteine levels.68

    An improved understanding of environmental factors that influence XFS may offer insight into lifestyle changes that reduce the burden of XFS.

    XFS in the eye

    On slit-lamp examination, exfoliative material is found on the anterior lens capsule in a central disc and peripheral band (double concentric ring) pattern (figure 2). As Lindberg noted, dilated examination may be required to visualise subtle signs of exfoliation on the peripheral lens capsule. The most common sign of XFS is deposits of grey-white material on the anterior lens.69 With pupillary dilation, during early stages of XFS, there is a subtle translucent precapsular layer of exfoliation material visible on the lens surface, and over time, three zones can be detected which include a homogeneous central disc, a clear intermediate zone and a granular peripheral zone.69 The peripheral zone is always seen, whereas the central zone may be absent in one-fifth of eyes.70 The intermediate zone is thought to be due to rubbing of the iris over the lens.71

    Figure 2
    Figure 2

    Image of exfoliation material on the lens capsule, demonstrating classic findings of central disc, lucid interval (arrowhead) and peripheral band. A moderate stage nuclear cataract is also present.

    Additional clinical characteristics are associated with pigment dispersion and include peripupillary iris transillumination defects, loss of pupillary ruff, moderate to heavy variegated (irregular) trabecular meshwork pigmentation (figure 3) and pigmentation of the corneal endothelium sometimes in the pattern of a Krukenberg spindle. Pigment anterior to Schwalbe’s line, referred to as Sampaolesi’s line, is another pigmentary feature of XFS, which can indicate early disease of the contralateral eye in unilateral cases (figure 3).

    Figure 3
    Figure 3

    Goniophotograph of an angle of an eye with XFS demonstrating variegated (irregular) pigment. There is also a meandering line anterior to the meshwork in the peripheral cornea termed ‘Sampaolesi’s line’. This feature is also commonly seen in XFS, particularly in the inferior angle; however, it is non-specific for the condition. Photograph courtesy of Dr Robert Ritch, MD. XFS, exfoliation syndrome.

    Increased variegated trabecular meshwork pigmentation is also a notable indicator of XFS. Compared with individuals with primary open-angle glaucoma (POAG), those with XFS tend to have more pigmentation in addition to more advanced glaucomatous damage. It is important to note that pigment dispersion is possible after pharmacological pupillary dilation, which can result in elevated IOP. Maximal pigment liberation has been noted 1 hour postdilation, whereas maximum IOP elevation occurs 1–4 hours postdilation. Thus, careful monitoring of patients with XFS postdilation is recommended, especially in those with extensive postdilation pigment release.16 72

    Exfoliative glaucoma

    Exfoliative glaucoma (XFG) is typically an aggressive disease, with a poorer prognosis compared with POAG. Evidence suggests that those with IOP within normal limits do not require special monitoring or management to prevent conversion to high pressure,73 although annual pressure checks are recommended. However, patients with XFS may have large fluctuations in IOP, which may make single measurements of IOP unreliable. Patients with XFS are more likely to convert from ocular hypertension to glaucoma and have a greater baseline IOP at glaucoma diagnosis compared with POAG.74 Similarly, patients with XFG may experience larger IOP fluctuations, greater visual field loss and disc damage, reduced response to medications, more rapid progression and require surgical management.47 75–78

    Pressure-independent factors are also believed to play a role in glaucomatous damage as suggested by disc changes occurring in patients with unilateral involvement and equivalent IOP among eyes.79 Pressure-independent risk factors including abnormal ocular and retrobulbar perfusion and abnormality of elastic tissue of the lamina cribrosa increase risk for glaucomatous damage.80

    A considerable proportion (9% to 18%) of patients with XFS have occludable angles,81 82 and as a result, the peripheral anterior chamber depth should be assessed prior to dilation to avoid inducing acute angle-closure glaucoma. This also underscores the importance of gonioscopy to verify angle status and mechanism of glaucoma in XFS.

    For patients with XFG, the target IOP range needs to be defined, and patients may need to be followed more carefully than patients with POAG as IOP can rise rather abruptly.83 In addition to lowering IOP, therapy should ideally aim to interfere with the pathogenesis of the disease. Initial management to lower IOP using a prostaglandin analogue is favoured due to its efficacy, long duration of action and potential interference with the disease process. Latanoprost has been shown to reduce aqueous concentrations of TGF-β1, MMP-2 and TIMP-2.84

    Effective prostaglandin analogues include bimatoprost, travoprost and latanoprost.83 85–87 In a crossover study, a significantly higher number of patients obtained target diurnal IOP taking bimatoprost (45%) compared with latanoprost (28%), P=0.001.86 Konstas et al found that both latanoprost and travoprost are effective at reducing IOP in XFG over 24 hours.87 The effectiveness of timolol in XFG compared with chronic OAG varies across studies with some studies demonstrating decreased,88 similar89 or improved hypotensive effects.90 When comparing latanoprost to timolol, latanoprost is associated with a narrower range of diurnal IOP fluctuation.91

    Cholinergic drugs are effective by increasing aqueous outflow via the trabecular meshwork and lowering IOP.16 The International Collaborative Exfoliation Syndrome Treatment Study evaluated latanoprost and 2% pilocarpine qhs compared with timolol in patients with XFS and glaucoma. Patients receiving a combination of latanoprost and pilocarpine had increased IOP reduction compared with patients receiving timolol or timolol and dorzolamide, P=0.0003. In addition, patients receiving combination of latanoprost and pilocarpine had improved outflow at 1 year and decreased trabecular meshwork pigmentation inferiorly at 2 years when compared with patients on timolol or timolol/dorzolamide.92

    Laser trabeculoplasty is an effective option following medical therapy, as an adjunct, or as initial therapy. If angles are open, argon laser trabeculoplasty (ALT) and selective laser trabeculoplasty (SLT) have both been shown to be effective in XFG.93 94 A study of initial ALT demonstrated improved IOP and reduced progression of glaucomatous damage compared with medical management with pilocarpine over 2 years of follow-up.95 96 It is important to note that reductions in IOP are not permanent with laser trabeculoplasty. ALT has been effective in early disease, with approximately 20% of patients developing late rises of IOP within 2 years of treatment.97 One study described 50% failure of ALT in XFG at 1 year compared with 19% failure in patients with OAG.98 A 6-month randomised trial compared SLT and ALT in patients with XFG or XFS and increased IOP and found that the reduction in IOP was similar among both groups (P=0.56). Additionally, a similar proportion of patients with XFG in both SLT and ALT groups had an IOP reduction of at least 20% at the 6-month follow-up visit.99 Although rare, case reports demonstrate IOP spikes and corneal decompensation with SLT in exfoliation patients.100

    If IOP remains uncontrolled following medical and/or laser treatment, surgical management is warranted. Results of trabeculectomy appear to produce similar efficacy and safety outcomes compared with those in POAG.101 Given that XFG can be very aggressive and patients may present at an advanced stage of glaucoma damage, trabeculectomy offers a good option of attaining low IOP; however, complications are not infrequent and can be serious.47 A very high preoperative IOP can predispose patients to choroidal haemorrhage or effusion. In addition, decreased zonular support predisposes patients to anterior lens subluxation.47

    Glaucoma drainage device implantation is also a possibility, especially in eyes with previous conjunctival manipulation.102 103 Trabeculotomy as well as trabecular aspiration (TA) have been shown to be effective in the management of XFG.104 105 TA aims to improve trabecular outflow by removing pigment and exfoliative material.106 A prospective study evaluating TA in patients with uncontrolled XFG found that IOP decreased significantly at 18 months. After TA, 45% of patients did not require any medical management for IOP. In the same study, authors evaluated XFG and cataract and found that 2 years following combined TA and phacoemulsification or extracapsular cataract surgery, IOP decreased from 32.4 mm Hg preoperatively to 18.7 mm Hg postoperatively. In this subset of patients, 54% achieved IOP control without the need for any medication.106 Literature investigating TA in XFG remains limited; however, more recent studies have been conducted in which TA is used in conjunction with or compared with ab interno trabeculectomy with Trabectome. In one retrospective study of 30 patients, a triple surgical procedure of cataract extraction, Trabectome and TA was compared with cataract extraction and TA alone.107 The study found that the triple procedure group had a significantly greater reduction in IOP compared with the control group (38.4% vs 26.8%). Additionally, in a retrospective study of 27 patients with XFG, Trabectome and phacoemulsification were found to result in a greater reduction in IOP at 6 months and 1 year postoperatively compared with TA and phacoemulsification.108 The number of glaucoma medications between groups was not significantly different.

    There is some support for the use of ab interno trabeculectomy with Trabectome as well as the use of iStent, but prospective studies with longer follow-up are needed before one can recommend widespread use of these and possibly other microinvasive glaucoma surgical approaches.109 110 The theory behind using Trabectome in patients with XFG is that IOP elevation is largely a result of deposits of exfoliation material and pigment in the proximal aspect of the trabecular meshwork, which can be removed effectively with the ab interno trabeculectomy technique.111 A 1-year prospective study compared ab interno trabeculectomy to combination of ab interno trabeculectomy with cataract extraction and intraocular lens implantation in XFG and POAG. In the ab interno trabeculectomy group, preoperative IOP was 29 mm Hg in patients with XFG and 25.5 mm Hg in patients with POAG. Patients in the XFG group had a significantly higher decrease in IOP compared with patients with POAG, 12.3 mm Hg versus 7.5 mm Hg, respectively (P<0.01). The probability of success was 79.1% in XFG compared with 62.9 in POAG (P=0.004). In the combination of ab interno trabeculectomy and cataract surgery, preoperative IOP was 21.7 mm Hg in the XFG group and 19.9 mm Hg in the POAG group. Patients in the XFG group experienced a greater decrease in IOP compared with patients with POAG, 7.2 mm Hg versus 4.1 mm Hg, respectively (P<0.01).109 A retrospective cohort study evaluated consecutive patients with POAG, XFG and pigmentary glaucoma treated with iStent. In both POAG and XFG, IOP and antiglaucoma medications decreased significantly at 6 months postoperatively.110

    Deep sclerectomy has been proposed in XFG, and one study found that patients with XFG had significantly higher success following deep sclerectomy with an implant compared with patients with POAG.112 Although the procedure carries a steep learning curve, as a non-penetrating surgery, the technique facilitates reduced rates of complications compared with trabeculectomy including hyphema, choroidal detachment, inflammation and surgical-induced cataract.113 A 4-year follow-up of deep sclerectomy with a collagen implant in patients with XFG found that mean IOP decreased significantly from 29.9 mm Hg to 13.2 mm Hg. Complete success was achieved in 54% of patients, whereas qualified success was achieved in 90.9%.114

    The role of endoscopic cyclophotocoagulation (ECP) in XFG is minimal as exfoliation material accumulates on the ciliary body and zonules, and in our experience, the ciliary processes are poorly responsive to laser energy. In fact, increasing laser energy while performing ECP can result in rupture of ciliary processes with significant inadvertent haemorrhage.115

    Taken together, non-medical management of XFG is guided by mechanism, stage of glaucoma, degree of IOP elevation, ocular and systemic factors and patient and care provider preferences.

    Cataract formation as a consequence of XFS is hypothesised to result from changes in the composition of aqueous which ultimately disrupts lens metabolism. Cataract extraction can be challenging due to the potential weakness of the zonular apparatus and poor pupillary dilation. Accumulation of exfoliation material on the zonular fibres and ciliary processes can result in spontaneous fragmentation of zonules. In addition, age, shallow anterior chamber, small pupil size and angle pigmentation have been associated with zonular instability. Impaired pupillary dilation results from a combination of mechanical obstruction within the iris related to infiltration of extracellular matrix in the iris stroma, damage to the iris sphincter muscle and tendency for iridolenticular adhesions. Breakdown of the blood–aqueous barrier is also a characteristic of XFS, which can lead to intraocular bleeding with slight manipulation of ocular tissues and presents a risk for postoperative inflammation.46 Thus, it is imperative to perform a comprehensive preoperative examination and develop a surgical plan which anticipates intraoperative challenges.116 Phacoemulsification combined with glaucoma procedures does not appear to poorly influence success rates. Key recommendations to prevent complications during cataract extraction are summarised in box 1. In cases of subluxated or dislocated cataracts, the lens can be extracted using a variety of techniques including use of capsule tension segments, intracapsular cataract surgery or via a pars plana lensectomy/vitrectomy approach.48 117 118

    Box 1

    Pearls for cataract surgery in exfoliation syndrome132–135

    Capsulorhexis

    • Large enough to enable nucleus to prolapse into the anterior chamber as needed in order to reduce strain on zonules.

    Hydrodissection

    • Occasionally tap on centre of nucleus to decompress fluid pressure on weak posterior capsule.

    Phacoemulsification

    • Prevent anterior chamber collapse and protect corneal endothelium using cohesive as well as dispersive ophthalmic viscosurgical devices (OVD).

    Cortical removal

    • Use tangential vectors to carefully separate cortical material from capsular bag, particularly if a capsule tension ring (CTR) has been inserted.

    General considerations

    • Small pupil: consider cohesive OVD, mechanical and pharmacological dilation.

    • Zonular weakness: consider CTR or capsule tension segments. If diffuse weakness, could consider intracapsular or pars plana removal.

    • PCIOL: posterior chamber intraocular lens is generally well tolerated.

    • Potential for fibrinoid reaction postoperatively due to weak blood–aqueous barrier. Postop management should include aggressive anti-inflammatory treatment with steroids and non-steroidal agents.

    Systemic associations

    In 1992, exfoliation material was reported in visceral organs, skin, myocardium, meninges and vessel walls.9 10 These findings led to hypotheses for associations between XFS and non-ocular pathology. Systemic pathology with proposed associations to XFS includes cerebrovascular disease, aortic aneurysm, coronary artery disease, peripheral vascular disease, hypertension, neurosensory hearing loss, renal artery stenosis and Alzheimer’s-like dementia.11 The precise mechanism(s) underlying these various systemic pathologies remains unclear. However, oxidative stress, increased platelet aggregation, hyperhomocysteinemia and endothelial dysfunction are thought to be involved.119–121

    Systemic vascular disease

    There is increasing evidence that XFS is associated with both cardiovascular and cerebrovascular diseases.122 123

    Holló and colleagues investigated the relationship between LOXL1 gene SNPs and systemic vascular disease.124 There was a significant difference in allele distribution between patients with XFS and age-matched stroke patients; however, there was no difference in allele frequency between patients with XFS with and without systemic vascular disease. These results support the notion that genetic and environmental factors play a role in the incidence of systemic vascular pathology associated with XFS.

    It is important to note that although literature suggests XFS and cardiovascular as well as cerebrovascular pathology are closely associated,122 123 the literature does not demonstrate increased cardiovascular or all-cause mortality in those with XFS.125–129

    The mechanism by which exfoliation affects the vascular system remains to be elucidated. Exfoliation affects the elastic microfibrillar system, and elastin is a major component of the extracellular matrix of arteries and arterioles. There is evidence that deposition of exfoliation material within the vessel wall leads to increases in vascular resistance and decreases in blood flow, vascular dysregulation and altered parasympathetic vascular control.130 The tunica intima also contains an internal elastic lamina which if disrupted could increase the risk of atherosclerosis and thrombus formation. Interestingly, exfoliation and atherosclerosis also have in common oxidative stress and hyperhomocysteinuria. In smaller vessels (eg, within the optic nerve or vasa vasora or larger vessels), accumulation of exfoliation material could mechanically narrow the vessel lumen creating a tendency for occlusion and ischaemia.

    Although prevention of exfoliation and associated glaucoma is not yet a possibility, it is interesting that it was observed in the Reykjavik Eye Study, “… compared with those who consumed dietary fibre-rich vegetables, green or yellow vegetables, and fruit less than once a month in their 20s and 40s, those consuming the same food items once or twice every 2 weeks were found to be less likely to have XFS. The same applied to those consuming dietary fibre-rich foods once or twice every 2 weeks in their 40s and 60s.”131

    We suggest informing patients diagnosed with XFS that they may be at increased risk of cardiovascular and cerebrovascular diseases. It may also be prudent to have them follow-up with their general practitioner to discuss potential modifiable risk factors for heart disease and stroke.

    Future research questions

    Continued research in various areas is required to continue to develop an understanding of this disease which has important ocular and systemic associations.

    Further epidemiological studies of disease prevalence and incidence, which include standardised definitions of disease and appropriate sampling strategies, are required. These studies are necessary in order to understand population differences in disease prevalence (ie, racial, ethnic and geographical).

    There are certain aspects of the disease which remain enigmatic: why does angle-closure and/or glaucoma develop in certain individuals and not in others? Why is one eye often affected and not the other? Elucidating additional genetic and environmental factors important in disease pathophysiology is required. This understanding would offer additional insight into genotype–phenotype variations. Additionally, understanding the role of oxidative and other stressors and the modifications of factors to prevent disease would offer personalised care for patients.

    Nanotechnology and other approaches to improve understanding of how proteins/glycoproteins involved in XFS and XFG can be disrupted in order to prevent molecular assembly or break down particles may facilitate more effective cataract and glaucoma management.

    Further studies are also needed to optimise medical, laser and surgical management approaches to XFG. In particular, it would be helpful to know if early cataract surgery improves IOP control and alters the natural history of XFG. Additionally, for patients with early to moderate stage glaucoma, it would be helpful to know how effective and safe various types of microinvasive glaucoma surgeries are relative to each other as well as in comparison with trabeculectomy.

    If cardiovascular and cerebrovascular diseases are associated with XFS, understanding the clinical relevance and various modifiable risk factors to reduce morbidity associated with these conditions will be increasingly important.

    References

    1. ↵
      2. Lindberg JG
      . Clinical investigations on depigmentation of the pupillary border and translucency of the iris in cases of senile cataract and in normal eyes in elderly persons. Acta Ophthalmol Suppl 1989;190:1–96.
      OpenUrlPubMed
    2. ↵
      2. Tarkkanen A ,
      3. Kivelä T
      . Lindberg and the discovery of exfoliation syndrome. Acta Ophthalmol Scand 2002;80:151–4.doi:10.1034/j.1600-0420.2002.800206.x
      OpenUrlCrossRefPubMedWeb of Science
    3. ↵
      2. Lindberg JG
      . Kliniska undersökningar over depigmenteringen av pupillarranden och genomlysbarheten av iris vid fall av åldersstarr samt i normala ögon hos gamla personer: akademisk avhandling. Diss 1917.
    4. ↵
      2. Malling B
      . Untersuchungen über das verhältnis zwischen iridocyclitis und glaukom. Acta Ophthalmol 1923;1:215–31.doi:10.1111/j.1755-3768.1923.tb03148.x
      OpenUrl
    5. ↵
      2. Vogt A
      . Flaumige weisse pupillarsaum auflagerungen nach trepanation. Arch F Augenhk 1923;79:389–94.
      OpenUrl
    6. ↵
      2. Dvorak-Theobald G
      . Pseudo-exfoliation of the lens capsule: relation to true exfoliation of the lens capsule as reported in the literature and role in the production of glaucoma capsulocuticulare. Am J Ophthalmol 1954;37:1–12.
      OpenUrlPubMedWeb of Science
    7. ↵
      2. Ritch R
      . Exfoliation syndrome-the most common identifiable cause of open-angle glaucoma. J Glaucoma 1994;3:176–7.doi:10.1097/00061198-199400320-00018
      OpenUrlPubMed
    8. ↵
      2. Davis RE ,
      3. Schuman JS
      . Pseudoexfoliation syndrome: don’t brush it off. Br J Ophthalmol 2013;97:1091–2.doi:10.1136/bjophthalmol-2012-302417
      OpenUrlFREE Full Text
    9. ↵
      2. Streeten BW ,
      3. Li ZY ,
      4. Wallace RN , et al
      . Pseudoexfoliative fibrillopathy in visceral organs of a patient with pseudoexfoliation syndrome. Arch Ophthalmol 1992;110:1757–62.doi:10.1001/archopht.1992.01080240097039
      OpenUrlCrossRefPubMedWeb of Science
    10. ↵
      2. Schlötzer-Schrehardt UM ,
      3. Koca MR ,
      4. Naumann GO , et al
      . Pseudoexfoliation syndrome. Ocular manifestation of a systemic disorder? Arch Ophthalmol 1992;110:1752–6.doi:10.1001/archopht.1992.01080240092038
      OpenUrlCrossRefPubMedWeb of Science
    11. ↵
      2. Bettis DI ,
      3. Allingham RR ,
      4. Wirostko BM
      . Systemic diseases associated with exfoliation syndrome. Int Ophthalmol Clin 2014;54:15–28.doi:10.1097/IIO.0000000000000044
      OpenUrl
    12. ↵
      2. Kang JH ,
      3. Loomis S ,
      4. Wiggs JL , et al
      . Demographic and geographic features of exfoliation glaucoma in 2 United States-based prospective cohorts. Ophthalmology 2012;119:27–35.doi:10.1016/j.ophtha.2011.06.018
      OpenUrlCrossRefPubMedWeb of Science
    13. ↵
      2. Belovay GW ,
      3. Varma DK ,
      4. Ahmed IIK
      . Cataract surgery in pseudoexfoliation syndrome. Curr Opin Ophthalmol 2010;21:25–34.doi:10.1097/ICU.0b013e328332f814
      OpenUrlCrossRefPubMed
    14. ↵
      2. You QS ,
      3. Xu L ,
      4. Wang YX , et al
      . Pseudoexfoliation: normative data and associations: the Beijing eye study 2011. Ophthalmology 2013;120:1551–8.
      OpenUrl
    15. ↵
      2. Aasved H
      . The geographical distribution of fibrillopathia epitheliocapsularis, so-called senile exfoliation or pseudoexfoliation of the anterior lens capsule. Acta Ophthalmol 1969;47:792–810.
      OpenUrlPubMed
    16. ↵
      2. Ritch R
      . Ocular and systemic manifestations of exfoliation syndrome. J Glaucoma 2014;23:S1–S8.doi:10.1097/IJG.0000000000000119
      OpenUrl
    17. ↵
      2. Forsius H
      . Prevalence of pseudoexfoliation of the lens in Finns, Lapps, Icelanders, Eskimos, and Russians. Trans Ophthalmol Soc U K 1979;99:296–8.
      OpenUrlPubMedWeb of Science
    18. ↵
      2. Åström S ,
      3. Lindén C
      . Incidence and prevalence of pseudoexfoliation and open-angle glaucoma in northern Sweden: I. Baseline report. Acta Ophthalmol Scand 2007;85:828–31.doi:10.1111/j.1600-0420.2007.00992.x
      OpenUrlCrossRefPubMedWeb of Science
    19. ↵
      2. Hirvelä H ,
      3. Luukinen H ,
      4. Laatikainen L
      . Prevalence and risk factors of lens opacities in the elderly in Finland. A population-based study. Ophthalmology 1995;102:108–17.
      OpenUrlPubMedWeb of Science
    20. ↵
      2. Arnarsson A ,
      3. Damji KF ,
      4. Sverrisson T , et al
      . Pseudoexfoliation in the Reykjavik eye study: prevalence and related ophthalmological variables. Acta Ophthalmol Scand 2007;85:822–7.doi:10.1111/j.1600-0420.2007.01051.x
      OpenUrlCrossRefPubMedWeb of Science
    21. ↵
      2. Arnarsson A
      . Epidemiology of exfoliation syndrome in the Reykjavik Eye Study. Acta Ophthalmol 2009;87:1–17.doi:10.1111/j.1755-3768.2009.01806.x
      OpenUrl
    22. ↵
      2. Challa P
      . Genetics of pseudoexfoliation syndrome. Curr Opin Ophthalmol 2009;20:88–91.doi:10.1097/ICU.0b013e328320d86a
      OpenUrlCrossRefPubMedWeb of Science
    23. ↵
      2. Cashwell LF ,
      3. Shields MB
      . Exfoliation syndrome in the southeastern United States. I. Prevalence in open-angle glaucoma and non-glaucoma populations. Acta Ophthalmol Suppl 1988;184:99–102.doi:10.1111/j.1755-3768.1988.tb02637.x
      OpenUrlPubMed
    24. ↵
      2. Faulkner HW
      . Pseudo-exfoliation of the lens among the Navajo Indians. Am J Ophthalmol 1971;72:206–7.doi:10.1016/0002-9394(71)91616-3
      OpenUrlPubMedWeb of Science
    25. ↵
      2. Bedri A ,
      3. Alemu B
      . Pseudoexfoliation syndrome in Ethiopian glaucoma patients. East Afr Med J 1999;76:278–80.
      OpenUrlPubMed
    26. ↵
      2. Olawoye OO ,
      3. Pasquale LR ,
      4. Ritch R
      . Exfoliation syndrome in sub-Saharan Africa. Int Ophthalmol 2014;34:1165–73.doi:10.1007/s10792-014-9953-5
      OpenUrl
    27. ↵
      2. Luntz MH
      . Prevalence of pseudo-exfoliation syndrome in an urban south african clinic population. Am J Ophthalmol 1972;74:581–7.doi:10.1016/0002-9394(72)90816-1
      OpenUrlPubMedWeb of Science
    28. ↵
      2. Ball SF ,
      3. Graham S ,
      4. Thompson H
      . The racial prevalence and biomicroscopic signs of exfoliative syndrome in the glaucoma population of southern Louisiana. Glaucoma 1989;11:169–75.
      OpenUrl
    29. ↵
      2. Jonas JB ,
      3. Nangia V ,
      4. Matin A , et al
      . Pseudoexfoliation: normative data and associations. the central india eye and medical study. PLoS One 2013;8:e76770.doi:10.1371/journal.pone.0076770
    30. ↵
      2. Kim S ,
      3. Lim S-H ,
      4. Sung KR , et al
      . Prevalence of pseudoexfoliation syndrome and associated factors in south koreans: the korean national health and nutrition examination survey. Ophthalmic Epidemiol 2016;23:298–302.doi:10.3109/09286586.2015.1131992
      OpenUrl
    31. ↵
      2. Rao RQ ,
      3. Arain TM ,
      4. Ahad MA
      . The prevalence of pseudoexfoliation syndrome in Pakistan. Hospital based study. BMC Ophthalmol 2006;6:27.doi:10.1186/1471-2415-6-27
      OpenUrlCrossRefPubMed
    32. ↵
      2. Miyazaki M ,
      3. Kubota T ,
      4. Kubo M , et al
      . The prevalence of pseudoexfoliation syndrome in a japanese population. J Glaucoma 2005;14:482–4.doi:10.1097/01.ijg.0000185436.15675.b3
      OpenUrlCrossRefPubMedWeb of Science
    33. ↵
      2. Shazly TA ,
      3. Farrag AN ,
      4. Kamel A , et al
      . Prevalence of pseudoexfoliation syndrome and pseudoexfoliation glaucoma in upper Egypt. BMC Ophthalmol 2011;11:18.doi:10.1186/1471-2415-11-18
      OpenUrlPubMed
    34. ↵
      2. Yildirim N ,
      3. Yasar E ,
      4. Gursoy H , et al
      . Prevalence of pseudoexfoliation syndrome and its association with ocular and systemic diseases in Eskisehir, Turkey. International journal of ophthalmology 2017;10:128.
      OpenUrl
    35. ↵
      2. Summanen P ,
      3. Tönjum AM
      . Exfoliation syndrome among Saudis. Acta Ophthalmol 1988;66:107–11.doi:10.1111/j.1755-3768.1988.tb02639.x
      OpenUrl
    36. ↵
      2. Mitchell P ,
      3. Wang JJ ,
      4. Hourihan F
      . The relationship between glaucoma and pseudoexfoliation: the Blue Mountains Eye Study. Arch Ophthalmol 1999;117:1319–24.
      OpenUrlCrossRefPubMedWeb of Science
    37. ↵
      2. Elhawy E ,
      3. Kamthan G ,
      4. Dong CQ , et al
      . Pseudoexfoliation syndrome, a systemic disorder with ocular manifestations. Hum Genomics 2012;6:22.doi:10.1186/1479-7364-6-22
      OpenUrlCrossRefPubMed
    38. ↵
      2. Zenkel M ,
      3. Schlötzer-Schrehardt U
      . The composition of exfoliation material and the cells involved in its production. J Glaucoma 2014;23:S12–4.doi:10.1097/IJG.0000000000000123
      OpenUrl
    39. ↵
      2. Ritch R ,
      3. Prata TS ,
      4. de Moraes CGV , et al
      . Association of exfoliation syndrome and central retinal vein occlusion: an ultrastructural analysis. Acta Ophthalmol 2010;88:91–5.doi:10.1111/j.1755-3768.2009.01578.x
      OpenUrlCrossRefPubMed
    40. ↵
      2. Ziai Gharagozloo N ,
      3. Baker RH ,
      4. Brubaker RF
      . Aqueous dynamics in exfoliation syndrome. Am J Ophthalmol 1992;114:473–8.doi:10.1016/S0002-9394(14)71860-4
      OpenUrlPubMedWeb of Science
    41. ↵
      2. Schlötzer-Schrehardt U ,
      3. Naumann GO
      . Trabecular meshwork in pseudoexfoliation syndrome with and without open-angle glaucoma. A morphometric, ultrastructural study. Invest Ophthalmol Vis Sci 1995;36:1750–64.
      OpenUrlAbstract/FREE Full Text
    42. ↵
      2. Krishnadas R ,
      3. Nirmalan PK ,
      4. Ramakrishnan R , et al
      . Pseudoexfoliation in a rural population of southern India: the aravind comprehensive eye survey. Am J Ophthalmol 2003;135:830–7.doi:10.1016/S0002-9394(02)02271-7
      OpenUrlCrossRefPubMedWeb of Science
    43. ↵
      2. Thomas R ,
      3. Nirmalan PK ,
      4. Krishnaiah S
      . Pseudoexfoliation in Southern India: the andhra pradesh eye disease study. Investigative Opthalmology & Visual Science 2005;46:1170–6.doi:10.1167/iovs.04-1062
      OpenUrl
    44. ↵
      2. Anastasopoulos E ,
      3. Topouzis F ,
      4. Wilson MR , et al
      . Characteristics of pseudoexfoliation in the thessaloniki eye study. J Glaucoma 2011;20:160–6.doi:10.1097/IJG.0b013e3181d9d8bd
      OpenUrlCrossRefPubMedWeb of Science
    45. ↵
      2. Kanthan GL ,
      3. Mitchell P ,
      4. Burlutsky G , et al
      . Pseudoexfoliation syndrome and the long-term incidence of cataract and cataract surgery: the blue mountains eye study. Am J Ophthalmol 2013;155:83–8.doi:10.1016/j.ajo.2012.07.002
      OpenUrlCrossRefPubMed
    46. ↵
      2. Küchle M ,
      3. Nguyen NX ,
      4. Hannappel E , et al
      . The blood-aqueous barrier in eyes with pseudoexfoliation syndrome. Ophthalmic Res 1995;27 (Suppl 1):136–42.doi:10.1159/000267859
      OpenUrl
    47. ↵
      2. Ritch R ,
      3. Schlötzer-Schrehardt U
      . Exfoliation syndrome. Surv Ophthalmol 2001;45:265–315.doi:10.1016/S0039-6257(00)00196-X
      OpenUrlCrossRefPubMedWeb of Science
    48. ↵
      2. Conway RM ,
      3. Schlotzer-Schrehardt U ,
      4. Kuchle M , et al
      . Pseudoexfoliation syndrome: pathological manifestations of relevance to intraocular surgery. Clinical and Experimental Ophthalmology 2004;32:199–210.doi:10.1111/j.1442-9071.2004.00806.x
      OpenUrlCrossRefPubMedWeb of Science
    49. ↵
      2. Mohammed S ,
      3. Kazmi N
      . Subluxation of the lens and ocular hypertension in exfoliation syndrome. Pak J Ophthalmol 1986;2:77–8.
      OpenUrl
    50. ↵
      2. Chijiiwa T ,
      3. Araki H ,
      4. Ishibashi T , et al
      . Degeneration of zonular fibrils in a case of exfoliation glaucoma. Ophthalmologica 1989;199:16–23.doi:10.1159/000310008
      OpenUrlPubMedWeb of Science
    51. ↵
      2. Dark AJ ,
      3. Streeten BW ,
      4. Cornwall CC
      . Pseudoexfoliative disease of the lens: a study in electron microscopy and histochemistry. Br J Ophthalmol 1977;61:462–72.doi:10.1136/bjo.61.7.462
      OpenUrlAbstract/FREE Full Text
    52. ↵
      2. Küchle M ,
      3. Viestenz A ,
      4. Martus P , et al
      . Anterior chamber depth and complications during cataract surgery in eyes with pseudoexfoliation syndrome. Am J Ophthalmol 2000;129:281–5.doi:10.1016/S0002-9394(99)00365-7
      OpenUrlCrossRefPubMed
    53. ↵
      2. Lippe I ,
      3. Küchle M ,
      4. Naumann GOH
      . Pseudoexfoliation syndrome as a risk factor for acute ciliary block angle closure glaucoma. Acta Ophthalmol 1993;71:277–9.doi:10.1111/j.1755-3768.1993.tb05004.x
      OpenUrlPubMed
    54. ↵
      2. Thorleifsson G ,
      3. Magnusson KP ,
      4. Sulem P , et al
      . Common sequence variants in the loxl1 gene confer susceptibility to exfoliation glaucoma. Science 2007;317:1397–400.doi:10.1126/science.1146554
      OpenUrlAbstract/FREE Full Text
    55. ↵
      2. Wang L ,
      3. Yu Y ,
      4. Fu S , et al
      . LOXL1 Gene Polymorphism With Exfoliation Syndrome/Exfoliation Glaucoma. J Glaucoma 2016;25:62–94.doi:10.1097/IJG.0000000000000128
      OpenUrl
    56. ↵
      2. Founti P ,
      3. Haidich A-B ,
      4. Chatzikyriakidou A , et al
      . Ethnicity-Based differences in the Association of LOXL1 Polymorphisms with pseudoexfoliation/pseudoexfoliative glaucoma: a meta-analysis. Ann Hum Genet 2015;79:431–50.doi:10.1111/ahg.12128
      OpenUrl
    57. ↵
      2. Chen H ,
      3. Chen LJ ,
      4. Zhang M , et al
      . Ethnicity-based subgroup meta-analysis of the association of LOXL1 polymorphisms with glaucoma. Mol Vis 2010;16:167–77.
      OpenUrlPubMed
    58. ↵
      2. Tang JZ ,
      3. Wang XQ ,
      4. Ma HF , et al
      . Association between polymorphisms in lysyl oxidase-like 1 and susceptibility to pseudoexfoliation syndrome and pseudoexfoliation glaucoma. PLoS One 2014;9:e90331.doi:10.1371/journal.pone.0090331
    59. ↵
      2. Xiao Q ,
      3. Ge G
      . Lysyl oxidase, extracellular matrix remodeling and cancer metastasis. Cancer Microenviron 2012;5:261–73.doi:10.1007/s12307-012-0105-z
      OpenUrlCrossRefPubMed
    60. ↵
      2. Aung T ,
      3. Ozaki M ,
      4. Mizoguchi T , et al
      . A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome. Nat Genet 2015;47:387–92.doi:10.1038/ng.3226
      OpenUrlCrossRefPubMed
    61. ↵
      2. Aung T ,
      3. Ozaki M ,
      4. Lee MC , et al
      . Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci. Nat Genet 2017;49:993–1004.doi:10.1038/ng.3875
      OpenUrl
    62. ↵
      2. Aboobakar IF ,
      3. Allingham RR
      . Genetics of exfoliation syndrome and glaucoma. Int Ophthalmol Clin 2014;54:43–56.doi:10.1097/IIO.0000000000000042
      OpenUrl
    63. ↵
      2. Stein JD , et al
      . Geographic and climatic factors associated with exfoliation syndrome. Arch Ophthal 2011;129:1053–60.doi:10.1001/archophthalmol.2011.191
      OpenUrlCrossRefPubMedWeb of Science
    64. ↵
      2. Pasquale LR ,
      3. Jiwani AZ ,
      4. Zehavi-Dorin T , et al
      . Solar exposure and residential geographic history in relation to exfoliation syndrome in the United States and Israel. JAMA Ophthalmol 2014;132:1439–45.doi:10.1001/jamaophthalmol.2014.3326
      OpenUrl
    65. ↵
      2. Jiwani AZ ,
      3. Pasquale LR ,
      4. Syndrome E
      . and Solar Exposure: New Epidemiological Insights into the Pathophysiology of the Disease. International ophthalmology clinics 2015;55:13–22.
      OpenUrl
    66. ↵
      2. Lee RK
      . The molecular pathophysiology of pseudoexfoliation glaucoma. Curr Opin Ophthalmol 2008;19:95–101.doi:10.1097/ICU.0b013e3282f49cda
      OpenUrlCrossRefPubMedWeb of Science
    67. ↵
      2. Xu F ,
      3. Zhang L ,
      4. Li M
      . Plasma homocysteine, serum folic acid, serum vitamin B12, serum vitamin B6, MTHFR and risk of pseudoexfoliation glaucoma: a meta-analysis. Graefes Arch Clin Exp Ophthalmol 2012;250:1067–74.doi:10.1007/s00417-011-1877-4
      OpenUrlCrossRefPubMed
    68. ↵
      2. Pasquale LR ,
      3. Wiggs JL ,
      4. Willett WC , et al
      . The relationship between caffeine and coffee consumption and exfoliation glaucoma or glaucoma suspect: a prospective study in two cohorts. Investigative Opthalmology & Visual Science 2012;53:6427–33.doi:10.1167/iovs.12-10085
      OpenUrl
    69. ↵
      2. Vesti E ,
      3. Kivelä T
      . Exfoliation syndrome and exfoliation glaucoma. Prog Retin Eye Res 2000;19:345–68.doi:10.1016/S1350-9462(99)00019-1
      OpenUrlCrossRefPubMedWeb of Science
    70. ↵
      2. Ritch R
      . Exfoliation syndrome and occludable angles. Trans Am Opthalmol Soc 1994;92:845–944.
      OpenUrl
    71. ↵
      2. Layden WE ,
      3. Shaffer RN
      . Exfoliation syndrome. Am J Ophthalmol 1974;78:835–41.doi:10.1016/0002-9394(74)90307-9
      OpenUrlCrossRefPubMedWeb of Science
    72. ↵
      2. Shihadeh WA ,
      3. Ritch R ,
      4. Scharf B , et al
      . Delayed intraocular pressure elevation after pupillary dilation in exfoliation syndrome. Acta Ophthalmol 2011;89:560–2.doi:10.1111/j.1755-3768.2009.01744.x
      OpenUrlPubMed
    73. ↵
      2. Anastasopoulos E ,
      3. Founti P ,
      4. Topouzis F
      . Update on pseudoexfoliation syndrome pathogenesis and associations with intraocular pressure, glaucoma and systemic diseases. Curr Opin Ophthalmol 2015;26:82–9.doi:10.1097/ICU.0000000000000132
      OpenUrl
    74. ↵
      2. Bengtsson B ,
      3. Heijl A
      . A long-term prospective study of risk factors for glaucomatous visual field loss in patients with ocular hypertension. J Glaucoma 2005;14:135–8.doi:10.1097/01.ijg.0000151683.04410.f3
      OpenUrlCrossRefPubMedWeb of Science
    75. ↵
      2. Leske MC ,
      3. Heijl A ,
      4. Hyman L , et al
      . Predictors of long-term progression in the early manifest glaucoma trial. Ophthalmology 2007;114:1965–72.doi:10.1016/j.ophtha.2007.03.016
      OpenUrlCrossRefPubMedWeb of Science
    76. ↵
      2. Leske MC ,
      3. Heijl A ,
      4. Hussein M , et al
      . Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial. Arch Ophthalmol 2003;121:48–56.
      OpenUrlCrossRefPubMedWeb of Science
    77. ↵
      2. Heijl A ,
      3. Bengtsson B ,
      4. Hyman L , et al
      . Natural history of open-angle glaucoma. Ophthalmology 2009;116:2271–6.doi:10.1016/j.ophtha.2009.06.042
      OpenUrlCrossRefPubMedWeb of Science
    78. ↵
      2. Hyman L , et al
      . Natural history of intraocular pressure in the early manifest glaucoma trial. Arch Ophthal 2010;128:601–7.doi:10.1001/archophthalmol.2010.78
      OpenUrlCrossRefPubMed
    79. ↵
      2. Puska P ,
      3. Vesti E ,
      4. Tomita G , et al
      . Optic disc changes in normotensive persons with unilateral exfoliation syndrome: a 3-year follow-up study. Graefes Arch Clin Exp Ophthalmol 1999;237:457–62.doi:10.1007/s004170050261
      OpenUrlCrossRefPubMedWeb of Science
    80. ↵
      2. Nucci C ,
      3. Cerulli L ,
      4. Osborne NN , et al
      . Glaucoma: an open-window to neurodegeneration and neuroprotection. Newnes 2008.
    81. ↵
      2. Wishart PK ,
      3. Spaeth GL ,
      4. Poryzees EM
      . Anterior chamber angle in the exfoliation syndrome. Br J Ophthalmol 1985;69:103–7.doi:10.1136/bjo.69.2.103
      OpenUrlAbstract/FREE Full Text
    82. ↵
      2. Gross FJ ,
      3. Tingey D ,
      4. Epstein DL
      . Increased prevalence of occludable angles and angle-closure glaucoma in patients with pseudoexfoliation. Am J Ophthalmol 1994;117:333–6.doi:10.1016/S0002-9394(14)73141-1
      OpenUrlCrossRefPubMedWeb of Science
    83. ↵
      2. Prum BE ,
      3. Rosenberg LF ,
      4. Gedde SJ , et al
      . Primary open-angle glaucoma preferred practice pattern(®) guidelines. Ophthalmology 2016;123:P41–P111.doi:10.1016/j.ophtha.2015.10.053
      OpenUrl
    84. ↵
      2. Konstas AGP ,
      3. Koliakos GG ,
      4. Karabatsas CH , et al
      . Latanoprost therapy reduces the levels of TGF beta 1 and gelatinases in the aqueous humour of patients with exfoliative glaucoma. Exp Eye Res 2006;82:319–22.doi:10.1016/j.exer.2005.07.004
      OpenUrlCrossRefPubMedWeb of Science
    85. ↵
      2. Konstas AG ,
      3. Hollo G ,
      4. Astakhov YS , et al
      . Factors associated with long-term progression or stability in exfoliation glaucoma. Arch Ophthalmol 2004;122:29–33.doi:10.1001/archopht.122.1.29
      OpenUrlCrossRefPubMed
    86. ↵
      2. Konstas AGP ,
      3. Hollo G ,
      4. Irkec M , et al
      . Diurnal IOP control with bimatoprost versus latanoprost in exfoliative glaucoma: a crossover, observer-masked, three-centre study. Br J Ophthalmol 2007;91:757–60.doi:10.1136/bjo.2006.106690
      OpenUrlAbstract/FREE Full Text
    87. ↵
      2. Konstas AGP ,
      3. Kozobolis VP ,
      4. Katsimpris IE , et al
      . Efficacy and safety of latanoprost versus travoprost in exfoliative glaucoma patients. Ophthalmology 2007;114:653–7.doi:10.1016/j.ophtha.2006.07.064
      OpenUrlCrossRefPubMedWeb of Science
    88. ↵
      2. Aasved H ,
      3. Seland JH ,
      4. Slagsvold J
      . Timolol maleate in treatment of open angle glaucoma. Acta Ophthalmol 1979;57:700–8.doi:10.1111/j.1755-3768.1979.tb00519.x
      OpenUrlPubMed
    89. ↵
      2. Takki KK ,
      3. Klemetti A ,
      4. Valle O
      . The IOP-lowering effect of timolol in simple and capsular glaucoma. A multicenter study in Finland. Clin Exp Ophthalmol 1982;218:83–7.
      OpenUrl
    90. ↵
      2. Konstas AGP , et al
      . Effect of timolol on the diurnal intraocular pressure in exfoliation and primary open-angle glaucoma. Arch Ophthal 1997;115:975–9.doi:10.1001/archopht.1997.01100160145002
      OpenUrlCrossRefPubMedWeb of Science
    91. ↵
      2. Konstas AGP ,
      3. Mylopoulos N ,
      4. Karabatsas CH , et al
      . Diurnal intraocular pressure reduction with latanoprost 0.005% compared to timolol maleate 0.5% as monotherapy in subjects with exfoliation glaucoma. Eye 2004;18:893–9.doi:10.1038/sj.eye.6701345
      OpenUrlCrossRefPubMedWeb of Science
    92. ↵
      2. Angelilli A ,
      3. Ritch R ,
      4. Krupin T
      . The International Collaboration Exfoliation Syndrome Treatment (ICEST) study results. Presented at the annual meeting of the association for research in vision and ophthalmology. Fort Lauderdale, FL., 2009.
    93. ↵
      2. Koucheki B ,
      3. Hashemi H
      . Selective laser trabeculoplasty in the treatment of open-angle glaucoma. J Glaucoma 2012;21:65–70.doi:10.1097/IJG.0b013e3182027596
      OpenUrlPubMed
    94. ↵
      2. Kent SS ,
      3. Hutnik CML ,
      4. Birt CM , et al
      . A randomized clinical trial of selective laser trabeculoplasty versus argon laser trabeculoplasty in patients with pseudoexfoliation. J Glaucoma 2015;24:344–7.doi:10.1097/IJG.0b013e31829e55e4
      OpenUrl
    95. ↵
      2. Bergeå B ,
      3. Bodin L ,
      4. Svedbergh B
      . Primary argon laser trabeculoplasty vs pilocarpine. Acta Ophthalmol Scand 1995;73:216–21.doi:10.1111/j.1600-0420.1995.tb00271.x
      OpenUrlPubMed
    96. ↵
      2. Bergeå B ,
      3. Bodin L ,
      4. Svedbergh B
      . Primary argon laser trabeculoplasty vs pilocarpine II: Long-term effects on intraocular pressure and facility of outflow. Acta Ophthalmol 1994;72:145–54.doi:10.1111/j.1755-3768.1994.tb05008.x
      OpenUrlPubMed
    97. ↵
      2. Ritch R ,
      3. Podos S
      . Laser trabeculoplasty in the exfoliation syndrome. Bull N Y Acad Med 1983;59:339–44.
      OpenUrlPubMedWeb of Science
    98. ↵
      2. Spaeth GL ,
      3. Baez KA
      . Argon laser trabeculoplasty controls one third of cases of progressive, uncontrolled, open angle glaucoma for 5 years. Arch Ophthal 1992;110:491–4.doi:10.1001/archopht.1992.01080160069032
      OpenUrlCrossRefPubMedWeb of Science
    99. ↵
      2. Kent SS ,
      3. Hutnik CM ,
      4. Birt CM , et al
      . A randomized clinical trial of selective laser trabeculoplasty versus argon laser trabeculoplasty in patients with pseudoexfoliation. J Glaucoma 2015;24:344–7.doi:10.1097/IJG.0b013e31829e55e4
      OpenUrl
    100. ↵
      2. Bettis DI ,
      3. Whitehead JJ ,
      4. Farhi P , et al
      . Intraocular pressure spike and corneal decompensation following selective laser trabeculoplasty in patients with exfoliation glaucoma. J Glaucoma 2016;25:e433–7.doi:10.1097/IJG.0000000000000340
      OpenUrl
    101. ↵
      2. Desai MA ,
      3. Lee RK
      . The medical and surgical management of pseudoexfoliation glaucoma. Int Ophthalmol Clin 2008;48:95–113.doi:10.1097/IIO.0b013e318187e902
      OpenUrlPubMed
    102. ↵
      2. Gedde SJ ,
      3. Herndon LW ,
      4. Brandt JD , et al
      . Surgical complications in the Tube Versus Trabeculectomy Study during the first year of follow-up. Am J Ophthalmol 2007;143:23–31.doi:10.1016/j.ajo.2006.07.022
      OpenUrlCrossRefPubMedWeb of Science
    103. ↵
      2. Gedde SJ ,
      3. Schiffman JC ,
      4. Feuer WJ , et al
      . Treatment outcomes in the tube versus trabeculectomy study after one year of follow-up. Am J Ophthalmol 2007;143:9–22.doi:10.1016/j.ajo.2006.07.020
      OpenUrlCrossRefPubMedWeb of Science
    104. ↵
      2. Tanihara H ,
      3. Negi A ,
      4. Akimoto M , et al
      . Surgical effects of trabeculotomy ab externo on adult eyes with primary open angle glaucoma and pseudoexfoliation syndrome. Arch Ophthalmol 1993;111:1653–61.doi:10.1001/archopht.1993.01090120075025
      OpenUrlCrossRefPubMedWeb of Science
    105. ↵
      2. Jacobi PC ,
      3. Krieglstein GK
      . Trabecular aspiration: a new surgical approach to improve trabecular facility in pseudoexfoliation glaucoma. Int Ophthalmol 1994;18:153–7.doi:10.1007/BF00915964
      OpenUrlPubMed
    106. ↵
      2. Jacobi PC ,
      3. Dietlein TS ,
      4. Krieglstein GK
      . Bimanual trabecular aspiration in pseudoexfoliation glaucoma: an alternative in nonfiltering glaucoma surgery. Ophthalmology 1998;105:886–94.doi:10.1016/S0161-6420(98)95032-1
      OpenUrlCrossRefPubMed
    107. ↵
      2. Widder RA ,
      3. Dinslage S ,
      4. Rosentreter A , et al
      . A new surgical triple procedure in pseudoexfoliation glaucoma using cataract surgery, Trabectome, and trabecular aspiration. Graefes Arch Clin Exp Ophthalmol 2014;252:1971–5.doi:10.1007/s00417-014-2795-z
      OpenUrlCrossRefPubMed
    108. ↵
      2. Klamann MK ,
      3. Gonnermann J ,
      4. Maier AK , et al
      . Combined clear cornea phacoemulsification in the treatment of pseudoexfoliative glaucoma associated with cataract: significance of trabecular aspiration and ab interno trabeculectomy. Graefes Arch Clin Exp Ophthalmol 2013;251:2195–9.doi:10.1007/s00417-013-2408-2
      OpenUrlCrossRefPubMed
    109. ↵
      2. Ting JL ,
      3. Damji KF ,
      4. Stiles MC
      . Trabectome Study Group. Ab interno trabeculectomy: outcomes in exfoliation versus primary open-angle glaucoma. J Cataract Refract Surg 2012;38:315–23.doi:10.1016/j.jcrs.2011.08.043
      OpenUrlCrossRefPubMed
    110. ↵
      2. Klamann MK ,
      3. Gonnermann J ,
      4. Pahlitzsch M , et al
      . iStent inject in phakic open angle glaucoma. Graefes Arch Clin Exp Ophthalmol 2015;253:941–7.doi:10.1007/s00417-015-3014-2
      OpenUrl
    111. ↵
      2. Holló G ,
      3. Katsanos A ,
      4. Konstas AG
      . Management of exfoliative glaucoma: challenges and solutions. Clin Ophthalmol 2015;9:907.doi:10.2147/OPTH.S77570
      OpenUrl
    112. ↵
      2. Drolsum L
      . Deep sclerectomy in patients with capsular glaucoma. Acta Ophthalmol Scand 2003;81:567–72.doi:10.1111/j.1395-3907.2003.00186.x
      OpenUrlPubMed
    113. ↵
      2. Ambresin A ,
      3. Shaarawy T ,
      4. Mermoud A
      . Deep sclerectomy with collagen implant in one eye compared with trabeculectomy in the other eye of the same patient. J Glaucoma 2002;11:214–20.doi:10.1097/00061198-200206000-00009
      OpenUrlCrossRefPubMedWeb of Science
    114. ↵
      2. Mendrinos E ,
      3. Mansouri K ,
      4. Mermoud A , et al
      . Long-term results of deep sclerectomy with collagen implant in exfoliative glaucoma. J Glaucoma 2009;18:361–7.doi:10.1097/IJG.0b013e3181879e4e
      OpenUrlPubMed
    115. ↵
      2. Francis BA ,
      3. Kwon J ,
      4. Fellman R , et al
      . Endoscopic ophthalmic surgery of the anterior segment. Surv Ophthalmol 2014;59:217–31.doi:10.1016/j.survophthal.2013.03.010
      OpenUrl
    116. ↵
      2. Wong AL ,
      3. Chan TC ,
      4. Fong AH , et al
      . Clinical characteristics and surgical outcomes of phacoemulsification in true exfoliation syndrome. J Cataract Refract Surg 2014;40:82–6.doi:10.1016/j.jcrs.2013.06.022
      OpenUrl
    117. ↵
      2. Guzek JP ,
      3. Holm M ,
      4. Cotter JB , et al
      . Risk factors for intraoperative complications in 1000 extracapsular cataract cases. Ophthalmology 1987;94:461–6.doi:10.1016/S0161-6420(87)33424-4
      OpenUrlPubMedWeb of Science
    118. ↵
      2. Moreno-Montañés J ,
      3. Rodriguez-Conde R
      . Capsular tension ring in eyes with pseudoexfoliation. J Cataract Refract Surg 2002;28:2241–2.doi:10.1016/S0886-3350(02)01901-6
      OpenUrlPubMed
    119. ↵
      2. Akarsu C ,
      3. Unal B
      . Cerebral haemodynamics in patients with pseudoexfoliation glaucoma. Eye 2005;19:1297–300.doi:10.1038/sj.eye.6701776
      OpenUrlCrossRefPubMed
    120. ↵
      2. Visontai Z ,
      3. Merisch B ,
      4. Kollai M , et al
      . Increase of carotid artery stiffness and decrease of baroreflex sensitivity in exfoliation syndrome and glaucoma. Br J Ophthalmol 2006;90:563–7.doi:10.1136/bjo.2005.087908
      OpenUrlAbstract/FREE Full Text
    121. ↵
      2. Naji M ,
      3. Naji F ,
      4. Suran D , et al
      . [Systemic endothelial dysfunction in patients with pseudoexfoliation syndrome]. Klin Monbl Augenheilkd 2008;225:963–7.doi:10.1055/s-2008-1027633
      OpenUrlCrossRefPubMed
    122. ↵
      2. Wang W ,
      3. He M ,
      4. Zhou M , et al
      . Ocular pseudoexfoliation syndrome and vascular disease: a systematic review and meta-analysis. PLoS One 2014;9:e92767.doi:10.1371/journal.pone.0092767
    123. ↵
      2. Chung H ,
      3. Arora S ,
      4. Damji KF , et al
      . Association of pseudoexfoliation syndrome with cardiovascular and cerebrovascular disease: a systematic review and meta-analysis. Canadian Journal of Ophthalmology 2017.doi:10.1016/j.jcjo.2017.10.039
    124. ↵
      2. Holló G ,
      3. Gál A ,
      4. Kóthy P , et al
      . LOXL1 gene sequence variants and vascular disease in exfoliation syndrome and exfoliative glaucoma. J Glaucoma 2011;20:143–7.doi:10.1097/IJG.0b013e3181d9d8dd
      OpenUrlPubMed
    125. ↵
      2. Aström S ,
      3. Stenlund H ,
      4. Lindén C
      . Incidence and prevalence of pseudoexfoliations and open-angle glaucoma in northern Sweden: II. Results after 21 years of follow-up. Acta Ophthalmol Scand 2007;85:832–7.doi:10.1111/j.1600-0420.2007.00980.x
      OpenUrlPubMed
    126. ↵
      2. Ringvold A ,
      3. Blika S ,
      4. Sandvik L
      . Pseudo-exfoliation and mortality. Acta Ophthalmol Scand 1997;75:255–6.doi:10.1111/j.1600-0420.1997.tb00767.x
      OpenUrlPubMedWeb of Science
    127. ↵
      2. Shrum KR ,
      3. Hattenhauer MG ,
      4. Hodge D
      . Cardiovascular and cerebrovascular mortality associated with ocular pseudoexfoliation. Am J Ophthalmol 2000;129:83–6.doi:10.1016/S0002-9394(99)00255-X
      OpenUrlCrossRefPubMedWeb of Science
    128. ↵
      2. Svensson R ,
      3. Ekström C
      . Pseudoexfoliation and mortality: a population-based 30-year follow-up study. Acta Ophthalmol 2015;93:162–4.doi:10.1111/aos.12402
      OpenUrl
    129. ↵
      2. Tarkkanen A
      . Is exfoliation syndrome a sign of systemic vascular disease? Acta Ophthalmol 2008;86:832–6.doi:10.1111/j.1755-3768.2008.01464.x
      OpenUrlCrossRefPubMed
    130. ↵
      2. Andrikopoulos GK ,
      3. Alexopoulos DK ,
      4. Gartaganis SP
      . Pseudoexfoliation syndrome and cardiovascular diseases. World J Cardiol 2014;6:847–54.doi:10.4330/wjc.v6.i8.847
      OpenUrl
    131. ↵
      2. Arnarsson A ,
      3. Jonasson F ,
      4. Damji KF , et al
      . Exfoliation syndrome in the reykjavik eye study: risk factors for baseline prevalence and 5-year incidence. Br J Ophthalmol 2010;94:831–5.doi:10.1136/bjo.2009.157636
      OpenUrlAbstract/FREE Full Text
    132. ↵
      2. Manalil AG ,
      3. Mishra P ,
      4. S M , et al
      . CAtaract surgery in pseudoexfoliation syndrome. Journal of Evolution of Medical and Dental Sciences 2014;3:12403–10.doi:10.14260/jemds/2014/3642
      OpenUrl
    133. ↵
      2. Tanhehco T ,
      3. Chen SH
      . Pseudoexfoliation syndrome and cataract surgery. Int Ophthalmol Clin 2010;50:81–93.doi:10.1097/IIO.0b013e3181c5719c
      OpenUrlPubMed
    134. ↵
      2. Kaštelan S ,
      3. Tomić M ,
      4. Kordić R , et al
      . Cataract surgery in eyes with pseudoexfoliation (PEX) syndrome. J Clinic Experiment Ophthalmol 2013:1–9.
    135. ↵
      2. Fontana L ,
      3. Coassin M ,
      4. Iovieno A , et al
      . Cataract surgery in patients with pseudoex-foliation syndrome: current updates. Clin Ophthalmol 2017;11:1377–83.doi:10.2147/OPTH.S142870
      OpenUrl

    Footnotes

    • Contributors All authors equally participated in the inception and the development of the manuscript, including research and writing.

    • Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Patient consent Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.