Pseudoexfoliation Syndrome and Glaucoma

Sahib Tuteja; Marco Zeppieri; Harshika Chawla

Pseudoexfoliation Syndrome and Glaucoma

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Continuing Education Activity

Pseudoexfoliation syndrome is a chronic, age-related disorder of the extracellular matrix that results in the deposition of abnormal fibrillary (pseudoexfoliative) material within various body tissues. This condition manifests primarily in the anterior segment of the eye. Individuals with this condition can develop pseudoexfoliation glaucoma in the presence of chronic elevated intraocular pressure, glaucomatous optic neuropathy, and visual field damage. This activity reviews the evaluation and treatment of pseudoexfoliation syndrome and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

Review the risk factors for developing pseudoexfoliation syndrome (PEX) and pseudoexfoliation glaucoma (PEG).
Describe the clinical features of PEX and PEG.
Explain the risks associated with cataract surgery in PEX and PEG.
Summarize the management and follow-up of patients diagnosed with PEX and PEG.

Introduction

Pseudoexfoliation syndrome (PEX) is a systemic disorder that leads to the accumulation of extracellular material in various ocular tissues, [1] which presents primarily via its characteristic ocular manifestations.[2] PEX is considered an age-related microfibillopathy that affects different systemic organs and is characterized by a progressive chronic deposition and accumulation of extracellular greyish-white material in several organs.[3] PEX can lead to secondary glaucoma, known as pseudoexfoliative glaucoma (PEG), which is a major cause of blindness worldwide.

This systemic disorder is typically clinically diagnosed during routine ophthalmic examination with slit-lamp visualization of white, flaky fibrillar (pseudoexfoliative) material on the pupillary margin of the iris and the anterior lens capsule.[4] This condition affects the eyes, particularly the lens and the trabecular meshwork, which are responsible for regulating the flow of fluid in the eye.[5] Small flakes of material, resembling dandruff, tend to accumulate on the surface of the lens, the iris, and the ciliary body. This accumulation can cause increased intraocular pressure (IOP) inside the eye, leading to glaucoma and other vision problems. PEX is more common in individuals over the age of 60 and is often associated with a higher risk of cataract development. While there is currently no cure for PEX, early diagnosis, and treatment can help prevent or slow the progression of vision loss.

The history of PEX dates back to the early 20th century in 1917 when John G. Lindberg first described the characteristic flaky material found in the eyes of patients with glaucoma.[6] However, it wasn't until the 1950s that the term "Pseudoexfoliation" was used to describe the condition.[7] Initially, PEX was thought to be a benign age-related change in the eye, but as more research was conducted, it became clear that PEX was associated with an increased risk of glaucoma and other vision problems. Since then, PEX has been extensively studied, and numerous researchers have contributed to our understanding of the condition's pathogenesis, genetics, and clinical implications. Despite ongoing research, the exact cause of PEX remains unclear, and there is currently no cure for the condition.

PEX may be present unilaterally or bilaterally. PEX is strongly associated with raised intraocular pressures (IOP) in up to 44% of patients and subsequent development of pseudoexfoliation glaucoma (PEG), making it the most commonly identifiable cause of secondary open-angle glaucoma.[8] PEX is also associated with technically challenging cataract surgery: PEX eyes dilate poorly and have unstable lens zonules, which may lead to a higher risk of complications such as capsular bag rupture, zonular dialysis, and loss of vitreous.[9]

Etiology

PEX is characterized by the formation of white, flaky deposits on the lens and iris, which can cause several ocular complications, including cataracts, glaucoma, and corneal endothelial dysfunction. The exact etiology of PEX is not known, however, genetic susceptibility is supported by numerous genetic studies in population studies worldwide.[10] Variants of certain genes have been found to be more common in individuals with PEX and PEG, suggesting that they may play a role in the development of the condition.

A genetic predisposition has been shown for the following genes:

Lysyl oxidase-like 1 (LOXL1) enzyme is part of a family of copper-dependent monoamine oxidases secreted by fibroblasts and smooth muscle cells. These enzymes are involved in cross-linking collagen and elastin fibers in the extracellular matrix. Multiple single nucleotide polymorphisms (SNPs) in this gene are associated with PEX, and various high-risk alleles have been identified in different populations, with important associations between LOLX1 and PEX in individuals from Scandinavia, Europe, Asia, Africa, Australia, and North America.[11]
Chromosome 8p21, Clusterin (CLU) gene: Clusterin is a multifunctional glycoprotein that has been proposed to inhibit stress-induced aggregation of misfolded proteins. Clusterin downregulation has been shown to occur in all anterior segment tissues in PEX eyes, suggesting that its deficiency may be responsible for the chronic accumulation of abnormal extracellular fibrillar material in this condition.[12]
Calcium Voltage-Gated Channel Subunit Alpha 1 (CACNA1A): Gene variants could possibly influence calcium levels that may lead to PEX depositions.[13]
Chromosome 1p13.3, Glutathione transferase (GST) gene: GST has a role in protecting cells from oxidative damage. Polymorphisms of GST have been detected in Pakistani patients with PEX. However, no significant association was found in other patient populations.[14]
Fibulin-5 (FBLN5) gene: Studies have shown that downregulation of two variants of this gene that encode for this extracellular matrix protein have been associated with risks of developing PEG.[15]

PEX deposits are composed of different extracellular, molecular, and membrane proteins and enzymes that include tropoelastin, fibrillin-1, elastin, LOL1, amyloid, fibulin, vitronectin, clusterin, etc.[5] Genetic variants or mutations that cause dysregulation and production of these components can potentially be of importance in the genetic susceptibility for PEX and PEG.[16] Other genetic associations have also been discovered, including polymorphisms of the CNTNAP2 gene,[17] vimentin, [18] tumor necrosis factor-alpha, tumor growth factor beta 1, matrix metalloproteinase-1, and 3, proteasome maturation protein (POMP), transmembrane protein 136, semaphorin 6A (SEMA6A), etc.[10][19] Current studies have reported the presence of altered microRNA molecules, which regulate post-transcriptional gene expression, in the aqueous humor of individuals with PEX and PEG.[20]

Environmental factors that have been proposed to play a role in the development of PEX include exposure to sunlight and ultraviolet light,[21] long-term alcohol consumption,[22] excessive caffeine,[23] higher temperatures, climatic and geographical factors, diet, viral infection, and trauma or surgery involving the anterior segment.[11][24] Current studies have shown that factors associated with increased oxidative stress, production of free radicals, disruption of the blood-aqueous barrier, and limited antioxidant defense mechanisms can play important roles in the etiopathogenesis of PEX and PEG.[25][10]

The insoluble extracellular aggregates in the anterior chamber can decrease aqueous humor outflow and congestion in the trabecular meshwork, causing large fluctuations and increases in IOP, thus leading to PEG in some individuals with PEX. PEG is a type of secondary glaucoma as a result of PEX, which is a progressive disease that can lead to blindness if left untreated. Signs of this type of secondary glaucoma include irreversible optic nerve head and retinal nerve fiber layer damage and/or visual field defects,[26] which tend to be more severe and progress at faster rates when compared to primary open-angle glaucoma (POAG).[27][26]

Epidemiology

The prevalence of PEX increases markedly with age. It is estimated that up to 20% of the over-60 population may be affected.[4] PEX is found in all geographic populations with a significant variation in prevalence, which range from 0% to 38%.[28] In populations of Scandinavian, Northern European, and Mediterranean descent, the prevalence of PEX is estimated to be between 5% and 20%. Nordic and Eastern Mediterranean countries are most affected, and East Asian and Inuit populations have the lowest reported prevalence. Studies have reported that the prevalence of PEX can be as low as 0% in Greenland Inuits[29] and as high as 38 % in Navajo Nation Indians.[30]The variation in prevalence has been proposed to be due to epigenetics, the attitude of inhabitants, UV exposure, climatic conditions, proximity to the equator, dietary factors, oxidative stress mechanisms, genetic predisposition, etc.[31][32]

Risk Factors include:

Age (strongest risk factor; PEX rarely occurs below the age of 50, with an incidence increasing with age).[26][33]
Race (Nordic and Eastern Mediterranean populations have increased risk).[34]
high altitude and/or solar/cosmic radiation.[35][36]
Female sex (possible risk factor with more recent studies showing equal prevalence in males and females). Studies reporting on association with gender have produced conflicting results, and so the link remains unclear.[37]
Low consumption of dietary anti-oxidants, smoking, caffeine, alcohol, and factors that favor oxidative stress[10][25]

The diagnosis of secondary glaucoma or PEG is reached when PEX is associated with elevated and fluctuating IOP levels, in addition to functional alterations in computerized perimetry and/or defects in the optic nerve and retinal nerve fiber layer. PEG accounts for 25 % of individuals with open-angle glaucoma worldwide, in which PEX shows a cumulative probability to develop in PEG in 15% of cases within 10 years.[38] There is progressive damage and loss of retinal ganglion cells that cause irreversible peripheral vision loss in PEG.

Pathophysiology

PEX material is most readily found in the structures of the eye bathed by the aqueous. PEX is a systemic disorder that causes the accumulation of extracellular material in various other organs and body tissues including blood vessels, lungs, heart, liver, gallbladder, kidneys, meninges, and skin.[1][39]

The exact pathophysiological processes that underline PEX remain unclear. Still, it is now well known that PEX is a fibrillopathy. PEX material arises from the abnormal accumulation of elastic microfibrils composed of fibrillin-1, fibulin-2, vitronectin, the enzyme lysyl oxidase, and clusterin, amongst other proteins.[16] Fibrillin molecules aggregate to form microfibrils which are then crosslinked to form PEX fibrils.

Transforming growth factor-beta 1 (TGF-B1) is considered a key mediator of abnormal accumulation of PEX material. It has been shown to promote PEX material formation in vitro and, increased concentrations have been found in the aqueous humor of PEX eyes. There is evidence that oxidative stress plays a role in developing PEX.[40] Decreased levels of ascorbic acid and increased levels of oxidative stress markers have been found in aqueous humor. Iris hypoperfusion and anterior chamber hypoxia are also associated with PEX.

The vasoconstrictor endothelin-1 is found in increased concentrations in PEX, and nitric oxide (a vasodilator) is reduced. It has been suggested that this may further exacerbate cellular stress and lead to the processes behind the development of PEX. Accumulation of abnormal PEX fibrils may be promoted via a deficiency of clusterin, a molecular chaperone that inhibits aggregation of misfolded proteins. Moreover, the dysfunction of matrix metalloproteinases (MMPs) prevents the breakdown and clearance of this abnormal material.[4]

Histopathology

Light microscopy of anterior segment structures demonstrates deposition of PEX material on the iris pigment epithelium, anterior lens capsule, and corneal endothelium (See image of PEX).[41][42] Electron microscopy and immunohistochemical studies have demonstrated the production of PEX material by the non-pigmented epithelial cells of the ciliary body, iris pigment epithelium, pre-equatorial lens epithelium, and corneal endothelium.[43] PEX material seen on the anterior lens capsule and the zonular fibers is thought to be transmitted from the cellular tissues via the aqueous.[44]

Zonular weakness is a characteristic feature of PEX, and loosening of the zonular attachments to the basement membrane of the ciliary body is considered to be primarily responsible for this. This is aggravated by further weakness along the free zonular fibers and their attachment to the basement membrane of the lens capsule. Electron microscopies of conjunctival biopsies taken from fellow eyes in unilateral cases demonstrate the presence of subclinical pseudoexfoliative material, confirming that PEX is a bilateral condition with marked clinical asymmetry.[45][46]

History and Physical

PEX and PEG are typically diagnosed during a comprehensive eye exam. The presence of flaky deposits on the lens and iris is a hallmark of PEX, while an increase in IOP is a characteristic of PEG. Other tests that may be performed include visual field testing, optic nerve imaging, and gonioscopy. Patients are often asymptomatic but may present with peripheral visual field loss from secondary glaucoma or PEG. The diagnosis is made clinically via characteristic slit-lamp biomicroscopy and gonioscopic findings:

Slit Lamp Examination

The characteristic finding in PEX is the visualization of white, flaky, dandruff-like PEX material along the pupillary margin and anterior lens capsule (See image of PEX deposits on anterior structures). The anterior lens capsule shows a central disc and peripheral ring of PEX material with a clear intermediate zone maintained by pupillary abrasion. The whitish double concentric ring that is seen on the anterior portion of the lens is probably due to the movement of the iris over the lens. The central disc may be absent in up to 20% of cases, and the peripheral zone may not be completely visualized without the aid of pharmacological dilation.[47]

A thorough, systematic examination may reveal additional signs. The corneal endothelium may show deposition of PEX material that may be erroneously interpreted as keratic precipitates or inflammatory debris. Fine scattered pigment deposits are also present, which may form a vertical line known as a Krukenberg spindle, similar to what may be seen in pigment dispersion syndrome.[48] Studies have shown lower corneal endothelial cell counts and guttae in eyes with PEX.[49]

The aqueous humor may demonstrate PEX particles and mild flare from an impaired blood-aqueous barrier. The iris may demonstrate poor mydriasis secondary to atrophy of the dilator muscle and loss of elasticity due to PEX material accumulation within the iris stroma.[41] There may be a loss of pupillary ruff due to rubbing against the lens, and transillumination defects may be seen along the pupillary margin.[50] This is in contrast to the more mid-peripheral iris transillumination seen in pigment dispersion syndrome.

There may be phacodonesis or lens subluxation/dislocation secondary to zonular weakness. The fragility is thought to be due to the deposition of extracellular material on the zonules and ciliary processes and/or histological fiber alteration.[44] Studies have reported an increased incidence of nuclear sclerotic and subcapsular cataracts in PEX eyes compared to non-PEX eyes, although the pathophysiology is not yet understood.[51][52]

Gonioscopy

Gonioscopy is fundamental and should be performed in all patients with PEX during slit-lamp examination. PEX deposits may be visualized over angle structures. Patchy hyperpigmentation over the trabecular meshwork and Schwalbe line can be observed.[53] This hyperpigmentation may coalesce to form a band of hyperpigmentation on the Schwalbe line known as the Sampaolesi line.[54] In unilateral cases where no PEX material is visible in the fellow eye, trabecular meshwork pigmentation may be an early sign of PEX development. Up to 20% of PEX eyes may have occludable angles predisposing them to acute angle-closure glaucoma.[4][9]

Evaluation

All patients suspected of PEX should undergo a dilated slit-lamp examination and gonioscopy. Baseline IOP must be measured at the time of diagnosis and periodically due to the high risk of developing ocular hypertension and PEG.[55] Genetic testing of eyes is not routinely performed, considering that PEX is a clinical diagnosis.

The evaluation of patients suspected of PEG is identical to those suspected of primary open-angle glaucoma (POAG).[56]

To summarise, the clinical evaluation involves:

Visual examination of optic nerve head: This is evaluated using a slit lamp and condensing lens of sufficient magnification. The typical signs associated with glaucomatous damage include an increased cup-to-disc ratio (CDR) greater than 0.5, optic nerve cupping and notching (See image of glaucomatous optic nerve cupping), asymmetry of CDR between both eyes and disc hemorrhages.
IOP measurement: Glaucomatous damage in pseudoexfoliation is associated with raised IOP and shows marked variation in diurnal IOP levels. IOP should therefore be measured at multiple different times of the day. Goldmann applanation tonometry is the gold standard for assessment,[57] although clinicians should consider the effect of central corneal thickness on the measured value.[58]
Visual Field Analysis: Static computer automated perimetry is useful for a baseline investigation of glaucoma suspects and monitoring progression in those with confirmed glaucoma. Characteristic field defects are seen as with POAG, but those seen with PEG are typically more severe and tend to progress at a faster rate.[59]
Optical coherence tomography (OCT): Peripapillary retinal nerve fiber layer (RNFL) thinning is associated with glaucomatous damage. Inferotemporal thinning tends to be associated with early glaucomatous changes, whereas superotemporal thinning may be used to differentiate severe glaucoma from healthy controls.[60]

Treatment / Management

There is currently no treatment available to halt the deposition of PEX material in affected eyes. Management of this condition is primarily aimed at regular (at least annual) eye examinations for early detection and treatment of glaucoma.

Local eye drops: The first-line treatment of PEG is medical. IOP-lowering topical medications that are effective in PEG include prostaglandin analogs, beta-blockers, carbonic anhydrase inhibitors, or a combination of these. Pilocarpine is not recommended due to the risk of worsening angle-closure glaucoma and posterior synechiae formation. PEG is generally more resistant to medical therapy than POAG. Considering the aggressive nature and the risk of faster progression in PEX, the target IOP should be lower than those used to manage POAG.[59]

Selective laser trabeculoplasty (SLT): Laser treatment may be used as a first-line treatment or to avoid more invasive surgery. It is very successful in PEG eyes, reducing IOP by 30%. The increased effectiveness of SLT may be due to the increased pigmentation of the trabecular meshwork, which leads to increased absorption of laser energy. SLT, however, is not permanent, and a significant proportion of patients may require further surgery in the long term. Argon laser trabeculoplasty (ALT), which induces a greater histopathological effect on the trabecular meshwork due to the stronger energy laser applied for a longer time, has also been reported to be useful as a temporary regulation treatment of IOP in PEG.[61] SLT has shown to be less destructive and can be repeatable, thus a viable alternative to traditional ALT.[62]

Surgery: Similar to POAG, surgical management of PEG may be considered following the failure of maximal medical therapy and/or SLT.[63] Trabeculectomy in PEG patients has shown similar outcomes as with POAG patients, without an increased risk of complications.[64] Glaucoma drainage devices and alternative methods like canaloplasty and viscocanalostomy may also be considered, although target pressures after surgery do not tend to be low, thus local eyedrops may still be needed in some patients.[65] If there is a component of angle closure secondary to cataract or anterior lens movement secondary to zonular laxity, laser iridoplasty or cataract extraction may be beneficial.[66]

Cataract surgery may be challenging in PEX eyes due to poor mydriasis, corneal endotheliopathy, zonular instability, and lens subluxation.[67] Zonular laxity may predispose to zonular dialysis, compromised blood-aqueous barrier, capsular bag rupture, and subsequent loss of vitreous.[68] There is also an increased risk of postoperative complications, which include increased inflammation, iris vascular leaks, spikes in IOP, corneal edema, capsular opacification, capsular phimosis, and late intra-ocular lens (IOL) decentration.[69] PEX patients often need a more aggressive and longer duration of treatment with postoperative steroids. Therefore, it is essential to evaluate all eyes undergoing cataract extraction for the presence of pseudoexfoliation to aid surgical planning, prognostication, and follow-up.[67]

Current studies in the literature have shown that new treatments for PEG are constantly being studied. These alternatives to traditional treatment are still being performed in preclinical and animal models, and include magnetic phage display,[70] microRNAs,[71]gene therapies,[72] stem cell therapy,[73] nanotechnology,[74] immunotherapy,[75] and photobiomodulation.[76]

Differential Diagnosis

Pigment dispersion syndrome: Corneal endothelial changes are similar to those of PEX (Krukenberg spindle).[77] Iris transillumination demonstrates mid-peripheral atrophy as compared to the pupillary border defects seen in PEX. Gonioscopy shows posterior bowing of the iris and more homogenous trabecular meshwork pigmentation than the patchy pigmentation seen in PEX.[78]
True exfoliation of the lens capsule: This is a rare disorder where the superficial and deeper layers of the anterior lens capsule separate in association with exposure to infrared radiation. Slit-lamp examination shows a thin white membrane emanating from the lens into the anterior chamber.[79]
Amyloidosis: Amyloid can appear similar to PEX material and deposit within the anterior segment structures.[80]
Primary open-angle glaucoma: There are no signs of white, flaky deposits on the anterior segment of the eye.[81]
Primary angle-closure glaucoma: Elevated IOP is due to angle closure without the presence of PEX material.[82]

Prognosis

PEX is significantly associated with the development of glaucoma. In one study, 44% of patients diagnosed with PEX developed ocular hypertension requiring treatment or glaucoma within 15 years of follow-up. In patients diagnosed with unilateral PEX, the risk of the fellow eye developing clinically evident PEX was 29% by 15 years.[8] When compared to POAG, PEX eyes have higher IOPs with an increased diurnal variation. There is a rapid progression of nerve damage, and subsequent field loss may be worse than POAG.

Complications

PEX eyes may be complicated by progression to ocular hypertension or glaucoma (PEG). Cataract surgery may be challenging in these eyes because of corneal endotheliopathy, poor mydriasis, lens subluxation, and zonular instability.[67] Cataract surgical complications include corneal edema, compromised blood-aqueous barrier, capsular opacification, spikes in IOP, capsular phimosis, increased inflammation, zonular dialysis, capsular bag rupture, iris vascular leaks, and late intra-ocular lens (IOL) decentration.[68] PEX and PEG patients tend to require more frequent follow-ups and aggressive therapies in the presence of elevated IOP and signs of glaucomatous functional and anatomical progression.

Deterrence and Patient Education

Patients should be advised to seek annual eye screening to develop ocular hypertension and/or glaucoma. Patients on medical therapy must be advised on the importance of treatment adherence in preventing the progression of glaucomatous damage. Those undergoing cataract surgery must be counseled regarding the increased risks associated with surgery and the possible need for further surgery if there are associated complications. They should be advised of the risk of IOL decentration years following the surgery. PEX is significantly associated with cardiovascular and cerebrovascular disease, and patients may be advised to seek optimization of vascular risk factors with their primary care physician.[83]

Enhancing Healthcare Team Outcomes

Untreated glaucoma may lead to severe peripheral vision loss, followed by central visual loss. Patient outcomes can be improved through ophthalmologist collaboration with other healthcare professionals within the community setting. Community optometrists are well-equipped to perform routine eye examinations, monitor patients’ intraocular pressures, and perform perimetry testing. They are aiming to refer all glaucoma suspects to secondary care. Patients diagnosed with glaucoma need to be closely monitored and provided with ongoing education. The primary care physician can work with patients to treat co-morbidities that may impair the self-administration of eye drops such as arthritis of the hands and optimize vascular risk factors that may be elevated in this patient group. [Level 5]

(Click Image to Enlarge)

Slit lamp photograph of a left eye demonstrating pseudoexfoliation material on the pupillary margin
Contributed by Sahib Tuteja, MBChB

(Click Image to Enlarge)

Individual with pseudoexfoliation syndrome (PEX) and cataract. PEX is clinically diagnosed with slit-lamp visualization of white, flaky fibrillar (pseudoexfoliative) material on the pupillary margin of the iris and the anterior lens capsule.
Contributed by Mutali Musa, OD.

(Click Image to Enlarge)

Glaucomatous optic nerve cupping in a patient with pseudoexfoliation glaucoma (PEG).
Contributed by Marco Zeppieri, MD, PhD. Image courtesy of Paolo Brusini, MD.

Details

References

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