Exfoliation Glaucoma

Educational Objectives

The goal of this program is to improve the management of exfoliation glaucoma (XFG). After hearing and assimilating this program, the clinician will be better able to:

1. Recognize the genetic basis and pathogenesis of XFG.
2. Summarize the clinical features and management of XFG.

Summary

Exfoliation glaucoma (XFG): characterized by deposition of white, fluffy material in the anterior surface of the lens; Schlötzer-Schrehardt (2009) described the ultrastructure of the pseudoexfoliation material (PEX; also, exfoliation material [XFM]), which has a characteristic distribution (zonules and fibrillar core); electron microscopic immunogold labelling demonstrated LOXL1 proteins as part of PEX in the nonpigmented epithelial cells; XFM is produced by all the cells in the eye, with extensive expression of LOXL1 in the aqueous humor outflow system

Epidemiology: XFG is the most common identifiable cause of open-angle glaucoma (OAG; ≥25%); ≈50% of patients with exfoliation syndrome (XFS) develop XFG (characterized by accumulation of XFM all over the body) over time; contributing factors include genetic and environmental factors

XFG genetics: Allingham et al (2001) analyzed Icelandic families and observed that XFS runs in the family; XFG is a common and complex disease and not a Mendelian disorder; after genome-wide association study (GWAS), Thorleifsson et al (2007) found that LOXL1 gene is associated with XFG; Williams et al (2010) found that LOXL1 risk allele in the European population is protective in the Black South African population; variations in the LOXL1 gene alone is not sufficient for XFG, and other factors are required; Aung et al (2017) conducted GWAS of patients worldwide and identified a total of 7 loci for XFG, including LOXL1 gene

Exfoliation syndrome: a systemic disease with defects in elastin fibers and accumulation of XFM throughout the body (eg, heart) including ocular manifestations; increased incidence of cardiovascular and cerebrovascular diseases has been reported; Utah Population Database — Wirostko et al (2016) analyzed women with XFS and reported higher risk for pelvic organ prolapse; further studies reported higher risk for inguinal hernia, chronic obstructive pulmonary disease, and sleep apnea in patients with XFS; PEX in heart — Schlötzer-Schrehardt demonstrated characteristic deposition of PEX in the eye and heart of patients with XFS; eye manifestations — involvement of trabecular meshwork (TM) leads to OAG; early-onset cataract is not uncommon; lens zonules may be affected; other complications include dislocation of intraocular lens (IOL), insufficient mydriasis, defects in blood-aqueous barrier (leads to increased inflammation in the anterior chamber [AC]), and corneal endothelial decompensation

Pathogenesis of XFG: mechanical — involvement of TM leads to high intraocular pressure (IOP); vascular — impairment of ocular blood flow; structural — systemic defects in elastin fibers; elastosis of the optic nerve head (ONH); in the early stages, deposition of XFM in the inner wall of the Schlemm canal (SC) leads to outflow resistance; in the later stages, accumulation of XFM can obliterate the SC; in XFG, deposition of XFM in the optic nerve sheath is substantial; in elastosis of the ONH, deposition of XFM leads to disorganization of the lamina cribrosa, with the characteristic moth-eaten fragmented appearance

Clinical diagnosis: identification of XFM on the lens capsule may be difficult; XFM may be identified in the pupillary margin (dandruff-like deposits); on gonioscopy, look for XFM in the AC angle; zonules may be covered with XFM; curvilinear deposits of XFM may be identified on the IOL; pigment-related signs — pigment dispersion after dilation; pigment deposition can be identified on TM (eg, dirty-looking TM in a blue-eyed patient); patients with peripupillary iris atrophy may have iris transillumination defects along the pupillary margin extending to the periphery, identified on intense retroillumination (infrared detection may not be necessary)

Clinical signs: include high IOP, increased IOP fluctuations, difficult dilation of the pupil, unequal pupils and pupillary responses, increased aqueous flare (due to breakdown of blood-aqueous barrier), phacodonesis, IOL donesis, and iris hemorrhage after pupil dilation (due to deposition of XFM in iris blood vessels in end-stage XFG); asymmetry — ≈50% of patients present with unilateral involvement of the eyes, which is a precursor to bilateral involvement (conversion rate, 15%-40%)

Prognosis of XFG: XFG has a serious clinical course, with worse prognosis; patients can have high IOP with marked diurnal fluctuations (acute OAG); compromised lens zonules can lead to angle-closure glaucoma; thick cornea is not necessarily a good sign (rule out asymmetry)

Management: XFG has an aggressive course; often, early surgery may be necessary; minimally invasive glaucoma surgery is an option for first-line treatment; cataract surgery — exercise caution; adequate planning is necessary; preoperatively, look for compromised zonules, phacodonesis, and AC depth (asymmetry); during surgery, assess zonular weakness (difficulty puncturing the anterior capsule); premium IOLs are not appropriate for patients with XFG; check for vitreous prolapse; the speaker prefers a relatively large rhexis and capsule polishing to avoid phimosis and dislocation of IOL; postoperatively, in the short term, patients are prone to inflammation and IOP spike; data indicate that IOP increases 4 hr after surgery in patients with XFS and glaucoma; the speaker prefers timolol plus brimonidine eye drops (Combigan) to reduce IOP

Early-onset XFS: XFS typically occurs during old age (>60s); however, East African population have an early onset and higher rate of prevalence; the prevalence of XFS is 40% in Somali patients; the prevalence of XFS is high in Ethiopian patients and increases with age (eg, ≈70% in patients 80 yr of age), with an early onset

Readings

Allingham RR, Loftsdottir M, Gottfredsdottir MS, et al. Pseudoexfoliation syndrome in Icelandic families. Br J Ophthalmol. 2001;85(6):702-707. doi:10.1136/bjo.85.6.702; Aung T, Ozaki M, 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(7):993-1004. doi:10.1038/ng.3875; Schlötzer-Schrehardt U. Molecular pathology of pseudoexfoliation syndrome/glaucoma--new insights from LOXL1 gene associations. Exp Eye Res. 2009;88(4):776-785. doi:10.1016/j.exer.2008.08.012; Schlötzer-Schrehardt U, Khor CC. Pseudoexfoliation syndrome and glaucoma: from genes to disease mechanisms. Curr Opin Ophthalmol. 2021;32(2):118-128. doi:10.1097/ICU.0000000000000736; Schlötzer-Schrehardt U, Naumann GOH. Ocular and systemic pseudoexfoliation syndrome. Am J Ophthalmol. 2006;141(5):921-937. doi:10.1016/j.ajo.2006.01.047; Thorleifsson G, Magnusson KP, Sulem P, et al. Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma. Science. 2007;317(5843):1397-1400. doi:10.1126/science.1146554; Williams SEI, Whigham BT, Liu Y, et al. Major LOXL1 risk allele is reversed in exfoliation glaucoma in a black South African population. Mol Vis. 2010;16:705-712.; Wirostko BM, Curtin K, Ritch R, et al. Risk for exfoliation syndrome in women with pelvic organ prolapse: A Utah Project on Exfoliation Syndrome (UPEXS) Study. JAMA Ophthalmol. 2016;134(11):1255-1262. doi:10.1001/jamaophthalmol.2016.3411.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Kuchtey was recorded at the 23rd Annual Downeast Ophthalmology Symposium, held September 27-29, 2024, in Bar Harbor, ME, and presented by The Maine Society of Eye Physicians and Surgeons. For more information about upcoming CME activities from this presenter, please visit https://maineeyemds.com. Audio Digest thanks Dr. Kuchtey and The Maine Society of Eye Physicians and Surgeons for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.00 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.00 CE contact hours.

Lecture ID:

OP630401

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.