Ocular Pathology

Anatomy and pathology of the human eye. Use it to review eye pathology for Ophthalmology Board Review or OKAP.

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Sunday, January 27, 2008

Exfoliation Syndrome

Exfoliation Syndrome (pseudoexfoliation) text contributions by Vicki Chan, M.D.
Definition: Exfoliation syndrome is characterized by the pathologic deposition of grey white flakey and fibrillary extracellular material on anterior segment structures often associated with chronic open-angle glaucoma.
Prevalence/Incidence: Exfoliation syndrome is the most common identifiable cause of open-angle glaucoma worldwide and accounting for 6-42% of open angle glaucoma between the ages of 50 and 70. Increased intraocular pressure occurs in ~ 20% of patients with exfoliation syndrome. Exfoliation syndrome is quite common in Iceland ~10% of the population at large (Arnarrson et al 2007). The prevalence increases markedly with age. In Sweden the incidence was 2.1% at age 66 and 25% at age 87 (Astrom et al. 2007).
History: Exfoliation syndrome was first described by John G. Lindberg in 1917.
Etiology: A number of nongenetic factors, including dietary factors, autoimmunity, infectious agents, and trauma, have also been hypothesized to be involved in pathogenesis. Upregulated genes in this syndrome include fibrillin-1, latent transforming growth factor B-binding protein (LTBP)-1 and LTBP-2, the cross-linking enzyme transglutaminase (TGase)-2, TIMP-2, A-kinase anchor protein (AKAP)-2, apolipoprotein D, and the adenosine receptor (AdoR)-A3. Preliminary linkage analyses identified three putative gene loci: 2p16, 2q35-36, and 3q13-q21.
Clinical Presentation: Exfoliation syndrome may present with white-grey, fibrillar-granular deposits in the anterior chamber, including focal retrocorneal flakes and classic "target-like" lens deposits. Patients often have elevated intraocular pressures, secondary to blockage of aqueous outflow, either by accumulation of fibrils in the trabecular meshwork or pupillary blockage from lens destabilization. Gonioscopy may reveal an inferior, scalloped pigmented deposition just anterior to Schwalbe's line, referred to as Sampaolesi's line (unnumbered black arrows). Patients also have rigid irises with reduced dilating properties, which may be secondary to fibril deposition in the stroma and muscle. Degenerative changes may create the "moth-eaten" pattern of peripupillary atrophy (red arrows in figure); degeneration of iris blood vessels can also manifest in spontaneous hematomas; and the destruction of the blood-aqueous barrier can present with flare and pseudouveitis. Exfoliation syndrome is associated with complications from zonular rupture and posterior displacement of the lens during cataract surgery. The syndrome may also be associated with cardiovascular and cerebrovascular morbidities.

Histological Findings: The hallmark of exfoliation syndrome is the pathologic production and accumulation of an abnormal fibrillar extracellular material in anterior segment tissues. The material is multifocally produced in the lens epithelium, nonpigmented ciliary epithelium, trabecular endothelium, corneal endothelium, vascular endothelial cells, and virtually all cell types of the iris. These bundles of fibrils may cover the lens zonule (black arrows white number 1) and anchorage sites in the nonpigmented ciliary epithelium, destabilizing the zonule and increasing the risk of lens dislocation. Under the dissecting microscope one can see the fibrillar material deposited on the posterior iris and ciliary processes (white arrows 1). The posterior iris epithelium has accentuated ridges or circumferential folds (white arrows 2) that often have a sawtooth appearance on microscopy black arrow 2 . Light microscopy of anterior chamber structures (posterior cornea, ciliary body, lens capsule, etc.) will reveal collections of "filings" standing on end (black arrow 3). In the figure, deposition of fibrils (number 3) are seen on the surface of the lens capsule (number 4) with the subjacent anterior capsular epithelium (number 5) and lens fibers (lower number 5). There may be accumulated material within Descemet's membrane and the lens capsule.
Electron microscopy can verify these as abnormal fibrils by a periodicity (fibril banding) of approximately 50 nanometers. In the image shown (22,000 magnification) numerous fibrils are seen with a distinctive banding pattern (arrow 6). One of the hypotheses about pathogenesis of pseudoexfoliation syndrome posits that there is overproduction or expression of microfibrils by a variety of cells. As a result of various factors, it is suggested that the microfibrils cross link with one another to form aggregates. Supporting this hypothesis, there are areas in which the fibrils aggregate to form darker complex masses (arrow 7). Staining for HNK-1 carbohydrate epitope and LTBP-1 may also help in confirming the diagnosis.
Treatment: Exfoliation syndrome is strongly associated with nuclear sclerosis. Complications are often related to the weakened zonules. Secondary glaucoma often will require combination therapy and close follow up. Of note, exfoliation patients may have small, "pseudonormal" optic discs that must be monitored carefully. Argon laser trabeculoplasty often has an immediate pressure lowering effect, with reported initial success rates up to 80%.
1. Hammer T, Schlotzer-Schrehardt U, Naumann GO. Unilateral or Asymmetric
Pseudoexfoliation: An Ultrastructural Study. Arch Ophthamol. 2001;119:1023-1031.
2. Schlotzer-Schrehardt U, Naumann GO. Ocular and systemic pseudoexfoliation syndrome. Am J Ophthalmol. 2006;141:921-937.
3. Schlötzer-Schrehardt U, Zenkel M, Küchle M, et al. Role of transforming growth factor-β1 and its latent form binding protein in pseudoexfoliation syndrome. Exp Eye Res. 2001;73:765–780.
4. Zenkel M, Pöschl E, Mark K et al. Differential gene expression in pseudoexfoliation syndrome. Invest Ophthalmol Vis Sci. 2005;46:3742–3752.
Arnarsson A, Damji KF, Sverrisson T, Sasaki H, Jonasson F. Pseudoexfoliation in the Reykjavik Eye Study: prevalence and related ophthalmological variables. Acta Ophthalmol Scand. 2007;85:822
6. Astrom et al. Acta Ophthalmol Scand. 2007 Dec;85(8):832-7. Epub 2007 Nov 6.

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