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Exfoliation Syndrome

Current Concepts in True Exfoliation Syndrome

Teekhasaenee, Chaiwat MD

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doi: 10.1097/IJG.0000000000000907
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Abstract

True exfoliation syndrome (TEX) (capsular delamination or schisis) is a unique condition whereby characteristic lamellar separation of the anterior lens capsule occurs. Because the delaminated membrane is remarkably thin and translucent, and initial detachment occurs peripherally along the zonular insertions, the condition tends to be overlooked on routine examination with inadequate mydriasis. For nearly a century after it was first described in 1922,1 121 true exfoliation (TEX) cases have been reported in 37 English and Japanese articles.2–38 Most were small case series consisting of 1 to 3 patients with insufficient details. We recently reported a prospective study in 259 patients, more than double the number of the total of previously reported cases.39 Our study has revealed several new findings and described a new theory of pathogenesis, expanded clinical spectrum, and classification of the disease.

PATIENT CHARACTERISTICS AND RISK FACTORS

True exfoliation has been classically reported in individuals who have been chronically exposed to intense heat. Earlier reported patients were workers in steel, glass, and furnace factories. Although modern occupational safety standards and protective measures against intense infrared exposure significantly reduce the incidence of work-related TEX, reports of the condition continue in patients with other associated factors including trauma,40 inflammation,16,17 radiotherapy,6 and laser iridotomy.3,12 However, most were idiopathic.3,7,12,18,19,41 Of our 259 patients, 248 were idiopathic, whereas 11 were associated with intense heat (10) and trauma (1). None had intraocular inflammation or radiotherapy. In total, 55 idiopathic patients had undergone laser iridotomy; however, the association between TEX and laser remained unclear because of their noncorresponding locations. In total, 47 housewives had a long history of cooking at least 3 meals daily over 40 years using a traditional stove with a front charcoal combustion chamber. As the cooking stove emits thermal radiation far lower than the steel or glass furnace, which typically can reach temperatures of up to 1500°C, a relationship between cooking heat and TEX needs further investigation.

Most reported patients whose ages could be documented had advanced ages in or beyond the eighth decade.6,7,8,11 The mean age of the 121 previously reported patients was 76.9±10.6 years (range, 45 to 93 y).2–38 The patients in our study were similar, with a mean age at presentation of 75.2±7.1 years (range, 52 to 97 y). The peak incidence of diagnosis was during the seventh decade. Increased mortality or cataract surgery may account for the declining prevalence after 80 years. Aging appears to be a significant risk factor.

True exfoliation occurs in all races, but appears predominate in Asians. Among the 121 previously reported patients whose races were specified, there were 45 Japanese, 34 Chinese, 18 white, 1 Korean, 1 Arab, and 1 black. Our patients belong to Thai or Chinese ethnic groups with dark brown irides. It has been postulated that dark brown irides, small anterior chamber depth and aqueous volume of Asian eyes, and tropical solar radiation may increase heat formation while simultaneously decrease heat dissipation in the anterior chamber.39

A study of 12 patients showed that the condition was twice as prevalent in men.7 However, in another report, 33% of 18 patients were men.11 A review of 115 previously reported patients whose sex was documented revealed that TEX prevalence was 1.5 times greater in women.2–38 There was no sex predilection in our 248 idiopathic patients. It is possible that occupational TEX may be observed more frequently in men who usually outnumber women in the at-risk occupations. However, idiopathic TEX seems to occur equally between sexes.

Idiopathic TEX occurs sporadically without a familial tendency, whereas occupational TEX may be prevalent among relatives who tend to gather in the same factories. Two patients with idiopathic TEX in our series were sister and brother; however, inheritance was undetermined, since other members of the family were not examined and exposure to the same environment might be a common factor.

Laterality of disease involvement had never been studied. Of 96 reported patients whose laterality was mentioned, 42 (43.7%) had bilateral involvement. In our study in which laterality was specifically determined, nearly 90% of patients with idiopathic or heat-related TEX developed TEX bilaterally, whereas those associated with trauma had ipsilateral involvement.39 Those with bilateral involvement had disease staging and detachment locations symmetrically between eyes. Those with unilateral involvement were younger and in the earlier stages of delamination than those with bilateral TEX. They eventually developed TEX in the contralateral eye.39

A study showed a high prevalence of hyperopia in 17 patients, whose spherical equivalent varied from +1.00 to +7.25 D.7 A relationship between the anatomy of the hyperopic lens and TEX was postulated. However, later reports did not confirm this association. The spherical equivalents in our patients ranged from −14 to +4 D.39

THE CLINICAL SPECTRUM

True exfoliation was classically diagnosed when a broad floating membrane was observed on the anterior lens. We have shown that the condition can be recognized earlier before a detached flap occurs. We have proposed a new clinical classification system dividing TEX into 4 successive stages based on characteristic changes in the anterior capsule, including annular capsule thickening with a distinct splitting margin (stage 1), segmental inward detachment along the margin exhibiting a crescentic flap lying on the anterior lens (stage 2), a floating and folding translucent membrane with a serpentine free edge behind the iris (stage 3) and a broad membrane within the pupil (stage 4) (Fig. 1). The delamination occurs unevenly around the eye and typically affects first the nasal and/or temporal quadrant(s) and progressively involves the inferior and superior quadrants successively. The extent of delamination also varies in various locations, resulting in multiple stages in a single eye. Regardless of disease advancement, the detachment never progresses beyond the photopic pupil. Tearing of the advanced expansive membrane in stage 4 is commonly observed. Eyes manifesting an intraoperative double-ring sign (DRS) alone without preoperative diagnosis of a detached membrane are considered precursors or formes frustes of TEX.2,4,5,39

FIGURE 1
FIGURE 1:
Slit-lamp photographs of true exfoliation syndrome in various stages. A, Stage 1 pale sector with distinct margin (arrow). B, Stage 2 flipped crescent flap with sharp terminal (arrows). C, Stage 3 centrally curled membrane with wavy glistening edge (arrow). D, Stage 4 floating membrane with pigment deposition within pupil (arrow). Figure 1 can be viewed in color online at www.glaucomajournal.com.

PATHOGENESIS OF TEX

The anterior lens capsule is a modified basement membrane with a lamellar structure. During development, the lens epithelium continuously secretes new capsular material, adding to the inner layer of the anterior capsule. Capsular delamination can occur at various depths of the anterior capsule, although it preferentially affects the outer third (Figs. 2A–C).

FIGURE 2
FIGURE 2:
Histologic studies of true exfoliation syndrome in various stages. A, Light micrograph of stage 1 excised anterior capsule stained with toluidine blue showing surface-parallel lamella separation between inner two thirds and outer third of capsule with characteristic tapered rim. B, Light micrograph of stage 2 excised anterior capsule stained with hematoxylin and eosin revealing tapered rim and lamella dehiscence (lower left arrow) not only at detached margin but also in central capsule away from the edge (upper right arrow). C, Transmission electron microscopy of stage 3 excised anterior capsule (×2000) demonstrating lamella separation and vesicular degeneration along splitting plane (arrow). D, Scanning electron microscopy of stage 4 dislocated lens (×20) illustrating peeling membrane (arrows) and complete absence of anterior zonules while persistence of posterior and meridional zonules. Figure 2 can be viewed in color online at www.glaucomajournal.com.

Several mechanisms to account for the delamination have been suggested. In heat-related TEX, it has been proposed that absorption of infrared radiation by the iris generates heat that injures the underlying lens epithelium. Abnormal secretion by the degenerative epithelium leads to an anomalous capsular lamellar structure and subsequent dehiscence.1 Histologically, a thickened stratified structure,5 perpendicular fibrils,31 and vesicular degeneration6,24,26 in the capsule, and degenerative lens epithelium5,8,23,26,31 have been described (Fig. 2C). The generated heat is also believed to directly activate proteolysis in the capsule, disrupting interfibrillar cement.14 Abnormal capsular protein has been isolated in a single case report.18 The heat-induced hypothesis logically explains why the delamination originates behind the iris rather than in the pupillary zone, although the latter receives direct exposure.3,7,12 In TEX associated with uveitis, it was hypothesized that the anterior capsule was weakened by inflammation, and that delamination was precipitated by repeated pharmacological mydriasis.17

Our study showed that idiopathic and heat-related TEX are histologically and clinically similar.39 We demonstrated that initial capsular rupture always develops along the innermost insertions of disrupted anterior zonules.39 Eyes with longer anterior zonules have initial capsular splitting situated more centrally than those with shorter zonules. A detached flap occurs exclusively in areas that lack the anterior zonules. The detachment terminates abruptly wherever the remaining zonules exist (Fig. 3A). The disruption begins with zonular disinsertion followed by degeneration toward the ciliary end (Fig. 3A). Ultrastructural studies showed lamellar separation not only along the detached margin, but also in the central capsule away from the detached margin. Our findings are consistent with previous reports.4,5,24 Imaging with ultrasound biomicroscopy, optical coherence tomography, and Scheimpflug photography demonstrated generalized thickening and hyperreflectivity of the affected capsule before the zonular disruption. The findings suggest that the structural alterations are the primary event that diffusely affects the capsule and consequently leads to zonular disinsertion. It has been shown that the anterior capsule is thinnest along the zonular insertions regardless of age. The thinning in an individual increases with aging.42 It is possible that the zonular insertions may represent the most fragile part of the anterior capsule. Zonular disinsertion aggravates the weakness and provokes the initial splitting. When a detached flap develops, we have proposed that physiological iris movement and impeded aqueous flow in the narrow iris-lens channel mechanically peel the flap toward the center. Our theory explains why the detached membrane always curls and progresses centrally, and never progresses beyond the photopic pupil, where iris-capsule contact is absent.

FIGURE 3
FIGURE 3:
Slit-lamp photographs showing: remaining junctional zonules between stage 2 flipped crescent flap (white arrows) and stage 1 (green arrow) splitting edge, and ciliary remnants of degenerative zonules along the lens equator (red arrow) (A). Two parallel stage 3 curled flaps (arrows) with a narrow space in between (B). Specular reflection of a stage 2 membrane with abrupt termination along the detached margin and umbilicated nodules (arrow) (C). Pigment deposition along free edge and anteriorly curled underside of a stage 3 flap (arrows) (D). Figure 3 can be viewed in color online at www.glaucomajournal.com.

DOUBLE DELAMINATION

Double delamination is a new finding in our study.39 The outer and inner detachments occur separately resulting in combination of detached flaps in different stages. Although occurring independently, the second delamination frequently appears in the location where the most advanced initial detachment exists. The second flap also follows the first in morphology and orientation resulting in 2 parallel curling flaps (Fig. 3B). The flaps never attach or combine together and a narrow space always presents in between. Ultrastructurally, the outer detachment occurs deeper in the capsule than the inner one.

SPECULAR MICROSCOPY

Specular reflection of the affected capsule characteristically terminates sharply along the detached edge.39 Isolated or clusters of umbilicated nodules are frequently observed adjacent to the detached margin (Fig. 3C).

PIGMENT DEPOSITION

Pigment deposition on the detached membrane is another new finding that commonly occurs in our patients with brown irides.39 The extent and prevalence of the deposition increase with the delamination. Over 95% of the eyes with stages 3 to 4 develop pigment deposition. The pigment is believed to derive from the rubbing of the posterior iris against the floating membrane. Undulating folds and waving edges of the membrane not only scrape the iris, but also knead the released tissue. The kneading mixes and aggregates detached melanin and tissue debris into larger adhesive particles along the points of contact including the splitting margin, free edge, and anteriorly curled underside of the membrane (Fig. 3D). The pigment adhesion on the membrane is firm enough to withstand forceful anterior chamber irrigation. It can persist on the membrane for up to 2 years.

CATARACT AND LENS DISLOCATION

There was a high prevalence of cataract in reported eyes with TEX. Almost all patients with either heat-induced or idiopathic TEX had symptomatic cataracts, predominantly nuclear sclerosis, requiring surgery.2–39 It was suggested that the detached capsule could exhibit abnormal permeability, which disturbs lens metabolism leading to cataract formation.19,43 Further investigation is needed to establish this association, as aging and/or heat exposure1 also intrinsically cause cataract. In addition, several patients were incidentally diagnosed to have TEX during examination for cataract or cataract surgery. If an association really exists, it needs to be determined, which is the primary event.

Although phacodonesis was uncommonly reported in previous studies,6,8 it occurred in 10% of our 259 consecutive patients with or without lens dislocation.39 The lens displacement occurred only anteriorly, resulting in acute (12) and chronic (2) secondary angle closure in 14 patients. Scanning electron microscopy of the dislocated lenses revealed a complete absence of anterior zonules but persistence of posterior and meridional zonules, suggesting that the dislocation was primarily associated with a lack of anterior zonular support (Fig. 2D). Spontaneous dislocation of in-the-bag intraocular lens has also been reported in association with absence of the anterior zonules.32

True exfoliation often masquerades as partial capsulorhexis (DRS) that should be recognized to avoid capsule-related complications. However, radial tears of the capsule were uncommonly reported3,20,28 and most patients underwent uneventful phacoemulsification.2,8,11,13,15,24,26,27,39 In the absence of anterior zonular support, inadvertent aspiration of the anterior capsular tag during cortical aspiration could effortlessly break the posterior zonules. Similarly, the spontaneously dislocated or subluxated lenses were also easily expressed.39

GLAUCOMA

Of the 121 previously reported patients, open-angle and angle-closure glaucoma had been reported in 9 (7.4%) and 14 (11.6%) patients, respectively.1–11,14–39 Possible association between glaucoma and TEX has been suggested.7,8,11 In our series, 47 (19.5%) patients developed primary open-angle glaucoma, 26 (10.0%) had primary angle-closure glaucoma, and 15 (5.8%) were primary angle-closure suspects.39 Although the high prevalence of glaucoma in our study favored the association, it might also represent biased patient recruitment from glaucoma clinics.

TRUE VERSUS (PSEUDO)EXFOLIATION SYNDROME (XFS)

TEX and XFS commonly manifest detached flaps from the anterior lens surface. The flaps are sufficiently characteristic to be distinguished from each other. In TEX, the detached flap derives from the superficial layer of the anterior capsule exhibiting a thin, translucent, centrally curled membrane with a smooth glistening edge. The detachment initiates along the zonular insertions of disrupted anterior zonules and progresses centrally. In XFS, the detached flap consisting of exfoliation material appears as a granular, hazy membrane with a serrated turbid edge. The detachment in XFS occurs along the outer and inner edges of the central disc and peripheral ring, resulting in 2 separate flaps curling inward and outward, respectively. Pigment deposition on the flaps of the 2 conditions also differs. In TEX, the pigment deposition occurs as discrete granules along the free edge and anteriorly curled underside of the membrane, and in XFS as finer, radially oriented particles in the mid-periphery of the anterior lens. The “dandruff” exfoliation material and the classic 3-ring sign are pathognomonic for XFS. Although TEX and XFS are separate unrelated entities, they can occur together in 1 eye.37,44

CONCLUSIONS

Aging, intense heat exposure and trauma are risk factors for TEX. Initial capsular splits occur along the innermost insertions of disrupted anterior zonules. The peeling progresses centrally in association with iris movement and aqueous flow. Major associated ocular complications include cataract, partial capsulorhexis masquerade (DRS), phacodonesis, lens and intraocular lens dislocation, and glaucoma. The condition is not uncommon but tends to be overlooked.6 Lack of understanding of the earlier disease manifestation (stages 1 to 2), failure to maximally dilate the pupil, difficulty in detecting the exceedingly thin and transparent membrane, and unawareness of its potential complications by clinicians may account for the small number of patients in previous reports. We believe TEX has been underdetected and underreported.

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Keywords:

pseudoexfoliation; true exfoliation; capsular delamination; anterior zonular disruption; angle-closure; phacodonesis; lens dislocation; cataract; double-ring sign; glaucoma

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