Ординатура / Офтальмология / Английские материалы / Applied Pathology for Ophthalmic Microsurgeons_Naumann, Holbach, Kruse_2008

Table 6.3.3. Aqueous flare values (photon counts/ms) in normal controls, pseudoexfoliation (PEX) with or without secondary open-angle glaucoma (SOAG) and primary open-angle glaucoma (POAG) (statistics: Mann-Whitney test) (from Küchle et al. 1995)

jority of intraocular PEX deposits cannot be observed by direct biomicroscopy, and the accumulations on zonules, ciliary processes (Fig. 6.3.4f), and trabecular meshwork may be only detected on gonioscopy or cycloscopy or may be visualized by high resolution ultrasound biomicroscopy (Naumann et al. 1998; Inazumi et al. 2002).

In addition to deposits of PEX material, several other clinical signs aid in the diagnosis. Pigment loss from the peripupillary iris pigment epithelium and its deposition on anterior chamber structures is a hallmark of PEX syndrome. Further PEX-associated clinical signs that can alert the clinician to the presence of PEX include phacodonesis, iris stroma atrophy, iris hemorrhages after pupillary dilation, increased aqueous flare values, posterior synechiae, elevated intraocular pressure, and insufficient pupillary dilation, particularly if asymmetrically present. An atypical cornea guttata may precede the full clinical picture for decades. The differential diagnosis of PEX syndrome is presented in Table 6.3.3.

6.3.3.2

Masked PEX Syndrome

In cases of circular posterior synechiae, which frequently form in PEX eyes, particularly under miotic therapy, the evaluation of the anterior lens surface may be hindered and PEX deposits may be masked by the synechiae (Fig. 6.3.4g) (Mardin et al. 2001). In these cases, high resolution ultrasound biomicroscopy may be useful to reveal PEX deposits on the lens or zonules (Inazumi et al. 2002; Naumann et al. 1998). The presence of “spontaneous” posterior synechiae without any other obvious cause should alert the clinician to suspect PEX.

6.3.3.3

Early Stages of PEX Syndrome

The classical picture of lens deposits represents, however, a very late stage of the disease, which is preceded by a long, chronic, preclinical course. Early recognition

is critical for reducing operative complications due to PEX. By thorough biomicroscopic examination, a dif- fuse-matte homogeneous film on the surface of the anterior lens capsule can be observed prior to the formation of obvious PEX deposits (Fig. 6.3.4h) (Naumann et al. 1998; Tetsumoto et al. 1992). To visualize these early changes at the slit lamp, it has been suggested to place the slit beam at 45 degrees to the axis of observation, reducing the light source, and focus temporally from the center of the lens to highlight the subtle deposits on the lens surface (Ritch and Schlötzer-Schrehardt 2001). Electron microscopy shows this surface film to consist of a layer of microfibrils, a precursor of PEX fibrils, diffusely deposited on the entire surface of the anterior lens capsule from the aqueous humor (Dark et al. 1990; Tetsumoto et al. 1992) (Fig. 6.3.5). As the precapsular layer becomes thicker, focal defects begin to form in the mid-peripheral zone by abrasive movements of the iris, often in the upper nasal quadrant (“mini-PEX”) (Fig. 6.3.4h), which further enlarge and become confluent to form the classical picture of manifest PEX syndrome (Figs. 6.3.3, 6.3.5).

Additional clinical signs, which help alert the ophthalmologist to the presence of these early stages, comprise peripupillary atrophy of the iris pigment epithelium, melanin dispersion associated with pupillary dilation, increased trabecular pigmentation, and poor mydriasis (Table 6.3.1) (Prince et al. 1987; Tetsumoto et al. 1992). As PEX often is an asymmetric condition (see below), comparison with the fellow eye is diagnostically helpful in highlighting these early changes.

6.3.3.4

Asymmetry of Involvement

For unknown reasons, PEX patients can present clinically with either unilateral or bilateral involvement, which may be markedly asymmetric. Unilateral involvement is often regarded as a precursor to bilateral involvement. PEX syndrome manifests unilaterally in about 50 – 70 % of patients and the conversion rates from clinically unilateral to bilateral disease were found to vary from 15 % to 40 % within 5 years (Ritch and Schlötzer-Schrehardt 2001). Clinically, the involved eye often has a poorer visual acuity, more advanced lens opacity, higher intraocular pressure, a smaller pupil, and a more pronounced trabecular pigmentation than the noninvolved fellow eye.

However, in the majority of clinically unilateral cases, there are subtle histopathological and ultrastructural changes in the fellow eye suggesting that all cases are in fact asymmetric (Hammer et al. 2001; Kivelä et al. 1997). PEX material has been shown to be almost invariably present on electron microscopy in the conjunctiva (Prince et al. 1987) and in the iris, particularly in the dilator muscle and blood vessel walls, of the clini-

cally uninvolved fellow eye (Hammer et al. 2001; Kivelä et al. 1997). These early changes may account for the clinical signs characteristic of early stages, such as melanin dispersion, peripupillary atrophy, insufficient mydriasis, and blood-aqueous barrier defects leading to increased aqueous flare values measured by laser tyndallometry (Küchle et al. 1995). They further support the concept of PEX syndrome as a generalized, basically bilateral disorder with a clinically marked asymmetric presentation.

6.3.4

Surgical Pathology

6.3.4.1

Lens, Ciliary Body, and Zonular Apparatus

Lens opacification occurs in a high proportion of eyes with PEX syndrome and is the most common cause of PEX patients to require surgical intervention. An increased incidence of cataract, most commonly of a nuclear type, is known to be associated with PEX syndrome (Hietanen et al. 1992) and may be causally linked to the presence of ocular ischemia, anterior chamber hypoxia (Helbig et al. 1994), reduced protection against ultraviolet radiation by lower levels of ascorbic acid in the aqueous humor (Koliakos et al. 2003), and abnormal aqueous composition such as increased growth factor levels in the aqueous humor evident as “PEX hydropathy.”

The zonules are affected early in the course of the PEX process (Fig. 6.3.6a). The zonular fibers may sepa-

rate from their attachments to the ciliary body and lens and produce a characteristic phacodonesis or inferior displacement of the lens (Fig. 6.3.6b) (Bartholomew 1970; Freissler et al. 1995). The zonular fibers proper may be intact or partially fragmented; however, in cases associated with phacodonesis or lens subluxation, marked degenerative changes of the zonular fibers are observed. Weakening of the zonular support and subsequent laxity of the lens allows lens movement to occur. Especially in the prone position, anterior lens movement can occur resulting in pupillary or even ciliary block predisposing to angle-closure glaucoma, which is more common in eyes with PEX (Ritch 1994b; von der Lippe et al. 1993). Miotics may exacerbate forward movement of the iris-lens diaphragm and cause attacks of pupillary block angle-closure glaucoma. This pronounced instability of the zonular apparatus is easily understood by analyzing the underlying histopathologic alterations of the zonules and their attachments at the lens and ciliary body (see below).

Although the changes of the anterior lens capsule are important for diagnosis, they are relatively harmless. In the classic manifestation, a “target” pattern of deposited PEX material is recognizable with a dilated pupil (Figs. 6.3.4a, 6.3.7a) (Vogt 1925). It consists of a loosely attached central disc of fibrillar PEX material (Fig. 6.3.7b), which is separated from the peripheral zone with nodular PEX aggregates (Fig. 6.3.7c) by a 1- to 2-mm-wide clear intermediate zone produced by removal of the deposits by iris movements. The central disc, corresponding to the size of the pupil, appears to result from diffuse sedimentation of PEX material from

Fig. 6.3.8. Schematic representation of the presumed origin of lenticular PEX material (AH aqueous humor, CD central disc, GZ granular zone, LC lens capsule, LE lens epithelium, PCL precapsular layer, PZ preequatorial zone)

the aqueous, whereas the peripheral granular zone builds up by undisturbed accumulation of nodular PEX aggregates produced by the iris pigment epithelium; the intermediate clear zone is created by abrasive

movements of the peripupillary iris during pupillary movement (Fig. 6.3.8) (Naumann et al. 1998).

The anterior and posterior lens capsules proper appear to be morphologically normal and have been reported to have a similar mean thickness and elasticity compared to control eyes. In contrast, the preequatorial capsule, corresponding to the proliferative zone of the lens epithelium and the zone of zonular anchorage, is associated with significant alterations and dangers for the intraocular surgeon. In this area, active production of PEX material occurs by the preequatorial lens epithelium. Exuberant bundles of PEX fibrils appear to originate from the adjacent lens epithelial cells, which disrupt the capsule proper and invade the zonular lamella, resulting in separation of the zonules from their insertion onto the capsule (Schlötzer-Schrehardt and Naumann 1994) (Figs. 6.3.7d, 6.3.9a, b). These alterations are usually not visible on clinical examination, being hidden behind the iris, but give rise to a marked instability of the zonular attachment to the lens (Fig. 6.3.10).

Similarly, at their origin and anchorage in the nonpigmented ciliary epithelium, the zonular bundles are separated from their connection to the disrupted epi-

thelial basement membrane by locally produced, intercalating PEX fibers (Fig. 6.3.9c, d) (Schlötzer-Schre- hardt and Naumann 1994). Zonular disintegration may be further facilitated by degenerative changes of the freely suspended zonular fiber bundles between ciliary body and lens, which are focally infiltrated by PEX material containing proteolytic enzymes (Fig. 6.3.9e, f). Every ophthalmologist planning intraocular surgery in patients with PEX syndrome should recall these alterations of the zonular apparatus. As they are biomi-

croscopically not visible, they “must be kept in mind.” They present a real risk particularly in advanced stages.

Production of PEX material by the remaining lens epithelial cells continues to occur after extracapsular cataract extraction and may cause late decentration or even subluxation of the lens implant within the capsular bag (Fig. 6.3.6c, d) (Auffahrt et al. 1996).

Z

PEX

NPE

e

Fig. 6.3.9. e, f Freely suspended zonular bundles (Z) passing alongside the nonpigmented ciliary epithelium (NPE) are infiltrated (E) and disrupted (F) by PEX material

c

d

a, b

BM

PEX

f

6.3.4.2 Iris

PEX syndrome has a multitude of effects on iris tissues with clinical importance. Numerous histopathologic studies have demonstrated that virtually all iris cell types (epithelial cells, fibrocytes, melanocytes, vascular endothelial cells, pericytes, and smooth muscle cells) are involved in PEX material production and deposition including the posterior pigment epithelium, dilator and sphincter muscles, anterior border layer, stromal fibroblasts and melanocytes, and blood vessels (Fig. 6.3.11) (Asano et al. 1995; Naumann et al. 1998). This abnormal metabolic activity disturbs their normal function and leads to progressive tissue damage.

Clinically, the PEX iris is characteristically rigid with reduced dilating properties (Carpel 1988), which has been attributed to a combination of PEX fiber deposition in the stroma and muscle tissues along with degenerative changes of sphincter and dilator muscles (Fig. 6.3.12a, c) (Asano et al. 1995).

Concomitantly, the pigment epithelial cells in the pupillary ruff and sphincter regions show marked degenerative changes with focal membrane ruptures and

Fig. 6.3.10. Schematic representation of the typical localizations of zonular alterations in PEX syndrome; PEX material production and zonular infiltration is indicated by arrows and arrowheads. a Origin of zonular fibers in the nonpigmented ciliary epithelium. b Zonular anchorage within the nonpigmented ciliary epithelium. c Freely suspended zonular bundles passing along the ciliary processes. d Zonular attachment to the anterior lens capsule (BM basement membrane, LC lens capsule, LE lens epithelium, NPE nonpigmented ciliary epithelium, Z zonular fibers, ZL zonular lamella)

b

PEX

PEX

liberation of melanin granules (Fig. 6.3.12a, b) (Asano et al. 1995). These changes result in a diagnostically important peripupillary atrophy and characteristic “moth-eaten” transillumination defects in the peripupillary region (Fig. 6.3.13a–c) accompanied by a char-

acteristic pattern of pigment deposition on the iris surface, trabecular meshwork, corneal endothelium, and other anterior segment structures (Fig. 6.3.13d, e) (Prince et al. 1987). Additionally, dispersion of melanin granules following pharmacological dilatation due to

e

g

Fig. 6.3.13. (Cont.)

rupture of degenerative pigment epithelial cells may be marked and even result in an acute rise in intraocular pressure (Fig. 6.3.13a). In the absence of other causes for melanin dispersion, PEX should always be considered in the differential diagnosis of this phenomenon.

Involvement of the iris stromal vessels has major functional consequences. PEX fibers are deposited in the wall of iris vessels associated with degeneration of smooth muscle cells, pericytes, and endothelial cells up to complete destruction of the vessel wall (Fig. 6.3.12a, d) (Asano et al. 1995). In advanced stages, iris blood vessels may become obliterated (Fig. 6.3.12e) resulting in iris hypoperfusion and reduced partial pressure of oxygen in the anterior chamber (Helbig et al. 1994). On fluorescein or indocyanine green angiography, changes including iris vessel dropout and dye leakage may be seen (Fig. 6.3.13g, h) (Brooks and Gillies 1983; Parodi et al. 2000). Cataract formation and altered behavior of corneal endothelial cells (see below) have also been attributed to anterior chamber hypoxia in PEX eyes.

“Spontaneous” intrastromal hemorrhages after mydriasis indicate significant vascular damage and friability and may be more common than appreciated, but overlooked particularly in brown irides (Fig. 6.3.13f) (Naumann et al. 1998) because the small hemorrhages are

f

h

Table 6.3.4. Differential diagnosis of pseudoexfoliation syndrome

True exfoliation of the lens capsule (infrared or “glassblowers” cataract)

Fibrin or inflammatory precipitates on anterior lens capsule Melanin dispersion

Diabetes ”Senile”

Idiopathic “melanin dispersion syndrome,” pigmentary glaucoma (both in young myopes)

Uveitis, Fuchs’ heterochromia complicata Trauma

Intraocular tumors

Segmental iris necrosis (e.g., chronic angle-closure glaucoma, pupillary block, herpes zoster)

Long-standing mydriasis Senile iridoschisis

Marfan syndrome (homocystinuria)

hidden in iris stroma crypts. In lightly pigmented blue irides such hemorrhages are more easily recognized.

Another important consequence of the iris vasculopathy is a chronic breakdown of the blood-aqueous barrier in eyes with PEX syndrome (Küchle et al. 1995). Clinically this may manifest as a pseudouveitis with elevated aqueous flare and formation of posterior syn-