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

a

b

c

Fig. 5.5.12. Aging changes of the lens fibers. a Age-related nuclear cataract caused by nuclear sclerosis. b Electron micrograph of nuclear lens fibers of a 17-year-old individual. c Electron micrograph of nuclear lens fibers of a 86-year-old individual

Moreover, the site of the anterior zonular insertion becomes displaced more centrally with age (Sakabe et al. 1998). Thus, the width of the zonule-free area of the anterior capsule reduces from about 7.5 mm in young adults (age 20) to 6.5 mm in the eighth decade, so that the insertion may intrude into the region selected for capsulorrhexis during surgery (Farnsworth and Shyne 1979; Stark and Streeten 1984; Sakabe et al. 1998). To create the capsulorrhexis within the zonule-free zone, it is recommended to stay within the central 6.8-mm area of the anterior capsule, which is the average diame-

a

b

Fig. 5.5.13. Long anterior zonules. a, b Centrally displaced insertion of anterior zonules on the anterior lens capsule in a 66- year-old patient (from Moroi et al. 2003)

ter of the zonule-free zone (Sakabe et al. 1998). The origin of the zonule from the pars plana is also thought to move anteriorly with age (Farnsworth and Shyne 1979).

It has to be considered that a small percentage of cataract patients may disclose an unusual centrally displaced anterior zonule insertion, a phenomenon which has been described as “long anterior zonule syndrome” (Moroi et al. 2003) (Fig. 5.5.13).

5.5.4.3

Biochemical Changes

As the lens ages, it changes in color from colorless to pale yellow to darker yellow in adulthood, and brown or even black in old age (brunescence of the lens). These changes in coloration, which are limited to the nucleus, are thought to result from biochemical production and accumulation of yellow-pigmented fluorescent protein derivatives and advanced glycation end products. They result in an increased absorption of both ultraviolet and visible light, particularly the blue part of the spectrum, and an age-related shift in the spectral

transmission of the lens. In addition, there is an age-re- lated increase in light scattering of the nucleus due to the accumulation of insoluble high molecular weight aggregates of crystallins and nonenzymatically glycated proteins (Berman 1994; Bron et al. 2000). The increased capacity of the lens to absorb light, in combination with the increased scattering properties of the lens, results in a decrease in transparency. This increase in the amount of absorbed light is accompanied by an age-related loss in antioxidant levels (e.g., catalase, superoxide dismutase, ascorbate, glutathione, glutathione peroxidase), which, therefore, increases the amount of photo-oxidative stress and damage to the lens (Hockwin 1993; Ohrloff and Hockwin 1983; Dawczynski and Strobel 2006).

5.5.5

Surgical Pathology of the Lens

by the presence of some remnants of lens tissue or capsule. It may be associated with developmental abnormalities, such as microcornea, or it may occur as a result of partial or complete absorption of the lens in congenital cataract from rubella.

5.5.5.1.2

Duplication of the Lens (Biphakia)

A metaplastic change in surface ectoderm may prevent the invagination of the lens placode and thereby the formation of a single vesicle, which may lead to a duplication of the lens. This extremely rare condition is usually associated with corneal metaplasia and coloboma of the iris and choroid.

5.5.5.1.3 Microspherophakia

5.5.5.1.5

Lenticonus and Lentiglobus

In both lenticonus and lentiglobus, an abnormality of the central lens curvature occurs, associated with thinning of the lens capsule and deficiency of epithelial cells in the affected region (Fig. 5.5.15). It may be caused by traction of a persisting hyaloid artery on the posterior lens surface or the presence of a weak, underdeveloped lens capsule (Gibbs et al. 1993; Lang and Naumann 1983). The resultant protrusion of the lens surface may be more conical, as in lenticonus, or spherical, as in lentiglobus. The protrusion may be anterior or, more commonly, posterior and measures 2 – 7 mm in diameter. The abnormality may occur sporadically or may be inherited as an autosomal recessive trait or in association with other abnormalities, such as Alport syndrome or oculocerebral syndrome of Lowe.

Histopathologically, the lens capsule is considerably thinned in the affected area. For instance, the thickness of the anterior lens capsule in Alport syndrome is reduced to 4 µm and shows an abnormal ultrastructure

with numerous cleft-like dehiscences facilitating capsular rupture (Streeten et al. 1987) (Fig. 5.5.15b). The central epithelial cells appear degenerative in these regions.

Both lenticonus and lentiglobus may cause lenticular myopia with irregular astigmatism and an oil droplet reflex on retinoscopy. The conditions are commonly associated with progressive circumscribed opacification of the posterior pole fibers. Spontaneous rupture of the extended lens capsule may frequently occur, particularly at the edge of the ectasia.

5.5.5.1.6

Persistent Hyperplastic Primary Vitreous

Persistent hyperplastic primary vitreous (PHPV) is a common developmental anomaly of unknown cause, in which the embryonic hyaloid artery and primary vitreous fail to regress normally (Fig. 5.5.16) resulting in an abnormal lenticular development and secondary changes of the retina and the globe (microphthalmia). The condition is almost invariably unilateral and is

characterized by the presence of a vascularized membrane behind the lens. Eyes with PHPV frequently develop cataract, which may range from a tiny opacity to posterior polar cataract over a widespread vascularized plaque up to a total hypermature white cataract (Fig. 5.5.17), and atrophy of the globe or glaucoma. In addition, the pupil often does not dilate well. The ciliary processes are connected to the retrolental plaque. Surgical removal of the vascular membrane and associated cataract in order to preserve the eye is advisable, but surgery for PHPV is complicated by a higher rate of retinal detachment and most children will develop amblyopia. Without modern imaging methods the entity was often confused with retinoblastoma (see Goldberg, 1997; see also 5.6).

a

Elongated ciliary processes

PHPV

A. + V. hyaloidea

Fig. 5.5.16. Schematic representation of persistent hyperplastic primary vitreous

b

5.5.5.2

Lens Dislocations (Ectopia Lentis)

Any defect of the zonules (developmental abnormalities or degenerative alterations) can lead to partial (subluxation) or complete (luxation) displacement of the lens from its normal position. Ectopia lentis can occur as an isolated entity, congenital or spontaneous in adult age, in association with a number of systemic connective tissue diseases, or secondary to trauma, intraocular tumors, uveitis, PEX syndrome, hypermature cataracts, and other causes (Table 5.5.4; Nelson and Maumenee 1982). Traumatic ectopia is by far the most common cause of lens displacement. The majority of isolated zonular defects is congenital and developmental and usually leads to a bilateral and symmetric dislocation of the lens and/or anomaly in shape. When a lens is dislocated, the metabolic relationships with other structures are compromised, leading to opacifications in later stages. Posterior displacement of the lens may cause lens-induced uveitis.

5.5.5.2.1

Isolated Dislocation

A congenital, isolated dislocation of the lens (ectopia lentis simplex), frequently occurring upward and temporally, can result from maldevelopment of the zonules due to a genetic defect in the fibrillin-1 gene on chromosome 15 (Kainulainen et al. 1994). This is sometimes

Table 5.5.4. Major causes of ectopia lentis

I.Congenital and hereditary lens dislocation

1. Isolated

1.1.Simple ectopia lentis

1.2.Ectopia lentis et pupillae

2.Ocular disease

2.1.Congenital glaucoma

2.2.Aniridia (hemiphakia)

2.3.Megalocornea

3.Systemic disease

3.1.Marfan’s syndrome

3.2.Homocystinuria

3.3.Weill-Marchesani syndrome

3.4.Rare conditions (Ehlers-Danlos syndrome, hyperlysinemia, sulfite oxidase deficiency, Refsum disease, Crouzon syndrome, osteogenesis imperfecta, Sturge-Weber syndrome, Beals’ syndrome)

II. Acquired causes

1.Trauma (blunt and penetrating)

2.Uveitis

3.Hypermature cataract

4.Intraocular tumors

5.High myopia/buphthalmus

6.Uveal staphyloma

7.Ciliolenticular block

III.Unknown etiology

1. Pseudoexfoliation syndrome

associated with a coloboma-like defect of the lens border in the affected region. Ectopia lentis, mostly downward, can also occur spontaneously in older age due to a general degeneration of the zonules (Malbran et al. 1989). Rarely, a simultaneously dislocated lens and pupil can be observed (ectopia lentis et pupillae), which is associated with other abnormalities of the iris (Cruysberg and Pinckers 1995).

5.5.5.2.2

Systemic Diseases and Lens Dislocation

A usually bilateral, progressive dislocation of the lens may be also associated with a number of systemic conditions. The four most important systemic lens displacement syndromes are Marfan’s syndrome, homocystinuria, Weill-Marchesani’s syndrome, and PEX syndrome.

Marfan’s Syndrome

This autosomally dominant inherited syndrome is characterized by ocular, cardiovascular, and skeletal anomalies with variable expressivity (Maumenee 1981; Nemet et al. 2006). Due to a segmental zonular defect, the lens is usually displaced upward and temporally in 60 – 80 % of the patients (Fig. 5.5.18a). The cause of this disease is a genetic defect in the gene for fibrillin-1 on chromosome 15 (Lee et al. 1991). Histopathologically, the rarefied zonules may be focally fragmented or totally lacking (Cross and Jensen 1973). In addition, the anterior chamber angle may have an “undifferentiated” appearance: The ciliary processes are elongated and the fibers of the ciliary muscle reach as far as Schwalbe’s line (Burian et al. 1960). The iris shows sector-shaped hypopigmentation of the posterior pigment epithelium. The dilator muscle is sometimes focally absent; hence, pharmacologic dilatation of the pupil is often incomplete.

Homocystinuria

This autosomal-recessive disorder commonly affects blond individuals. It is characterized by a risk toward generalized systemic vascular thromboses and associated symptoms resembling those of Marfan’s syndrome. However, lens dislocation typically occurs inferonasal in more than 90 % of patients due to a progressive degeneration of the entire zonular apparatus (Fig. 5.5.18b) (Hagee 1984). Histopathologically, a pathognomonic layer of amorphous PAS-positive material, consisting of fragmented zonular fibrils, may be identified near the origin of the zonular fibers on the surface of the nonpigmented ciliary epithelium of the pars plicata (Cross and Jensen 1973). The zonular fibers separate from the ciliary epithelium and retract to their

insertion at the anterior lens capsule – visible as a rim of shrunken undulated zonular fibers in the periphery of the lens. The cause of this disease is a lack of the enzyme cystathionine- q -synthetase (Mudd et al. 1964). Therefore, a lack of cysteine for the formation of the cysteine-rich zonular fibers may be causally involved in zonular alterations.

Marchesani’s Syndrome

This autosomal-recessive disorder is associated with small body size, brachycephaly, brachydactyly, and microspheric lenses, which usually subluxate inferiorly or

anteriorly in most patients due to a progressive degeneration of the zonular fibers. The ocular findings of this syndrome are practically identical to those of homocystinuria (Jensen et al. 1974).

Pseudoexfoliation Syndrome

Due to a pronounced weakness of the zonular fibers, eyes with PEX syndrome have a higher risk of phacodonesis and lens subluxation, which can occur in about 5 % of patients either spontaneously or after minor trauma (Fig. 5.5.18c) (Bartholomew 1970; Freissler et al. 1995). This zonular instability results from a me-

chanically loosened anchorage of the zonular fibers into the basement membranes of ciliary epithelium and lens epithelium by locally produced intercalating PEX fibers (Schlötzer-Schrehardt and Naumann 1994).

Aniridia with Hemiphakia

Aniridia is a rare bilateral congenital autosomal dominant hereditary condition characterized by the absence of the iris and numerous defects of corneal, lens, optic nerve, and retinal tissues. It is caused by a mutation in the PAX6 gene on chromosome 11 and is associated with cataract and ectopia lentis in up to 60 % of patients (Fig. 5.5.18e). In sporadic cases a Wilms’ tumor of the kidney should be excluded (Miller syndrome).

5.5.5.2.3 Traumatic Luxation

Blunt or perforating trauma is the most frequent cause of lens displacements (Völcker 1984) (Fig. 5.5.18f). Traumatic (sub)luxations are not progressive, but often associated with secondary cataracts, particularly contusion rosettes (Asano et al. 1995). The lens may be dislocated into the vitreous or the anterior chamber.

5.5.5.3 Cataracts

Lenticular opacification still remains the most common cause of visual reduction and the leading cause of avoidable blindness worldwide (Sommer 1977; Thylefors 1999; Resnikoff et al. 2004). The classification of cataracts can be based on the time of development (congenital, infantile, juvenile, senile), on the localization of opacifications (polar, capsular, subcapsular, cortical, equatorial, nuclear), on the pattern of opacification (coronary, zonular, cuneiform, etc.), or on the etiology (primary, secondary). The detailed description of the various cataract types is beyond the scope of this chapter, which focuses on general mechanisms of cataract formation instead. Table 5.5.5 summarizes the major clinical forms. Examples for congenital and secondary cataracts are presented in Figs. 5.5.19 – 5.5.21. Agerelated or senile cataract is the most prevalent type of cataract and cataract extraction is the most frequently performed surgical procedure. Significant advances in the surgical methods for cataract extraction, from intracapsular to extracapsular and phacoemulsification techniques, have allowed the development of rapid, small-incision surgery and markedly reduced recovery time.

Lenses from individuals with Alzheimer’s disease disclose beta-amyloid deposits in the cytoplasm of supranuclear/deep cortical lens fibers. These deposits may be related to the equatorial supranuclear cataracts typically observed in Alzheimer patients (Goldstein et al. 2003). Because cerebral beta-amyloid plaques represent a hallmark of Alzheimer’s disease, detection of these specific deposits in the lens might be a means for early diagnosis of Alzheimer’s disease.

5.5.5.3.1

Basic Mechanisms of Cataract Formation

Transparency of the lens results from a close, regular packing of anucleate fiber cells and a highly ordered, evenly distributed, spatial arrangement of lens crystallins, causing minimal light scatter. Opacification results from zones of increased light scattering, which may be caused by a breakdown of fiber regularity, by intraand extracellular fluid accumulations, by products of membrane degradation, by crystalline precipitates, or by

macromolecular protein aggregates within the fiber cells (Figs. 5.5.22, 5.5.23). However, cataracts should be distinguished from physiological aging changes including various degrees of nuclear sclerosis.

Numerous individual causes of cataracts exist, and often multiple factors act together. An association with cataractogenesis has been established for UV-A irradiation, smoking, alcohol consumption, and systemic

diseases such as diabetes mellitus, PEX syndrome or myotonic dystrophy. Certain intraocular diseases (uveitis, retinal dystrophies) are associated with “complicated cataracts.” Among the most important factors contributing to cataract formation are oxidative and osmotic stress, caused by ultraviolet light and a disturbance in the osmotic balance between the aqueous and the lens substance. In senile cataracts, increased ab-