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

the retina (“tobacco dust”), or in the vitreous, may be the only indication of a preexisting retinal hole. In the later and complicated stages, identification of the hole or defect may be impossible because the opaque peripheral vitreous becomes condensed and may obscure the inner surface of the retina. Secondary pre-retinal membranes distort the funnel-shaped detachment and may overlie the preexisting hole. On the other hand, a hole may enlarge as a detachment progresses.

Post-traumatic tears – mostly after severe contusion

– in an otherwise normal retina are more likely to be found in histopathological specimens. These can occur at any anatomical location in the tissue and may complicate penetrating wounds or follow concussion or compression injury. Large peripheral defects, expanding for more than 3 clock-hours, should be referred to as “giant retinal tears.” Prior to the pars plana vitrectomy era, giant retinal tears have been associated with a high risk of proliferative vitreoretinopathy (PVR) and a poor prognosis. In this event, vitreous may remain attached to the retina behind the tear, which interferes with surgical attempts to reattach the retina. In contrast, the term “retinal dialysis” is used for separation of the retina from the RPE at the ora, which may occur spontaneously or bilateral in the inferior temporal quadrant and has a better prognosis.

5.6.2.3.3

Exudative Detachment

The delicate balance of fluid movement within the globe is easily disturbed and the mechanisms involved in metabolic control of water and solute transfer are sensitive to inflammatory mediators. Exudative detachments are most often seen in collateral to malignant melanoma of choroid. The choroid contains a permeable vasculature and the choroidal stroma exerts osmotic pressure on the water which passes through the retina and through the photoreceptor retinal pigment epithelial interface. Fluid movement is probably impeded or modulated by the retinal pigment epithelial monolayer, which consists of hexagonal cells attached by zonulae occludentes. The architecture of the RPE cell, with its apical processes and basal infoldings, suggests a capacity for “ion” transport (see Sect. 5.6.2.3.1).

A convincing explanation for the pathogenesis of exudative retinal degeneration could be leakage of pro- tein-rich fluid from a diseased retinal circulation as seen in congenital vascular malformations, e.g., retinal angiomas or in exudative retinal vasculopathy [Coats’ disease, familial exudative vitreoretinopathy (FEVR)]. Furthermore, granulomatous and non-granulomatous inflammatory disease cause exudative detachment. Similarly, exudation through the walls of choroidal vessels occurs in persisting ocular hypotony.

Table 5.6.6. Causes of exudative retinal detachments

General diseases

Malignant arterial hypertension

Renal insufficiency

Eclampsia

Collagen disease

Rare hematologic disease

Uveitis

Vogt-Koyanagi-Harada

Scleritis

Other severe infectious and other uveitis

Neoplastic disease

Malignant melanoma of choroid

Metastasis

Retinoblastoma

Lymphoma

Retinal vascular disease

Coats’

Angiomatosis retinae

Retinopathy of prematurity

Familial exsudative vitreoretinopathy (FEVR)

Idiopathic or with congenital anomalies

Uveal effusion

Pit of the optic disc

Colobomatous detachment (morning glory)

Others

Subretinal neovascularization

Excessive laser or cryocoagulation

Ocular hypotony

A primary or secondary neoplasm in the choroid can disturb the function of the choriocapillaris and lead to plasma leakage. Neovascularization in age-related macular degeneration will inevitably lead to subretinal exudation.

The uveal effusion syndrome is a rare entity and results in a ring-like detachment of anterior choroid and retina, simulating a malignant melanoma. Uveal effusion syndrome can be idiopathic or associated with rheumatoid scleritis (> 50 % of cases).

The histological features of exudative retinal detachment are usually investigated in choroidal tumors with associated detachment. The retinal structure remains intact better in the region with the smallest distance to the choriocapillaris.

5.6.2.3.4

Central Serous Retinopathy

Central serous retinopathy is a form of exudative detachment of the macula, which is usually self healing, and which occurs in the macular region in young adults and may be recurrent. There is fluid accumulation both in the subretinal space and/or in the sub-RPE space.

The etiology of central serous retinopathy is poorly understood and pathological material is sparse (Mazzuca and Benson 1986; Smiddy et al. 1990). The four

published descriptions show a simple accumulation of fluid between the photoreceptors and the pigment epithelium (Gass et al. 1973) and an inconspicuous choroidal disturbance in RPE fluid transport mechanisms.

It is noteworthy that a similar effusion is observed in aphakia or as an agonal event in eyes removed at autopsy (Lee 2002).

Optical coherence tomography (OCT) may provide additional information (Montero et al. 2005) (Fig. 5.6.16). These authors describe the characteristic features observed in patients with a clinical diagnosis of central serous retinopathy using the OCT ophthalmoscope. In a study by van Velthofen, the characteristics of active CSR (n = 29) included large neurosensory detachment (23/ 29), subretinal hyperreflective deposits (20/29), and pigment epithelial detachment (15/29) (van Velthofen 2005).

Interestingly, high-resolution OCT demonstrates changes in the foveal photoreceptor layer in CSR that are highly correlated with visual acuity loss and may predict visual recovery after macular reattachment (Piccolino et al. 2005).

5.6.2.3.5

Traction Detachment

Today, traction detachment is rarely seen in the oph- thalmo-pathological laboratory, although many experimental studies are available (Hui et al. 1988). Nevertheless, surgically excised membranes are obtained from surgical specimens, e.g., in proliferative diseases or PVR (detailed in Sect. 5.6.4.2).

A severe form of PVR with traction detachment occurs frequently following trauma. Fibrous ingrowth from any form of scleral and uveal perforation incorporates spindle cells which originate from scleral or choroidal fibroblasts. Traction exerted in this manner can displace the retina across the pars plana. In rare cases, the posterior retina remains attached. Traction detachment may also occur in pseudophakic or aphakic patients, when the vitreous prolapses and there is kinking and distortion of the retinal periphery behind the vitreous base. This sometimes gives the impression that there is sufficient strength in the condensed vitreous to exert traction (Lee 2002).

Furthermore, traction is a dominant feature of preretinal neovascularization in ischemic disease of the retina (particularly diabetic vasoproliferative retinopathy) (see Sect. 5.6.2.7). Hemorrhage, due to any cause, stimulates macrophagic infiltration and fibrovascular ingrowth.

5.6.2.3.6

Special Forms of Retinal Detachment

The pathology of inherited vitreoretinopathy resembles peripheral reticular degeneration. It takes the form of

atrophy and schisis in the inner retina, which is associated with vitreous condensation and traction on the retina and disc (see Lang 1990).

For differentiation of inherited disorders both clinical examination and linkage analysis of markers flanking the COL2A1 gene associated with Stickler syndrome type 1, the loci for Wagner disease/erosive vitreoretinopathy (5q14.3), high myopia (18p11.31 and 12q21-q23), and non-syndromic congenital retinal non-attachment (10q21) can be used (van Velthofen 2005).

Hereditary X-linked retinoschisis may also be due to abnormalities in the vitreous, but the current hypothesis favors an abnormality in the Müller cells in the inner part of the retina (Condon et al. 1986; George et al. 1996). There is severe visual loss in males at an early age, and this is due to splitting in the nerve fiber layer which progresses to cyst formation. The abnormal gene (XRLS1) in this condition is coated on chromosome 22 at the Xp22.2 locus (see Sect. 5.6.2.4).

Hereditary progressive arthro-ophthalmopathy (Stickler syndrome) is an autosomal dominant condition due to a point mutation at the gene locus (COL2A1) on chromosome 12, where the control of the normal synthesis of type II collagen occurs. Since this collagen type is found in cartilage, abnormalities are found in the cartilage of joints and the ossicles in the middle ear. Myopia and paravascular lattice degeneration feature in the ocular manifestations, but the salient feature is the presence of condensed vitreous strands at the periphery with optically empty spaces in the central vitreous.

Familial exudative vitreoretinopathy is an inherited, bilateral peripheral vascular disease in children, with no association with prematurity (see Sect. 5.6.2.6). The pattern of inheritance is autosomal dominant. Unlike other inherited diseases, expression of FEVR may be asymmetrical between the two eyes. The clinical course is slowly progressive and rarely stable. Its presentation may be confined to a peripheral avascular zone and a reduced angle kappa or it may lead to a falciform or a rhegmatogenous retinal detachment. The presence of hyalinized preretinal membranes and hyalinized blood vessels surrounded by astrocytes may be an important diagnostic histological feature (Boldreay et al. 1985; Glazer et al. 1995). Retinal exudates and a peripheral fibrovascular mass result from the leakage of peripheral vessels, forming aneurysms, tubular dilatation, and neovascularization, indicating a progressive disease. Such abnormalities must be treated by laser or cryotherapy to stop exudation. Usually, repetitive applications of retinopexy are necessary. The main goal of treatment is the occlusion of abnormal retinal vessels to avoid complications such as tractional retinal detachment and the re-growth of vitreous membranes. The involvement of Wnt signaling in the pathogenesis of FEVR is currently the subject of discussion. Frizzled-

4 (Fz4), a presumptive Wnt receptor, and Norrin, the protein product of the Norrie’s disease gene, function as a ligand-receptor pair.

5.6.2.4

Retinoschisis (Fig. 5.6.8)

A schisis of the retina is found in two distinct entities: frequently as a degenerative change, a consequence of traction from neovascular disease, and as a consequence of trauma or uveitis (Zimmerman and Naumann 1968) and rarely in X-linked juvenile retinoschisis.

Degenerative retinoschisis was first described by Bartels (1933). Straatsma and Foos described two

forms based on histopathology, typical or flat retinoschisis and reticular or bullous retinoschisis (Straatsma et al. 1973). A schisis detachment follows the clinically more severe reticular form (Byer 1986).

In degenerative retinoschisis, there is a coalescence of microcystoid intraretinal lesions as a result of degen-

Retinal defect

Proliferating

RPE cells

c

Fig. 5.6.8. a Retinal detachment and retinoschisis. Together with an old detachment additional schisis may develop. Much more rarely a detachment develops from a schisis with holes in the inner and outer layer. b RPE proliferation clump behind detached retina. c Retinoschisis in old detachment

Fig. 5.6.8. d Secondary retinoschisis overlying cavernous hemangioma of the choroid. e, f Long-standing retinal detachment. Disciform fibrous macular degeneration with inner hole of the retinoschisis (arrow)

d

e

f

eration of neuroretinal and glial supporting elements in the periphery (Lewis 2003). This area enlarges slowly accumulating acid mucopolysaccharide sensitive to hyaluronidase (Zimmermann 1960). As a consequence, separation or splitting of the retina into an inner and an outer layer occurs with severing of neurons and ruptures of Müller cells leading to irreversible loss of visual function – relevant if it extends more centrally.

In typical retinoschisis, the retinal separation occurs deeper in the retina (at the level of the outer plexiform layer) as compared to reticular retinoschisis (inner plexiform layer). Thus, histopathology of typical retinoschisis shows that the inner layer contains the ILM, retinal vessels, and inner plexiform layer, while the outer layer has portions of the outer plexiform, outer nuclear, and photoreceptor layers.

Cyst formation in typical retinoschisis (or typical cystoid degeneration) begins in the outer plexiform layer and was referred to as “edema” by Blessig and Ivanoff. The phenomenon is termed Blessig-Ivanoff cysts (see Sect. 5.6.2.1). The transparent inner layers frequently demonstrate whitish dots representing lipid carrying glial cells after they have phagocytosed retinal tissue. The aspect of forged metal results from remnants of torn Müller cells in the outer layer. There is an absolute scotoma in the area of schisis, which is due to the interruption between photoreceptors and ganglion cells (while a relative scotoma occurs in retinal detachment).

In contrast, reticular retinoschisis demonstrates an extremely thin inner wall consisting of the ILM, remnants of the nerve fiber layer, attenuated blood vessels, and a complete loss of the supporting radial pillars. Of note, the schisis is mainly located vitreal to the neuronal layer. Holes in the outer layer can progress to schisis detachment.

Degenerative retinoschisis is “idiopathic” with no relation to a genetic, vascular, nutritional or tractive etiology. Typical retinoschisis occurs in 1 % of patients, and reticular retinoschisis in 1.6 % of the analyzed autopsy eyes (Straatsma 1973, 1986). There is an increasing incidence of 3.7 % in patients older than 10 years, but 7 % in patients above age 40 years. Eighty-two percent of the cases are bilateral (Straatsma 1968). Retinoschisis is most commonly found in the temporal-inferi- or quadrant.

A rhegmatogenous retinal detachment rarely occurs in eyes with retinoschisis and retinal breaks. Retinoschisis without retinal breaks in either layer does not cause retinal detachment. In retinoschisis, inner retinal holes are rare and probably occur in less than 4 % of cases (Byer 1968, 1986). The incidence of tractional retinal tears in retinoschisis is extremely low. However, retinal tears, secondary to posterior vitreous detachment, may be important in causing progressive rhegmatogenous retinal detachment. Outer retinal holes are

more common than inner retinal breaks, and they are present in 23 % of autopsy cases and in up to 17 % of clinical series (Byer 1986; Zimmermann 1960). They can be single or multiple, can be very large in size, and show a prominent rolled posterior border.

There are two types of retinal detachment associated with retinoschisis: a localized and relatively stable form with outer retinal holes only, and a symptomatic, rapidly progressive detachment with retinal breaks in both layers.

In advanced cases, occlusive vascular changes over areas of acquired retinoschisis were observed. There was intraretinal leakage of the dye from deep capillaries and pooling of the dye in cystic cavities near the margin of the retinoschisis (Tolentino et al. 1976).

5.6.2.4.1

X-Linked Retinoschisis

Mutations in the retinoschisin gene, RS-1, cause juvenile X-linked retinoschisis (XLRS), a dystrophy characterized by delamination of the inner retinal layers, leading to visual impairment. Although the retinoschisin protein (RS) is expressed most abundantly in photoreceptors in the outer retina, XLRS disease affects the innermost retinal layers, including the nerve fiber layer that contains retinal ganglion cells (RGCs).

All major classes of adult retinal neurons, with the possible exception of horizontal cells, express RS protein and mRNA, strongly suggesting that retinoschisin in the inner retina is synthesized locally rather than being transported, as earlier proposed, from distal retinal photoreceptors (Takada et al. 2004).

Foveal lesions vary from predominantly radial striations, microcystoid lesions, honeycomb-like cysts, or their combinations to non-cystic-appearing foveal changes, such as pigment mottling, loss of the foveal reflex, or an atrophic-appearing lesion. Evidence of smaller perifoveal cysts on OCT imaging suggests their location being primarily within the inner nuclear layer of the retina. The findings on OCT images are consistent with the hypothesis of a primary Müller cell defect (Apushinkin et al. 2005a, b). In view of their more radial arrangement in Henle’s layer, this fits with perifoveal slitlike changes.

There is no direct correlation between visual acuity, foveal thickness, and the cystic area.

A limited change in visual acuity was observed in our cohort of 38 patients with XLRS even over an extended period. However, patients with pigment mottling or an atrophic-appearing lesion have a more visual impairment compared to those with a cystic-appear- ing foveal change (Apushinkin et al. 2005a, b).

Surgical or medical treatment for X-linked retinoschisis is not available.

Table 5.6.7. Differential diagnosis of macula hole and its early stages

Preretinal: Macular pucker with pseudoforamen

Intraretinal: Cystoid maculopathy

Subretinal: Central serous macular detachment Solar retinopathy

Central drusen

5.6.2.5 Macular Hole

A macular hole seriously affects visual acuity. Until recently a satisfactory form of treatment was not available. This topic requires detailed discussion. While only 5 – 15 % of the macular holes are a result of blunt trauma or a consequence of high myopia (Reese et al. 1967; McDonnell et al. 1982), 83 % of the macular holes in clinical practice are “idiopathic” (Freemann 1993). Ten percent of the macular holes are bilateral (Aaberg 1970). Several hypotheses for the pathogenesis of full thickness macular holes have been suggested including cystoid foveal degeneration and systemic vascular disease. From early investigations of the fine structure of the vitreous (Sect. 5.6.1.2), it was suggested that a premacular bursa in the vitreous leads to the formation of a hole by mechanical forces due to fluid motion and countercurrents in the premacular bursa during ocular movements (McDonnel 1982; James 1980; Aaberg 1970; Yaoeda 1967; Noyes 1971; Collins 1900). In some cases, an apparent operculum containing fibrous astrocytes and Müller cells over the macular hole was confirmed (Ho et al. 1998) and removal of this membrane led to a marked visual improvement.

The frequent association between cellophane membranes and macular holes indicates a possible common pathogenic pathway. Macular hole without evidence of an epiretinal membrane and macular pucker possibly represent two aspects of the same disease, which can be termed traction maculopathy or “vitreomacular traction syndrome.” (Fig. 5.6.9). Various intermediate stages between macular hole and macular pucker are in favor of the hypothesis that the condition of the vitre-

Fig. 5.6.10. Optical coherence tomography (OCT) demonstrating vitreomacular traction (upper) leading to an impending hole characterized by foveal cyst formation, with the presence of a cystic cavity beneath the elevated retina, a stage 2 macular hole (middle), and spontaneous closure of the hole after vitreous detachment; a small cystic cavity beneath the elevated retina is still present

ous and the activity of cellular proliferation modulate the disease (see Sect. 5.6.2.6) (Fig. 5.6.10). It is important to distinguish idiopathic macular holes and their initial stages from other diseases such as central serous retinopathy, solar retinopathy, cystoid macular edema, central drusen and macular pucker with pseudo-holes (Fig. 5.6.11–5.6.17).

ILM

500 µ

150-200 µ

RPE

a

500 µ

No vessels, no rods, no GC

b

c

Fig. 5.6.11a–d. Cross sections through macular regions close to the foveola. a Scheme with dimensions: Ganglion cells (GC), Nerve-fiber-layer (NF), retinal pigmentepithelium (RPE) b Retinal ganglion cells bare the foveola region. b–d From different eyes

Fig. 5.6.11d

Fig. 5.6.12a, b. Cystoid macular edema. Confluent cystoid spaces. Note the preserved layer of photoreceptors (PAS)

Fig. 5.6.13. Cystoid maculopathy with macular folds. Detachment of the internal limiting membrane (arrows), Alcian blue

a

b

a

b

Fig. 5.6.14. Cystoid maculopathy. a Cross sections close to foveola. b Cystoid spaces in the inner and outer plexiform layer. Inner limiting membrane (ILM), outer limiting membrane (OLM), middle limiting membrane (MLM) (PAS)

According to Gass, four stages of macular hole are distinguished (Gass 1988, 1995) (Fig. 5.6.18). Characteristic of stage 1a are a yellowish spot at the macula (100 – 200 µm diameter), a lack of a foveal depression, and an attached posterior vitreous. The spot can then expand to 200 – 300 µm, forming a ring visible on funduscopy (stage 1b). While in the early stages of macula hole no histology is available, OCT has contributed to a better understanding of the delicate structural changes in macular hole formation. According to Gass, the yellowish spot may be due to the xanthophyll enrichment in photoreceptors and is more visible after a foveal detachment (Gass et al. 1995). It is a matter of debate as to

whether it is located in the inner or outer retinal layers (Tso 1980). Following a retinal dehiscence at the umbo, a passive enlargement of the “occult” hole occurs beneath the semiopaque, contracted vitreous cortex bridging the edges of the hole. The radial retraction of the photoreceptors results in the ring phenomenon. It is well recognized that 30 – 50 % of stage 1a and 1b lesions will arrest or resolve spontaneously often with resolution symptoms in some eyes (Gass 1988; Johnson 1988; Kokame et al. 1995). In such cases, arrest usually occurs following vitreofoveal separation (Kokame et al. 1995), although some authors have suggested that anterior vitreofoveal traction occurs as a result of shrinkage

Fig. 5.6.16. Macular hole after severe contusion

Fig. 5.6.17. Fixed macular folds after reversible ocular hypotony syndrome (PAS stain)

Stage 0: normal

Stage 1a: foveolar detachment

Stage 2: impending hole

Stage 3: full thickness macular hole