Ординатура / Офтальмология / Английские материалы / Ocular Pathology_6th edition_Yanoff, Sassani_2009

A

t

td

rd

B C

Fig. 11.21 Typical and reticular microcystoid degeneration. A, Typical microcystoid degeneration (td) starts just posterior to the ora serrata. Reticular cystoid degeneration (rd) is present just posterior to the typical microcystoid degeneration. B, A transitional zone from typical to reticular cystoid degeneration is seen. The typical microcystoid degeneration is to the right (shown under increased magnification in C; t, transitional zone; td, middle retinal layers; rd, inner retinal layers).

(B and C, Courtesy of Dr. RY Foos.)

A.Microcystoid peripheral degeneration of the neural retina appears clinically as myriad, tiny, interconnecting channels in the peripheral neural retina, especially temporally.

B.All persons 8 years of age or older show the lesion. It may also be present at birth, with increasing neural retinal involvement up to the seventh decade of life.

C.The tendency is toward relatively equal bilateral involvement.

1.The temporal neural retina is involved more than the nasal, and the superior sectors are a ected more than the inferior.

2.Relative neural retinal sparing occurs in the nasal and temporal horizontal meridians (the greatest sparing nasally).

D.The degeneration always seems to begin at the ora serrata. From there, it extends posteriorly and circumferentially.

E.Histologically, spaces within the neural retina (cysts) are located in the outer plexiform and adjacent nuclear layers.

1.Early, the cysts are limited to the middle layers of the neural retina. Later, they may extend to the external and internal limiting membranes of the neural retina.

2.Although they appear empty in hematoxylin and eosin-stained sections, they contain hyaluronic acid, which is best seen with special stains.

The septa separating the cysts are composed of glial–axonal tissue rich in the cytochrome oxidase enzyme system.

3.As microcysts coalesce, an intraneural retinal macrocyst or retinoschisis cavity is formed when the macrocyst is at least 1.5 mm in length (one average disc diameter).

Pars plana cysts (see Fig. 9.11) are intercellular cysts of the nonpigmented layer of ciliary epithelium and may be filled with hyaluronic acid. They may also contain the protein of multiple myeloma.

II.Reticular peripheral cystoid degeneration (see Fig. 11.21)

A.Reticular peripheral cystoid degeneration appears clinically posterior to typical peripheral microcystoid degeneration.The subsurface retinal vasculature arborizes into

fine branches throughout the reticular lesion.

B.The condition is seen in approximately 13% of autopsy eyes and is bilateral in approximately 41%. It can be found in every decade of life without a clear relationship to aging.

C.The inferior and superior temporal regions, each

involved to approximately the same extent, are more a ected than the inferior and superior nasal regions.

Typical microcystoid peripheral degeneration of the neural retina is always found as an accompanying neural retinal lesion. In some instances, the reticular lesion may become partially surrounded by the posterior extension of typical microcystoid peripheral degeneration. A number of macroscopic features distinguish reticular from typical microcystoid peripheral degeneration. The retinal vasculature, when traced from uninvolved neural retina posteriorly, arborizes into fine branches throughout the reticular lesion, whereas only the larger vessels are apparent in typical lesions. In reticular lesions, the neural retina is less transparent than in typical lesions. The lateral and posterior borders of reticular lesions are linear and angular, often coinciding with the course of large retinal arte-

A

C

E

rioles and venules; typical lesions usually have a smoothly rounded margin.

D.Histologically, the neural retinal cysts of reticular peripheral cystoid degeneration are located in the nerve

fiber layer of the neural retina.

1.Early, the cysts are located completely within the nerve fiber layer; later, they may extend from the internal limiting membrane to the inner plexiform layer.

B

D

Fig. 11.22 Typical microcystoid degeneration. A, Gross specimen shows that typical microcystoid degeneration starts just posterior to ora serrata. B, Gross appearance in cross-section. C, Scanning electron microscopic appearance (receptors at bottom). D, Both top and bottom stained for acid mucopolysaccharides; bottom digested with hyaluronidase before staining. Note disappearance of positive staining in microcyst. E, Diphosphopyridine nucleotide diaphorase (nitro-blue tetrazolium method). Glial–neuronal columns show dense precipitate of formazan, signifying the presence of the cytochrome oxidase system. (C, Courtesy of Dr. RC Eagle, Jr.)

2.The cysts contain hyaluronic acid.

3.Similar nerve fiber layer cystic changes can be seen in the neural retina in areas adjacent to the retinoschisis cavity in juvenile retinoschisis (p. 437 in this chapter).

Degenerative Retinoschisis

I.Retinoschisis—typical degenerative senile (adult) type (Fig. 11.23)

Retinoschisis may be defined as an intraneural retinal tissue loss or splitting at least 1.5 mm in length (one disc diameter). It is differentiated from a neural retinal cyst by its configuration—namely, a neural retinal cyst has approximately the same diameter in all directions (and usually a narrow neck), whereas the diameter of retinoschisis parallel to the neural retinal surface is greater than the diameter perpendicular to the surface.

A.Typical retinoschisis is seen in approximately 4% of patients, and is bilateral over 80% of the time.

B.It is most common after the age of 40 and rare before the age of 20 years.

C.Characteristically, it is found in the peripheral inferior temporal quadrant (approximately 70% of cases), with

the superior temporal quadrant (approximately 25%) the next most common site; little tendency exists for the retinoschisis to progress posteriorly, but the posterior border is postequatorial in approximately 75% of cases.

The splitting of neural retinal tissue in the area of retinoschisis results in an absolute scotoma. Occasionally, the retinoschisis

involves only the macular area. In most of the macular cases, ocular trauma seems to be the initiating factor.

D.The inner layer of retinoschisis has a characteristic beaten-metal or pitted appearance and frequently has tiny, glistening, yellow-white dots.

The glistening yellow-white dots have been thought to be reflections from the remnants of ruptured glial septa clinging to the internal limiting membrane of the neural retina. However, the dots are not found in all cases, and biomicroscopy shows that they seem to lie internal to the neural retinal internal limiting membrane. Probably, the glial remnants cause an uneven external surface to the inner wall of the retinoschisis cavity and produce the beaten-metal appearance.

E.Neural retinal holes tend to be small and numerous in the inner wall and large and singular in the outer wall (just the reverse of juvenile retinoschisis).

Although retinoschisis can mimic a neural retinal detachment, clinical examination usually shows the difference. In difficult

cases, photocoagulation may help to distinguish one from the other. After photocoagulation, a detached neural retina usually shows no blanching effect, but in retinoschisis the outer layer becomes blanched. Rarely, however, blanching can occur with rhegmatogenous neural retinal detachment. Another difference is that retinoschisis shows an absolute scotoma but neural retinal detachment usually shows a relative scotoma.

F.Histologically, a splitting is seen in the outer plexiform layer and adjacent nuclear layers.The cavity is filled with a hyaluronidase-sensitive acid mucopolysaccharide, presumably hyaluronic acid.

1.As the area of the retinoschisis enlarges,the involved neural retina is destroyed.

2.The inner wall in advanced retinoschisis is usually made up of the internal limiting membrane, the inner portions of Müller cells (remnants of ruptured glial septa), remnants of the nerve fiber layer, and blood vessels.

3.The outer wall mainly consists of the outer plexiform layer, the outer nuclear layer, and the photoreceptors.

4.Bridging the gap between the inner and outer walls are occasional strands or septa composed of compressed and fused remnants of axons, dendrites, and

Müller cells.

Senile retinoschisis may develop from a coalescence of the cysts of microcystoid degeneration. Microcystoid degeneration, however, is present in 100% of people older than 8 years of age. Senile retinoschisis is present in approximately 4% of people. Therefore, if senile retinoschisis does arise from peripheral microcystoid degeneration, it does so only in a small number of cases. The cause of the progression to retinoschisis is unknown.

II.Retinoschisis—reticular degenerative (adult) type (see Fig.

11.23)

A.Reticular retinoschisis is found in approximately 2% of autopsy cases, and is bilateral approximately 16% of the time.

1.A band of typical microcystoid degeneration always separates the schisis from the ora serrata.

2.It may occur concomitantly with typical degenerative retinoschisis.

B.It is most common after the fifth decade and rare before the fourth.

C.It has a predilection for the inferior temporal quadrant.

D.Round or oval holes may be present in the outer wall, but rarely in the inner wall.

E.Histologically, the inner wall of the schisis is composed of the neural retinal internal limiting membrane and minimal remnants of the nerve fiber layer.

1.The outer wall is made up of receptors and outer nuclear and plexiform layers.

2.The area of involvement is similar to that found in juvenile retinoschisis (see p. 437 in this chapter).

Secondary Microcystoid Degeneration and

Retinoschisis

I.Microcystoid degeneration and retinoschisis have been found in a variety of pathologic conditions such as longstanding neural retinal detachment, choroidal tumors (especially malignant melanomas, hemangiomas, and metastatic carcinomas), age-related macular degeneration

(ARMD), retinopathy of prematurity, Coats’ disease, retinal angiomatosis, diabetic retinopathy, uveitis, parasitic disease, and aplastic anemia.

II.Histologically, secondary microcystoid degeneration and retinoschisis are similar to the primary typical type, except that in the secondary form the cystoid spaces do not usually contain an acid mucopolysaccharide.

In infants, retinoschisis secondary to trauma may have a cleavage plane much more internal in the neural retina than does the typical senile type or the usual secondary type. This internal cleavage plane resembles the area of involvement in reticular retinoschisis and in hereditary juvenile retinoschisis.

Paving Stone (Cobblestone) Degeneration

(Peripheral Chorioretinal Atrophy;

Equatorial Choroiditis)

I.The lesions of paving stone degeneration (Fig. 11.24) tend to increase in incidence and in size with age and with axial length of the eye.

They are present in approximately 25% of autopsy cases

and bilateral in approximately 38%.

II.The lesions are located primarily between the ora serrata and equator and are separated from the ora serrata by normal neural retina.

A.The lesions are nonelevated,sharply demarcated,yellowwhite, single or multiple, separate or confluent, and often contain prominent choroidal vessels.

B.They are most common in the inferior temporal quadrant (approximately 78%), with the inferior nasal

quadrant the next most common site (approximately

57%).

The lesions often coalesce and extend in a band with scalloped borders, from temporal to nasal areas in the inferior neural retina.

III.Histologically, the lesions are characterized by:

A.Neural retinal thinning in an area devoid of pigment epithelium and an intact Bruch’s membrane with the neural retina closely applied to it.

With artifactitious detachment of the neural retina (e.g., after

fixation) the neural retina in the area of the paving stone degeneration remains attached. Paving stone degeneration, therefore, is not a predisposing factor for neural retinal detachment and may actually protect against it neural retinal detachment.

B.An absent choriocapillaris (especially at the center of the lesion) or a partially obliterated choriocapillaris or sometimes only minimal abnormalities such as thickening of the walls of the choriocapillaris; the choroid is otherwise normal

C.Hypertrophy and hyperplasia of the pigment epithelium at the lesion’s margin

D.The overlying neural retina in the posterior pole thins and degenerates, a ecting mainly the outer layers.

E.The peripheral neural retina also becomes thin and atrophic and, therefore, more susceptible to neural retinal tears.

Peripheral Retinal Albinotic Spots

I. Areas of hypopigmentation in the neural retinal periphery are caused by depigmentation of the RPE.

II.Although the lesions are probably degenerative, a congenital cause cannot be ruled out.

Myopic Retinopathy

I.Myopia of a small or moderate degree is not usually associated with neural retinal degenerative changes.

II.Progressive, pathologic, or “high” myopia (greater than 6 diopters of myopia) a ects the neural retina most severely in the posterior pole and in the periphery.

A.The globe is mainly enlarged in its posterior third, with thinning of the sclera.

B.Surrounding the optic disc and usually extending temporally (but possibly extending in any direction) to involve the posterior pole, the thinned sclera bulges posteriorly to form a staphyloma that is lined by a thin and atrophic choroid.

C.Bruch’s membrane may develop small breaks (lacquer cracks) through which connective tissue may grow beneath the RPE.

The breaks in Bruch’s membrane in the macular region may lead to CNV and a small hemorrhage that later organizes and becomes pigmented. This appears clinically as a small, dark, macular lesion known as Fuchs’ spot (actually a “mini” exudative macular degeneration).

Macular Degeneration

Idiopathic Serous Detachment of the RPE

(Fig. 11.25)

I.The condition occurs mainly in men between the ages of

20 and 55 years.

A.It is characterized by a sharply demarcated, domeshaped elevation of the RPE.

B.Fluorescein angiography shows early and persistent filling of the whole area of detachment.

II.Serous RPE detachments have a good prognosis, and probably are a variant of idiopathic central serous choroidopathy.

A.Most RPE detachments are between one-fifth and one-half disc diameter, rarely reaching two disc diameters.

B.Most resorb or flatten, leaving behind a disturbance of pigmentation.

Tears or rips in the RPE result in a profound reduction in vision. When serous RPE detachments occur in patients older than 50 years of age, they may be accompanied by CNV. A flattened or notched border of a detached RPE is an important sign of occult CNV, and may be visualized using indocyanine green angiography. Serous RPE detachments may occur as a component of idiopathic central choroidopathy or in association with entities such as ARMD (dry or exudative types), angioid streaks, or POHS. The detachments should be distinguished from multiple vitelliform lesions, a variant of Best’s disease (see p. 442 this chapter).

Idiopathic Central Serous Choroidopathy (Central

Serous Retinopathy; Central Angiospastic

Retinopathy) (See Fig. 11.25)

I.Typically, idiopathic central serous choroidopathy occurs in healthy young adults (most commonly men) between the ages of 20 and 40 years, often after emotional stress.

A positive association exists between central serous retinopathy and gastroesophageal reflux disease (GERD). Also, circulating glucocorticoid and mineralocorticoid levels are abnormal in many patients who have central serous retinopathy and may contribute to its pathogenesis. Other risk factors include systemic steroid use; pregnancy; alcohol, antibiotic, antihistamine, and tobacco uses; autoimmune disease; untreated hypertension; and previous ocular surgery.

II.The symptoms are those of metamorphopsia, positive scotoma, and micropsia.

III.The condition recurs in approximately one-fourth to onethird of patients and occasionally may become bilateral.

IV. Clinically the involved area, most often in the macula, shows fluid under the neural retina. Because the area is not sharply demarcated from normal retina, the borders of the detached neural retina are fuzzy. Often tiny white spots are seen in the area.

V.A localized detachment of the neural retina may be associated with a tiny detachment of the RPE.

A.Early fluorescein angiography shows a tiny “beacon” of light, which is fluorescein entering the sub-RPE space.

B.Fluorescein then spreads slowly into the large subneural retinal space, classically showing smokestack and umbrella configurations in the early phases. In the late phases, the fluorescein fills the subneural retina space incompletely so that the boundaries of neural retina detachment are not sharply demarcated and show fuzzy borders.

Neural retinal detachments may spread inferiorly, resulting in inferior hemispheric RPE atrophic tracts or

gutters.

VI. The basic defect appears to be in Bruch’s membrane or the choriocapillaris, or both, but the underlying cause is unknown.

VII. Most cases heal spontaneously with restoration of normal vision.

Sometimes the course is prolonged. Tiny yellow precipitates, probably lipid-filled macrophages, are often seen on the outer surface of the detached neural retina. A chronic course may result in irreversible changes in the RPE and neural retina. Such changes may also result from recurrent attacks. Idiopathic central serous choroidopathy can be simulated by secondary central serous retinopathy, secondary to ocular conditions such as peripheral choroidal malignant melanoma (see Fig. 17.34), choroidal hemangioma, and pars planitis, or such systemic entities as thrombotic thrombocytopenic purpura, malignant hypertension, eclampsia, and Harada’s disease. Although idiopathic central serous choroidopathy typically involves the posterior pole, it can occur in any part of the posterior half of the eye, including regions nasal to the optic disc.

Drusen

I.Drusen (Figs 11.26 and 11.27) are focal or di use basement membrane products produced by the RPE and admixed with other materials that may become trapped in

the drusen as they pass through them in transit between the RPE and choriocapillaris.

The word drusen is plural; druse is the singular form—similar to dellen (plural) and delle (singular).

A.Drusen tend to be found mainly in four regions of the fundus: (1) in the distribution of the major vascular arcades; (2) in the macular region; (3) a combination of (1) and (2); and (4) in a peripheral distribution.

B.Drusen vary considerably in size (see later), ranging from 30 to 50 μm, or even larger when confluent.

RPE, like other ocular epithelia, may react to a variety of insults or stimuli by producing abnormal quantities of basement membrane. The variable structure of the basement membrane accumulations undoubtedly mirrors the aberrant biochemical

activities conducted by the producing cell (e.g., more glycoprotein → more homogeneous or vacuolated basement membrane, more collagen → more filamentous or fibrous basement membrane). The basement membranes so produced are exaggerations of the normal varieties of thin, multilaminar, and thick. In contrast to these exaggerations of the normal or age-related changes, the deposition or addition of materials not normally present in basement membranes (e.g., fibrin, amyloid, or various metals such as silver and copper) would produce more complex pathologic basement membranes. The Bruch’s membrane component of RPE, similar to the intima of arteries and arterioles, shows increased deposition of cholesterol with age.

II.Drusen consist of at least two fundamentally di erent focal types.*

A.The first focal type, nodular (“hard,” discrete) drusen, consists of a focal thickening of the RPE basement membrane (see Fig. 11.26).

1.These are congenital or acquired early in life and have a relatively good prognosis. They are small,

yellow or yellow-white spots or discrete RPE lesions measuring approximately 50 μm.

2.Nodular drusen have a rather random distribution, appearing as isolated drusen, scattered about in the posterior pole, without a recognizable pattern.

3.When they occur in great numbers, they may, in later life, be associated with the development of the second type of drusen (see later).

4.By fluorescein angiography, some show early fluorescence and late staining.

5.The presence of nodular drusen probably does not represent a high risk factor for the development of exudative (wet) ARMD; it is unclear whether it represents a high risk factor for the development of dry (nonexudative) ARMD.

*Personal communication from Dr. JDM Gass.

6.Histologically (see Fig. 11.26), nodular drusen have an eosinophilic, PAS-positive, amorphous appearance and are located external and contiguous to, or replace, the original, thin basement membrane of the RPE (i.e., between RPE basement membrane and Bruch’s membrane). The overlying RPE is usually atrophic, whereas the adjacent RPE is frequently hyperplastic.

7.The so-called basal laminar (cuticular) drusen (see

Fig. 11.26) are one form of nodular drusen.

Basal laminar drusen should not be confused with the electron microscopist’s terminology of basal laminar and basal linear deposits (confluent drusen or diffuse thickening of the inner aspect of Bruch’s membrane), both of which are associated with, or are a form of, large drusen (see later).

a.Basal laminar drusen are yellowish, punctiform, and uniform in size.

b.Unlike the aforementioned nodular drusen, basal laminar drusen have a recognizable pattern of distribution, appearing in clusters in the posterior pole.

c.They may appear in early adulthood and occur with equal frequency in black, Hispanic, and white patients.

d.Fluorescein angiography shows focal areas of hyperfluorescence in the early arteriovenous phase, giving a “stars-in-the-sky” or “milky-way” appearance.

e.Patients who have basal laminar drusen may also acquire soft drusen with increasing age; the presence of soft drusen represents a high risk factor for the development of ARMD.

f.Histologically, basal laminar drusen consist of nodular protrusions of the inner side of a thickened RPE basement membrane.

g.Basal laminar (cuticular) drusen phenotype are

highly associated with the Tyr402His variant of the complement factor H (CFH) gene

8.Nodular drusen may become calcified, lipidized, cholesterolized, or, infrequently, vascularized.

B.The second, focal type is a limited separation of the relatively normal basement membrane of the RPE from its attachment to Bruch’s membrane at the inner collagenous zone by a wide variety of materials that di er in consistency from bone to fluid.

1.These usually are acquired at 50 years of age or later and represent the earliest sign of ARMD.

2.The second type of drusen may be impossible to di erentiate by clinical methods or by light microscopy from small detachments of the RPE.

3.One form of this second type is large (“soft,” exudative, flu y) drusen (see Fig. 11.27).

a.Large drusen are bigger than nodular drusen, appear less dense and more flu y, and when quite large are indistinguishable from small detachments of the RPE.

A subset of large drusen are confluent drusen (“diffuse” drusen), which appear clinically as diffuse yellow deposits and histopathologically as confluent large drusen.

b.Large drusen may develop under, and engulf or encompass, nodular drusen.

c.Fluorescein angiography usually shows staining of the drusen, although some may appear hypo-

fluorescent, presumably because of lipid accumulation.

d.The presence of large drusen represents a highrisk factor for the development of dry (atrophic) and exudative (wet) ARMD.

4.Histologically, large drusen consist of an amorphous, PAS-positive material, which is indistinguishable from an RPE detachment.

a.Basal laminar deposits consist of banded basement membrane (“wide-spaced collagen”) material located between (external to) the basal plasmalemma of the RPE and the internal surface of Bruch’s membrane.

PAS stains basal laminar deposits as brushlike deposits along the inner aspect of the RPE basement membrane.

b.Basal linear deposits refer to material located external to the basement membrane of the RPE

(i.e., in the innermost layer of Bruch’s membrane).

Large drusen may result from localized detachments of basal laminar deposits (localized small detachments may appear clinically as large drusen and large detachments as serous RPE detachments), from localized detachments of basal linear deposits (confluent drusen—often appear clinically as a serous RPE detachment), or from localized accumulations of basal linear deposits (appear clinically as large drusen). Basal laminar and basal linear deposits, both of which are often present in the same eye, may be difficult to differentiate clinically and by light microscopy, although by light microscopy, the PAS-positive brushlike appearance of the basal laminar deposit (see Fig. 11.27C) is helpful in making the distinction. The amount of basal laminar deposit correlates strongly with the histologic presence of ARMD.

c.Large drusen may become calcified, lipidized, cholesterolized, or, infrequently, vascularized.

C.Reticular pseudodrusen

1.Reticular pseudodrusen appear as a yellow, interlacing network 125 to 250 μm wide, appearing first in the superior outer macula, and then extending circumferentially and beyond.

2.They do not fluoresce with fluorescein or indocyanine green angiography.

a.They are best seen with red-free light or the He-Ne laser of the scanning laser ophthalmoscope.

b.They may be an important risk factor for the development of exudative ARMD.

3.Histologically, the changes are choroidal and do not represent an accumulation of basal laminar and linear deposits or drusen.

An almost total absence of the small vessels that normally occupy the middle choroidal layers and that also lie between the large choroidal veins seems to cause the clinically seen reticular pattern.

Age-Related Dry Macular Degeneration (Dry, Atrophic, or Senile Atrophic Macular Degeneration)

I.Dry ARMD (Figs 11.28 and 11.29) is characterized by a gradual reduction of central vision.

A. The cause is unknown.

The photoreceptor gene, ABCR (ATP-binding cassette transporterretina; also known as STGD1) on chromosome 1p21 is mutated in Stargardt’s disease. Approximately 18.7% of cases of dry ARMD also have mutations in the ABCR gene. In one large family, which had mainly dry ARMD, the ARMD segregated as an autosomal-domi- nant trait localized to chromosome 1q25–q31. A small fraction of patients with ARMD may actually have a late-onset variant of Best’s disease. The alleles of the apolipoprotein (apoE) gene are the most consistently associated with ARMD. The ε4 allele seems to be protective or delaying and the ε2 allele seems to accelerate the course of ARMD. Autosomal-dominant ARMD can be caused by mutations (e.g., 208delG mutation) in the FSCN2 gene, as may autoso- mal-dominant retinitis pigmentosa (RP).

B.The risk increases with age, especially 75 years and older, and in women.

In first-degree relatives of patients who have “late” ARMD, ARMD develops at an increased rate at a relatively young age. Perhaps 25% of all late ARMD is genetically determined.