Neural (Sensory) Retina

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Neural (Sensory) Retina

Normal Anatomy

I. The neural retina (Figs. 11.1–11.3) is a highly specialized nervous tissue, in reality a part of the brain that has become exteriorized.

Although the terms neural retina and sensory retina are proper, in this chapter, because of “customary” usage, the terms retina, neural retina, and sensory retina are often used interchangeably. The terms refer to all the “layers” of the retina exclusive of its retinal pigment epithelium (RPE), which is discussed separately (see Chapter 17). The term neurosensory retina is redundant.

A. Traditionally, the retina, from the RPE externally to the internal limiting membrane internally, is divided into 10 layers (see Fig. 11.2B).

B. The neural retina has the equivalent of both white matter (plexiform and nerve fiber layers) and gray matter (nuclear and ganglion cell layers).

C. The glial cells are represented mostly by large, all-pervasive, specialized Müller cells and, less noticeably, by small astrocytes (and possible oligodendrocytes) of the inner neural retinal layers.

D. As in the brain, a vasculature is present in which the endothelial cells possess tight junctions, producing a blood–retinal barrier.

Fig. 11.1 Normal retina. A, The anatomic fovea (retinal pit, fovea centralis, clinical macula) is approximately the same size as the optic nerve head and is clearly seen in this child’s eye as a central, horizontally oval ring reflex. B, A retinal trypsin digest preparation shows the dark optic nerve head, the arterioles (which have a small surrounding capillary-free zone and are narrower and darker than the venules), the retinal capillaries, the venules, and the avascular area in the central fovea, the foveal avascular zone. C, The ring reflex of the anatomic fovea (clinical macular reflex ring), as seen in A, is caused by a change in the light reflex as the retinal internal limiting membrane changes from its normal thickness to a thin basement membrane in the central fovea. D, Increased magnification of the anatomic central foveola (clinical fovea) shows, toward the right, the loss of all layers of the neural (sensory) retina except for the photoreceptors, the external limiting membrane, the outer nuclear layer, the outermost portion of the outer plexiform layer, and a thin internal limiting (basement) membrane. (D, Courtesy of Dr. RC Eagle, Jr.)

Fig. 11.2 Normal retina. A, The anatomic macula (posterior pole) is recognized by the multilayered ganglion cell layer, present between the inferior and superior retinal vascular arcades, and from the optic nerve temporally for a distance of approximately four disc diameters (16 mm). This periodic acid–Schiff stain clearly shows the internal limiting (basement) membrane. B, The retina consists of two major parts: the retinal pigment epithelium and the neural (sensory) retina. The latter can be divided into nine layers: (1) photoreceptors (rods and cones); (2) external limiting membrane [terminal bar (zonulae adherentes)—attachment sites of adjacent photoreceptors and Müller cells]; (3) outer nuclear layer (nuclei of photoreceptors); (4) outer plexiform layer (axonal extensions of photoreceptors), which contains the middle limiting membrane (desmosome-like attachments of photoreceptor synaptic expansions); (5) inner nuclear layer (nuclei of bipolar, Müller, horizontal, and amacrine cells); (6) inner plexiform layer (mostly synapses of bipolar and ganglion cells); (7) ganglion cell layer (here a single layer of contiguous cells, signifying a region outside the macula); (8) nerve fiber layer (axons of ganglion cells); and (9) internal limiting membrane (basement membrane of Müller cells) (nr, neural retina; c, choroid; im, internal limiting membrane; nf, nerve fiber layer; gc, ganglion cell layer; ip, inner plexiform layer; in, inner nuclear layer; mm, middle limiting membrane; op, outer plexiform layer; on, outer nuclear layer; em, external limiting membrane; pr, photoreceptors; rpe, retinal pigment epithelium). C, Increased magnification of the photoreceptors shows the inner segments to be cone- and rod-shaped. (B, Modified with permission from Fine BS, Yanoff M: Ocular Histology: A Text and Atlas, 2nd edn. Hagerstown, MD, Harper & Row, 1979 : 113. © Elsevier 1979; C, courtesy of Dr. RC Eagle, Jr.)

Fig. 11.3 Normal retina. Schematic drawing superimposing anatomic terminology on fundus topography. The central capillary ring is also called the perifoveal capillary ring. ILM, internal limiting membrane; XLM, external limiting membrane. (Modified with permission from Fine BS, Yanoff M: Ocular Histology: A Text and Atlas, 2nd edn. Hagerstown, MD, Harper & Row, 1979 : 113. © Elsevier 1979.)

II. Foveomacular region of the neural retina

A. Clinicians often confuse the proper use of the terms fovea, macula, and posterior pole (see Fig. 11.3).

1. For convenience and practicality, the three clinical terms correspond best to the three anatomic terms foveola, fovea (centralis), and area centralis (often called histologic macula). The clinical fovea, therefore, equals the anatomic foveola; the clinical macula equals the anatomic fovea; and the clinical posterior pole equals the anatomic area centralis (“histologic macula”).

2. The anatomic fovea or fovea centralis (which corresponds to the clinical macula) is a depression or pit in the neural retina that is approximately the same size, especially in horizontal measure, as the corresponding optic disc (i.e., 1.5 mm).

3. The anatomic foveola (which corresponds to the clinical fovea) is a small (∼350 µm diameter) reddish disc—that is, the floor of the fovea; it is a major portion of the foveal avascular zone (l500 to 600 µm diameter).

4. The anatomic macula (which corresponds to the clinical posterior pole) comprises an area larger than the anatomic fovea.

a. The term macula is derived from the term macula lutea.

b. It is equated with the histologic appearance of more than a single layer of ganglion cells (i.e., area centralis).

c. The anatomic macula actually encompasses an area contained just within the optic nerve and the superior and inferior retinal temporal arcades, and extends temporally approximately two disc diameters beyond the central fovea.

1) The ganglion cell layer is a continuous, single-cell layer everywhere in the neural retina except in the macular region, where it thickens to form a multilayer.

2) The darkness of the central area of the anatomic macula as seen in fluorescein angiograms is caused by four factors: (1) the yellow pigment (xanthochrome) present mainly in the middle layers of the central macular retina; (2) the central avascular zone; (3) the taller, narrower RPE cells, which contain more melanin granules per unit than elsewhere; and (4) the increased concentration in the central macular RPE of lipofuscin, which acts as an orange filter in filtering out the fluorescence.

III. The retina is susceptible to many diseases of the central nervous system, as well as to diseases affecting tissues in general. In addition, the highly specialized photoreceptor cells are subject to their own particular disorders.

Congenital Anomalies

Albinism (Fig. 11.4)

I. When albinism is restricted to the eyes (ocular albinism), it most frequently is inherited as an X-linked recessive.

II. When the skin is also involved (oculocutaneous albinism), it most frequently is inherited as an autosomal recessive.

III. The conditions are noted at birth.

A. Nystagmus, decreased acuity, a hypopigmented fundus, often increased transillumination of light through the iris (pink or “rabbit” eyes), and a hypopigmented fundus are noted.

B. Color vision is normal. Nyctalopia does not occur.

IV. Histology

A. The RPE is depleted of pigment.

B. Macromelanosomes may be present within the RPE.

V. Chédiak–Higashi syndrome

A. Inheritance is autosomal recessive.

B. The condition is one of the immunodeficiency diseases (see Chapter 1) and is associated with a lack of resistance to infection and generalized lymphadenopathy. The condition is fatal from generalized infection, usually during the second decade of life.

C. Histologically, macromelanosomes may be found in the generally depigmented RPE. The uvea shows decreased pigmentation.

Albinoidism is outlined in Box 11.1.

Fig. 11.4 Albinism. A, Albino patient uses dark eyelid and eyebrow makeup to cover lack of pigment. B, Another patient shows typical albinotic fundus. C, Histologic serial sections through the macula of another patient fail to demonstrate any fovea. (C, Courtesy of Prof. GOH Naumann.)

Box 11.1

Albinoidism

Oculocutaneous or ocular hypopigmentation without nystagmus and photophobia

A Hair-Bulb Tyrosinase Test Positive

1. Autosomal-dominant albinoidism

2. Punctate oculocutaneous albinoidism

3. Autosomal-dominant albinoidism and deafness

4. Ocular depigmentation and Apert’s syndrome

5. Waardenburg-like syndrome

6. Hypopigmentation–immunodeficiency disease

B Hair-Bulb Test Negative

1. Menke’s syndrome

2. Prader–Willi syndrome

(Modified from Kinnear PE, Jay B, Witkop CJ Jr et al.: Albinism. Surv Ophthalmol 30:75, 1985.)

Grouped Pigmentation (Bear Tracks)

I. Grouped pigmentation (see Fig. 17.22) is unilateral (85% of cases), nonprogressive, and presents as multiple, discrete, well-circumscribed, flat, uniformly pigmented areas resembling a bear’s footprints.

II. It affects a single sector-shaped retinal area whose apex points to the optic disc in approximately 60% of cases. It affects several separate sectors in approximately 28% of cases, or it is distributed over the entire fundus in approximately 12% of cases.

III. Histologically, hypertrophy of the RPE and large, football-shaped pigment granules (macromelanosomes) are seen. The overlying receptors may show degeneration.

The histologic appearance of grouped pigmentation is almost identical to that of congenital hypertrophy of the RPE and probably represents a clinical variant (see Chapter 17).

Coloboma

I. The typical coloboma “of the choroid” (see Fig. 9.8) involves the region of the embryonic cleft (fetal fissure; i.e., inferonasally) and is bilateral in 60% of patients. The coloboma may involve the total region, a large part of it, or one or more small isolated parts.

II. Histologically, the RPE seems to be primarily involved and is absent in the area of the coloboma.

A. The neural retina is atrophic and gliotic and may contain rosettes.

B. The choroid is partially or completely absent, and the RPE is usually hyperplastic at the edge of the coloboma.

The sclera may be thinned or even absent in the area of the coloboma, and the neural retina may herniate through in the form of a cyst (microphthalmos with cyst), undergo massive glial proliferation (massive gliosis), or both (see Chapter 14).

Retinal Dysplasia

See Chapter 18.

Lange’s Fold

I. Lange’s fold (Fig. 11.5; see also Fig. 10.6) is an inward fold of neural retina at the ora serrata only seen in infants’ and children’s eyes.

II. The fold is an artifact of fixation. It is not present in vivo or in an enucleated, nonfixed eye. However, it is a useful artifact because it helps to identify an eye in tissue section as that of a child.

The consistent axial and forward direction of Lange’s fold may be related to the vitreous base–zonular adhesion to the inner neural retinal surface that, in infants, seems to be stronger than the peripheral neural retina–RPE adhesion.

Congenital Nonattachment of the Retina

I. Nonattachment of the neural retina (see Fig. 18.24) is normal in the embryonic eye; persistence after birth is abnormal.

II. The condition is frequently associated with other ocular abnormalities, such as microphthalmos, persistent hyperplastic primary vitreous, and colobomas.

III. Histologically, the neural retina and nonpigmented epithelium of the ciliary body are separated from the pigment epithelium of the neural retina and ciliary body. The neural retina may be normal, completely dysplastic, or anything in between.

The space between the neural retina and the RPE closes progressively during fetal life. If something should happen shortly before birth to reverse this trend and rapidly separate the two layers, a congenital neural retinal detachment, secondary in nature, would result. A retinal dialysis (disinsertion), usually located inferotemporally, may develop in utero and lead to a secondary congenital or developmental neural retinal detachment.

Neural Retinal Cysts

I. A cyst of the neural retina (see Fig. 11.56) is defined arbitrarily as an intraneural retinal space whose internal–external diameter is greater than the thickness of the surrounding neural retina and of approximately equal dimension in any direction.

Retinoschisis, on the other hand, is an intraneural retinal space whose internal–external diameter is smaller than the thickness of the surrounding neural retina and much smaller than the width of the space lying parallel to the neural retina. Cyst is a poor term because a cyst, by definition, is an epithelium-lined space. However, the term (e.g., intraretinal, intracorneal, intrascleral) is frequently used to describe an intratissue space not necessarily lined by epithelium.

II. Congenital neural retinal cysts have been reported in the periphery, usually the inferior temporal region, and in the macula.

III. Histologically, the cysts are usually lined by gliotic neural retina and are filled with material that is periodic acid–Schiff (PAS)-positive but negative for acid mucopolysaccharides.

Myelinated (Medullated) Nerve Fibers

I. Myelinated nerve fibers (MNF; Fig. 11.6) usually occur as a unilateral condition, somewhat more common in men than in women.

A. They are seen in approximately 0.5% of eyes. MNF usually appear at birth or in early infancy and then remain stationary.

B. Rarely, MNF occur after infancy and can progress.

Fig. 11.6 Myelinated nerve fibers. A, Child referred by pediatrician because of suspected retinoblastoma. Massive myelinated nerve fibers present. B, Gross specimen from another patient shows a patch of myelinated nerve fibers that fan out in an upper temporal direction from the vicinity of the optic disc. Note that the heavily myelinated patch has characteristic feathered edges. C, Plastic-embedded thin section shows that the entire nerve fiber layer of the neural retina is thickened by myelination. D, Increased magnification shows myelination of nerve fibers (ganglion cell axons) just above ganglion cell layer (m, myelination of nerve fiber layer axons; g, ganglion cells; c, capillary; ip, inner plexiform layer).

II. Clinically, they appear as an opaque white patch or arcuate band with feathery edges.

The area of myelination clinically is most commonly found continuous with the optic disc, but it may be seen in other parts of the neural retina. In autopsy studies, however, only approximately one-third of cases show myelination continuous with the optic nerve; perhaps myelination of the neural retina away from the optic nerve is overlooked clinically. Rarely, the condition may be inherited. The area of myelination may become involved in multiple sclerosis.

III. Histologically, myelin (and possibly oligodendrocytes) is present in the neural retinal nerve fiber layer, but the region of the lamina cribrosa is free of myelination.

Oguchi’s Disease

I. Oguchi’s disease, inherited as an autosomal-recessive trait, is a form of congenital stationary night blindness (see later in this chapter).

Forsius–Erikson syndrome (Åland Island eye disease) is also a form of congenital stationary night blindness.

II. The color of the fundus is unusual, varying from shades of gray to yellow; the neural retina may be involved totally or segmentally. Mizuo’s phenomenon, a more normal-appearing fundus in the dark-adapted state, is present. The fundus changes may be the result of changes within the rods.

III. Histologically, the cones are more numerous than usual.

A. Almost no rods are present, especially in the temporal area.

B. Between the cones and the RPE is a nondescript, amorphous material containing pigment granules.

Foveomacular Abnormalities

I. Hypoplasia

A. Hypoplasia is characterized by a total or nearly total absence of the clinically seen macular yellow, an absence or irregularity of the foveal reflexes, and an irregular distribution of perifoveal capillaries.

B. Frequently, it is associated with hereditary anomalies such as aniridia, achromatopsia, X-linked hemeralopia, ocular and systemic complete and incomplete albinism, and microphthalmos.

II. Dysplasia (coloboma of macula)

A. Many, if not most, of the foveomacular dysplasias or colobomas are secondary to congenital toxoplasmosis (see Chapter 4).

B. Hereditary forms have been described with both a dominant and a recessive autosomal pattern.

Leber’s Congenital Amaurosis

I. Leber’s congenital amaurosis (LCA) is a heterogeneous group of infantile tapetoretinal degenerations characterized by connatal blindness, nystagmus, and a markedly reduced or absent response on the electroretinogram (ERG).

The differential diagnosis of connatal blindness includes hereditary optic atrophy, congenital optic atrophy, retarded myelinization of the optic nerve, albinism, aniridia, congenital cataracts, macular “coloboma,” and achromatopsia. Only Leber’s congenital amaurosis, however, shows an absent or markedly diminished response on ERG. At least 18 LCA genes have been reported with the most common mutated genes CEP290 and GUCY2D.

II. An autosomal-recessive inheritance pattern predominates, although a few cases of dominant transmission have been reported.

Senior–Loken syndrome is an autosomal recessive oculorenal condition, characterized by nephronophthisis and early childhood-onset of LCA. It is associated with mutations in five of the NPHP genes. Variations in some genes (e.g., NPHP5 and NPHP6) can cause different phenotypes in different individuals.

III. The fundus shows a polymorphous picture, including a normal appearance, arteriolar narrowing, optic pallor, granular or salt-and-pepper appearance or bone spicule pigmentation (especially with increasing age), diffuse white spots, a nummular pigmentary pattern, and a local or diffuse chorioretinal atrophy with various pigmentary changes.

A variety of associated ocular findings include ptosis, keratoconus, strabismus, cataract, macular colobomas, and a “bull’s-eye” maculopathy. Systemic associations include mental retardation, hydrocephalus, and the Saldino–Mainzer syndrome (familial nephronophthisis and cone-shaped epiphyses of the hands).

IV. A low incidence of associated neurologic disease occurs, such as a form of psychomotor retardation and electroencephalographic abnormalities.

V. Histologically, the neural retina appears normal, completely disorganized, or anything in between. In early cases, outer segments of the rods and cones are missing, the cones form a monolayer of cell bodies, and the rods tend to cluster in the periphery and sprout neuritis.

Inherited Retinal Arteriolar Tortuosity

I. Inherited retinal arteriolar tortuosity is characterized by spontaneous retinal hemorrhages that resolve without sequelae. The small retinal arterioles show mild to severe tortuosity, especially in the macula.

II. It is inherited as an autosomal-dominant trait.

Vascular Diseases

Definitions

I. The neural retinal circulation is predominantly arteriolar, not arterial, because very soon after the central retinal artery enters the neural retina (usually by the first intraneural retinal bifurcation), it loses its internal elastic lamina and continuous muscular coat and therefore becomes an arteriole.

III. The inner half of the neural retina (approximately) is supplied by the retinal circulation (retinal capillaries); the outer half is supplied by the choroidal circulation (choriocapillaris).

Clinically, the largest retinal vessels are known by common usage as arteries and veins (rather than arterioles and venules). These terms are carried over into ophthalmic pathology.

Retinal Ischemia

Causes

I. Choroidal vascular insufficiency

A. Choroidal tumors such as nevus, malignant melanoma, hemangioma, and metastatic carcinoma may “compete” with the outer layers of the neural retina for nourishment from the choriocapillaris.

B. Choroidal thrombosis caused by idiopathic thrombotic thrombocytopenic purpura, malignant hypertension, collagen diseases, or emboli may occlude the choriocapillaris primarily or secondarily through effects on the choroidal arterioles. Rarely, large areas of choriocapillaris may be occluded chronically by such materials as accumulating amyloid, with surprisingly good preservation of the overlying neural retina.

II. Retinal vascular insufficiency

A. Large-artery disease anywhere from aortic arch to central retinal artery

1. Atherosclerosis shows patchy subendothelial lipid deposits and erosion of media.

a. The ocular manifestations of the aortic arch syndrome are similar to those seen in carotid artery occlusive disease, except that the aortic arch syndrome causes bilateral ocular involvement that tends to be severe.

b. Embolic manifestations (Figs. 11.7 and 11.8; see also Fig. 5.54)

Amaurosis fugax is a common symptom. Preceding this symptom, Hollenhorst plaques (cholesterol emboli), less commonly, platelet–fibrin emboli, and, rarely, atrial myxoma emboli may be observed in retinal arterioles.

1) Emboli are the most common cause of central retinal artery occlusion (CRAO) and originate in ulcerous plaques or thrombosis of mainly the internal carotid arteries. The emboli consist of cholesterol (Hollenhorst plaque), fibrinous, or calcific plaque materials.

2) Emboli (e.g., cholesterol, platelet–fibrin emboli, atrial myxoma, talc in drug abusers) to the visual system can cause amaurosis fugax; visual field defects; cranial nerve palsies; central or branch retinal artery occlusion; hypotensive retinopathy (venous stasis retinopathy) and the ocular ischemic syndrome (see later); narrowed retinal arterioles; and neovascularization of the iris, optic disc, or neural retina.

3) Rarely, ocular emboli cause a condition masquerading as temporal (cranial; giant cell) arteritis.

Fig. 11.7 Retinal vascular emboli. A and B, Different fundi with Hollenhorst plaques. C, Fundus shows emboli probably originating in ulcerous plaques or thrombosis of the internal carotid arteries.

Fig. 11.8 Hollenhorst plaque. A, Clinical appearance of cholesterol embolus just before enucleation in eye of 67-year-old man who had carotid artery stenosis. B, Histologic section of enucleated eye shows cholesterol embolus in retinal artery on right side of optic nerve. C, High magnification of embolus. Note foreign-body giant cell reaction around cholesterol clefts.

2. Takayasu’s disease usually occurs in young women (frequently Japanese), shows an adventitial giant cell reaction, also involves the media, and produces intimal proliferation with obliteration of the lumen.

Takayasu’s syndrome (aortic arch syndrome) occurs in older patients of either sex and differs from the “usual” type of atherosclerosis only in its site of predilection for the aortic arch. Another cause is syphilitic aortitis.

3. CRAO has many causes, including atherosclerosis, emboli, temporal arteritis, collagen diseases, homocystinuria, and Fabry’s disease. Broadly, CRAO can be divided into four types: (1) nonarteritic (NA-CRAO), (2) NA-CRAO with cilioretinal artery sparing, (3) transient NA-CRAO, and (4) arteritic CRAO.

Rarely, bilateral CRAO may occur. It usually involves elderly patients. The annualized incidence for white patients is approximately 1.9% per 100,000.

4. Collagen diseases, allergic granulomatosis, and midline lethal granuloma syndrome may all involve the larger retinal vessels, causing neural retinal ischemia.

5. Temporal (cranial; giant cell) arteritis (see Chapter 13)

B. Arteriolar and capillary disease of neural retinal vasculature

1. Arteriolosclerosis is associated with hypertension.

2. Branch retinal artery occlusion has many causes, including emboli (see Figs. 11.7 and 11.8), arteriolosclerosis, diabetes mellitus, arteritis, dysproteinemias, collagen diseases, and malignant hypertension.

Susac’s syndrome consists of the triad of encephalopathy, branch retinal artery occlusion, and hearing loss, most common in women. The cause is uncertain, but it is thought to be an autoimmune disease.

3. Diabetes mellitus (see Chapter 15)

4. Malignant hypertension, toxemia of pregnancy, hemoglobinopathies, collagen diseases (Fig. 11.9), dysproteinemias, carbon monoxide poisoning, and blood dyscrasias of many kinds may involve the small retinal vessels and cause neural retinal ischemia.

Fig. 11.9 Fatal systemic lupus erythematosus in a 26-year-old woman. A, Gross specimen shows numerous cotton-wool spots. B, Trypsin digest of retina. Large dark area is optic disc. Retinal arterioles have characteristic capillary-free zone and are darker and slightly narrower than retinal venules. C and D, Increased magnification of two different areas to show fibrinoid necrosis in transition area between end arteriole and capillary.

Leukemic retinopathy commonly occurs in both acute and chronic leukemia. The findings include venous tortuosity and dilatation, perivascular sheathing, retinal hemorrhages (including white-centered hemorrhages, simulating Roth’s spots), leukemic infiltrates, cotton-wool spots, optic nerve infiltration, peripheral neural retinal microaneurysm formation, extensive capillary dropout, and even a proliferative retinopathy similar to sickle-cell retinopathy.

Complications of Retinal Ischemia

I. If localized, field defects may result. If massive, complete loss of vision may occur.

II. The ocular ischemic syndrome (OIS; ischemic oculopathy)

A. OIS results from chronically reduced ocular blood flow through the ophthalmic artery (or the carotid artery).

1. In the anterior segment, OIS is manifested by aqueous flare, iris neovascularization, secondary angle-closure glaucoma, and cataract. OIS may be the presenting sign of serious cerebrovascular or ischemic heart disease.

2. In the posterior segment, OIS is manifested by venous stasis (or hypotensive) retinopathy characterized by narrowed retinal arterioles; dilated, nontortuous, beaded, retinal veins; cystoid macular edema; mid-peripheral dot-and-blot neural retinal hemorrhages; optic disc and neural retinal neovascularization; neural retinal detachment; and, ultimately, phthisis bulbi.

Unlike what occurs with chronically reduced ocular blood flow, acutely reduced ocular blood flow does not result in venous stasis retinopathy but, rather, is characterized by 10 or more microinfarcts (cotton-wool spots) of the neural retina.

III. Although the incidence of iris neovascularization is usually thought to be 1–5% in eyes after central retinal artery occlusion, some studies have suggested a much higher incidence, in the range of 18%. It is most rare after branch retinal artery occlusion.

Histology of Retinal Ischemia

I. Early (Fig. 11.10; see also Figs. 11.9 and 11.15D)

A. The neural retina shows coagulative necrosis of its inner layers, which are supplied by the retinal arterioles.

1. The neuronal cells become edematous during the first few hours after occlusion of the artery.

2. The intracellular swelling accounts for the clinical gray neural retinal opacity.

B. If the area of coagulative necrosis (see Chapter 1) is small and localized, it appears clinically as a cotton-wool spot.

1. The cotton-wool spot observed clinically (Fig. 11.11; see also Fig. 11.9) is a result of a microinfarct of the nerve fiber layer of the neural retina.

2. The cytoid body, observed microscopically (see Figs. 11.9 and 11.11), is a swollen, interrupted axon in the neural retinal nerve fiber layer.

Histologically, the swollen end-bulb superficially resembles a cell, hence the term cytoid body. A collection of many cytoid bodies, along with localized edema, marks the area of the microinfarct. A cotton-wool spot represents a localized accumulation of axoplasmic debris in the neural retinal nerve fiber layer. They result from interruption of orthograde or retrograde organelle transport in ganglion cell axons (i.e., obstruction of axoplasmic flow). Ischemia is the most common cause of focal interruption of axonal flow in the neural retinal nerve fiber layer that results in a cotton-wool spot. However, any factor that causes focal interruption of axonal flow gives rise to similar accumulations.

C. If the area of coagulative necrosis is extensive, it appears clinically as a gray neural retinal area, blotting out the background choroidal pattern.

The clinically seen gray area is caused by marked edema of the inner half of the neural retina. It is noted several hours after arterial obstruction and becomes maximal within 24 hours. With complete coagulative necrosis of the posterior pole (e.g., after a central retinal artery occlusion), the red choroid shows through the central fovea as a cherry-red spot. The foveal retina has no inner layers and is supplied from the choriocapillaris; therefore, no edema or necrosis occurs in the central fovea and the underlying red choroid is seen.

Fig. 11.10 Central retinal artery occlusion. A, Recent onset shows gray edema of neural retina at posterior pole exaggerating normal redness of foveal disc (i.e., cherry-red spot). Note tiny temporal cilioretinal artery has preserved a small temporal juxtapapillary island of normal neural retina. B, Trichrome-stained section shows an organized thrombus (t) occluding the central retinal artery in the optic nerve (v, vein). C, Histologic section of early stage shows edema of inner neural retinal layers and ganglion cell nuclei pyknosis. Patient had a cherry-red spot in fovea at time of enucleation (im, inner limiting membrane; ng, swollen nerve fiber and ganglion layers; in, inner nuclear layer; op, outer plexiform layer; on, outer nuclear layer; pr, photoreceptors). D, Histologic section of late stage shows a homogeneous, diffuse, acellular zone replacing the inner plexiform, ganglion cell, and nerve fiber layers of the neural retina. Note thin inner nuclear layer.

Fig. 11.11 Cotton-wool spots. A, Clinical appearance of cotton-wool spots. B, Microinfarct of nerve fiber layer produces aggregates of ruptured and enlarged axons (cytoid bodies). Cytoid bodies, observed clinically as cotton-wool spots, lie just under internal limiting membrane. C, Nucleoid of cytoid body consists of dense mass of filamentous material, the edge of which is more detailed in inset. D, Marked swelling of axon (a) in nerve fiber layer two hours after experimental central retinal artery occlusion (m, axonal mitochondrion). (D, From Kroll AJ: Experimental central retinal artery occlusion. Arch Ophthalmol 79:453, 1968, with permission. © American Medical Association. All rights reserved.)

II. Late (see Fig. 11.10)

A. The outer half of the neural retina is well preserved.

B. The inner half of the neural retina becomes “homogenized” into a diffuse, relatively acellular zone. Usually, thick-walled retinal blood vessels are present.

Because the glial cells die along with the other neural retinal elements, gliosis does not occur. The boundaries between the different retinal layers in the inner half of the neural retina become obliterated. In central retinal artery occlusion, the inner neural retinal layers become an indistinguishable homogenized zone. In retinal atrophy secondary to glaucoma, to transection of the optic nerve, or to descending optic atrophy, however, the neural retinal layers, although atrophic, are usually identifiable.

Retinal Hemorrhagic Infarction (Fig. 11.12)

Causes and Risk Factors of Hemorrhagic Infarction

I. The many causes (or associations) include chronic primary open-angle glaucoma, atherosclerosis of the central retinal artery, arteriolosclerosis of the retinal arterioles, systemic hypertension, diabetes mellitus, polycythemia vera, mediastinal syndrome with increased venous pressure, dysproteinemias, and collagen diseases.

Arterial vascular disease is commonly present in retinal vein occlusion and is probably related to its cause. Also, CRVO may occur in Reye’s syndrome (encephalopathy and fatty degeneration of viscera), which has a typical diphasic course, with a mild viral illness followed by severe encephalitic symptoms, especially coma. Other risk factors for retinal vein occlusion include black race, male sex, hypertension, end-organ damage in diabetics, and obstructive sleep apnea.

II. Significant risk factors are systemic hypertension, open-angle glaucoma, and male sex. Race, diabetes mellitus, coronary artery disease, and stroke do not appear to be significant risk factors.

Fig. 11.12 Central retinal vein occlusion. A, Typically, widespread hemorrhages and sheets of blood are seen in the fundus. B, A histologic section shows blood throughout all layers of the neural retina. C, With healing, a glial scar is formed. A special stain for iron (Perl’s stain) is positive (blue) throughout the retina (em, epiretinal membrane; br, blue staining of retina; w, wrinkled internal limiting membrane; c, choroid; s, sclera). (A, Courtesy of Dr. AJ Brucker.)

Types of Hemorrhagic Infarction

I. Occlusion of central retinal vein, branch retinal vein, or venule

A. CRVO may be considered to consist of two distinct types.

1. Nonischemic retinopathy (~65% of cases, but approximately one-fourth of these eyes will convert to the ischemic type)

a. The retinal arterial pressure in CRVO is normal or high, unlike the low arterial pressure found in ocular ischemic syndrome (OIS).

The term venous stasis retinopathy is also used for nonischemic retinopathy, but it is more appropriately used for the retinopathy of OIS (see earlier).

b. The condition is probably caused by a reversible, complete occlusion of the central retinal vein, usually behind the lamina cribrosa in the substance of the optic nerve or where the vein enters the subarachnoid space, and is not accompanied by significant hypoxia.

c. Retinal hemorrhages vary from a few, flame-shaped and punctate, to large numbers. Those in the peripheral neural retina tend to be punctate and more numerous than those in the center. Cotton-wool spots are absent or sparse.

d. Retinal capillary perfusion is usually normal so that the choroidal background is easily seen. Dilated and leaking retinal capillaries may be seen with fluorescein angiography.

e. Two subgroups may be identified: One subgroup involves young people in whom some evidence suggests that the condition is probably inflammatory in origin, caused by phlebitis of the central retinal vein that produces venous thrombosis (see discussion of papillophlebitis, later in this subsection); a second subgroup involves older people who have arteriosclerosis, which probably plays an important role in the venous occlusion.

The second subgroup may consist of two types: One (sometimes called incomplete occlusion) shows normal retinal arterial circulation and normal or slightly slowed retinal venous circulation; the other (sometimes called venous stasis retinopathy) shows slow retinal arterial and venous circulation. Both show normal capillary perfusion.

2. Ischemic (hemorrhagic) retinopathy

a. It is caused by occlusion of the central retinal vein at, or anterior to, the lamina cribrosa, associated with retinal ischemia that leads to significant retinal hypoxia.

1) Few venous collateral channels are available to the central retinal vein at, or anterior to, the lamina cribrosa; therefore, severe obstruction of retinal venous flow results.

2) Approximately 35% of cases fall into the ischemic group. If untreated iris neovascularization occurs in most eyes that have ischemic CRVO.

b. Neural retinal hemorrhages are usually gross and extensive (“blood and thunder” fundus). Cotton-wool spots and retinal capillary nonperfusion are prominent, resulting in partial or complete obscuration of the underlying choroidal pattern. The optic nerve head is usually edematous.

Extensive retinal capillary closure one month after vein occlusion (central or branch) or extensive leakage and a broken capillary arcade at the fovea, as determined by fluorescein angiography, indicates a poor visual prognosis. When neovascularization of the neural retina or iris develops, it is invariably in those patients who have extensive retinal capillary closure.

3. CRVO occur in 8–20% of patients who already have chronic primary open-angle glaucoma or in whom it will develop.

In at least 80% of eyes that have CRVO uncomplicated by neovascularization of the iris, the intraocular pressure is lower in the eye with the occlusion than in the normal fellow eye. The reduction of intraocular pressure is greater (1) in those eyes with CRVO than in those with branch-vein occlusion, (2) in those eyes with ischemic retinopathy than in those with nonischemic retinopathy, and (3) in patients who have high pressures in their fellow eyes. The pressure reductions persist for at least two years after occlusion.

4. Bilateral CRVO may occur as part of the acquired immunodeficiency syndrome (AIDS).

B. Branch retinal vein occlusion (BRVO)

1. BRVO occurs approximately three times more frequently than CRVO. In approximately two-thirds of cases, the superior temporal neural retinal vein is involved. Most of the remaining cases show involvement of the inferior temporal retinal vein.

a. Rarely, the inferior (or superior) branch of the central retinal vein may be involved, resulting in an inferior (or superior) hemispheric vein occlusion.

b. A hemispheric vein occlusion behaves like an ischemic CRVO.

c. Retinal vascularity is strongly correlated with vitreous fluid levels of sVEGFR-2, VEGF, slCAM-1, IL-6, PTX3, and PEDF.

2. The occlusion most often occurs in the fifth or sixth decade of life and develops at an arteriovenous crossing.

3. If significant and widespread retinal capillary nonperfusion is present, neovascularization of the optic nerve head, neural retina, or both develops in a high percentage of cases. Iris neovascularization does not occur.

It is important to differentiate retinal venous collaterals from neovascular areas. The former prove to be beneficial, whereas the latter may require therapy.

4. Visual acuity may be decreased because of cystoid macular edema (~50% of cases) or foveal hemorrhage. After BRVO, significant improvement in vision beyond 20/40 is uncommon.

II. Papillophlebitis (retinal vasculitis, mild and moderate papillary vasculitis, benign retinal vasculitis, optic disc vasculitis)

A. Papillophlebitis is characterized by a unilateral, partial, reversible CRVO presumably caused by venous inflammation. It usually occurs in young, healthy men and exhibits a benign, somewhat protracted course.

B. Ophthalmoscopic findings include edema of the optic nerve head, peripapillary neural retina, and sometimes macula; retinal venous dilatation and tortuosity; and scattered, superficial, mid-peripheral retinal hemorrhages.

C. The prognosis for vision is excellent.

The main sequelae are perivenous sheathing of large veins at the posterior pole and dilated venules over the optic nerve head.

III. Terson’s syndrome (see Chapter 12)

Complications of Hemorrhagic Infarction

I. Macular hemorrhagic infarction may result in permanent loss of vision.

II. Leakage of fluid into the macula may result in cystoid macular edema.

III. Iris neovascularization (clinically seen rubeosis iridis)

A. Iris neovascularization (see Figs. 9.13 and 9.14) occurs mainly with ischemic CRVO; it rarely occurs with nonischemic CRVO or BRVO.

B. Approximately 60% of patients older than 40 years of age have iris neovascularization after ischemic CRVO (rarely after nonischemic CRVO). Iris neovascularization usually does not appear before six weeks after occlusion, usually becomes established before six months, and, if untreated, causes neovascular glaucoma.

Early, the anterior chamber angle may show neovascularization for 360° and yet still be open and cause secondary open-angle glaucoma. This stage tends to be fleeting, peripheral anterior synechiae develop, and secondary closed-angle glaucoma ensues. The glaucoma is called neovascular glaucoma. Iris neovascularization is rare in people who are younger than 40 years of age at the time of their CRVO.

IV. Neovascularization of the neural retina (Fig. 11.13) occurs mainly with BRVO; it rarely occurs with ischemic or nonischemic CRVO.

Fig. 11.13 Central and branch retinal vein occlusion. Clinical (A) and fluorescein (B) appearance of ischemic central retinal vein occlusion. If neovascularization develops (high probability in this case), it will be of the iris. Clinical (C) and fluorescein (D) appearance of branch retinal vein occlusion. If neovascularization develops, it will be of the neural retina or optic nerve or both. E, Histologic section of new blood vessels (n, neovascularization) budding off from a retinal venule.

V. Neural retinal detachment secondary to branch retinal vein occlusion may occur when the vein occlusion is severe and accompanied by marked capillary nonperfusion and leakage.

VI. Optociliary shunt vessels (i.e., usually large veins connecting the choroidal and retinal circulations at the optic nerve head) may develop after CRVO.

Optociliary shunt vessels are mainly seen in three clinical situations: as congenital anomalies; as the result of CRVO; and in association with orbital tumors, especially optic nerve sheath meningiomas. The vessels may also be seen in optic nerve juvenile pilocytic astrocytomas (gliomas), arachnoid cysts, optic nerve colobomas and drusen, and with chronic atrophic optic disc edema.

VII. Exudative neural retinal detachment

Histology of Retinal Hemorrhagic Infarction (See Fig. 11.12)

I. Early—hemorrhagic necrosis of neural retina

A. Massive intraneural retinal hemorrhage involves all the neural retinal layers.

1. The hemorrhage frequently spreads within the nerve fiber layer of the neural retina (see Fig. 15.18) and appears clinically in sheets or flame-shaped.

2. Rarely, the hemorrhage spreads into the potential submembranous (between internal limiting membrane and nerve fiber layer) space and appears clinically as anteriorly placed neural retinal pockets of blood (“subhyaloid” hemorrhage).

B. Cytoid bodies (see Fig. 11.11) are common histologically but may be masked by the hemorrhages clinically. As the hemorrhages resorb, hard, waxy exudates may appear (see Chapter 15 and later in this chapter).

C. Optic disc edema usually accompanies the hemorrhagic necrosis of the neural retina in the acute phase.

II. Late—organization of hemorrhage and gliosis

A. The architectural pattern of the neural retina, especially the inner neural retinal layers, is frequently disrupted. Thick-walled blood vessels are seen in the neural retina.

B. Gliosis (“scarring”) is usually seen in the inner neural retinal layers.

C. Hemosiderosis of the retina (see Fig. 11.12C) is present, with the hemosiderin often located in macrophages.

Hypertensive and Arteriolosclerotic Retinopathy¹

I. Hypertensive retinopathy (Fig. 11.14)

A. Grade I: a generalized narrowing of the arterioles

B. Grade II: grade I changes plus focal arteriolar spasms

C. Grade III: grade II changes plus hemorrhages and exudates

1. Flame-shaped (splinter) hemorrhages (see Figs. 11.12–11.14; see also Fig. 15.18) are characteristic and present in the nerve fiber layer.

2. Dot-and-blot hemorrhages (see Figs. 11.13 and 15.18) may be seen in the inner nuclear layer with spreading to the outer plexiform layer.

3. Cotton-wool spots (see Figs. 11.11 and 11.14; see earlier in this chapter) are characteristic.

Cotton-wool spots may be seen in many conditions, such as collagen diseases, CRVO, blood dyscrasias, AIDS, and multiple myeloma.

4. Hard (waxy) exudates may be seen; these are lipophilic exudates located in the outer plexiform layer (see Figs. 11.14, 15.13, and 15.16).

When the exudates are numerous in the macula and lie in the obliquely oriented and radially arranged fiber layer of Henle, they appear as a macular star.

D. Grade IV: all the changes of grade III plus optic disc edema

Necrosis, thinning, clumping, and proliferation of the RPE may occur as a result of obliterative changes in the choriocapillaris in malignant hypertension. Four types of fundus lesions associated with choroidal vascular changes have been recognized clinically: (1) pale yellow or red patches bordered to a varying extent by pigment deposits; (2) black, isolated spots of pigment with a surrounding yellow or red halo caused by complete obstruction of terminal choroidal arterioles and choriocapillaris by fibrin thrombi (Elschnig’s spots; see Fig. 11.14D); (3) linear chains of pigment flecks along the course of a yellow-white sclerosed choroidal vessel (Siegrist’s spots); and (4) yellow or red patches of chorioretinal atrophy.

Fig. 11.14 Hypertensive retinopathy. A, Trypsin digest preparation of retina from hypertensive patient shows narrowing of arterioles (darker, narrower vessels). B, Left eye from patient with marked hypertension and grade III hypertensive retinopathy. Note cotton-wool spots (areas of axoplasmic flow backup) and macular star (exudates in Henle’s outer plexiform layer of neural retina). C, Grade IV hypertensive retinopathy shows optic disc edema. D, The presence of Elschnig’s spots is a late manifestation.

II. Arteriolosclerotic retinopathy (Fig. 11.15)

A. Grade I: an increase in the arteriolar light reflex

Subintimal hyalin deposition and a thickened media and adventitia cause the normally transparent arteriolar wall to become semiopaque, producing an increased light reflex.

B. Grade II: grade I changes plus arteriolovenular crossing defects

The semiopaque wall of the arteriolosclerotic arteriole, which shares a common adventitia with the venule where they cross, obscures the view of the underlying venule. This results in the clinically seen arteriolovenular crossing defects, or “nicking.”

C. Grade III: grade II changes plus “copper-wire” arterioles

The arteriolar wall becomes sufficiently opaque so that the blood column can only be seen by looking perpendicularly through the surface of the wall (i.e., looking through the thinnest area). The arteriole has a burnished or copper appearance due to reflection of light from the thickened and partially opacified wall.

D. Grade IV: grade II changes plus “silver-wire” arterioles

The wall becomes totally opaque so that the blood column in the lumen cannot be seen. The light is then reflected completely from the surface of the thickened vessel, giving a white or silver appearance. The lumen of the arteriole may or may not be patent. Patency can best be determined by fluorescein angiography.

Fig. 11.15 Arteriolosclerotic retinopathy. A, Fundus shows grade II hypertensive changes (narrowing and focal spasms of arteriole) and grade II arteriolosclerotic changes [increased arteriolar light reflex and arteriolovenular (AV) crossing defects]. Note dilatation or banking of end of venule distal (to left) of AV defect and narrowing of proximal end. Dilatation caused by backup of venous blood secondary to constriction at crossing by arteriolar adventitia. B, Trypsin digest preparation of retina shows AV crossing defect caused by mild arteriolosclerosis involving the common adventitial sheath. C, Grade IV arteriolosclerotic changes characterized by silver-wire appearance in superior and inferior retinal arterioles. Other arterioles show grade III arteriolosclerotic changes characterized by copper-wire appearance. D, Thickened retinal vessel stained with periodic acid–Schiff (on far left of neural retina) shows arteriolosclerosis. Inner layers of neural retina show marked edema and necrosis of ganglion cells secondary to acute central retinal artery occlusion.

Hemorrhagic Retinopathy

I. Neural retinal hemorrhages (see Figs. 11.12 and 15.18) may be caused by many diseases, such as diabetes mellitus (see Chapter 15), sickle-cell disease, retinal venous diseases, hypertension, blood dyscrasias, leukemias, polycythemia vera, subacute bacterial endocarditis, cytomegalovirus retinitis, acute retinal necrosis (ARN), lymphomas, idiopathic thrombocytopenia, trauma, multiple myeloma, pernicious anemia, collagen diseases, carcinomatosis, anemia, and many others.

Anemia or thrombocytopenia alone rarely causes neural retinal hemorrhages. Anemia and thrombocytopenia combined, however, not infrequently result in neural retinal hemorrhages; when the two are severe (hemoglobin <8 g/100 ml and platelets <100,000/mm), neural retinal hemorrhages may occur in 70% of patients.

II. Histologically, the size and anatomic location of the hemorrhage determine its clinical appearance (see Fig. 15.18).

III. Roth’s spots

A. Roth’s spots are a special type of neural retinal hemorrhage characterized by a white center and associated with bacterial endocarditis.

It was Litten who described the association (Litten’s sign) and referred to it as Roth’s spots.

B. The white spots probably represent capillary rupture, extravasation, and formation of a central fibrin–platelet plug rather than septic microabscesses.

Idiopathic Macular Telangiectasia (Idiopathic Juxtafoveolar Retinal Telangiectasis)

See Chapter 18.

Retinal Arterial and Arteriolar Macroaneurysms

I. Macroaneurysms of the retinal arteries and arterioles (Fig. 11.16) may be congenital or acquired.

A. Congenital entities include angiomatosis retinae and the diseases of Eales, Leber, and Coats.

B. Acquired macroaneurysms occur in people (most often women) who have hypertension or arteriosclerosis, or both, and less often have diabetic retinopathy, retinal vein occlusion, retinal arteritis, cytomegalovirus retinitis, radiation and sickle-cell retinopathies, hyperviscosity entities, Takayasu’s disease, and aortic arch syndromes.

Fig. 11.16 Retinal arteriolar macroaneurysm (RAM). A, RAM is surrounded by exudation. B, RAM shown clearly in fluorescein angiogram. In another case, RAM shown in periodic acid–Schiff-stained trypsin digest preparation (C) and in cross section (D). (C and D, Courtesy of Dr. BW Streeten; case shown in C and D reported in Fichte C, Streeten BW, Friedman AH: A histopathologic study of retinal arterial aneurysms. Am J Ophthalmol 85:509. © Elsevier 1978.)

II. Most macroaneurysms involute spontaneously without sequelae.

III. The macroaneurysms may be associated with circinate retinopathy, intraneural retinal hemorrhage, subneural retinal hemorrhage, or even intravitreal hemorrhage.

Hemorrhage in the neural retina along with a subneural retinal hemorrhage (“dumbbell shape”) should alert the clinician to the possibility of macroaneurysm.

IV. Histologically, spherical or fusiform aneurysms arise from arteriolar walls.

Sickle-Cell Disease

I. Sickle-cell disease (Figs. 11.17 and 11.18) is caused by a point mutation in the hemoglobin gene.

A. Polymerization of the abnormal hemoglobin subunits in an anoxic or acidic environment results in the typical sickle configuration of the erythrocytes.

B. The sickled erythrocytes are much more rigid than normal ones and cause occlusions of small vessels.

Fig. 11.17 Sickle-cell hemoglobin C disease. A, The perfusion of the retina stops abruptly at the equator, resulting in nonperfusion of the peripheral retina. B, Trypsin digest of the equatorial region of the retina (in this case, of sickle-cell hemoglobin C disease) shows that peripheral blood vessels are devoid of cells and are nonviable. Arteriolovenular collaterals (av) are noted in the equatorial region. C, A peripheral arteriole is occluded by sickled red blood cells. (A–C, Periodic acid–Schiff stain; case reported in Eagle RC, Yanoff M, Fine BS: Hemoglobin SC retinopathy and fat emboli to the eye: A light and electron microscopical study. Arch Ophthalmol 92:28, 1974. © American Medical Association. All rights reserved.)

Fig. 11.18 Sickle-cell hemoglobin C disease. A, A sea fan is present at the equator and a sunburst is seen below the sea fan. B, A histologic section shows that the sea fan lies between the internal surface of the retina and the vitreous body. The neovascularization proceeds from a retinal arteriole into the subvitreal space and then back into a retinal venule. (A, Courtesy of Dr. MF Rabb.)

II. The retinopathy is most severe with sickle-cell hemoglobin C disease (SC disease) but may also occur in other sickle hemoglobinopathies, including sickle thalassemia, sickle-cell disease, and even in occasional cases of sickle-cell trait.

III. Classification of retinopathy

A. Stage I: peripheral arteriolar occlusion (between the equator and the ora serrata)

1. The primary site of occlusion appears to be at the precapillary arteriole level.

2. The most likely cause of the occlusion is obstruction of the small precapillary arterioles by sickled erythrocytes.

B. Stage II: peripheral arteriolovenular anastomoses (AVA; most commonly in the temporal quadrant)

1. AVA appear to be the initial vascular remodeling at the junction of the perfused central and nonperfused peripheral neural retina in the region of the equator.

2. The development of AVA most likely is not a neovascular process but, rather, represents the formation of preferential vascular channels from pre-existing vessels.

C. Stage III: neovascular and fibrous proliferations

1. New vessels arise from pre-existing AVA, on the venular side.

2. When a neovascular patch remains relatively isolated from neighboring patches and coalescence does not occur, the characteristic sea fan anomaly may be observed, most commonly in SC disease.

The characteristic fibrovascular extraretinal formation is called a sea fan because of its resemblance to the marine invertebrate sea fan, Geogonia flabellum.

3. Areas of retinal pigment epithelial hypertrophy, hyperplasia, and migration (black sunbursts), which develop after intraneural and subneural retinal hemorrhage, may occur in all stages, occur posterior to the equator, and may be seen most commonly in sickle-cell disease but also in SC disease.

4. Salmon-patch hemorrhage, single or multiple, may occur in sickle-cell disease and SC disease.

a. It is usually found in the mid-periphery adjacent to a retinal arteriole.

b. Initially, the hemorrhages are bright red (but not quite the same red as hemorrhages in a nonsickler), but within a few days they become salmon (orange-red)-colored.

c. Within weeks, the lesions evolve into yellow or yellow-white nodules or plaques. Further resolution results in intraneural retinal retinoschisis, a focal patch of thinned neural retina, or a pigmented scar.

The pigmented scar is called a black sunburst (see earlier) and results from the resolution of a salmon patch.

D. Stage IV: vitreous hemorrhage (usually arising from a neovascular patch)

E. Stage V: neural retinal detachment. The detachment of the neural retina may be nonrhegmatogenous (traction) or rhegmatogenous (caused by a neural retinal tear).

IV. The pathogenesis of sickle-cell retinopathy is probably related to local hypoxia (secondary to sickled erythrocytes occluding preretinal arterioles), similar to what occurs in diabetes mellitus, retinopathy of prematurity, carotid occlusive disease, and Takayasu’s disease.

Eales’ Disease (Primary Perivasculitis of the Retina)

I. Eales’ disease occurs typically in young men, usually in their third decade.

It occurs most commonly in the Indian subcontinent.

II. More than 90% of the cases are bilateral.

III. The disease progresses slowly; rapid progression, however, is common as a late event.

A. Initially, a slight, localized edema of the peripheral neural retina involves only the small venous branches. Exudates around the involved vessels or sheathing of the vessels can be seen.

B. Next, the larger venules become involved. Neovascularization develops from venules in the neural retina and the new vessels enter the subvitreal space, where they are vulnerable to hemorrhage.

C. A fibrous membranous component develops (i.e., retinitis proliferans). Shrinkage and traction by the fibrovascular membranes may cause a secondary neural retinal detachment.

The total progression is similar to that in diabetic retinopathy. Rarely, a central form occurs and affects the large central venules. Fluorescein shows obliteration of the venules, producing large areas of capillary nonperfusion toward the neural retinal periphery.

IV. The cause of the disease is unknown.

Retinopathy of Prematurity

See Chapter 18.

Hemangioma of the Retina

I. Hemangioma of the neural retina, a hamartomatous lesion, may be associated with similar cavernous hemangiomas of brain and with angiomatous hamartomas of skin, or it may occur alone.

II. Cavernous hemangioma of the neural retina as an isolated finding is rare.

A. The hemangioma is congenital, benign, stationary, unilateral, most frequent in women, composed of clusters of dark red saccular aneurysms containing venous blood, and rarely the source of intraocular hemorrhage.

B. They are not usually discovered before adulthood, when they may be discovered as an incidental finding or may become symptomatic secondary to an overlying serous neural retina detachment.

Rarely, they may be associated with retinal neovascularization.

III. Histologically, a cavernous type of hemangioma of the neural retina is seen.

Hereditary Hemorrhagic Telangiectasia (Rendu–Osler–Weber Disease)

See Chapter 7.

Disseminated Intravascular Coagulation

I. Disseminated intravascular coagulation (DIC; Fig. 11.19) is a syndrome in which a physiologic imbalance occurs between clotting and lysis of clot.

A. Inappropriate triggers to coagulation result in endothelial injury stimulating the intrinsic cascade, or tissue factor stimulating the extrinsic cascade.

DIC can develop secondary to septicemia in patients who have AIDS.

B. Characteristically, disseminated microthrombi form in small vessels, especially in the kidneys, heart, and brain.

C. Coincident with microthrombi formation, a gradual depletion of coagulation factors, platelets, and fibrin ensues, resulting in a change from a hypercoagulable to a hypocoagulable state.

1. Clinically, gross hemorrhage, thrombosis, or both, or only disordered coagulation parameters, may be found.

2. Detection of the cross-linked fibrin degradation fragment, D-dimer, in patients at risk for DIC is strong evidence for the diagnosis.

a. D-dimer confirms that both thrombin and plasmin generation have occurred.

b. Laboratory D-dimer measurements are less sensitive but highly specific, whereas the fibrinogen degradation product (FDP) test is more sensitive but less specific; performing the two tests in tandem (screening with FDP and confirming with D-dimer) maximizes sensitivity and specificity.

Fig. 11.19 Disseminated intravascular coagulation (DIC). Phosphotungstic acid hematoxylin shows fibrin clot in vessel in pars plicata of ciliary body (A) and in retinal arteriole (B) in an infant who had DIC. (Case reported in Ortiz JM, Yanoff M, Cameron JD et al.: Disseminated intravascular coagulation in infancy and in the neonate: Ocular findings. Arch Ophthalmol 100:1413, 1982. © American Medical Association. All rights reserved.)

II. Histologically, fibrin thrombi are noted most frequently in the choriocapillaris, often in the macular region with secondary neural retinal detachment. Fibrin thrombi may be found in capillaries in the retina, iris, ciliary body, and optic nerve.

Inflammations

Nonspecific Retinal Inflammations

Secondary retinitis is usually caused by a vasculitis.

A. It may be secondary to keratitis, iridocyclitis, choroiditis, or scleritis.

B. Perivasculitis occurs around venules with the perivascular infiltrate composed of lymphocytes and plasma cells.

Specific Retinal Inflammations (See Chapters 2–4)

I. A toxic, exudative retinopathy may occur with carbon monoxide intoxication.

II. Septic retinitis of Roth (Roth’s spots) occurs with a bacteremia, especially with subacute bacterial endocarditis (see earlier in this chapter).

III. Endogenous mycotic retinitis (e.g., candidiasis) results from fungus infection.

IV. Viral retinitis

A. Herpes simplex retinitis (see Chapter 8)

1. Type 1 herpes simplex virus produces lesions in nongenital sites, including the mouth, cornea (see Fig. 8.13), skin above the waist, and in the central nervous system.

a. Type 1 virus is a rare cause of retinitis in children and adults.

b. The virus may cause encephalitis.

2. Type 2 herpes simplex virus (see Fig. 3.6) is transmitted as a venereal infection, usually producing lesions below the waist, except in newborns, in whom it may infect any organ. Approximately 20% of neonates infected with type 2 virus have ocular manifestations, including retinitis.

B. Cytomegalic inclusion disease (see Chapter 4)

V. Acute posterior multifocal placoid pigment epitheliopathy (APMPPE), also called acute multifocal ischemic choroidopathy, tends to occur in young women and shows multifocal, gray-white placoid lesions at the level of the RPE and involving predominantly the posterior pole but occurring anywhere in the fundus.

Fluorescein angiography during the acute phase of the disease process shows early blockage of background fluorescence, followed by later staining of the lesions, similar to the findings in Dalen–Fuchs nodules. Cerebral vasculitis may accompany APMPPE. Indocyanine green videoangiopathy suggests choroidal hypoperfusion as the underlying cause.

A. The lesions resolve rapidly but may leave permanent retinal pigment epithelial alterations.

B. The acute process may result from a primary retinal pigment epithelial inflammation, an acute multifocal choroiditis (choriocapillaris), or random occlusions of the precapillary arterioles feeding the lobules of the choriocapillaris.

C. The histology is unknown.

VI. Acute retinal pigment epitheliitis is characterized by an acute onset, mainly in the posterior pole, that resolves fairly rapidly, usually in 6–12 weeks.

A. The acute lesion is a deep, fine, dark gray, sometimes black spot, often surrounded by a halo and that may disappear with healing.

In the choroidal phase, fluorescein angiography shows a window defect of the depigmented halo that surrounds the lesion. The defect does not change in size or shape, nor leak dye, during the later phases of the angiogram.

B. The cause and histology are unknown.

VII. Acute macular neuroretinopathy

A. Acute macular neuroretinopathy, a rare condition, tends to occur bilaterally in young women and shows subtle, reddish-brown, wedge- or tear-shaped (pointing to the fovea) lesions in the fovea.

1. The symptoms are scotomata and minimal depression of visual acuity, which may be transient or permanent. An associated recent systemic immunologic disturbance is common and suggests an immune-based cause.

2. Fluorescein angiography is negative or shows mild dilatation and faint hypofluorescence of the lesion.

Rarely, acute macular neuroretinopathy and multiple evanescent white-dot syndrome (MEWDS; see later) occur in the same patient. Because of overlap and transitional cases, the idiopathic entities acute macular neuroretinopathy, MEWDS, acute idiopathic blind-spot enlargement syndrome, multifocal choroiditis, or pseudopresumed ocular histoplasmosis syndrome (POHS) may be classified together under the term acute zonal occult outer retinopathy (AZOOR).

B. The cause and histology are unknown.

VIII. Birdshot retinopathy (vitiliginous retinochoroidopathy; diffuse inflammatory salmon-patch choroidopathy)

A. The aqueous shows elevated levels of proinflammatory and T-cell cytokines, indicating that an inflammatory autoimmune, ocular disease may be the cause.

A strong association exists with the human leukocyte antigen (HLA)-A29 (especially HLA-A29.2 subtype) in vitro (approximately 80–90% of patients who have birdshot retinopathy are HLA-A29-positive) and with cell-mediated responses to S-antigen. Also, elevated EA rosettes and C4 complement level may be seen. Patients who have Lyme disease (see Chapter 4) may also carry the HLA-A29 antigen; conversely, patients who have birdshot retinopathy and carry the HLA-A29 antigen may also have antibodies against Borrelia burgdorferi. It is still unclear, however, whether this is a cause-and-effect relationship.

B. The condition, which has an ultimately poor visual prognosis, is characterized by:

1. A quiet eye (rarely red or injected, but not painful), usually in children or young adults with minimal, if any, anterior segment inflammation but chronic inflammation in the vitreous

2. Usually bilateral, and fairly symmetric, retinal vascular leakage (retinal vasculitis), especially in the macula, so that cystoid macular edema and optic disc edema may result

3. Distinctive, multiple, cream-colored or depigmented spots, usually discrete, and mostly around the optic disc, radiating out toward the equator

4. Development of disc pallor, diffuse RPE changes, macular edema, and narrowed retinal arterioles over a period of 6–24 months (ERG abnormalities may be found)

5. Enhanced depth OCT may show extramacular retinal and choroidal changes not seen in conventional OCT.

C. The histology is unknown.

IX. Acute retinal necrosis (ARN) (Fig. 11.20)

A. ARN, which may affect both healthy and immunocompromised people, consists of acute peripheral necrotizing retinitis, retinal arteritis, and vitreitis. Approximately 50% of cases are bilateral.

B. After 1–3 months, neural retinal detachments develop, followed by proliferative vitreoretinopathy.

C. The condition is caused most commonly by the varicella–zoster virus (46%) and also by herpes simplex virus types 1 (25%) and 2 (21%).

1. ARN may result from activation of latent, previously acquired infection, usually herpes zoster dermatitis (shingles). Rarely, ARN may develop during the course of primary varicella–zoster (chickenpox) infection.

2. Viral antibodies have been found in intrathecally produced cerebrospinal fluid from patients who have ARN, suggesting central nervous system involvement.

D. Histologically, by light microscopy, Cowdry type A intranuclear inclusions, and by electron microscopy, intranuclear aggregates of viral particles can be seen in the areas of disorganized, necrotic retina.

Fig. 11.20 Acute retinal necrosis. A, Fundus view is cloudy because of vitreous reaction. B, Neural retina shows sharp demarcation from necrotic retina on right and viable retina on left. Intranuclear inclusion bodies found in necrotic retina. C, Electron micrograph shows herpes-like virus capsids in nucleus. (Presented by Dr. JDM Gass at the meeting of the Eastern Ophthalmic Pathology Society, 1981.)

X. Multiple evanescent white dot syndrome (MEWDS)

A. This transient chorioretinopathy affects young adults, mainly women, is unilateral, and has an acute onset of decreased visual acuity and paracentral scotomas.

B. Multiple, small, white or gray-white dots occur at the level of the superficial choroids–RPE posteriorly to mid-peripherally.

C. Vitreal cells, reduced visual acuity, and abnormalities in the ERG and early receptor potential may be found.

1. Fluorescein leakage occurs from optic nerve head capillaries along with late staining of the RPE. Late indocyanine green angiography shows dual-layered highly specific, small, hypofluorescent lesions overlying larger hypofluorescent lesions.

2. Enhanced SD-OCT show specific abnormalities in the photoreceptor layer that resolve as the condition recovers.

3. Rarely, choroidal neovascularization (CNV) may occur. Also rarely, MEWDS and acute macular neuroretinopathy occur in the same patient.

Acute idiopathic blind-spot enlargement without optic disc edema may be a subset of MEWDS. Because of overlap and transitional cases, the idiopathic entities acute macular neuroretinopathy, MEWDS, acute idiopathic blind-spot enlargement syndrome, multifocal choroiditis, or POHS may be classified together under the term acute zonal occult outer retinopathy (AZOOR).

D. The cause and histology are unknown.

XI. Unilateral acute idiopathic maculopathy (UAIM)

A. UAIM occurs in young adults who experience sudden, severe visual loss (to 20/200 or worse), often after a flu-like illness, caused by an exudative maculopathy.

1. Initially, an irregular neural retinal detachment overlying a smaller, grayish thickening at the RPE level is noted.

2. Fluorescein angiography shows early irregular hyperfluorescence and hypofluorescence at the RPE level, followed in the late phase by complete staining of the overlying neural retina detachment (similar to the late staining of an RPE detachment).

3. A rapid and complete resolution usually takes place (vision 20/25 or better).

4. Some cases show eccentric macular lesions, subneural retinal exudation, papillitis, and bilaterality; association with pregnancy and human immunodeficiency virus may also occur.

XII. Diffuse unilateral subacute neuroretinitis (see Chapter 4)

XIII. Retinal pigment epitheliopathy associated with the amyotrophic lateral sclerosis/parkinsonism–dementia complex (ALS/PDC) of Guam, especially in the native Chamorro population

A. Approximately 10% of the Chamorro population have a pigment epitheliopathy that resembles ophthalmomyiasis; the rate is approximately 50% among those who have ALS/PDC.

B. Histologically, focal areas of attenuation of the RPE and a reduced amount of intracellular pigment correlate with the fundus lesions.

1. No larvae are found.

2. The pathogenesis is unknown.

XIV. Acute multifocal retinitis

A. Acute multifocal retinitis usually occurs in otherwise healthy, young to middle-aged adults who experience acute loss of vision, often preceded by a flu-like prodrome.

B. The areas of retinitis tend to be posterior and localized to the inner retina, varying in size from 100 to 500 µm in diameter. The retinal lesions are often multiple and bilateral.

1. Vision usually returns to normal without treatment in 1–4 weeks.

2. Optic disc edema may occur.

3. Fluorescein angiography shows early hypofluorescence and late staining of retinal lesions.

4. Occasional patients have a history of a cat scratch and test positively for Bartonella henselae antibodies (most patients test negatively).

XV. Serpiginous choroiditis (see Chapter 9)

Injuries

See Chapter 5.

Degenerations

Definitions

Degenerations are a result of previous disease (i.e., ocular “fingerprints” left by prior disease).

Microcystoid Degeneration

I. Typical peripheral microcystoid degeneration (PMD; Blessig–Iwanoff cysts) (Figs. 11.21 and 11.22)

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

B. All persons eight 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 affected 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).

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.)

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.)

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

A. RPCD appears clinically posterior to typical PMD. 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 affected than the inferior and superior nasal regions.

Typical PMD 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 arterioles and venules; typical lesions usually have a smoothly rounded margin.

D. Histologically, the neural retinal cysts of RPCD 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. The cysts contain hyaluronic acid.

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 more than 80% of the time, most commonly after the age of 40 and rarely before the age of 20 years.

B. Characteristically, it is found in the peripheral inferior temporal quadrant (~70% of cases), with the superior temporal quadrant (~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.

C. 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.

D. 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. Also, retinoschisis shows an absolute scotoma, but neural retinal detachment usually shows a relative scotoma.

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

3. 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 eight years of age. Senile retinoschisis is present in less than 4% of people. Therefore, if senile retinoschisis does arise from peripheral microcystoid degeneration, it does so only in a small number of cases.

Fig. 11.23 Typical and reticular cystoid degeneration. A, A large, dome-shaped retinoschisis is present. Glistening yellow-white dots are seen on its surface. B, Gross appearance of retinoschisis. Also note detachment of vitreous base (upper left), the result of previous trauma. C, Histologic section shows on left-side rupture of middle limiting membrane and of restraining glial–neuronal columns, cleaving neural retina into inner and outer layers (i.e., typical retinoschisis). D, Here, on left side, cleaving of the neural retina takes place in the inner layers (i.e., reticular retinoschisis).

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. It may occur concomitantly with typical degenerative retinoschisis.

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

B. It is most common after the fifth decade and rare before the fourth and has a predilection for the inferior temporal quadrant.

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

D. 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 later in this chapter).

Secondary Microcystoid Degeneration and Retinoschisis

I. Microcystoid degeneration and retinoschisis have been found in a variety of pathologic conditions, such as long-standing 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%.

Fig. 11.24 Paving stone degeneration. A, Typical circumferential lesions near ora serrata. B, Retinal pigment epithelium ends abruptly in area of degeneration. Bruch’s membrane is intact, but the overlying neural retina (especially outer layers) and the underlying choroid show atrophic changes.

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, yellow-white, single or multiple, separate or confluent, and often contain prominent choroidal vessels.

B. They are most common in the inferior temporal quadrant (~78%), with the inferior nasal quadrant the next most common site (~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 a 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 is present at the lesion’s margin.

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.

Familial congenital albinotic retinal pigment epithelial spots (polar bear tracks), a rare congenital anomaly, generally involve the peripheral retina with macular sparing.

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 six diopters of myopia) affects the neural retina most severely in the posterior pole and in the periphery, because the globe is mainly enlarged in its posterior third, with thinning of the sclera.

A. 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.

B. 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).

C. The overlying neural retina in the posterior pole thins and degenerates, affecting mainly the outer layers. The peripheral neural retina also becomes thin and atrophic and, therefore, more susceptible to neural retinal tears.

D. The underlying choroidal macula is thinner than normal and is related to decreased vision and lacquer cracks.

Macular Degeneration

Idiopathic Serous Detachment of the RPE (Fig. 11.25)

I. The condition, characterized by a sharply demarcated, dome-shaped elevation of the RPE, occurs mainly in men between the ages of 20 and 55 years. 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 it 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 vitelliform disease (see later in this chapter).

Fig. 11.25 Detachments of the retinal pigment epithelium and neural retina. The schematic histology drawings in the upper panels correspond with the schematic drawings of the fundus in the lower panels. A, A small, simple retinal pigment epithelium (RPE) detachment. B, A large RPE detachment. C, A small RPE detachment with an overlying neural retina (NR) serous detachment. The triple drawings of the fundus represent (i) before fluorescein injection, (ii) the early fluorescein stage, and (iii) the late fluorescein stage. Note that the RPE detachments are sharply demarcated and completely fill with fluorescein in the late stage, whereas the NR serous detachment has fuzzy borders and does not fill completely in the late stage.

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 one-third 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.

Fundus autofluorescence shows multiple distinct patterns. 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. 17.37), 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 diffuse 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 items 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.

Fig. 11.26 Nodular (“hard”) drusen. Clinical (A) and fluorescein (B) appearance of nodular drusen, which have a random distribution scattered in the posterior pole. C, Basal laminar drusen appear in clusters in the posterior pole. Scanning electron microscopic (D) and gross (E) appearance of nodular drusen. F, Histologic section shows an eosinophilic nodular druse external and contiguous to the original thin basement membrane of the retinal pigment epithelium (RPE; i.e., between RPE basement membrane and Bruch’s membrane). (D and E, Courtesy of Dr. RC Eagle, Jr.)

Fig. 11.27 Large (“soft”) drusen. A, Clinical appearance of large drusen scattered in the posterior pole. B, An amorphous material is present between retinal pigment epithelium and Bruch’s membrane. Note the presence of tiny blood vessels in material. C, Brushlike appearance helps identify the basal laminar deposit. D, OCT showing soft retinal drusen. (C, Courtesy of Dr. RC Eagle, Jr.)

II. Drusen consist of at least two fundamentally different focal types, which by fluorescein angiography, some show early fluorescence and late staining.²

A. The first focal type, nodular (“hard,” discrete) drusen, consists of small, yellow or yellow-white spots or discrete RPE lesions measuring approximately 50 µm (see Fig. 11.26).

1. Nodular drusen are congenital or acquired early in life and have a rather random distribution, appearing as isolated drusen, scattered about in the posterior pole, without a recognizable pattern.

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

3. 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.

4. 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.

5. The so-called basal laminar (cuticular) drusen (see Fig. 11.26) are one form of nodular drusen and appear yellowish, punctiform, and uniform in size. Nodular drusen may become calcified, lipidized, cholesterolized, or, infrequently, vascularized.

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. Unlike the aforementioned nodular drusen, basal laminar drusen have a recognizable pattern of distribution, appearing in clusters in the posterior pole. They may appear in early adulthood and occur with equal frequency in black, Latino, and white patients.

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

c. 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.

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

e. Basal laminar (cuticular) drusen phenotype are highly associated with the Tyr402His variant of the complement factor H (CFH) gene.

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 differ in consistency from bone to fluid.

1. These are usually acquired at 50 years of age or later and represent the earliest sign of ARMD and may be impossible to differentiate by clinical methods or by light microscopy from small detachments of the RPE.

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

a. Large drusen are bigger than nodular drusen, appear less dense and more fluffy, 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. They may become calcified, lipidized, cholesterolized, or, infrequently, vascularized.

c. Fluorescein angiography usually shows staining of the drusen, although some may appear hypofluorescent, presumably because of lipid accumulation.

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

3. 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. Reticular pseudodrusen

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

2. Best seen with red-free light or the He-Ne laser of the scanning laser ophthalmoscope, they do not fluoresce with fluorescein or indocyanine green angiography. This is an important risk factor for the development of age-related ARMD (~50% develop it).

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.

Dry Age-Related 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 transporter-retina; 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. A small fraction of patients with ARMD may actually have a late-onset variant of Best vitelliform 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 autosomal-dominant retinitis pigmentosa (RP). Hepatic lipase (LIPC) gene, located on chromosome 15q22, is also associated with ARMD. The TT genotype of the ARMS2 A69S (locus on 10q26) polymorphism is a major contributor to ARMD. The Y402H polymorphism in the complement factor H (CFH) on chromosome 1q is associated with lifetime incidence of early ARMD and progression of early to late ARMD. A cumulative effect of high-risk alleles in CFH, Arms2, and VEGFA is associated with a younger onset of retinal neovascularization and less response to therapy.

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.

1. Risk factors include the following: high intake of saturated fat and cholesterol (monosaturated fats may be preventative); exposure to sunlight; soft and perhaps hard drusen; a dose-related relationship exists between smoking and ARMD, especially the exudative form; both blue iris color and abnormal skin sun sensitivity; a modest association exists between increased systolic blood pressure and pulse pressure and increased 10-year incidence of ARMD; elevated C-reactive protein and hyperhomocysteinemia are independent risk factors; smoking (10 pack-years or more); cataract surgery; small globe; and the presence of CFH CC genotype.

2. The use of statins, increased intake of fish and shellfish in the diet, and vitamin supplements may be positive risk factors in preventing or delaying ARMD. Conversely, patients with ARMD have an increased risk of coronary heart disease.

C. There is a significantly less chance of both dry and wet ARMD in blacks relative to whites. By age 80 years, the chance of developing dry ARMD is lower in Latinos than in whites.

Fig. 11.28 Dry, age-related macular degeneration. A, Basophilia in region of Bruch’s membrane commonly found as an aging change. Note choriocapillaris partially obliterated and small “detachment” of neural retina from retinal pigment epithelium, which is impossible to differentiate from a large druse. Such changes may be precursors to some senile degenerations in macular region. B, An oil red-O stain is positive for fat in another druse. C, Another case shows basophilia of Bruch’s membrane and a probable artifactitious hemorrhage into neural retina. D, A von Kossa stain is strongly positive for calcium in Bruch’s membrane (note “crack” in the fragile Bruch’s membrane).

Fig. 11.29 Dry age-related macular degeneration. A, The patient showed drusen and other abnormalities of the retinal pigment epithelium (RPE) in the form of increased translucency, pigment mottling, and pigment loss. No subretinal choroidal neovascularization (CNV) was present in this eye. However, CNV was present in the other eye. B, A histologic section of another eye shows irregular degeneration of the RPE and the outer retinal layers, as well as cystic changes in the outer plexiform layer. C, Another level of the same eye shows similar retinal changes along with a thrombus (t) in a choroidal artery. Whether the choroidal thrombosis is related to the retinal changes in atrophic macular degeneration is unknown (nr, neural retina; c, choroid; s, sclera; b, Bruch’s membrane).

II. Clinically, the retinal damage is limited to the foveomacular area and causes a gradual and subtle visual loss (never sudden or dramatic, as in exudative ARMD).

The complaint of abrupt loss of vision in a patient who has dry ARMD should alert the clinician to the possibility of the development of superimposed subneural retinal neovascularization.

A. Pigment disturbances (e.g., increased and decreased pigmentation) are seen in the macula.

Pigmentary macular changes may also be seen in inherited diseases such as Bardet–Biedl syndrome, Bassen–Kornzweig syndrome, Batten–Mayou disease, central RP, Cockayne’s syndrome, cone–rod dystrophy, familial hypobetalipoproteinemia, Hallervorden–Spatz syndrome, Hallgren’s syndrome, Hooft’s syndrome, patterned dystrophy of the RPE, Pelizaeus–Merzbacher disease, Refsum’s disease, Stargardt’s disease, and others.

B. The RPE atrophy tends to spread and form well-demarcated borders, called geographic atrophy. The underlying choriocapillaris is atrophic.

1. The atrophic areas, which are often bilateral and relatively symmetric, are multifocal in approximately 40% of eyes.

2. The atrophic areas tend to follow the disappearance or flattening of soft drusen, RPE detachment, or reticular mottling of the RPE.

Fundus autoflourescence is an excellent way to visualize and evaluate RPE cell loss.

III. The changes are usually bilateral and found in people older than 50 years of age. The rate of significant visual loss is approximately 8% per year.

IV. Histologically, the following changes may be seen:

A. The choriocapillaris may be partially or completely obliterated. Bruch’s membrane may be thickened and may show basophilic changes.

B. The RPE may show atrophy with depigmentation, hypertrophy, or even hyperplasia.

C. In both dry and wet ARMD, RPE, photoreceptors, and inner nuclear cells die by apoptosis.

D. The neural retina often shows microcystoid or even macrocystoid (retinoschisis) degeneration.

1. Hole formation may occur in the inner wall of the macrocyst.

2. Rarely, total hole formation may occur, leaving the macular retinal ends with rounded, smooth edges.

The aforementioned changes, characterized as age-related macular choroidal degeneration and often noted clinically by the presence of drusen (see earlier), also occur in, and are related to the cause of, idiopathic serous detachment of the RPE, idiopathic central serous choroidopathy, and exudative ARMD. Soft or hard drusen may predispose the eye to the development of dry ARMD. Each year, 16,000 people in the United States become blind from ARMD. ARMD is the most prevalent cause of legal blindness in white adults in the United States (a similar frequency of blindness is seen in the dry and exudative forms, but the blindness tends to be more profound in the exudative form).

3. The normal aging phenomenon of slow, steady rod loss is accompanied in ARMD by cone degeneration so that eventually only degenerative cones remain; ultimately, all photoreceptors may disappear.

4. The RPE and Bruch’s membrane in postmortem eyes containing nonexudative and exudative AMD have increased iron content, some of which is chelatable. The iron may generate highly reactive hydroxyl radicals that may contribute to the development of AMD.

E. In addition to the well-known aging changes of the RPE, including drusen and an increase in cell lipofuscin, the cell, in situ, can also undergo a change known as lipidic degeneration, the noxious stimulus for which is unknown (see Fig. 17.44).

F. With aging, Bruch’s membrane shows, in addition to drusen, increased amounts of calcium and lipid.

Age-Related Exudative Macular Degeneration (Exudative, Wet, or Senile Disciform Macular Degeneration; Kuhnt–Junius Macular Degeneration)

I. Typically, exudative ARMD (Fig. 11.30) occurs mainly in people 60 years of age or older. The cause is unknown.

The photoreceptor gene, ABCR (also known as STGD1) on chromosome 1p21 is mutated in Stargardt’s disease. Approximately 3% of cases of wet ARMD also have mutations in the ABCR gene. The complaint of abrupt loss of vision in a patient who has dry ARMD should alert the clinician to the possibility of the development of superimposed subneural retinal vascularization. Exudative ARMD in patients younger than 60 years of age most commonly is caused by the following, in decreasing frequency: high myopia; POHS; angioid streaks; and miscellaneous hereditary, traumatic, or inflammatory disorders.

A. The risk increases with age, especially 75 years or older, and in women. The three-year incidence of wet ARMD is approximately 10 per 1000 Americans 65 years or older.

B. No sex predilection exists, and the degeneration is often bilateral.

C. The main risk factor is age-related macular choroidal degeneration (soft drusen, pigment epithelial disturbances, and loss of foveal reflex).

D. High intake of saturated fat and cholesterol is also associated with an increased risk for early ARMD.

E. Consumption of foods rich in certain carotenoids (e.g., dark-green leafy vegetables) may decrease the risk for development of ARMD.

F. Exudative ARMD may be associated with moderate to severe hypertension, particularly among patients receiving antihypertensive therapy. A modest association exists between increased systolic blood pressure and pulse pressure and increased 10-year incidence of ARMD.

G. Hyperopia may also be a risk factor.

I. A high serum level of the antioxidant enzyme plasma glutathione peroxidase is associated with a significant increase in late ARMD prevalence.

J. An approximately fivefold risk for late-stage ARMD (especially exudative ARMD) exists in eyes that have previously had cataract surgery.

K. The presence of CFH CC genotype increases the risk 144-fold.

L. Possessing the LOC387715 (rs 10490924) variant may increase the risk (if homozygous for both variants, an earlier development of neovascular AMD may occur).

Patients who have unilateral exudative ARMD have a 12–15% chance every year for development of exudative ARMD in the other eye. Patients who have large, soft, confluent drusen are at the greatest risk for development of exudative ARMD in the second eye. Systemic hypertension is another risk factor for the development of subneural retinal (choroidal) neovascularization.

Fig. 11.30 Exudative age-related macular degeneration. A, The patient had subretinal neovascularization followed by numerous episodes of hemorrhage, resulting in an organized scar. B, A small vessel (c, capillary) has grown through Bruch’s membrane (b) into the subretinal pigment epithelial space, resulting in hemorrhage and fibroplasia. C, The end stage of the process shows a thick fibrous scar between the choroid and the outer retinal layers (trichrome stain). Note the good preservation of the retina, except for the complete degeneration of the photoreceptors (nr, neural retina; st, scar tissue; c, choroid; s, sclera; b, Bruch’s membrane). (Case in B reported in Frayer WC: Elevated lesions of the macular area: A histopathologic study emphasizing lesions similar to disciform degeneration of the macula. Arch Ophthalmol 53:82, 1955. © American Medical Association. All rights reserved.)

II. Evolution of exudative ARMD

A. Early degenerative changes are seen in the choriocapillaris and in Bruch’s membrane in the macular area, manifested clinically as drusen, especially soft drusen; collectively, these changes are called age-related macular choroidal degeneration.

1. Large, soft drusen seem to predispose the eye to exudative ARMD.

2. Each year, 16,000 people in the United States become blind from ARMD.

The age-related macular choroidal degenerative changes may remain stationary or lead to idiopathic serous detachment of the RPE, idiopathic central serous choroidopathy, or dry or exudative ARMD.

3. ARMD is the most prevalent cause of legal blindness in the United States; a similar frequency of blindness is seen in the dry and the exudative forms.

1. The new vessels grow from the choroid (from the choriocapillaris) through Bruch’s membrane, usually under the RPE, rarely between the RPE and neural retina, or in both regions. The size of the membrane may be best estimated by OCT.

Sub-RPE neovascularization is characteristic of age-related “wet” macular degeneration, whereas subneural retinal neovascularization (CNV) is characteristic of POHS. CNV, also called subretinal neovascularization (i.e., neovascularization under the RPE, between the RPE and neural retina, or in both regions), may also develop from new vessels growing from the choroid around the end of Bruch’s membrane in the juxtapapillary region. CNV may occasionally occur in the periphery. Granulomatous reaction to Bruch’s membrane, with multiple multinucleated giant cells, may play a role in the breakdown of Bruch’s membrane and be a stimulus for neovascularization in some cases.

2. Two fundamentally different types of CNV arise from the choroid: types 1 and 2.

a. Type 1, the most common type, consists of subretinal pigment epithelial neovascularization—it occurs primarily in people older than 50 years of age, often in association with ARMD. The CNV develops in eyes that show diffuse, age-related macular choroidal degeneration in the choriocapillaris–Bruch’s membrane–RPE complex.

b. Type 2 consists of subneural retinal neovascularization—it occurs primarily in people younger than 50 years of age, POHS being the prototype. The CNV develops in an area of focal scarring, the choriocapillaris–Bruch’s membrane–RPE complex being normal elsewhere.

C. All of the aforementioned factors produce an altered state of the internal choroid and external retina, predisposing the eye to the development of serous and hemorrhagic phenomena.

D. Finally, a hemorrhage between Bruch’s membrane and RPE occurs (hematoma of the choroid).

E. Although the hemorrhage may remain localized, it usually breaks through the RPE under the neural retina; rarely, it may extend into the choroid, the neural retina, or even the vitreous. Organization of the hemorrhage is accompanied by RPE proliferation and fibrous metaplasia.

1. Ingrowth of mesenchymal tissue forms granulation tissue.

2. A disciform fibrovascular scar forms in the macular region, causing degeneration of the macular RPE and neural retina, and central vision is irreversibly impaired.

F. Retinal angiomatous proliferation (RAP)

1. RAP is a distinct form of occult CNV associated with proliferation of intraneural retinal capillaries in the paramacular neural retina and a contiguous telangiectatic response that has a progressive vasogenic sequence.

2. RAP is an “upside-down” form of exudative ARMD, starting initially in the neural retina and ultimately connecting to subneural CNV.

3. Three stages have been described:

a. Stage I—intraretinal neovascularization (IRN) originating from the deep capillary plexus in the paramacular neural retina

b. Stage II—IRN extends posteriorly into the subneural space (subneural retinal neovascularization)

c. Stage III—IRN anastamosing with CNV

III. Histologically, the following features are noted:

B. The subretinal (sub-RPE or subneural retinal) membranes consist of a cellular and an extracellular matrix component.

1. The cellular component contains RPE, inflammatory cells (mainly lymphocytes, plasma cells, and macrophages), vascular endothelium, glial cells, myofibroblasts, photoreceptor cells, fibrocytes, and erythrocytes.

2. The extracellular matrix component contains fibrin; collagen types I, III, IV, and V; fibronectin; laminin; acid mucopolysaccharides; and lipid.

3. Transforming growth factor-β₁ (TGF-β₁) and basic growth factor are present in the major cell types (vascular endothelium, fibroblasts, and RPE cells) and possibly may play a role in the development of the neovascular complex.

Surgically excised human subfoveal fibrovascular membranes have been shown to express vascular endothelial growth factor (VEGF), both VEGF mRNA and protein.

C. Basically, the pathologic process is that of a localized granulation tissue associated with diffuse, soft drusen.

Rarely, the CNV is in the choroid (i.e., intrachoroidal neovascularization).

Exudative Macular Degeneration Secondary to Focal Choroiditis (Juvenile Disciform Degeneration of the Macula)

I. Most patients with this degeneration are younger than 50 years of age, have greater than 50% bilateral involvement, show a high incidence of macular hemorrhagic phenomena, and usually have irreversibly damaged central vision; both sexes are affected equally.

II. Most cases probably occur secondary to focal inflammatory cell infiltration of the choroid.

III. Five subdivisions have been identified:

A. Exudative (wet) macular detachment secondary to multifocal choroiditis (POHS; Fig. 11.31)—the most common type

1. POHS occurs in otherwise healthy young adults, with the initial symptom being sudden blurring of vision in one eye.

Although most patients in the United States who have POHS show a positive skin reaction to intracutaneous injection of 1 : 1000 histoplasmin and chest radiographic evidence of healed pulmonary histoplasmosis, the fungal organism has never been cultured or demonstrated satisfactorily in a histologic section from a typical retinal lesion in a nonimmunologically deficient patient. The cause, therefore, remains open to question. In Germany, where histoplasmosis is extremely rare, a condition called punctate inner choroidopathy is not uncommon. It is indistinguishable clinically from presumed histoplasmic choroiditis found in the United States, where almost all the patients have negative skin tests for histoplasmosis.

2. Early, a yellowish-white or gray, circumscribed, slightly elevated area of choroidal infiltration is present in the macular region.

Overlying RPE disturbances soon appear, resulting in a small, dark greenish macular ring.

3. CNV develops.

CNV is characteristic of POHS, whereas sub-RPE neovascularization is characteristic of “wet” ARMD. Smoking is a risk factor for choroidal neovascularization development.

4. Serous and hemorrhagic disciform detachment of the neural retina may ensue.

5. Multiple, small to tiny, sharply circumscribed, punched-out white defects are scattered about the fundus.

6. An irregular area of peripapillary degeneration of the choroid and RPE is frequently seen.

7. HLA-B7 is found in association with POHS.

8. Histologically, the peripheral lesions show either a chronic nongranulomatous or a granulomatous inflammatory infiltrate in the choroid. The typical acute macular lesions have not been examined histologically.

a. Overlying Bruch’s membrane and RPE may or may not be involved.

b. Excised subretinal membranes are composed of fibrovascular tissue between Bruch’s membrane and RPE and probably represent nonspecific granulation tissue.

1) The cellular component contains RPE, inflammatory cells (mainly lymphocytes, plasma cells, and macrophages), vascular endothelium, glial cells, myofibroblasts, photoreceptor cells, fibrocytes, smooth muscle cells, and erythrocytes.

2) The extracellular matrix component contains 20- to 25-nm collagen fibrils, 10-nm collagen fibrils, and fibrin.

3) TGF-β₁ and basic growth factor are present in the major cell types (vascular endothelium, fibroblasts, and RPE cells) and may possibly play a role in the development of the neovascular complex.

Fig. 11.31 Presumed histoplasmic choroiditis. A and B, An irregular area of peripapillary degeneration of the choroid is seen in each eye. The A shows subneural retinal neovascularization. C, Peripheral, tiny, sharply circumscribed, punched-out lesions are seen. D, Histologic section shows a chorioretinal granulomatous inflammation along with scarring. E, Increased magnification of chorioretinal inflammation. (Case presented by Dr. TA Makley, Jr. at the meeting of the Verhoeff Society, 1983.)

B. Idiopathic subretinal (choroidal) neovascularization

1. Idiopathic subretinal neovascular membranes occur in the absence of any associated disorder, tend to occur in younger people, and may regress spontaneously.

2. The cellular component contains RPE, macrophages, vascular endothelium, glial cells, myofibroblasts, photoreceptor cells, and erythrocytes.

3. The extracellular matrix component contains 20- to 25-nm collagen fibrils, 10-nm collagen fibrils, and fibrin.

C. Exudative macular detachment secondary to focal peripapillary choroiditis—the patients have negative histoplasmin skin tests and no peripheral fundus lesions. Their macular lesions are probably caused by an underlying peripapillary choroiditis.

D. Exudative macular detachment secondary to focal macular choroiditis—the patients have negative histoplasmin skin tests, no peripheral fundus lesions, and no peripapillary choroiditis. Their macular lesions are probably caused by an underlying, focal, macular choroiditis.

E. Exudative macular detachment secondary to Toxocara canis (see Chapter 4).

Idiopathic Polypoidal Choroidal Vasculopathy

I. Idiopathic polypoidal choroidal vasculopathy (IPCV), a subtype of ARMD, has a predilection for members of darkly pigmented races (rarely, it may be associated with sickle-cell retinopathy).

II. Clinical characteristics

A. Reddish-orange, spheroidal, polyp-like structures, presumably aneurysmal dilatations of the inner choroidal vascular network with distinct fundus autofluorescence findings

B. Multiple, recurrent, serosanguineous detachments of the RPE and neural retina, secondary to leakage and bleeding from the peculiar choroidal vascular lesions

IPCV can resemble ARMD. The former, however, is more common in the peripapillary area, usually has no associated drusen, and is most common in nonwhite patients.

C. Occasional vitreous hemorrhage and relatively minimal fibrous scarring

III. Histopathology

A. The network of peripapillary vessels seen on fluorescein angiography and indocyanine green angiography correspond to branches of the short posterior ciliary arteries.

B. The elevated polypoidal and tubular lesions correspond to large, thin-walled cavernous vascular channels and choroidal. Intra-Bruch’s membrane neovascularization is in continuity with the vascular channels.

Cystoid Macular Edema (Irvine–Gass Syndrome)

See Chapters 5 and 15.

Toxic Retinal Degenerations

I. Chloroquine (Fig. 11.32) and hydroxychloroquine

A. The characteristic but nonspecific “bull’s-eye” macular degeneration appears to be directly related to the total dosage of chloroquine.

1. The bull’s-eye macular degeneration indicates advanced, irreversible damage.

Other causes of bull’s-eye macula include ARMD, chronic macular hole, Bardet–Biedl syndrome, benign concentric annular macular dystrophy, clofazimine toxicity, cone–rod dystrophy, dominant cystoid macular dystrophy, fenestrated sheen macular dystrophy, fucosidosis, Hallervorden–Spatz syndrome, hereditary ataxia, neuronal ceroid lipofuscinosis (Batten’s disease), olivopontocerebellar atrophy, quinacrine therapy for malaria, RP, Sjögren–Larsson syndrome, Stargardt’s disease, UAIM, and uvi ursi herbal toxicity.

2. Serious vision impairment rarely occurs if the daily dose of chloroquine does not exceed 250 mg (and 6.5 mg/kg of body weight for hydroxychloroquine).

A baseline complete ocular examination should be done within the first year of starting therapy. The baseline examination should include automated threshold testing with a white 10-2 protocol and, if available, testing with one or or more of the following: spectral domain (SD)-OCT, multifocal (mf) ERG, fundus autofluorescence (FAF), and fundus photography. Annual screening should be initiated no later than five years after starting therapy and should include automated 10-2 fields and, if available, SD-OCT, mfERG, and FAF. Time-domain OCT, fluorescein angiography, full-field ERG, Amsler grid and color vision testing, and EOG are no longer recommended.

In following patients, examination every three months is recommended (probably less frequent examinations would suffice—that is, first follow-up in six months and then annually). At the initial examination, the patient is given a color vision test and instructed in the use of the Amsler grid. At subsequent visits, color vision testing is performed, and confirmation of the proper use of the Amsler grid is obtained.

3. Corneal deposition of drug is seen in 90% of patients who use chloroquine but in less than 5% who use hydroxychloroquine.

B. Night blindness is usually the first symptom.

1. Patients may show extinguished ERGs but have normal or minimally abnormal final dark adaptation thresholds, differentiating advanced chloroquine retinopathy from RP.

2. After chloroquine is stopped, the degree of retinopathy and its rate of progression are determined by the total dose of the drug and the patient’s susceptibility to it.

C. Histologically, RPE abnormalities, destruction of receptors and ganglion cells, and pigment migration into the macular neural retina are seen.

As seen by electron microscopy, degenerative changes occur in most of the ocular tissues in the human eye. The changes are prominent in the neural retinal neurons, where they appear as curvilinear structures and membranous cytoplasmic bodies.

Fig. 11.32 Chloroquine retinopathy. Clinical (A) and fluorescein (B) appearance of left eye. C and D, Another patient more severely afflicted. E, Cytoplasm of retinal ganglion cell contains myriad clusters of curvilinear structures (ct) and membranous cytoplasmic bodies (mcb). Bodies better seen in top inset, probable continuity of curvilinear structure with membraneous body seen at free arrows. Bottom inset shows retinal ganglion cell by light microscopy. (C and D, Courtesy of Dr. AJ Brucker; E, from Ramsey MS, Fine BS: Chloroquine toxicity in the human eye: Histopathologic observations by electron microscopy. Am J Ophthalmol 73:229. © Elsevier 1972.)

II. Many other drugs, such as canthaxanthin, chlorpromazine, chloramphenicol, deferoxamine, indomethacin, quinine, sparsomycin, thioridazine, and vitamin A, may cause a retinopathy, usually of a secondary pigmentary type.

Postirradiation Retinopathy

I. Postirradiation retinopathy may occur months to years after irradiation (X-rays, ⁶⁰Co, or radon seeds) of the eye, usually for cure or control of retinoblastoma, malignant melanoma, or lid, orbital, or sinus neoplasm. Usually, a latent period of 12 months or more elapses before a retinopathy develops.

II. The neural retina may show capillary occlusion and capillary microaneurysms, telangiectatic vessels, neovascularization, hard exudates, cotton-wool spots, hemorrhages, and signs of arteriolar or venular occlusion—all caused by retinal vascular obliteration secondary to the irradiation.

Bone Marrow Transplant Retinopathy

I. A retinopathy develops in perhaps 60% of patients who survive at least six months after bone marrow transplantation for the therapy of acute leukemia. An optic neuropathy also develops in many of these patients.

II. The main finding is an occlusive microvascular retinopathy that can cause macular edema and proliferative retinopathy.

Cancer-Associated Retinopathy (Paraneoplastic Syndrome; Paraneoplastic Retinopathy; Paraneoplastic Photoreceptor Retinopathy; Melanoma-Associated Retinopathy)

I. The paraneoplastic syndrome (PNS) is a consequence of remote effects of tumors on different organ systems, sometimes years before the tumor is apparent.

A. The neurologic PNS may involve any site—for example, myasthenic syndrome associated with lung carcinoma or other malignant neoplasms (Lambert–Eaton syndrome), myasthenia gravis associated with thymoma, opsoclonus associated with neuroblastoma, cancer-associated retinopathy (CAR) in the face of a distant carcinoma or lymphoma, and melanoma-associated retinopathy (MAR) associated with a cutaneous melanoma.

B. Histologically, the inner nuclear and ganglion cell layers of the neural retina show a reduced thickness, whereas the photoreceptors appear preserved.

II. CAR is most commonly associated with small cell lung carcinoma, but many other carcinomas and lymphomas can cause it.

Rarely, PNS, rather than causing eye involvement, can cause orbital involvement in the form of an orbital myositis.

A. Visual loss may predate the discovery of the distant cancer. Typically, the visual loss is progressive and evolves over weeks to months.

B. Clinical, ERG, and histopathologic evidence shows dysfunction and death of neural retinal photoreceptors.

C. Sera of patients with CAR may contain antibodies that react with photoreceptors and ganglion cell antigen (e.g., recoverin).

D. It is thought that autoantibodies developed against a cancer cell antigen cross-react with certain components of neural retinal cells and cause CAR.

III. MAR is associated with cutaneous malignant melanoma.

A. Usually, a relatively acute onset of night blindness occurs months to years after a diagnosis of cutaneous malignant melanoma has been made.

B. Patients typically have a sensation of shimmering lights, elevated dark-adapted thresholds, and an ERG resembling that found in some forms of stationary night blindness.

C. Unlike CAR, photoreceptor function is intact, but the signal between photoreceptors and second-order neural retinal interneurons is defective.

D. It is thought that autoantibodies developed against a melanoma cell antigen cross-react with certain components of neural retinal cells and cause MAR. The identity of the retinal bipolar antigen recognized by MAR autoantibodies helps to make the diagnosis of MAR.

Idiopathic Macular Holes

I. The pathogenesis of idiopathic macular holes (IMH) is not known.

A. IMH may be bilateral and tend to occur in eyes that do not have a posterior vitreous detachment.

1. Given a full-thickness macular hole in one eye, a 13–31 % chance exists for development of a full-thickness hole in the other eye.

2. If the first eye has an incomplete hole, a 19–24% chance exists of eventual bilaterality.

Patients who have a unilateral macular hole and a normal fellow eye that does not have a posterior vitreous detachment have a 16% five-year incidence of full-thickness hole formation in the fellow eye.

B. It appears that vitreous contraction or separation may play an important role in the development of IMH. Reduced choroidal thickness, as seen with OCT, may also play a role.

1. The primary mechanism is postulated to be a spontaneous, usually abrupt, focal contraction of the prefoveal cortical vitreous, which elevates the neural retina in the central foveal region.

2. Spontaneous complete vitreous separation from the fovea could reverse the process.

Although the vitreous seems to play a role, some studies suggest that most IMH develop in the absence of posterior vitreous detachment and that the pathogenesis of IMH may be independent of posterior vitreous detachment.

II. The development of IMH can be divided into three stages:

A. Stage 1: tractional detachment or impending macular hole

1. Stage 1-A has a characteristic biomicroscopic appearance of a yellow spot (increased visibility of the neural retinal pigment xanthophyll), and stage 1-B has a characteristic appearance of a yellow ring and loss of the foveolar depression in the absence of a posterior vitreous detachment.

A hole may be covered by semiopaque contracted prefoveal cortical vitreous bridging the yellow ring (stage 1-B occult hole). Stage 1-B occult holes become manifest (stage 2 holes) either after separation of the contracted prefoveal cortical vitreous from the retina surrounding a small hole or as an eccentric can-opener-like tear in the contracted prefoveal cortical vitreous, at the edge of larger stage 2 holes.

B. Stage 2: small hole formation

1. Increased traction causes a tangential tear, usually at the foveal edge.

2. Tractional elevation of Henle’s nerve fiber layer along with intraneural retinal central foveal cyst formation is the initial feature of macular hole formation.

Most (~75%) stage 2 macular holes, both centric and eccentric, especially when they show pericentral hyperfluorescence, progress to stage 3 or 4.

C. Stage 3: large hole formation

Over several months or longer, the tear enlarges to a fully developed, one-third disc diameter-sized hole.

III. Histologically, in membranes stripped out during vitrectomy for stage 1 IMH, an acellular collagenous tissue layer is found.

A. Membranes from stages 2 and 3 IMH show an increased number of glial cells (fibrous astrocytes) and other cells such as RPE (often the predominant cell), fibrocytes, and myofibroblasts.

B. Depending on the constituents of the membrane, immunohistochemical staining is positive for cytokeratin, glial fibrillary acidic protein, vimentin, actin, and fibronectin.

Light Energy Retinopathy

See Chapter 5.

Traumatic Retinopathy

See Chapter 5.

Hereditary Primary Retinal Dystrophies

Definitions

I. Dystrophies are primary phenomena that are inherited and tend to be bilateral and symmetric.

II. They may remain stationary or be slowly progressive.

III. Many retinal dystrophies may be genetically determined by the process of apoptosis (see Chapter 1).

Juvenile Retinoschisis (Vitreous Veils; Congenital Vascular Veils; Cystic Disease of the Retina; Congenital Retinal Detachment)

I. Juvenile retinoschisis (Fig. 11.33) is a bilateral condition, tends to be slowly progressive, and often culminates in extensive chorioretinal atrophy with macular involvement.

A. Retinoschisis may be defined as an intraneural retinal tissue loss or splitting at least 1.5 mm in length (one average disc diameter).

B. It is differentiated from a neural retinal cyst by its configuration; that is, 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.

Fig. 11.33 Juvenile retinoschisis. A, The characteristic foveal lesion, resembling a polycystic fovea, is shown. Typically, no leakage is present when fluorescein angiography is performed. B, A histologic section of another eye shows a large temporal peripheral retinoschisis cavity. C, A histologic section of another area of the same eye shows a splitting in the ganglion and nerve fiber layers of the retina—the earliest finding in juvenile retinoschisis. The area of pathology is the same as that seen in reticular microcystoid degeneration and retinoschisis. (A, Courtesy of Dr. AJ Brucker; B and C, case reported in Yanoff M, Rahn EK, Zimmerman Le: Histopathology of juvenile retinoschisis. Arch Ophthalmol 79:49–53, 1968. © American Medical Association. All rights reserved.)

II. Most often, it is inherited as an X-linked recessive trait, but occasionally it occurs as an autosomal-recessive trait and then usually without macular involvement, or as an autosomal-dominant trait, often with macular involvement.

Genetic linkage studies have localized the retinoschisis gene to the p22.2 region of the X chromosome (Xp22), designated the XRLS1 gene.

III. Ophthalmoscopic appearance

A. Approximately 50% of patients have a translucent, veil-like membrane that bulges into the vitreous, has a neural retinal origin, and usually occurs in the inferior temporal quadrant. This membrane, really a retinoschisis cavity, has retinal vessels coursing over its inner wall, which frequently contains large round or oval holes. The outer wall of the cavity may contain small holes.

B. Foveal retinoschisis is present in almost all cases. It appears clinically much like the polycystic fovea seen in Irvine–Gass syndrome, but without fluorescein leakage.

1. OCT shows foveomacular retinoschisis is most frequent in the inner nuclear layer.

2. OCT shows extramacular retinoschisis equally frequent in the inner nuclear layer, outer nuclear layer, and ganglion cell/nerve fiber layers.

C. Infantile cystoid maculopathy has been reported in infants; the findings are indistinguishable ophthalmoscopically from the macular lesions of juvenile retinoschisis.

Foveal and peripheral retinoschisis have been seen in a woman who has homozygous, X-linked retinoschisis. Familial foveal retinoschisis is similar to juvenile retinoschisis in the foveal appearance and has an autosomal-recessive inheritance pattern, but it does not show typical peripheral retinoschisis. Cone–rod dystrophy may be associated with familial foveal retinoschisis.

IV. Histologically, in the region of the retinoschisis, the neural retina shows a cleavage at the level of the nerve fiber and ganglion cell layers; in areas away from the schisis, the neural retina shows a “looseness” or microcystic degeneration that mainly involves the nerve fiber layer and, to a lesser extent, the ganglion cell layer.

A. Mutation of the RS1 gene appears to give rise to a dysfunctional adhesive protein, resulting in defective cellular adhesion that eventually leads to schisis formation.

B. The area of neural retinal involvement is similar to that found in reticular peripheral cystoid degeneration and retinoschisis, but it is different from the middle-layer neural retinal involvement of typical microcystoid peripheral neural retinal degeneration and retinoschisis.

C. In juvenile retinoschisis, the neural retinal spaces appear empty and do not stain for acid mucopolysaccharides.

V. Goldmann–Favre vitreoretinal dystrophy has an autosomal-recessive heredity, and it consists of juvenile retinoschisis and the following:

A. Vitreous degeneration and liquefaction and the formation of preretinal strands and cords along with a secondary pigmentary and degenerative changes of the retina resembling RP

B. Cataracta complicata lens opacities and leakage of fluorescein from retinal vessels

C. Hemeralopia with abolition of the ERG response and a progressive decrease in vision function

VI. Wagner’s vitreoretinal dystrophy (Table 11.1) consists of:

A. Juvenile retinoschisis plus marked vitreous syneresis, no posterior pole involvement, normal dark adaptation but a subnormal ERG, and cataracta complicata lens opacities.

The polymorphous ocular signs of this disease may also include myopia, retinal pigmentation, neural retinal breaks, patchy areas of thinned RPE, chorioretinal atrophy, narrowing and sheathing of retinal vessels, extensive neural retinal areas of white with pressure, lattice degeneration of the neural retina, marked neural retinal meridional folds, and optic atrophy. The condition should be differentiated from snowflake vitreoretinal degeneration (SVD), a hereditary vitreoretinal degeneration characterized by multiple, minute, whitish-yellow dots in the peripheral neural retina. The genetic locus for SVD is in a region of chromosome 2q36, flanked by D28S2158 and D2S2202.

B. An autosomal-dominant heredity—mutations that cause Wagner’s disease (and also erosive vitreoretinopathy) type I are linked to markers on the long arm of chromosome 5 (5q13–14) and type II the COL2A1 gene on locus 12q13–14.

Many cases previously reported as Wagner’s syndrome (and also Pierre Robin syndrome) probably represent Stickler’s syndrome (hereditary progressive arthro-ophthalmopathy). Stickler’s syndrome (see Table 11.1), which has an autosomal-dominant inheritance pattern and shows ocular, orofacial, and skeletal abnormalities, can be divided into three types: Type I is caused by mutations in the COL2A1 gene on chromosome 12q13–14 in the nonhelical 3′ end of the type II procollagen gene; type II COL11A1 gene on locus 1p21; and type III COL11A2 gene on 6p22–23.

TABLE 11.1

Clinical Findings in Syndromes with Wagner-Like Vitreoretinal Degenerations

Disease	Systemic Findings	Refractive Error	Vitreous Veils and Perivascular Lattice	Retinal Detachments	Cataract
A. With Ocular Symptomatology Only
1. Wagner’s syndrome	Normal	Moderate myopia; occasionally severe myopia	Yes	None	Mild childhood; mature by 35–40 years
2. Jansen’s syndrome	Normal	Low hypermetropia or moderate myopia; occasionally severe myopia	Yes	Yes	Cortical opacities in teens; mature in fourth decade
B. With Associated Systemic Anomalies
1. Hereditary arthro-ophthalmopathy with marfanoid habitus (Stickler’s syndrome)	Micrognathia, cleft palate, joint laxity, epiphyseal dysplasia	Moderate to severe myopia; occasionally mild myopia	Yes	Yes	Common
2. Hereditary arthro-ophthalmopathy with Weill–Marchesani-like habitus	Low normal stature, cleft palate, joint stiffness, epiphyseal dysplasia, deafness	Moderate to severe myopia; occasionally mild myopia	Yes	Occasional	Common
3. Short stature, type undetermined	Below third percentile in stature, cleft palate, epiphyseal dysplasia, deafness	Severe myopia	Yes	None	No
4. Kniest’s syndrome	Adult height 106–145 cm, abnormal facies, cleft palate, joint limitation, epiphyseal dysplasia, deafness	Severe myopia	Yes	Occasional	Occasional
5. Diastrophic variant	Adult height 102 cm, bifid uvula, torus planitus, loose joints, epiphyseal dysplasia, deafness	Severe myopia	Yes	Yes	Yes
6. Spondyloepiphyseal dysplasia congenita	Adult height 84–128 cm, loose joints, epiphyseal dysplasia	Mild hypermetropia to severe myopia	Yes	None	No

Choroidal Dystrophies

See Chapter 9.

Stargardt’s Disease (Fundus Flavimaculatus)

I. Stargardt’s disease (Fig. 11.34) is inherited as an autosomal-recessive trait [the photoreceptor gene ABCR or ABCA4 (also known as STGD1) on chromosome 1p21 is mutated in Stargardt’s disease].

The mechanism involved in the loss of vision is not known, although all-trans-retinol dehydrogenase, a photoreceptor outer-segment enzyme, may be defective in Stargardt’s disease. Rarely, Stargardt’s disease is inherited as an autosomal-dominant trait. Linkage analysis of families with autosomal-dominant Stargardt-like macular dystrophy has shown the disease gene in one family on 13q34 and on 6q14 in other families. The gene responsible for dominant Stargardt macular dystrophy is a retinal photoreceptor-specific gene, ELOVL4.

Fig. 11.34 Stargardt’s disease (fundus flavimaculatus). A, Characteristic yellow-white flecks and an annular zone of foveal retinal pigment epithelial atrophy (“bull’s-eye” maculopathy) are present. B, A scanning electron micrograph of an enucleated eye from the brother of the woman whose eye is shown in A demonstrates that the yellow-white flecks are caused by irregular pisciform aggregates of enormous retinal pigment epithelium (RPE) cells, surrounded by a mosaic of smaller, relatively normal RPE cells. C, Fluorescein angiography performed on the patient shown in A reveals a characteristic damping out of the background choroidal fluorescence (dark fundus). D, A histologic section of the eye of the patient in B shows that the fluorescein effect is caused by enlarged lipofuscin-containing RPE cells, which act as a fluorescent filter. (B and D, Case reported in Eagle RC Jr, Lucier AC, Bernardino VB et al.: Retinal pigment epithelial abnormalities in fundus flavimaculatus: A light and electron microscopic study. Ophthalmology 7:1189. © Elsevier 1980.)

II. Stargardt’s disease consists of two parts that may occur simultaneously or independently: a macular dystrophy and a flecked neural retina (fundus flavimaculatus).

A. The macular dystrophy component

1. Initially, it is confined to the posterior pole, eventually leading to loss of central vision.

2. Reduced visual acuity is the initial symptom, and it is usually first noted between the ages of eight and 15 years.

3. In the early stages of reduced visual acuity, the macula may appear normal. Later, a horizontally oval area of atrophy and pigment dispersal develops in the fovea.

4. Ophthalmoscopically, the macula takes on a “beaten-bronze atrophy” caused by a sharply defined RPE atrophy.

a. The macula also shows a bull’s-eye configuration (see previously in this chapter for differential diagnosis of bull’s-eye macula).

b. The peripheral neural retina may show areas that resemble RP.

Stargardt’s original report described numerous shark-fin-shaped spots around the papillofoveal area characteristic of fundus flavimaculatus (see later). Fundus flavimaculatus and Stargardt’s disease represent different ends of a spectrum of the same disease, the former in its pure form consisting of a pericentral tapetoretinal dystrophy and the latter in its pure form consisting of a central tapetoretinal dystrophy, but usually showing considerable overlap.

5. Dark adaptation and ERG are normal or only mildly abnormal in the purely central type, but are subnormal in the perifoveal and peripheral neural retinal type. Electrophysiologic testing serves as the best prognostic indicator.

6. Fluorescein angiography shows fluorescence of the central fovea without leakage, often in a bull’s-eye configuration, suggesting defects in the RPE but an intact Bruch’s membrane.

a. In addition, in approximately 86% of cases, fluorescein angiography shows a dark fundus picture with a generalized diminution of background fluorescence.

b. An increased amount of lipofuscin-like material in the RPE causes the decreased fluorescence.

7. Histologically, there is a complete disappearance of the RPE and of the visual elements in the macular area.
The inner layers of the neural retina may show cystoid degeneration and calcium deposition.

B. The flecked neural retina (fundus flavimaculatus) component

The differential diagnosis of flecked neural retina includes ARMD, autosomal-dominant central pigmentary sheen dystrophy, crystalline dystrophy, benign familial fleck neural retina, Bietti’s crystalline dystrophy, canthaxanthine (skin-tanning agent), central and peripheral drusen retinopathy, cystinosis, dominant drusen of Bruch’s membrane (Doyne’s honeycomb dystrophy), familial flecked retina with night blindness, flecked retina of Kandori, fundus flavimaculatus, glycogen storage disease (GSD), gyrate atrophy, Hollenhorst plaques, Kjellin’s syndrome, juxtafoveal telangiectasis, oxylosis (primary, or secondary to long-standing neural retinal detachment, methoxyflurane general anesthesia, or ingestion of an oxalate precursor such as ethylene glycol, i.e., antifreeze), retinitis punctata albescens, ring 17 chromosome, Sjögren–Larsson syndrome, Sorsby’s pseudoinflammatory macular dystrophy, talc retinopathy (intravenous drug abusers), tamoxifen (antiestrogen medication), and nitrofurantoin medications.

1. Fundus flavimaculatus shows ill-defined, yellowish spots shaped like crescents, shark fins, fishtails, fish, or dots located at the level of the RPE that follow a consistent pattern of radial expansion and a systematic decay of autoflourescence, reflecting changing lipofuscin and melanin composition in the RPE.

2. Approximately 50% of eyes show a Stargardt-type macular dystrophy with a decrease in visual acuity.

3. The peripheral neural retina may show areas that resemble RP.

4. Dark adaptation and ERG are usually normal but may be subnormal.

5. Fluorescein angiography does not cause fluorescence of the spots in early lesions, and not all the spots fluoresce in late lesions.

a. The fluorescein shapes are irregular, soft, and fuzzy and show a marked tendency for confluence. A characteristic “dark fundus” is present.

b. The fluorescein pattern clearly differentiates the spots from drusen.

6. Histologically, the RPE is solely involved—hence the abnormal electro-oculogram (EOG)—and shows the following:

a. PAS positivity and increased autofluorescence

b. Displacement of the nucleus from near the base of the cell to the center or apical surface

c. An increased amount of pigment granules, most of which are lipofuscin-like, in the center or near the apical surface of the cell, often at the level of the displaced nucleus

d. Great variation in RPE cell size, from much larger than normal to normal

Dominant Drusen of Bruch’s Membrane

Doyne’s Honeycomb Dystrophy; Malattia Lèventinese; Hutchinson–Tay Choroiditis; Guttate Choroiditis; Holthouse–Batten Superficial Choroiditis; Family Choroiditis; Crystalline Retinal Degeneration; Iridescent Crystals of the Macula; Hyaline Dystrophies

I. Dominant drusen of Bruch’s membrane is a bilateral, symmetric, progressive disease whose onset is usually between 20 and 30 years of age.

A. It involves the posterior pole predominantly and results in loss of vision.

1. The posterior polar lesion consists of moderate- to large-sized drusen, resembling soft drusen.

2. Although there may be subtle differences, dominant drusen can be considered to be synonymous with Doyne’s honeycomb dystrophy and malattia lèventinese.

B. It is inherited as an autosomal-dominant trait.

The gene responsible has been mapped to the short arm of chromosome 2 (2p16–21) in both dominant drusen and malattia lèventinese. Other families map to 1q25–q31 and 6q14.

II. Dark adaptation and ERG are normal.

III. Fluorescein angiography shows multiple, sharply defined fluorescent spots or flecks (see previously in this chapter for differential diagnosis of fleck retina) corresponding to the clinically seen lesions; some confluence of fluorescent areas occurs, but there is no leakage of dye.

IV. Histologically, the lesions appear as large, soft drusen between the RPE and Bruch’s membrane. The predominant ultrastructural features include deposition of a material composed of tubelike structures, vesicles, and membranous material between the basement membrane of the RPE and the inner collagenous layer of Bruch’s membrane.

Best Vitelliform Disease

Vitelliform Foveal Dystrophy; Vitelliform Macular Degeneration; Vitelliruptive Macular Degeneration; Exudative Central Detachment of the Retina—Macular Pseudocysts; Cystic Macular Degeneration; Exudative Foveal Dystrophy

I. Best vitelliform disease (BVD; Fig. 11.35) is a bilateral, symmetric, progressive disease involving the RPE of the macular area with resultant loss of vision. Its onset is usually before 15 years of age. Juvenile and adult forms exist.

Juvenile vitelliform macular dystrophy (VMD2) is the second most common inherited maculopathy (Stargardt’s disease is the most common). The prevalence in Denmark is 1.5 per 100,000 individuals.

A. Both forms have an autosomal-dominant mode of transmission with diminished penetrance and a highly variable expression. The BVD genes lies on the long arm of chromosome 11 (11q13), the BEST1 gene, and on 6p21.2, the PRPH2 gene.

BVD can occur as an autosomal-recessive and compound heterozygous BEST1 mutation.

Fig. 11.35 Best’s disease (vitelliform foveal dystrophy). A, Fundus picture of a patient with Best’s disease shows a “scrambled-egg” appearance of the fovea in the right eye (left) and a typical “egg yolk” appearance in the left eye (right). B, Another eye from a 28-year-old man with Best’s disease was enucleated after an accidental death. Electron micrograph shows cells of retinal pigment epithelium in the involved area are engorged by abnormal lipofuscin granules. (B, Adapted from Weingeist TA, Kobrin JL, Watzke RC et al.: Histopathology of Best’s macular dystrophy. Arch Ophthalmol 100:1108, 1982. © American Medical Association. All rights reserved.)

B. Approximately 1% of all cases of macular degeneration are attributable to BVD.

II. Ophthalmoscopically, the central macula takes on an early egg-yolk appearance (the color is probably caused by lipofuscin pigment) that later becomes “scrambled” and pigmented.

The vitelliform material is probably located in the sub-RPE area, in the subneural retinal area, and in the photoreceptor area. The egg-yolk appearance of the macula is not always present and sometimes may never occur. The fundus may show only very slight changes or resemble the terminal stage of extensive central inflammatory chorioretinitis, or any stage in between.

III. Dark adaptation and ERG are usually normal.

A. EOG shows an abnormal light-peak/dark-trough ratio in affected patients as well as in carriers.

B. Fluorescein angiography shows no leakage into the yellow deposits but, rather, a transmission (window) defect in the area.

Multiple vitelliform cysts, macular and extramacular, may develop in patients who have BVD. The cysts typically obstruct choroidal fluorescence and do not stain during the early phases, thus differentiating them from idiopathic serous detachment of the RPE.

IV. Histologically, RPE cells show a generalized enlargement, flattening, and engorgement by abnormal lipofuscin and pleomorphic melanolipofuscin granules, most pronounced in the fovea. The outer nuclear layer attenuation is prominent.

A. Pseudovitelliform macular degeneration can occur with nonspecific RPE changes, cuticular or basal laminar drusen, detachment of the RPE, and perifoveal retinal capillary leakage.

B. The visual acuity is decreased but usually stabilizes.

C. Dry ARMD may develop in some cases and, rarely, some of these pseudovitelliform lesions develop full-thickness holes.