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

A

nr

s

B

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).

C

1.Risk factors:

a.High intake of saturated fat and cholesterol

b.Exposure to sunlight

c.Soft and perhaps hard drusen

d.A dose-related relationship exists between smoking and ARMD, especially the exudative form

e.Both blue iris color and abnormal skin sun sensitivity

f.A modest association exists between increased systolic blood pressure and pulse pressure and increased 10-year incidence of ARMD

g.Elevated C-reactive protein and hyperhomocysteinemia are independent risk factors.

h.Smoking (10 pack-years or more)

i.Presence of CFH CC genotype

The use of statins and vitamin supplements may be positive risk factors in preventing or delaying ARMD.

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. Patients who have dry ARMD do not complain of visual distortion, as do those who have acute neural retinal detachments.

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–Merz- bacher disease, Refsum’s disease, Stargardt’s disease, and others.

B.The RPE atrophy tends to spread and form welldemarcated borders, called geographic atrophy.

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.

3.The underlying choriocapillaris is atrophic.

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.

B.Bruch’s membrane may be thickened and may show basophilic changes.

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

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. 17.41).

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) rarely occurs in people younger than 60 years of age.

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, in decreasing frequency: high myopia; POHS; angioid streaks; and miscellaneous hereditary, traumatic, or inflammatory disorders.

A.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.

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

The 3-year incidence of wet ARMD is about 10 per 1000 Americans 65 years and older.

C.No sex predilection exists and the degeneration is often bilateral.

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

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

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

1.Exudative ARMD may be associated with moderate to severe hypertension, particularly among patients receiving antihypertensive therapy.

A modest associaton exists between increased systolic blood pressure and pulse pressure and increased 10-year incidence of ARMD.

2.Hyperopia may also be a risk factor.

F.A dose-related relationship between smoking and

ARMD, especially the exudative form and smoking 10 pack-years or more, has been found.

Patients who have unilateral exudative ARMD have a 12% to 15% chance every year for development of exudative ARMD in the other eye. Patients who have large, soft, confluent drusen

A

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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.

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

H.About a fivefold risk for late-stage ARMD (especially exudative ARMD) exists in eyes that have previously had cataract surgery.

I.Presence of CFH CC genotype increases the risk 144-fold.

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

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.

b

c

B

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: Arch Ophthalmol 53:82, 1955. © American Medical Association. All rights reserved.)

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.

B.The age-related macular choroidal degeneration becomes complicated by neovascular invasion.

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.

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 di erent types of CNV arise from the choroid: types 1 and 2.

a.Type 1, the most common type, consists of subretinal pigment epithelial neovasculariza- tion—it occurs primarily in people older than

50 years of age, often in association with

ARMD.

The CNV develops in eyes that show di use, age-related macular choroidal degeneration in the choriocapillaris–Bruch’s membrane–RPE complex.

b.Type 2 consists of subneural retinal neovascular- ization—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.

F.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.

3.Central vision is irreversibly impaired.

G.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—the IRN extends posteriorly into the subneural space (subneural retinal neovascularization).

c.Stage III—IRN anastamosing with CNV.

III. Histologically, the following features are noted:

A.Age-related choroidal macular degenerative changes, as described previously, are seen.

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

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, 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.

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.

C.Basically, the pathologic process is that of a localized granulation tissue associated with di use, 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 over 50% bilateral involvement, show a high incidence of macular hemorrhagic phenomena, and usually have irreversibly damaged central vision; both sexes are a ected 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.Presumed ocular histoplasmosis syndrome (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 focal hemorrhagic chorioretinopathy 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.

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 granulomatous inflammatory infiltrate in the choroid.

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

b.The typical acute macular lesions have not been examined histologically.

c.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

20to 25-nm collagen fibrils, 10-nm colla-

gen fibrils, and fibrin.

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

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 20to 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 p. 90, Chapter 4).

Idiopathic Polypoidal Choroidal Vasculopathy

I.Idiopathic polypoidal choroidal vasculopathy (IPCV) 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

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 arteies

B.The elevated polypoidal and tubular lesions correspond to large, thin-walled cavernous vascular channels and choroidal

C.Intra-Bruch’s membrane neovascularization is in continuity with the vascular channels.

Cystoid Macular Edema (Irvine–Gass Syndrome)

See pp. 122–123 in Chapter 5 and p. 606 in Chapter 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.

2.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.

a. 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).

In following patients, examination every 3 months is recommended (probably less frequent examinations would suffice, i.e., first follow-up in 6 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.

b.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, di erentiating 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.

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 of the eye, usually for cure or control of retinoblastoma, malignant melanoma, or lid, orbital, or sinus neoplasm.

The irradiation source may be X-rays, 60Co, or radon seeds. 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 6 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 e ects of tumors on di erent organ systems, sometimes years before the tumor is apparent.

A.The neurologic PNS may involve any site (e.g., myasthenic syndrome associated with lung carcinoma or other malignant neoplasms (Lambert–Eaton syndrome), myasthenia gravis associated with thymoma, opsoclonus associated with neuroblastoma, cancerassociated 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.

B.Typically, the visual loss is progressive and evolves over weeks to months.

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

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

E.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.The 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% chance exists for development of a full-thick- ness hole in the other eye.

2.If the first eye has an incomplete hole, a 19% chance exists of bilaterality in 48 months.

Patients who have a unilateral macular hole and a normal fellow eye that does not have a posterior vitreous detachment have a 16% 5-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.

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 macu lar 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 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 (approximately 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 pp. 155 in Chapter 5.

Traumatic Retinopathy

See pp. 144–145 in 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 p. 23 in 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.

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

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, veillike 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.

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 autosomalrecessive inheritance pattern, but 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.