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

rior pole, tapetoretinal degeneration with atrophy of the RPE and “sclerosis” of the choroid, and, in many patients, sparkling yellow crystals in the superficial marginal cornea.

It is inherited as an autosomal-recessive trait (4q35-tel) and usually has its onset in the third decade of life.

A closely related entity, including clinical, systemic, and pathologic findings (crystals and granular dense material—similar to that found in cholesterol storage disease—in abnormal lysosomes of circulating lymphocytes, but not in cornea) but with an autoso- mal-dominant inheritance pattern, a limited expression of the disease, no corneal involvement, a female preponderance, and a later age at onset, has been named autosomal-dominant crystalline dystrophy.

II.Ophthalmoscopically, many fine, dotlike crystalline opacities are present at the level of the RPE along with scattered aggregates of retinal pigment (see p. 441 in this chapter for di erential diagnosis of fleck neural retina).

The corneal involvement consists of tiny crystals deposited in the peripheral cornea and the superficial layers of the limbal conjunctival substantia propria.

III.Both the ERG and EOG may be abnormal.

A.Fluorescein angiography shows atrophy of the choriocapillaris confined to the areas of geographic atrophy of the RPE.

B.Central or paracentral scotomas can be demonstrated on visual field testing.

IV. Histology

A.The peripheral corneal and limbal conjunctiva deposits are lipid and contained in fibroblasts.

1.Although the deposits resemble cholesterol (or cholesterol ester) and complex lipid inclusions, their exact nature is unknown.

2.Biochemical studies have shown that the crystalline liposomal material is not cholesterol.

B.Similar lipid inclusions may be found in circulating lymphocytes, suggesting that a systemic abnormality of lipid metabolism is the cause.

C.The globe may show advanced panchorioretinal atrophy.

Crystals and complex lipid inclusions are found in choroidal fibroblasts.

Sorsby Fundus Dystrophy (Sorsby’s

Pseudoinflammatory Macular Dystrophy;

Hereditary Macular Dystrophy)

I.Sorsby fundus dystrophy (SFD) is a bilateral, symmetric disease with a late onset, usually in the fifth decade, and an autosomal-dominant or, rarely, recessive inheritance pattern.

The autosomal-dominant variety seems to be related to a Ser181Cys mutation in chromosome 22 of exon 5 of the gene coding for the tissue inhibitor of metalloproteinases 3 (TIMP3) .SFD is caused by mutations in the gene-encoding tissue inhibitor of metalloproteinases-3 (an extracellular matrix protein), the TIMP3 gene.

II.Onset is acute with loss of central vision and an inflam- matory-like macular lesion showing edema, hemorrhages

(sometimes in the macula of both eyes), and exudates.

A.Often, white to yellow spots at the level of Bruch’s membrane are present early in the course of the condition (see p. 441 in this chapter for di erential diagnosis of fleck neural retina).

B.Healing takes place slowly; CNV is a rare occurrence.

C.Over a few decades, the process extends slowly toward

the periphery, leaving a spreading area of choroidal atrophy and some pigment deposition.

III.Early, dark adaptation and ERG are normal, but later the

ERG becomes subnormal. Fluorescein early in the course of the condition shows delayed filling of the central cho-

riocapillaris; later, extensive defects in the RPE are noted.

IV. Histology

A.Marked atrophy of the outer neural retina occurs along with a discontinuous RPE and atrophy of the choriocapillaris and choroid.

B.A 3-μm-thick deposit is seen in Bruch’s membrane.

The deposits resemble those found in late-onset retinal degeneration, an autosomal-dominant disorder characterized by onset of night vision problems in midlife, and in ARMD.

HEREDITARY SECONDARY

RETINAL DYSTROPHIES

Angioid Streaks

I.Angioid streaks (Fig. 11.38) may be found most often in pseudoxanthoma elasticum (Grönblad–Stranberg syndrome) and idiopathically.

A.The streaks may also be found in acromegaly, Bassen–

Kornzweig syndrome (abetalipoproteinemia), choriocapillaris atrophy involving the posterior eyegrounds, chromophobe adenoma, di use lipomatosis, dwarfism, epilepsy, facial angiomatosis, fibrodysplasia hyperelastica (Ehlers–Danlos syndrome), hemoglobinopathies, hereditary spherocytosis, hyperphosphatemia, idiopathic thrombocytopenic purpura, lead poisoning, neurofibromatosis, osteitis deformans (Paget’s disease), and trauma.

The hemoglobinopathies include sickle-cell HbSS,

HbSC, HbS (thalassemia), and HbAS (trait) diseases; hemoglobin H disease (HgH); and β-thalassemia major (homozygous), intermedia, and minor.

B.The mode of hereditary transmission depends on the primary cause.

II.CNV and hemorrhages in and around the macula frequently complicate the condition and may lead to exuda-

tive (disciform) macular degeneration.

III.Histologically, Bruch’s membrane shows basophilia and is broken and interrupted at the sites of the “streaks.”

A.Fibrovascular tissue usually fills the break.

B.The contiguous RPE may be abnormal.

Sjögren–Larsson Syndrome

I.Sjögren–Larsson syndrome consists of congenital, lowgrade, stationary mental deficiency, congenital ichthyosis, and symmetric spastic paresis of the extremities that tends to involve the legs more than the arms.

A.It is inherited as an autosomal-recessive trait.

B.The syndrome is caused by deficient activity of fatty aldehyde dehydrogenase, a transmembrane protein that

is part of the microsomal enzyme complex fatty alcohol–nicotinamide adenine oxidoreductase.

II.Approximately 20% to 30% of patients have fundus abnormalities consisting predominantly of depigmented, pale areas in the macular region and neural retinal flecks (see p. 441 in this chapter for di erential diagnosis of fleck

neural retina).

III.No histologic studies have been done, but the pathologic process is presumed to be at the level of the RPE.

Mucopolysaccharidoses

See p. 298 in Chapter 8; RP-like fundus changes may be found in approximately 20% of the patients. Types IV (Morquio) and VI (Maroteaux–Lamy) are usually excepted.

Mucolipidoses

I.The mucolipidoses are a group of storage diseases (Hurler variants) that exhibit signs and symptoms of both the mucopolysaccharidoses and sphingolipidoses (Table 11.4).

II.With the exception of Austin-type sulfatidosis, renal excretion of uronic acid-containing mucopolysaccharides is normal.

One important feature that differentiates mucolipidoses from mucopolysaccharidoses is that the conjunctival cells in the former group contain single membrane-limited vacuoles filled with fibrillogranular material as well as lamellar bodies, whereas in the latter group lamellar bodies are only occasionally observed. Membranous inclusion bodies are the most characteristic neuronal cellular abnormality in the sphingolipidoses, and similar lamellar storage bodies have been noted in Fabry’s disease. Thus, the accumulation of both membranous and fibrillogranular inclusion bodies, suggestive of defects in the degradation of both lipids and complex carbohydrates, is the hallmark of the ultrastructural lesion in the mucolipidoses.

Ceramide is the long-chain amino alcohol called sphingosine to which a long-chain fatty acid is joined by an amide bond to the nitrogen atom on carbon 2 of sphingosine.

A.The stored portion is characteristic for each separate disease.

B.Tay–Sachs disease

1.Tay–Sachs disease is the prototypical lysosomal sphingolipid storage disease.

2.Tay–Sachs disease is a uniformly fatal (by 3 to 5 years of age), inherited (autosomal-recessive), neurodegenerative disease found in infants of Central or East European Jewish ancestry, caused by

a profound disturbance of the lysosomal hydrolase β-hexosaminidase A (HEX A or GM2-gangliosidase).

3.Clinically, the hallmark is a cherry-red spot in the central fovea.

Sphingolipidoses

I.The sphingolipidoses (Fig. 11.39 and Table 11.5) are a

group of diseases that have in common the storage of a complex lipid called ceramide.

The ganglion cells, enlarged by storage material, render the neural retina relatively opaque, especially in the posterior pole (anatomic macula) where the ganglion cells are multilayered, giving the neural retina a milky orange

appearance. The foveal retina, however, has no inner layers, and therefore no ganglion cells, so that the underlying normal red choroid is seen as a cherry-red spot.

4.Histologically, the ganglion cells become “ballooned”by the massive intralysosomal accumulation (storage) of lipophilic membranous bodies consisting of the sphingolipid GM2-ganglioside.

II.To detect patients and carriers, assay procedures are available for all the sphingolipidoses.

Other Lipidoses

I.Schilder’s disease and the Pelizaeus–Merzbacher syn- drome—these primarily a ect the white matter (optic

nerve) with secondary degeneration of the neural retina (see Chapter 13).

II.Late infantile-type galactosialidosis—macular cherryred spot, corneal clouding, and β-galactosidase and sialidase deficiency characterize the disease, which is a syndrome that combines clinical features of several storage diseases (mucopolysaccharidoses, sphingolipidoses, and mucolipidoses) and is inherited as an autosomal-recessive trait.

III.Wolman’s disease

A.Although similar to Niemann–Pick disease clinically,

Wolman’s disease di ers in that it has cholesterol and triglycerides rather than phospholipids deposited in foam cells.

1.Wolman’s disease has an autosomal-recessive inheritance pattern and is characterized by hepatospleno-

megaly, malabsorption, adrenal calcification, and death in early infancy.

2.The cause is a deficiency of a lysosomal acid esterase.

B.Histologically, neural retinal ganglion cells are swollen and contain foamy cytoplasm. Sudanophilic droplets, both free and in macrophages, are found in the sclera, cornea, and ciliary body.

IV. Primary familial hyperlipoproteinemia

A.Five types of hyperlipoproteinemia may be distinguished by paper electrophoresis.

B.The main ocular findings include eruptive xanthomas, conjunctival xanthomas, arcus juvenilis and senilis, lipid keratopathy, iris xanthomas, choroidal xanthomas, lipemia retinalis, retinal hemorrhages, and adult-onset

Coats’ disease.

Disorders of Carbohydrate Metabolism

I. Diabetes mellitus (see Chapter 15)

II.Lafora’s disease (Fig. 11.40)

A.Lafora’s disease is caused by a deficiency of an unknown enzyme.

1.As a result, polyglucosans are stored in the tissues in di erent stages of aggregation.

2.The disease is inherited as an autosomal-recessive trait.

B.The disease starts in preadolescence or early adolescence and is characterized by Unverricht’s syndrome, which consists of myoclonic seizures, grand mal attacks, pro-

gressive ataxia, dysarthria, dyskinesia, amaurosis, and dementia. The disease is relentlessly progressive, with death occurring 4 to 10 years after its onset.

C.Histologically, basophilic, spherical, laminated deposits (Lafora bodies) are found in the ganglion cells and inner nuclear layer of the neural retina, in the optic nerve, and in the brain. An amorphous, basophilic deposit is found in heart, striated muscle, and liver cells.

Lafora bodies consist of a long-chain polysaccharide amylo- pectin-like material, similar to that found in type IV glycogenosis (Anderson).

III.Glycogen storage disease

A.Type I GSD (von Gierke’s disease) is inherited as an autosomal-recessive trait and caused by a deficiency of the enzyme glucose-6-phosphatase, which results in glycogen storage in the tissues.

1.Bilateral, symmetric, yellowish, nonelevated, discrete, paramacular neural retinal lesions resembling drusen are found (see p. 441 in this chapter for di erential diagnosis of fleck neural retina).

2.No histopathologic data are available, but the lesions are presumed to be at the level of the

RPE.

B.Type II GSD (Pompe) is caused by a deficiency of the enzyme α-1,4-glucosidase (acid maltase).

1.As a result, glycogen is stored in the tissue.

2.The disease is inherited as an autosomal-recessive trait.

More than 70 mutations have been identified in tha α- glucosidase gene.

3.No clinical ocular signs are present.

4.Histologically, lysosomal glycogen is found in neural retinal ganglion cells and pericytes and in smooth and striated ocular muscles.

Type III GSD (Forbes) is caused by amylo-1,6-glucosidase

(debrancher) deficiency; type IV GSD (Anderson) is caused by α-1,-4-glucan: α-1,4-glucan 6-glucosyl transferase (brancher) deficiency; type V GSD (McArdle– Schmid–Pearson) is caused by muscle phosphorylase (myophosphorylase) deficiency; type VI GSD (Hers) is caused by hepatic phosphorylase deficiency; type VII GSD is caused by phosphoglucomutase deficiency; type VIII

GSD is caused by hepatic phosphorylase deficiency (normal after glucagon or epinephrine administration); type IX GSD is caused by hepatic phosphorylase deficiency (no change after glucagon or epinephrine administration). Types III, IV, and VI through IX have no known ocular findings.

Primary Oxalosis (Fig. 11.41)

I.The condition is inherited as an autosomal-recessive trait, is characterized by hyperoxaluria, is usually fatal (renal failure) before the third decade of life, and has two variants.

A.Type I is caused by a deficiency of the cytoplasmic enzyme α-ketoglutarate glyoxylate carboligase.

B.Type II is caused by a deficiency of δ-glyceric dehydrogenase.

C.Clinically a maculopathy, often large, pigmented, and geographic, occurs along with RPE flecks (see p. 441 in this chapter for di erential diagnosis of fleck neural retina).

Secondary oxalosis may be caused by ingestion of an oxalate precursor such as oxalic acid, ethylene glycol (antifreeze), or rhubarb; hyperabsorption of oxalate after small-bowel resection; renal failure; sarcoidosis; chronic renal failure; cirrhosis of the liver; or after general anesthesia with the anesthetic agent methoxyflurane.

II.Histologically, in primary oxalosis, oxalate crystals are found in the RPE.

The crystals correspond to the clinically seen flecked neural retina. In secondary oxalosis, the oxalate crystals can be found in the walls of retinal blood vessels.

Osteopetrosis

I.Osteopetrosis, caused by an inborn error of metabolism in which the basic metabolic defect is unknown, has infantile (juvenile) and adult forms.

A.In the infantile form (which is lethal in the first decade if not treated by bone marrow transplantation), visual loss, pendular nystagmus, ptosis, squint, optic disc edema, optic atrophy, and exophthalmos may be seen.

A dysfunction of the monocyte–macrophage system-derived osteoclast leads to failure of cartilage and bone resorption so that the primary spongiosa cannot be removed and converted to more mature bone. New bone formation continues and mineralization of persisting cartilage occurs (endochondral ossification). Spread of abnormal bone into the marrow spaces leads to lethal failure of hematopoiesis.

An autosomal-recessive inheritance pattern is seen.

B.In the adult form, a good prognosis exists without treatment.

An autosomal-dominant inheritance pattern is seen.

II.Histologically, in the infantile form, degeneration of rods, cones, and the outer nuclear layer may be found as well as atrophy and gliosis of the neural retinal ganglion cell and nerve fiber layers and of the optic nerve.

Neural retinal degeneration may occur in the absence of any bone pressure on the optic nerves. The degeneration therefore is probably a primary dystrophy and an integral part of the disease.

Homocystinuria

I.Homocystinuria (see p. 385 in Chapter 10) is an autoso- mal-recessive disease caused by a deficiency in the enzyme cystathionine synthetase, resulting in an increased concentration of homocysteine, homocystine, or a derivative of homocysteine.

SYSTEMIC DISEASES INVOLVING THE RETINA

Hereditary Secondary Retinal Dystrophies

See pp. 450–454 in this chapter.

Diabetes Mellitus

See pp. 602–618 in Chapter 15.

Hypertension and Arteriolosclerosis

See pp. 408–411 in this chapter.

Collagen Diseases

See pp. 182–184 in Chapter 6. Rheumatoid arthritis, scleroderma, periarteritis nodosa, systemic lupus erythematosus, dermatomyositis, and temporal arteritis can all cause retinal vasculitis with secondary retinal hemorrhages and exudates.

Blood Dyscrasias

Leukemia (Fig. 11.42), lymphoma, aplastic anemia, sickle-cell anemia, and macroglobulinemia can all cause retinal vascular problems or infiltrates.

Demyelinating Diseases

See pp. 510–511 in Chapter 13. Primary white matter (optic nerve) disease followed by secondary retinal atrophy may be found in multiple sclerosis, neuromyelitis optica, and di use cerebral sclerosis (Schilder’s, Krabbe’s, and Pelizaeus–Merzbacher diseases, and metachromatic leukodystrophy).

Many systemic diseases may also have retinal manifestations.

TUMORS

Glia

I.Ordinary neural retinal gliosis

A. The disorder may be intraneural retinal, epiretinal (Figs 11.43 to 11.45), preretinal (see Fig. 11.53C), or postretinal (subneural retina; see Figs 11.45 and 11.53C).

Preretinal or epiretinal membranes* may be composed of glia (astrocytes as well as Müller cells), RPE, fibrous or myofibroblas-

equator.

III.Histologically, the peripheral retina may show atrophy of its outer layers with inward migration of pigment-filled macrophages.

retinal surface, whereas epiretinal refers specifically to membranes lying on

the surface of the neural retina. Most ophthalmologists refer to elevated membranes as preretinal membranes and to closely applied membranes as epiretinal membranes. Epiretinal membranes a ect approximately 12% of the

population.

tic tissue, fibroinflammatory tissue, cortical vitreous, or any combination of these; all are nonvascular membranes—if they have a vascular component, they are called neovascular (preretinal or epiretinal) membranes. Nonvascular membranes may grow in the macular area and surround, but spare, the fovea, thus simulating a foveal hole (i.e., pseudolamellar hole; see Fig. 11.43A).

B.It is found in such diverse conditions as otherwise normal eyes, chronic neural retinal detachment, most types of chronic secondary glaucoma, chronic retinitis or chorioretinitis, CRVO, diabetic retinopathy, and

after several surgical procedures such as scleral buckling, cataract extraction, retinal cryopexy, and laser retinal photocoagulation.

Epiretinal macular membranes that occur after retinal surgery are commonly called macular pucker.

The early form of epiretinal membranes “cellophane macular reflex” is more common in Latinos than in whites. The more severe form “preretinal macular fibrosis” (macular pucker) occurs equally in Latinos and whites.