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

Early in the acute phase, a demarcation line is seen clinically that separates the peripheral avascular neural retina from the vascular. Functioning arteriovenous collaterals occur in the region of the demarcation line. Microvascular abnormalities in the area include capillary tufts, collaterals, capillary-free zones, and neovascular membranes. Regression is evidenced by capillaries from the collaterals growing into the avascular neural retina. Cicatrization is characterized by both persistence of the vascular abnormalities of the proliferative phase and organization of the avascular neural retina into a contracting scar.

3.The young vessels break through the internal limiting membrane and grow into the subvitreal space.

4.A glial fibrocellular component develops; as it shrinks or contracts, a neural retinal detachment takes place.

The neural retinal detachment may be rhegmatogenous

(usually with round or oval neural retinal breaks without

opercula near the equator) or nonrhegmatogenous. Least common is an exudative type of neural retinal detachment that may occur secondary to peripheral vascular changes associated with ROP.

Clinically important vitreous organization and vitreous hemorrhage are predictive for the development of retinal detachment.

5.The macula and posterior retinal vessels are displaced temporally.

6.The earliest neural retinal changes are seen in the periphery of the temporal neural retina.

7.Hemorrhagic areas may be seen.

8.Glaucoma, usually a chronic secondary closedangle type, may occur in later years.

IV. Toxocara endophthalmitis (Fig. 18.19; see also p. 90 in Chapter 4): Toxocara endophthalmitis is the third most common lesion simulating retinoblastoma.

V. Coats’ disease (Fig. 18.20)

E

A.Coats’ disease is a unilateral (rarely bilateral) exudative neural retinal detachment that mainly a ects boys between 18 months and 18 years of age, but with most cases occurring in an older age group than retinoblastoma.

In bilateral cases, long-term follow-up of the least affected eye is necessary so that late complications can be identified and treated adequately in order to prevent visual loss. Presentation in middle age can occur with typical Coats’ disease findings, including unilateral disease, male preponderance, vascular tel-

angiectasis, lipid exudation, macular edema, and areas of capillary nonperfusion with adjacent filigree-like capillaries. In adult-onset disease; however, there tends to be a limited area of involvement, slower apparent progression of disease, and hemorrhage near larger vascular dilations compared to the childhood disease.

1.The clinical spectrum of Coats’ disease may be classified as a subtype of idiopathic retinal telangiectasis with exudation.

a.Patients with typical and atypical Coats’ disease are classified as severe, focal, juxtafoveal, or associated (with another disease) forms of idiopathic retinal telangiectasis with exudation.

b.Idiopathic retinal telangiectasis with exudation can be viewed as a spectrum of disease, synonymous with Coats’ disease.

It has been postulated that the spectrum of disease severity seen in idiopathic retinal telangiectasis with exudation may be due to second somatic mutations in genes with an existing germline mutation (the two hit theory) and a mosaic phenotype.

Coats’ plus encompasses a progressive familial syndrome of bilateral Coats’ disease, characteristic cerebral calcification,leukoencephalopathy,slow preand postnatal linear growth, and defects of bone marrow and integument.

3.Coats’ disease is the second most common lesion simulating retinoblastoma.

4.Clinically, Coats’ disease may often be confused with retinoblastoma and presents as a pseudoglioma; rarely, retinoblastoma may simulate Coats’ disease. Aqueous LDH may be elevated in both

Coats’ disease and retinoblastoma.

Bilateral cataract and Coats’ disease have been reported in a child with Turner’s syndrome and in a 3-month-old low- birth-weight infant.

B.Leber’s miliary aneurysms (retinal telangiectasis) consists of fusiform and saccular dilatations (macroaneurysms) of venules and arterioles that surround a di usely dilated capillary bed, and represents the earliest stage of Coats’ disease.

1.The lesion tends to be unilateral in male patients and shows a propensity for a temporal (especially superior temporal) and parafoveal location,although any retinal quadrant can be a ected.

2.The capillary bed shows coarse dilatation (telangiectasis), microaneurysms, and areas of nonperfusion. Arteriovenous communications may be seen.

3.The telangiectatic vessels leak fluid.

a.Leakage of fluid varies in amount from patient to patient, and even in the same patient at different times.

b.Coats’ disease occurs when su cient leakage of fluid results in subneural retinal exudation.

c.The a ected globe tends to be significantly smaller than the uninvolved eye, unlike patients with retinoblastoma.

Acute open-angle glaucoma secondary to lipid crystals in the anterior chamber accompanying retinal detachment in Coats’ disease may occur. Coats’-type retinal telangiectasis has accompanied Kabuki make-up syndrome or Niikawa–Kuroki syndrome. Coats’ disease

may present as a prominent subfoveal nodule with peripheral retinal exudates in a 6-year-old boy.

C.Histologic characteristics are telangiectatic retinal vessels, an eosinophilic transudate (predominantly in a partially necrotic outer neural retinal layer), and a rich subneural retinal exudate containing foamy macrophages and evidence of cholesterol crystals.

Rarely, the cholesterol can be seen in the anterior chamber (cholesterolosis). Large, foamy cells in the neural retina and subneural retinal fluid probably arise from retinal pigment epithelial cells and macrophages. Rarely, intraocular bone formation in Coats’ disease can cause confusion with retinoblastoma when calcium is seen by ultrasonography or CT.

D.Di erential diagnosis

1.Idiopathic juxtafoveolar retinal telangiectasis

(IJRT)

a.IJRT may be divided into four groups: (1) men with uniocular involvement, intraneural retinal lipid exudation, and telangiectasis largely con-

fined to the temporal half of the juxtafoveolar area; (2) mostly men with symmetric areas of telangiectasis a ecting the temporal half of the juxtafoveolar areas and minimal intraneural retinal exudation; (3) both sexes with symmetric involvement of all of the parafoveolar capillary bed and minimal exudation; and (4) telangiectasis with occlusive perifoveolar capillary changes and familial optic disc pallor.

b.The visual acuity prognosis in groups 1 to 3 is relatively good.

c.Ultrahigh-resolution optical coherence tomography (OCT) demonstrates: lack of correlation between retinal thickening on OCT and leakage on intravenous fluorescein angiography, loss and disruption of the photoreceptor layer, cyst-like structures in the foveola and within internal retinal layers such as the inner nuclear or ganglion cell layers, a unique internal limiting membrane draping across the foveola related to an underlying loss of tissue, intraretinal neovascularization near the fovea, and central intraretinal deposits and plaques.

d.Visual prognosis in IJRT depends upon type and clinical features; however, long-term prognosis for central vision is poor. Nevertheless, some therapies, such as combined treatment with photodynamic therapy and intravitreal triamcinolone, have resulted in regression of subfoveal neovascular membrane associated with IJRT.

2.A subgroup of familial retinal telangiectasis a ects men and women, tends to be bilateral, and has a temporal parafoveal location.

3.Other forms of unilateral neural retinal telangiectasis may be associated with neural retinal angiomatosis, neural retinal capillary and cavernous

hemangioma,combined hamartoma of neural retina and retinal pigment epithelium, radiation retinopathy and branch retinal vein occlusion (both of which can produce an identical clinical appearance to Coats’ disease), and retinal arterial macroaneurysm.

4.Other forms of bilateral neural retinal telangiectasis may occur with ROP, retinitis pigmentosa, diabetic retinopathy, sickle-cell (SC) disease, sarcoidosis, hypogammaglobulinemia, muscular dystrophy, or Eales’ disease.

VI. Norrie’s disease (Fig. 18.21)

A.It is a bilateral condition that starts in early childhood.

B.Norrie’s disease is transmitted in an X-linked recessive inheritance pattern.

1.A putative gene for Norrie’s disease has been isolated on chromosome Xp11.1.

Many disease-causing sequence variants have been identified; however a report of 14 French families with the

disease has raised the question whether there has been misdiagnosis, phenocopies, or the existence of other X- linked or autosomal genes, the mutations of which would mimic the Norrie phenotype.

a.Most mutations that cause Norrie’s disease are deletions, frameshifts, or nonsense (premature stop) mutations, all null mutations producing no functional protein.

b.The retinal dysplasia and gliosis found in Norrie’s disease most probably result from the lack of a functional protein product.

2.Sons of female carriers have a 50% risk for expressing the gene.

An extremely rare case of Norrie’s disease has been reported in a girl who showed a mutation in the third exon (T776-A; Ile 123-Asn) identical to the mutation found in her two uncles, in whom Norrie’s disease had been diagnosed.

3.The prevalence of Norrie’s disease is approximately

0.001%.

C.It is characterized by deafness (approximately one-third of patients), mental retardation (approximately one-half to two-thirds of patients), cataract, and pseudoglioma.

1.In infancy, a gray, vascularized mass is seen behind the lens in each eye.

2.At approximately 1 year of age, corneal degeneration starts; cataracts follow by 2 years of age.

3.In early childhood, the eyes, which were of normal size, start to shrink and become atrophic.

4.The major pathologic event in the neural retina appears to occur before 25 weeks of gestation.

D.The histology is nonspecific, but hemorrhagic neural retinal detachment and neural retinal necrosis are common.

The cause may be neural retinal dysgenesis occurring early in the embryo (third to fourth gestational month) and involving the inner wall of the optic cup.

Norrin is the protein product of the Norrie disease gene. Norrin appears to play a crucial role in hyaloid vessel regression and in sprouting angiogenesis during retinal vasculature development, especially in the development of deep capillary networks. Ectopic norrin induces growth of ocular capillaries and restores normal angiogenesis in Norrie disease mutant mice. Norrin and Frizzled-4 (Fz4) function as a ligand-receptor pair and play a vital role in the vascular development of the eye and ear. Therefore, they may play an important role in the development of Norrie’s disease.

VII. Incontinentia pigmenti (Bloch–Sulzberger syndrome; Fig.

18.22)

A. Incontinentia pigmenti starts in infancy.

It is a rare X chromosome-linked disorder, which is usually lethal in most male embryos so that the female-to-male ratio ranges from 20 to 37 :1 (see later).

a.The most frequent mutation, which accounts for >80% of new mutations, has been mapped

to Xq28 and is a deletion of part of the nuclear factor-kappaB essential modulator (NEMO) gene (NEMODelta4–10), although other mutations have been reported. Mutations of NEMO that do not abolish nuclear factor-kappaB activity permit male survival, causing an allelic variant of incontinentia pigmenti called hypohidrotic ectodermal dysplasia. A mutation in exon 7 of

NEMO gene has been reported, which results in selection against the mutated X chromosome in this X-linked disease.

b.Molecular studies are required, in particular, of families with a ected males lacking supernumerary X chromosomes to determine the exact mutation of the NEMO gene involved.

c.Incontinentia pigmenti associated with Klinefelter’s syndrome (47,XXY), hypomorphic alleles, and somatic mosaicism are three mechanisms for survival of males carrying a NEMO mutation.

The identification of an incontinentia pigmenti patient with a 650-kb duplication at the X chromosome breakpoint in a patient with 46,X,t (X;8) (q28;q12) and nonsyndromic mental retardation is further evidence for Xq28 being an unstable region of the human chromosome.

B.The dermal lesions can be divided into four stages:

1.An initial vesiculobullous stage of inflammatory papules, blisters, and pustules that are characterized histopathologically by acanthosis, keratocyte necrosis, epidermal spongiosis, and massive epidermal eosinophil infiltration.

The cause for the eosinophil accumulation has not yet been determined; however, it has been suggested that the release of cytokines during the initial inflammatory stage of incontinentia pigmenti induces epidermal expression of eotaxin, which may play a role in the epidermal accumulation of eosinophils. Late recurrence of the inflammatory first stage of incontinentia pigmenti may occur, suggesting that mutated cells can persist a long time in the epidermis. These recurrences may be triggered by infections.

2.A verrucous pigmented stage (noted at a few months of life and lasting several months)

Painful subungual tumors consistent with the late verrucous stage of incontinentia pigmenti have been reported, including involvement of more than one generation of the same family.

3.A pigmented nonelevated stage (noted at approximately 4 to 6 months of life)

4.An atrophic stage.

Whorled scarring alopecia corresponds to the lines of Blaschko, is permanent, and can be used as a marker for affected adult women who may no longer have other cutaneous manifestations.

C.Central nervous system involvement consists of calvarial deformities, microcephaly, convulsions, paresis, and mental retardation

D.Ocular findings are strabismus, nystagmus, vortex

(whorl-like) keratitis, blue sclera, myopia, and pseudoglioma.

1. Intraocular calcification and retinal detachment in this disorder have suggested the misdiagnosis of retinoblastoma; however, the presence of characteristic skin lesions can be helpful in making the correct diagnosis.

E.Dental abnormalities (e.g., delayed dentition and missing and peg-shaped teeth) are usually present. Permanent anterior teeth with a longer crown and a shorter root may be related to incontinentia pigmenti.

Cardiovascular anomalies and cerebral infarction

are also rare complications.

G.The inheritance pattern is X-linked dominant, but girls predominate.

Boys are hemizygous (i.e., they have only one of any of the genes found in the X chromosome). Thus, a mutant X chromosomal gene that codes for a structural protein (hence a dominant gene) would be the equivalent of a homozygous autosomal-dominant mutation that is usually lethal or sublethal for boys. It is thought that male fetuses with incontinentia pigmenti are aborted spontaneously, which is why the condition occurs almost exclusively in girls.

H.The histology is nonspecific.

1.The RPE may show nodular proliferation and contain increased lipofuscin.

2.Nonrhegmatogenous neural retinal detachment, foveal hypoplasia, intraocular hemorrhage, and neural retinal necrosis are common.

The neural retinal changes are similar to those seen in ROP and familial exudative retinopathy. Fluorescein studies of incontinentia pigmenti have shown changes consistent with an initial obliterative endarteritis starting peripherally and proceeding centrally. The arterioles ultimately become occluded. The differential diagnosis of incontinentia pigmenti includes conditions that cause peripheral neural retinal nonperfusion, preneural retinal neovascularization, infantile neural retinal detachment, and foveal hypoplasia.

VIII. Massive neural retinal fibrosis is caused by organization of a massive neural retinal hemorrhage in the newborn. Organization, fibrogliosis, and contracture may simulate growth of a retinoblastoma.

IX. Metastatic retinitis

X.Endogenous endophthalmitis

A.Rarely, endogenous endophthalmitis presents clinically in such a fashion as to simulate retinoblastoma.

B.The ocular findings are usually the primary findings and overshadow the systemic infection.

C.Causes include streptococcal,cytomegalovirus,Candida, and idiopathic endophthalmitis.

XI. Congenital nonattachment of neural retina (Fig. 18.23; see p. 398 in Chapter 11)

XII. Secondary neural retinal detachment XIII. Juvenile retinoschisis (see Fig. 11.33)

XIV. Medulloepithelioma (“diktyoma”; see Figs 17.17 and

17.18)

XV. Melanogenic neuroectodermal tumor of the retina (primary malignant melanoma of the retina) may simulate retinoblastoma in infants.

XVI. Leukocoria may be caused by congenital cataract and be confused with a retinoblastoma.

XVII.Solitary, large retinal astrocytoma may mimic retinoblastoma both clinically and ultrasonographically without clinical findings of tuberous sclerosis or neurofibromatosis.

A.Retinal astrocytomas may enlarge, and be accompanied by retinal detachment and vitreous seeding, which can lead to the erroneous diagnosis of retinoblastoma or melanoma.

B.Further complicating the diagnostic picture, retinoblastoma and retinal astrocytoma have been reported to

occur in the same eye.

XVIII.Intraocular heterotopic brain tissue can produce leukocoria.

XIX. Osteoporosis–pseudoglioma syndrome is characterized by severe juvenile-onset osteoporosis and congenital or earlyonset blindness. It is a rare disorder that is autosomal

recessive in inheritance. It can be accompanied by muscular hypotonia, ligament laxity, mild mental retardation, and seizures. The involved gene is the low-density lipoprotein receptor-related family member LRP5 located on chromosome 11q11–12.

XX.Inflammatory pseudotumor in a 1-year-old girl has simulated retinoblastoma, resulting in enucleation.

Discrete Retinal or Chorioretinal Lesions

I.Small endophytic tumors

A.Retinal hamartomas

1.Tuberous sclerosis (see Chapter 2)

2.Neurofibromatosis (see Chapter 2)

B.Myelinated (medullated) nerve fibers (see Fig. 11.6)

C.Coloboma of choroid (see pp. 338–339 in Chapter

9)

D.Retinochoroiditis—when deposits of white exudates are present on the neural retina, retinochoroiditis is easily confused with retinoblastoma.

II.Small exophytic tumors

A.Coats’ disease may occur as a localized posterior lesion.

B.Larval (Toxocara canis) granulomas may present in posterior locations.

C.Choroiditis or acute exudative retinitis with subneural retinal exudate

D.von Hippel–Lindau angiomatosis (see p. 29 in Chapter 2)

E.Proliferative lesions of retinal pigment epithelium

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