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

1950, whereas since 1950, only approximately 5% of cases of sympathetic uveitis have also had PE. The marked reduction in the association of the two diseases is probably attributable to advances in the management of penetrating wounds. It has been suggested that sympathetic uveitis represents a forme fruste of Vogt–Koyanagi–Harada (VKH) syndrome (see subsection on Vogt–Koyanagi–Harada Syndrome (Uveomeningoencaphalitic Syndrome), later). The relationship between the two entities is still uncertain.

C.Humanleukocyteantigen(HLA)-DRB1*04,DQA1*03, and DQB1*04 are significantly associated with sympathetic uveitis.

Both the clinical manifestations and immunogenetic background of sympathetic uveitis and VKH syndrome (see later) are quite similar.

IV. Histologically, sympathetic uveitis has certain characteristics that are suggestive of the disorder but not diagnostic.

A.Sympathetic uveitis is a clinicopathologic diagnosis, never a histologic diagnosis alone.

The uveal inflammatory reaction tends to be more vigorous in black than in white patients.

B.The following four histologic findings are characteristic of both sympathizing and exciting eyes:

1.Di use granulomatous uveal inflammation composed predominantly of epithelioid cells and lymphocytes. Eosinophils may be plentiful. Plasma cells are few or moderate in number. Neutrophils are rare or absent

2.Sparing of the choriocapillaris

3.Epithelioid cells containing phagocytosed uveal pigment

4.Dalen–Fuchs nodules (i.e., collections of epithelioid cells lying between Bruch’s membrane and the retinal pigment epithelium with no involvement of

the overlying neural retina and sparing of the underlying choriocapillaris*)

Because the signs of the trauma are usually in the anterior portion of the eye, the posterior choroid is the best place to look for the granulomatous inflammation. Typically the neural retina is not involved, except near the ora serrata. Localized neural retinal detachments may be seen, especially in areas where Dalen–Fuchs nodules coalesce.

C.Other findings:

1.Tissue damage caused by the trauma

2.Extension of the granulomatous inflammation into the scleral canals and optic disc

Because uveal tissue is normally found in the scleral canals and in the vicinity of the optic disc, evisceration, which

does not reach these areas, does not protect against sympathetic uveitis. If surgery is being done to prevent sympathetic uveitis, the procedure must be an enucleation, not an evisceration.

Phacoanaphylactic (Phacoimmune)

Endophthalmitis

I.PE (Fig. 4.3) is a rare, autoimmune, unilateral (sometimes bilateral if the lens capsule is ruptured in each eye), zonal, granulomatous inflammation centered around lens material. It depends on a ruptured lens capsule for its development.

Spontaneous rupture of the lens in Behçet’s disease can cause PE.

*Some studies suggest that most of the epithelial cells occurring in the Dalen– Fuchs nodule are derived from monocytes and macrophages. Some cells may also come from transformation of retinal pigment epithelial cells.

II.The disease occurs under special conditions that involve an abrogation of tolerance to lens protein.

Lens proteins are organ-specific but not species-specific. Lens proteins, if exposed to the systemic circulation, are normally recognized as “self.” If they were not, PE would occur regularly, instead of rarely, after disruption of the lens capsule.

A.PE may result from the breakdown or reversal of central tolerance at the T-cell level. Small amounts of circulating lens protein normally maintain T-cell tolerance, but it may be altered as a result of trauma, possibly through the adjuvant e ects of wound contamination or bacterial products, or both.

B.After the abrogation of tolerance to lens protein, antilens antibodies are produced. The antibodies reach the lens remnants in the eye and an antibody–antigen reaction takes place (PE).

B.Epithelioid cells and occasional (sometimes in abundance) multinucleated inflammatory giant cells are seen beyond the neutrophils.

C.Lymphocytes, plasma cells, fibroblasts, and blood vessels (granulation tissue) surround the epithelioid cells.

D.Usually the iris is encased in, and inseparable from, the inflammatory reaction.

E.The uveal tract usually shows a reactive, chronic nongranulomatous inflammatory reaction.

Sometimes, however, the same trauma that ruptures the lens and sets o the PE initiates a sympathetic uveitis and results in a di use, chronic, granulomatous inflammation.

Presumably the lens protein that leaks through an intact capsule (e.g., in a mature or hypermature lens) is denatured (unlike the nondenatured lens protein that escapes through a ruptured lens capsule). Thus, it is incapable of acting as an antigen and eliciting an antibody response. The denatured lens protein, however, may incite a mild foreign-body macrophagic response. The macrophages, swollen with engulfed denatured lens material, may block the anteriorchamber drainage angle and cause an acute secondary open-angle glaucoma called phacolytic glaucoma (see p. 384 in Chapter 10).

III.Histologically, in addition to the findings at the site of injury, a zonal granulomatous inflammation is found.

A.Activated neutrophils surround and seem to dissolve or eat away lens material, probably releasing proteolytic enzymes, arachidonic acid metabolites, and oxygenderived free radicals.

Foreign-Body Granulomas

I.Foreign-body granulomas may develop around exogenous foreign bodies that are usually introduced into the eye at the time of a penetrating ocular wound, or they may develop around endogenous products such as cholesterol or blood in the vitreous.

An unusual cause of inflammatory granuloma of the conjunctiva is the synthetic fiber found in teddy bears, called a (“teddy-bear”) granuloma.

Rarely, blood in the vitreous incites a marked foreign-body inflammatory response. When this occurs, the intravitreal hemorrhage almost is invariably traumatic in origin, rather than spontaneous.

II.Histologically, a zonal type of granulomatous inflammatory reaction surrounds the foreign body.

A

C

NONTRAUMATIC INFECTIONS

Viral

I.Cytomegalic inclusion disease (salivary gland disease; Fig.

4.4)

A.Cytomegalic inclusion disease is caused by systemic infection with the salivary gland virus, cytomegalovirus

(CMV), an enveloped herpesvirus formed by an icosahedral capsid and a double-stranded DNA.

CMV is huge, containing more than 200 genes (compared with its modest relative, herpes simplex virus, which contains only

84genes). It is estimated that CMV infects 80% to 85% of people by 40 years of age. In otherwise healthy, immunocompetent people, CMV infection usually runs a benign, asymptomatic course (rarely, a heterophile-negative mononucleosis syndrome occurs). After primary exposure, CMV may establish a latent infection and the virus genome may persist in cells undetectable by conventional culture assays.

1.Congenital: characterized by retinochoroiditis, prematurity, jaundice, thrombocytopenia, anemia, hepatosplenomegaly, neurologic involvement, and intracranial calcification

B

Fig. 4.4 Cytomegalic inclusion disease. A, The fundus picture shows the characteristic hemorrhagic exudation (“pizza-pie” appearance) along the retinal vessels. B, Histologic section shows the relatively normal neural retina sharply demarcated on each side from the central area of coagulative retinal necrosis, secondary to the infection. The choroid shows a secondary mild and diffuse granulomatous inflammation.

C, Increased magnification shows typical eosinophilic intranuclear inclusion bodies (ii) and small, round basophilic and cytoplasmic inclusion bodies (ci). (A, Courtesy of Dr. SH Sinclair; B and C, presented by Dr. Daniel Toussaint at the meeting of the Verhoeff Society, 1976.)

Cytomegalic inclusion disease is the most common viral infection of the neonate, with an incidence of 5 to 20 per 1000 live births. Most of the infants are asymptomatic at birth. The differential diagnosis consists of the TORCH syndrome (toxoplasmosis, rubella, CMV, and herpes simplex; see p. 62 in Chapter 3).

2. Acquired: mainly found in patients whose immune mechanisms have been modified [e.g., acquired immunodeficiency syndrome (AIDS), acute leukemia, malignant lymphomas, chemotherapy, and immunosuppressive therapy for renal transplantation]

CMV retinitis occurs in approximately 30% of patients with AIDS (35% have bilateral CMV retinitis at time of presentation, and up to 75% will become bilateral). Patients who have AIDS and have a low CD4+ and CD8+ T-lymphocyte cell count are at a high risk for the development of CMV retinitis. CMV retinitis in patients with and without AIDS, treated with highly active antiretroviral therapy, has a similar course, except the incidence of retinal detachment is higher in the AIDS’ patients.

B.Clinically, a central retinochoroiditis seen in the congenital form is similar to that seen in toxoplasmosis.

1.The acquired form starts with scattered, yellowwhite retinal dots or granular patches that may become confluent and are associated with sheathing of adjacent vessels and retinal hemorrhages (characteristic hemorrhagic exudation with “pizza-pie” or “cottage cheese with catsup” appearance).

2.Neural retinal detachments may develop in 15% of a ected eyes.

3.Other ocular findings include iridocyclitis, punctate keratitis, and optic neuritis.

A periphlebitis that mimics acute frosted retinitis may occur. Other conditions that may mimic CMV retinitis include other herpesviruses, measles, syphilis, fungal retinitis (Cryptococcus neoformans and Candida albicans), toxoplasmosis, and acute retinal necrosis.

4.Immune recovery uveitis, associated with the potent antiviral therapies, refers to a condition in which heightened intraocular inflammation occurs in some patients who have pre-existing CMV retinitis.

C.Histologically, a primary coagulative necrotizing retinitis and a secondary di use granulomatous choroiditis are seen.

1.The infected neural retinal cells show large eosinophilic intranuclear inclusions and small, multiple, basophilic intracytoplasmic inclusions.

2.In areas of healed retinitis, clinically seen focal yellow-white plaques contain calcium when examined histologically.

The cytoplasmic inclusions consist of numerous virions closely associated with dense masses of matter (periodic acid–Schiff-positive on light microscopy) that are highly characteristic of CMV. An additional highly characteristic feature is the presence of the virions in a mass of viral subunit material that forms a lacy, centrally located pattern in the nucleus. The nucleolus is marginated and free of virions. Clumping of peripheral chromatin is lacking.

3.The location and character of the retinal vascular changes in AIDS indicate an ischemic pathogenesis, most profound in CMV retinitis.

II.Varicella/herpes zoster virus (VZV; Figs 4.5 and 4.6)

A.VZV causes varicella (chickenpox) and herpes zoster

(shingles).

1.The virus, a member of the herpesvirus family, consists of a lipid envelope surrounding an icosahedral nucleocapsid with a central, double-stranded DNA core; only the enveloped virions are infectious.

2.Congenital infection is rare (di erential diagnosis consists of the TORCH syndrome; see p. 62 in

Chapter 3).

3.In immunocompetent individuals, VZV is a major cause of the acute retinal necrosis syndrome (see p.

417 in Chapter 11).

A

C

B.Ocular complications occur in approximately 50% of cases of herpes zoster ophthalmicus:

1.Cornea: dendritic ulcer (rare), ulceration, perforation, peripheral erosions, bullous keratopathy, epidermidalization (keratinization), band keratopathy, pannus formation, stromal vascularization, hypertrophy of corneal nerves, ring abscess, granulomatous reaction to Descemet’s membrane, and endothelial degeneration

2.Anterior-chamber: iridocyclitis followed by peripheral anterior synechiae, exudate, and hyphema

3.Iris: patchy necrosis and postnecrotic atrophy (mimics iris after attack of acute angle closure glaucoma), chronic nongranulomatous inflammation, and anterior-surface fibrovascular membrane

4.Ciliary body: patchy necrosis of anterior portion, especially of circular and radial portions of ciliary muscle

5.Choroid: chronic nongranulomatous inflammation and, less commonly, granulomatous inflammation

6.Lens: cataract and posterior synechiae

7.Neural retina: perivasculitis and vasculitis

8.Vitreous: mild mononuclear inflammatory infiltrate

9.Sclera: acute or chronic episcleritis and scleritis

10.Optic nerve: perivasculitis and chronic leptomeningitis

B

Fig. 4.6 Herpes zoster. A, Patient with herpes zoster ophthalmicus developed chronic herpes keratitis and then corneal perforation; the eye was enucleated. B, Nongranulomatous inflammatory infiltrates centered around ciliary nerves in posterior episclera (no granulomatous inflammation present), shown with increased magnification in C.

11.Long posterior ciliary nerves and vessels: striking perineural and, less commonly, intraneural nongranulomatous and occasionally granulomatous inflammation and perivasculitis and vasculitis

C.Histologically, the most characteristic findings are lymphocytic (chronic nongranulomatous) infiltrations involving the posterior ciliary nerves and vessels, often in a segmental distribution, and a di use or patchy necrosis involving the iris and pars plicata of the ciliary body.

1.Granulomatous inflammatory lesions may also be seen.

2.Inclusion bodies have not been demonstrated in the chronic inflammatory lesions.

Bacterial

I.Tuberculosis (Mycobacterium tuberculosis; Figs 4.7 and 4.8)

A.Tuberculosis has re-emerged as a serious public health problem, mainly because of the human immunodeficiency virus (HIV) epidemic and newly developed resistance to standard antibiotic therapy.

It is estimated that about one-third of the world’s population is infected by Mycobacterium tuberculosis. It may present in

children initially as a preceptal cellulitis unresponsive to systemic antibiotic therapy.

B.Tubercle bacilli reach the eye through the blood stream, after lung infection.

Tubercle bacilli survive within macrophages because they secrete eukaryocyte-like serine/threonine protein kinase G within macrophage phagosomes, inhibiting phagosome–lyso- some fusion and mediating intracellular survival of mycobacterium. Rarely, intraocular tuberculosis can occur without obvious systemic infection.

1.The most common form of ocular involvement is a cyclitis that rapidly becomes an iridocyclitis and may also spread posteriorly to cause a choroiditis.

Tuberculous choroiditis may mimic serpiginous choroiditis.

2.Clinically, mutton-fat keratic precipitates are seen on the posterior surface of the cornea and deep infiltrates in the choroid, often in the posterior pole.

Retinal tuberculosis usually spreads from an underlying choroiditis. The involvement may become massive to form a large tuberculoma involving all the coats of the eye (i.e., a panophthalmitis). Tuberculoprotein hypersensitivity may play a role in the pathogenesis of phlyctenules and Eales’ disease.

C.Miliary tuberculosis usually causes a multifocal, discrete (sarcoidal, tuberculoidal) granulomatous choroiditis.

D.Histologically, the classic pattern of caseation necrosis consists of a zonal type of granulomatous reaction around the area of coagulative necrosis.

1.A smooth, acid-fast bacillus can be demonstrated by acid-fast (Ziehl–Neelsen) or fluorescent acidfast stains.

2.The polymerase chain reaction, prepared from formaldehyde-fixed and para n-embedded tissue, can be helpful in making the diagnosis.

II.Leprosy (Hansen’s disease; M. leprae; Fig. 4.9)

Distinction in gene expression correlates with and accurately classifies the clinical forms of the disease

A.In lepromatous leprosy, the lepromin test (analogous to the tuberculin test) is negative, suggesting little or no immunity.

Genes belonging to the leukocyte immunoglobulin-like receptor (LIR) family are significantly upregulated in lesions of lepromatous patients suffering from the disseminated form of the infection.

1.The prognosis is poor.

2.Lepromas of the skin result in leonine facies and neurologic changes.

3.The eyeballs are involved, usually in their anterior portions.

4.Histologically, a di use type of granulomatous inflammatory reaction, known as a leproma, is present.

a.The leproma shows large, pale-staining histiocytes that are called lepra cells when their cytoplasm is amorphous and Virchow’s cells when vacuolated.

b.The lepra cells and Virchow’s cells teem with beaded bacilli (no immunity).

c.The lepromas involve mainly cornea, anterior sclera, and iris.

The bacteria may grow better in the cooler, anterior portion of the eye, rather than in the warmer, posterior portion, just as they do in the cooler skin instead of in the warmer, deeper structures of the body.

B.In tuberculoid leprosy, the lepromin test is positive, suggesting immunity.

1.The prognosis is good.

2.A neural involvement predominates with hypopigmented (vitiliginous), hypoesthetic lesions and thickened nerves.

The ulnar nerve is particularly vulnerable, leading to the characteristic claw hand.

3.The ocular adnexa and orbital structures are involved, especially the ciliary nerves, but not the eyeballs.

4.Histologically, a discrete (sarcoidal, tuberculoidal) type of granulomatous inflammatory reaction is seen, mainly centered around nerves.

a.The individual nodules tend to be much more variably sized than those in sarcoidosis or miliary tuberculosis.

b.Organisms are extremely hard to find (good immunity) and are usually located in an area of nerve degeneration.

III.Syphilis (Treponema pallidum; Fig. 4.10)

A.Both the congenital and acquired forms of syphilis may produce a nongranulomatous interstitial keratitis (see p.

267in Chapter 8) or anterior or posterior uveitis.

The two most commonly used nontreponemal tests (which detect antibody to cardiolipin–lecithin–cholesterol antigen)

are the Venereal Disease Research Laboratory (VDRL) and the rapid plasma reagin. The treponemal tests (which detect antibody against treponemal antigens) include the fluorescent treponemal antibody absorption test (FTA-ABS), hemagglutination treponemal test for syphilis, T. pallidum hemagglutination assay, and the microhemagglutination test. Routine screening with VDRL and FTA-ABS is recommended in patients who have unexplained uveitis or other ocular inflammation.

Syphilis may occur in immunologically deficient patients (e.g., those with AIDS).

B.Syphilis, a venereal disease, is divided into three chronologically overlapping stages.

T ehnonvenereal treponematoses caused by subspecies

T. p. pertenue (yaws) and T. p. endemicum (bejel) are morphologically indistinguishable from T. pallidum, and display only subtle immunologic di erences.

1.Primary stage: characterized by an ulcerative lesion, chancre, occurring at the site where T. pallidum penetrates the skin or mucous membrane. Primary lesions heal spontaneously in 2 to 8 weeks and rarely cause systemic symptoms.

2.Secondary stage: the period when the systemic treponemal concentration is greatest, usually 2 to 12 weeks after contact.

a.This stage may be manifest by fever, malaise, lymphadenopathy, and mucocutaneous lesions.

b.The secondary stage subsides in weeks to months but may recur within 1 to 4 years.

3.Tertiary stage: the late sequelae such as cardiovascular e ects and neurosyphilis. Focal granulomatous vascular lesions (gummas) can a ect any organ.

C.The common form of posterior uveitis is a smoldering, indolent, chronic, nongranulomatous inflammation.

1.Disseminated, large, atrophic scars surrounded by hyperplastic retinal pigment epithelium (part of the di erential diagnosis of “salt-and-pepper” fundus) characterize the lesions.

2.A more virulent type of uveitis may occur with a granulomatous inflammation.

In the nongranulomatous and granulomatous forms, the overlying neural retina is often involved.

D.Histologic findings

1.The chronic nongranulomatous disseminated form of posterior choroiditis:

a.In the atrophic scar, the outer neural retinal layers, the retinal pigment epithelium, and the inner choroidal layers disappear.

b.Dehiscences in Bruch’s membrane may be present through which neural retinal elements may “invade” the choroid.

c.Bruch’s membrane may be folded into the atrophic, sclerosed choroid.

d.Scattered lymphocytes and plasma cells may be present.

e.The Treponema spirochete is a helical bacterium

5 to 15 μm in length and less than 0.18 μm in width, and can be demonstrated in the ocular tissue with special stains, often in areas devoid of inflammatory cells.

T. pallidum belongs to the same family (Spirochaetaceae) as Borrelia (see later) and Leptospira.

2.The granulomatous form of posterior chorioretinitis:

a.The inflammatory process usually involves the choroid and the overlying neural retina and is quite vascular.

b.Epithelioid cells, lymphocytes, and plasma cells are seen.

c.Spirochetes can be demonstrated in the inflammatory tissue.

3.The preceding two types of reactions may also involve the anterior uvea.

Spirochetes may be obtained by aspiration of aqueous from the anterior chamber and identified by dark-field microscopy.

IV. Lyme disease (Borrelia burgdorferi; Fig. 4.11)

A.Lyme disease is a worldwide, tickborne, multisystem disorder, heralded by a red rash and erythema migrans, which forms at the site of the tick bite, usually within 4 to 20 days.

1.It enlarges with central clearing (forming a ring), and can last several weeks.

2.It may return and become chronic (erythema chronicum migrans).

B.The tick, an Ixodes species, transmits the infectious agent, B. burgdorferi, through its bite.

T ehenzyme-linked immunosorbent assay (ELISA) and the indirect immunofluorescence antibody are the most commonly used tests to diagnose Lyme disease.

C.Like syphilis, Lyme disease is divided into three chronologically overlapping stages. Not all patients exhibit each stage, and the signs and symptoms are variable within each stage.

1.Stage 1 is characterized by the local erythema migrans, which may be accompanied by flulike symptoms, including headache, fever, malaise, and lymphadenopathy.

Ocular findings include follicular conjunctivitis and photophobia.

2.Stage 2 occurs within days, weeks, or even months and reflects systemic dissemination of the spirochete.

a.Multiple skin lesions may occur (e.g., the purple nodule, lymphocytoma, especially on the earlobe or breast).

b.Other findings include cardiac problems, arthritis (rare in stage 2), and the neurologic triad of meningitis, cranial neuritis, and painful radiculitis.

Ocular findings include blepharitis, blepharospasm, iridocyclitis, uveitis, neuroretinitis, vitritis, pars planitis, macular edema, anterior ischemic optic neuropathy (ANION), optic neuritis, optic neuropathy, temporal arteritis, pseudotumor cerebri, optic disc edema, optic disc pallor, cranial ocular nerve palsies, Horner’s syndrome, and Argyll–Robertson pupil.

3.Stage 3 can follow a disease-free period and may last years.

a.“Lyme arthritis” is the hallmark of stage 3, appearing in over 50% of untreated cases.

b.Other findings include acrodermatitis chronica atrophicans and late neurologic sequelae, especially an encephalopathy.