Granulomatous Inflammation

Published on 20/03/2015 by admin

Last modified 22/04/2025

Print this page

This article have been viewed 3761 times

Granulomatous Inflammation

Introduction

Chronic granulomatous inflammation is a proliferative inflammation characterized by a cellular infiltrate of epithelioid cells [and sometimes inflammatory giant cells, lymphocytes, plasma cells, polymorphonuclear leukocytes (PMNs), and eosinophils; see Chapter 1].

Post-Traumatic

Sympathetic Uveitis [Sympathetic Ophthalmia (SO), Sympathetic Ophthalmitis]

I. SO (Figs 4.1 and 4.2) is a bilateral, diffuse, granulomatous, T-cell-mediated uveitis that occurs from two weeks to many years after penetrating or perforating ocular injury and is associated with traumatic uveal incarceration or prolapse.

A. Although the uveitis may start as early as five days or as late as 50 years after injury, well over 90% of cases occur after two weeks but within one year. Most of these (80%) occur within three weeks to three months post-injury.

B. Removal of the injured eye before sympathetic uveitis occurs usually completely protects against inflammation developing in the noninjured eye.¹ Once the inflammation starts, however, removal of the injured (“exciting”) eye probably has little effect on the course of the disease, especially after 3–6 months.

SO has been reported in nontraumatized eyes in a few isolated cases. However, unless the whole eye is serially sectioned and carefully examined for evidence of perforation, the clinician can never be sure that some long-forgotten penetrating ocular wound is not present. A diagnosis of sympathetic uveitis in the absence of an ocular injury should be viewed with marked skepticism.

C. SO affects approximately 0.03 per 100,000 persons per year and accounts for approximately 1 to 2% of uveitic patients. Greater than 50% of patients maintain a functional visual acuity better than 20/50. The condition seems to be decreasing in occurrences in recent years.

Fig. 4.1 Sympathetic uveitis. A, Large, “greasy,” mutton-fat keratic precipitates (KPs: collections of epithelioid cells, lymphocytes, and plasma cells on posterior surface of cornea) seen in patient with sympathetic uveitis. B, Another patient had a perforating injury to his eye. The other (sympathizing) eye developed photophobia and mutton-fat KPs; the injured (exciting) eye was enucleated. Radiograph of enucleated eye shows two metallic foreign bodies in eye. C, Gross specimen shows massive, diffuse thickening of choroid. D, Granulomatous inflammation fills and thickens the choroid (see also Fig. 4.2A and B). The Perl stain is positive (blue) for iron in the large, dark foreign body in the choroid. (B–D, Courtesy of Dr. TH Chou.)

Fig. 4.2 Sympathetic uveitis. A, Enucleated eye from Fig. 4.1B and C shows diffuse thickening of the choroid (shown with increased magnification in B) by granulomatous inflammation. The pale areas represent epithelioid cells, and the dark areas consist mainly of lymphocytes. C, Sparing of the choriocapillaris and pigment phagocytosis by epithelioid cells is seen. Note granulomatous inflammation of scleral canal in lower right corner (reason why evisceration does not protect against sympathetic uveitis). D, Dalen–Fuchs nodule of epithelioid cells between retinal pigment epithelium and Bruch’s membrane is seen. Underlying choriocapillaris is spared, and overlying neural retina is free of inflammatory process. (Courtesy of Dr. TH Chou.)

II. Blurred vision and photophobia in the noninjured (sympathizing) eye are usually the first symptoms. Vision and photophobia worsen concurrently in the injured (exciting) eye, and a granulomatous uveitis develops (see Fig. 4.1A).

Glaucoma may develop due to blockage of the angle by cellular debris or peripheral anterior synechiae. Hypotony may occur from decreased aqueous output by the inflamed ciliary body.

III. The cause appears to be a delayed-type hypersensitivity reaction of the uvea to antigens localized on the retinal pigment epithelium or on uveal melanocytes.

A. The lymphocytic infiltrate consists almost exclusively of T lymphocytes.

B. B cells found in some cases, usually of long duration, may represent the end stage of the disease.

Phacoanaphylactic endophthalmitis (PE) was found in approximately 25% of patients who had sympathetic uveitis in cases submitted to the Armed Forces Institute of Pathology before 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 titled Vogt–Koyanagi–Harada Syndrome (Uveomeningoencaphalitic Syndrome)]. The relationship between the two entities is still uncertain.

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

IV. Histologically, SO 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. Diffuse 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).²

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, Phacoantigenic, or Phacogenic) Endophthalmitis

I. Phacoanaphylactic endophthalmitis (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.

Fig. 4.3 Phacoanaphylactic endophthalmitis. A, The patient had an iridencleisis in 1971. The eye was injured by blunt trauma in an automobile accident in May 1973. In September 1973, signs of an anterior uveitis developed. Note the small mutton-fat keratic precipitates just to the right of the corneal slit-lamp section in the lower third of the picture. The eye was enucleated in May 1974. B, The enucleated globe shows iris in the subconjunctival tissue. The lens remnant, mainly nucleus, shows a zonal type of granulomatous reaction, consisting of surrounding epithelioid cells and giant cells, in turn surrounded by lymphocytes and plasma cells, in turn surrounded by granulation tissue. The lens capsule is ruptured posteriorly. C, Under increased magnification, the typical zonal pattern is seen around the remnant of the lens nucleus (periodic acid–Schiff stain).

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

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 effects 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).

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 anterior chamber drainage angle and cause an acute secondary open-angle glaucoma called phacolytic glaucoma (see 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, releasing proteolytic enzymes, arachidonic acid metabolites, and oxygen-derived free radicals.

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 off the PE initiates a sympathetic uveitis and results in a diffuse, chronic, granulomatous inflammation.

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.

II. 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.

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

Nontraumatic Infections

Viral

I. Cytomegalic inclusion disease (salivary gland disease; Fig. 4.4)

A. Cytomegalic (CMV) inclusion disease is caused by systemic infection with the salivary gland virus, cytomegalovirus, 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 84 genes). It is estimated that CMV infects 80–85% 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

CMV disease is the most common viral infection of the neonate, with an incidence of 5–20 per 1000 live births. Most of the infants are asymptomatic at birth. The differential diagnosis consists of the TORCH syndrome (see 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]

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. In the antiviral therapy era, non-CMV ocular opportunistic infections are rare.

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

1. The acquired form starts with scattered, yellow-white 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 affected 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 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 diffuse 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.

Fig. 4.4 Cytomegalic inclusion disease. A, The fundus picture shows the characteristic sector 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.)

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 (differential diagnosis consists of the TORCH syndrome; see Chapter 3).

3. In immunocompetent individuals, VZV is a major cause of the acute retinal necrosis syndrome (see Chapter 11).

Following herpes zoster ophthalmicus, patients have a nine times greater risk of developing cancer than patients without herpes zoster ophthalmicus. Also, the risk of anterior uveitis increases the year following VZV.

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 segment: 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, anterior-surface fibrovascular membrane, patchy necrosis of anterior portion of ciliary body, especially of circular and radial portions of ciliary muscle, and cataract and posterior synechiae

4. Posterior segment: chronic nongranulomatous choroiditis (commonly, granulomatous inflammation), retinal perivasculitis and vasculitis, mild mononuclear vitreal inflammatory infiltrate, and acute or chronic episcleritis and scleritis; optic nerve: perivasculitis and chronic leptomeningitis; and 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 diffuse or patchy necrosis involving the iris and pars plicata of the ciliary body. Granulomatous inflammatory lesions also may be seen. Inclusion bodies have not been demonstrated in the chronic inflammatory lesions.

Fig. 4.5 Herpes zoster. A, Ophthalmic branch of trigeminal nerve involved, including tip of nose; the patient had iritis. B, Evisceration specimen from another patient who had herpes zoster ophthalmicus shows corneal thickening, scarring, and inflammation. C, Increased magnification shows granulomatous inflammation, with epithelioid cells and inflammatory giant cells, mainly centered around Descemet’s membrane (granulomatous reaction to Descemet’s membrane).

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.

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 approximately 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 bloodstream, after lung infection.

Tubercle bacilli survive within macrophages because they secrete eukaryocyte-like serine/threonine protein kinase G within macrophage phagosomes, inhibiting phagosome–lysosome 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.

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. Tuberculoprotein hypersensitivity may play a role in the pathogenesis of phlyctenules and Eales’ disease. Tuberculous choroiditis may simulate serpiginous choroiditis (called tuberculous serpiginous-like choroiditis).

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. Smooth, acid-fast bacilli can be demonstrated by acid-fast (Ziehl–Neelsen) or fluorescent acid-fast stains.

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

Fig. 4.7 Tuberculosis. A, Archeology college student presented with a granulomatous posterior choroiditis. Active pulmonary tuberculosis was documented; antituberculous therapy was instituted. Appearance of lesion 2 months (B) and 16 months (C) later. At time of last photograph (C), the tuberculosis was considered cured.

Fig. 4.8 Tuberculosis. A, Tuberculous zonal granuloma involves retina and choroid. Caseation necrosis is present. B, In the middle of the field, typical acid-fast organisms are shown by the Ziehl–Neelsen method. (Courtesy of Dr. AH Friedman.)

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

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

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. Lepromas of the skin result in leonine facies and neurologic changes. The eyeballs are involved, usually in their anterior portions.

2. Histologically, a diffuse type of granulomatous inflammatory reaction, known as a leproma, is present.

a. Lepromas, which involve mainly cornea, anterior sclera, and iris, show 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).

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. The prognosis is good.

1. A neural involvement, particularly the ulnar nerve (leads to claw hand), predominates with hypopigmented (vitiliginous), hypoesthetic lesions, and thickened nerves.

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

3. 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 difficult to find (good immunity) and are usually located in an area of nerve degeneration.

Fig. 4.9 Lepromatous leprosy. A, Leonine facies present in patient who had lepromatous leprosy. Note involvement of left eye, shown with closer view in B. C, Many “clear” cells are seen with hematoxylin and eosin-stained section. D, Same cells are teeming with acid-fast leprous organisms (red) as seen with the Ziehl–Neelsen method. (A and B, Courtesy of Dr. B Blaise; C and D, courtesy of Dr. P Henkind.)

III. Syphilis (Treponema pallidum; Fig. 4.10)

A. Both the congenital and acquired forms of syphilis may produce a nongranulomatous interstitial keratitis (see Chapter 8) or anterior or posterior uveitis. Syphilis may occur in immunologically deficient patients (e.g., those with AIDS).

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 may be considered in patients who have unexplained uveitis or other ocular inflammation.

B. Syphilis, a venereal disease, is divided into three chronologically overlapping stages.
The nonvenereal treponematoses caused by subspecies T. p. pertenue (yaws) and T. p. endemicum (bejel) are morphologically indistinguishable from T. pallidum and display only subtle immunologic differences.

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 2–8 weeks and rarely cause systemic symptoms.

2. Secondary stage: The period when the systemic treponemal concentration is greatest, usually 2–12 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 1–4 years.

3. Tertiary stage: The late sequelae such as cardiovascular effects and neurosyphilis. Focal granulomatous vascular lesions (gummas) can affect 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 differential diagnosis of “salt-and-pepper” fundus) characterize the lesions.

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

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

b. Bruch’s membrane may be folded into the atrophic, sclerosed choroid. Scattered lymphocytes and plasma cells may be present.

c. The Treponema spirochete is a helical bacterium 5–15 µm in length and less than 0.18 µm in width, and it can be demonstrated in the ocular tissue with special stains, often in areas devoid of inflammatory cells.

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

b. 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.

Fig. 4.10 Syphilis. A, Small, round translucent nodules are seen in the conjunctiva of the inferior fornix. B, Biopsy of nodules shows numerous granulomas under the conjunctival epithelium (ce, surface conjunctival epithelium; gr, granulomatous reaction in substantia propia). C, Increased magnification reveals epithelioid cells in the inflammatory nodules. D, A special stain, Dieteria, demonstrates spirochetes (s) in the inflammatory infiltrate. (Case reported in Spektor FE, Eagle RC, Nichols CW: Granulomatous conjunctivitis secondary to Treponema pallidum. Ophthalmology 88:863. © PubMed Central 1981.)

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 4–20 days. The rash enlarges with central clearing (forming a ring), can last several weeks, and may return and become chronic (erythema chronicum migrans).

B. The tick, an Ixodes species, transmits the infectious agent, B. burgdorferi, through its bite. The enzyme-linked immunosorbent assay (ELISA) and the indirect immunofluorescence antibody are the most commonly used diagnostic tests.

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.

c. 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 more than 50% of untreated cases.

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

c. Ocular findings include stromal keratitis, episcleritis, orbital myositis, and cortical blindness.

D. The pathologic mechanisms include direct invasion of tissues by the spirochete, vasculitis and small-vessel obliteration, perivascular plasma cell infiltration, and immunologic reactions.

Fig. 4.11 Lyme disease. Lyme disease can cause a choroiditis (A) or an optic neuritis (B and C). Another patient had a chronic bilateral uveitis with a unilateral exudative retinal detachment and inflammatory pupillary membrane. Surgical iridectomy and membrane excision were performed. Spirochetes (Borrelia burgdorferi) were demonstrated by silver stain (D) and cultured in MKP medium (in the 16th subculture) from the excised tissue. (A–C, Courtesy of Prof. GOH Naumann; D, courtesy of Prof. HE Völcker and reported by Preac-Mursic V, Pfister HW, Spiegel H et al.: First isolation of Borrelia burgdorferi from an iris biopsy. J Clin Neuroophthalmol 13:155. © North American Neuro-Ophthalmology Society 1993.)

V. Streptothrix (Actinomyces; Fig. 4.12)

A. The organism responsible for streptothrix infection of the lacrimal sac (see Chapter 6) and for a chronic form of conjunctivitis belongs to the class Schizomycetes, which contains the genera Actinomyces and Nocardia. The organism superficially resembles a fungus, but it is a bacterium, best classified as an anaerobic and facultative capnophilic bacterium of the genus Actinomyces.

B. Histologically, the organisms (weakly gram-positive and acid-fast) are seen in colonies as delicate, branching, intertwined filaments surrounded by necrotic tissue with little or no inflammatory component (e.g., the lacrimal cast from the nasolacrimal system).

The colonies can be seen macroscopically as gray or yellow “sulfur” granules. Inflammatory giant cells are seen occasionally.

Fig. 4.12 Streptothrix (Actinomyces). A, Clinical appearance of acute canaliculitis. B, Smear of lacrimal cast stained with peridic acid–Schiff shows large colonies of organisms. (A, Courtesy of Dr. HG Scheie.)

VI. Cat-scratch disease [CSD: Bartonella (previously called Rochalimaea) henselae, cat-scratch bacillus]

A. CSD is a subacute regional lymphadenitis following a scratch by a kitten or cat (or perhaps a bite from the cat flea, Ctenocephalides felis), caused by the cat-scratch bacillus, B. henselae, a slow-growing, fastidious, gram-negative, pleomorphic bacillus, which is a member of the α₂ subgroup of the class Probacteria, order Rickettsiales, family Rickettsiaceae.

1. Systemic manifestations in severe cases include splenohepatomegaly, splenic abscesses, mediastinal masses, encephalopathy, and osteolytic lesions.

2. Ocular findings include Parinaud’s oculoglandular fever (see Chapter 7), neuroretinitis, branch retinal artery or vein occlusion, multifocal retinitis (retinal white-dot syndrome), focal choroiditis, intraretinal white spots, macular hole, optic disc edema associated with peripapillary serous retinal detachment, optic nerve head inflammation, and orbital infiltrates.

3. CSD antigen skin test and serologically indirect immunofluorescence assay test are positive in infected patients.

CSD may occur in immunologically deficient patients (e.g., AIDS; see Chapter 1). Infection with Bartonella may also cause bacillary angiomatosis in immunologically deficient patients.

B. The contemporary infections caused by the Bartonella species include CSD, bacillary angiomatosis, relapsing bacteremia, endocarditis, and hepatic and splenic peliosis. CSD is the most common, affecting an estimated 22,000 people annually in the United States.

C. The domestic cat and its fleas are the major reservoir for B. henselae.

D. Histopathologically, the characteristics are discrete granulomas (which in time become suppurative) and follicular hyperplasia with general preservation of the lymph node architecture.

1. Warthin–Starry silver stain demonstrates the cat-scratch bacillus in tissue sections.

2. Electron microscopy shows extracellular rod-shaped bacteria.

VII. Tularemia (Francisella tularensis, also called Pasteurella tularensis; Fig. 4.13)

A. The common ocular manifestation of tularemia is Parinaud’s oculoglandular syndrome [i.e., conjunctivitis and regional (preauricular) lymphadenopathy, which may progress to suppuration].

B. Histologically, a granulomatous inflammation is found in the involved tissue. Organisms are extremely difficult to demonstrate histologically in the granulomatous tissue.

Fig. 4.13 Tularemia. A, Corneal ulcer and conjunctival granulomas developed in inflamed right eye. Palpable right preauricular node present. B, Central neutrophilic microabscess surrounded by granulomatous inflammation. Francisella tularensis cultured. (Presented by Dr. H Brown at 1996 combined meeting of Verhoeff and European Ophthalmic Pathology Societies and reported by Steinemann TL, Sheikholeslami MR, Brown HH et al.: Oculoglandular tularemia. Arch Ophthalmol 117:132. © American Medical Association 1999.)

VIII. Other bacterial diseases

A. Crohn’s disease (see Chapter 3)

B. Rhinoscleroma is a chronic, destructive granulomatous disease caused by Klebsiella rhinoscleromatis, a gram-negative, encapsulated rod. The infection can spread from the nose, pharynx, and larynx to involve the nasolacrimal duct, lacrimal sac, and other orbital structures.

Fungal

The prevalence of ocular fungal dissemination is less than 1% among fungemic inpatients.

I. Blastomycosis (Blastomyces dermatitidis, thermally dimorphic fungus)

A. North American blastomycosis may involve the eyes in the form of an endophthalmitis as part of a secondary generalized blastomycosis that follows primary pulmonary blastomycosis, or it may involve the skin about the eyes in the form of single or multiple elevated red ulcers.

1. Cutaneous blastomycosis does not usually become generalized.

2. Involvement of the cornea, sclera, eyelid, and orbit, as well as choroiditis, endophthalmitis, and panophthalmitis, can occur.

B. Histologically, the use of special stains demonstrates single budding cells in a granulomatous reaction.

II. Cryptococcosis (Cryptococcus neoformans, Torula histolytica)

A. Cryptococcosis, also called torulosis, has increased in frequency because the causative agent is an opportunistic fungus that infects immunocompromised patients, especially those who are HIV-positive.

B. The fungus tends to spread from its primary pulmonary involvement to central nervous system tissue, including the optic nerve and retina.

C. Histologically, special stains demonstrate the budding organism surrounded by a thick, gelatinous capsule, often in inflammatory giant cells in a granulomatous reaction.

III. Coccidioidomycosis (Coccidioides immitis)

A. Coccidioidomycosis, endemic to the arid soils of the southern, central, southwestern, and western United States and Mexico, usually starts as a primary pulmonary infection that may spread to the eyes and cause an endophthalmitis. Rarely, it may present as an anterior segment ocular coccidioidomycosis without any clinical evidence of systemic involvement.

B. Histologically, spherules containing multiple spores (endospores) are noted in a granulomatous inflammatory reaction.

IV. Aspergillosis (Aspergillus fumigatus; Fig. 4.14B and C)

A. Aspergillosis can cause a painful fungal keratitis, a very indolent chronic inflammation of the orbit, or an endophthalmitis; the latter condition is usually found in patients on immunosuppressive therapy.

B. Histologically, septate, branching hyphae are frequently found in giant cells in a granulomatous reaction.

Fig. 4.14 Fungal endophthalmitis. A, Immunosuppressed patient developed endophthalmitis. Note “snowball” opacities in the vitreous (near the optic nerve head, just to right of opacities). Candida albicans was cultured from the blood. B and C, Another patient experienced decreased vision in his right eye, followed by renal failure two months after a kidney transplantation. He died one month later. The histologic section shows microabscesses (m) in the vitreous body characteristic of fungal infection (bacterial infection causes a diffuse vitreous abscess). C, Scanning electron microscopy demonstrates septate branching Aspergillus hyphae. (C, Courtesy of Dr. RC Eagle, Jr.)

V. Rhinosporidiosis (Rhinosporidium seeberi)

A. Rhinosporidiosis is caused by a fungus of uncertain classification.

B. The main ocular manifestation of rhinosporidiosis is lid or conjunctival infection.

C. Histologically, relatively large sacs or spherules (200–300 µm in diameter) filled with spores are seen. The organisms may be surrounded by a granulomatous reaction but are more likely to be surrounded by a nongranulomatous reaction of plasma cells and lymphocytes.

VI. Phycomycosis (mucormycosis, zygomycosis; see Fig. 14.7)

A. The family Mucoraceae of the order Mucorales, in the class of fungi Phycomycetes, contains the genera Mucor and Rhizopus, which can cause human infections called phycomycoses, usually in patients who have severe acidosis [e.g., diabetes, burns, diarrhea, and immunosuppression (see Chapter 14)] or iron overload (e.g., in primary hemochromatosis).

The term mucormycosis should only refer to those infections caused by agents in the genus Mucor. Because the hyphae of species in the two genera, Mucor and Rhizopus, look identical histologically, and because Mucor may be difficult to culture, the term phycomycosis (or zygomycosis) is preferred to mucormycosis.

B. The fungi can infect the orbit or eyeball, usually in patients with acidosis from any cause, but most commonly from diabetes mellitus.

C. Histologically, the hyphae of Mucor and Rhizopus are nonseptate, very broad (3–12 µm in diameter), and branch freely.

1. Unlike most other fungi, the Mucoraceae readily take the hematoxylin stain and are easily identified in routine hematoxylin and eosin-stained sections.

2. Typically, the hyphae infiltrate and cause thrombosis of blood vessels, leading to infarction.

3. Inflammatory reactions vary from acute suppurative to chronic nongranulomatous to granulomatous.

VII. Candidiasis (Candida albicans; see Fig. 4.13A)

A. Candida albicans may cause a keratitis or an endophthalmitis.

B. The endophthalmitis is most likely to occur in patients who have an underlying disease that has rendered them immunologically deficient. The increased incidence of disseminated candidiasis correlates with the use of chemotherapy and the increase in immunologically deficient patients.

C. Histologically, budding yeasts and pseudohyphal forms are seen surrounded by a chronic nongranulomatous inflammatory reaction, but sometimes by a granulomatous one.

VIII. Histoplasmosis (Histoplasma capsulatum)
Disseminated histoplasmosis with ocular involvement can be seen in immunologically deficient patients (e.g., in HIV-positive persons; see Chapter 11).

IX. Sporotrichosis (Sporotrichum schenkii)

A. Ocular involvement in sporotrichosis is usually the result of direct extension from primary cutaneous lesions of the lids and conjunctiva eroding into the eye and orbit.

1. Lesions in adjacent bony structures may encroach on ophthalmic tissues.

2. Less frequently, ocular and adnexal lesions may result from hematogenous dissemination of the fungus.

B. Histologically, the fungi are seen as round to cigar-shaped organisms, 3–6 µm in length, often surrounded by granulomatous inflammation.

X. Pneumocystis carinii (PC; Fig. 4.15)

A. PC pneumonia is a common opportunistic infection in patients who have AIDS. The causative organism exists exclusively in the extracellular space.

B. Previously classified as a protozoan, molecular genetic evidence has shown that PC has more morphologic similarities to a fungus than to a protozoan and is now classified as a fungus.

C. Clinically, choroidal lesions are yellow to pale yellow, usually seen in the posterior pole.

1. An association exists between PC and CMV in immunologically deficient patients so that PC choroiditis and CMV retinitis can exist concurrently in the same person.

2. In addition, PC and Mycobacterium avium-intracellulare, two opportunistic organisms, have been reported in the same choroid at the same time in a patient with AIDS.

D. Histologically, choroidal lesions show “cysts,” few or no inflammatory cells, and characteristic abundant, eosinophilic, frothy material, probably composed of dead and degenerating microorganisms.

Fig. 4.15 Pneumocystis carinii. Scattered choroidal infiltrates can be seen in the fundus clinically (A) and in the gross specimen (B) in a patient who had acquired immunodeficiency syndrome (AIDS). C, The characteristic foamy, eosinophilic, and mostly acellular choroidal infiltrate is seen between dilated capillaries. D, An example of the electron microscopic appearance of P. carinii (arrows), previously thought to be a protozoan parasite of the Sporozoa subphylum but now believed to be a fungus. (Case presented by Dr. NA Rao at the meeting of the Verhoeff Society, 1989.)

Parasitic

I. Protozoa

A. Toxoplasmosis (Toxoplasma gondii; Figs 4.16 and 4.17)

1. The definitive host of the intracellular protozoan T. gondii is the cat, but many intermediate hosts (e.g., humans, rodents, and fowl) are known.

2. The parasite primarily invades retinal cells directly.

3. Clinically, the infestation starts as a focal area of retinitis, with an overlying vitritis. Approximately 80% of children with congenital toxoplasmosis show chorioretinal lesions.

4. The lesions slowly clear centrally, destroying most of the retina and choroid, and become pigmented peripherally so that “healed” lesions appear as atrophic white scars surrounded by a broad ring of pigment. Immunoglobulin G (IgG) is the major class involved in the humoral immune response to T. gondii, followed by IgA.

5. Years later, reactivation can occur in the areas of the scars, or sometimes in new areas.

Even after the fifth decade, ocular toxoplasmosis remains an important cause of posterior uveitis. A subgroup of Fuchs’ heterochromic iridocyclitis has an association, which may be causal, with toxoplasmic retinochoroiditis. Atypical, severe toxoplasmic retinochoroiditis in the elderly can mimic acute retinal necrosis.

6. Both congenital and acquired forms are recognized.

a. The congenital form is associated with encephalomyelitis, visceral infestation (hepatosplenomegaly), and retinochoroiditis.

If a woman has dye-test antibodies when pregnancy is established, she will not transmit the disease to her fetus. If dye-negative, some risk exists of her transmitting toxoplasmosis to her infant if she acquires the disease during pregnancy (there is a 14% chance of the child showing severe manifestations of the disease). If the woman acquires toxoplasmosis during the first trimester, pregnancy may cause activation of ocular disease in the mother.

b. The acquired form usually presents as a posterior uveitis and sometimes as an optic neuritis.

The acquired form, usually a retinitis, rarely a scleritis, may occur in persons who have immunologic abnormalities of many types, especially in AIDS.

7. Histologically, the protozoa are found in three forms: free, in pseudocysts, or in true cysts.

a. Rarely, the protozoa may be found in a free form in the neural retina.

1) The free parasite, called a trophozoite, resides in an intracellular vacuole that is completely unable to fuse with other endocytic or biosynthetic vacuoles.

2) The protozoa are seen in an area of coagulative necrosis of the neural retina, sharply demarcated from the contiguous normal-appearing neural retina, or rarely in the optic nerve.

b. Commonly, a protozoan enters a retinal cell (neural retina or retinal pigment epithelium) and multiplies in the confines of the cell membrane. All that is seen histologically, therefore, is a group of protozoa surrounded by the retinal cell membrane; the whole assemblage is called a pseudocyst.

c. If the environment becomes inhospitable, an intracellular protozoan (trophozoite) may transform itself into a bradyzoite, surround itself with a self-made membrane, multiply, and then form a true cyst that extrudes from the cell and lies free in the tissue.

1) It is found in the late stage of the disease, at the time of remission.

2) The true cyst is resistant to the host’s defenses and can remain in this latent form indefinitely.

d. The underlying choroid, and sometimes sclera, contains a secondary diffuse granulomatous inflammation.

Fig. 4.16 Toxoplasmosis. A, Acute attack in right eye in 12-year-old girl (white spots on blood vessels represent granulomatous cellular reaction on surface of retina). B, Early pigmentation present 7 years later. C, Twelve years later, lesion looks like “typical” toxoplasmosis.

Fig. 4.17 Toxoplasmosis. A, Histologic section showing an acute coagulative retinal necrosis, whereas the choroid shows a secondary diffuse granulomatous inflammation. B, A toxoplasmic cyst is present in the neural retina; note the tiny nuclei in the cyst. C, In another section, free forms of the protozoa are present in the necrotic neural retina. The tiny nuclei are eccentrically placed and the opposite end of the cytoplasm tends to taper, shown with increased magnification in D.

B. Malaria (Plasmodium)

1. Ocular complications occur in approximately 10–20% of malarial patients and include conjunctival pigmentation; conjunctival, epibulbar, and retinal hemorrhages; keratitis; optic neuritis; peripapillary edema; and temporary loss of vision.

2. Histologically, in a case of Plasmodium falciparum malaria, cytoadherence and rosetting of parasitized erythrocytes partially occluded small retinal and uveal blood vessels; malarial pigment (hemozoin) can be demonstrated by polarized light.

C. Microsporidiosis (Encephalitozoon, Enterocytozoon, Nosema, and Pleistophora)

1. Diseases caused by microsporidia, which are obligate intracellular parasitic protozoa, have increased in prevalence because of the increase in the prevalence of AIDS.

2. Clinically, ocular findings include punctate epithelial keratopathy, keratitis, and keratoconjunctivitis.

3. Histologically, extracellular and intracellular spores are found in and around degenerating keratocytes. Electron microscopy shows encapsulated oval structures, approximately 3.5–4 µm in length and 1.5 µm in width.

D. Acanthamoeba species (A. casttellani, A. polyphaga, A. culbertsoni; see Chapter 8)

II. Nematodes

A. Toxocariasis (Toxocara canis; see Fig. 18.20)

1. Ocular toxocariasis is a manifestation of visceral larva migrans (i.e., larvae of the nematode T. canis). Rarely, Toxocara cati may also cause toxocariasis.

a. One eye tends to be involved, usually in children 6–11 years of age.

b. Rarely, bilateral ocular toxocariasis can be demonstrated by aqueous humor ELISA.

c. Often, the child’s history shows that the family possesses a puppy rather than an adult dog.

2. The condition may take at least three ocular forms:

a. Leukokoria with multiple retinal folds radiating out toward the peripheral retina, where the necrotic worm is present

b. A discrete lesion, usually in the posterior pole and seen through clear media

c. A painless endophthalmitis

3. In all three forms, the eye is not inflamed externally; the only complaint is loss of vision; and only one eye is involved.

Although the condition presumably follows widespread migration of larvae, only one eye is involved and only one worm is found. No inflammatory reaction occurs until the worm dies. The eosinophil appears to be the major killer cell of Toxocara. Toxocaral fluorescent antibody tests may be helpful in making the diagnosis of toxocariasis.

4. Histologically, a granulomatous inflammatory infiltrate, usually with many eosinophils, surrounds the necrotic worm. The infiltrate is zonal, with the necrotic worm surrounded by an abscess containing eosinophils, neutrophils, and necrotic debris; granulomatous inflammation surrounds the abscess.

Splendore–Hoeppli phenomenon is a local eosinophilic, amorphous precipitate consisting of debris (mainly from eosinophils) and granular material (probably an antigen–antibody complex). It is presumed to be caused by a parasite, perhaps a nematode, but the exact cause is unclear.

B. Diffuse unilateral subacute neuroretinitis (DUSN; unilateral wipe-out syndrome)

1. DUSN, which typically affects young, healthy people, is probably caused by more than one type of motile, subneural retinal, nematode roundworm, which if seen clinically can be destroyed by focal photocoagulation.

2. The early stage of the disease is characterized by unilateral vision loss, vitritis, mild optic disc edema, and successive crops of multiple, evanescent, gray-white, deep retinal lesions.

3. Over a period of many months, widespread, diffuse, focal depigmentation of the retinal pigment epithelium develops, accompanied by retinal arterial narrowing, optic atrophy, severe vision loss, and electroretinographic abnormalities.

4. Worms seen in the fundi of patients from the southern United States seem to be approximately one-half the size of those seen in patients from the northern and western United States, and the exact type of the small variant roundworm is not known. The large nematode variant is probably not caused by Toxocara but by the raccoon roundworm larva, Baylisascaris procyonis.

C. Trichinosis (Trichinella spiralis; Fig. 4.18)

1. The nematode T. spiralis is obtained by eating undercooked meat, classically pork that contains the trichina cysts.

2. Clinically, the lids and extraocular muscles may be involved as the larvae migrate systemically.

3. Histologically, the larvae encapsulate or encyst in striated muscle and cause little or no inflammatory reaction. If the larvae die before they encapsulate, however, a zonal granulomatous inflammatory reaction around the necrotic worm results.

Fig. 4.18 Trichinosis. A, Acute trichinosis with orbital involvement. Note swelling of lids. B, Top two cysts are empty; bottom cyst shows larva of Trichinella spiralis (pork nematode); seen with increased magnification in C. (A, Courtesy of Dr. ME Smith.)

D. Loa loa (Fig. 4.19)

1. The adult L. loa filarial worm wanders in the subcutaneous tissues. It may wander into the periorbital tissues and eyelids and often into the subconjunctival tissues, where its length makes it easily visible.

2. Histologically, little inflammatory reaction occurs while the worm is alive.

Fig. 4.19 Loa loa. A, Adult L. loa filarial worm present under conjunctiva. Note: Position of end of worm changes (left to right—pictures taken a few minutes apart). B, Worm grasped by forceps during removal. C, Worm almost completely removed. D, Removed worm. (Courtesy of Dr. LA Karp.)

E. Dracunculiasis (Dracunculus medinensis; guinea worm; serpent worm)

1. Dracunculiasis, caused by the obligate, nematode parasite, D. medinensis, affects the skin, subcutaneous tissues, and orbit.

2. Histologically, the worm, when dead, is surrounded by an abscess.

III. Cestoidea (tapeworms)

A. Cysticercosis (Cysticercus cellulosae; Fig. 4.20)

1. Cysticercus cellulosae is the larval stage of the pork tapeworm Taenia solium. The larvae, or bladderworms, hatch in the intestine, and the resultant systemic infestation is called cysticercosis.

Cysticercosis is the most common ocular tapeworm infestation and the most common parasitic infection of the central nervous system. The prognosis in untreated cases is uniformly poor. The best chance for cure is early surgical removal, although destruction of the parasite in situ by diathermy, light coagulation, or cryoapplication may prove successful.

2. The bladderworm has a predilection for the central nervous system and eyes. It induces no inflammatory response when alive.

3. Histologically, the necrotic bladderworm is surrounded by a zonal granulomatous inflammatory reaction that usually contains many eosinophils.

Fig. 4.20 Cysticercosis. A, Fundus picture shows bladderworm in vitreous. B and C, A 6-year-old girl had eye enucleated because of suspected retinoblastoma. Gross specimen shows bladderworm cyst over optic nerve head. D, Scolex area with hooks (birefringent to polarized light) and sucker is surrounded by a granulomatous reaction. (A, Courtesy of Dr. AH Friedman.)

B. Hydatid cyst (Echinococcus granulosus)

1. The onchospheres of the dog tapeworm E. granulosus may enter humans and form a cyst called a hydatid cyst that contains the larval form of the tapeworm. In this form, the tapeworms appear as multiple scolices provided with hooklets; each scolex is the future head of an adult tapeworm.

2. In humans, the tapeworm has a predilection for the orbit.

3. Histologically, multiple scolices are seen adjacent to a thick, acellular, amorphous membrane that represents the wall of the cyst.

C. Coenurus (Multiceps multiceps)

1. Coenurus is a large, single bladderworm (larval cystic stage of M. multiceps), 5 cm or more in diameter. It contains several hundred scolices.

2. The bladderworm may involve the subconjunctival or orbital regions, or it may occur in the eye.

3. The adult tapeworm mainly has the domestic dog as its definitive host, but it may also be found in other animals. The larval stage is usually found in sheep, but primates can be involved as incidental intermediate hosts.

4. Histologically, multiple inverted scolices line up against an outer cuticular wall.

IV. Trematodes (flukes): Schistosomiasis (Schistosoma haematobium, S. mansoni, and S. japonicum)

A. Trematodes of the genus Schistosoma can cause a chronic conjunctivitis or blepharitis in areas of the world where they are endemic.

B. The eggs of schistosomes hatch in water into miracidia, which penetrate snails, undergo metamorphosis, and form cercariae. The cercariae emerge from the snail and enter the skin of humans as metacercariae or adolescariae.

C. Histologically, the eggs and necrotic adult worms incite a marked zonal granulomatous inflammatory response.

V. Ophthalmomyiasis (fly larva)

A. Myiasis is a rare condition in which fly larvae (maggots) invade and feed on dead tissue. Numerous different causative agents may be found (e.g., Cochliomyia macellaria, Oestrus ovis, Gasterophilus species, Hypoderma bovis, and Cuterebera species).

B. Usually the larvae can be seen macroscopically, but exact identification relies on microscopic features.

VI. Retinal pigment epitheliopathy associated with the amyotrophic lateral sclerosis/parkinsonism–dementia complex of Guam—see Chapter 11.

VII. Many other parasites, including Leishmania (leishmaniasis), Trypanosoma (trypanosomiasis), Ascaris lumbricoides (ascariasis), and Dirofilaria (dirofilariasis), can cause ocular infestations.

Nontraumatic Noninfectious

Sarcoidosis (Figs. 4.21–4.26)

I. Sarcoidosis is a systemic disease, affecting black people predominantly and having an equal sex incidence.

II. Systemic findings include hypercalcemia, bilateral hilar adenopathy and lung parenchymal changes, peripheral lymphadenopathy, skin lesions varying from extensive erythematous infiltrates to nondescript plaques and papules, hepatosplenomegaly, occasional enlargement of lacrimal and salivary glands, and osteolytic lesions of distal phalanges. Central nervous system findings are seen in 5% of sarcoid patients, usually the result of basilar meningitis with infiltration or compression of adjacent structures.

III. The most common ocular manifestation is an anterior granulomatous uveitis that occurs in approximately one-fifth of people who have sarcoidosis.

A. Other findings include millet-shaped eyelid nodules; bilateral, white, focal discrete, conjunctival spots; nodular infiltrates in the bulbar conjunctiva; episcleral nodules; interstitial keratitis with a predilection for the lower half of the cornea; band keratopathy (especially with hypercalcemia); secondary closed-angle glaucoma; retinochoroidal granulomas; central or peripheral retinal neovascularization (sea fan); neovascularization of the optic nerve; retinal periphlebitis; “candle-wax drippings” (taches de bougie) on or near retinal vessels; retinal hemorrhages; whitish masses in dependent portion of vitreous; optic disc edema; optic neuritis; proptosis; and extraocular muscle palsies.

The retinal form of sarcoidosis is rare and carries a grave prognosis for life because of its association with central nervous system sarcoidosis. Another rare form that occurs in childhood is necrotizing sarcoid granulomatosis, which shows features of both sarcoidosis and Wegener granulomatosis. The CD4/CD8 ratio in vitreous fluid is of high diagnostic value.

IV. Histologically, a noncaseating, granulomatous, inflammation of the discrete (sarcoidal, tuberculoidal) type, frequently with inflammatory foreign-body giant cells, is found.

A. Most of the granulomatous nodules are approximately the same size.

B. Slight central necrosis may be seen, but caseation is rare.

C. Star-shaped, acidophilic bodies (asteroids); small, macrophage-related, calcium oxalate, birefringent, ovoid bodies; and spherical or ovoid, basophilic, calcium oxalate, frequently laminated, birefringent bodies (Schaumann bodies) may be found in, or surrounded by, epithelioid or inflammatory foreign-body giant cells. These bodies may also be seen in conditions other than sarcoidosis.

D. Small granulomas may be present histologically in the submucosa of the conjunctiva even in the absence of visible clinical lesions.

1. The yield of positive lesions is higher, however, if a nodule is seen clinically.

2. A biopsy of conjunctiva from the lower cul-de-sac may help to establish the diagnosis of sarcoidosis even when no clinically visible lesions are seen.

A conjunctival biopsy is a safe and simple method for diagnosing sarcoidosis in a high percentage of suspected patients. It is important that the pathologist take sections from at least three levels and a “ribbon” of tissue (approximately 6–8 sections) on each slide from the three levels. From the resultant 18–24 sections, granulomas may be found in only 1 or 2.

Fig. 4.21 Sarcoidosis. A, Skin lesions in sarcoidosis. B, Biopsy shows granulomatous inflammation in the dermis.

Fig. 4.22 Sarcoidosis. A, The patient shows numerous, small, round, translucent granulomas in the conjunctival fornix. B, A conjunctival biopsy reveals a discrete granuloma composed of epithelioid cells and surrounded by a rim of lymphocytes and plasma cells. Such granulomas may be found histologically even if no conjunctival nodules are noted clinically.

Fig. 4.23 Sarcoidosis. A, The iris is involved in the granulomatous process and shows numerous large granulomas. B, Slit-lamp section shows many mutton-fat keratic precipitates on the posterior corneal surface. C, Granulomas and peripheral anterior synechiae are noted in the angle of the anterior chamber.

Fig. 4.24 Sarcoidosis. A, The enucleated globe shows an infiltrate in the ciliary body. B, The infiltrate consists of a discrete granulomatous inflammation.

Fig. 4.25 Sarcoidosis. A, White cellular masses (“balls”) are seen in the vitreous compartment on the surface of the inferior neural retina, along with early “candle-wax drippings.” B, Candle-wax drippings are caused by perivascular, retinal, granulomatous infiltration. White balls are caused by accumulations of granulomatous inflammation in the vitreous. C, A large Dalen–Fuchs nodule is seen in this case of sarcoidosis. (B and C, Reported by Gass JDM, Olson CL: Sarcoidosis with optic nerve and retinal involvement. Arch Ophthalmol 94:945. © American Medical Association 1976.)

Fig. 4.26 Sarcoidosis. A, Patient with sarcoidosis presented with bilateral optic disc edema. B, Fluorescein angiogram. C, Granuloma involving edge of optic disc and adjacent retina. D. Sarcoid granulomas involve optic nerve meninges. (A and B, Courtesy of Dr. AJ Brucker; case in C, reported by Gass JDM, Olson CL: Sarcoidosis with optic nerve and retinal involvement. Arch Ophthalmol 94:945. © American Medical Association 1976.)

Granulomatous Scleritis

I. Granulomatous scleritis, anterior or posterior (see Fig. 8.64), is associated with rheumatoid arthritis (or other collagen disease) in approximately 15% of patients (see section on Scleritis in Chapter 8), and approximately 45% have a known systemic condition.

Up to 42% of patients who have scleritis have an associated uveitis. Acute scleritis may occur in Wegener’s granulomatosis and porphyria cutanea tarda.

II. Histologically, a zonal type of granulomatous inflammatory infiltrate surrounds a nidus of necrotic scleral collagen.

A. Typically, the inflammation is in the sclera between the limbus and the equator.

B. The lesions, which may be focal or diffuse, closely resemble subcutaneous rheumatoid nodules but have more plasma cells around the periphery.

The sclera may become thickened or markedly thinned (see Fig. 8.63). An intense nongranulomatous anterior uveitis may accompany the scleritis. Pseudorheumatoid nodule (granuloma annulare) is a necrobiotic granuloma that usually occurs in subcutaneous tissue but can occur in the episclera and orbit. Immune complex vasculitis occurs.

Chalazion

See Chapter 6.

Xanthogranulomas (Juvenile Xanthogranuloma and Langerhans’ Granulomatoses; Histiocytosis X)

See Chapter 9 and subsection on Reticuloendothelial System in Chapter 14.

Granulomatous Reaction to Descemet’s Membrane

I. In approximately 10% of eyes with corneal ulcer or keratitis that are examined histologically, a granulomatous reaction to Descemet’s membrane is found (see Fig. 4.5B and C). Most frequently, the corneas have a disciform keratitis with or without a history of herpes simplex or zoster keratitis.

II. The peculiar reaction to Descemet’s membrane may be the result of altered antigenicity of the membrane and subsequent development of an autosensitivity reaction.

Chédiak–Higashi Syndrome

See Chapter 11.

Allergic Granulomatosis and Midline Lethal Granuloma Syndrome

See section on Collagen Diseases in Chapter 6.

Weber–Christian Disease (Relapsing Febrile Nodular Nonsuppurative Panniculitis)

See Chapter 6.

Vogt–Koyanagi–Harada Syndrome (Uveomeningoencephalitic Syndrome)

I. VKH syndrome (Fig. 4.27) is a multisystem disorder that reflects the integration of Vogt–Koyanagi syndrome with Harada’s disease.

A. Although mainly a syndrome of adults, it rarely occurs in children, even those as young as four years of age.

B. VKH syndrome consists of a severe, acute, often bilateral, anterior uveitis associated with vitiligo (leukodermia), poliosis (whitened hair or canities), alopecia, and dysacusia. Perilimbal vitiligo in VKH syndrome is called Sugiura sign.

1. Harada’s disease consists primarily of a posterior granulomatous uveitis, usually bilateral and associated with bilateral serous retinal detachments, accompanied by fluctuating meningeal symptoms, both central and peripheral.

2. Glaucoma, cataract, subretinal neovascularization, late subretinal fibrosis, and Sugiura’s sign (perilimbal vitiligo) may occur.

C. The cerebrospinal fluid shows increased protein levels and pleocytosis.

Melanin-laden macrophages may be found in the cerebrospinal fluid in the early stages (within 25 days) of the onset of VKH syndrome.

Fig. 4.27 Vogt–Koyanagi–Harada syndrome. A, Patient shows vitiligo, poliosis, and alopecia. B, Diffuse thickening of choroid by granulomatous inflammation resembles that seen in sympathetic uveitis. However, unlike in sympathetic uveitis, inflammation does not spare choriocapillaris and has broken through the retinal pigment epithelium into the subneural retinal area. (A, Case reported in Fine BS, Gilligan JH: The Vogt–Koyanagi syndrome: A variant of sympathetic ophthalmia. Report of two cases. Am J Ophthalmol 43:433. © Elsevier 1957; B, case presented at the 1980 Verhoeff Society meeting by Dr. H Inomata and reported in Fine BS, Gilligan JH: The Vogt-Koyanagi syndrome: report of two cases. Am J Ophthalmol 43:433, 1957.)

II. Autoaggressive cell-bound responses to uveal pigment may play a role in the histogenesis of VKH syndrome.

A. VKH syndrome is associated with HLA-DR53, HLA-DR4, and HLA-DQ4 antigens (and HLA-DR1 in Hispanic patients).

B. VKH may be a syndrome of combined allelic predisposition in which DQA1*0301 acts as the primary and HLA-DR4 acts as an additive factor, whereas DQB1*0604 may be protective, in the development of the prolonged form of the syndrome.

It has been suggested that sympathetic uveitis represents a forme fruste of VKH syndrome. Rarely, VKH syndrome can occur after cutaneous injury such as laceration, burn, and contact dermatitis. Thus, both the clinical manifestations and the immunogenetic background of sympathetic uveitis and VKH syndrome are quite similar.

C. Also, T lymphocytes are decreased in the peripheral blood.

III. Histologically, a chronic, diffuse, granulomatous uveitis, closely resembling sympathetic uveitis, is seen.

A. Multiple histologic sections, however, usually show one or more areas in the posterior segment where the inflammatory reaction does not spare the choriocapillaris and involves the overlying neural retina.

B. An accompanying disciform degeneration of the macula is common. Immunocytology shows that the uveal infiltrates are composed of T lymphocytes and HLA-DR+ macrophages; nondendritic-appearing CD1 (Leu-6)-positive cells are localized to the choroid in close proximity to melanocytes. Scattered plasma cells and T lymphocytes occur in the retina.