The agents causing this type of inflammation are low-grade irritants including traumatically introduced foreign material or endogenous material such as keratin, lipid, blood, cholesterol, and lens protein, and infectious agents of low virulence such as viruses, fungi, protozoa, helminths, and bacteria that are obligate intracellular parasites. Infectious agents can often be identified histopathologically with the use of special stains such as acid-fast stains, silver stains, and periodic acid-Schiff (PAS) stain. Granuloma formation may be due to specific cyto-kines distributed in tissue that differ from the cyto-kines of acute inflammation or the cytokines associated with wound repair. There are also some granulomatous systemic inflammations for which the cause is still unknown, such as sarcoidosis and rheumatoid arthritis.

SYMPATHETIC UVEITIS (SYMPATHETIC OPHTHALMIA)

Sympathetic uveitis is a T-cell-mediated, bilateral, diffuse granulomatous uveitis that occurs after penetrating ocular trauma or surgery.^1–5 The injury of ten involves uveal incarceration or prolapse. Although the inflammation may start as early as 5 days or as late as 50 years after injury, more than 90% of cases occur 3 weeks to 3 months after injury.^6,7 A review of cases submitted to the Armed Forces of Pathology before 1950 revealed phacoanaphylactic endophthalmitis, another presumed autosensitivity disease, in 25% of patients with sympathetic uveitis. Only 5% of the sympathetic uveitis cases submitted after 1950 had associated phacoanaphylactic endophthalmitis. The marked reduction in cases manifesting both diseases probably is attributable to advances in the management of penetrating wounds.

Usually, removal of the injured eye before sympathetic uveitis occurs completely protects the noninjured eye against inflammation. Rarely, sympathetic uveitis has been reported to develop in the sympathizing (noninjured) eye after the injured eye has been enucleated.⁸ Once the inflammation starts, however, removal of the exciting eye probably has little effect on the course of disease.^9,10 Some evidence suggests that the prognosis for vision may be favorably affected by early enucleation of the exciting eye. Sympathetic uveitis in nontraumatized eyes has been reported in a few isolated cases. A diagnosis of sympathetic uveitis in the absence of an ocular injury, however, should be viewed with skepticism.¹¹ Unless the whole eye is sectioned serially and examined carefully for evidence of perforation, one cannot rule out the presence of some long-since-forgotten penetrating ocular wound.

The acute onset of sympathetic uveitis generally is heralded by symptoms of blurred vision and photophobia in the sympathizing eye. Vision and photophobia worsen concurrently in the exciting eye, and a granulomatous uveitis develops. Biomicroscopy often reveals mutton-fat keratic precipitates in both eyes (Fig. 1). These precipitates consist of collections of epithelioid cells plus lymphocytes, macrophages, multinucleated giant cells, and pigment on the posterior surface of the cornea. Ocular hypertension may develop due to blockage of the angle by cellular debris or peripheral anterior synechiae. Occasionally, hypotonia occurs from decreased aqueous output by the inflamed ciliary body.

The cause appears to a delayed type of hypersensitivity reaction of the uvea to antigens localized on the retinal pigment epithelium (RPE), uveal melanocytes, and photoreceptors.¹² The lymphocytic infiltrate consists almost exclusively of T lymphocytes, mainly suppressor-cytotoxic T cells.^13–15 Sympathetic uveitis also shares many histologic features with Vogt-Koyanagi-Harada disease. The relation between the two diseases remains uncertain.^16–19

Sympathetic uveitis is a clinicopathologic diagnosis alone²⁰ (Fig. 2). There are four characteristic histologic findings of both the sympathizing and the exciting eye:

1. Diffuse uveal thickening is caused by a granulomatous inflammation composed predominately of epithelioid cells and lymphocytes. Sometimes eosinophils are plentiful, but plasma cells typically are few or moderate in number and neutrophils are rare or absent. Often the anterior segment is distorted by the trauma, and in these cases the posterior choroid is the best place to look for evidence of granulomatous inflammation.
   
2. The choriocapillaris and the posterior retina are spared from the inflammatory process.^17,21 Granulomatous inflammation may involve the ora serrata.
   
3. Many of the epithelioid cells contain phagocytosed uveal pigment.^22,23
   
4. Collections of epithelioid cells lying between Bruch's membrane and the RPE are called Dalen-Fuchs nodules. These cells are derived primarily from circulating monocytes and macrophages.¹⁴ Some of the cells may be derived from RPE cells.²⁴ Localized retinal detachments may be present, particularly overlying coalescing Dalen-Fuchs nodules.⁶
   

Granulomatous inflammation may extend into the uveal tissue that normally is present in the scleral canals and in the vicinity of the optic disc. Therefore, an evisceration that leaves behind the sclera and optic nerve does not protect a patient against sympathetic uveitis. If surgery is performed to prevent sympathetic uveitis, it must be an enucleation.²⁵

PHACOANAPHYLACTIC (PHACOANTIGENIC) ENDOPHTHALMITIS

Phacoanaphylactic endophthalmitis is a unilateral (sometimes bilateral if the lens capsule is ruptured in each eye),¹⁷ zonal granulomatous inflammation centered around lens material. It depends on a ruptured lens capsule for its development.^26–28 The disease is thought to be a result of a breakdown in tolerance to lens protein liberated through a rupture in the lens capsule.

Antibodies are formed against these lens proteins. The antibodies reach the lens remnants in the eye, and an antibody-antigen reaction called phacoanaphylactic endophthalmitis occurs. Lens protein is normally recognized by the immune system as self. The condition may be considered an autoimmune disease process that results from the breakdown or reversal of central tolerance to lens protein at the T-cell level.²⁹ Small amounts of circulating lens protein normally maintain T-cell tolerance, but tolerance may be altered pathologically as a result of trauma, possibly through the adjuvant effects of wound contamination.^16,30

Histologically, in addition to the findings of trauma sufficient to rupture the lens capsule, a zonal granulomatous inflammation is found surrounding the injured lens. Neutrophils envelop and seem to dissolve the lens protein (Fig. 3). They are surrounded by epithelioid cells and occasional (sometimes abundant) multinucleated giant cells. Lymphocytes, plasma cells, fibroblasts, and blood vessels (granulation tissue) surround the epithelioid cells. Usually, if the lens is not dislocated posteriorly by the trauma, the iris also is encased in this inflammation and inseparable from it. The uveal tract generally shows a reactive, chronic nongranulomatous inflammatory reaction. On occasion, however, the same trauma that ruptures the lens capsule and produces the phacoanaphylactic endophthalmitis also sets off a sympathetic uveitis. As surgical techniques for repairing traumatized globes have improved, these two conditions do not accompany each other as frequently as they once did.

Unlike the lens protein that escapes through a ruptured lens capsule, the lens material that leaks through an intact lens capsule in mature or hypermature cataracts presumably is denatured. This denatured protein incites a macrophagic response but apparently is incapable of acting as an antigen and eliciting an antibody response. The macrophages, swollen with their engulfed denatured lens material, may block the anterior drainage angle and cause an acute secondary open-angle glaucoma called phacolytic glaucoma.³¹

FOREIGN BODY GRANULOMAS

Foreign body granulomas may develop around exogenous foreign bodies that generally are introduced into the eye at the time of a penetrating wound (Fig. 4).^32–34 They also may develop around endogenous products such as blood, cholesterol, keratin, or lipid. Blood in the vitreous, on rare occasions, incites a foreign body inflammatory response.³⁵ When this occurs, the intravitreal hemorrhage almost invariably is traumatic in origin, rather than spontaneous. Histologically, a zonal type of granulomatous inflammatory reaction surrounds the foreign body.^33,36

VIRAL

Cytomegalic Inclusion Disease (Salivary Gland Virus)

Cytomegalic inclusion disease is caused by the cytomegalovirus (CMV), a herpes virus with a double-stranded DNA core. Congenital and acquired forms of the disease exist. Cytomegalic inclusion disease is the most common viral infection of the neonate, with an incidence of 5 to 20 per 100 live births. The congenital infection is characterized by low birth weight, jaundice, retinochoroiditis, hepatosplenomegaly, and neurologic involvement. Clinically, the central retinochoroiditis is similar to congenital toxoplasmosis except for the lack of hemorrhage in toxoplasmosis. Laboratory testing reveals thrombocytopenia, anemia, and intracranial calcifications. Most infected infants are asymptomatic at birth.

The adult form is found mainly in patients who are immunosuppressed due to chemotherapy, cancer,⁴⁰ or organ transplants⁴¹ or who are immunodeficient due to human immunodeficiency virus (HIV) infection.^42–46 CMV retinitis is the most common ocular infection in patients with acquired immune deficiency disease (AIDS). The adult acquired CMV form starts with scattered, white retinal dots or granular patches that may become confluent.^41,42 These may begin in the peripheral or central retina and are associated with sheathing of retinal vessels and retinal hemorrhages.^47,48

Histologically, a primary, coagulative, necrotizing retinitis and a secondary, diffuse, granulomatous choroiditis are seen. This choroidal infiltrate is minimal in AIDS patients with CMV retinitis. The infected retinal cells show large eosinophilic intranuclear inclusions and small, multiple, basophilic intracytoplasmic inclusions, both of which are highly characteristic of CMV.^49,50 The intracytoplasmic inclusions consist of numerous virions closely associated with dense masses of matter (PAS positive on light microscopy). The intranuclear inclusions are formed by the presence of virions within a mass of viral subunit material that forms a lacy, centrally located pattern in the nucleus.⁵⁰ The nucleolus is marginated and free of virions. Clumping of peripheral chromatin is lacking (Fig. 5).

Herpes Zoster Ophthalmicus

Ocular complications occur in more than 50% of cases of herpes zoster ophthalmicus.⁵¹ Corneal complications include dendritic ulcer (rare), ulceration, perforation, peripheral erosions, bullous keratopathy, pannus formation, stromal vascularization, hypertrophy of the corneal nerves, ring abscess, granulomatous reaction to Descemet's membrane, and endothelial degeneration. Peripheral anterior synechiae, exudate, and hyphema may be present in the anterior chamber. A chronic nongranulomatous anterior uveitis usually develops. A fibrovascular membrane of the anterior surface of the iris, posterior synechiae, and cataract formation can complicate the inflammation. A mild mononuclear infiltrate may be found in the vitreous. A perivasculitis and vasculitis may be present in the retina, optic nerve, and long posterior ciliary vessels. The varicella virus has also been detected in progressive outer retinal necrosis, an extremely rapid retinal infection found in AIDS patients.⁵² Chronic nongranulomatous inflammation is also seen in the choroid, long posterior nerves, and optic nerve meninges.⁵³ Less commonly, a granulomatous inflammation may involve the choroid. Acute and chronic inflammation of the sclera and episclera also is a complication in herpes zoster ophthalmicus.

Histologically, the most characteristic findings are the lymphocytic (chronic nongranulomatous) infiltration involving the posterior ciliary nerves and vessels, frequently in a segmental distribution. This may result in a diffuse or patchy necrosis and atrophy of the iris and pars plicata (Fig. 6). Granulomatous inflammatory lesions surrounding areas of necrosis also may be seen, most commonly in the choroid or surrounding Descemet's membrane.⁵⁴ Inclusion bodies have not been demonstrated in the chronic inflammatory lesions.^55,56

BACTERIAL

Mycobacteria

TUBERCULOSIS (Mycobacterium tuberculosis). The hematogenous spread of the tubercle bacilli from the lungs is the major route for intraocular infection. HIV-infected patients are at high risk for infection. The most common form of ocular involvement with tuberculosis is a uveitis (choroidal tubercles are most common) that may spread to involve the retina.^57–59 The involvement may become massive to form a large tuberculoma involving all coats of the eye (panophthalmitis). Clinically, mutton-fat keratic precipitates are seen on the posterior surface of the cornea. Histologically, the classic pattern of caseation necrosis consists of a zonal type of granulomatous reaction around the areas of coagulative necrosis. A smooth, acid-fast bacillus can be demonstrated by special stains.⁶⁰

LEPROSY (Mycobacterium leprae). There are two forms of leprosy, lepromatous leprosy and tuberculoid leprosy.

In lepromatous leprosy, the lepromin test (analogous to the tuberculin test) is negative, suggesting little or no immunity. The prognosis is poor. Lepromas of the skin result in leonine facies and neurologic changes. Most often, the anterior portion of the eye is involved with inflammation.^61–63 Histologically, a diffuse type of granulomatous inflammation containing lepra cells, histiocytes with amorphous cytoplasm, and Virchow cells, histiocytes with vacuolated cytoplasm, is present, mostly in the anterior portion of the eye. This is thought to be due to the fact that the bacteria grow better in the cooler anterior portion than the warmer posterior portion of the eye, similar to the skin being more involved than deeper structures of the body.

In tuberculoid leprosy, the leproma test is positive, suggesting immunity. The prognosis is good. A neural involvement predominates, with hypopigmented (vitiliginous), hypoesthetic lesions and thickened nerves. The ulnar nerve is particularly vulnerable, leading to the characteristic claw hand. The ocular adnexa and orbital structures are involved, especially the ciliary nerves, but not the eyeballs. Histologically, a discrete (sarcoid, tuberculoid) type of granulomatous inflammatory reaction is seen, centered mainly around nerves. The individual nodules tend to be of much more varied sizes than those in sarcoidosis or miliary tuberculosis. Because there is good immunity, organisms are much harder to find and are generally located in an area of nerve degeneration.

NONTUBERCULOUS MYCOBACTERIA (Mycobacterium chelonei, M. fortuitum, M. avium-intracellulare).

These opportunistic organisms can cause periocular infection,⁶⁴ keratitis,⁶⁵ granulomatous uveitis, which may be asymptomatic if in the choroid, or a panophthalmitis. The infection is seen most often in immunocompromised patients. Histologically, discrete granulomatous inflammation within the uvea or inflammatory, necrotic masses may be present. Acid-fast bacilli are detected within the cytoplasm of macrophages as well as free within the necrotic tissue (Fig. 7).⁷⁴

Spirochetes

LYME DISEASE. There are three overlapping chronologic stages of Lyme disease, caused by the spirochete Borrelia burgdorferi.⁶⁷ The bacteria are transmitted by the Ixodes dammini tick. Within 4 to 20 days of a tick bite, the first stage is heralded by a red rash, erythema migrans, at the site of the bite. Flulike symptoms, including fever, swollen lymph nodes, and malaise, are often present at this stage. ocular findings at this stage may include a follicular conjunctivitis. The second state of the disease occurs weeks to months later and has systemic findings, including skin lesions, cardiac and central nervous system symptoms, and arthritis. At this stage ocular signs may include blepharoconjunctivitis, bilateral granulomatous uveitis, neuroretinitis, cranial nerve palsies, and pupil abnormalities. Stage three can occur months to years after a disease-free period and is characterized by Lyme arthritis, which occurs in more than 50% of untreated patients. Central nervous system disease and keratitis, scleritis, and extraocular muscle inflammation may occur. Enzyme-linked immunosorbent assays, Western blot analysis, or PCR can detect antibody against the Borrelia antigens.⁶⁸

SYPHILIS (Treponema pallidum). Both the congenital and acquired forms of syphilis may produce a nongranulomatous interstitial keratitis or anterior uveitis.^69,70 The common form of posterior uveitis is a smoldering, indolent, chronic, nongranulomatous inflammation. It is characterized by disseminated, large, atrophic scars surrounded by hyperplastic RPE. A more virulent type of uveitis may occur with a granulomatous inflammation.⁷¹ Both the nongranulomatous and the granulomatous forms of uveitis often involve the overlying retina⁷² and can also involve the anterior uvea.⁷³ When anterior chamber involvement occurs, spirochetes may be obtained by aspiration of aqueous from the anterior chamber. The uveitis often occurs during the secondary and tertiary phases of the infection, when skin lesions and central nervous system findings are present (Fig. 8). Histologic findings in the nongranulomatous disseminated form of posterior choroiditis include atrophy and scarring of outer retinal layers, RPE, and inner choroidal layers. Scattered lymphocytes and plasma cells may be present. Dehiscences in Bruch's membrane may occur, through which retinal elements may invade the choroid. Bruch's membrane may be folded into the atrophic, sclerosed choroid. The treponema spirochetes can be demonstrated in the ocular tissue with special stains, often in areas devoid of inflammatory cells. In the granulomatous form of posterior chorioretinitis, the inflammatory process generally involves the choroid and overlying retina and is quite vascular. Epithelioid cells, lymphocytes, and plasma cells are seen. Treponemas can be demonstrated in the inflammatory tissue with the Warthin-Starry stain.

Streptothrix

Actinomyces and Nocardia organisms are responsible for Streptothrix infection of the lacrimal sac and a chronic form of conjunctivitis. The organisms are gram-positive and weakly acid-fast bacteria.⁷⁵ Histologically, the organisms are seen as delicate, branching, intertwined filaments surrounded by necrotic tissue (Fig. 9). Occasionally, giant cells are seen, but usually there is little inflammatory component. The colonies can be seen macroscopically as gray or yellow “sulfur” granules.

Cat-Scratch Disease

Bartonella henselae (formerly Rochalimaea henselae)⁷⁶ can cause Parinaud's ocular glandular fever, neuroretinitis, and orbital infiltrates. Cat-scratch disease is a subacute regional lymphadenopathy and can have systemic manifestations, including an antecedent flulike illness, splenomegaly, mediastinal masses, and encephalopathy. B. henselae, a pleomorphic gram-negative rod, is also thought to be the causative agent of bacillary angiomatosis and trench fever. In immunodeficient patients, it can cause a retinitis that is indistinguishable from CMV retinitis.⁷⁷ A scratch from a cat or kitten or a bite from the cat flea can cause the disease. Cat-scratch disease antigen skin tests, indirect fluorescent antibody tests, blood tests, and PCR may be helpful in diagnosing the disease.^78–80 Histologically, a discrete granulomatous inflammation can be seen within lymph nodes with organisms detected by the Warthin-Starry stain.⁸¹

TULAREMIA (Francisella tularensis). The granulomatous conjunctivitis and regional (preauricular) lymphadenopathy caused by tularemia is called Parinaud's oculoglandular syndrome. The organism is very difficult to culture, and thus diagnosis is made by serologic testing. Organisms are transmitted to humans through insect bites.⁸²

WHIPPLE DISEASE (Tropheryma whippelii). Whipple disease may cause a chronic bilateral granulomatous uveitis, vitreous hemorrhage, or optic nerve swelling. The organisms are PAS-positive, diastase-resistant bacilli. The organism has been identified histopathologically in a vitrectomy specimen. PCR may also be helpful in confirming the diagnosis.⁸³

FUNGAL

Phycomycosis (Mucormycosis, Zygomycosis)

The human infection phycomycosis is caused by the genera Mucor and Rhizopus in the class of fungi Phycomycetes. The infection is most commonly found in patients with severe acidosis, most often due to diabetes but also to diarrhea, burns, or immunosuppression. The fungi have a predilection for blood vessels and can infect the eyelids, eyeball, and orbit.⁸⁴

Histologically, the broad, nonseptate hyphae are readily seen on hematoxylin-and-eosin staining within thrombosed blood vessels.⁸⁵ Nongranulomatous and granulomatous as well as acute suppurative inflammation may be present (Fig. 10).

Candidiasis

Candida albicans may cause a keratitis or a chorioretinitis that may extend to become an endophthalmitis if systemic antifungal therapy is delayed.^86,87 The endophthalmitis is most likely to occur in patients with an underlying disease that has rendered them immunologically deficient.^88,89 The increased incidence of disseminated candidiasis in recent years correlates with the use of modern chemotherapy and with the emergence of AIDS. Histologically, budding yeasts and pseudohyphal forms usually are seen surrounded by a chronic nongranulomatous reaction, but sometimes they are seen surrounded by a granulomatous reaction.⁸⁶

Blastomycosis, cryptococcus, coccidioidomycosis, aspergillosis, and histoplasmosis are all systemic fungal infections that can spread to the eye. Most often the primary infection is pulmonary.^88,90,91 Often the patients are immunosuppressed or immunodeficient.⁹² There may be eyelid,⁹³ corneal, uveal,^94,95 or orbital⁹⁶ involvement or a panophthalmitis. Organisms have been identified within a diffuse, zonal granulomatous infection in the uvea (Fig. 11).

The main ocular manifestation of rhinosporidiosis (Rhinosporidium seeberi) is a lid or conjunctival infection.^98,99 Large sacs or spherules are filled with spores. A nongranulomatous or, less likely, granulomatous inflammation may surround the organisms.

Ocular involvement in sporotrichosis (Sporothrix schenkii) is usually the result of direct extension from primary cutaneous lesions of the lid and conjunctiva eroding into the eye and orbit. Less frequently, the ocular and adnexal lesions result from hematogenous dissemination of the fungus.¹⁰⁰ The organisms are found surrounded by a granulomatous inflammation.

PARASITIC

Toxoplasmosis

The definitive host of the intracellular protozoan Toxoplasma gondii is the cat, but many intermediate hosts (e.g., humans, rodents, and fowl) are known. The parasite primarily invades retinal cells directly. Both congenital and acquired forms of toxoplasmosis are recognized.¹⁰¹ 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 the fetus.¹⁰² If she is dye-negative at the beginning of pregnancy, there is some risk of her transmitting toxoplasmosis to the fetus if she acquires the disease during pregnancy. There is a 14% chance that the child will show severe manifestations of the disease. If toxoplasmosis is acquired during the first trimester of pregnancy, it may cause activation of ocular disease in the mother.

The acquired form of toxoplasmosis usually presents as a posterior uveitis.^103,104 The acquired form may occur in persons who have immunologic abnormalities of many types.¹⁰⁵ Histologically, the protozoa are found in three forms: free, in pseudocysts, or in true cysts.¹⁰⁶ They usually are seen in an area of coagulative necrosis of the retina.¹⁰⁷ The underlying choroid (and sometimes sclera) contains a secondary diffuse granulomatous inflammatory infiltrate.^108,109

In rare instances, the protozoa may be found free within the retina. Commonly, a protozoan enters a retinal cell and multiplies within 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 formation being called a pseudocyst. An intracellular protozoan may surround itself by a self-made membrane, multiply, and then form a true cyst that extrudes from the cell and lies free in the tissue. True cysts are found in the late stage of the disease, at the time of remission (Fig. 12).

Nematode

TOXOCARIASIS. Ocular toxocariasis is a manifestation of visceral larva migrans, the larva of the nematode Toxocara canis. Toxocariasis generally involves one eye and usually occurs in children 6 to 11 years of age. Often, the child's history shows that the family owns a puppy rather than an adult dog. Nematodiasis is not a correct term for the condition because nematodes other than Toxocara, such as Onchocerca, also can infest the eye. Three ocular forms of the condition may exist: leukocoria with multiple retinal folds radiating out toward the peripheral retina, where the necrotic worm is present; a discrete lesion, usually in the posterior pole and seen through clear media; and a painless endophthalmitis. In all three forms, the eye is not inflamed externally; the only complaint is loss of vision. Although the condition presumably follows widespread migration of larvae, only one eye is involved and only one worm can be found. No inflammatory reaction occurs until the worm dies. The eosinophil appears to be the major killer of T. canis.¹¹⁰ Toxocaral fluorescent antibody tests may be helpful in diagnosing toxocariasis.^111,112 Histologically, a zonal granulomatous inflammatory infiltrate is present. An abscess containing eosinophils, neutrophils, and necrotic debris surrounds the necrotic worm.¹¹³ Granulomatous inflammatory tissue surrounds the abscess (Fig. 13).¹¹¹

TRICHINOSIS. The nematode Trichinella spiralis is acquired by eating undercooked meat, usually pork that contains the trichina cysts. Clinically, the lids and extraocular muscles may be involved as the larvae migrate systemically.¹¹⁴ 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 reaction results around the worm.

LOA LOA. The adult Loa loa filarial worm wanders in the subcutaneous tissues. It may wander into the periorbital and lid tissues, and often into the subconjunctival tissue, where its size and long, slender shape make it easily visible.¹¹⁵ Little inflammatory reaction occurs while the worm is alive.

OTHER NEMATODES. Diffuse unilateral subacute neuroretinitis¹¹⁶ (DUSN; unilateral wipeout syndrome) may be caused by a motile subretinal roundworm, most likely a nematode but probably not T. canis. The raccoon roundworm larva, Baylisascaris procyonis,¹¹⁷ and the larval form of certain flies, most commonly Cuterebra,¹¹⁸ are possible causes of DUSN and of visceral larva migrans. 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. Over a period of many months, widespread, diffuse, and focal depigmentation of the RPE develops, accompanied by retinal artery narrowing, optic atrophy, severe vision loss, and an abnormal electroretinogram. Focal laser photocoagulation of the worm can be performed with little increase in inflammation if it can be identified.^119,120 Worms seen in the fundi of patients from the southern United States seem about half the size of those seen in patients from the northern United States.^121,122

Tapeworm

CYTICERCOSIS.Cyticercus 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. The bladderworm has a predilection for the central nervous system and eyes. It is the most common ocular tapeworm infection. It induces no inflammatory response when alive.¹²³ The prognosis in untreated cases is uniformly poor. Histologically, the necrotic bladderworm is surrounded by a zonal granulomatous inflammatory reaction that generally contains many eosinophils. Early surgical removal provides the best chance for cure, although destruction of the parasite in situ by diathermy, light coagulation, or cryoapplication also may prove successful.^123–125

HYDATID CYST. The oncospheres of the dog tapeworm Echinococcus granulosus may enter humans and form a cyst called a hydatid cyst that contains the larval form of the tapeworm.¹²⁶ In this form, the tapeworms appear as multiple scoleces with hooklets. Each scolex is the future head of an adult tapeworm. In humans, the tapeworm has a predilection for the orbit. On histologic examination, multiple scoleces are seen adjacent to a thick, acellular, amorphous membrane that represents the wall of the cyst (Fig. 14).

COENURUS. Coenurus is a large, single bladderworm (larval cyst stage) of Multiceps multiceps, 5 cm or more in diameter. It contains several hundred scoleces. The bladderworm may involve the subconjunctival or orbital regions or occur within the eye.¹²⁷ The definitive host of the adult tapeworm is the domestic dog, although it may be found in other animals. The larval stage usually is found in sheep, but primates can be accidental intermediate hosts. Histologically, multiple inverted scoleces are seen lining up against an outer cuticular wall.

Schistosomiasis

The trematode Schistosoma (S. haematobium, S. mansoni, and S. japonicum), which is endemic in some areas of the world, can cause a chronic conjunctivitis or blepharitis. The eggs of schistosomes hatch in water into miracidia that penetrate snails, undergo metamorphosis, and form cercariae. The cercariae emerge from the snails and enter the skin of humans as metacercariae or adolescariae. The eggs and necrotic adult worms incite a marked zonal granulomatous inflammatory response.¹²⁸

SARCOIDOSIS

Sarcoidosis is a systemic disease that primarily affects black people, with equal sex incidence. Systemic findings include bilateral hilar adenopathy, 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,¹²⁹ osteolytic lesions of distal phalanges, and central nervous system findings such as seventh-nerve palsy, encephalitis, arachnoiditis, and basilar meningitis.

Ocular involvement occurs with a prevalence of 25% to 50%. The most common ocular manifestation of sarcoidosis is an anterior uveitis that occurs in about 20% of people with sarcoidosis. Mutton-fat keratic precipitates characteristically accompany the anterior uveitis. Other anterior ocular findings include millet-shaped eyelid nodules, 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), and secondary closed-angle glaucoma.

Posterior ocular findings may include retinochoroid granulomas, peripheral retinal neovascularization (sea-fan),¹³⁰ neovascularization of the optic nerve, optic disc edema, optic neuritis, retinal periphlebitis, “candle wax drippings” on or near retinal vessels, retinal hemorrhage, and whitish masses in the dependent portion of the vitreous. The retinal form of sarcoidosis is rare, and it carries a grave prognosis for life because it often is associated with central nervous system sarcoidosis.^131,132 Proptosis,¹³³ orbital granulomas,¹³⁴ and extraocular muscle palsies¹³⁵ are also seen.

The Kveim test appears to be based on an immunologic reaction associated with persistent lymphadenopathy of diverse causes and is not specific to sarcoidosis. Elevated serum or tear angiotensin-converting enzyme levels¹³⁶ and, to a lesser extent, serum collagenase levels may be helpful in assessing the activity of sarcoidosis.^137,138 Hahzaki-Wesenberg bodies may be found in macrophages or free in peripheral portions of lymph nodes in patients with sarcoidosis, isolated lymphoid tumors, or hyperplastic lymph nodes associated with carcinoma of the head and neck. The bodies are a form of ceroid and not, as thought previously, bacteria or other infectious agents. They are not, therefore, pathognomonic for sarcoidosis. Small granulomas may be present histologically in the submucosa of the conjunctiva even without visible clinical lesions. The yield of positive lesions is higher, however, if a nodule is seen clinically. A biopsy of conjunctiva from the lower cul-de-sac may help to establish the diagnosis of sarcoidosis even when there are no clinically visible lesions. 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 (about six to eight sections) on each slide from the three levels. From the resultant 18 to 24 sections, granulomas may be found in only 1 or 2 sections.^139–141

Histologically, a noncaseating, granulomatous, inflammatory infiltrate of the discrete (sarcoid, tuberculoid) type, frequently with foreign body giant cells, is found.^142,143 Most of the granulomatous nodules are approximately the same size. Slight central necrosis may be seen, but caseation is rare. Star-shaped, acidophilic bodies (asteroids) and spherical or ovoid, basophilic, calcific, frequently laminated bodies (Schaumann's bodies) may be found in epithelioid or giant cells. They may also be seen in conditions other than sarcoidosis (Fig. 15).

GRANULOMATOUS SCLERITIS

Granulomatous scleritis is associated with rheumatoid arthritis^144–146 or other systemic immune-mediated diseases¹⁴⁷ in about 15% of patients, but about 45% of patients with scleritis have a known systemic condition.¹⁴⁸ Histologically, a zonal type of granulomatous inflammatory infiltrate surrounds a nidus of necrotic scleral collagen. Typically, the inflammation is in the sclera between the limbus and the equator. 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. An intense nongranulomatous anterior uveitis may accompany the scleritis. Pseudorheumatoid nodule (granuloma annulare) is a necrobiotic granuloma that usually occurs in the episclera and orbit (Fig. 16).¹⁴⁹

GRANULOMATOUS REACTION TO DESCEMET'S MEMBRANE

In about 10% of eyes with corneal ulcer or keratitis examined histologically, a granulomatous reaction to Descemet's membrane is found. Most frequently, the corneas have a disciform keratitis with or without a history of herpes simplex or zoster keratitis.^150–152 The peculiar reaction to Descemet's membrane may be the result of altered antigenicity of the membrane and subsequent development of an autosensitivity reaction (Fig. 17).

VOGT-KOYANAGI-HARADA SYNDROME (UVEOMENINGOENCEPHALITIC SYNDROME)

Vogt-Koyanagi-Harada syndrome is a multisystem disorder that reflects the integration of Vogt-Koyanagi syndrome with Harada's disease.^153,154 Vogt-Koyanagi syndrome consists of a severe, acute, often bilateral anterior uveitis associated with vitiligo (leukoderma), poliosis (whitened hair or canities), alopecia, and dysacusis. Harada's disease consists primarily of a posterior granulomatous uveitis, usually bilateral, which is associated with bilateral serous retinal detachments.¹⁵⁵ These ocular signs are accompanied by fluctuating meningeal symptoms, both central and peripheral. The cerebrospinal fluid shows increased protein levels and pleocytosis. Sugiura's sign, perilimbal vitiligo, may be present.¹⁵⁶ The disease is more common in women and has a predilection for darkly pigmented races.¹⁵⁷

Autoaggressive cell-bound responses to uveal pigment and genetic influences¹⁵⁸ may play a role in the histogenesis of Vogt-Koyanagi-Harada syndrome. Also, T lymphocytes are decreased in the peripheral blood.^159,160 Histologically, there is a chronic, diffuse, granulomatous uveitis that closely resembles sympathetic uveitis.^{14,18,154,161} The uveal infiltrates are composed of T lymphocytes. Melanocytes are thought to be the autoimmune target of this inflammation. 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 retina. An accompanying disciform degeneration of the macula is common.¹⁶²

FAMILIAL CHRONIC GRANULOMATOUS DISEASE OF CHILDHOOD

Familial chronic granulomatous disease of childhood is characterized by chronic suppurative lymphadenitis, eczematoid dermatitis, osteomyelitis, hepatosplenomegaly, pulmonary infiltrates, and abscesses of soft tissue caused by saprophytic organisms. Chorioretinitis may be a common finding.¹⁶³ The disease has an uncertain inheritance pattern.¹⁶⁴ Pigmented lipid histiocytes and hypergammaglobu-linemia are features.¹⁶⁵ Humoral immunity, cell-mediated immunity, and inflammatory responses are normal. The polymorphonuclear leukocytes in these patients ingest bacteria but do not kill them because of a deficiency in leukocyte hydrogen peroxide production. Further, lysosomal hydrolytic enzymes (acid phosphatase and β-glucuronidase) are released in decreased amounts by neutrophils during phagocytosis, resulting in abnormal (lessened) degranulation of the neutrophils.

Histologically, suppurative and granulomatous inflammatory lesions characteristically coexist. The suppurative component may be secondary to infection, whereas the granulomatous component is in response to living or inert intracellular organisms or debris.

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