Many different components make up the immune system, including cellular elements such as neutrophils, lymphocytes, and macrophages, and soluble elements such as cytokines, complement, and antibodies. Each of these components has unique but interdependent functions within the immune system. For example, cytokines (i.e., small proteins that serve as intercellular signals) such as interleukin-2 (IL-2) are produced by leukocytes to stimulate and attract other cellular elements to the area of an insult. These recruited cells then produce additional cytokines, antibodies, and so forth, which act to contain and destroy the stimulus. These components are required for normal functioning of the immune system.

MAJOR HISTOCOMPATIBILITY COMPLEX

The major histocompatibility complex (MHC) is a region of genes that encodes for the production of small proteins found on the surface of cells. These proteins serve to present antigen in a recognizable form to other effector cells of the immune system, such as T lymphocytes. The term major histocompatibility complex is derived from the original description of these molecules in relation to their function in the rejection of transplanted tissues. The MHC system is made up of three subclasses: I, II, and III. All are located on chromosome 6. MHC class I molecules are found on all nucleated cells. This molecule class functions in the regulation of the actions of CD8+ cytotoxic T cells, especially in the defense against viral infection. Viral antigen present within a cell is processed and presented on the cell surface in association with an MHC class I molecule. This presentation serves to activate CD8+ T cells (see description below) to destroy the infected cell, thus preventing further viral production. MHC class II molecules are present only on certain cells of the immune system, such as macrophages and other antigen-presenting cells. Processed antigen is presented in association with MHC class II molecules to CD4+ helper T cells. MHC class III molecules consist of complement and are not true histocompatibility markers. These molecules play a role in the recruitment of neutrophils and other inflammatory cells and in the amplification of the inflammatory process.

The MHC system in humans is termed the human leukocyte antigen (HLA) system, because these molecules were first discovered on the surface of leukocytes. In the human, MHC class I antigens consist of HLA types A, B, and C. MHC class II molecules consist of HLA type D. It is now known that HLA molecules play an important role in an organism's susceptibility to certain inflammatory diseases. The exact mechanism by which HLA molecules predispose an individual to disease is not known, but several theories exist that are summarized in Table 1.

TABLE 1. Proposed Mechanisms of Human Leukocyte Antigen Disease Association

  Unique presentation of disease-inducing peptide
  Errors in development of the T-cell receptor repertoire
  Infectious agents that carry a molecular mimic of a self peptide
  Unmasking sequestered antigens that bind upregulated class II

INFLAMMATORY CELL TYPES

The hallmark of acute inflammation is the polymorphonuclear leukocyte, or neutrophil. The most numerous of the circulating leukocytes, neutrophils live an estimated 2 to 3 days in circulation. Their primary function is in phagocytosis of foreign material. Neutrophils are attracted by C5a (an activated complement component), IL-8, fibrin breakdown products, and neutrophil chemotactic factor, as well as other substances.¹

Lymphocytes are the hallmark of chronic inflammatory infiltrates, although they may be present from the onset of inflammation. Lymphocytes are divided into B and T types as well as natural killer cells. After their production in the bone marrow from pluripotent stem cells, B and T lymphocytes undergo differentiation in the fetal liver/adult bone marrow and thymus, respectively. It is here that these cells gain the ability to recognize antigen. T cells are characterized by the presence of T-cell receptors (TCRs) on their surface, of which two main types exist. TCR-1 cells (5% to 10% of circulating T cells) function primarily as cytotoxic cells. TCR-2 cells (90% to 95% of circulating T cells) can be further divided into those that carry the CD4 surface marker and recognize antigen in the context of MHC class II molecules and those that carry the CD8 marker and recognize antigen in association with MHC class I molecules. The CD4 positive subset of T cell, also know as the helper T cell, can again be further subdivided into Th1 and Th2 type cells. Th1 cells produce IL-2 and interferon-γ and promote the functions of cellular immunity. Th2 cells produce IL-4, IL-5, IL-6, and IL-10, which help regulate the functions of macrophages and stimulate B cells to produce antibodies (humoral immunity).^1,2

After stimulation by helper T cells in association with binding to their target antigen, B cells produce specific antibody directed to the antigen recognized. Further stimulation leads to their differentiation into plasma cells. As plasma cells produce antibodies, they may accumulate excess amounts within their cytoplasm, producing amorphous eosinophilic structures, referred to as Russell bodies.

Mononuclear cells provide important functions in the areas of antigen presentation and phagocytosis. Mononuclear cells are widely distributed in the body, both in circulating form as well as resident tissue monocytes/macrophages such as Kupffer cells in the liver, alveolar macrophages in the lung, serosal macrophages, and microglia in the brain and retina.¹

In addition to the above cell types, eosinophils and basophils/mast cells participate in immune reactions as well, usually in relation to allergic stimuli or parasitic invasion (Fig. 1A).

TABLE 2. Features of Selected Cytokines

A more complete discussion of the various components of the immune system, the inflammatory cascade as it relates to the ocular environment, and its unique modifications is contained elsewhere in this series.

RELATION TO ORGANISM

Stimuli can be classified as exogenous (i.e., coming from outside the organism) or endogenous (i.e., coming from within the organism). Under this scheme, a septic emboli from an infected heart valve that lodges in the eye and produces a bacterial endophthalmitis would be termed endogenous, whereas an acute bacterial endophthalmitis occurring after cataract surgery would be termed exogenous, even though both might be caused by the same bacterial species. This scheme is useful in helping to emphasize whether the source is within the organism, prompting an evaluation to identify this source.

ANATOMIC

Here the portion of the eye that is primarily involved in the inflammatory process is used with the modifying suffix -itis to characterize the disease process. Thus, involvement of the cornea with an inflammatory process secondary to herpes simplex is a keratitis, whereas the same viral organism, affecting the retina, becomes a herpetic retinitis (also known as acute retinal necrosis). (Conditions may have multiple names; some developed before the actual etiology of the condition were fully elucidated.) Similarly, one can have an iridocyclitis, vasculitis, papillitis, choroiditis, scleritis, or myositis, for example. When more than one anatomic structure is involved, anatomic terms can be combined, resulting in entities such as keratouveitis, sclerouveitis, and retinochoroiditis. The structure primarily involved is listed first, followed by those with secondary involvement. Further modifying terms such as multifocal, focal, and diffuse also can be used. When an inflammatory process involves an ocular cavity and its adjacent structures, the term endophthalmitis is used. When the inflammatory process extends to involve the outer coats of the eye, Tenon's capsule, and orbit, the term panophthalmitis is used.¹² Although not necessarily infectious processes, panophthalmitis and endophthalmitis are used most often in this context. Exceptions such as phacoanaphylactic endophthalmitis or “sterile” endophthalmitis exist.

ETIOLOGIC AGENT

Inflammation within the eye may be induced by any number of sources, exogenous or endogenous, as detailed above. When caused by an endogenous noninfectious condition, the actual process at work may not be known or may be associated with a systemic condition or marker, such as HLA-B27-associated anterior uveitis. When caused by an infectious condition, any microbial agent can serve as the initiating organism, including bacteria, fungi, viruses, protozoa, and helminths. It obviously is important to differentiate infectious from noninfectious causes, as the former causes are potentially curable with appropriate antimicrobial therapy.

TEMPORAL COURSE AND HISTOPATHOLOGIC PATTERN

When faced with a condition of uncertain etiology, samples of intraocular fluids; tissues such as iris, retina, and choroid; or both can be obtained.^13,14 It is in these situations that the ophthalmic pathologist can be of maximal benefit by helping to establish the pattern of inflammation present, as well as the presence of any infectious agents. The advent of modern molecular biologic techniques such as in situ hybridization, polymerase chain reaction, and in situ polymerase chain reaction now allows detection of specific DNA sequences from infectious organisms within the tissue or fluid^15,16 and will no doubt be of increasing importance in ocular diagnosis.

In these situations, the inflammatory condition may be characterized by its time course and characteristic cellular makeup into acute inflammation and chronic inflammation. In acute inflammation, the onset of disease typically is sudden with rapid onset of pain, photophobia, and decreased visual acuity. Based on the histopathologic pattern, acute inflammation can be further divided into acute suppurative inflammation, such as in an infectious endophthalmitis due to virulent bacteria after cataract surgery; or acute nonsuppurative inflammation, such as in an HLA-B27-associated anterior uveitis (see Fig. 1) or Behçet's disease (BD). Suppurative inflammation is characterized predominately by the presence of neutrophils and their byproducts, collectively known as pus. Suppurative inflammation is characteristic of acute bacterial infections, such as the case mentioned of acute postoperative bacterial endophthalmitis. Certain bacterial species such as staphylococci commonly produce this type of inflammation and are referred to as pyogenic (pus-producing) bacteria. Conversely, acute nonsuppurative inflammation is that which does not produce a purulent material. The predominant cell type in acute nonsuppurative inflammation remains the neutrophil, but there is no formation of purulent material.

In contrast to acute inflammation, with chronic inflammation, the onset of disease typically is slower, such as in a Propionibacterium acnes endophthalmitis, in which signs of persist inflammation may not appear until several weeks after surgery. Whatever the etiology of the inflammation, when it persists for an extended period, typically longer than 6 weeks in cases of uveitis, it is termed chronic. Based again on histopathologic pattern, chronic inflammatory processes can be divided into the two broad categories of chronic granulomatous inflammation and chronic nongranulomatous inflammation. Granulomatous inflammation is typified by the formation of granulomas, with the presence of epithelioid histiocytes against a background of lymphocytes and plasma cells. Multinucleated giant cells may or may not be present. This tissue pattern is produced in response to certain bacterial or fungal infections such as Mycobacterium tuberculosis and Aspergillus as well as noninfectious processes such as retained foreign bodies, lipid extrusion from a ruptured chalazion, and sarcoidosis. Chronic nongranulomatous inflammation thus is defined by the lack of these findings, with the predominate feature being an infiltration of lymphocytes and plasma cells.

Acute nongranulomatous uveitis typically does not result in the need for enucleation or even biopsy; therefore, histopathologic examination of human eyes in the acute stages of the disease is rare. When enucleation is needed, it usually is at the end stage of the disease, when all attempts to preserve vision or comfort or both have failed. Thus, most histopathologic descriptions of human uveitis are from chronically inflamed eyes and show mostly an infiltration with chronic inflammatory cells (Fig. 2). Most of the information regarding events in acute uveitis has been gained from the use of various animal models of uveitis. Several models exist, but all are based on a similar principle: that of bypassing the normally existing state of self-tolerance and stimulating an organism to attack its own ocular tissues. This is accomplished by the subcutaneous inoculation of various substances (including retinal S antigen, interphotoreceptor retinoid-binding protein [IRBP], and melanin-associated proteins) into laboratory animals. A variable period later, depending on the specific model, uveitis develops, which can then be studied. In experimental autoimmune anterior uveitis, inoculation of Lewis rats with melanin-associated proteins produces primarily anterior segment disease,^17–20 with minimal retinal involvement. Perhaps the most widely studied animal model of endogenous posterior uveitis is experimental autoimmune uveoretinitis (EAU), induced by the inoculation of either the retinal S antigen or IRBP into susceptible strains of animals. Other models of uveitis include bacterial product-induced intraocular inflammation. In endotoxin-induced uveitis, injection of bacterial endotoxins directly into the vitreous cavity or systemically produces inflammation localized primarily to the anterior segment in Lewis rats.²¹

Early events in EAU include expression of adhesion molecules on the surface of retinal vascular endothelium, allowing the adherence of circulating leukocytes and subsequent infiltration into the retina.^22,23 In Lewis rats, the acute cellular infiltrate is composed of neutrophils and primarily affects the retina (Fig. 3) and anterior segment.²⁴ CD4+ T cells have been found necessary for the development of EAU²⁵ and are stimulated by presentation of antigen in the setting of MHC class II-expressing cells.²⁶ There is likely a genetic susceptibility to the development of EAU,²⁷ which may help explain occurrence of uveitis in only certain individuals. Once initiated, much of the damage resulting from EAU, and most likely in human uveitis, is caused by the production of numerous oxygen-derived radicals (e.g., superoxide, hydrogen peroxide, hydroxyl radicals, peroxynitrite), which directly attack the photoreceptor layer, producing oxidative damage to these sensitive light-sensing cells.^28–30

REPRESENTATIVE NONGRANULOMATOUS HUMAN UVEITIC ENTITIES IN WHICH PATHOLOGY IS KNOWN

Behçet's Disease

Behçet's disease is a systemic inflammatory disease predominantly involving the skin, genitalia, and eyes, where it may manifest as a panuveitis. The disease is most commonly encountered in Japan and in the Mediterranean basin area, along the historic “silk route,” an ancient trade route that connected China and imperial Rome, initially developing between 100 BC and the fifth century AC. Disease characteristics and severity vary among patients from different geographic locations, specifically inside or outside the silk route. At least five different sets of diagnostic criteria have been proposed; therefore, an international consensus classification was developed and published in 1991 (Table 3).³¹

TABLE 3. Behçet's Disease Diagnostic Criteria*

  Diagnosis requires the presence of:

  Recurrent oral ulceration

  Minor aphthous, major aphthous, or herpetiform ulceration observed by physician or patient, which recurred at least 3 times in one 12-month period and at least two of the following:

  Aphthous ulceration or scarring, observed by physician or patient

  Anterior uveitis, posterior uveitis, or cells in vitreous on slit-lamp examination; or retinal vasculitis observed by ophthalmologist

  Erythema nodosum observed by physician or patient, pseudofolliculitis, or papulopustular lesions; or acneiform nodules observed by physician in postadolescent patients not receiving corticosteroid treatment

  Read by physician at 24---24 hours

According to some reports, an association with HLA-B51 is present in 81% of Asian patients versus 13% of white patients.³² The pathogenic significance of HLA-B51 is unknown. It has been shown by polymerase chain reaction methods that the pathogenic gene may exist near the HLA-B region, probably between it and the tumor necrosis factor (TNF) region.³³ Selected human heat shock protein (HSP)-derived peptides (specifically from a 60-kd HSP) show some homology to microbial HSPs and may act as epitopes for T-cell activation in BD.^32,34–37 These human epitopes are uveitogenic when injected in Lewis rats with an adjuvant.³⁷ One suggested mechanism for BD is that repeated exposure to an antigen may result in positive selection of antigen-specific T cells. Through molecular mimicry mechanisms, these T cells may recognize human HSPs, among other targets, as their autoantigens and therefore initiate an inflammatory response against them.³² The HLA-B51 phenotype itself seems to promote neutrophil hyperfunction, as evident by hyperactive chemotaxis of neutrophils from HLA-B51-positive patients.³⁸ Similarly, the ability of neutrophils to generate superoxide seems to correlate with the presence of the B51 phenotype, regardless of the presence of BD.³⁸ T lymphocytes of patients with BD have a lower threshold for production of interferon gamma than do those of control subjects when exposed to low concentrations of staphylococcal enterotoxins. Thus, these patients have an antigen-inspecific T-cell hyperreactivity, with abnormalities in signal transduction triggered by perturbation of TCRs, which may play a role in the pathogenesis of BD.³⁹

A Japanese national survey of BD has shown that ocular symptoms occur in 86% of patients with BD.⁴⁰ Common clinical presentations include anterior uveitis with hypopyon (Fig. 4), vitritis, retinal vasculitis (Figs. 5 and 6), and chronic ischemic optic neuropathy. The hypopyon in BD has been shown to be composed of neutrophils⁴¹ and, in its later stages, lymphocytes as well.⁴² The disease tends to have a remitting-relapsing clinical course and carries a high potential for visually devastating complications.

Histopathologic data about Behçet's uveitis come from a few pathologic reports on enucleated, blind, painful eyes with chronic disease.⁴³ Light microscopy usually shows a panuveitis with infiltrating polymorphonuclear leukocytes, lymphocytes, plasma cells, and macrophages (Fig. 7). Immunohistochemical studies have shown a perivascular choroidal infiltration of activated CD4+ , but not CD-8+ , T cells,^44,45 as well as focal aggregates of B cells and plasma cells, with increased expression of cell adhesion molecules on vascular endothelial cells.⁴³ These findings imply a mixture of cellular and humoral components in the pathogenesis of Behçet's ocular vasculitis, in which CD4+ cells activate B cells, resulting in enhanced local production of antibodies and immune complex deposition.⁴³ However, the nature of the antigen in the complex is not known.

Intermediate Uveitis

Intermediate uveitis, as manifested in the classic pars planitis subtype, is characterized by a chronic vitritis with fibrosis over the inferior pars plana and peripheral retina. The inferior vitreous typically shows white aggregates of inflammatory cells or “snowballs.” Patients usually have minimal external inflammatory signs but report symptoms of floaters and reduced visual acuity, which result from both vitreous opacification and the often-accompanying cystoid macular edema (CME). Other complications may include cataract, glaucoma, cyclitic membrane formation, peripheral retinal neovascularization, macular epiretinal membrane, and retinal detachment. Phthisis may follow in rare, severe cases. This idiopathic condition should be differentiated from other disease entities that may present similarly, such as peripheral toxocariasis, toxoplasmosis, sarcoidosis, and Lyme disease. There is a well-documented association with multiple sclerosis,^46–51 as well as evidence for the association of both conditions with the HLA-DR15 allele, coding for one of the two HLA-DR2 subtypes.^47,49,51

Pars planitis tends to occur in young adults and generally runs a benign course. Most histopathologic data, however, are derived from severely complicated cases that required enucleation and therefore represent the most severe consequences of this entity. The iris and ciliary body usually are reported to be minimally, if at all, inflamed.^52–55 The anterior part of the choroid may reveal a lymphoid cell infiltration in some patients. In other patients with chronic, uncomplicated pars planitis, eyes obtained at autopsy showed no uveal inflammation.⁵³

Much attention has been given to the histopathologic nature of the “snowbanks,” which has been studied by both light and electron microscopy.^{52,54,56–58} These fibrovascular-glial proliferations are found over the inferior pars plana and peripheral retina. They are composed of dense connective tissue derived from condensed, collapsed vitreous and often are vascularized. These vessels may reveal features of high endothelial venules (Fig. 8). Such endothelia are known to play a role in the homing of activated lymphocytes.⁵⁴ The cellular elements of these membranes include fibroglial cells that are believed, based on their electron microscopic characteristics, to represent fibrous astrocytes, as well as nonpigmented ciliary epithelial cells, fibroblasts, and lymphocytes (Fig. 9).^{52–55,59,60} The vitreous is infiltrated by chronic inflammatory cells, and despite the nongranulomatous nature of the inflammatory component in the snowbanks, vitreous snowballs have been reported to consist of epithelioid cell granulomas.⁵²

The retina often shows a perivasculitis, CME, and epiretinal membrane formation. Inflammation-induced contraction of the vitreous body may cause CME and, through breaks in the inner limiting membrane, predispose to epiretinal fibrous proliferation.⁵³ However, prostaglandins and cytokines released from inflammatory cells also may play a role in the development of CME as well.

Fuchs' Heterochromic Iridocyclitis

Fuchs' heterochromic iridocyclitis (FHI) is a chronic, typically unilateral, nongranulomatous anterior uveitis. There usually are no acute inflammatory symptoms or signs and no synechiae formation. Characteristic clinical signs include iris hypochromia and atrophy with diffuse, stellate keratic precipitates, a chronic low-grade iridocyclitis, fine pathologic anterior chamber angle vessels, and cataract formation. The pupil may be dilated and sluggishly reactive. Secondary glaucoma occurs in 15% to 27%.^61–66

FHI was considered unusual in the past, accounting for only 1.8% of cases of anterior uveitis in a series of 600 patients.⁶⁷ However, this clinical entity probably has been underdiagnosed because of its subtle findings. In a series of 77 patients from Fearnley and Rosenthal,⁶³ only about half of patients with FHI were diagnosed correctly. The prevalence of FHI in later studies has increased to as high as 8%.⁶⁸

Several theories have been raised regarding the pathophysiology of FHI. None has been proved systematically, and the etiology remains largely unknown. An ischemic mechanism has been suggested based on perfusion defects seen on anterior segment fluorescein angiography^69,70 and the iris neovascularization. This hypothesis also is supported by histopathologic findings of hyalinized iris blood vessels in patients with FHI.⁷¹ However, these changes may be secondary to inflammation or to other primary insults. A possible association exists between FHI and ocular sympathetic denervation. FHI has been reported in eyes with Horner's syndrome⁷² and, as a part of hemifacial atrophy (Parry-Romberg syndrome), an idiopathic inflammatory disorder characterized by sympathetic denervation and chronic neurotrophic changes of the ipsilateral facial and intracranial structures.^73–75 Electron microscopic studies on irides of patients with FHI indeed have shown membranous degeneration of nerve fibers. This may account for the defective melanin production in the irides of patients with FHI.⁷⁶ This finding, however, was not reported in an earlier, larger series by Wobmann.⁷⁷ Infectious agents, particularly Toxoplasma gondii, have been associated with the development of FHI, although it is controversial whether a true association exists.^78–82 An association with retinitis pigmentosa also has been reported.^83–86 It is therefore possible that FHI represents a syndrome, rather than a single entity, and is the result of different pathogenic events. Further discussion can be found in two comprehensive reviews by Loewenfeld and Thompson⁶¹ and by Jones.⁸²

Beginning with Fuchs' original article in 1906,⁸⁷ several histopathologic reports have been published on FHI. Although there are no pathognomonic findings, typical features include a chronic, nongranulomatous inflammatory infiltration of the iris, ciliary body and trabecular meshwork with plasma cells, lymphocytes, and monocytes.^{61,71,76,82,87,88}

Despite the nongranulomatous nature of FHI, there is the occasional formation of iris nodules. Other findings include iris stromal atrophy and depigmentation, iris blood vessel wall hyalinization, and iris sphincter atrophy.⁶¹ An interesting clinicopathologic sign is the occasional presence of minute, glistening iris crystals (Fig. 10) representing Russell bodies. Although not specific, this finding seems to be typical of FHI and probably is more common than realized previously.^89–93 It probably reflects chronic local production of immunoglobulins in the inflamed iris. This assumption also may be supported by the high fraction of immunoglobulin G₁ (IgG₁) subclass found in the aqueous of patients with FHI.⁹⁴ Electron microscopic studies by Melamed and associates⁷⁶ show an abundance of plasma cells and the presence of immature melanin granules within melanocytes.

Ocular Inflammatory Disease Related to the Acquired Immunodeficiency Syndrome

Infection with the human immunodeficiency virus (HIV) produces a progressive loss of CD4+ T cells, resulting in an increased susceptibility to certain opportunistic infections, many of which may involve the eye primarily or as part of a generalized somatic infection. In fact, approximately 95% of patients with the acquired immunodeficiency syndrome (AIDS) have some ocular manifestation of the disease, including noninfectious ones, whereas 75% have infectious manifestations.⁹⁵ Because CD4+ T cells are required for the formation of granulomas,⁹⁶ infectious entities that might usually result in granulomatous inflammation do not necessarily do so in individuals with AIDS. The viruses cytomegalovirus (CMV) and herpes zoster or simplex, as well as the protozoan Toxoplasma gondii may produce necrotizing retinitises, which are difficult to distinguish clinically. In addition, infectious choroiditises from Pneumocystis carinii, Cryptococcus neoformans, and mycobacterial species may occur, which are likewise difficult to distinguish based on clinical findings alone.^97,98 The profound immunosuppression produced by HIV infection also has resulted in an increase in the incidence of well-known infectious entities that had been in decline, such as tuberculosis.⁹⁹

Discussed below are examples of the more common infectious ocular diseases in patients with AIDS. A more complete discussion can be found in the review by Kuo and Rao.⁹⁵

CYTOMEGALOVIRUS RETINITIS. CMV retinitis is the most common opportunistic ocular infection in patients with HIV. Before the AIDS era, it was a rare disease, seen mostly in immunosuppressed patients, such as after renal transplantation. It typically manifests as a hemorrhagic, necrotizing retinitis with minimal vitreous inflammation. A sharp demarcation may exist between atrophic, affected areas and healthy retina. Because of the thin, fragile nature of the damaged retina, CMV retinitis often is complicated by rhegmatogenous retinal detachment. Risk for development of CMV retinitis is greatest when the CD4+ cell count is below 50/mm³.

Pathologic findings in a series of 35 autopsy eyes reported by Pepose and associates¹⁰⁰ revealed CMV retinitis in 34%, with findings of retinal hemorrhages, exudative or rhegmatogenous retinal detachment, and neutrophilic infiltration of the retina and choroid. Immunohistochemical evidence for viral antigens was found throughout the neurosensory retinal layers, the retinal pigment epithelium, and rarely in the choroid, but not in retinal vascular endothelial cells. In contrast, Read and colleagues¹⁰¹ showed by dual immunohistochemical staining the presence of CMV antigen within retinal vascular endothelial cells. It was theorized that the endothelium may in fact be the initial site of infection in the retina and that dislodged endothelial cells may be a mechanism of spread of the lesions.

Other histologic findings include full-thickness retinal necrosis and inclusion bodies within large cells that probably are neurons. Two types of inclusion bodies may be seen: eosinophilic bodies measuring 0.5 to 1 μm and larger and basophilic bodies measuring 5 to 10 μm with an owl's eye appearance (Fig. 11). Multinucleated giant cells also may be seen, which probably represents syncytium formation resulting from cytopathic viral effects. Electron microscopy shows viral particles wrapped in a double-walled envelope within the nucleus and cytoplasm of infected cells.^102–105 These envelopes may appear empty after antiviral therapy with ganciclovir.^100,105,106 Retinal necrosis may be followed by calcification.^104,107

PROGRESSIVE OUTER RETINAL NECROSIS. Descriptively named, progressive outer retinal necrosis is a progressive, multifocal, necrotizing inflammation of the outer retina. Unlike CMV retinitis, it is not associated with significant retinal vasculitis. Caused by the varicella zoster virus, it often follows an episode of cutaneous zoster.¹⁰⁸ Rutzen and associates¹⁰⁹ reported the histopathology from two cases of progressive outer retinal necrosis requiring retinal biopsy. Retinal necrosis was present in one, with the other showing only retinal atrophy (Fig. 12). Both revealed herpes group viral DNA. Unlike the typical occlusive vasculitis seen in CMV retinitis, retinal vessels were patent in the case with retinal necrosis.

TOXOPLASMOSIS RETINOCHOROIDITIS. Toxoplasmosis accounts for 1% to 5% of AIDS-related retinal infections and usually is acquired as opposed to being congenital.¹¹⁰ Toxoplasmosis in the immunocompromised host differs in its clinical manifestations to that of the immunocompetent host. There tends to be less intraocular inflammation, lack of a preexisting pigmented chorioretinal lesion, and larger, more hemorrhagic areas of involvement, which may be bilateral.^110–112 Histopathologic analysis of cases of toxoplasmosis in patients with AIDS shows the presence of Toxoplasma cysts, necrosis of the retina, and a minimal lymphocytic infiltrate within all layers of the retina (Fig. 13).¹¹⁰ In addition, the choroid shows the presence of histiocytes, plasma cells, and eosinophils.¹¹³

TABLE 4. Classification of Endophthalmitis

  Infectious endophthalmitis

  Postoperative

  Acute postoperative endophthalmitis
  Delayed-onset endophthalmitis (onset >6 weeks postoperatively)
  Conjunctival filtering bleb associated

  Sterile uveitis
  Phacoanaphylactic endophthalmitis
  Sympathetic ophthalmia

ACUTE INFECTIOUS POSTOPERATIVE ENDOPHTHALMITIS

Acute postoperative endophthalmitis has been reported to occur after cataract extraction in between 0.07% and 0.13% of cases.^114–117 Advanced age, male sex, intracapsular cataract extraction, and anterior vitrectomy have been associated with an increased risk of postoperative endophthalmitis.¹¹⁸ The most common cause of acute postoperative bacterial endophthalmitis after cataract extraction is coagulase-negative Staphylococcus species,^119,120 such as S. epidermidis. The likely source of organisms is from the normal flora of the conjunctiva, with inoculation into the eye at the time of surgery.^121–126 It has been reported that in up to 29% of eyes undergoing cataract extraction, bacteria can be cultured from the aqueous humor at the time of surgery.¹²⁵ Because the incidence of postoperative endophthalmitis is more than two orders of magnitude lower than 29%, factors other than the mere presence of bacteria must play a role in the development of endophthalmitis. Experimental studies in rabbits have shown that a certain “threshold” inoculum size must be reached before sustainable infection can be achieved; otherwise, the ocular inflammatory reaction results in “autosterilization” of the intraocular environment.¹²⁷ Similarly, in a rabbit model of S. epidermidis endophthalmitis, a more severe disease resulted when a larger inoculum of bacteria was injected, which persisted for a longer period than did the disease produced when a smaller number of bacteria were injected.¹²⁸ It is possible as well that a genetic susceptibility to infectious endophthalmitis exists.¹²⁹

Patients with acute postoperative bacterial endophthalmitis may present with decreased visual acuity, pain, redness, and intense anterior chamber inflammatory reaction with hypopyon, corneal edema, vitritis, and retinitis. Suspicion must be high and treatment rapid and broad in scope to cover the most likely organisms. Typically, multiple intravitreous antibiotics to cover both gram-positive and gram-negative organisms are injected in the office setting after sampling of the aqueous and vitreous humors for culture. Neither systemic antibiotics nor immediate vitrectomy has been shown to be of benefit, except vitrectomy when visual acuity is light perception or worse at presentation.¹³⁰

DELAYED-ONSET ENDOPHTHALMITIS

Differentiation of delayed-onset infectious endophthalmitis from endogenous autoimmune-mediated uveitis occurring in a patient who happens to be postcataract extraction is difficult at best.¹³¹ Both may respond initially to corticosteroid use, but similarly, both may become resistant to such therapy. It has been shown that bacteria can adhere to the surface of intraocular lenses, and thus their implantation may increase the risk of endophthalmitis.¹³² Certain clinical clues, such as the presence of a white plaque within the capsular bag, may be helpful. Suspicion must be high for infection, and definitive diagnosis usually requires sampling of the ocular contents, either through aqueous humor tap or vitreous sampling (by tap or biopsy) for culture or detection of bacterial DNA by the polymerase chain reaction or both.¹⁵ The most common organisms resulting in this type of infection are the coagulase-negative Staphylococcus species,¹³³P. acnes, as well as fungi.¹³⁴ When conservative therapy with antibiotics alone fails to eradicate the infectious agent, surgical removal of the intraocular lens may be required.¹³⁵

CONJUNCTIVAL FILTERING BLEB-ASSOCIATED ENDOPHTHALMITIS

Infection in eyes with previous glaucoma-filtering procedures may present as a localized blebitis or a frank endophthalmitis with vitreous involvement.¹³⁶ Similar to other cases of acute postoperative endophthalmitis, Staphylococcus species are the most common isolates in the acute setting.¹³⁶ When bleb-associated infection occurs later, however, other organisms in addition to Staphylococcus species may be responsible, including Streptococcus species and Haemophilus influenzae.^137,138

POSTTRAUMATIC ENDOPHTHALMITIS

Gram-positive cocci remain the most common cause of posttraumatic endophthalmitis. However, while one series from southern India reported the most common isolate was Streptococcus species,¹³⁹ others have reported a higher incidence of S. epidermidis¹⁴⁰ or Bacillus species, perhaps the most feared etiologic agent in posttraumatic endophthalmitis,¹⁴¹ because of its generally poor visual outcome.

ENDOGENOUS INFECTIOUS ENDOPHTHALMITIS

Less common than exogenous endophthalmitis, endogenous endophthalmitis results from the hematogenous spread of organisms from a site distant to the eye. The finding of an endogenous endophthalmitis should prompt an immediate and thorough search for the source. In one series, endocarditis and the gastrointestinal tract were the most common primary sources of organisms, with the most common causes being streptococcal species and Staphylococcus aureus. In most patients, visual outcome was poor.¹⁴² Other organisms, some uncommon pathogens to the eye, also can cause endogenous endophthalmitis, among them Neisseria meningitidis,¹⁴³Listeria monocytogenes,¹⁴⁴Serratia marcescens,¹⁴⁵Rickettsia conorii,¹⁴⁶Nocardia,¹⁴⁷ and Ochrobactrum anthropi.¹⁴⁸ When fungi are the responsible endogenous agents, Candida species are most common, followed by Aspergillus species.¹⁴⁹

HISTOLOGY OF INFECTIOUS ENDOPHTHALMITIS

Histopathologic examination of eyes with acute bacterial endophthalmitis typically shows an infiltration of polymorphonuclear leukocytes with the formation of suppurative inflammation and destruction of ocular structures (Fig. 15). Depending on the duration of the inflammation, chronic inflammatory cells can be seen as well.

CORNEA

Any process that decreases the clarity of the cornea results in a decrement in acuity. This may occur secondary to corneal edema from endothelial cell dysfunction caused by inflammation, opacification due to scarring with ingrowth of fibrovascular pannus, or opacification due to a deposition of material on or within the cornea, such as in band keratopathy.

The corneal endothelium functions to maintain a state of relative dehydration of the corneal stroma, which permits the orderly arrangement of the stromal lamellae and, thus, transparency.¹⁵⁰ Because the corneal endothelium does not regenerate, loss of endothelial cells results in the enlargement of adjacent endothelial cells to compensate. With continued damage and loss, these enlarged cells are unable to maintain the required degree of fluid transport and corneal edema results, eventually involving the entire stroma and finally the epithelium (Fig. 16).¹⁵⁰ Edema of the corneal epithelium results in the failure of the hemidesmosomes between the basal epithelium and Bowman's membrane, with subsequent bullae formation. Bullae may rupture, and eventually a fibrovascular tissue grows to cover the defect, resulting in corneal scarring (Fig. 17).

Prolonged inflammation may result in the deposition of calcium along Bowman's membrane, which typically occurs within the intrapalpebral space, producing a bandlike appearance (Fig. 18). Pathologically, the calcium usually is limited to Bowman's membrane and the anteriormost aspect of the corneal stroma (Fig. 19).¹⁵¹ This form of corneal degeneration is more common in children, such as in patients with juvenile rheumatoid arthritis-related uveitis, but can be seen in any chronic inflammatory condition.

IRIS, ANGLE, AND ANTERIOR CHAMBER

An integral portion of inflammation is the release of fibrin and other inflammatory mediators into the intraocular environment. The presence of these factors in the aqueous humor may result in the formation of adhesions between the iris and underlying lens capsule, termed posterior synechiae (Fig. 20); or iris and peripheral cornea, termed peripheral anterior synechiae. Development of posterior synechiae for 360 degrees of the pupillary margin results in a secluded pupil and prevents the normal flow of aqueous from the posterior chamber to the anterior chamber. Assuming aqueous production continues, the resultant increased pressure in the posterior chamber results in the forward bowing of the mid and peripheral iris, producing iris bombé. Development of iris bombé may result in elevated intraocular pressure as the peripheral iris occludes the trabecular meshwork. If apposition between the peripheral iris and trabecular meshwork continues, then the previously described peripheral anterior synechiae may form, making the angle closure permanent (Fig. 21). This is hastened if active inflammation is present at the time of apposition. Timely creation of an alternate bypass channel for aqueous flow from the posterior to anterior chambers of the eye (before the development of peripheral anterior synechiae) allows equalization of the pressure and resolution of iris bombé. This bypass channel may be created using the argon or neodymium:YAG (Nd:YAG) lasers (and is then called a peripheral iridotomy) or surgically, by removing a piece of peripheral iris through a limbal incision (termed a peripheral iridectomy). With active inflammation, the generally larger opening of the surgical iridectomy may be preferred to decrease the chance of the opening from closing because of fibrosis. If fibrosis continues, then growth of a membrane may occur across the pupillary space as well. When the pupil is covered, it is said to be occluded (Fig. 22). Because of the common mechanism of formation, seclusion and occlusion of the pupil often are seen, at least somewhat, in tandem.

Neovascularization of the iris may occur due to ischemia because of inflammation or from nonischemically induced upregulation of vascular endothelial growth factor production by Müller cells during uveitis.¹⁵² Regardless of the underlying mechanism, growth of new vessels on the iris surface may extend to involve the angle. This fibrovascular membrane may then contract, resulting in angle closure glaucoma as well as the turning out of the pupillary margin, or ectropion uvea.

Atrophy may occur in the iris after an inflammatory insult. Ischemia due to a localized occlusive vasculitis, such as in herpes zoster-related uveitis, may result in characteristic atrophy of the iris stroma with clinically evident transillumination defects. Damage may occur to any portion of the iris, including the stroma, dilator or constrictor muscles or both, and pigment epithelium.

LENS

The lens, in the face of an intact capsule and lack of maturity of cataract, is rarely if ever primarily involved in an inflammatory process. Formation of a cataract as a result of inflammation, steroid use, or the combination, however, is common. The lens epithelium, which normally is located only anteriorly, may migrate posteriorly to form a posterior subcapsular cataract. Damage or insult to the lens may result in fibrous metaplasia of the lens epithelium and formation of anterior subcapsular cataracts as well (see Fig. 22). Localized cataract may be induced by posterior synechiae formation. In addition, the presence of posterior synechiae makes cataract extraction difficult because of poor pupillary dilation and localized fibrosis, making the capsulorhexis more challenging. In advanced cases, calcification of the lens may occur.

CILIARY BODY

Production of aqueous humor is vital for the continued health of the ocular structures. Aqueous provides the necessary intraocular pressure that allows the eye to maintain its shape and provides nutrition for the nonvascular corneal endothelium and lens epithelium. Inflammation of the ciliary body, as in acute or chronic iridocyclitis, may result in a decrease in aqueous production and thus the characteristic finding of reduced intraocular pressure. In vivo studies of the human ciliary body during acute anterior uveitis show an enlarged cross-sectional area and occasional epithelial cyst formation.¹⁵³ Pathology of the ciliary body in cases of chronic feline uveitis shows infiltration with chronic inflammatory cells,¹⁵⁴ findings that are typical for human cases as well. Continued inflammation in the eye may result in the formation of a fibrous membrane stretching from ciliary process to ciliary process, across the retropupillary space (Fig. 23). Contraction of this fibrotic cyclitic membrane may result in ciliary body detachment with decreased production of aqueous humor, eventually leading to chronic hypotony if the process is not reversed.

VITREOUS

It is unknown whether the vitreous body itself can be the primary target of an inflammatory attack or whether it is always merely the repository for cells and inflammatory mediators as a result of inflammation of adjacent structures. Regardless, similar to the processes that lead to pupillary membrane formation, the inflammatory debris found in the vitreous can undergo organization and fibrosis to produce traction on the retina and resultant retinal detachment or simply a hazy or sometimes opaque media.

In addition, inflammation may lead to the formation of neovascularization of the optic nerve¹⁵⁵ or retina,¹⁵⁶ possibly secondary to ischemia of the retina. These new vessels are fragile and grow into the vitreous cavity. With development of a posterior vitreous detachment, these vessels may tear, producing a vitreous hemorrhage.¹⁵⁶ Blood within the vitreous cavity, at the least, results in temporary opacification of the optical media but also may lead to fibrous organization with membrane formation, similar to that described above and with the anterior chamber and ciliary body.

RETINA

Inflammation of the intraocular environment may lead to alterations in normal retinal function that are transient or permanent, even if the retina is not directly involved in the inflammatory process. Perhaps the most common type of retinal involvement is CME, in which fluid collects within the outer plexiform layer of the retina due to leakage from perifoveal capillaries. The characteristic petaloid pattern seen on fluorescein angiography (Fig. 24) is from the vertical anatomic arrangement of the fibers in Henle's layer, which confines the fluid to several large spaces with surrounding smaller spaces.¹⁵⁷ The pathophysiology of CME is not completely understood but most likely relates to breakdown of the blood-ocular barrier in the perifoveal capillaries, possibly because of the effects of prostaglandins. A perivasculitis may develop, such as that seen early in the course of EAU in the Lewis rat.¹⁵⁸

Inflammation may result in the formation of a thin, fibrous epiretinal membrane on the surface of the internal limiting membrane. Similar to other fibrous membranes, there is a contractile component to these membranes, which may result in distortion of the retina and a significant decrease in visual acuity.^159,160

Long-term loss of retinal function is mediated primarily by free radical-mediated damage to the retina.¹⁶¹ The tissue damage is mediated mainly by phagocytic inflammatory cells, such as macrophages, by the release of various proteolytic enzymes, arachidonic acid metabolites, cytokines, and free radicals. Tissue damage is caused by peroxidation of lipid cell membranes by peroxynitrite, which is formed from nitric oxide and superoxide.¹⁶¹

Breakdown of the outer blood-ocular barrier (i.e., the tight junctions between the retinal pigment epithelial cells) allows exudation of fluid beneath the retina, producing detachment. Because of the high protein content of this fluid, the retinal detachment is characterized by shifting subretinal fluid. Subretinal fibrosis may occur in this setting. The retinal pigment epithelial cells may undergo atrophy or conversely undergo hyperplasia or hypertrophy in response to an inflammatory insult.

CHOROID

Diseases such as Vogt-Koyanagi-Harada syndrome and sympathetic ophthalmia (both granulomatous inflammatory processes) primarily affect the choroid, causing diffuse choroidal thickening, which is evident on ultrasonography¹⁶² and histopathologically (Fig. 25). The inflammation in these conditions, which is presumed to be directed against a component associated with the melanocyte, results in the destruction of choroidal melanocytes and their absence in chronic cases.¹⁶³

Disruption of Bruch's membrane in inflammatory processes may predispose to the development of choroidal neovascular membranes. Inflammatory entities in which choroidal neovascular membranes have been reported to occur include Vogt-Koyanagi-Harada syndrome,¹⁶⁴ serpiginous choroiditis,¹⁶⁵ acquired syphilis,¹⁶⁶ sarcoidosis,¹⁶⁷Toxoplasma retinochoroiditis,¹⁶⁸ multifocal choroiditis,¹⁶⁹ toxocariasis,¹⁷⁰ and after Candida chorioretinitis.¹⁷¹ These lesions may be managed similarly to other choroidal neovascular membranes with laser photocoagulation or subretinal surgery.¹⁷² Histopathologic analysis shows a fibrovascular membrane.

OPTIC NERVE

Inflammatory processes such as sarcoid can directly involve the optic nerve,¹⁷³ but more common is the situation in which damage to the optic nerve occurs secondary to glaucoma. Many of the mechanisms in which glaucoma may be induced in the inflamed or previously inflamed eye already have been described, including angle closure due to growth of a neovascular membrane across the trabecular meshwork with contracture, peripheral anterior synechiae induced by apposition of the iris to the peripheral cornea (which may be the result of iris bombé), and anterior rotation of the lens or iris diaphragm due to ciliary body edema.^174–176 Retinal detachment also has been reported to result in angle closure because of this mechanism.¹⁷⁷ Intraocular pressure may be elevated transiently by inflammatory cells and debris blocking aqueous outflow through the trabecular meshwork. The trabecular meshwork itself may be inflamed, producing a “trabeculitis” and decreased aqueous outflow. This may be seen most often in cases of herpesvirus-related uveitis.¹⁷⁸

Regardless of the underlying mechanism, persistent elevation of the intraocular pressure may result in progressive optic nerve damage, manifesting histopathologically as loss of nerve fibers and ganglion cells with “cupping” of the optic nerve head (Fig. 26).

END STAGE OF INFLAMMATORY OCULAR DISEASES

When failure to adequately control intraocular inflammation occurs, the eye inevitably undergoes a progressive loss of function and normal organization. Components of the eye undergo atrophy as detailed above, including the iris and retina. Uncontrolled glaucoma results in optic atrophy with nerve fiber layer loss and dropout of ganglion cells. In the pediatric patient, elevated intraocular pressure may result in the development of buphthalmos. Conversely, eyes may undergo atrophy with shrinkage, termed atrophia bulbi. Here the globe retains its normal anatomic structures but becomes smaller and hypotonus. With hypotony, the eye becomes soft and the tension created by the extraocular muscles may produce a squared-off appearance to the globe.¹² When the internal contents of the eye become disorganized, in association with shrinkage of the overall globe, then phthisis bulbi is said to exist.¹² Metaplasia of cellular elements, especially the retinal pigment epithelium, may occur and result in the formation of cancellous bone within the phthisical eye (Fig. 27).^179,180

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