Abstract
The choroid provides the main blood supply to the eye and plays a key role in eye physiology. Different entities can compromise its structure and function, having a striking impact on vision. Knowing the histology of the normal eye is fundamental for the correct understanding of the pathologic processes. This chapter is therefore organized into pathological subcategories defined as congenital, inflammatory, and neoplastic processes. The correlation between these different entities and the histopathology would allow us to have the right interpretation of the interaction between the eye, the patient, and the disease, opening the field to different treatments and improving quality among health providers.
Keywords
Choroid histology, Choroid histopathology, Inflammation, Infection, Neoplastic processes, Immunohistochemistry
Anatomy, Embryology, and Histology of the Choroid
The choroid is a pigmented and highly vascularized component of the uveal tract in the eye, allowing for light absorption and providing oxygen and nutrients to the outer retina. Anatomically, the choroid extends from the ora serrata to the optic nerve head and is located at the posterior two-thirds of the eye between the sclera and retina. Anteriorly, it is followed by the ciliary body and the iris. It’s thickness varies in humans from 0.1 mm anteriorly and 0.22 mm posteriorly ( Fig. 3.1 ); however, it decreases by age 90 years to about 80 μm. The choroid is composed of vessels that are derived from the anastomosis of branches of the ophthalmic artery; these are the posterior ciliary arteries and penetrate the sclera posteriorly, approximately 6 mm far from the optic nerve. The arteries then branch into terminal arterioles that supply feed into the choriocapillaris lobules. These subsequently drain into venules that merge to form the four to five vortex veins at the equator of the sclera.
The arteries and the arterioles of the choroid are surrounded by a nerve fiber plexus that receives sympathetic and parasympathetic innervation, the latter from the pterygopalatine ganglion of the facial nerve. Single choroidal ganglion cells have also been noted to be present near the larger choroidal arteries. The functional significance of this innervation is yet unclear. The nerve fibers stain positive for nitric oxide synthase and vasoactive intestinal peptide; hence, the theory that these regulate blood flow through the choroidal vessels or serve as mechanoreceptors.
The choroid is derived from the neural crest and periocular mesenchyme. The choriocapillaris begins to develop at 4–5 weeks age of gestation. The endothelium of the choriocapillaris flattens to a single cell layer and develops fenestrations at 9 weeks. By the end of the first trimester, the fetal choriocapillaris resemble the adult form. The rest of the choroid begins development at 15 weeks, during which arterioles and venules begin to form, and by 22 weeks, the major arteries and veins are distinguishable.
Histologically, the choroid is divided into five layers, starting from the retina to the sclera ( Fig. 3.2 ): (1) Bruch’s membrane; (2) choriocapillaris; two layers of vasculature—(3) Sattler’s layer; (4) Haller’s layer—and (5) suprachoroidea.
- 1.
Bruch’s membrane is composed of elastic materials surrounded by collagenous tissue and is approximately 2–4 μm thick. It can be divided into five segments: the basement membrane of the retinal pigment epithelium (RPE); inner collagenous zone; elastic layer; outer collagenous zone, and basement membrane of the choriocapillaris endothelium.
- 2.
The choriocapillaris layer consists of a capillary network that is crucial to supply the RPE, photoreceptors, outer plexiform, and the outer aspect of the inner nuclear layer. The endothelial cells present in this layer are fenestrated, allowing free exchange of fluids between the retina and choroid. The area of the choroid underlying the fovea has the highest density of capillaries in the choriocapillaris layer, having a thickness of 10 μm and thinning out to 7 μm in the periphery.
- 3.
Sattler’s layer consists of the smaller arterioles that feed into the choriocapillaris layer and produce a lobular shaped capillary bed.
- 4.
Haller’s layer is the outer vascular layer that comprises the larger vessels. The stroma that is intermingled in between the blood vessels consists of nerves and many cells, including numerous large melanocytes, fibrocytes, nonvascular smooth muscle cells, mast cells, macrophages, and lymphocytes.
- 5.
The suprachoroid is the outermost layer of the choroid, known to be a transition layer that is about 30 μm thick (Forrester et al .). Histologically, this layer is artifactually enlarged after the embedding and processing of the tissue. This layer is composed of collagen, fibroblasts, and melanocytes.
Histopathology
Congenital Disorders: Coloboma
Choroidal coloboma is characterized as a failure of the inner and outer layers to fuse along the optic fissure. Typical colobomas of the choroid occur in the region of the fetal fissure, whereas atypical examples occur elsewhere. Complete uveal colobomas extend from the lower nasal region of the disk to the pupillary margin of the iris. Typical colobomas often show an abnormally thin and somewhat ectatic sclera. The outermost vascular and pigmented layers of the choroid are usually missing and are represented by atrophic nonpigmented mesodermal remnants. The choroidal defect is covered by dysplastic retina. The pigmented layer of the retina may end at the edge of the coloboma, or a few small atypical cells may extend beyond this point. The neural portion of the retina is rarely normal. Commonly, it blends with undifferentiated choroid to form an attenuated intercalary membrane that bridges the defect. Occasionally, the retina folds inward over the lip of the fissure and is continued as a membrane composed of one or two layers of cells in which rods, cones, glial cells, rosettes, and cysts can be recognized.
The pathologic picture of atypical colobomas is similar to that of the typical ones, except that more choroidal and retinal elements are present. The pathogenesis of this type of defect is obscure.
Inflammatory Disease
Nongranulomatous inflammation
Nongranulomatous uveal inflammations are the most common types of uveitis and usually present as iridocyclitis, characterized by an unspecific type of inflammatory reaction. The origin is frequently unknown. They can be suppurative or nonsuppurative. Suppurative nongranulomatous inflammation is an acute nongranulomatous purulent inflammatory reaction in which the predominant cell type is the polymorphonuclear leukocyte. It is usually secondary to bacterial infection. Nonsuppurative nongranulomatous inflammation can be either acute or chronic. In the acute inflammation, the predominant cell type is the neutrophil, and in chronic inflammation it is the lymphocyte and the plasma cell.
In histopathology, nongranulomatous processes can be defined as a predominantly exudative and alterative process. Contrary proliferative changes are subtle (i.e., granulomas, lymphoid aggregates, and exuberant granulation tissue). Plasma cells commonly predominate, and plasmacytoid cells and Russell’s bodies quite often are numerous. These cell types are particularly characteristic of nongranulomatous iritis, and since they are believed to be linked with antibody production, this form of uveitis may represent a local tissue response to antigenic stimulation.
As a sequelae of uveitis, the choroid may show focal or diffuse areas of atrophy or scarring. Retinochoroiditis or chorioretinitis may destroy Bruch’s membrane and the RPE, furthermore, the choroid and retina may become fused by fibrosis, and a chorioretinal scar or adhesion results.
Behçet’s disease
Behçet’s disease (syndrome) is characterized by retinal vasculitis, recurrent bilateral iridocyclitis with hypopyon, aphtous ulcers of the mouth and genitalia, dermatitis, arthralgia, thrombophlebitis, and neurologic disturbances. The disease is most common in men, especially between the ages of 20 years and 30 years. Also, men have more severe involvement and are at a greater risk of vision loss than women. Prevalence of Behçet’s disease worldwide ranges between 0.1/1000 and 1/10,000, with a significant presence in Asia. The lesions of the skin and mucous membrane most often appear before those of the eyes. Ocular inflammation occurs in about 70–80% of the patients. The etiology is unknown, and the disease appears to be more common in the Mediterranean countries.
Regarding ophthalmic examination, fluorescein angiography shows choroidal involvement. In addition, choroidal thickening has been shown using A-scan ecography, and more recently, enhanced depth imaging optical coherence tomography (EDI-OCT) has become an excellent tool to visualize choroidal layers and confirm its thickening in Behçet’s syndrome.
Pathological examination of the eyes diagnosed as Behçet’s disease shows a serohemorrhagic exudate containing polymorphonuclear leukocytes in the vitreous and in the anterior and posterior chambers. There are extensive areas of retinal necrosis. Depending on the stage of the disease, mononuclear and polymorphonuclear leukocytes can be found in the choroid. The choroidal infiltrate is predominantly composed of CD4 T lymphocytes, with some B lymphocytes and plasma cells ( Fig. 3.3 ).
Acute retinal necrosis
Acute retinal necrosis was first described in 1971 as an acute unilateral panuveitis with periarteritis that progressed to diffuse necrotizing retinitis. It is now known to be associated with the herpes family of viruses, most commonly varicella zoster virus and herpes simplex virus (HSV). HSV consists of linear double-stranded DNA packaged in an icosahedral capsid and covered by a lipid-containing membrane. HSV-1 is usually responsible for initial infections in children and for most herpetic eye infections in all ages. HSV-2, usually responsible for genital herpes, may rarely cause ocular disease in neonates, through contamination at birth by the mother’s genital herpes, or adults. Neonatal HSV most commonly causes a nonfollicular conjunctivitis followed by keratitis, but can also cause retinochoroiditis or chorioretinal scarring, iritis, cataracts, optic atrophy or neuritis, and microphthalmia. The differential diagnosis consists of the TORCH syndrome (toxoplasmosis, rubella, cytomegalovirus, and herpes simplex).
Histopathology shows that infected areas can have both acute and chronic nongranulomatous inflammation, and intranuclear inclusions may be seen. HSV can be detected by monoclonal antibodies, such as the avidin–biotin complex immunoperoxidase technique, and by in situ DNA hybridization method using viral genome segments.
Subacute Sclerosing Panencephalitis
Subacute sclerosing panencephalitis is a chronic progressive disease of the central nervous system in children and young adults, which produces an intracellular infection of the brain, retina, and lymphoid tissue. The disease usually emerges 5–7 years after the child has had an uneventful measles infection. The ocular findings consist mainly of macular degeneration, optic atrophy, and peripheral retinochoroidal lesions.
Histologically, the neural retina is necrotic, is infiltrated by lymphocytes, and shows conglomerations of multinucleated cells. Intranuclear inclusion bodies in retinal cells can be seen with light and electron microscopy.
Granulomatous Inflammation
Granulomatous inflammation is a type of chronic inflammation characterized by a cellular infiltrate of histiocytes. In addition, lymphocytes, plasma cells, and polymorphonuclear cells, such as eosinophils and neutrophils, may be also observed.
Tuberculosis
Tuberculosis is an infectious disease caused by the acid-fast bacilli Mycobacterium tuberculosis and is characterized pathologically by the formation of granulomas with a central area of caseous necrosis. The most frequent route through which the bacilli reaches the eye is the blood stream. Cyclitis is the most common form of ocular involvement, which could rapidly spread posteriorly to cause a choroiditis, and this may occur either in association with clinically apparent pulmonary tuberculosis or in isolation, with no clinical or laboratory evidence of pulmonary infection.
In tuberculous posterior uveitis, the ocular changes can be divided into four groups: choroidal tubercles, choroidal tuberculoma, subretinal abscess, and serpiginous-like choroiditis.
- 1.
Choroidal tubercles: These are the most common intraocular manifestation of tubercular posterior uveitis. Clinically, the tubercles appear as small white to yellowish nodules with unlimited borders and could be uni- or bilateral ( Fig. 3.4 ). Usually there are no more than five tubercles; however, there may be many. They may be associated with serous detachment of the retina. When a tubercle continues to grow and becomes a solitary mass, it is called tuberculoma. When the infection resolves, the margins become sharp and the mass could turn yellow or white with pigmentation in the periphery.
Figure 3.4
Fundus picture of the left eye of a patient with tuberculosis. Two whitish nodules corresponding to choroidal tubercles (arrowhead) are shown; the smallest one is below the inferior temporal artery.
- 2.
Choroidal tuberculoma: This is less common than the tubercles and can happen anywhere in the choroid. It usually presents as a yellowish and large unique subretinal mass ranging from 4 to 14 mm, accompanied with an exudative retinal detachment. Neoplasias and infective abscess are the differential diagnosis.
- 3.
Subretinal abscess: Multiplication of the bacilli inside the granuloma could cause a yellowish abscess formation. They can occur from liquefaction necrosis within a tubercular granuloma. If not treated, these abscesses can rupture into the vitreous and result in endophthalmitis.
- 4.
Serpiginous-like choroiditis: The exact mechanism of serpiginous-like choroiditis in tuberculosis remains unknown. It may represent an immune-mediated hypersensitivity reaction in the presence of few acid-fast bacteria in the choroid or RPE. The lesions are usually multifocal, bilateral, noncontiguous to optic disc, and are commonly associated with mild vitreous inflammation. There are two distinct clinical patterns: discrete, multifocal choroiditis lesions that are initially noncontiguous but later progress to form diffuse lesions with an active edge, resembling serpiginous choroiditis; and less commonly, a solitary, plaque-like lesion.
Histopathology
The disease is characterized pathologically by the formation of one or multiple granulomas. The histology of the granuloma reveals central necrosis surrounded by histiocytes/epithelioid cells mixed with multinucleated giant cells—eosinophils, neutrophils, and Langhans giant cells ( Fig. 3.5 ).
These inflammatory phagocytes in turn are surrounded by lymphocytes. The necrotic area usually contains few bacteria, which can be visualized on Ziehl–Neelsen acid-fast stain as red rod-shaped organisms. However, several organisms can also be seen in the necrotic macrophages that line caseous necrosis. In some granulomas, the organisms can be seen in multinucleated giant cells ( Fig. 3.3 ) or they may not be detected by the histologic staining techniques. The development of granulomas reflects a T-cell-driven response to the organisms.
In the choroid, these tubercles/tuberculomas may involve all layers of the choroid. In the early stages, the overlying RPE remains normal but is disrupted during later stages as the tubercles increase in size. The surrounding choroid is essentially normal except for some lymphocytic infiltration.
Toxoplasmosis
Ocular toxoplasmosis is a parasitic infection of the eye caused by the protozoan Toxoplasma gondii . Infections may be congenital or acquired through the ingestion of uncooked and infected meat, contaminated vegetables, or water.
It been estimated that more than one-third of the world’s population have been infected by T. gondii and is responsible for the majority of granulomatous uveitis.
It is probably not by chance that the three main immune-privileged areas of the body—the placenta, the brain, and the eye—are major targets of this parasite in humans. The unique immunological milieu may provide preconditions for a specific balance between parasite invasion and host resistance.
This disease typically affects the posterior pole of the eye, and the lesions can be solitary or multiple and can further be subclassified as active or scaring. Active lesions are gray-white and accompanied by exudation, vasculitis, and choroiditis ( Fig. 3.6 ).
The normally clear vitreous is compromised and becomes hazy due to the infiltration of inflammatory cells. The patient will generally not complain of pain, but rather of an increase in floaters and a possible decrease in vision in the affected eye. The scarring begins from the periphery of the lesion and progresses toward the center with variable pigmentation changes.
A more aggressive disease, bilateral and multifocal, appears in the immunocompromised or elderly. Recurrent toxoplasmic retinochoroiditis is not associated with systemic symptoms and is related to patient age. Ocular lesions are often asymptomatic and may develop many years after T. gondii infection. Conditions that require treatment include a lesion that threatens the macula, optic nerve, or a large retinal vessel; induces a large hemorrhage; and causes severe inflammation. The treatment of choice is a combination of sulfadiazine, pyrimethamine, and folinic acid.
T. gondii primarily affects the retina and secondarily the choroid, although choroidal lesions do not occur in the absence of retinal infection.
Serologic studies can help to make the diagnosis. In immunocompetent patients, IgG remains positive for a long period of time. Meanwhile, Immunoglobulin M (IgM) remains positive for 2–4 weeks and represents primary infection.
Transplacental transmission of T. gondii to the fetus during pregnancy is another important route of infection. The mother can transmit toxoplasmosis to the fetus if infected primarily by T. gondii during pregnancy or a few months prior to conception. It is more rare that the parasite is transmitted earlier in gestation, but this results in more severe outcomes. Acquired transmission is through ingestion of rare meat or vegetables and water infected with T. gondii . Males and garden work increase risk of exposure to the parasite.
Yamamoto et al . showed that patients with a diagnosis of congenital ocular toxoplasmosis had significantly lower lymphocyte proliferative responses and delayed-type hypersensitivity skin reactions, and secreted significantly less IL-2 and interferon (IFN) IFN-g in response to 5 μg/mL soluble toxoplasma tachyzoite antigen (STAg) than did patients with a diagnosis of acquired ocular toxoplasmosis. The diminished response to toxoplasma antigens by T cells from patients with congenital disease suggests that T. gondii -specific T cells could have been deleted or anergized through exposure to toxoplasma antigens during the prenatal period.
Histopathology
Histopathological confirmation may be obtained by enucleation or chorioretinal biopsies. The toxoplasma cysts, bradyzoites, and tachyzoites can be identified with hematoxylin and eosin, immunohistochemistry, or by polimerase chain reaction (PCR). However, the majority of the cases are diagnosed clinically. Although the parasite is confined to the retina, breaks in Bruch’s membrane will permit the contact of the choroid with the infectious antigen, thereby causing an antiinflammatory response.
Ocular toxoplasmosis often presents as extensive granulomatous inflammatory infiltration of the choroid and areas of necrosis in Bruch’s membrane ( Fig. 3.7 ). In immunocompromised patients, the inflammatory infiltrate may be minimal or absent; therefore, the focal areas of necrosis are important clues to make the correct diagnosis of toxoplasmosis.
Syphilis
Syphilis is an infectious and venereal disease caused by Treponema pallidum , a helical spirochete bacterium 5–15 μm in length and less than 0.18 μm in width. In the eye, choroidal involvement manifests as syphilitic uveitis and, while rare, is increasing in the developed world. In the United States, the rate of primary and secondary syphilis in 2013 more than doubled compared to figures in 2000 (5.3 cases vs 2.1 per 100,000 population). This trend is potentially linked to unprotected sex in the era of effective HIV treatment.
Syphilitic uveitis presents in two different forms: a chronic nongranulomatous posterior choroiditis or a granulomatous posterior chorioretinitis. The later represents a more aggressive form.
Treponema spp. can be demonstrated in the ocular tissue. Spirochetes can be obtained through aspiration of aqueous humor from the anterior chamber and identified by dark-field microscopy. Polymerase chain reaction may also be used for bacterial detection.
The lesions can appear as disseminated, large atrophic scars surrounded by hyperplastic RPE ( Fig. 3.8 ).
Diagnosis begins with ophthalmologic examination but requires serologic testing, such as Venereal Disease Research Laboratory and Fluorescent Treponemal Antibody Absorption Test, for confirmation.
Syphilitic uveitis can present as a nonspecific anterior, intermediate, posterior, or panuveitis. Posterior manifestations include vitreous inflammation, chorioretinitis, retinal vasculitis, branch vein occlusion, serous detachment, and rarely, necrotizing retinitis. It is also known that posterior syphilitic uveitis can mimic any kind of eye diseases and has a distinctive pattern, known as posterior placoid chorioreitinitis.
Ocular syphilis with active lesions is treated in the same manner as neurosyphilis. Parenteral penicillin is the drug of choice.
Histopathology
Chronic nongranulomatous choroiditis is a smoldering, indolent, chronic, nongranulomatous inflammation. In histopathological sections, the outer neural retinal layers, the RPE, and the inner choroidal layers merge in an atrophic scar. Neural retinal elements are seen in the choroid, once they prolapse through area of dehiscence that occurs in Bruch’s membrane. Bruch’s membrane may be folded into the atrophic, sclerosed choroid. Scattered lymphocytes and plasma cells may also be present.
In granulomatous chorioretinitis, the inflammation occurs in the choroid and neural retina and can be quite vascular. Syphilis granuloma manifests similarly in other parts of the body; the most characteristic findings are the presence of nonnecrotizing, epithelioid granulomas, surrounding blood vessels with a perigranulomatous lymphocytic and plasma cell infiltration ( Fig. 3.9 ).
Vogt–Koyanagi–Harada syndrome
Vogt–Koyanagi–Harada (VKH) syndrome is a bilateral granulomatous uveitis that is associated with integumentary, auditory, and central nervous manifestations. Skin involvement may be through vitiligo, poliosis, and alopecia; ear symptoms include dysacusis and tinnitus; and central nervous system can manifest with meningeal signs, nerve palsies, mental status changes, and hemiparesis.
The pathogenesis underlying VKH is thought to be autoimmune, with T cells mounting a response against melanocytes. There are acute and chronic stages of the disease, with the former responding well to corticosteroid treatment; chronic disease may have recurrent bouts of acute activity. In the eye, VKH presents with posterior uveitis or diffuse granulomatous panuveitis, in association with serous exudative detachment and disc hyperemia, secondary to increased permeability and leakage of the choroidal vessels. Anterior segment inflammation can also occur concomitantly with subclinical posterior uveitis. Chronic VKH can lead to the pathognomonic sunset glow fundus, corresponding to the degeneration of the RPE. Chronic VKH can also develop into peripapillary atrophy and subretinal fibrosis leading to neovascularization, which are poor prognostic factors.
Diagnostic modalities are utilized in the diagnosis and in monitoring response to treatment. Extended depth optical coherence tomography (ED-OCT) shows focal hyporeflectivity of the inner choroid in eyes with VKH. Thickening of the choroid can also be seen in OCT in acute phases of VKH; in contrast, the choroidal layer thins during the convalescent phase. Fluorescein angiogram (FA) and indocyanine green (ICG) angiography are also of great utility in the visualization of the choroidal vasculature.
Histopathology
The histopathology of the choroid depends on the stage of the disease. In acute VKH, there is generalized granulomatous inflammation of the choroid with uveal thickening. This is due to the infiltration with lymphocytes, macrophages, epitheloid cells, and plasma cells. The sensory retina may be detached from the pigment epithelium by a protein exudate with eosinophils. Dalen–Fuchs nodules, which are clusters of macrophages, and RPE cells located over Bruch’s membrane may also be observed ( Fig. 3.10A ). In early stages, the choriocapillaris is usually spared.
Acute VKH resembles sympathetic ophthalmia (SO) histopathologically, especially in the early stages of the disease; correlation with clinical history and a possible inciting trauma points more definitively toward SO. Acute VKH may be distinguished from SO on two characteristics: serous retinal detachment is more common in VKH, and involvement of the choriocapillaris is less frequent in SO.
In contrast, the choroidal inflammation in chronic VKH is nongranulomatous. Infiltrates are still primarily lymphocytic, and there is marked thinning of the uvea. There may be obliteration of the choriocapillaris ( Fig. 3.10B ). Dalen–Fuchs nodules are absent; instead, there is loss of the melanin granules in the RPE. Nearby these are focal areas of hyperpigmentation, which are compensatory hyperproliferations of RPE; these tend to be arranged in papillary or tubular patterns. Chronic recurrent VKH resembles acute VKH on histopathology, characterized by granulomatous inflammation and Dalen–Fuchs nodules but with less uveal thickening and loss of choroidal melanocytes.
Sarcoidosis
Sarcoidosis is a noninfectious inflammatory granulomatous disease that may involve any or multiple systems, most commonly the lungs, lymph nodes, skin, the central nervous system, and the eye. The eye may be affected in up to 50% of patients with sarcoidosis and may be the first or an early site of involvement, especially in African-American patients. Clinically, patients usually present with gradual and painless decline in vision or with floaters.
Anterior uveitis is the most frequent ocular manifestation, occurring in 76% of patients. Sarcoid nodules or tubercles, which are discrete, solid granulomatous masses, may present on the lids, lacrimal glands, palpebral conjunctiva, and iris and trabecular meshwork. Posterior segment involvement is reported in 14–28% of patients, and these can present as posterior uveitis and sarcoid nodules of the optic nerve, retina, and choroid ; vitritis with or without inflammatory snowballs, retinal vasculitis, chorioretinitis, vascular occlusions, macular edema, papilledema, and retinal detachment.
Choroidal infiltrates are reported to be uncommon in patients diagnosed with sarcoidosis, with an incidence of 5.5% in isolation and 12% in association with other posterior segment abnormalities. Involvement of the choroid in sarcoidosis is usually in association with involvement of the vitreous and the retina, which is also a negative prognostic factor. Upon identification of a choroidal mass, involvement of the optic nerve and the central nervous system must be ruled out; the latter results in increased morbidity and mortality. Peripheral chorioretinal atrophic lesions have also been associated with severe cardiac involvement in sarcoidosis.
Typically, the choroidal infiltrates in sarcoidosis are characterized to be small, circumscribed, yellow, or white and located mostly at the periphery. On occasion, these infiltrates have been described to be plaque-like and confluent or may present as a single elevated white mass.
ICG can detect choroidopathy not visible with FA in patients with sarcoidosis; findings include hypofluorescent and hyperfluorescent plaques and segmental choroidal vascular wall staining. On ED-OCT, an active choroidal infiltrate appears as localized hyporeflective choroidal thickening, while quiescent ocular sarcoidosis will show subfoveal choroidal thinning.
Histopathology
Pathognomonic of sarcoidosis are the sarcoid nodules or tubercles; on histology, these are circumscribed noncaseating granulomas composed primarily of lymphocytes in association with Langerhans giant cells and macrophages. Tubercles of the same size are usually seen in isolation, although these may sometimes coalesce. Clusters of the epitheloid and Langerhans cells are usually surrounded by lymphocytes or plasma cells and may either be separated by connective tissue or form conglomerates ( Fig. 3.11 ).
Also observed are perivascular exudates that correlate with “candle-wax drippings” on indirect ophthalmoscopy, perivascular lymphocytic and neutrophilic infiltration, and vascular sheathing. Acid fast and Gomori methenamine silver stains for fungi and bacteria, respectively, should be negative, and there should be no signs of a foreign body inciting the reaction.
Sarcoidosis resembles other granulomatous diseases on histology, such as histoplasmosis, leprosy, and tuberculosis based on the discrete pattern in which cellular infiltration is arranged ; the infrequency of necrosis and the occasional distinctive asteroid and Schaumann bodies can be seen on sarcoid nodules.
Sympathetic ophthalmia
SO is a Type 4 delayed hypersensitivity inflammatory reaction against the RPE or uveal melanocytes. This reaction is stimulated by a traumatic or postoperative insult to the eye, which can lead to infiltration of the opposing eye. Full development of the disease can take 3 months in 80% of cases and up to 1 year in 90% of cases after injury. However, 6 months after the injury, removal of the injured eye has little effect on the disease progression. Immunogenetic makers human leukocyte antigen (HLA)-DRB1*04 and DQA1*03 are significantly associated with SO; these markers are also associated with VKH syndrome; therefore, their clinical manifestations are quite similar. Although histology can be used to characterize SO, it remains a clinical diagnosis.
Histopathology
It is characterized as a diffuse granulomatous T-cell infiltration of the uveal tissue. A granuloma is primarily composed of epitheliod cells, which are activated macrophages resembling epithelial cells that are surrounded by lymphocytes. Lymphocytic infiltration consists mostly of T-cell lymphocytes; however, B cells comprise of 20% of the lymphocytes in most cases. This massive infiltration leads to choroidal thickening. Many eosinophils are present, whereas plasma cells are fewer in number, and the presence of neutrophils is rare.
In early stages, the infiltrating epithelioid cells contain phagocytosed uveal melanin granules. Moreover, epithelial cells are nested in small and scattered areas with eosinophils in the lymphocytic zones. As the lesion grows, these nests converge, giving an appearance of areas with dark and light staining on histological sections; areas that stain pale and darkly correspond to epitheliod cell and lymphocytic cell infiltration, respectively. Infiltration can further extend from the choroid into the sclera or into the optic nerve.
An important feature that distinguishes this disease from other granulomatous endophthalmititis is that it does not involve massive destruction of the pigmented epithelium and retina. The infiltrative inflammatory response typically does not involve Bruch’s membrane and the choriocapillaris. Dalen–Fuchs nodules are present mostly in the periphery in between Bruch’s membrane and the RPE. The nodule are composed of epitheloid cells, histiocytes, and depigmented RPE cells. Immunohistochemical analysis of Dalen–Fuchs nodules reveals that macrophages are positive for CD68 and RPE cells are positive for cytokeratin 18. Although characteristic of SO, Dalen–Fuchs are only observed in 25–42% of cases.
Histopathology
Congenital Disorders: Coloboma
Choroidal coloboma is characterized as a failure of the inner and outer layers to fuse along the optic fissure. Typical colobomas of the choroid occur in the region of the fetal fissure, whereas atypical examples occur elsewhere. Complete uveal colobomas extend from the lower nasal region of the disk to the pupillary margin of the iris. Typical colobomas often show an abnormally thin and somewhat ectatic sclera. The outermost vascular and pigmented layers of the choroid are usually missing and are represented by atrophic nonpigmented mesodermal remnants. The choroidal defect is covered by dysplastic retina. The pigmented layer of the retina may end at the edge of the coloboma, or a few small atypical cells may extend beyond this point. The neural portion of the retina is rarely normal. Commonly, it blends with undifferentiated choroid to form an attenuated intercalary membrane that bridges the defect. Occasionally, the retina folds inward over the lip of the fissure and is continued as a membrane composed of one or two layers of cells in which rods, cones, glial cells, rosettes, and cysts can be recognized.
The pathologic picture of atypical colobomas is similar to that of the typical ones, except that more choroidal and retinal elements are present. The pathogenesis of this type of defect is obscure.
Inflammatory Disease
Nongranulomatous inflammation
Nongranulomatous uveal inflammations are the most common types of uveitis and usually present as iridocyclitis, characterized by an unspecific type of inflammatory reaction. The origin is frequently unknown. They can be suppurative or nonsuppurative. Suppurative nongranulomatous inflammation is an acute nongranulomatous purulent inflammatory reaction in which the predominant cell type is the polymorphonuclear leukocyte. It is usually secondary to bacterial infection. Nonsuppurative nongranulomatous inflammation can be either acute or chronic. In the acute inflammation, the predominant cell type is the neutrophil, and in chronic inflammation it is the lymphocyte and the plasma cell.
In histopathology, nongranulomatous processes can be defined as a predominantly exudative and alterative process. Contrary proliferative changes are subtle (i.e., granulomas, lymphoid aggregates, and exuberant granulation tissue). Plasma cells commonly predominate, and plasmacytoid cells and Russell’s bodies quite often are numerous. These cell types are particularly characteristic of nongranulomatous iritis, and since they are believed to be linked with antibody production, this form of uveitis may represent a local tissue response to antigenic stimulation.
As a sequelae of uveitis, the choroid may show focal or diffuse areas of atrophy or scarring. Retinochoroiditis or chorioretinitis may destroy Bruch’s membrane and the RPE, furthermore, the choroid and retina may become fused by fibrosis, and a chorioretinal scar or adhesion results.
Behçet’s disease
Behçet’s disease (syndrome) is characterized by retinal vasculitis, recurrent bilateral iridocyclitis with hypopyon, aphtous ulcers of the mouth and genitalia, dermatitis, arthralgia, thrombophlebitis, and neurologic disturbances. The disease is most common in men, especially between the ages of 20 years and 30 years. Also, men have more severe involvement and are at a greater risk of vision loss than women. Prevalence of Behçet’s disease worldwide ranges between 0.1/1000 and 1/10,000, with a significant presence in Asia. The lesions of the skin and mucous membrane most often appear before those of the eyes. Ocular inflammation occurs in about 70–80% of the patients. The etiology is unknown, and the disease appears to be more common in the Mediterranean countries.
Regarding ophthalmic examination, fluorescein angiography shows choroidal involvement. In addition, choroidal thickening has been shown using A-scan ecography, and more recently, enhanced depth imaging optical coherence tomography (EDI-OCT) has become an excellent tool to visualize choroidal layers and confirm its thickening in Behçet’s syndrome.
Pathological examination of the eyes diagnosed as Behçet’s disease shows a serohemorrhagic exudate containing polymorphonuclear leukocytes in the vitreous and in the anterior and posterior chambers. There are extensive areas of retinal necrosis. Depending on the stage of the disease, mononuclear and polymorphonuclear leukocytes can be found in the choroid. The choroidal infiltrate is predominantly composed of CD4 T lymphocytes, with some B lymphocytes and plasma cells ( Fig. 3.3 ).
