Overview
Uveitis can be infectious or noninfectious in origin. Although the most common etiology of uveitis is considered to be immune-mediated in developed countries, there remain many cases of uveitis caused by infectious agents. Infectious uveitis can become latent, smoldering, and chronic and mimic autoimmune uveitis. While autoimmune uveitis responds to corticosteroids or immunosuppressive chemotherapy, such treatment may worsen infectious uveitis. It is, therefore, essential to identify cases of chronic uveitis caused by microbes in order to initiate specific and appropriate antimicrobial therapy. The diagnosis of infectious uveitis can be established in most cases based on patient demographics, mode of onset of and morphology of the lesions, and the association with other systemic infectious diseases. Laboratory testing and imaging techniques are important tools that help refine the diagnosis. In this chapter, some of the major bacterial, viral, and parasitic infections leading to uveitis are discussed.
Herpesviruses
Herpes group of viruses are ubiquitous in nature and can be found in nearly all animal species. Several different herpesviruses have been described so far and eight of them are found in humans: herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), varicella-zoster virus (VZV), human cytomegalovirus (CMV), Epstein–Barr virus (EBV) and human herpesviruses 6, 7, and 8 (HHV-6, HHV-7, and HHV-8).
Herpes simplex retinitis has been discussed in Chapter 80 . This section therefore covers CMV, EBV, and VZV.
Cytomegalovirus
Clinical background
Key symptoms and signs
CMV retinitis commonly affects the peripheral retina and symptoms of early disease may be minimal or absent. Blurring, floaters and central scotomas may develop with the affection of the central retina.
Historical development
CMV eye disease was first reported in 1947, being a rare clinical entity mostly seen in adults under medical immunosuppression. In the 1980s, with the acquired immunodeficiency syndrome (AIDS) pandemic, CMV became a frequent form of posterior uveitis. In the mid-1990s, before the introduction of highly active antiretroviral therapy (HAART), about 30% of patients with AIDS developed CMV retinitis during their lifetime. However, the introduction of HAART achieved a 75% reduction in the incidence of CMV retinitis.
Epidemiology
About half of the normal population has antibodies against CMV. However, CMV infection in immunocompetent hosts does not usually produce symptomatic disease. The mode of transmission is by direct person-to-person contact and the virus is shed predominantly in urine, saliva, and semen. Most of the CMV retinitis cases result from reactivation of previously acquired disease. In patients with AIDS, CMV is one of the most common opportunistic infection. CMV retinitis usually presents in an advanced disease stage and is strongly associated with a low CD4+ T-cell count below 50 cells/mm 3 .
Diagnostic workup
The diagnosis is principally based clinically, with the typical clinical features in an immunocompromised patient. Detection of anti-CMV antibody from the vitreous and/or aqueous humor (and comparing it with the serum levels using the Goldmann–Witmer coefficient) can be helpful in selected cases. Viral culture and polymerase chain reaction (PCR) from ocular tissue (if other malignant entities are suspected) or fluid can demonstrate the existence of viral DNA, but it is important to remember that this does not directly confirm the diagnosis of CMV retinitis, because CMV can persist in the tissue without causing disease.
Differential diagnosis
CMV retinitis must be differentiated from retinitis due to HSV or VZV, syphilitic retinitis, toxoplasma retinochoroiditis, intraocular lymphomas and fungal infections.
Treatment
The first step is to improve, if possible, the immune status of the patient. In AIDS, HAART therapy has demonstrated immune reconstruction and is beneficial not only for prevention, but also for treating CMV retinitis. Systemic and local anti-CMV drugs are needed in almost all AIDS patients. The most common include ganciclovir, foscarnet, and cidofovir. Others approved for treatment include fomivirsen and valganciclovir. These drugs are usually administered systemically, but in patients with intolerance or progression, intravitreal (injections or implants) ganciclovir or foscarnet can also be considered. The size of the lesion will be the main sign to evaluate the response to the treatment. In chronic immunocompromised patients, the anti-CMV therapy must be maintained indefinitely.
Prognosis and complications
Rhegmatogenous retinal detachment (RD) is a common complication of CMV retinitis. This is usually associated with retinal necrosis and multiple retinal breaks. A vitrectomy with silicone oil tamponade has been shown to be an effective treatment for patients who have an RD caused by CMV retinitis.
The course of CMV retinitis in the HAART era shows that the rate of retinitis progression is decreased compared with the pre-HAART era, even among those with low CD4+ T-cell counts. The incidence of visual impairment during follow-up after CMV retinitis is substantially lower among patients who receive HAART, especially those observed to have immune recovery. However, among patients with CD4+ T-cell counts less than 50 cells/mm 3 , while on HAART, the rates were more similar to those from the pre-HAART era.
Pathology
CMV retinitis is a slowly expanding lesion, usually beginning as a small, white, retinal infiltrate ( Figure 83.1 ). Initially, it can simulate a cottonwool spot, commonly present in human immunodeficiency virus (HIV) retinopathy. The clinical features, representing distinct manifestations of the same entity, are mainly:
- 1.
Granular, white, multifocal satellite lesions of patchy retinitis (may represent infection of a terminal vessel) with limited or no retinal hemorrhage. This variant often shows a central atrophic zone.
- 2.
Arc-shaped solitary expanding patch of retinitis, usually concurrent with multiple retinal hemorrhages and no atrophic zone in the center of the lesion. This variant is normally referred to as “fulminant” retinitis and is probably caused by infection of the major vascular arcades.
- 3.
Sometimes, in CMV retinitis, the perivasculitis may be predominant with some retinal necrosis. This variant is called “frosted-branch angiitis CMV retinitis.” The degree of vitritis in these patients is typically low because of the extreme immunosuppression.
Etiology
CMV, a human herpesvirus, is an omnipresent microbe in the general population, but it seldom causes clinically apparent disease in an immunocompetent individual. Neonates and immunocompromised patients are the main groups at risk for CMV retinitis, which is the most frequent cause of blindness among patients with AIDS.
Pathophysiology
After primary infection, CMV remains in its host, establishing a latent infection typical for all herpesviruses. CMV generally reactivates from latency associated with T-cell impairment. In most cases, the retina is infected via hematogenous spread. Damage of capillary endothelial cells caused by HIV infection probably facilitates the passage of CMV-infected cells through the blood–retinal barrier.
Epstein–Barr virus
Clinical background
Key symptoms and signs
EBV may affect the eye in many different ways, usually as conjunctivitis or uveitis, and often occurs in primary infec tions in the context of infectious mononucleosis. Follicular conjunctivitis is the most frequent ocular feature. Severe bilateral iritis and iridocyclitis have also been reported. Almost all structures of the posterior segment can be affected. Macular edema, retinal hemorrhages, punctate outer retinitis with secondary subretinal neovascularization, and subretinal fibrosis may occur. Multifocal choroiditis and other posterior-segment pathologies are uncommon and have been described in patients with infectious mononucleosis and, more recently, in patients suffering from X-linked lymphoproliferative disorder, AIDS, or even in otherwise healthy individuals.
Historical development
EBV was first isolated in 1964 from a cultured Burkitt’s lymphoma cell line. During recent decades, EBV has been implicated in a broad spectrum of human diseases like infectious mononucleosis, anaplastic nasopharyngeal carcinoma, and B-cell lymphomas, among others.
Epidemiology
EBV infection is distributed worldwide. Antibodies against EBV can be detected in approximately 90% of the population but only a few suffer from ocular disease.
Transmission requires contact with body fluids, primarily saliva, but also through blood transfusions. Primary infection is usually subclinical or leads to mild symptoms typical of a nonspecific viral illness, but in some cases it takes the clinical picture of infectious mononucleosis, especially when it affects adolescents.
Diagnostic workup
Serum antibody titers against EBV may be helpful, especially if the initial high levels are followed by a subsequent decrease coinciding with the resolution of the acute phase. Other techniques like PCR or biopsy of the affected tissues may also be helpful in selected cases.
Differential diagnosis
Posterior-segment findings may appear similar to those caused by tuberculosis, syphilis, or sarcoidosis. Retinal and choroidal infiltrations may be confused with acute phases of toxoplasmosis, histoplasmosis, or white-dot syndromes.
Treatment
Ocular disease is commonly self-limiting and no treatment is indicated. Uveitis sometimes requires corticosteroid therapy. Severe cases, especially those rare instances where the posterior segment is affected, may require similar antiviral agents as those used in acute retinal necrosis syndrome: intravenous aciclovir, ganciclovir, brivudine, valganciclovir, and foscarnet.
Prognosis and complications
The panuveitis and choroiditis in patients with EBV infection can be complicated by macular edema and cataract formation. Visual prognosis is usually poor in patients with chronic smoldering chorioretinitis leading to subretinal neovascularization or cystoid macular edema.
Pathophysiology
EBV shows B-cell tropism. However, the precise role of this virus in associated diseases is not well understood, but defective immunosurveillance against the virus may permit an uncontrolled proliferation of EBV-infected cells.
EBV belongs to the gamma herpesvirus family.
Varicella-zoster virus
Clinical background
Key symptoms and signs
Systemic manifestations
Systemic manifestations consist of general malaise, fever, and headache. Subsequently, the characteristic papules, macules, vesicles, and, later, crusting occur with VZV.
Ocular manifestations
Ocular manifestations include trabeculitis, iridocyclitis, acute retinal necrosis ( Figure 83.2 ), and variants of necrotizing herpetic retinopathy. Inflammation of the endothelium occurs relatively early in the course of disease and leads to stromal and epithelial edema. Endotheliitis is typically accompanied by signs of mild anterior-chamber inflammation. Keratic precipitates often appear under affected regions of the cornea and they can be either small or large (mutton fat). Iridocyclitis tends to occur within 1–2 weeks of disease onset, but can appear many months later. Later, inflammation is mediated by an immune reaction against persistent viral antigen presence in the corneal stroma. Sectoral occlu sion of the iris vasculature leads to atrophic sectoral patches in approximately 20% of cases and can produce hypopigmentation or, infrequently, hyperpigmentation, and iris sphincter damage.
Historical development
Giovanni Filippo provided the first description of the varicella virus. Herpesvirus infections of the uvea were characterized in the late 1970s and Culbertson and associates proved the pathogenic connection of herpesviruses in 1982.
Epidemiology
Ninety percent of the population demonstrates serologic evidence of exposure to VZV by age 60, but only 20% will have experienced an episode of viral reactivation.
Diagnostic workup
The diagnosis is based on a typical clinical picture of unilateral involvement, corneal hypoesthesia, and pattern of keratic precipitates, mild flare and cells in the anterior chamber with foci of iris stromal sectorial atrophy. Aqueous humor aspirates can be analyzed for antibodies directed against VZV by enzyme-linked immunosorbent assay (ELISA). Viral DNA within the aqueous can be detected by PCR technology.
Differential diagnosis
Other viruses of the herpes family, like CMV, EBV, and HSV, can mimic iridocyclitis caused by VZV. Syphilis, tuberculosis, leprosy, lymphogranuloma venereum, and chronic myelomonocytic leukemia can also be considered.
Treatment
Systemic antivirals are the mainstay management of VZV uveitis – usually oral aciclovir but also famciclovir and valaciclovir (a prodrug of aciclovir). Topical corticosteroids are used to control iridocyclitis and the inflammatory manifestations of corneal disease, including disciform keratitis, endotheliitis, and keratouveitis. In the acute stages, cycloplegic agents are used to relieve the discomfort of photophobia and prevent the formation of synechiae.
Prognosis and complications
The most frequent ocular complication is secondary glaucoma. Posterior pole complications can develop and these include cystoid macular edema, epiretinal membrane, papillitis, retinal fibrosis, and detachment. VZV uveitis typically runs a chronic course and visual prognosis is dependent on the severity of complications and its treatment.
Pathology
Histologic reports on VZV uveitis have revealed perineuritis and perivasculitis with infiltration by chronic inflammatory cells consisting of plasma cells and lymphocytes. Occlusive vasculitis plays an important role in sectoral iris atrophy.
Etiology
Primary infection with VZV causes varicella disease (“chickenpox”) and reactivation of the virus leads to zoster (“shingles”).
Pathophysiology
VZV establishes its latent phase in the satellite cells of sensory ganglia; the thoracic and lumbar dermatomes are most frequently involved clinically. The trigeminal ganglion is often also infected. In the pathogenesis of persistent or recrudescent viral ocular disease, immune reactions against viral antigens and against tissue autoantigens produced from viral damage play a major role.
HSV-1, HSV-2, VZV, and HHV-8 belong to the subfamily of alpha herpesviruses. The clinical picture of various forms of intraocular inflammation caused by alpha herpesviruses is similar and therefore it may be difficult to distinguish VZV from HSV. Nevertheless, HSV as a cause of iridocyclitis and trabeculitis is often overlooked. Corneal lesions ( Figure 83.3 ) or a history of herpetic keratitis in an eye with iritis must be considered herpetic in origin unless proven otherwise. A high degree of suspicion for HSV anterior uveitis must be maintained in unilateral involvement diminished corneal sensation and typical iris stromal atrophy. This condition responds promptly to aciclovir therapy, which may be required chronically. Diagnosis of HSV can be confirmed by PCR testing of the aqueous humor for herpetic DNA ( Box 83.1 ).
- •
Cytomegalovirus retinitis: slowly expanding white infiltrate in the peripheral retina
- •
Granular, white, multifocal satellite lesions of patchy retinitis with limited or no retinal hemorrhages
- •
Arc-shaped solitary expanding patch of retinitis with multiple retinal hemorrhages
- •
Extensive perivasculitis with “frosted-branch angiitis” appearance
- •
- •
Epstein–Barr virus: follicular conjunctivitis is the most frequent ocular feature
- •
Anterior and posterior uveitis may occur
- •
- •
Varicella-zoster virus: anterior/posterior-segment findings
- •
Keratitis
- •
Iritis/iridocyclitis
- •
Trabeculitis
- •
Acute retinal necrosis
- •
- •
Herpes simplex virus: spectrum of ocular signs similar to varicella-zoster virus; high degree of suspicion if:
- •
Corneal hypoesthesia
- •
Iris stromal atrophy and transillumination defects
- •
Other viruses causing uveitis are summarized in Table 83.1 .
| Disease | Organism | Ocular signs and symptoms | Transmission | Treatment |
|---|---|---|---|---|
| Rift Valley fever | Plebovirus | Anterior uveitis | Mosquito | Ribavirin * |
| Vitritis | Culex | RVF MP-12 vaccine * | ||
| Macular exudative lesions | Aedes | |||
| Retinal edema | ||||
| Retinal hemorrhage | ||||
| Retinal vasculitis | ||||
| Measles | Morbillivirus | Retinopathy | Respiratory secretions | Self-limiting |
| Retinitis | Gamma-globulin | |||
| Retinochoroidal atrophy | IFN-alpha | |||
| Macular star | Inosiplex | |||
| Papillitis | IVIg + Inosiplex | |||
| Arteriolar attenuation | Vitamin A | |||
| Rubella | Rubella virus | Pigmentary retinopathy | Transplacental | Self-limiting |
| Retinitis | Transcervical | Systemic steroids | ||
| Subretinal neovascularization | Respiratory secretions | |||
| Subretinal hemorrhages | ||||
| Disciform scarring | ||||
| Optic neuritis | ||||
| Retinal detachments |
Bartonella
Clinical background
Key symptoms and signs
Systemic manifestations include myalgia, malaise, fatigue, low-grade fever, and lymphadenopathy. Ocular manifestations are typically unilateral and can present in both immunocompetent and immunocompromised patients. Neuroretinitis appears to be most common and is usually unilateral, with optic disc edema ( Figure 83.4 ) and a macular star. A multifocal retinitis and/or choroiditis can also develop, as can chorioretinitis, serous macular detachments, intraretinal hemorrhages, cottonwool spots, Parinaud’s oculoglandular syndrome, conjunctivitis, anterior and posterior uveitis, and vascular lesions of the optic nerve.
Historical development
Barton described the first human Bartonella infection in 1909. Foshay created the term “cat-scratch fever” in 1932. Sweeny and Drance made the correlation between intraocular inflammation and cat-scratch disease (CSD) in 1970.
Epidemiology
CSD has been shown to be a worldwide zoonotic infection with the reservoir for Bartonella henselae in domestic cats. CSD is the leading cause of regional lymphadenopathy in children and young adults worldwide. Prevalence of neuroretinitis in the context of CSD is approximately 1–2%. The infection is not known to be transmitted from human to human. The prevalence of CSD in the USA is approximately 22 000 cases per year.
Diagnostic workup
The diagnosis of CSD is primarily based on clinical features supported by laboratory testing with detection of DNA of B. henselae by PCR technology using a very small sample of serum or other body fluids. Other tests include enzyme immunoassay (EIA) and Western blot test.
Differential diagnosis
Other causes of regional lymphadenopathy and conjunctivitis include tularemia, sporotrichosis, tuberculosis, syphilis, lymphogranuloma venereum, leprosy, and Yersinia . Neuroretinitis may be seen in syphilis, tuberculosis, toxoplasmosis, varicella, herpes simplex, toxocariasis, leptospirosis, and infectious mononucleosis. A macular star with vitritis can be seen in toxoplasmosis and vascular disorders such as anterior ischemic optic neuropathy, acute systemic hypertension, and increased intracranial pressures.
Treatment
There are no formalized guidelines which one can follow to treat the ocular complications associated with B. henselae . Despite this, several groups have used oral ciprofloxacin, prednisone, and doxycycline, with favorable responses. Elevated immunoglobulin (Ig) M or IgG titers for B. henselae can be suggestive of current or past infection.
Prognosis and complications
CSD typically runs a self-limiting course in immunocompetent hosts. Antimicrobial therapy in immunocompromised hosts results in a dramatic response and hence these have been recommended for severe ocular or systemic complications of CSD. Visual prognosis of most patients with CSD-associated neuroretinitis is therefore excellent.
Etiology
B. henselae , one of the four human species of Bartonella , has been implicated as the cause of CSD. This species predominantly causes neuroretinitis, while the three others cause endocarditis ( B. elizabethae ), Carrion’s disease ( B. bacilliformis ), and trench fever ( B. quintana ). Regnery et al showed that 86% of patients with CSD had B. henselae antibodies as compared to 6% of those who were healthy patients. PCR assays have shown that infected cats harbor fleas infected by B. henselae . Transmission from cat to cat occurs via the cat flea Ctenocephalides felis . It is thought to be central to the pathogenesis of CSD in human beings, perhaps by dropping contaminated feces on to the fur and dander of infested cats. The predominant mode of transmission of B. henselae is through a cat bite or scratch.
Pathophysiology
The exact pathophysiology of CSD-associated neuroretinitis is not completely understood. Intraocular infection or direct involvement of the optic nerve by B. henselae has been implicated ( Box 83.2 ). The ocular findings may also represent a parainfectious inflammatory response.
- •
Zoonosis
- •
Reservoir of B. henselae in cats
- •
Affects children and young adults
- •
Presents with oculoglandular syndrome
- •
Neuroretinitis may be the foremost ocular manifestation
- •
Oral antibiotics (tetracyclines) and oral corticosteroids may be used for treatment
Syphilis
Clinical background
Key symptoms and signs
Systemic manifestations
Primary syphilis is characterized by a chancre at the inoculation site that appears 2–6 weeks after infection and resolves about 4 weeks after its appearance. If untreated, the disease progresses to secondary syphilis, with generalized maculopapular rash and lymphadenopathy. The rash typically affects the palms and soles, and can be accompanied by fever, malaise, headache, nausea, hair loss, mouth ulcers, and joint pain. At this stage, the eyes are affected in 10% of cases. Then, during the latent stage, there are no evident systemic disease manifestations, and the infection is not contagious. This stage can last for the patient’s lifetime. Tertiary syphilis can affect any system, but mainly the cardiovascular (aortitis, aortic aneurysm, aortic valve insufficiency) and neurologic system (meningovascular syphilis, tabes dorsalis). The typical lesion in this stage is the gumma, which is a granuloma, and can be found anywhere in the body.
Ocular manifestations
Most patients with syphilitic uveitis develop it during the latent stage of the infection. Anterior uveitis may be unilateral or bilateral, granulomatous, or nongranulomatous. It can present with iris nodules or atrophy, anterior-chamber cells with or without anterior vitritis, dilated iris vessels, interstitial keratitis, and lens dislocation. Syphilis can affect the posterior segment ( Figure 83.5 ), most commonly causing chorioretinitis. The fundus lesions are usually grayish yellow in color. Other manifestations include disc edema, arterial or venous vasculitis, vitritis, intermediate uveitis, serous RD, neuroretinitis, and necrotizing retinitis. Complications include glaucoma, cataracts, macular edema, and choroidal neovascular membranes.
Historical development
Schaudin and Hoffman isolated the spirochete in 1905 from the skin lesions of infected patients.
Epidemiology
Although it was the second leading cause of uveitis before the 1940s, currently it comprises about 1–2% of all uveitis cases.
Diagnostic workup
Available nonspecific serological tests that quantify the amount of serum anticardiolipin antibody are the rapid plasma reagin (RPR) and the Venereal Disease Research Laboratory (VDRL). The results depend on the status of infection and treatment. Titers are usually high in active infection, but drop when the disease is not active (latent infection or after successful treatment). Specific tests measure the amount of serum antibody against treponemal antigens. The fluorescent treponemal antigen absorption test (FTA-ABS) is the one mostly used. This test becomes positive during the secondary stage of syphilis and remains positive for the patient’s lifetime. This test is more sensitive during the latent stage, which is when uveitis usually develops. With the microhemagglutination assay for T. pallidum (MHA-TP) test, treponemes can be visualized by incubating infected body fluid (from chancre or skin pustule) with fluorescent-tagged antibody and visualizing it under dark-field microscopy. The T. pallidum particle agglutination test (TP-PA) is used to confirm a positive FTA-ABS. Patients with uveitis who are diagnosed with syphilis must have examination of the cerebrospinal fluid.
Differential diagnosis
Syphilitic uveitis must be differentiated from other causes of granulomatous uveitis like tuberculosis, leprosy, sarcoidosis, and herpes. It is also in the differential diagnosis of intermediate uveitis and therefore may be confused with Lyme disease or sarcoidosis.
Treatment
Penicillin is the treatment of choice in syphilis, either intramuscular or intravenous. As syphilitic uveitis is considered a form of neurosyphilis, the intravenous regimen is favored. Alternative treatments for penicillin-allergic patients include doxycycline or tetracycline. Penicillin desensitization is another option for these patients.
Prognosis and complications
Complications from syphilitic uveitis include cataracts, glaucoma, macular edema, epiretinal membranes, RD, chorioretinitis, and neovascular memebranes. Complications secondary to treatment include Jarisch–Herxheimer reaction manifesting as fever, myalgia, malaise, and headache.
Syphilis, if recognized early and treated appropriately, can result in a cure. If untreated, prolonged syphilitic disease can permanently damage the eye and can result in significant morbidity and mortality due to cardiovascular complications.
Etiology
Syphilis is an infection caused by the spirochete Treponema pallidum . It can mimic many different diseases throughout its course, for which is has been called the “great imitator” ( Box 83.3 ). It can persist in the affected person for a lifetime, and if left untreated can progress through four stages. It is a sexually transmitted disease, which enters the body through the genitals, mouth, or skin breaks.
