Infectious Sources of Uveitis

Determining the infectious agent is often the first step in determining the treatment.

IRFAN KHAN, MD • ASHVINI K. REDDY, MD

The evaluation and management of patients with ocular inflammation can be challenging due to subtle ocular and systemic exam findings, the presence of uveitis masquerades, and the recognition that other patient factors and a careful history may be critical for making a correct diagnosis.

Assessing a patient with uveitis is in some ways very systematic, because it is important to perform a comprehensive history and physical examination. At the same time, further diagnostic workup tends to be focused and tailored to what is garnered from the initial evaluation. Ordering inappropriate and excessive testing can often lead to more questions than answers.

An integral aspect of management is determining whether the observed inflammation is autoimmune or whether there is a potentially infectious etiology. Before a patient is treated with corticosteroids or other immunomodulatory therapy, it is prudent to consider the possibility of several common infectious causes of uveitis because steroid monotherapy can lead to fulminant infection that can be both sight- and life-threatening.

TOXOPLASMOSIS

Intraocular infection with the parasite Toxoplasma gondii is one of the most common causes of posterior uveitis worldwide.¹ Initially believed to solely represent reactivation of congenital infection, it is now accepted that newly acquired postnatal infection is an important cause of the retinochoroiditis seen in ocular toxoplasmosis.²

The classic fundus appearance of ocular toxoplasmosis is a unilateral focus of creamy, white retinochoroiditis adjacent to a variably pigmented chorioretinal scar.³ There is typically significant overlying vitritis.

Fluorescein angiography often reveals an associated retinal vasculitis both adjacent to and remote from the active region of retinitis. Anterior-chamber cells often occur in the setting of active retinitis and may be associated with elevated intraocular pressure.

Atypical presentations of ocular toxoplasmosis include optic nerve involvement (pure papillitis or retinitis centered at the optic nerve). Other rare presentations described in the literature include a punctate outer retinal inflammatory response, a Coats-like retinopathy, retinal vascular occlusion, optic disc granuloma, and scleritis.^4-5

Determination of the immune status of an individual with ocular toxoplasmosis is critical because immunocompromised individuals frequently demonstrate a fulminant course. Patients with AIDS are susceptible to acute and reactive infections.

Congenital toxoplasmosis develops in 30% to 50% of infants whose mothers are first infected during pregnancy, with 70% to 90% of affected infants developing retinochoroiditis.^1-2

The diagnosis of ocular toxoplasmosis is based on the characteristic clinical findings in the majority of cases. Serological testing for T. gondii plays little role in the diagnosis of ocular toxoplasmosis because of the high seropositivity in many populations. Its primary use remains the exclusion of toxoplasmosis as the cause of posterior uveitis when serum IgG is absent.

Toxoplasma-specific polymerase chain reaction (PCR) performed on ocular fluid samples is a more sensitive and specific method of diagnosing infection, although its yield seems to be less than PCR for herpes viruses.

Treatment of Ocular Toxoplasmosis

Initial treatment for ocular toxoplasmosis is variable and, to some extent, regional.⁶ In an immunocompetent individual, the infection and resultant inflammatory response is expected to remit spontaneously without treatment in one to two months.

Most providers choose to treat when there is reduction in visual acuity, a lesion located within the temporal arcades or adjacent to the optic disc, or vitreous haze above grade 1+. Because there is no antimicrobial agent that has been shown to cure infection in the human host, the goal of treatment is to limit multiplication of the parasite during episodes of active retinitis.

Classic triple-drug therapy refers to the combination of pyrimethamine-sulfadiazine and systemic corticosteroid. Newer treatment regimens include trimethoprim-sulfamethoxazole monotherapy, azithromycin monotherapy (often in sulfa-allergic patients), and both oral and intravitreal clindamycin.^7,8

Rothova et al⁹ compared classic triple therapy, the combination of clindamycin, sulfadiazine, and systemic corticosteroid, and the combination of trimethoprim, sulfamethoxazole, and corticosteroid in the treatment of ocular toxoplasmosis. There were no significant differences in the duration of active retinitis or the rates of recurrence among the different treatment groups. Additionally, trimethoprim-sulfamethoxazole may be used to prevent recurrent attacks of ocular toxoplasmosis when taken orally three times weekly.

SYPHILIS

The famous early 20th century physician Sir William Osler once stated, “He who knows syphilis knows medicine.” Undoubtedly, Osler was referring to the myriad manifestations of this spirochetal disease, which also applies to the spectrum of ophthalmic inflammatory diseases that can result from infection.

Syphilis is caused by the spirochete Treponema pallidum, an organism transmitted almost exclusively by sexual contact. In addition, transplacental spread can cause congenital infection.

The infection occurs in phases. Primary syphilis is characterized by a chancre, an erythematous papule that evolves into a painless ulcer at the site of inoculation. If untreated, those with primary syphilis progress to secondary syphilis four to 10 weeks after the appearance of the chancre.

Secondary syphilis is typified by lymphadenopathy and a maculopapular rash that often presents on the palms and soles. Ocular inflammation can occur during secondary syphilis, with conjunctivitis and anterior uveitis being the most common early findings.

Finally, untreated individuals may develop tertiary syphilis after a variable period of latency, with the manifestations ranging from characteristic skin lesions (gummas) to cardiac and central nervous system involvement.

Ocular disease may occur in any phase of infection, with chancres of the eyelid and conjunctiva reported during primary syphilis and inflammation of essentially any portion of the ocular surface, adnexa, and uveal tract described in secondary or tertiary syphilis. In tertiary syphilis, posterior findings are believed to predominate, with chorioretinitis, neuroretinitis, and occlusive vascular disease all being observed.

With the manifestations of ocular disease caused by syphilis being so variable, diagnosis rests on high clinical suspicion and serologic testing. Obtaining syphilis serology remains a part of nearly every uveitis workup.

Since its discovery in 1943, the antibiotic penicillin has been the mainstay in therapy for syphilis. The presence of ocular disease warrants treatment with IV penicillin for 10 to 14 days, even if cerebrospinal fluid analysis is normal.¹⁰

Finally, the diagnosis of syphilis necessitates testing for HIV, because coinfection is common due to similar risk factors.^11,12 In addition, some reports have suggested that individuals with HIV coinfection may have an increased risk of ocular complications from syphilitic uveitis and may be prone to developing a rapidly progressive retinitis.

VIRAL UVEITIS

While a comprehensive review of all of the viruses that may contribute to ocular inflammatory disease is beyond the scope of this discussion, Herpesviridae is a family of viruses that are ubiquitous and present worldwide.

The herpes virus family includes herpes simplex virus (HSV), varicella zoster virus (VZV), and cytomegalovirus (CMV). They share a common feature of life-long persistence of their genome within their hosts after initial infection and the potential for future reactivation. Herpes viruses are regarded as an important cause of infectious anterior uveitis. HSV, VZV, and CMV have all been associated with recurrent, acute, and chronic anterior uveitis.¹³

HSV-associated anterior uveitis is typically recurrent in nature, with patients presenting with IOP elevation, injection and moderate anterior chamber cells, and flare with granulomatous or nongranulomatous keratic precipitates.¹⁴ Careful examination may reveal the presence of corneal scars in 33% of cases and reduced corneal sensation. There may be dilated iris blood vessels and segmental iridoplegia.

Additionally, there may be visible sectoral iris transillumination defects from previous episodes of inflammation. VZV may present similarly in association with classic V1 zoster or more atypically without dermopathy. VZV anterior uveitis is more likely to develop a chronic inflammatory picture.

CMV anterior uveitis¹⁵ may be acute or chronic, with the acute form often presenting with marked IOP elevations and minimal anterior-chamber cells. The iris may manifest patchy or diffuse stromal atrophy.

In both the acute and chronic forms of CMV anterior uveitis, the keratic precipitates may be distributed in a ring pattern to form coin-shaped lesions, which are pathognomonic of CMV. In contrast to HSV and VZV, which have a worldwide distribution, CMV anterior uveitis has predominantly been reported among Chinese and Japanese individuals.

Acute Retinal Necrosis

Additionally, these same viruses can cause a necrotizing retinitis referred to as acute retinal necrosis (ARN) syndrome.¹⁶ The clinical features of this syndrome include a rapid onset of panuveitis, with retinal vasculitis and progressive peripheral retinitis (Figure 1). Rapid circumferential spread occurs within days. The destructive nature of the disorder is related to the rapid extension of vasculitis involving both retinal and choroidal vessels and occlusive periarteritis.

Figure 1. Fluorescein angiography demonstrating peripheral vascular nonperfusion in acute retinal necrosis.

Because approximately one-third of patients may develop involvement of the second eye, prompt antiviral treatment is critical. Even after successful treatment, the resulting retinal thinning and atrophy predispose to the development of retinal breaks and detachments.

While ARN syndrome is more commonly associated with VZV and HSV, CMV can cause its own characteristic retinitis in immunocompromised individuals (Figure 2). While classically observed in patients with AIDS and CD4+ counts less than 50 cells/mL (up to a 35% incidence when at this level), CMV retinitis can also occur with iatrogenic immunosuppression, such as in individuals who are post-organ transplantation.

Figure 2. CMV retinitis with frosted branch angiitis and retinitis.

In contrast to ARN, CMV retinitis¹⁷ is a relatively slowly progressive disease, with observed white-colored infiltrates that are more dense when in the posterior pole and that have a more granular appearance peripherally. The infiltrates may have significant associated retinal hemorrhage and often appear along retinal vessels. While anterior-chamber and vitreous cells may be present, they are typically minimal, even in cases of severe retinitis, reflecting the immunocompromised state of the patient.

The diagnosis of both viral anterior uveitis and retinitis can be aided with PCR to detect the presence of viral DNA in small samples of aqueous humor. The yield from diagnostic paracentesis can be enhanced if performed prior to instituting antiviral therapy and when active cells or IOP elevation is present for viral anterior uveitis.¹⁸ Serology is typically not helpful in the diagnosis of viral ocular inflammation because there is very high seroprevalence of antibodies against these viruses in most populations.

Prior to modern antiviral therapy and highly active antiretroviral therapy, the severity of viral retinitis and its potential for involvement of both eyes and resultant blindness necessitated IV antiviral therapy. Today, many patients are treated successfully on an outpatient basis with agents such as valacyclovir (Valtrex, GlaxoSmithKline, Philadelphia, PA)¹⁹ and valganciclovir (Valctye, Genentech, South San Francisco, CA).

TUBERCULOSIS

Exposure and latent infection with Mycobacterium tuberculosis is estimated to occur in one-third of the world’s population. While only a small portion of these individuals will manifest signs of intraocular tuberculosis, a high index of suspicion is necessary to make this diagnosis.^20,21

While tests such as the purified protein derivative skin test and Quantiferon (Valencia, CA) TB Gold test have high positive predictive values with regard to diagnosing past TB exposure, diagnosing active infection remains a significant challenge,²² particularly in the eye, in which culture, biopsy, and even PCR have poor yields.

There are some characteristic uveitic presentations that can be suggestive of intraocular tuberculosis. In a series reporting patients in the Netherlands with presumed TB uveitis, the most common presentation was a bilateral retinal vasculitis. In addition, a significant proportion of patients presented with a serpiginous-like chorioretinitis.²³

Management of tuberculous uveitis often involves an infectious disease expert and/or a public health department.

CONCLUSION

Prior to beginning any immunosuppressive therapy for uveitis, it is imperative to consider possible infectious etiologies. Infectious uveitis often requires specific antimicrobial therapy to result in resolution or suppression.

It is important to note that, even in cases of infectious uveitis, corticosteroids and other immunosuppressants are used in conjunction with antimicrobial therapy to suppress the potentially damaging associated intraocular inflammatory responses and to limit structural complications, such as retinal traction, anterior-segment synechiae, and cystoid macular edema.

Finally, the immune status of an individual with suspected infectious uveitis must be determined because the presentations may vary and be more severe in individuals with concurrent HIV infection or immunosuppression. RP

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