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Clinical Update: Retina
Ocular Toxoplasmosis: Complex Variations on a Theme
Up to a third of the world’s population is infected with the protozoan Toxoplasma gondii, and it’s the most common retinal infection in the United States, with nearly 5,000 cases of symptomatic ocular disease reported each year.
Those facts sound straightforward, but the epidemiology and medical management of Toxoplasma infections are anything but. Multiple sources of exposure, geographic differences in severity and a wide variety of treatment options create a complex picture. And with little interest from pharmaceutical companies in clinical trials, toxoplasmosis remains a largely neglected disease, said Rubens Belfort Jr., MD, PhD, professor of ophthalmology and chief of the Instituto da Visão of the Universidade Federal de São Paulo in Brazil.
Still, researchers and clinicians are continually refining their command of this challenging disease, with the overarching goal of finding a treatment that can eradicate the resistant form—the tissue cyst—which can hide dormant for years within the retina.
Prevalence and Severity
The prevalence of toxoplasmosis varies significantly around the world, ranging from as low as 2 percent to as high as 20 percent.1 That variation has sometimes been simplistically attributed to dietary habits (such as a higher consumption of raw meat), a warm and wet climate or large local populations of cats. But those factors don’t tell the whole story, said Gary N. Holland, MD, director of the Ocular Inflammatory Disease Center at the University of California, Los Angeles. Local outbreaks have revealed that drinking water, and possibly even dust blowing in the air, can be contaminated with oocysts.2 The interaction of many different factors may affect the epidemiology of toxoplasmosis, factors that include the infective parasite stage and genotype of the parasite, as well as the age and health of the host.
Why symptoms vary, or even fail to materialize. Dr. Holland said that Toxoplasma can remain asymptomatic in many individuals, or it may cause symptoms in a seemingly erratic fashion in various body systems. “For most people with normal immune systems, T. gondii is not particularly virulent and infection does not result in clinically apparent disease. However, the parasite is able to encyst, establishing a latent infection in a variety of tissues throughout the body, including the eye,” he said. “The factors that allow reactivation of parasites from those tissue cysts—and the factors that account for severe ocular disease in a minority of infected individuals—have not been established but are currently under investigation. One major influence appears to be the genetic makeup of different parasite strains. This influences virulence, but it is likely that other factors, including the integrity of the individual’s immune system, which in turn can be affected by factors such as aging, are also important.”
Newborns infected in utero, for example, are at higher risk for symptomatic disease due to their immature immune systems, said Dr. Holland. Likewise, waning immunity in the elderly can influence the severity of symptoms, as well as the risk for recurrence. 3 Variability also extends to the presence and severity of ocular symptoms, such as floaters, blurred vision, pain, redness and photophobia.
Genetics of the parasite. “In recent years, we’ve also come to realize that there are unique endemic strains in different parts of the world that vary considerably in virulence,” said Dr. Holland. For example, several new genotypes of T. gondii have been isolated in Brazil, suggesting that the genetic makeup of disease-causing strains is more varied than previously thought.4 Different strains potentially may have different effects on immune response, may vary in terms of tissue penetration and abilities to encyst and may contribute to different clinical outcomes in different locales.5
Fortunately, advances in molecular biology are providing new information about typing of the strains, said Dr. Belfort. Genotyping and serotyping are helping to sort out why some patients develop a worse clinical picture than others and why some countries, such as Brazil, have a higher incidence of ocular toxoplasmosis than others. More virulent strains of T. gondii in food animals, for example, may be partly to blame.
Congenital vs. acquired infection. Ocular toxoplasmosis was traditionally thought to result from congenital infection. Now it’s believed that most people with ocular toxoplasmosis have acquired their infections postnatally, said Dr. Holland, but all infected persons, regardless of how and when they were first exposed, are at risk for reactivation. “Once someone acquires a Toxoplasma gondii infection, that person is still at risk for eye disease months or years later,” said Dr. Holland, adding that many have transient eye inflammation at the time of the initial systemic infection, which suggests that parasites have furtively made their way to the eye. So even when the classic lesion is absent, a subclinical infection of tissue cysts may be present in the retina, which is the reason people remain at risk for later, clinical disease.
Diagnosis Still Mostly Clinical
Dense infiltration of the retina in a focal lesion with retinal necrosis is the hallmark of ocular toxoplasmosis, although the classic appearance of reactivation is a healed scar with a focus of inflammation at its border, said Dr. Holland.
“Serologic evidence of exposure to T. gondii serves as supportive evidence,” said Lihteh Wu, MD, consulting surgeon of ophthalmology in the vitreoretinal section at the Insituto de Cirugía Ocular in San José, Costa Rica. Analysis of intraocular fluids can be helpful in special cases such as in patients with AIDS, since ocular lesions in these patients can be due to other infections, Dr. Wu said.
“We have been doing PCR not only in the vitreous, but also in the aqueous and in the serum,” said Dr. Belfort, “because it is a reliable tool in the diagnosis of patients we are not sure about, especially those with chronic lesions that may be caused by herpes or other infectious agents.”
The “look” of the infection. Clinically, congenital and acquired infections may appear very similar, said Dr. Belfort. “After years of infection, it is impossible to differentiate between them.” Acquired infections, however, are more likely to be unilateral, with a lower prevalence of macular lesions, he said. “In our experience, about 10 percent of acquired toxoplasmosis cases develop ocular lesions, but only a small number of patients notice symptoms and are left with scars. During the acute phase of an acquired infection, the ocular lesion may be very subtle and the patient asymptomatic, which explains why many cases were not recognized in the past.”
Dr. Holland cautioned colleagues to take care in the evaluation of immunosuppressed patients, such as those on immunosuppressant drugs. “With the AIDS epidemic, CMV retinitis became the most common cause of a necrotizing retinopathy seen by most ophthalmologists, so they put it at the top of their list of differential diagnoses for any immunodeficient patient,” he said. “But among other immunosuppressed patients, toxoplasmosis is probably the most common ocular opportunistic infection.”
Immunocompromised patients may develop a more severe form of the disease, said Dr. Wu. “It may be characterized by extensive multifocal, often bilateral, retinal necrosis and panuveitis.”
Treat New and Recurrent Disease
Variation in the severity of the disease can make clinical trials more challenging. And the disease tends to be self-limiting, said Dr. Holland, which makes it difficult to confirm whether or not treatment is effective.
Acute stage: hastening healing. During the active stage of retinitis, the goal of treatment is to stop retinal damage by hampering multiplication of parasites, said Dr. Wu. “Systemic steroids are often added to avoid further damage to the retina from inflammation.” The ideal medication for ocular toxoplasmosis would not only attack the parasite, said Dr. Wu, but also concentrate in the eye, penetrate the cyst wall, have few adverse effects and be effective against both bradyzoites, the dormant form in tissue cysts, and tachyzoites, the proliferating form. No treatment currently fills all these criteria, and no clinical trial has strongly supported one approach over another.
Current regimens for active toxoplasmic retinitis include various oral combinations of
Doses may vary, but are not dependent on whether the disease is acute or recurrent, systemic or ocular, Dr. Belfort said. Dr. Holland added that dosing is not dependent on initial vs. recurrent disease or systemic vs. ocular disease, and, in fact, there is considerable variation among physicians regarding both drugs and doses chosen. (He discusses the available options at length in a report in the American Journal of Ophthalmology.6)
Pyrimethamine and sulfadiazine are still the most commonly administered drugs, said Dr. Holland, but for convenience, an accepted alternative is TMP/SMX, which is composed of drugs in the same classes with similar actions. Dr. Belfort uses TMP/SMX as a standard approach for both acute infections and prophylaxis.
For acute disease, Dr. Belfort gives one “double strength” tablet twice a day for four to six weeks. “Depending upon the case, we keep treating with one tablet a month for many months,” he said.
Resistant and recurrent infections. Because dormant tissue cysts are resistant to all antibiotics, chronic treatment may be needed to prevent multiple reactivations. “The risk of recurrence appears greatest in the first years after an episode of toxoplasmic retinochoroiditis,” said Dr. Wu.
For prophylaxis, Dr. Belfort gives one TMP/SMX tablet three times a week for many months or years. “We use it in cases with a high risk of developing severe lesions and especially in cases where one eye is already lost and the other has a scar close to the macula or optic disc,” he said. “We also use it in children who are not verbal and cannot communicate if they have ocular problems. These children often would otherwise come in too late for treatment.”
Dr. Holland relies on a protocol similar to that of Dr. Belfort. In cases where patients are allergic to sulfonamides, he uses atovaquone.