PERSPECTIVE

Reconsidering the Pathogenesis of Ocular Toxoplasmosis

GARY N. HOLLAND, MD
To review recent observations regarding the sources of Toxoplasma gondii infection and rates of ocular involvement in cases of infection acquired after birth, and to reconcile them with older observations and widely held beliefs about the pathogenesis of ocular toxoplasmosis. METHOD: A review of pertinent reports from the medical literature. RESULTS: There are several potential sources and routes of infection, including inhalation of spores and ingestion of contaminated drinking water, that were previously unrecognized. Ocular involvement in cases of acquired infection appears to be more common than heretofore believed. A variety of host and parasitic factors may inuence rates of ocular infection and the characteristics of ocular disease.
See also pp. 407 412, 413 420, and 421 425.
CONCLUSIONS: PURPOSE:

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The scars from which recurrent toxoplasmic retinochoroiditis arise may be the result of remote, acquired infections in many cases, rather than the residua of congenital infections, as commonly assumed. A better understanding of the epidemiology of T. gondii infection, as well as the host and parasitic factors that inuence disease presentation, is important for developing strategies for prevention and management of ocular toxoplasmosis. (Am J Ophthalmol 1999;128: 502505. 1999 by Elsevier Science Inc. All rights reserved.)

Accepted for publication July 8, 1999. From the University of California, Los Angeles, Ocular Inammatory Disease Center, the Jules Stein Eye Institute, and Department of Ophthalmology, University of California, Los Angeles, School of Medicine, Los Angeles, California. This work was supported in part by Research to Prevent Blindness, Inc, New York, New York, and the David May II Endowed Professorship (Dr Holland). Dr Holland is a recipient of a Research to Prevent Blindness, Inc, Lew R. Wasserman Merit Award. Reprint requests to Gary N. Holland, MD, Jules Stein Eye Institute, 100 Stein Plaza, UCLA, Los Angeles, CA 90095-7003.

frequently identied causes of uveitis, and Toxoplasma gondii remains the most common pathogen to infect the retina in otherwise healthy individuals.13 In North America, most cases encountered by ophthalmologists are characterized by a discrete focus of necrotizing retinitis at the border of a preexisting retinochoroidal scar, suggesting recurrence of disease from parasites that remained in the scar after a previous episode of disease. In a frequently quoted study, Smith and Ganley4 found that 0.6% of residents in one area of Maryland had retinochoroidal scars consistent with previous episodes of toxoplasmic retinochoroiditis. In a survey conducted in Alabama, at least 0.6% of individuals were believed to have ocular toxoplasmosis, and investigators reported that the rate might be as high as 8.8%.5 Thus, a substantial number of individuals may be at risk for recurrent disease. Using a nonprimate model of ocular toxoplasmosis, Culbertson and associates,6 Newman and associates,7 and Webb and associates8 provided evidence that recurrent disease is most likely caused by reactivation of live tissue cysts located at the borders of scars. Proliferating parasites are believed to be responsible for tissue destruction, whereas hypersensitivity reactions to the parasite are responsible for associated inammatory signs, including retinal vasculitis, anterior uveitis, vitreous inammatory reactions, and retinal edema. The source of the original infection, however, has been a subject of debate. For many years, it has been widely accepted that nearly all scars are the residua of congenital infections and that ingestion of undercooked meat is the major source of primary, acquired infection in pregnant women and others. Recent observations have challenged these traditional beliefs. It is instructive to review the evidence that led investigators to conclude that recurrent disease almost always arose from congenital infections. In a classic 1973 publication, Perkins9 argued that, whereas the prevalence of T. gondii infection increases with age, ocular disease does not, being most common in the second and third decades of life. If ocular toxoplasmosis arose from acquired infection, one would expect the rate of ocular disease to increase with age as well. Furthermore, he argued that patients with ocular disease do not have higher antibody titers than seropositive individuals without ocular disease, as would be
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expected if eye disease occurred at the time of initial infection. It has also been reported that on islands in the South Pacic, where populations have high rates of seropositivity, there are very low rates of ocular disease.10 In such populations, the majority of infections occur before the age of pregnancy. Because the fetus is protected by maternal antibodies, the rate of congenital infections in those populations is extremely low. A link between congenital infections and ocular disease is thus suggested by the absence of both in these populations. Also, because of the protection conferred by maternal antibodies, congenital infections are rare in more than one offspring in populations where rst infections are seen during pregnancy. Ocular toxoplasmosis in multiple siblings has been uncommon in studies of populations with high rates of congenital infection, again suggesting a link between congenital infection and ocular disease. The rate of ocular lesions in congenitally infected individuals is reported to be as high as 85% without treatment.11,12 In contrast, the rate of ocular involvement in individuals with postnatally acquired T. gondii infection has been thought to be low; most estimates have placed the prevalence between 1% and 3%.1 Perkins9 placed the prevalence between 2% and 3% based on a review of published case reports. He also reported that only two (7.7%) of 26 individuals known to be infected with T. gondii during laboratory accidents developed ocular disease. In an epidemic of acquired toxoplasmosis that occurred in Atlanta, Georgia, in 1977, only one (3.6%) of 28 infected individuals examined 4 years after initial infection had ocular lesions.13,14 Most of the aforementioned evidence is circumstantial and subject to considerable bias. Published cases do not necessarily represent the whole populations from which they are drawn. The assumption that most recurrences develop in the second and third decades is drawn in part from a report by Friedmann and Knox in 1969.15 This report described patients at a tertiary care center and thus was subject to referral bias, possibly describing only the most severe cases. Recent reports have contradicted traditional views about the pathogenesis of ocular toxoplasmosis. Many of the new observations have arisen from studies performed in the area of Erechim, a city located in an agricultural region of Rio Grande do Sul, a state in southern Brazil, where there is an extremely high rate of toxoplasmosis.16 Seropositivity is nearly universal, and, in contrast to reports from the South Pacic, there is also a high rate of ocular disease, with approximately 18% of the population having retinochoroidal scars. Furthermore, there are many families with multiple, nontwin siblings who have ocular toxoplasmosis. In contrast to the report by Perkins, the rate of ocular disease does increase with age in this Brazilian population. Findings from an epidemic of acquired T. gondii infection on Victoria Island, in British Columbia, Canada,17,18 VOL. 128, NO. 4 PATHOGENESIS
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are also in stark contrast to those from the previous Atlanta epidemic. Among 100 conrmed cases of new infection, 97 individuals underwent ophthalmoscopic examination and 20 (20.6%) of these individuals had ocular disease, indicating a high rate of ocular involvement with acquired disease. Interestingly, the proportion of seropositive patients with ocular involvement was similar to the proportion of individuals with retinochoroidal scars in southern Brazil, where nearly all individuals in the population are seropositive. Recent serologic studies suggest that ocular toxoplasmosis is more commonly associated with acquired infection than previously believed.19 21 Although the prevalence of such infections cannot be derived from these studies, they do provide important information regarding the individuals in whom acquired ocular infection occurred. In contrast to assumptions made by Perkins, acquired ocular lesions do not necessarily occur in patients with symptomatic systemic disease. Also, patients with acquired ocular disease tend to be older than those with ocular disease who do not have serologic evidence of recent infection. There are other factors that should be considered with regard to the original source of retinochoroidal scars. It is known that ocular lesions can be a late occurrence in patients with congenital T. gondii infections. For example, Loewer-Sieger and associates22 reported that only one of 12 infants with well-documented congenital toxoplasmosis had ocular lesions at age 1 year. When the same population of individuals was reexamined at age 18 years, nine of 11 had ocular disease, suggesting that clinically inapparent ocular infections exist that reactivate later in life. Histopathologic studies conrm that tissue cysts can exist in normal-appearing retina.1,23 Late development of ocular lesions can also occur with acquired infections. The one individual who developed ocular disease in the Atlanta epidemic was an 11-year-old girl who had no ocular lesions on examination 1 year after infection but was found to have a retinal scar 3 years later.14 Holland and associates24 described a series of 10 patients with acquired T. gondii infection and intraocular inammation; in four of these cases, patients developed late retinitis or retinochoroidal scars, suggesting that their retinas had been infected at the time of acquired disease, although necrotizing retinal lesions were not present initially. One must reconcile these new ndings with the older, conicting observations. Although the application of new serologic tests,19,21 longer follow-up, and better study designs might result in different statistics if previous studies were repeated today, it is entirely possible that true differences do exist between various populations. Recent studies have suggested that a variety of parasitic and host factors may inuence disease presentations. Also, it is possible that age at time of infection, duration of exposure, route of infection, and parasitic load, as well as unrecognized cofactors, may all inuence disease presentation. 503

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With regard to parasitic factors, it is well known that T. gondii isolates vary in their antigenic structure and behavior in mice. Sibley and Boothroyd25 studied 28 strains of T. gondii and found that virulent strains had an identical genotype, whereas nonvirulent strains were polymorphic. Darde and associates26 were able to place 35 isolates into ve groups based on parasitic enzyme systems; each group had a different pathogenicity. It is well known that host immune function plays an important role in toxoplasmosis. Immunosuppressed patients, including those with acquired immunodeciency syndrome (AIDS), are susceptible to severe life-threatening and vision-threatening T. gondii infections. It is likely that more subtle changes in immune function also affect disease presentation. Johnson and associates27 described a series of elderly patients with severe ocular toxoplasmosis. They hypothesized that the severity of disease was related, at least in part, to the waning of cellular immune function that occurs with aging. Several of the elderly patients described by Johnson and associates had serologic evidence of acquired infection. It is interesting to note that the median age of patients who developed ocular lesions in the Victoria Island epidemic was 54 years, whereas the median age of infected patients without ocular lesions was 27.7 years.18 Ongkosuwito and associates21 found that among patients with primary toxoplasmic retinochoroiditis (lesions not arising from scars), those with evidence of recently acquired infection were signicantly older than those with more remote infections. Studies of human leukocyte antigens (HLA) suggest that there may be a host immunogenetic inuence on disease presentation. Suzuki and associates28 found that HLA-DQ3 was associated with toxoplasmic encephalitis in patients with AIDS. With regard to ocular disease, Nussenblatt and associates29 found no association between HLA types and the presence of ocular toxoplasmosis, but Meenken and associates30 found that HLA-Bw62 was associated with certain measures of ocular disease severity (bilaterality and macular involvement) in patients with congenital infection and toxoplasmic retinochoroiditis. These observations have led to a series of revised hypotheses regarding the pathogenesis of recurrent ocular toxoplasmosis. It is likely that acquired T. gondii infection involves the retina more commonly than heretofore believed. Initial retinal infections may be subclinical in many cases because host defenses prevent proliferation of organisms and development of clinically apparent retinal lesions. These organisms encyst and do not reactivate for months or years. Ongkosuwito and associates21 have shown that 50% of patients with primary toxoplasmic retinochoroiditis have evidence of remote, rather than recently acquired, infection. Alternatively, new ocular infections might result from dissemination of organisms from remote, nonocular sites of infection. First reactivations may often be mild or asymptomatic, resulting in retinochoroidal scars that do not come to the attention of 504 AMERICAN JOURNAL
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an ophthalmologist. Only later, with subsequent, more severe reactivations, does ocular disease become apparent. In many cases, recurrent toxoplasmic retinochoroiditis may, therefore, be a manifestation of remote, acquired T. gondii infection, rather than being a sequela of congenital disease. Retinal lesions associated with well-documented acquired infections can reactivate in a manner similar to that seen with congenital infections.18,20,31 A better understanding of the source of initial infection in patients with recurrent toxoplasmic retinochoroiditis has important implications for prevention of disease transmission, and possibly for treatment. If establishment of retinal infections with acquired disease is more common than heretofore believed, it is important to reconsider sources of infection. Ingestion of tissue cysts has traditionally been assumed to be the major route by which infection occurs. Sources include raw or undercooked meat (especially pork and lamb), or materials contaminated through contact with unwashed hands and cooking surfaces. Infection can also occur through ingestion of unwashed fruit and vegetables contaminated by oocysts, and possibly by ingestion of eggs or unpasteurized milk that contains trophozoites. It is also known that disease is occasionally transmitted by blood products and organ transplantation. Epidemiologic evidence from the Atlanta and Victoria Island epidemics suggest that previously unrecognized sources of infection may exist. In Atlanta, it was concluded that infection occurred through inhalation of sporulated oocyts present in dust from a riding stable frequented by cats, the denitive host for T. gondii.13 On Victoria Island, an uncovered municipal reservoir providing unltered water to local residents was implicated as the source of infection.17 Infected, feral cats were identied in the land surrounding the reservoir. Although acquired infection was conrmed in 100 individuals during the Victoria Island epidemic, it has been estimated that the total number of infected individuals might have been as high as 7,718.17 If the entire population of infected individuals has retinal infections at the same rate that was seen in the 100 conrmed cases of systemic infection, there are potentially hundreds of individuals who may be at risk for recurrent disease in coming years. This possibility provides additional stimulus to improve efforts at prevention of T. gondii transmission. Systemic infection with T. gondii usually results in no more than a transient lymphadenopathic syndrome in otherwise healthy individuals. If many of these individuals are also acquiring subclinical retinal infections at the same time, it may be appropriate to reconsider more aggressive treatment of acquired infection, which is usually not treated because of the self-limited nature of the systemic illness. Whether or not additional study will show these suggestions to be appropriate, it is clear that the new information emerging about T. gondii and host-parasite interactions will lead to improvements in both the understanding and management of ocular disease. OPHTHALMOLOGY OCTOBER 1999

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