American Journal of Ophthalmology
Volume 137, Issue 1 , Pages 1-17, January 2004

Ocular toxoplasmosis: a global reassessment:☆

part II: disease manifestations and management

Presented at the annual meeting of the American Academy of Ophthalmology, Nov 16, 2003.

  • Gary N. Holland, MD

      Affiliations

    • Ocular Inflammatory Disease Center, Jules Stein Eye Institute and the Department of Ophthalmology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, California, USA.
    • Corresponding Author InformationInquiries to Gary N. Holland, MD, Jules Stein Eye Institute, 100 Stein Plaza, UCLA, Los Angeles, CA, USA 90095-7003; fax: (310) 794-7906

Accepted 13 October 2003.

Article Outline

Abstract 

Purpose

To update clinical information about ocular toxoplasmosis. Part II reviews the spectrum of disease manifestations and factors that influence severity of disease. Implications for disease management are discussed.

Design

Literature review.

Methods

Selected articles from the medical literature, information from several recent scientific meetings, and the author's personal experiences were reviewed critically in preparation for the LX Edward Jackson Memorial Lecture.

Results

The appearance of toxoplasmic retinochoroiditis lesions varies with duration of active retinal infection and intensity of inflammation. Severe ocular disease occurs in immunocompromised hosts. Older patients who are recently infected with Toxoplasma gondii may have a higher prevalence of ocular involvement and more severe ocular disease because of altered host defenses. Most disease-producing isolates of T. gondii belong to one of three clonal lineages (types I, II, III); type I has been associated with severe disease in both animals and human beings. Many observational studies suggest a benefit of short-term antimicrobial therapy for toxoplasmic retinochoroiditis in immunocompetent patients, although the efficacy of these treatments has not been proven in randomized clinical trials. Intermittent trimethoprim/sulfamethoxazole treatment was associated with fewer recurrences than placebo during a 20-month randomized clinical trial.

Conclusions

Variations in disease characteristics may be related to host, parasite, or environmental factors. The genotype of the infecting parasite appears to be an important determinant of disease severity in immunocompetent patients. Secondary prophylaxis may reduce the rate of recurrences in high-risk patients. A better clinical understanding of ocular toxoplasmosis can lead to more effective prevention and treatment strategies.

 

Recent clinical observations and laboratory findings have led to a reassessment of many concepts about ocular toxoplasmosis. The goal of this LX Edward Jackson Memorial Lecture has been to provide a more complete understanding of the clinical features of the disease based on this new information.

The following topics were discussed in Part I:1 the prevalence of Toxoplasma gondii infection and ocular involvement, sources of T. gondii infection, the risk of ocular involvement with congenital and postnatally acquired infections, and the course of ocular disease. Information regarding the course of disease provides insights into disease mechanisms. Part II will discuss the clinical manifestations of disease, factors that influence the severity of disease, and the implications of this clinical information for prevention and treatment strategies.

The 1957 XIV Edward Jackson Memorial Lecture, presented by Michael J. Hogan, MD,2 also dealt with the clinical features of ocular toxoplasmosis. It was published soon after the initial description of ocular toxoplasmosis in adults,3 and has served as a point of reference for the more recent observations described in this presentation.

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Spectrum of disease manifestations 

In 1957, studies were still being performed to clarify which of the many forms of uveitis could be attributed to T. gondii infection. Through the use of serologic tests and other investigations, Hogan2 argued that toxoplasmosis was a cause of focal retinitis, but was not a cause of other, nonspecific forms of intraocular inflammation. Since that time, reports have typically described the “classic” appearance of toxoplasmic retinochoroidtitis as a focus of retinitis arising from the border of a retinochoroidal scar (Figure 1), but there can be considerable variation in the clinical features of disease.4, 5, 6, 7, 8 A review of the literature describing “atypical” cases suggests that they do not represent fundamentally different forms of the disease, however. Knowledge of the various presentations of ocular toxoplasmosis is important for the clinician; diagnosis can be difficult in some cases,9, 10 and attention to the characteristics of ocular toxoplasmosis may give some insights into disease mechanisms.

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  • FIGURE 1. 

    Recurrent toxoplasmic retinochoroiditis in an immunocompetent adult patient. There is a “satellite lesion” associated with pre-existing retinochoroidal scars and a mild overlying vitreous inflammatory reaction.

Friedmann and Knox6 described three specific “forms” of disease: large destructive lesions, punctate inner lesions, and punctate deep lesions. Small, partial thickness lesions involving the inner or outer layers of the retina have also been described in patients with acquired immunodeficiency syndrome (AIDS);11, 12 these small lesions are presumably the earliest manifestations of infection, as most reported patients with AIDS and ocular toxoplasmosis have had extensive areas of full-thickness retinal necrosis (FIGURE 2, FIGURE 3).11, 12, 13, 14, 15 Immunocompetent patients can develop clusters of small, partial thickness retinal lesions, a condition termed “punctate outer retinal toxoplasmosis” by some investigators.16, 17 Lesions are typically <1,000 μm in diameter and found in the posterior pole. Most reported patients have been young. Although sometimes considered a distinct form of disease, punctate outer retinal toxoplasmosis shares many features with more “typical” lesions. Despite the cluster of lesions, there is usually only one focus of active disease at any given time. Active inflammatory disease resolves without treatment, leaving hyperpigmented scars, and recurrences develop as “satellite” lesions. Silveira and associates18 have shown that the spectrum of lesions associated with typical toxoplasmic retinochoroiditis includes similar tiny, nonspecific foci of pigment, and “classic” lesions can also be found amid clusters of small retinochoroidal scars in any part of the retina (Figure 1).

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  • FIGURE 2. 

    The right fundus of a severely immunocompromised patient with AIDS, showing two large foci of extensive retinal necrosis. The inferior focus was complicated by an exudative retinal detachment. There were no pre-existing retinochoroidal scars.

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  • FIGURE 3. 

    The same fundus shown in Figure 1, photographed 4 months later. The patient was initially treated with pyrimethamine and sulfadiazine; no corticosteroids were given. Inflammatory signs improved rapidly, and there was no enlargement of lesions after the start of therapy. At this point in time, pyrimethamine alone was being given as long-term “maintenance therapy.” All retinochoroidal scars appear to be inactive.

Neuroretinitis has also been described as a unique presentation of ocular toxoplasmosis.19, 20 Many of the reported cases have occurred at the time of seroconversion; thus, this presentation may fall within a spectrum of intraocular inflammatory reactions that are seen in association with recent T. gondii infection, possibly in response to subclinical infection of the retina.1, 21 Papillitis can occur in response to optic nerve or peripapillary retinal infections (Figure 4). 22 Patients with these various exudative reactions should be evaluated carefully for evidence of recent, systemic infection or for signs of retinitis or retinochoroidal scars.

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  • FIGURE 4. 

    The left optic disk of a 17-year-old girl with recurrent parapapillary toxoplasmic retinochoroiditis with exudation and optic disk swelling. A pre-existing hyperpigmented retinochoroidal scar is present at the inferonasal optic disk margin. The patient was treated with a 4-week course of pyrimethamine, sulfadiazine, and prednisone, with complete resolution of the optic disk swelling and retinochoroiditis. Vision improved to 20/20 in the eye.

Many studies have focused on specific features of ocular disease, including the number, size, and location of lesions. In nearly all cases, immunocompetent patients will have only one focus of active retinal disease, even if there are multiple retinochoroidal scars. In contrast, multiple active retinal lesions in one or both eyes can occur in immunocompromised patients.11, 12, 13, 14, 15, 23 Bosch-Driessen and associates24 have also shown that multifocal disease is more common in patients whose immune defenses were suppressed with corticosteroids as sole therapy.

With regard to lesion size, Friedmann and Knox6 showed that lesions greater than one disk area persist longer and are associated with a greater risk of complications (retinal detachment, cataract, cystoid macular edema, glaucoma, chronic intraocular inflammatory reactions) and more vision loss than smaller lesions. Rothova and associates25 also reported a significant, positive relationship between the size of retinal lesions and duration of active disease.

Extensive T. gondii infection of the retina can be confused with necrotizing herpetic retinopathies. This presentation has been described most commonly in patients with AIDS (FIGURE 2, FIGURE 3),9, 10, 11, 12, 13, 14, 15 those receiving immunosuppressive drug therapy,26, 27, 28 and in elderly individuals (Figure 5), 9, 10, 29, 30 but can occur in younger, immunocompetent patients as well.9, 10 Elkins and associates13 have described features of disease that may help to distinguish this presentation of toxoplasmic retinochoroiditis from viral infections, such as cytomegalovirus retinitis; these features include a thick, more densely yellow-white appearance to the lesion; borders with a distinct, smooth-contoured edge; and lack of hemorrhage.

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  • FIGURE 5. 

    Extensive toxoplasmic retinochoroiditis involving the macula and superior retina in a 77-year-old man. There were also two isolated foci of active retinochoroiditis inferiorly. The presence of Toxoplasma gondii DNA in a vitreous humor specimen was confirmed by polymerase chain reaction technique. Despite 4 months of therapy with pyrimethamine, sulfadiazine, clindamycin, and prednisone, disease remained active. (Photographs courtesy of Emilio M. Dodds, MD).

There are some data to suggest that the location of lesions does not occur as a random event. Mets and associates31 showed that 52 (58%) of 89 newborns with congenital T. gondii infection and ocular disease had macular lesions, which is substantially higher than the number expected if lesions were distributed randomly, considering the fact that the anatomic macula comprises only approximately 5% of the total retinal area. Other investigators have also shown a disproportionately high frequency of macular lesions.5, 6 Congenital T. gondii infection at an early stage of retinal development could favor macular involvement. Anatomic and microvascular differences between the macula and the peripheral retina might create a microenvironment that also influences the location of lesions following either congenital or postnatally acquired infections. For example, a study of postmortem eyes from individuals with no known ocular disease or immune systemic dysfunction showed that macrophages, which participate in host defenses against T. gondii infection, were significantly less common in the macula than in the peripheral retina.32

The presence of macular lesions has traditionally been considered to be a sign of congenital toxoplasmosis, but does not distinguish reliably between congenital and postnatally acquired infections (Figure 6). Bosch-Driessen and associates24 showed a high prevalence of macular lesions among patients with known congenital infections (11 [46%] of 24 eyes), but in only a small proportion of their patients was it known whether infection had been congenital or postnatally acquired. This percentage was reported to be statistically higher than the percentage for all other patients in the series, but was not confirmed to be statistically higher than the percentage for those known to have postnatally acquired infections (4 [21%] of 19 eyes; P = .116, Fisher exact chi-square test). Macular lesions are present in at least 38% of patients with serologic evidence of postnatally acquired infection in southern Brazil (Claudio Silveira, MD, presented at the International Conference on Toxoplasmosis: Biology, Clinical Practice, and Public Health, Copenhagen, Denmark, 23–25 June 2003). The emphasis on severe ocular disease in patients with congenital toxoplasmosis that is found in the literature may, in part, be a function of ascertainment bias; these patients can also have mild ocular disease. Although the prevalence of ocular involvement is higher with congenital infection than with postnatally acquired infection, congenital toxoplasmosis does not seem to be associated with any unique ocular disease characteristics.

Inflammatory reactions vary tremendously among patients. With the exception of transient inflammatory reactions at the time of T. gondii infection,21 intraocular inflammation does not occur in the absence of retinal lesions. Partial thickness lesions involving the deep layers of the retina are generally associated with little or no vitreous humor inflammation.6, 16, 17 Other factors that may predict levels of inflammation require further study. Hogan5 expressed the opinion that the severity of vitreous humor inflammation was unrelated to the size of retinal lesions. In contrast, a retrospective study of 210 patients from seven sites in North America, South America, and Europe found that increased levels of both anterior chamber and vitreous humor inflammatory reactions were related to larger size (P values <.01), but not location, of retinal lesions (Emilio M. Dodds, MD, presented at the International Conference on Toxoplasmosis: Biology, Clinical Practice, and Public Health, Copenhagen, Denmark, 23–25 June 2003).

Inflammatory reactions frequently involve the choroid subjacent to the area of retinal infection, and occasionally result in clinically apparent scleritis,33 but T. gondii is rarely identified in ocular tissues other than the retina. Exceptions have involved immunocompromised hosts; parasites are occasionally identified in choroid or sclera of patients with AIDS who have extensive retinal infections.11, 34 Rehder and associates35 described a patient with AIDS who developed an iris nodule that contained T. gondii in the absence of retinal lesions, but this case was highly unusual.

A variety of complications of toxoplasmic retinochoroiditis have been described, including rhegmatogenous retinal detachments,36 exudative retinal detachments, retinal vessel occlusions,37 subretinal neovascularization, epiretinal membrane formation, and macular edema.4, 8, 38 In general, they occur only in patients with severe ocular disease. Rhegmatogenous retinal detachments, for example, have been related to the severity of inflammation.36 Macular edema is believed to be uncommon,38 for unknown reasons. Prolonged infections, intense inflammation, and complications can occasionally lead to phthisis or enucleation.3, 10

Many publications also refer to “typical” scars of healed toxoplasmic retinochoroiditis lesions, but there is a spectrum to the appearance of scars as well, with variable amounts of pigmentation and loss of choroidal tissue. The area of a scar that is seen clinically can be smaller than the area of inflamed retina during the active stage of the disease (this phenomenon can be seen in FIGURE 6, FIGURE 7 of Part I1). The degree of pigmentation within and surrounding scars may reflect the extent to which the retinal pigment epithelium is damaged during the active stage of disease. In some elderly patients, lesions seem to heal with less severe scarring than would be expected from the extent of infection (Figure 7). Lesions with little associated inflammation may heal with minimal scarring.16, 17 None of these issues has been studied in any systematic manner, however.

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  • FIGURE 7. 

    Extensive scarring of the retina following resolution of an episode of presumed toxoplasmic retinochoroiditis in a 75-year-old man. Despite extensive retinal infection, severe, excavated retinochoroidal scarring did not occur. (Photograph courtesy of Allan E. Kreiger, MD). A similar case is illustrated in Figure 5 of the following publication: Johnson MW, Greven GM, Jaffe GJ, et al. Atypical, severe toxoplasmic retinochoroiditis in elderly patients. Ophthalmology 1997;104:48–57.

Although ocular toxoplasmosis has traditionally been discussed in terms of “typical” and “atypical” lesions, with the implication that there are various unique forms of disease, it is probably more instructive to consider all of these presentations as falling within a spectrum of disease that differs only in severity. The duration of active retinal infection (i.e., proliferation of tachyzoites) and the intensity of the associated inflammatory reaction appear to be the major factors accounting for variations in the characteristics of ocular toxoplasmosis. The fact that disease manifestations vary markedly among individuals raises questions regarding the factors that influence the severity of ocular disease. An understanding of these factors would help to predict outcomes and to plan therapies.

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Factors related to disease severity 

Hogan2 speculated that the “virulence” of the infecting parasite may determine the type of disease caused by T. gondii in human beings. He wrote: “Infection with organisms of low virulence also may result in milder infections . . .” At the time, there was no evidence of such a relationship in human beings; his speculation arose from the observation that different parasite isolates were associated with markedly different mortality rates in laboratory animals, but the biological basis for this phenomenon was unknown. In fact, he wrote: “All strains appear to be serologically and biologically identical, but differ considerably in their virulence.” As discussed in the following text, a biological basis for the observed differences between isolates has been found, suggesting that the infecting parasite may indeed influence the severity of human disease, as predicted by Hogan.

Virulence must be considered in context, however. A variety of factors, such as inoculum size, determines severity of disease caused by a particular isolate in animals. Also, different animal hosts may have markedly different susceptibility to disease from the same isolate. Recent studies have begun to clarify the host and parasite factors that influence the severity of human disease and environmental factors that may influence host-parasite interactions.

Host factors 

Patient Age. A variety of observations suggest that clinical features of ocular toxoplasmosis are related to age of the host. The distribution of active toxoplasmic retinochoroiditis episodes in relation to patient age has been remarkably similar in many reports (FIGURE 8, FIGURE 9, FIGURE 10). 6, 24, 39 Patients in their second through fourth decades of life account for most observed episodes. In 1969, Friedmann and Knox6 found that the mean age of “initial episodes” of ocular toxoplasmosis was 25.3 years (median within the 20 to 24 year age group; mode, 10 to 14 year age group) (Figure 8). In 1999, Gilbert and associates39 found that the mean age for “first episodes” among patients in England was 26.5 years (mean age for all episodes was 31.1 years) (Figure 9). Bosch-Driessen and associates24 found that 215 (78%) of 274 observed episodes of active ocular toxoplasmosis were in patients aged 15 to 45 years (mean age, 31.1 years) (Figure 10). Methodological differences make it difficult to compare these series directly, but the fact that the same basic pattern has been reported from different clinical settings during different time periods suggests that there is a true relationship between episodes of active disease and relatively young age.

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  • FIGURE 8. 

    Ocular toxoplasmosis at a tertiary referral center in Maryland. The open and cross-hatched bars correspond to data presented in Figure 5 of the following publication: Friedmann CT, Knox DL. Variations in recurrent active toxoplasmic retinochoroiditis. Arch Ophthalmol 1969;81:481–493. The bars identify the ages at which 158 known episodes of toxoplasmic retinochoroiditis occurred in 63 patients. The cross-hatched portion of the bars identify those episodes associated with vision loss. Superimposed on the original figure are narrower solid bars that demonstrate the age at enucleation of all cases with a diagnosis of ocular toxoplasmosis in the records of the Armed Forces Institute of Pathology during the same era. This previously unpublished figure was provided by David L. Knox, MD.

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  • FIGURE 9. 

    Symptomatic ocular toxoplasmosis among an unscreened, British-born population in four areas of England. Age at presentation for all patients (n = 87) and for patients reporting no previous episode (n = 41). Figure and original legend reprinted with permission from Gilbert RE, Dunn DT, Lightman S, et al. Incidence of symptomatic Toxoplasma eye disease: Aetiology and public health implications. Epidemiol Infect 1999;123:283–289 by Cambridge University Press.

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  • FIGURE 10. 

    Ocular toxoplasmosis in the Netherlands. Total number of attacks (n = 274) of ocular toxoplasmosis according to age for 60 patients followed for at least 5 years. Figure and original legend reprinted from Bosch-Driessen LE, Berendschot TT, Ongkosuwito JV, Rothova A. Ocular toxoplasmosis: Clinical features and prognosis of 154 patients. Ophthalmology 2002;109:869–878 with permission from the American Academy of Ophthalmology.

A number of factors may contribute to this pattern. Friedmann and Knox6 hypothesized that hormonal changes that occur during adolescence account for a higher rate of recurrent disease; at the time of their report, it was assumed that most observed episodes were recurrences of congenital disease. If most cases of ocular toxoplasmosis are actually associated with postnatally acquired infection, the low number of patients with active toxoplasmic retinochoroiditis who are under 10 years of age may be attributable to the low prevalence of infection in that age group. Also, young children who do have active disease may fail to report symptoms. In some areas, including southern Brazil, adolescents and young adults are known to have the highest rates of T. gondii infection,18, 40, 41, 42 which might explain the larger number of observed episodes of ocular disease in those age groups. It is possible that new infections occur most frequently among younger patients in the United States as well. Although a cross-sectional study showed a steady rise of seroprevalence with increasing age in the United States40 (see Figure 2 in Part I1) seroprevalence does not necessarily reflect the age at which infection occurs. If risk of infection is now lower for all age groups than in the past, a cohort effect could explain the reported relationship between seroprevalence and age; higher seroprevalence in older groups would reflect infection that occurred when that cohort was younger and the risk of infection was higher. A drop in the rate of recurrences over time, as discussed in Part I,1 could then be one contributing factor to the lower number of observed episodes in older age groups.

The lower number of observed episodes among older age groups in these publications6, 24, 39 does not necessarily mean that the risk of ocular disease after recent T. gondii infection decreases with age, however. An assessment of risk would also require knowledge of the age distribution of the total populations from which the cases were drawn and the seroprevalence for each age group, which was not provided. Data from other studies suggest that older patients actually have a higher risk of ocular involvement following recently acquired T. gondii infection than younger patients. Researchers in The Netherlands have found that most patients with ocular toxoplasmosis who have serologic evidence of recent infection are older.24, 43 Patients whose ocular toxoplasmosis was first seen when they had serologic evidence of remotely acquired infection had a mean age of 29.9 years, while patients whose ocular toxoplasmosis was first seen while they had serologic evidence of recent infection had a mean age of 50.6 years.24 Also, patients with primary retinal lesions (defined as those not associated with pre-existing retinochoroidal scars) were older than those with recurrent lesions.24 Among 22 patients with ocular toxoplasmosis and serologic evidence of recent T. gondii infection studied by Montoya and associates,44 the mean age was a similar 50.2 years (median, 51.5 years; range, 16 to 79 years). In the 1995 Victoria epidemic, the mean age of infected patients without retinal lesions was approximately 28 years, whereas the mean age of infected individuals with eye disease was 54 years.45 The consistency of these various observations suggest that older patients have a higher risk of developing ocular lesions following recently acquired T. gondii infection, although this relationship cannot be confirmed without data regarding seroprevalence in the elderly populations from which the series were drawn.

In addition to a higher prevalence of ocular involvement, older patients may have ocular disease of greater severity. Among 34 reported patients described in two publications that focused specifically on older patients29, 30 (mean age, 67.1 years; median age, 67.5 years; range, 50 to 87 years), at least 22 patients had severe disease in terms of multiple active lesions, large lesions (>3 disk areas in size), prolonged disease (>8 weeks in duration), or a combination of these factors. In addition, 20 patients (59%) did not have pre-existing retinochoroidal scars, and at least 14 patients (41%) had anti-T. gondii IgM antibodies, suggesting that infection was recently acquired. Thus, the severity of disease could not be attributed to the cumulative effect of many years of recurrences in this older population.

The two series described above are subject to reporting bias, but various other studies that did not select patients on the basis of age also suggest that older patients have more severe ocular disease. Additional analysis of data published by Friedmann and Knox6 shows that fewer of their patients aged 20 to 39 years had loss of “useful vision” (P = .099, Fisher exact chi-square test), and a greater proportion of them had brief episodes of disease (shorter than the mean duration of all episodes, P = .079) than either younger or older patient groups. Almost twice as many patients older than 40 years of age had prolonged episodes when compared with patients aged 20 to 39 years (46% vs 24%, respectively). In southern Brazil, the rate with which retinal lesions develop during the first 2 years after postnatally acquired T. gondii infection is greater among patients older than 40 years of age than among those who are younger (P = .095, Kaplan-Meier analysis, unpublished data, Claudio Silveira, MD, presented at the International Conference on Toxoplasmosis: Biology, Clinical Practice, and Public Health, Copenhagen, Denmark, 23–25 June 2003). Although each of these associations is weak, when considered together, they suggest a pattern of ocular disease that is more severe in older individuals.

Immune status 

The AIDS epidemic has provided dramatic evidence that host defenses are important for limiting the severity of ocular toxoplasmosis.11, 12, 13, 14, 15, 23, 34, 35 Not only do patients with AIDS develop extensive disease, but lesions frequently reactivate if treatment is discontinued.11 Similar disease can be seen in patients receiving immunosuppressive drug therapy.26, 27, 28 Severe ocular toxoplasmosis in elderly patients has also been attributed to alterations in host immunity.29 Aging is associated with complex changes in both adaptive and innate immune mechanisms that increase the prevalence and severity of many infections in the elderly;46, 47 changes involve lymphocytes, natural killer cells, macrophages, and cytokine production, all of which are known to be involved in host defenses against T. gondii.

It is less clear whether variations in immune function contribute to differences in severity of ocular disease among younger individuals who are considered to be immunocompetent. One approach to the study of this question has involved the search for associations between disease and specific human leukocyte antigen (HLA) types. It has been shown that major histocompatibility genes influence the severity of toxoplasmosis in animal models.48 It has also been reported that HLA-DQ3 is associated with toxoplasmic encephalitis in patients with AIDS49 and with hydrocephalus in newborns with congenital toxoplasmosis.50 With regard to the eye, Nussenblatt and associates51 did not find a higher frequency of any HLA types in people with ocular toxoplasmosis when compared with the general population. An alternative approach has been to search for relationships between HLA types and severity of ocular disease in people known to be T. gondii-infected. In a study of 52 patients with congenital T. gondii infection and ocular lesions, Meenken and associates52 found relationships between HLA-B62 and signs that they considered to be reflections of severe ocular disease: the presence of macular lesions (relative risk [RR] 2.76 [P = .006]) and bilateral disease (RR 3.32 [P = .007]). It is interesting to note that HLA-B62 and HLA-DQ7 (a split-product of HLA-DQ3) have both been associated with the acute retinal necrosis syndrome (RR 2.71 [P = .04] and RR 5.20 [P = .0004], respectively).53 The fact that severe ocular disease attributable to different infectious agents may be associated with the same HLA types suggests a possible immunogenetic influence on host responses to necrotizing infections of the retina. A preliminary study has failed to identify associations between HLA types and measures of severe ocular disease among T. gondii-infected adults in Brazil (Lewis KG, Silveira C, Matteucci VE, et al. Lack of association between HLA types and severity of ocular disease in Toxoplasma gondii-infected individuals. Presented at the 2002 Annual Meeting of the Association for Research in Vision and Ophthalmology, Ft. Lauderdale, FL, Abstract #4295, 9 May 2002). Results to date do not rule out the possibility of such associations, but, if they exist, relative risk values are probably low, which would be consistent with the fact that there are many other influences on disease characteristics.

Another approach has been the study of lymphocyte function and cytokines. Yamamoto and associates54 found that cytokine profiles with stimulation of peripheral blood mononuclear cells (PBMC) by T. gondii-associated antigens differed between various groups of patients. Among 80 patients believed to have postnatally acquired infections on the basis of historical and serological evidence, those with ocular lesions (n = 40) had high levels of interleukin (IL)-1 and tumor necrosis factor (TNF)-α, while those without ocular lesions (n = 40) had high levels of IL- 12 and interferon (IFN)-γ. Among 30 patients believed to have congenital infections (all of whom had ocular disease), there were decreased levels of IL-2 and IFN-γ, as well as decreased PBMC proliferation to soluble toxoplasmic antigen and absent delayed-type skin reactions. They considered these findings to be evidence of tolerance among congenitally infected individuals. Although groups could be distinguished by their cytokine profiles, the results did not suggest a unifying hypothesis as to how changes in immune function account for variations in the ocular manifestations of disease. Also, the relevance of PBMC characteristics to disease in the unique immunological milieu of the eye is uncertain. Furthermore, immunological reactions may change over time, and the observed profiles do not necessarily reflect immunological events at the time of infection or development of ocular lesions. Additional work will be required to determine whether differences in immune function among immunocompetent patients is an important influence on ocular disease severity.

Pregnancy 

Many investigators have noted an association between pregnancy and recurrences of toxoplasmic retinochoroiditis.4, 6, 24, 55 Friedmann and Knox6 observed active toxoplasmic retinochoroiditis during five pregnancies (four patients among a population of 63 patients with ocular toxoplasmosis), but nine other pregnancies in women with histories of ocular toxoplasmosis were not associated with recurrences. More recently, Bosch-Driessen and associates24 reported that seven (9%) of 82 women with ocular toxoplasmosis developed recurrences during pregnancy; the total number of pregnancies for the entire population was not known. Such series could be biased if women are monitored more frequently for ophthalmic problems during pregnancy or if women are more likely to seek medical attention for ophthalmic problems during pregnancy. The pattern of disease in individual patients suggests that the association may be causal, however. Four of the seven women with recurrent disease during pregnancy that were reported by Bosch-Driessen and associates24 had recurrences during every subsequent pregnancy. It has been hypothesized that this relationship is attributable to hormonal or immunological changes that occur during pregnancy.55

Parasite factors 

T. gondii has a unique population structure; genetic analyses have shown that the vast majority of parasites isolated in North America and Europe, and perhaps in other areas of the world, fall into one of only three closely related genotypes, identified as types I, II, and III.56 There is little within-type genetic variation. Population studies also suggest that the three types are descendants of just two ancestral strains (termed A and E) that were crossed relatively recently in evolutionary history.57 Each genetic locus of this haploid organism has an allele derived from one or the other of the two ancestral strains; the three genotypes are defined by different mixtures of these alleles. The fact that only three of the large number of possible allelic combinations have come to predominate over broad geographic and host ranges indicates a survival advantage of these specific clonal lineages.

This survival advantage may be attributed, in part, to a biologic trait not shared with other related coccidian parasites of human beings: an ability to infect intermediate hosts directly via ingestion of tissue cysts (as occurs when one intermediate host eats tissue from another through carnivorism, scavenging, or contamination of livestock feed with animal parts). Because the progeny of asexual reproduction are infectious to other intermediate hosts, the sexual reproduction cycle can be circumvented, with the perpetuation of a limited number of genotypes. Despite the fact that ingestion of oocysts (through contamination of food stuff by cat feces) also results in infection, and the fact that there can be a mixing of these cycles (cats eating birds, mice, and other small animals that may be infected with tissue cysts, while herbivores graze on land where cats have defecated), unique recombinants from sexual reproduction are seen with a much lower frequency than are members of the three dominant genotypes. Their success may also be related to greater oral infectivity when compared to ancestral strains or closely related parasites, such as Neospora sp., which lack direct oral infectivity.58 Type II parasites are particularly infectious by the oral route, which may explain the fact that they are the most commonly identified isolates, as discussed below.58

The three parasite types have different potentials for causing disease in animal models.59 Even with small inocula, type I strains are known to be highly virulent in mice, while types II and III are not. Investigations are being performed to understand the basis for differences in pathogenicity between parasite types. Genetic mapping studies have identified loci common to type I parasites that contribute to virulence.60 Virulence is not attributable to a single gene; it varies with the interaction of different combinations of specific alleles at multiple loci. Studies have shown that virulence may be related to variations in the specific host immune responses that are generated by different parasite types and to differences between types in their ability to migrate across physiologic barriers.61 A similar relationship between infecting parasite type and disease in human hosts has been suspected,62 but has been more difficult to study, because the source of infection is rarely known, and parasites are rarely isolated from the host.

In one study, the RH strain of T. gondii (a type I parasite) was found to be less sensitive to pyrimethamine in vitro than a type II and a type III parasite.63 This study suggests that the infecting parasite type might influence response to treatment, but in vivo studies will be required to confirm that possibility.

Studies have shown that the majority of T. gondii infections among immunocompromised patients in North America and Europe are attributable to type II parasites, although types I and III can also be identified in a substantial number of cases.56, 64, 65, 66 Type II parasites also predominate among congenital infections in North America and France,56, 64, 65 but type I parasites were found more commonly in a study of congenital infections in Spain.66 The association between type II parasites and disease in many studies may simply reflect a disproportionately high percentage of infection with type II parasites in food animals of the same geographic areas.64 In contrast, a study of chickens in Brazil showed that most infected birds had type I parasites; some had type III parasites, but none had type II parasites.67 Type I parasites have also been isolated from both pigs and at least two individuals with ocular toxoplasmosis from the area of Erechim, in southern Brazil, where there is a high prevalence of endemic toxoplasmosis.59, 68 It is intriguing to speculate that the increased prevalence of ocular toxoplasmosis in southern Brazil is attributable to a predominance of type I parasites in the environment; considering the limited number of isolates studied, much additional work will be needed to confirm this hypothesis.

A type I parasite has been implicated in an epidemic of T. gondii infection in the town of Santa Isabel do Ivai, also in southern Brazil. A municipal water supply is believed to have been the source of infection, based on epidemiological studies. A large volume of water from the municipal supply was subsequently passed through filters, which were then fed to various animals. Type I parasites were eventually isolated from these animals (Lilian M.G. Bahia- Oliveira, PhD, Universidade Estadual do Norte Fluminense, Campos dos Goytacazes, Rio de Janeiro State, Brazil, and Tovi Lehmann, PhD, United States Centers for Disease Control and Prevention, personal communications, August 2003). A type I parasite was isolated from a newborn with congenital T. gondii infection at the time of the 1995 Victoria epidemic,69 although there is, as yet, no other confirming evidence that the epidemic was caused by a type I parasite. In contrast, a wild cougar living in close proximity to the uncovered reservoir implicated as the source of infection in that epidemic was found to be infected with an “exotic” parasite (not a member of the three dominant clonal lineages) that was most closely related to type II parasites.58, 69

There is some evidence of a relationship between genotypes of T. gondii and severity of ocular toxoplasmosis in human beings. In one study, Grigg and associates70 studied vitreous humor obtained from 12 individuals with severe toxoplasmic retinochoroiditis who required surgery for repair of retinal detachments or who underwent vitreous humor biopsy for diagnostic purposes; parasite DNA extracted from the vitreous humor was used to identify the infecting parasite type. Specimens from six patients without evidence of immunosuppression all contained DNA from type I parasites or recombinants with type I alleles; three of the recombinants appeared to have similar genetic characteristics, and were considered possibly to be members of an additional clonal group, labeled “type IV” by the investigators. The other six patients were known to be immunocompromised. Their specimens had DNA from a variety of parasite types; DNA from types I, III, and IV parasites were found in one specimen each, while DNA from type II parasites was found in three specimens. It is noteworthy that none of the immunocompetent patients was infected with type II or type III parasites, despite the fact that those types are more prevalent causes of infection in human beings.

Such studies have led to the following hypothesis regarding the relative contribution of host and parasite factors to the severity of ocular toxoplasmosis. In immunocompetent patients, the infecting parasite type will be a major influence on the characteristics of ocular disease; severe disease may occur if the person is infected with a type I parasite (or with a unique, virulent recombinant or exotic), but no ocular disease or only mild ocular disease will result if the person is infected with a type II (or possibly a type III) parasite. In contrast, host factors will be more important in immunocompromised patients, severe disease being possible from any parasite type. While this hypothesis may represent an oversimplification of complex relationships between host and parasite, it can serve as a foundation upon which future studies are built. There is some support for this hypothesis with respect to nonocular disease; in a study of cerebral and extracerebral disease, Honoré and associates65 found that type III parasites caused disease in seven (10%) of 71 immunocompromised patients, but in none of 19 immunocompetent patients. In contrast, type I parasites caused disease in four (21%) of the 19 immunocompetent patients, but in only 10 (14%) of the 71 immunocompromised patients.

Using traditional techniques, it will be difficult to test this hypothesis directly. Invasive procedures to obtain ocular tissues and fluids for polymerase chain reaction analysis of parasite DNA cannot be justified in most cases. Almost never will specimens be obtained from patients with mild disease. An alternative approach is to identify host anti-T. gondii antibodies in the blood that are type-specific. Kong and associates71 used an enzyme-linked immunosorbent assay to show that a differential profile of specific antibodies to eight short synthetic peptides, corresponding to immunogenic regions of T. gondii antigens GRA6 and GRA7, can discriminate reliably between infection with type II parasites and infection with type I or type III parasites in animals. They also used their assay to predict correctly the infecting parasite type for eight patients with toxoplasmosis for whom the infecting parasite type was known.

As a research tool, this assay could be used in population-based studies to determine whether there are relationships between specific disease characteristics and the infecting parasite type.62 The ability to distinguish between type II and non-type II parasites alone will provide important information, in view of the fact that type II parasites appear to be the cause of most human infections in North America and Europe. It will be interesting to determine whether the majority of infected patients without ocular lesions have antibodies against type II parasites, while those with features of severe disease have a higher prevalence of antibodies against non- type II parasites.

Much work needs to be done to determine the sensitivity and specificity of the assay and the duration with which these type-specific antibodies persist. Also, the assay cannot as yet distinguish between infections with type I and type III parasites, which encode for nearly identical GRA6 and GRA7 proteins. The study of additional peptides derived from other antigens should eventually allow the discrimination between infections with type I and type III parasites. With a sufficient number of subjects, investigators may ultimately be able to identify the spectrum of disease caused by different parasite types. This type of assay may have clinical applications as well. It could provide confirmation of a suspected source of parasites in epidemics, and it could influence treatment decisions.

Environmental factors 

A variety of situational (“environmental”) factors may influence the characteristics of disease. In murine models, disease severity will be altered not only by the type of mouse and the strain of parasite, but by the stage of the parasite (oocyst, tachyzoite, bradyzoite), route of inoculation, and amount of inoculum as well.67 Oocysts are more virulent than tissue cysts of the same isolate.67, 72 Sporozoites, contained within oocysts, are more resistant to digestive chemicals after ingestion than bradyzoites,72 which offers one possible explanation for this observation. Whether oocysts are also more virulent than tissue cysts in human beings is unknown, but it has been suggested that the high prevalence of symptomatic, nonocular disease in the 1977 Atlanta epidemic (95%) might be attributable, in part, to infection with oocysts, rather than tissue cysts.72

Environmental factors might also contribute to an increased frequency with which ocular toxoplasmosis is seen in some situations. In London, the prevalence of symptomatic toxoplasmic retinochoroiditis is higher in black individuals born in west Africa than in the general population.39, 73 They also have a higher prevalence of ocular toxoplasmosis than black individuals living in London who were born in east Africa, the West Indies, or in Britain, suggesting that conditions in their geographic region of origin, rather than race per se, influenced the risk of disease. The higher prevalence of ocular disease may simply reflect a higher prevalence of T. gondii infection in the population. In a northern California study, active toxoplasmic retinochoroiditis was more common among Hispanic patients (8.64 cases/100,000 population) than among non-Hispanic patients (2.56 cases/100,000 population; odds ratio 4.4, P = .07; unpublished data, David C. Gritz, MD, MPH, Francis I. Proctor Foundation for Research in Ophthalmology, University of California, San Francisco and Kaiser Permanente Medical Group, Northern California Region; personal communication, July 2003), and it is known from an unrelated study that the prevalence of T. gondii infection among Mexican-Americans is higher than among the general United States population in some age groups.40 The higher prevalence of T. gondii infection seen in some geographic areas and in some racial/ethnic groups may be due to cultural factors that cause different exposures in terms of parasitic stage, amount of inoculum, or age of infection.

It is also the impression of some clinicians that environmental factors may partially account for variations in the severity of ocular disease between geographic regions. For example, it has been suggested that younger age of infection and larger amounts of inoculum might contribute, in part, to both the high prevalence and increased severity of ocular toxoplasmosis among T. gondii-infected individuals in southern Brazil.41, 42 In one study, inflammatory reactions and the sequelae of such inflammation in patients with toxoplasmic retinochoroiditis (elevated intraocular pressure, posterior synechiae) were found to be more severe among patients in South America than among those in North America and Europe, although treatment practices did not differ between regions (Emilio M. Dodds, MD, presented at the International Conference on Toxoplasmosis: Biology, Clinical Practice, and Public Health, Copenhagen, Denmark, 23–25 June 2003). Such results are subject to many confounding factors, however, including referral bias and access-to-care issues, and will require further investigation.

Studies of disease severity 

Severity of disease appears to be controlled by a combination of diverse, and sometimes unrelated, factors. It has been difficult to draw conclusions about these factors from the existing medical literature, because most studies have been uncontrolled; disease severity has not been defined in any consistent or quantitative manner; and in some studies outcome measures may not have been relevant to the specific factor being studied. Factors believed to be appropriate measures of disease severity are listed in Table 1. It has also been difficult in the past to segregate study populations into groups on the basis of factors that may influence disease severity, such as the time when infection was acquired or the genotype of the infecting parasite. The new serologic tests described above may aid in this effort.

TABLE 1. Ocular Toxoplasmosis: Appropriate Measures of Disease Severity for Use in Clinical Research
1.Presence or absence of retinal lesions in Toxoplasma-gondii-infected individuals
2.Interval from time of infection to development of retinal lesions (rarely known)
3.Number of retinal lesions (including bilaterality)
4.Location of lesions a.Presence of macular lesions
5.Size of retinal lesions a.Active retinochoroiditis b.Retinochoroidal scars
6.Levels of intraocular inflammatory reactions a.Aqueous humor cells, flare b.Vitreous inflammatory reactions
7.Duration of active disease a.Retinochoroidal lesions b.Inflammatory reactions
8.Complication of inflammation a.Anterior segment i.Posterior synechiae ii.Elevated intraocular pressure b.Posterior segment i.Retinal detachments (1)Exudative (2)Rhegmatogenous ii.Retinal vessel occlusionsiii.Subretinal neovascularization iv.Cystoid macular edema v.Epiretinal membranes
9.Character of retinochoroidal scars (?) a.Depth of excavation b.Pigmentation
10.Recurrence rates*

* Rate should be expressed as a time-dependent measure, reported in relation to the interval since last episode of active disease, if possible.

Because there are multiple influences on disease severity, multivariate analyses will be important. Age and duration of infection appear to have a substantial influence on disease manifestations; it will be particularly important to control for these confounders when comparing groups for other suspected risk factors.

Time-dependent factors deserve special consideration. In particular, the way in which disease recurrence rates are studied needs to be addressed. Many studies in the past have simply listed the total number of recurrences or the mean number of recurrences per year that are experienced by a patient during follow-up. Even the latter measure is not appropriate if there has been differential follow-up among study subjects, because of recent observations suggesting that the rate of disease recurrences decreases over time.1 For the same reason, a patient's own prior rate of recurrences should not be used as an historical control for prospective studies investigating the effect of treatment on recurrences.

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Implications for disease management 

Soon after toxoplasmosis was identified as a cause of retinal disease in adults, investigators began to treat patients with combinations of sulfonamides and antimalarial agents, based on results from animal studies. In 1958, Hogan2 stated that “occasional patients seem to show a response,” but added that “Daraprim [pyrimethamine] and sulfadiazine therapy of acquired toxoplasmosis was found to be disappointing . . .” Nevertheless, the combination of pyrimethamine, sulfadiazine, and prednisone remains the most commonly used therapy for ocular toxoplasmosis among uveitis specialists,74, 75 despite continuing reservations about efficacy.

For many years, it has been hoped that a vaccine could be developed that would prevent infection and that an effective and safe cysticidal drug would be identified that would cure existing infections. It is unlikely that either goal will be achieved in the near future. Thus, new strategies must be developed that will reduce the risk of infection and treat chronic infection more effectively with currently available drugs. A better understanding of the sources and routes of infection, populations at highest risk for infection, and the nature and course of clinical lesions (providing clues to disease mechanisms) will help in this effort.

Prevention 

For many years, programs for prevention of infection have been focused on pregnant women; postnatally acquired infections among other groups of healthy individuals have generally been considered to be benign. If, however, most eye disease is associated with postnatally acquired T. gondii infections, it may be appropriate to place greater emphasis on preventing these infections as well. Recognition that contaminated water may be a source of infection in some settings should stimulate efforts to eliminate that mode of disease transmission. Techniques have been developed to identify oocysts in water.76

The fact that the eye can be infected subclinically, with development of vision- threatening disease years later, has raised the issue of treating even mild cases of systemic toxoplasmosis resulting from postnatally acquired infection as a possible means of preventing ocular disease.18, 21 To do so selectively will require a better understanding of which patients are at greater risk for ocular infection and disease.

Treatment 

In a systematic review of the medical literature, Stanford and associates77 identified only three prospective, randomized, placebo-controlled clinical trials for the treatment of ocular toxoplasmosis in immunocompetent patients (the same information can be found in a Cochran Library review by Gilbert and associates78). None of these clinical trials confirmed that short-term drug therapy was effective for treatment of active toxoplasmic retinochoroiditis. The review should not be interpreted to mean that treatment has no effect, however. Although it is clear that current short-term treatments do not prevent recurrent disease, and it has been difficult to demonstrate that treatment alters the natural history of active disease, there has been observational evidence of treatment effects in some patients. For example, in a nonrandomized study, Rothova and associates25 found a relationship between treatment with pyrimethamine/sulfadiazine and reduction of lesion size, determined by comparing the size of active retinal inflammatory lesions to the size of resulting inactive retinochoroidal scars. Unknown, however, is the functional status of the retinal tissue surrounding the scar that had been inflamed. Thus, the practical benefit of this observed treatment effect remains to be determined. Other potential benefits of treatment, such as a reduction in the duration of disease, could not be demonstrated. Nevertheless, based on accumulated experience, most uveitis specialists agree that treatment of toxoplasmic retinochoroiditis is warranted, although there is no consensus regarding the best treatment regimens.74, 75

The lack of an easily demonstrated treatment benefit in human beings is in stark contrast to extensive evidence from animal studies that antimicrobial drugs are highly effective for treatment of active toxoplasmosis (usually expressed in terms of reduced mortality). Although a treatment effect has been difficult to confirm for immunocompetent patients, there are certain situations when anti-T. gondii drug treatment appears to have dramatic effects in human beings. For example, chronically active toxoplasmic retinochoroiditis in patients with AIDS will rapidly become inactive with treatment (Figures 2 and 3).11, 13, 14, 15 Whereas some newer antimicrobial agents, including atovaquone and azithromycin, reduce the number of tissue cysts in animal models,79 recurrences have not been prevented with short-term therapy using either atovaquone80, 81 or azithromycin82 in human beings. These various discrepancies have perplexed investigators for years. A better understanding of the nature of retinal lesions and events occurring during the course of active disease might provide information that will impact therapeutic strategies.

O'Connor7 hypothesized that a lack of treatment effect in patients whose retinal lesions are characterized by thickened granulomata might be related to failure of drug to penetrate the lesions and reach parasites. More prolonged antimicrobial therapy in such cases, especially with agents having some cysticidal activity, might, therefore, be more effective. In contrast, the rapid response to drug treatment of lesions in patients with AIDS would relate to the fact that there is less inflammatory material and less thickening of lesions in this population, thereby allowing greater drug penetration. Clinical trials that target specific populations or patients having lesions with specific characteristics might be more successful at demonstrating treatment effects.

An understanding of the relationship between the infecting parasite and the nature of the resulting disease may eventually help to make therapeutic decisions. For example, if the infecting parasite type could be identified easily on the basis of a serological test, and it was confirmed that certain parasite types were associated with a substantially increased risk of severe ocular disease, decisions to use potentially toxic drugs could be made in a more rational manner. If parasite types are found to differ in drug susceptibility in vivo, the choice of agents could be individualized on the basis of the infecting parasite.

Defining the role of corticosteroids in the management of ocular toxoplasmosis more precisely will also require a better understanding of disease; specifically, the contribution of inflammation to tissue destruction in various situations needs to be clarified. Several seemingly contradictory clinical observations regarding inflammation require reconciliation. Histopathologic studies of eyes from immunocompromised patients with toxoplasmic retinochoroiditis show a lack of inflammatory cells in infected retina,11, 28 and corticosteroid therapy has not been necessary to control toxoplasmic retinochoroiditis in immunocompromised patients.11 Corticosteroid therapy without the concurrent use of antimicrobial agents, even in immunocompetent patients, can lead to severe tissue destruction (FIGURE 11, FIGURE 12).83, 84 These observations suggest that parasite proliferation, rather than inflammation, is the major cause of tissue damage in those cases. As noted above, however, reduced immune responses in elderly individuals or other patients with immune dysfunction may limit some aspects of tissue destruction. Also, despite the potential detrimental effects of corticosteroids, many uveitis specialists have, in fact, seen patients who were initially treated with corticosteroids alone, and who did well. It is likely that there are substantial qualitative differences in the inflammatory responses that occur among various groups of patients. Also, different parasite types may elicit unique immune responses with different consequences to host tissue. An understanding of these differences may ultimately allow an individualized approach to the use of corticosteroids in the management of ocular toxoplasmosis.

  • View full-size image.
  • FIGURE 11. 

    The right fundus of a 38-year-old woman with recurrent toxoplasmic retinochoroiditis after receiving a periocular injection of corticosteroid without concurrent antimicrobial therapy. She was originally seen with a satellite lesion (thin black arrow) at the border of a pre-existing retinochoroidal scar (in the area of the thick black arrow). The injection was given during the healing phase of the satellite lesion, and resulted in marked increase in inflammation (shown here) and recrudescence of the retinochoroiditis (area identified by the white arrow). Inflammation gradually subsided over a 6-month period during which she was treated with pyrimethamine, sulfadiazine, and clindamycin.

  • View full-size image.
  • FIGURE 12. 

    The same fundus shown in Figure 11, photographed 2 years later. The area of the recrudescent lesion (white arrow) is more deeply excavated than the original scar (the area of scarring farthest from the optic disk) or the site of the satellite lesion from which the recrudescence developed.

Vision loss can first occur with reactivation of lesions6 indicating the need to develop strategies for the prevention of recurrences. Silveira and associates85 showed a statistically significant reduction in recurrence rates among patients in southern Brazil given intermittent trimethoprim/sulfamethoxazole over a 20-month period. To apply this strategy of secondary prophylaxis appropriately, it will be necessary to identify those patients at greatest risk for recurrences and to gain a better understanding of the interval during which recurrences are most likely to occur, so that people who would not benefit from treatment will not be exposed unnecessarily to the toxic effects of antimicrobial drugs. Although these issues must be addressed, secondary prophylaxis appears to be an important new management strategy.

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Summary 

Listed below are some of the important refinements to our understanding of ocular toxoplasmosis that have resulted from clinical studies over the past five decades, grouped by the major topics covered in Parts I1 and II of this presentation. Also mentioned are issues that deserve additional investigation.

•Burden of disease: The prevalence of T. gondii infection varies between geographic regions and between population groups on the basis of numerous factors. The risk of ocular involvement also varies markedly, but is less well understood. Precise data for the prevalence of ocular toxoplasmosis in the United States are unknown, but 2% of T. gondii-infected individuals may be a reasonable estimate.1 Even at this low proportion, there is a substantial burden of disease, in terms of vision loss and the need for medical care.

•Sources of infection: While undercooked meat and food contaminated with oocysts from cat feces remain the major sources of infection, contaminated water may be an important additional source in some settings.

•Congenital versus postnatally acquired infection: Congenital T. gondii infection is associated with a higher risk of ocular involvement than postnatally acquired infections. Numerous lines of evidence indicate that the majority of individuals with ocular toxoplasmosis were infected with T. gondii after birth, however, because of the much larger pool of individuals with such postnatal infections.

•Course of disease: Initial retinal infection may be subclinical, with development of retinal lesions months or years later. Tissue destruction is probably attributable both to proliferation of T. gondii and to inflammatory reactions, but the relative importance of each factor may vary between hosts. In many patients, sucessive recurrences appear to develop from the same position on specific retinochoroidal scars; recurrences do not seem to be randomly distributed among scars in patients with multifocal disease. This observation, discussed in Part 1,1 suggests the possibility that not all scars contain tissue cysts. The frequency of recurrent toxoplasmic retinochoroiditis appears to decrease over time, suggesting that tissue cysts may have a finite lifespan in human hosts. Patients can periodically have mild, transient recurrences of inflammation without evidence of active retinochoroiditis. Attention to these various observations may help to understand disease mechanisms, ultimately with implications for choice of therapy. Re-infection with T. gondii might explain some clinical observations, and should be investigated with new techniques that can differentiate between parasite types.

•Spectrum of clinical manifestations: Disease features are probably more diverse than traditionally taught, yet most, if not all, “atypical” forms of disease appear to be part of a spectrum of the same basic disease process of retinal infection with stimulation of a host immune response. Variations in disease manifestations and severity depend on the duration of active retinal infection and the characteristics of the accompanying inflammatory reactions.

•Factors related to disease severity: Variations in disease presentation probably result from a combination of host, parasite, and environmental factors. Immunocompromised patients with T. gondii infection are at risk for severe ocular disease. Patient age appears to have an important influence on disease presentation; both the prevalence of ocular involvement and the severity of ocular disease may be increased in older patients, but this issue has never been studied in a systematic manner. The immune dysfunction that occurs with aging probably contributes to these associations. The genotype of the infecting parasite also appears to be an important determinant of disease severity, particularly in immunocompetent hosts. The ability to identify parasite types may provide new insights into disease pathogenesis and may, ultimately, be an important diagnostic and prognostic tool. Attention to these host and parasite factors may help to predict who is at risk for severe disease, and may suggest new targets for therapeutic intervention.

In 1958, Hogan2 concluded his Edward Jackson Memorial Lecture with a comment regarding the need for further clinical studies of ocular toxoplasmosis. That need persists to this day; only with a clear understanding of the clinical features of disease can the knowledge gained from laboratory-based, molecular biological investigations be applied appropriately to the management of this global disease.

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Acknowledgments 

Statistical analyses of unpublished data from scientific meetings cited in the text, as well as additional analyses of previously published data, were performed by Fei Yu, Ph.D., Jules Stein Eye Institute Clinical Research Center, David Geffen School of Medicine at UCLA, University of California, Los Angeles. Figures 1 and 4 were reprinted from Holland GN, O’Connor GR, Belfort R, Remington JS. Toxoplasmosis. In Pepose JS, Holland GN, Wilhelmus, KR, eds. Ocular Infection & Immunity. St Louis: Mosby-Year Book, Inc. pp. 1183–1223, 1996 with permission from Elsevier Science. Portions of the photographic montages shown in Figures FIGURE 2, FIGURE 3, FIGURE 11, FIGURE 12 and 12 contain images that appeared in the same chapter.

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Afterword: on global collaboration 

Wilder's 1952 confirmation of ocular toxoplasmosis in adults3 effected a sea change in our understanding of this disease and in our approach to the evaluation and management of patients with uveitis. It is worth noting, however, that during the first half of the 20th century, ocular toxoplasmosis had been suspected, even years earlier, in other countries of the world, including Brazil, Germany,86 and Sweden.87 Had communication between investigators around the world been easier in that era, recognition of ocular toxoplasmosis in adults might have occurred sooner.

In the current “information age,” the situation has changed substantially. Reports from Brazil41, 42 stimulated my own reassessment of the disease, as it did for many others. The recent evolution of our concepts regarding ocular toxoplasmosis has been based on an exchange of critical observations from investigators in Europe, North and South America, and other parts of the world.

Among the many people who have contributed to my understanding of toxoplasmosis, I would like to acknowledge specifically a number of individuals who have assisted me with research projects and with whom I continue to collaborate. In keeping with the theme of global collaboration, they are listed below by the countries in which they work. Argentina: Emilio M. Dodds, MD; Austria: Talin Barisani-Asenbauer, MD; Brazil: Lilian M. G. Bahia de Oliveira, PhD, Rubens Belfort, Jr., MD, PhD, Raquel Goldhardt, MD, Cristina Muccioli, MD, Claudio Silveira, MD; Canada: Andrew J. Burnett, MD, Michael E. Grigg, PhD; France: Antoine P. Brezin, MD, PhD; the Netherlands: Aize Kijlstra, PhD, Aniki Rothova, MD, PhD; Switzerland: Jean D. Vaudaux, MD; United Kingdom: Ruth Gilbert, MD, MScEpid, FRCPCH, Elizabeth M. Graham, FRCP, DO, FRCOphth, Miles R. Stanford, MD, FRCOphth; United States of America: John C. Boothroyd, PhD, David A. Bruckner, DSc, Emmett T. Cunningham, MD, PhD, MPH, Mehmet Z. Doymaz, PhD, J. P. Dubey, MVSc, PhD, Robert E. Engstrom, Jr., MD, Robert Y. Foos, MD, Ben J. Glasgow, MD, David C. Gritz, MD, MPH, Jeffrey L. Jones, MD, MPH, Ralph D. Levinson, MD, Marilyn B. Mets, MD, Jose G. Montoya, MD, Robert B. Nussenblatt, MD, G. Richard O'Connor, MD, Jack S. Remington, MD, Kayur H. Shah, MD, L. David Sibley, PhD, Justine R. Smith, MBBS, PhD, Jamie M. Weisz, MD, Fei Yu, PhD.

Several of these individuals deserve special mention. I began my study of ocular toxoplasmosis with Dr. G. Richard O'Connor, Professor Emeritus of Ophthalmology at the University of California, San Francisco, and former Director of the Francis I. Proctor Foundation, and we have continued to work together during the past 20 years. Drs. Rubens Belfort, Cristina Muccioli, and Claudio Silveira of the Federal University of São Paulo have graciously included me in their ongoing studies of ocular toxoplasmosis; they have proven that international collaboration can work well. Drs. John C. Boothroyd of Stanford University and Michael E. Grigg of University of British Columbia have helped me to bring basic science discoveries about the biology of Toxoplasma gondii into the arena of patient-based research, and Dr. Jeffrey L. Jones of the United States Centers for Disease Control and Prevention has contributed his expertise in epidemiology to a better understanding of ocular toxoplasmosis. To each of these individuals I owe a special debt of gratitude.

I would also like to thank Dr. David L. Knox of Johns Hopkins University for providing me with additional, unpublished data from his influential 1969 study6 describing the clinical characteristics of toxoplasmic retinochoroiditis.

In an editorial accompanying the first issue of the American Journal of Ophthalmology, Dr. Edward Jackson called for cooperation between ophthalmologists in the dissemination of information; he stated that “the benefits [that cooperation] will bring are still indefinite and lay [sic] in the future. But they are nonetheless real, and they will come to us as fast as we come to understand their value . . .”88 The global study of ocular toxoplasmosis has provided evidence of his foresight.

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References 

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☆ Supported, in part, by Research to Prevent Blindness, Inc., New York, NY, the Skirball Foundation, Los Angeles, CA, and the David May II Endowed Professorship. Additional support was provided by the Emily Plumb Estate and Trust Gift for resources utilized in the Jules Stein Eye Institute Clinical Research Center. Dr. Holland is a recipient of a Research to Prevent Blindness Physician-Scientist Award.Additional material for this article can be found on ajo.com. doi:10.1016/j.ajo.2003.10.032

PII: S0002-9394(03)01319-9

doi:10.1016/j.ajo.2003.10.032

American Journal of Ophthalmology
Volume 137, Issue 1 , Pages 1-17, January 2004

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