**1. Introduction**

Ocular toxoplasmosis (OT) is a major cause of posterior uveitis worldwide but its incidence and prevalence are difficult to establish precisely. In 1993, a survey in a French Hospital Service of Ophthalmology showed that OT was seen in less than 1 per thousand outpatients [1]. In a study performed in Germany, toxoplasmosis accounted for 4.2 % of all cases of uveitis at a referral centre [2]. Around 5000 people develop symptomatic OT each year in the United States [3]. OT is a complication of both acute acquired and reactivated congenital in immunocompetent but particularly in immunocompromissed individuals and its severity can be influenced by variation in parasite isolates, parasitic load, route of infection and hostrelated factors such as immune function, age and pregnancy. Diagnosis is usually based on ophthalmological examination and is confirmed by the response to specific treatment, but also by biological assays including local antibody production, PCR and western blot. All these points will be detailed below.

### **2. A complication of acquired and congenital infections**

Classically, retinochoroiditis secondary to acquired toxoplasmosis was considered an exceptional event in immunocompetent individuals, and was usually defined as a periodic reactivation of latent cysts associated with undiagnosed congenital infections. But recent data, based on ophthalmological examination, seem to establish that acquired infection might be responsible for most cases. This fact was particularly demonstrated by outbreaks reported in Canada, Brazil and India. In Canada, amongst 100 individuals infected during a water-borne outbreak, 19 had OT [4]. In southern Brazil 17.7% of 1,042 individuals examined had OT with lesions in 0.9% of 1- to 8-year-olds and in 21.3% of all individuals older than 13, suggesting that in this population, the disease was a sequel of postnatal rather

© 2012 Dupouy-Camet et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

than congenital infection [5]. In India, Balasundaram et al. [6] described ocular involvement due to toxoplasmosis in 248 patients who had active retinochoroiditis and toxoplasmic serology suggesting recently acquired disease. Delair et al. [7] analysed 425 cases of OT, 100 (23.5%) were acquired, 62 (14.6%) were congenital, and 263 (61.9%) were of unknown origin. At the time of the study, the mean age of the patients with congenital OT was 9.1 +/- 8.8 years, and 21.7 +/- 12.6 years in the patients with the acquired disease (p < 0.001). Bilateral OT was only found in 4% of acquired cases and in 43.5% of congenital cases (p < 0.001) and in acquired infections, visual acuity was significantly less impaired than in congenital infections. In the United Kingdom, 50% of OT in children was acquired after birth and no clear clinical distinction could be made between acquired and congenital toxoplasmosis (CT) [8]. However, other authors have identified clinical presentations specific to each group. Montoya et al. (1996) observed that patients with post-natal acquired toxoplasmic retinochoroiditis had mostly unilateral lesions without old scars or involvement of the macula [9]. In case of congenital origin, the risk of ocular disease depends on the trimester of pregnancy when infection occurred, and on whether or not treatment was administered to the mother during pregnancy. In one study, a period exceeding 8 weeks between maternal infection and the beginning of treatment, female gender, and especially cerebral calcifications were risk factors for retinochoroiditis [10]. No significant association was found in other cohort studies between gestational age at maternal infection, prenatal treatment and the risk of developing OT [11, 12].

Risk Factors, Pathogenesis and Diagnosis of Ocular Toxoplasmosis 131

women can cause recurrences and these authors described four women having such recurrences in every pregnancy [19]. Garweg et al. [20] reported that recurrence occurred in approximately in 4 out of 5 patients and that the risk was higher two years after the first episode. Holland et al. [21] confirmed that the risk of recurrence was the highest immediately after an episode of active disease and that recurrence had a tendency to occur in clusters. Mice with different genetic backgrounds will have different susceptibilities to the parasite [22]. In humans, an increased frequency of the HLA-Bw62 antigen was observed in patients with severe OT [23]. In mother-child pairs from Europe and North America, ocular disease in CT was associated with polymorphisms in ABCA4 encoding the ATP-binding cassette transporter and in COL2A1 encoding type II collagen [24]. Evidence will be shown below that polymorphism in cytokine genes is also an important factor triggering OT

Currently, it is assumed that the population of *T. gondii* consists of 3 3 predominant clonal lineages, which differ at the DNA sequence level by 1% or less [25] but microsatellite analysis has shown the high diversity of that genus [26]. In Europe and the United States, type II is the most common cause of systemic *Toxoplasma* infection [27]. As early as 2001 Grigg et al. [28] suggested a possible correlation between severe retinal disease and atypical genotypes in immunocompetent patients as, in acquired OT, an unusual abundance of type I, or recombinant genotypes I/III were found. In Brazil, genetic studies have shown that genotypes of *T. gondii* involved in acquired OT were atypical, belonging to genotypes different from genotype II [29]. The differences in the frequency, size and multiplicity of retinochoroidal lesions may be explained by more virulent parasite genotypes that predominate in Brazil, but are rarely found in Europe. Khan et al. [30] compared 25 clinical and animal isolates of *T. gondii* from Brazil to previously characterised clonal lineages from North America and Europe. Genotypes of *T. gondii* strains isolated from Brazil were highly divergent when compared (by multilocus nested PCR analysis combined with sequencing of a polymorphic intron) to the previously described clonal lineages found in Europe. These atypical genotypes may also explain the high frequency (20% of 97 cases) of ocular involvement in the above mentioned Canadian outbreak where an atypical cougar isolate was suspected, and the 100-fold higher incidence of OT in patients born in Africa compared to patients born in Britain [31,32]. The distribution of genotypes was different in immunocompromised patients who reactivate a type II strain (if acquired in Europe), or a non–type II strain (if acquired in Africa or South America). However, direct genotyping of strains from aqueous or vitreous fluids of 20 French patients showed a predominance of the type II genotype in OT [33] so the possible link of OT

**5. Immune privileged status and cytokine responses are key factors in** 

The pathogenesis of OT is directly linked to the anatomical characteristics of the eye resulting in an immune privileged status. The presence of the hemato-retinal barrier and the

**4. Specific parasitic genotypes could be involved** 

with some specific genotypes is not yet clear.

**toxoplasmic retinochoroiditis** 

occurrence.

#### **3. Occurrence depends on host genetic background and immune status**

In mice, the severity of ocular damage is linked to many factors related to either host immunity or the parasite, such as inoculum size, infective stage (oocysts versus cysts), route of infection and the genotype of the infecting strain. However, these data are not well documented in humans. The acquired immune deficiency syndrome (AIDS) epidemic has dramatically reminded that effective host immunity was essential to limit the severity of ocular lesions. AIDS patients without highly active antiretroviral therapy can develop extensive and recurring lesions [13]. Similar lesions may also be encountered during the use of immunosuppressive drugs [9, 14]. Many studies have focused on elderly patients [15-17]. These patients can have large and multiple ocular lesions with severe vitritis and prolonged disease, in some instances similar to lesions encountered in immunocompromissed individuals, although they are otherwise healthy. Indeed, both cellular and humoral immune responses are modified with advancing age and probably contribute to the higher severity of OT in older patients [16]. A cross-sectional household study involving 499 individuals was undertaken in Minas Gerais state of Brazil, where infection with *T. gondii* is endemic. The frequency of OT increased significantly with age as approximately 50% of individuals above 60 years of age had lesions and older patients had a higher risk of OT following recently acquired infection compared to younger patients [18]. The factors responsible for recurrences are unknown, but trauma, hormonal changes and cellular or humoral immunosuppression appear to contribute to the release of parasites from tissue cysts. Bosch-Driessen et al. reported an increased incidence of recurrences after cataract surgery and during pregnancy [19]. The hormonal and immunological changes in pregnant women can cause recurrences and these authors described four women having such recurrences in every pregnancy [19]. Garweg et al. [20] reported that recurrence occurred in approximately in 4 out of 5 patients and that the risk was higher two years after the first episode. Holland et al. [21] confirmed that the risk of recurrence was the highest immediately after an episode of active disease and that recurrence had a tendency to occur in clusters. Mice with different genetic backgrounds will have different susceptibilities to the parasite [22]. In humans, an increased frequency of the HLA-Bw62 antigen was observed in patients with severe OT [23]. In mother-child pairs from Europe and North America, ocular disease in CT was associated with polymorphisms in ABCA4 encoding the ATP-binding cassette transporter and in COL2A1 encoding type II collagen [24]. Evidence will be shown below that polymorphism in cytokine genes is also an important factor triggering OT occurrence.

#### **4. Specific parasitic genotypes could be involved**

130 Toxoplasmosis – Recent Advances

treatment and the risk of developing OT [11, 12].

than congenital infection [5]. In India, Balasundaram et al. [6] described ocular involvement due to toxoplasmosis in 248 patients who had active retinochoroiditis and toxoplasmic serology suggesting recently acquired disease. Delair et al. [7] analysed 425 cases of OT, 100 (23.5%) were acquired, 62 (14.6%) were congenital, and 263 (61.9%) were of unknown origin. At the time of the study, the mean age of the patients with congenital OT was 9.1 +/- 8.8 years, and 21.7 +/- 12.6 years in the patients with the acquired disease (p < 0.001). Bilateral OT was only found in 4% of acquired cases and in 43.5% of congenital cases (p < 0.001) and in acquired infections, visual acuity was significantly less impaired than in congenital infections. In the United Kingdom, 50% of OT in children was acquired after birth and no clear clinical distinction could be made between acquired and congenital toxoplasmosis (CT) [8]. However, other authors have identified clinical presentations specific to each group. Montoya et al. (1996) observed that patients with post-natal acquired toxoplasmic retinochoroiditis had mostly unilateral lesions without old scars or involvement of the macula [9]. In case of congenital origin, the risk of ocular disease depends on the trimester of pregnancy when infection occurred, and on whether or not treatment was administered to the mother during pregnancy. In one study, a period exceeding 8 weeks between maternal infection and the beginning of treatment, female gender, and especially cerebral calcifications were risk factors for retinochoroiditis [10]. No significant association was found in other cohort studies between gestational age at maternal infection, prenatal

**3. Occurrence depends on host genetic background and immune status** 

In mice, the severity of ocular damage is linked to many factors related to either host immunity or the parasite, such as inoculum size, infective stage (oocysts versus cysts), route of infection and the genotype of the infecting strain. However, these data are not well documented in humans. The acquired immune deficiency syndrome (AIDS) epidemic has dramatically reminded that effective host immunity was essential to limit the severity of ocular lesions. AIDS patients without highly active antiretroviral therapy can develop extensive and recurring lesions [13]. Similar lesions may also be encountered during the use of immunosuppressive drugs [9, 14]. Many studies have focused on elderly patients [15-17]. These patients can have large and multiple ocular lesions with severe vitritis and prolonged disease, in some instances similar to lesions encountered in immunocompromissed individuals, although they are otherwise healthy. Indeed, both cellular and humoral immune responses are modified with advancing age and probably contribute to the higher severity of OT in older patients [16]. A cross-sectional household study involving 499 individuals was undertaken in Minas Gerais state of Brazil, where infection with *T. gondii* is endemic. The frequency of OT increased significantly with age as approximately 50% of individuals above 60 years of age had lesions and older patients had a higher risk of OT following recently acquired infection compared to younger patients [18]. The factors responsible for recurrences are unknown, but trauma, hormonal changes and cellular or humoral immunosuppression appear to contribute to the release of parasites from tissue cysts. Bosch-Driessen et al. reported an increased incidence of recurrences after cataract surgery and during pregnancy [19]. The hormonal and immunological changes in pregnant Currently, it is assumed that the population of *T. gondii* consists of 3 3 predominant clonal lineages, which differ at the DNA sequence level by 1% or less [25] but microsatellite analysis has shown the high diversity of that genus [26]. In Europe and the United States, type II is the most common cause of systemic *Toxoplasma* infection [27]. As early as 2001 Grigg et al. [28] suggested a possible correlation between severe retinal disease and atypical genotypes in immunocompetent patients as, in acquired OT, an unusual abundance of type I, or recombinant genotypes I/III were found. In Brazil, genetic studies have shown that genotypes of *T. gondii* involved in acquired OT were atypical, belonging to genotypes different from genotype II [29]. The differences in the frequency, size and multiplicity of retinochoroidal lesions may be explained by more virulent parasite genotypes that predominate in Brazil, but are rarely found in Europe. Khan et al. [30] compared 25 clinical and animal isolates of *T. gondii* from Brazil to previously characterised clonal lineages from North America and Europe. Genotypes of *T. gondii* strains isolated from Brazil were highly divergent when compared (by multilocus nested PCR analysis combined with sequencing of a polymorphic intron) to the previously described clonal lineages found in Europe. These atypical genotypes may also explain the high frequency (20% of 97 cases) of ocular involvement in the above mentioned Canadian outbreak where an atypical cougar isolate was suspected, and the 100-fold higher incidence of OT in patients born in Africa compared to patients born in Britain [31,32]. The distribution of genotypes was different in immunocompromised patients who reactivate a type II strain (if acquired in Europe), or a non–type II strain (if acquired in Africa or South America). However, direct genotyping of strains from aqueous or vitreous fluids of 20 French patients showed a predominance of the type II genotype in OT [33] so the possible link of OT with some specific genotypes is not yet clear.
