Ocular toxoplasmosis past, present and new aspects of an old disease
Introduction
To this day ocular toxoplasmosis (OT) remains a challenging ocular disease with many open questions with regard to disease manifestation, pathophysiology and its management. Our current understanding of OT evolved over the course of more than a century through careful clinical observation, epidemiological and parasitological studies.
Retinochoroidal scars – a clinical hallmark of OT – were probably already depicted in the mid 19th century (Fig. 1). Toxoplasmic retinochoroiditis as part of the disease manifestation of congenital toxoplasmosis in a newborn was first described by the Czech ophthalmologist Janku in 1923, and was considered an established medical fact almost two decades later (Janku, 1923, Wolf et al., 1939). After discovery of the parasite by Nicolle in 1907 (Nicolle, 1907, Nicolle and Manceaux, 2009), OT was recognised as an ocular pathology in adults by Wilder as late as 1952 (Wilder, 1952b, Wilder, 1952a). The seminal work of Hogan sparked and defined research on OT for the better part of the next two decades (Hogan, 1950, Hogan, 1956, Hogan, 1958a, Hogan, 1958b, Hogan et al., 1957, Hogan et al., 1964, Hogan et al., 1958). Most notably, already at this time the first treatment regimes were introduced in the shape of the antimalarial drug pyrimethamine in combination with sulphonamides and corticosteroids, which are still the most frequently prescribed agents until today (Perkins et al., 1956, Ryan et al., 1954) [see Section 2.5]. Whereas in the past – and with very limited success – clinical researchers attempted to subcategorise OT based on clinical parameters such as localisation of lesions, severity of inflammation, age of first manifestation, mode of infection and type of complications, OT today is understood as a disease with a broad spectrum of manifestations. Regardless of whether toxoplasmic retinochoroiditis occurs in immunocompromised and immunocompetent patients respectively, or whether OT is acquired congenitally or postnatally, no clear distinction between disease entities can be observed. The dogma that OT is an exclusive congenital disease eroded in the 1980s and today it is well recognised that postnatally acquired infection and subsequent ocular inflammation is the most frequent form of OT (Gilbert and Stanford, 2000). Based on advances in the recent decades, we know that OT is the most frequent form of infectious posterior uveitis representing up to 85% of all cases (Talabani et al., 2010). Where data are available pronounced geographical differences in disease prevalence can be observed. Particularly high prevalences are reported for South- and Latin America as well as Africa and parts of Asia, leading to speculations that a part from environmental and nutritional factors host and parasite genotype have a significant impact on the occurrence and clinical manifestation of OT [see Sections 3.1.1 Route of infection, environmental and parasite related factors contributing to infection and disease, 3.1.2 Classical clonotypes vs. emergence of atypical strains]. Similarly, environmental and socio-economic factors as well as alimentary habits influence the epidemiology of infection with Toxoplasma gondii in general.
Current controversies surrounding OT still focus on the precise role of different strains of T. gondii, host factors (i.e. genetic disposition), the optimal diagnostic approach and treatment (i.e. usefulness of corticosteroids) and the benefit of antiparasitic prophylaxis to prevent recurrences. OT is still an under- and often misdiagnosed ocular pathology and increased efforts have to be undertaken to reduce the disease burden of OT. In the long term, the current treatment goal, which focuses entirely on the preservation of vision without a curative option and the prevention of recrudescence, is an incomplete solution.
T. gondii is an obligate intracellular protozoan parasite that belongs to the phylum apicomplexa, subclass coccidia. The parasite exists in different morphologic and metabolic stages: Oocysts are the product of the parasite's sexual cycle in the intestine of all members of the felids (cat family) and release infectious sporozoites (Fig. 2). Tachyzoites are asexual forms that – through their rapid replication – damage host tissue, while cysts, which contain bradyzoites, represent the dormant stage of the parasite in tissues. During primary feline infection several million oocysts (10 × 12 μm in size) are shed in the faeces. Following sporulation sporozoites are released and may infect new hosts when ingested, giving rise to the tachyzoite stage. Tachyzoites (2–4 μm wide and 4–8 μm long) are crescentic or oval and are rapidly multiplying obligate intracellular stages of the parasite. Tachyzoites enter all nucleated cells by active penetration and form an intracytoplasmic vacuole. Following repeated replication, host cells are disrupted and tachyzoites invade neighbouring cells. The tachyzoite form causes a strong inflammatory response and tissue destruction and is therefore responsible for clinical manifestations of the disease. Under the pressure of the immune system, tachyzoites are transformed into bradyzoites that form cysts. Bradyzoites persist inside cysts for the life of the host (Fig. 2). Bradyzoites are morphologically similar to tachyzoites but multiply slowly, express stage-specific molecules and are functionally different (Lyons et al., 2002, Weiss and Kim, 2000). Tissue cysts containing between hundreds and thousands of bradyzoites are found in the retina, brain, skeletal and heart muscles. In immunocompromised patients bradyzoites may be released from cysts, transform back into tachyzoites and cause reactivation of the infection. Tissue cysts are infective stages for intermediate and definitive hosts via consumption of muscle or brain tissue. Humans can get infected by consumption of undercooked cyst-contaminated meat products or by sporulated oocysts which can be found in water, soil or vegetables.
After ingestion cysts (or oocysts) are disrupted and the bradyzoites (or sporozoites) are released into the intestinal lumen where they rapidly enter cells and multiply as tachyzoites. Immunodeficiency allows reactivated parasites to proliferate and cause severe disease whereas re-infection does not appear to cause clinically apparent disease (Elbez-Rubinstein et al., 2009, Holland et al., 1988b, Luft and Remington, 1992). Genetic examinations revealed that the population structure of T. gondii is mainly clonal. However, analyses in South-America found evidence for the existence of further clonal and non-clonal T. gondii lineages and, in addition, sexual recombinant strains. For many other regions of the world there is only limited or no information available on the genetic composition of the T. gondii population. The genetic diversity between lineages and strains may contribute to differences in virulence and epidemiological pattern of occurrence and there are reports indicating that the clinical pattern of OT might be influenced also by the genotype of the parasite [see Sections 3.1.1 Route of infection, environmental and parasite related factors contributing to infection and disease, 3.1.2 Classical clonotypes vs. emergence of atypical strains] (Shobab et al., 2013, Wendte et al., 2011).
T. gondii is a widespread parasite that infects almost all species of mammals and birds on all continents. Approximately 25–30% of the human population is infected with T. gondii. However, seroprevalence varies greatly between different countries (from 10 to 80%) and even within countries. Low seroprevalence has been reported from South East Asia, North America (Dubey and Jones, 2008) and Northern Europe (10–30%). Prevalences between 30 and 50% have been reported for Central and Southern Europe, whereas high seroprevalences are observed in Latin America and in tropical African countries (Fig. 3) (Robert-Gangneux and Darde, 2012). In countries with low and moderate seroprevalence, the seropositivity rates increase with age due to the lifelong but relative low risk of infection (Table 1). Interestingly, in countries with high seroprevalence, seropositivity rates plateau at relative young age (e.g. in Brazil at the age of 20–29 years). These differences in seropositivity rates are most probably explained by the different prevalence of Toxoplasma cysts and oocysts in the environment. However, even in countries with very high-seroprevalence some people remain seronegative throughout their life. The prevalence of toxoplasmic retinochoroiditis follows the same geographical pattern. Although congenital infection frequently results in chronic recrudescent retinochoroiditis, most cases of OT are acquired after birth (Talabani et al., 2010). Clinically, OT is the major cause of posterior uveitis in many countries but reliable epidemiological data are rare. In a German tertiary centre, 4.2% of all uveitis patients were accounted to T. gondii (Jakob et al., 2009). Pivetti-Pezzi et al. (1996) reported that 6.63% of uveitis patients were caused by T. gondii in an Italian ophthalmological reference centre. In a retrospective study in USA, OT was diagnosed in 8.4% of 2761 uveitis patients (London et al., 2011). Interestingly, many of these patients had immigrated from Mexico, Central or Southern America to the US further illustrating the high prevalence of OT in these geographical regions. A common feature of these studies was that patients with OT were relatively young (around 20 years), although OT may also develop in the elderly, when immunity to T. gondii wanes. Whereas in southern Brazil 17.7% had OT (Glasner et al., 1992) only 2% of people infected with T. gondii in the United States have had episodes of OT (Holland, 2003).
Section snippets
Ocular toxoplasmosis – clinical aspects
Necrotising retinochoroiditis is considered as the typical presentation of OT and characteristic to such a degree that often further diagnostic workup is not needed. However, even when this is the most frequent manifestation of OT, there is considerable clinical variation and the diagnosis can be rather cumbersome (Bosch-Driessen et al., 2002, Labalette et al., 2002, Smith and Cunningham, 2002). Knowledge of the various presentations of OT is important for the clinician and attention to
Route of infection, environmental and parasite related factors contributing to infection and disease
An important factor for the transmission of T. gondii to humans is the number of infected felids and resulting oocyst prevalence in the environment. Within ten days after oral ingestion of cysts, primary infected cats shed oocyst for 1–2 weeks. Remarkably, a single cat can pass more than 100 million non-sporulated oocysts, which become infective within 1–5 days after sporulation and remain viable for several months. Seropositivity rates in wild felids are in general very high and may be close
Animal models
For a long time experimental researchers have strived to establish animal models for OT. In the 1950s researchers spearheaded this endeavour by presenting a mouse and guinea pig model (Hogan, 1951, Hogan et al., 1958) and since then remarkable progress has been made. Animal OT models will be categorized along the following criteria: a) parasite entry; b) onset of disease and manifestation; c) self-limitation of ocular inflammation and models of recurrence; d) disease diagnostics e) parasite
Future directions
Although our knowledge on the pathogenesis, clinic and treatment of OT has substantially increased over the last years, many questions are still open. The following list summarises unresolved topics, which need to be addressed in future research:
Funding
The authors Maenz, Schlüter, Schares, Gross, and Pleyer received funding from the Federal ministry of education and research of Germany (BMBF) through the Toxonet 02 research collaboration.
Acknowledgements
The authors would like to thank Prof. Frank Seeber (RKI, Berlin) and Astrid Tenter (TiHo Hannover, Germany) for critically reading the manuscript and their helpful comments. Furthermore, we would like to thank Agatha Dukaczewska and Prof. Ignazio Tedesco for providing IHC eye sections and images of mice affected by OT.
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Percentage of work contributed by each author in the production of the manuscript is as follows: Maenz: 30%; Schlüter: 15%; Liesenfeld: 10%; Schares: 7.5%; Gross: 7.5%; Pleyer: 30%.