of new retinochoroidal lesions [4]. Usually, ocular toxoplasmosis (OT) is clinically diagnosed through recognition of a focal retinitis or retinochoroiditis in the setting of an adjacent or nearby retinochoroidal scar. Serum anti–T. gondii immunoglobulin G (IgG) antibodies support the diagnosis but are not always necessary. In immunocompromised individuals, however, OT lesions may be extensive or multifocal, complicating the diagnosis [10].

The laboratory diagnosis of toxoplasmosis is based on detection of circulating antibodies directed against T. gondii and/or the identification of the specific organism or its antigens using polymerase chain reaction (PCR). Toxoplasmosis therapy includes specific antiparasitic medication and corticosteroids. There are several regimens, with different drug combinations. Medications include pyrimethamine, sulfadiazine, clindamycin, trimethoprim–sulfamethoxazole, spiramycin, azithromycin, atovaquone, tetracycline, and minocycline. The prognosis of OT is usually good in immunocompetent individuals, as long as the macula, the optic nerve, and the papillomacular bundle are not directly involved [11].

The objective of this chapter is to describe the posterior pole manifestations of ocular toxoplasmosis as well as its pathogenesis, epidemiology, clinical findings, diagnosis, and current management.

Pathogenesis

Toxoplasma gondii is a ubiquitous protozoan parasite that infects up to 50% of the population [7]. While systemic infections are typically asymptomatic in immunocompetent patients, life-threatening disease may occur in newborns and in immunocompromised patients [12]. The parasite can be found in the host’s tissues and body fluids, such as saliva, milk, semen, urine, and peritoneal fluid. The morphology of the T. gondii varies depending on the stage of the life cycle and habitat. It can present in three forms, the tachyzoite, bradyzoite, and sporozoite, or oocyst [8], and these forms can be identified and studied histologically (see Fig. 6.1).

The tachyzoite, also called trophozoite, is the infectious form responsible for the acute phase of the disease. It is approximately 3–7 m(mu)m in length, 2–4 mm in diameter, and crescent-shaped. The tachyzoite encysts at the first sign of environmental stress, such as the host immune response or the presence of antibiotics. The encysted form, known as the bradyzoite, begins to appear as soon as 1 week following infection. Bradyzoites divide slowly inside a cellular vacuole, which eventually becomes part of the cyst’s capsule. The cysts are very resistant and can remain dormant in the host for years without reactivation or tissue damage. For reasons unknown, the cyst may rupture, causing reactivation of the disease and intense inflammation [8].

Oocysts of T. gondii are 10–12 mm and ovalshaped. They are found uniquely in the intestinal mucosa of cats. Once they are released, they can be spread to human beings or other animals through a variety of vectors. Although invariably thought to be ingested, the organism may also enter the host through other mucosal surfaces. Humans can also be infected secondarily by meat (pork and lamb particularly, as well as chicken in endemic areas, but probably not unprocessed beef) contaminated with Toxoplasma cysts (Fig. 6.2). The two forms of the organism that can be found in humans are bradyzoites, or tissue cysts, and tachyzoites (see Fig. 6.1c, d). Tissue cysts are up to 200 mm in diameter, contain hundreds to thousands of organisms, and have a propensity for cardiac tissue, muscle, and neural tissue, including the retina (see Fig. 6.1a) [13].

Humans can be infected by the infectious forms of either subcycle, that is, by eating undercooked meat containing tissue cysts, or through accidental ingestion of oocysts contaminating garden vegetables, water, or cat litter boxes. Rarely, T. gondii can be transmitted by blood transfusion, solid organ transplants, or in contaminated water or air. The life cycle of T. gondii is unusual in that the organism is capable of indefinite replication using either sexual or asexual subcycles [14]. After transmission, actively dividing tachyzoites disseminate via the blood stream and lymphatics (see Fig. 6.2) [15]. Up to 10% of infected individuals present with

retinal lesions [15, 16], and these infections account for half to one-third of all cases of posterior uveitis [15]. Most of the ocular cases occur months to years after initial infection, which is often asymptomatic.

The asexual cycle can occur in virtually any warm-blooded animal, ranging from chickens to sea otters to humans. Transmission occurs when an animal ingests bradyzoite-infected tissue through carnivorism or scavenging. Transmission can also occur accidentally through feed that is contaminated with animal parts.

Theoretically, this asexual portion of the organism’s life cycle could continue indefinitely via the food chain. Toxoplasma gondii’s sexual cycle occurs only in cats, where it includes full gametogenesis and mating within the intestinal epithelium and culminates in the generation of oocysts that are shed in the cat’s feces. These oocysts are highly infectious and extremely stable in the environment. Likewise, the asexual cycle can readily flow into the sexual side when a cat eats a mouse or bird infected with tissue cysts (see Fig. 6.2) [17].

Fig. 6.2 (A) The only known definitive hosts for Toxoplasma gondii are members of family Felidae (domestic cats and their relatives). Unsporulated oocysts are shed in the cat’s feces. (B) Although oocysts are usually only shed for 1–2 weeks, large numbers may be shed. (C) Oocysts take 1–5 days to sporulate in the environment and become infective. Intermediate hosts in nature (including birds and rodents) become infected after ingesting soil, water, or plant material contaminated with oocysts. Oocysts transform into tachyzoites shortly after ingestion. These tachyzoites localize in neural and muscle tissue and develop into tissue cyst bradyzoites. (D) Cats become infected after consuming intermediate hosts harboring tissue cysts. (E) Cats may also become infected directly by ingestion of sporulated oocysts. Animals bred for human consumption and wild game may also become infected

with tissue cysts after ingestion of sporulated oocysts in the environment. (F) Humans can become infected by any of several routes: eating undercooked meat of animals harboring tissue cysts; (G) consuming food or water contaminated with cat feces or by contaminated environmental samples (such as fecal-contaminated soil or changing the litter box of a pet cat); (H) blood transfusion or organ transplantation; and (I) transplacentally from mother to fetus. (J) In the human host, the parasites form tissue cysts, most commonly in skeletal muscle, myocardium, brain, and eyes; these cysts may remain throughout the life of the host. Diagnosis is usually achieved by serology, although tissue cysts may be observed in stained biopsy specimens. (K) Diagnosis of congenital infections can be achieved by detecting T. gondii DNA in amniotic fluid using molecular methods such as PCR

Since the 1950s, postnatally acquired infections have been attributed correctly either to ingestion of tissue cysts in raw or undercooked meat or to oocysts on unwashed vegetables that were contaminated with soil containing cat feces. Recent observations have suggested that these are not the only routes of infection, however. Contaminated drinking water, for example, may be an important source of infection in some situations [17].

Although T. gondii infects any nucleated cell in culture, human infections often involve the central nervous system (CNS) [15]. Toxoplasma gondii disseminates rapidly from the initial site of infection to secondary lymphoid tissues and then on to other organs. Dendritic cells are likely candidates as the “Trojan Horse” that T. gondii uses to travel to the spleen and draining lymph nodes. This hypothesis is supported by both in vitro studies and intraperitoneal infection models used to examine dendritic cell migration [18].

Montoya and Remington offer two explanations for preferential involvement of the CNS in toxoplasmosis: (1) ready passage of parasites across the blood-brain barrier or (2) poor clearance of parasites from immune-privileged site. It has been postulated that T. gondii is neurotropic because neurological deficits, including blindness, tend to make animal hosts easy prey, facilitating transmission of the parasite [15].

Tachyzoites may reach the retina by (1) migration from the brain via the optic nerve, (2) passage from the retinal circulation in infected monocytes or dendritic cells, or (3) direct infection of the retinal vascular endothelium by circulating tachyzoites. Different and/or multiple routes may account for retinal infection in different patients [15]. Host cell invasion begins with attachment of the parasite to the cell membrane and is complete when the parasite has actively penetrated the membrane, which typically takes less than 40 seconds [15, 19]. Invasion of host cells by T. gondii tachyzoites is believed to involve multiple receptor–ligand interactions, and differential expression of host receptors may be one mechanism underlying the variable infectivity observed between cell populations. Proteoglycans are important host cell receptors,

and the tachyzoite surface antigens known as SAGs are key ligands [15]. The ability of tachyzoites to infect a number of different cell lines has been correlated with the surface expression of sialic acid residues [15, 20].

Genetic analysis suggests that the majority of T. gondii strains identified in Europe and North America fall into one of three distinct genotypes (types I, II, and III, respectively) [14, 21–23]. Type I strains are very virulent (LD100 of one parasite). In contrast, types II and III strains are less virulent (LD50~103 and ~105, respectively). In humans, all three lineages cause disease, but they appear to differ in the tissues they affect and when they infect people. For example, type I strains are more often associated with postnatally acquired ocular infections, whereas type II strains are more associated with congenital infections and toxoplasmic encephalitis [18]. Some recent studies show more atypical (types IV and V) as well as mixed infections in many parts of the world, including Brazil, where they seem to be the rule. The high prevalence of this more virulent strain could also explain the phenomenon of reinfection and recent papers confirming that women may transmit toxoplasmosis to the fetus even when they are known to have had circulating anti–T. gondii IgG antibodies for many years. Difference in strain prevalence has also been suggested to explain varying rates of ocular involvement despite similar overall, populationbased seroprevalence rates [18].

It is well known that host immune function plays an important role in toxoplasmosis. Immunosuppressed patients, including those with acquired immunodeficiency syndrome (AIDS), are susceptible to severe life-threatening and vision-threatening T. gondii infections. It is likely that more subtle changes in immune function also affect disease presentation [24].

Clinical Manifestations

Ocular toxoplasmosis manifests predominantly from the second to the fourth decade of life (probably because most of the cases arise up to 10–20 years after the infection), with either primary

Fig. 6.3 Toxoplasmic retinochoroiditis (TRC). Visual acuity (VA) was 20/70. (a) Color fundus photograph of the right eye demonstrating an isolated active lesion along the inferotemporal vascular arcade. (b) Fluorescein angiography before intravitreal clindamycin and dexamethasone therapy reveals marked hyperfluorescence resulting from

leakage of dye from TRC lesion threatening the fovea. (c) A horizontal optical coherence tomography scans obtained through the fovea revealed loss of the normal foveal contour, diffuse macular thickening with subfoveal serous retinal detachment. The retina map analysis indicates a central macular thickness of 421 mm

OT (isolated retinal lesions not arising from scars) (Fig. 6.3), or recurrent OT (active retinal lesions associated with old inactive scars) (Fig. 6.4). Necrotizing retinitis associated to vitreous and anterior chamber inflammation is the hallmark of OT. Recent reports have confirmed that acquired infection can present with vitreitis or anterior uveitis in the absence of retinochoroiditis [25].

Manifestations include retinochoroidal infiltrates, vitreous humor cells and haze, and anterior chamber (AC) cells and flare. The severity of the inflammatory reactions varies substantially between patients, for reasons that are unknown [26].

There can be considerable variation in the clinical features of disease. 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 OT is important for the clinician—diagnosis can be difficult in

Fig. 6.4 Recurrent ocular toxoplasmosis. Note active retinal lesion associated with old inactive scar

some cases, and attention to the characteristics of OT may give some insights into disease mechanisms [27].

Friedmann and Knox described three specific “forms” of disease that can be related to the specific

strain causing the infection: large destructive lesions, punctate inner lesions, and punctate deep lesions [28]. Small, partial-thickness lesions involving the inner or outer layers of the retina have also been described in patients with AIDS; these small lesions are presumably the earliest manifestations of infection, as most reported patients with AIDS and OT have had extensive areas of full-thickness retinal necrosis (Figs. 6.5, 6.6a, b, and 6.7) [27, 29].

Immunocompetent patients can develop clusters of small, partial-thickness retinal lesions,

Fig. 6.5 Patients with the acquired immune deficiency syndrome (AIDS) and ocular toxoplasmosis may have extensive areas of full-thickness retinal necrosis that simulate acute retinal necrosis syndrome

a condition termed “punctate outer retinal toxoplasmosis” by some investigators. Lesions are typically <1,000 mm in diameter and found in the posterior pole. Although sometimes considered a distinct form of disease, punctate outer retinal toxoplasmosis shares many features with more “typical” lesions. Despite the occurrence of lesions in clusters in patients with punctate outer retinal toxoplasmosis, there is usually only one focus of active disease at any given time [27].

Generally active inflammatory disease resolves without treatment, leaving hyperpigmented scars, and recurrences develop as “satellite” lesions (see Fig. 6.4) [27]. On the other hand, there are many publications that also refer to “typical” scars of healed toxoplasmic retinochoroiditis (TRC) 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. The degree of pigmentation within and around 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 [27]. Lesions with little associated inflammation may heal with minimal scarring (Fig. 6.8) [27, 30]. Silveira et al. have shown that the spectrum of lesions associated with typical TRC includes similar tiny, nonspecific foci of

Fig. 6.6 (a, b) Patients with the acquired immune deficiency syndrome (AIDS) and ocular toxoplasmosis may have atypical presentations. This patient improved 1 week after highly active antiretroviral therapy, pyrime-

thamine and sulfadiazine (Reprinted with permission from Smith JR, Cunningham ET Jr. Atypical presentations of ocular toxoplasmosis. Curr Opin Ophthalmol. 2002;13:387–92)

pigment, and “classic” lesions can also be found amid clusters of small retinochoroidal scars in any part of the retina [27, 31].

Ocular toxoplasmosis can also be categorized into the congenital (Fig. 6.9a, b) or acquired

Fig. 6.7 Patients with the acquired immune deficiency syndrome and ocular toxoplasmosis may have concomitant extensive areas of full-thickness retinal necrosis of cytomegalovirus retinitis

(Fig. 6.10) forms. Congenital and acquired presentations can be divided into neonatal or late forms. Every newborn whose mother contracted toxoplasmosis during the pregnancy must receive treatment during the first year of life, independent of the presence of ocular involvement in the time of the birth. Congenital toxoplasmosis is most commonly acquired during the last trimester of pregnancy, and the infants are usually asymptomatic. Acquired toxoplasmosis (AT) can be concomitant when it occurs during systemic disease and delayed when there is a variable period of time (usually 5–10 years) between systemic and ocular disease [11].

Toxoplasmic retinochoroiditis is unilateral in 72–86% of cases [11]. The lesions can be solitary, multiple, or satellite (adjacent to a cicatricial lesion). T. gondii has a clear preference for the posterior pole, this location occurring in more than 50% of the cases. Typical congenital retinochoroiditis presents as a macular cicatricial lesion, consisting in radial deposition of pigment

Fig. 6.8 The retinal lesions in toxoplasmic retinitis in patients with acquired immune deficiency syndrome (AIDS) may be focal or diffuse, active in one or both eyes, and can cause visual impairment if left untreated. (a and c) Toxoplasmic retinitis before therapy. (b and d)

Toxoplasmic retinitis healed after therapy. Note that in patients with the acquired immune deficiency syndrome (AIDS), lesions with little associated inflammation may heal with minimal scarring (Courtesy of William R. Freeman, M.D.)

Fig. 6.11 Recurrent satellite lesions of toxoplasmosis. Note active retinal lesion associated with old inactive scar

around a central necrotic zone. Anterior uveitis is almost always a complication of retinochoroiditis. In fact, the presence of the parasite in the anterior segment without retinal involvement has only been demonstrated in immunocompromised patients [11].

Recurrences of retinal disease occur with both congenital and postnatally acquired infections. Typically, these recurrences manifest as “satellite lesions” at the border of a preexisting retinochoroidal scar (Figs. 6.4, 6.11, and 6.12), although in some patients, new “primary retinal lesions” (defined as those not arising from retinochoroidal scars) can develop far away from the preexisting scars, in areas of retina that had appeared clinically to be normal (see Fig. 6.10). Recurrences

Fig. 6.13 (a) Color fundus photograph of the right eye demonstrating an active papillary lesion secondary to toxoplasmic retinochoroiditis (TRC) along the inferotemporal vascular arcade. (b) Fluorescein angiography before intravitreal clindamycin and dexamethasone shows remarkable hyperfluorescence resulting from leakage of

dye from TRC. (c) A horizontal optical coherence tomography scan obtained through the papillomacular bundle demonstrated mild macular thickening with swelling of the optic disc. The retina map analysis indicates a central macular thickness of 256 mm. His visual acuity was 20/125

are generally assumed to be caused by the release of parasites from tissue cysts in the retina [17].

Symptoms of OT vary according to the age of the subject. Signs at birth may include fever, maculopapular rash, hepatosplenomegaly, microcephaly, seizures, jaundice, thrombocytopenia, and lymphadenopathy. The classic triad of CT is retinochoroiditis, hydrocephalus, and cranial calcifications [11]. Children usually present with reduced visual acuity, strabismus, nystagmus, and leukocoria. Teenagers and adults complain of decreased vision and floaters. If anterior uveitis is present, photophobia, pain, and hyperemia may be present [11].

However, toxoplasmosis can also affect the optic nerve in many ways. Atypical presentations

of ocular toxoplasmosis have been described: punctate outer retinitis, neuroretinitis, papillitis (Fig. 6.13), pseudo-multiple retinochoroiditis, intraocular inflammation without retinochoroiditis, unilateral pigmentary retinopathy, Fuchslike anterior uveitis, scleritis, and multifocal or diffuse necrotizing retinitis.

A variety of complications of TRC have been described, including rhegmatogenous retinal detachments, glaucoma, vitreous opacification (Figs. 6.12 and 6.14) or hemorrhage, retinal hemorrhage (Fig. 6.15), optic atrophy, exudative retinal detachments, retinal vessel occlusions, subretinal and choroidal revascularization (CNV), epiretinal membrane formation (Fig. 6.16a, b), and macular edema [11, 17, 32, 33]. In general, they

occur only in patients with severe ocular disease. Rhegmatogenousretinaldetachments,forexample, have been related to the severity of inflammation. Macular edema is believed to be uncommon [33],

Fig. 6.14 Acquired ocular toxoplasmosis with vitreitis

for unknown reasons (Fig. 6.17a, b). Prolonged infections, intense inflammation, and complications can occasionally lead to phthisis or enucleation [17, 34].

In OT visual acuity may range from 20/20 to 20/400, depending on the extent of macular or optic nerve involvement [34, 35]. Therefore, predicting future vision in a preverbal child should be done with caution. Of the patients followed from the newborn period and treated, 29% had bilateral visual impairment with the vision in the better eye being less than 20/40. Causes for this visual impairment in eyes with quiescent lesions included macular scars, dragging of the macula secondary to a peripheral lesion, retinal detachment, optic atrophy, cataract, amblyopia, phthisis, and other complications that can be prevented in some cases [34]. Tan et al. [35] have concluded that although visual impairment was associated with the presence of posterior pole lesions, just more than half of eyes affected by a posterior pole lesion had normal vision (6/12 or better), compared to 84% of those with peripheral lesions alone.