19.5  Infectious

19.5.1  Toxoplasmosis

19.5.1.1  Historical Context/Pathophysiology

Toxoplasmosis gondii is an obligate intracellular protozoan parasite with a worldwide distribution. It is the most common cause of infectious retinochoroiditis in both adults and children [1]. The organism was first described in 1908 by Nicolle and Manceaux after they observedtheparasitesinvariousorgansofCtenodactylus gondii, a North African rodent. The first ocular involvement was documented in 1923 by Janku, who reported parasitic cysts in the retina of an infant who had hydrocephalus, seizures, and unilateral microphthalmia [74].

The life cycle of T gondii is complex [75]. Cats are the definitive hosts and humans and a variety of other mammals serve as intermediate hosts. The sexual cycle begins in the gastrointestinal tract of the cat, where oocysts are shed in large numbers in the infected cat’s feces. In the environment, they undergo sporulation where they can be ingested by intermediate hosts or reingested by cats. The tachyzoite form of the organism, the rapidly dividing form observed in the acute phase of infection, can invade nearly all host tissue. As the host’s immune system responds, the tachyzoites convert to bradyzoites and form a tissue cyst that is resistant to host defenses and the latent form of the disease ensues.

Humans can acquire the disease through the environment by handling contaminated soil or cat litter or the consumption of contaminated water sources. The disease can also be acquired secondarily by ingesting undercooked infected meat such as pork, lamb, or chicken. Human infection can also be congenital, by transmission of tachyzoites to the fetus via the placenta following primary maternal infection. Forty percent of all maternal infections result in congenital infection, with the rate being highest during the third trimester [76, 77]. However, the severity of disease is inversely proportional to the gestational age at transmission.

When the organism reaches the eye through the bloodstream, depending on the host’s immune status, a clinical or subclinical focus of infection begins in the retina. If the host immune system responds appropriately, the tachyzoites convert to the resistant bradyzoites and a chronic latent infection ensues. If

the host’s immune function declines, the cyst wall may rupture, releasing organisms into the retina and reigniting the inflammatory process.

Histopathologically, the retina is seen to be the primary site of multiplying parasites; the overlying vitreous and underlying choroid and sclera often reveal contiguous inflammation. Adjacent to the foci of infection, the choroid shows granulomatous inflammation. A well-defined border delineates necrotic and unaffected retina. After healing, an area of retinal and choroidal necrosis is surrounded by a variable amount of pigment proliferation. Inactive toxoplasmosis cysts may be seen within or adjacent to this “punched-out” appearing chorioretinal scar [78, 79].

19.5.1.2  Clinical Findings/Natural History

Congenital infection ranges greatly in severity, from life-threatening to initially asymptomatic. Classically, congenitally acquired toxoplasmosis presents with retinochoroiditis, intracranial calcifications, and convulsions. There can also be varying degrees of hepatosplenomegaly, microcephaly, hydrocephalus, jaundice, rash, fever, and developmental delay. Chorioretinitis occurs in up to 80% of cases, and is bilateral in 85% of those affected (Fig. 19.5) [80, 81]. In children with mild congenital infection, retinal involvement can be subclinical and chronic, but as many as 85% develop retinochoroiditis after 3.7 years; 25% of these patients will become blind in at least one eye [80].

Acquired infection is now thought to play a more important role in the development of ocular toxoplasmosis in children and adults (Fig. 19.6) [82]. In North America, 10% of the population has a positive antibody titer in childhood, with this number growing to 80% of octogenarians [83]. Systemic acquired infection usually goes undiagnosed in humans; symptoms can include fever, lymphadenopathy, and sore throat.

Blurred vision and floaters are often the presenting symptoms of ocular toxoplasmosis. A granulomatous anterior uveitis is frequently observed, and the intraocular pressure can be elevated at presentation. Classically, fundoscopic examination in active disease reveals a white, focal retinitis with overlying moderate vitritis (socalled “headlight in fog”). The area of retinitis is often adjacent to a flat, old, atrophic scar (satellite lesion), reflecting the reactivation of previously quiescent disease. If there is no evidence of chorioretinal scarring,

a

c

Fig. 19.6  A 12 year old girl presented with counting fingers vision and a large focal area of retinitis along the inferior temporal arcade of the right eye (a). Four months after treatment for toxoplasmosis the lesion is atrophic and the vision is 20/20 (b). Another patient with ocular toxoplasmosis preand post-treatment (c, d)

b

d

b

d

suspicion should be raised for the presence of acquired disease. There is a predilection of the retinitis for the macula and posterior pole. There may be a perivasculitis in the vicinity with diffuse venous sheathing and segmental arterial sheathing, which is thought to arise from a hypersensitivity reaction to Toxoplasma antigens [84].

Genetics

There does not appear to be any genetic influence that alters human susceptibility to ocular toxoplasmosis.

Diagnosis/Treatment/Complications

Ocular toxoplasmosis in children is usually based on the clinical appearance of the fundus lesions, and is supported by serologic evidence of exposure to Toxoplasma organism. Indirect fluorescent antibody (IFA) and enzyme-linked immunosorbent assay (ELISA) are employed to detect specific anti-T gondii antibodies; these tests have a relatively high rate of false positive results, but lack of detection of the antibody essentially rules out the diagnosis of ocular toxoplasmosis [85]. In cases of suspected congenital ocular toxoplasmosis, the presence of IgM antibodies in infant serum is diagnostic for exposure, since maternal IgM antibodies do not cross the placenta. IgM antibody levels show an early rise in the acute phase of the disease, and remain detectable for less than 1 year. However, IgM antibody production is low during the newborn period, so IgA antibodies may also be useful in the diagnosis of congenital infection [86]. The presence of IgG antibodies in the serum of a newborn may indicate passive transfer of maternal antibodies, so its presence is less useful in the context of congenital infection. In the appropriate clinical context, the presence of IgM antibodies indicates acquired disease. IgG antibodies appear within the first 2 weeks following infection, and typically remain positive for life. More recently, the highly sensitive and specific polymerase chain reaction (PCR) has been employed to detect T gondii antigens in aqueous and vitreous samples [87, 88].

In immunocompetent patients, reactivated ocular toxoplasmosis has a self-limited course over about 1–2 months. For this reason, the mere presence of a focus of retinitis is not always an indication for treatment. Treatment is aimed at shortening the duration

of the active infection, with a goal limiting chorioretinal scarring and progression, reducing the frequency of inflammatory recurrences, and minimizing the complications associated with intraocular inflammation. Generally, small peripheral lesions heal spontaneously and may be followed conservatively. Relative indications for treatment include lesions near the optic disc or fovea, decreased visual acuity, large lesions (>1 disc diameter) irrespective of location, persistence of active disease for >1 mo, or multiple active lesions. Patients with moderate to severe vitritis are also treated aggressively. There is no consensus regarding the most efficacious regimen [89, 90].

The classic triple-drug therapy for ocular toxoplasmosis consists of pyrimethamine, sulfadiazine, and prednisone [91]. Quadruple therapy includes the addition of clindamycin. Pyrimethamine inhibits folic acid metabolism and can result in the hematological complications of leukopenia and thrombocytopenia, and thus folinic acid is added to the regimen. Weekly monitoring of leukocyte and platelet count is indicated during­ treatment. Systemic corticosteroids such as prednisone are employed to minimize collateral damage from the inflammatory response. They are generally begun at the time of antimicrobial therapy or within 48 h, but must never be used without appropriate antimicrobial coverage [90]. The use of depot injections of corticosteroids is contraindicated in ocular toxoplasmosis. Topically, however, corticosteroids are used liberally in the presence of prominent anterior segment inflammation. Cycloplegic agents can also be used to reduce pain and prevent formation of posterior synechiae. The duration of treatment varies depending on the patient’s response but usually lasts for 4–6 weeks. One treatment alternative if other drugs are not available or are not tolerated is trimethoprim/sulfamethoxazole combined with prednisone. Azithromycin has also been used successfully in combination with pyrimethamine and prednisone. Atovaquone is a newer antimicrobial that may be effective in combination with pyrimethamine [92]. Lastly, pars plana vitrectomy may be indicated in cases of retinal detachment secondary to vitreous traction or in cases where vitreous opacities persist.

In newborns with congenital toxoplasmosis, treatment is conducted in consultation with a pediatric infectious disease specialist. Drug therapy often consists of continuous therapy with pyrimethamine and sulfonamides for 1 year [93]. Treatment may help to