A typical lesion of recurrent toxoplasma retinochoroiditis at the edge of a previous scar poses little diagnostic challenge. Atypical lesions, however, may be difficult to diagnose. Multifocal lesions should be differentiated from causes of multifocal choroiditis including white dot syndromes. Extremely peripheral lesions may be confused with the snow banking of pars planitis. In a newborn, congenital ocular toxoplasmosis must be differentiated from other TORCH infections; cytomegalovirus (CMV), herpes simplex virus, and rubella. Congenital varicella syndrome and congenital syphilis are among the diagnostic considerations.

16.2.1.5  Immunocompromised Patients

Asymptomatic toxoplasmosis occurs with a high frequency in the general population [52]. It is usually subclinical, and patients present mostly with transient lymphadenopathy. In striking contrast, T. gondii infection in immunocompromised patients is typically aggressive and fulminant [53, 54]. The pattern of aggressive disease has been reported in many conditions characterized by immunosuppression, lymphoma, chemotherapy patients, organ transplant recipients, and patients with idiopathic severe acquired cellular immunodeficiency [32, 53, 55, 56].

Toxoplasmosis is the commonest AIDS associated nonviral intracranial infection [57, 58]. Acquired intracranial toxoplasmosis may be diagnostic of AIDS and may be its first manifestation [59]. In one study, it was found that among patients with AIDS and CNS disorders, 33% had toxoplasmosis [58]. Reports of ocular toxoplasmosis in AIDS patients are not as frequent [60, 61]. In one series, only 1 of 72 patients with AIDS had ocular toxoplasmosis [62], and in another series, 10–20% of the patients with AIDS had ocular toxoplasmosis [63].

Although it is believed that the high incidence of toxoplasmosis in immunosuppressed patients, including patients with AIDS, results from reactivation of latent infection [59, 64, 65], clinical findings suggest that the ocular lesion results from acquired disease or from organisms newly disseminated to the eye from nonocular sites; the disease may be multifocal and bilateral, the lesions are rarely associated with old scars and not infrequently lesions occur adjacent to retinal blood vessels [39].

In AIDS patients, ocular toxoplasmosis must be distinguished from retinal necrosis caused by CMV. CMV

is characterized by areas of necrosis with feathery borders usually along the vascular tree and often with extensive hemorrhages and little vitreous reaction. Toxoplasmosis is more likely the diagnosis if the patient has extensive retinal necrosis and a prominent inflammatory reaction in the vitreous and anterior chambers [39].

16.2.1.6  Diagnosis of Ocular Toxoplasmosis

Diagnosis of acquired ocular toxoplasmosis is mainly based on the clinical finding of typical retinal lesions with serology aiding in diagnosis. Detection of T. gondii specific IgG antibodies by immunofluorescent antibody test, indirect hemagglutination test, enzyme-linked immunosorbent assay (ELIZA), complement fixation, and direct agglutination can be done. IgG antibodies appear within 1–2 weeks after infection, peak at 1–2 month, and then fall at variable rates but remain detectable for life, thus absence of T. gondii specific IgG antibodies makes the diagnosis unlikely. The presence of T. gondii specific serum IgG antibodies establishes that patient has been exposed to the parasite in the recent or the distant past but does not establish T. gondii as an etiological agent of retinitis [66].

Detection of specific IgM to T. gondii antibodies by immunofluorescent antibody test and ELIZA is available. IgM develops 1–2 weeks after infection and persists at low titers for up to 1 year or longer and, therefore, does not necessarily indicate recent infection [67, 68]. False positive results are not infrequent [67]. Identification of specific anti T. gondii IgA antibodies by immunosorbent assay indicates recent infection and appears to be more specific for the diagnosis of congenital infection in the fetus and the newborn than the detection of IgM [69, 70]. Anti T. gondii IgE antibodies are also markers for the recent infection, but they disappear shortly after infection [71, 72]. Evaluation of the vitreous fluid by PCR for T. gondii DNA may be a useful tool for diagnosis when toxoplasmosis is considered in the differential diagnosis and when clinical presentation is not diagnostic or the response to treatment is not adequate [66].

16.2.1.7  Treatment

Not all patients with ocular toxoplasmosis require treatment as spontaneous resolution may occur without serious sequelae. Treatment does not eliminate the

bradyzoite form of the organism and thus does not prevent recurrence. Engstom et al. (1991) [73] have classified toxoplasmosis based upon location in the retina: Zone 1 is an area within the major temporal vascular arcades, Zone 2 is an area extending from Zone 1 to the clinical equator, and Zone 3 encompasses the remaining anterior retina to the ora serrata. Most clinicians will treat lesions located in Zones 1 and 2. Indications for treatment include decreased visual acuity, large lesions, severe vitritis, multiple lesions, chronic disease with persistence for more than 1 month, and ocular lesions associated with recently acquired infection.

Current antimicrobial agents for active toxoplasma retinitis include sulfadiazine, pyrimethamine, clindamycin, trimethoprim, sulphamethoxazone, atovaquone, and spiramycin. The combination of pyrimethamine and sulfadiazine with folinic acid rescue has been the treatment of choice for toxoplasmosis for 50 years [74]. These agents inhibit sequential steps in the synthesis of tetrahydrofolic acid, an essential precursor to purines and DNA [75]. When using pyrimethamine for treatment of ocular toxoplasmosis, patients should be monitored regularly for evidence of bone marrow toxicity, which can occur with treatment.

Trimethoprim–sulfamethoxazole is a fixed combination of antibiotic that also inhibits sequential steps in the synthesis of tetrahydrofolic acid–has been used in the treatment of active toxoplasmosis. It is well tolerated and is available for pediatric use as a suspension. The use of this combination agent reduces the need for monitoring the complete blood count, and it can be used without additional folinic acid therapy [75].

Clindamycin is another treatment option. Reported side effects include gastrointestinal upsets, diarrhea, and skin rash [76]. Atovaquone is a hydroxynaphthoquinone that has shown promise for the treatment of pneumocystis carinii pneumonia in patients with AIDS. It acts by selective inhibition of mitochondrial electron transport chain in protozoa. Also has been shown to have significant in vitro and in vivo activity against T. gondii [77, 78].

No major adverse side effects were attributable to the drug when used in children with malaria [79], though its use in pediatric toxoplasmosis has not been reported. Spiramycin has also been used by some for treatment of ocular toxoplasmosis, mostly in patients with known allergies to sulphonamides [73].

Topical steroids are used mainly for associated anterior segment inflammation [80]. Systemic corticosteroids are recommended for the treatment of lesions endangering the macula or the optic disc. Periocular injection is rarely used concurrently with antimicrobial therapy in patients with intolerance or contraindications to oral steroids and in patients with severe vitreous inflammation. The use of periocular steroids has been discouraged because of the potential to worsen the infection [75]. They are never administered without concurrent antibiotic therapy, and administration is typically delayed for 14–48 h after the start of antimicrobial therapy.

Other modalities are occasionally useful in the treatment of ocular toxoplasmosis, including laser photocoagulation [81], cryotherapy [82], and vitrectomy [36]. Laser is the most frequently used modality with the goal of encircling an active lesion with a region of photocoagulated retina and thus theoretically limiting spread of disease to adjacent retina [81]. Cryotherapy has been used for peripheral lesions in patients with contraindication to medical treatment. Vitrectomy has also been used in patients with active lesions to remove persistent vitreous opacities in otherwise quiet eyes [36].

The prognosis for retention of good vision after recurrence of acquired toxoplasma retinochoroiditis not involving the posterior pole is good, as spontaneous resolution usually occurs. Factors associated with poor visual outcome include central lesions, large lesions, and prolonged duration of the disease [23].

16.2.1.8  Treatment in Special Situations

Pregnant women: Because of the possibility of transmission of the disease to the fetus, treatment of pregnant women with recently acquired infection is often considered. Consultation with an obstetrician may be warranted before prescribing to a pregnant woman.

Newborns: Ocular lesions are usually inactive at birth, and specific treatment is not required. Neonates with active retinal lesions have been treated with a course of therapy lasting up to 1 year of age independent from the lesion resolution [73].Treatment of infected infants consists of combination therapy with pyrimethamine, sulfadiazine, and folinic acid. Spiramycin can be added to the regimen of treatment [17].