Important noninfective ocular entities that may be confused with CT include coloboma, persistent hyperplasic primary vitreous, and retinoblastoma [8].

Recurrent Toxoplasma lesions adjacent to retinochoroidal scars may resemble serpiginous choroiditis. Other conditions that are important in the differential diagnosis of ocular toxoplasmosis are necrotizing retinitis caused by herpes viruses (CMV, herpes simplex, herpes zoster), fungal retinitis (candidiasis, blastomycosis), septic retinitis, ocular toxocariasis, sarcoidosis, syphilis, and tuberculosis [8].

The atypical forms of OT, that were described above, deserve distinct differential diagnosis awareness. In cases of Toxoplasma neuroretinitis, other causes of neuroretinitis, such as cat scratch disease and viral syndromes, must be excluded.

Toxoplasma neuroretinitis should be differentiated from the optic neuritis associated with sarcoidosis and CMV [8].

Management

Antimicrobial therapy is absolutely required for systemic toxoplasmosis in newborns, pregnant woman, and immunosupressed patients and in acute symptomatic disease specially when threatening vision due to the anatomic location and/or severe inflammation. Patients with chronic toxoplasmosis do not require treatment when the disease is inactive, except in special cases where it is used to decrease the chance of recurrence as no treatment is effective at eliminating the tissue cyst.

In general, TCR resolves spontaneously within 6–8 weeks in most patients, although symptoms arising from the accompanying intraocular inflammation (e.g., floaters from the presence of vitreous cells) often take longer. Permanent visual impairment occurs when lesions affect the posterior pole (within the macular arcade or adjacent to the optic disc) or because of complications of inflammation (e.g., vitreous opacity, epiretinal membranes, retinal detachment) develop [4].

The lack of effective and early therapy for OT is responsible for the loss of eyesight in this parasitic disease. The experience in the treatment of OT in patients with AIDS has shown that antitoxoplasmic therapy is efficient. The problem is that recurrences are generally unavoidable, and in non-immunosupressed patients, the immune system also plays an important role causing destructive inflammation. Treatment has to be started before the process causes necrosis and destruction of the retina, and often the loss of vision is caused by recurrent bouts of the disease.

The type and duration of OT treatment should be individualized. It is determined by several factors such as, the immune status of the patient, severity of the inflammatory response, and if the site of the lesion is close to the macular area or optic nerve head. The current drugs are directed against active lesions but are unable to eradicate tissue cyts. Generally, initial antibiotic treatment includes oral pyrimethamine, sulfadiazine, and folinic acid. Folinic acid is usually added to decrease the risk of leukopenia and thrombocytopenia associated with pyrimethamine therapy [52]. However, a very well-tolerated therapy that has been used very effectively against OT is the combination of oral trimethoprim–sulfamethox- azole and clindamycin [53]. More recently, other antimicrobials, such as azithromycin and atovaquone, have been used successfully [54–56]. There is no controlled evidence showing that one treatment is better than the other or that the association of other drugs to sulfadiazine and pyrimethamine improves results. All of these regimens are associated with the potential for significant side effects; some of which may be treatment limiting [54, 55]. The purpose of

treatment is to limit retinal damage by inhibiting multiplication of the parasites during the active stage of infection. Systemic corticosteroids can be added to avoid further damage of the retina by the inflammation. Classically, the use of intraocular injection of corticosteroids is contraindicated in OT, but injection of short half-life agents, such as dexamethasone, may have a role in selected patients when used together with antitoxoplasmic agents.

We will briefly describe the characteristics of each of the more commonly used systemic antibiotics.

Pyrimethamine

This antibiotic interrupts the metabolic cycle of the parasite by inhibiting the dihydrofolatereductase enzyme, thereby preventing the conversion of folic acid to folinic acid, which is essential in both DNA and RNA synthesis. Adverse effects of pyrimethamine include doserelated bone marrow suppression (10%) with leukopenia, thrombocytopenia, and megaloblastic anemia, simulating folinic acid deficiency; these effects are reversible by interruption of treatment or administration of folinic acid. Dosage: Adults: 100 mg loading dose, followed by 25 mg/day for 30–60 days. Children: 4 mg/kg loading dose followed by 1 mg/kg/day divided in two doses. Newborns should be treated daily for the first 6 months and then three times/week for their first year of life [8].

Sulfonamides

Sulfonamides prevent normal utilization of paraminobenzoic acid (PABA) for the synthesis of folic acid by the parasites. Sulfonamides and pyrimethamine are synergistic, and the concentration of sulfonamides in the eye reaches 50–80% of the simultaneous serum concentration. Precipitation of sulfonamides in the urine may cause crystalluria, hematuria, and renal damage. Adequate hydration with

oral fluids to maintain a urine output of at least 1,500 ml/day should avoid the problem; hypersensivity reactions are quite variable and range from photosensitivity to a severe Stevens– Johnson type of reaction involving skin and mucous membranes. Dosage: Adults: 2 g loading dose followed by 1 g every 6 h for 30–60 days. Children: 100 mg/kg/day divided every 6 h. Newborns should be treated daily for their first year of life, with dosage of 100 mg/ kg/day divided into two doses [8].

Folinic Acid

Folinic acid is used as an adjuvant in therapy with antifolate agents such as pyrimethamine. Folinic acid can be utilized by human cells but not by T. gondii and prevents bone marrow suppression caused by pyrimethamine and other folinic acid antagonists. Dosage: 5–20 mg/day during pyrimethamine therapy depending on neutrophil count [8].

Clindamycin

Clindamycin inhibits ribosomal protein synthesis and has good ocular penetration. A skin rash occurs in 10% of the patients treated with clindamycin and diarrhea in 2–20%. Pseudomembranous colitis can develop 0.01–10% of patients treated with clindamycin, requiring immediate interruption of therapy and administration of vancomycin or metronidazole. Dosage: 300 mg every 6 h for 30–40 days. Children: 16–20 mg/kg/day divided every 6 h [8].

Azithromycin

administered for longer than 4 weeks. Furthermore, it penetrates readily into brain tissue. The concentrations of azithromycin in the ocular tissues are not yet known. Azithromycin has been considered for the treatment of OT because of its availability and limited toxicity and because it crosses the blood-brain barrier and appears to be widely distributed to brain tissue. However, resistant cases and recurrences have been reported [54]. Dosage: Adult: 1 g in the first day followed by 500 mg once daily for 3 weeks. Children ³6 months: 10 mg/kg on first day (maximum: 500 mg/day) followed by 5 mg/kg/day once daily (maximum: 250 mg/day) [11].

Trimethoprim and Sulfamethoxazole

The combination of trimethoprim and sulfamethoxazole has been evaluated as a potentially less-toxic alternative for treatment of toxoplasmosis. Grossman et al. were able to demonstrate that the combination of trimethoprim and sulfamethoxazole was synergistic and effective against otherwise lethal T. gondii infections in mice. Nguyen and Stadtsbaeder found a synergistic effect of trimethoprim and sulfamethoxazole against intracellular T. gondii replication in cell cultures. The most common side effects are mild gastrointestinal problems (nausea, vomiting, cramps, and occasionally diarrhea) and mild skin lesions (usually mild, diffuse maculopapular rashes) attributable to hypersensitivity to sulfamethoxazole. More serious skin hypersensitivity reactions, such as Stevens–Johnson syndrome, can occur but are rare [57]. Dosage: 160/800 mg every 12 h for 30–40 days [8].

Spiramycin

Azithromycin inhibits ribosomal protein synthesis [8]. Azithromycin is a nontoxic antibiotic that penetrates into phagocytic cells and reaches high intracellular and tissue concentrations. In vivo and in vitro efficacy against T. gondii has been reported, with an effect on the cystic form if

Spiramycin is less effective but also less toxic than the combination of pyrimethamine with sulfadiazine, so it is the drug of choice during pregnancy. Dosage: Pregnancy: 500 mg every 6 h for 3 weeks; regimen may be repeated after 21 days [8].

Atovaquone

Atovaquone is a hydroxynaphthoquinone that has shown promise for the treatment of

Pneumocystis carinii pneumonia in patients with acquired immune deficiency syndrome. Atovaquone, which acts by selective inhibition of mitochondria electron transport chain in protozoa, also has been shown to have significant in vitro and in vivo activity against T. gondii. In animal models, atovaquone has activity against the tissue cysts (bradyzoites). Atovaquone is associated with very few side effects in healthy patients and appears to be well tolerated in immunocompromised individuals [55]. Dosage: 750 mg every 6 h for 4–6 weeks [11].

Other alternative agents are the tetracyclines, but they are contraindicated during pregnancy and in childhood because of the resultant brown discoloration of the teeth and depression of bone growth [8].

Oral corticosteroids must be initiated at least 48 h after antiparasitic drugs. The usual initial dose in adults is 40 mg per day followed by tapering depending on clinical response. Generally, corticosteroids are suspended at least 10 days before the specific anti-toxoplasma drugs [11].

Topical therapy includes corticosteroids and mydriatic drugs. Corticosteroid frequency is indicated depending on the amount of inflammation on the anterior segment. In severe to moderated anterior uveitis, they are initiated every 1 or 2 h, with a gradual decline in dosage over time. Cycloplegic/mydriatic agents are used to prevent or reverse the formation of posterior synechiae and to relieve the pain caused by spam of the ciliary muscle [11].

Currently, there are three classic combination regimens for the treatment of OT: (1) pyrimethamine, sulfadiazine, folinic acid, and prednisone; (2) pyrimethamine, clindamycin, folinic acid, and prednisone; and (3) pyrimethamine, sulfadiazine, clindamycin, folinic acid, and prednisone [11]. However, in a survey among all members of the American Uveitis Society in 2001, the most commonly used drugs to treat typical cases of OT were pyrimethamine (65%), sulfadiazine (54%), clindamycin (42%),

Fig. 6.21 Illustration demonstrates the topographic location of the toxoplasmic retinochoroiditis lesion in the retina. Zone 1: Lesions located in an area between the temporal vascular arcades, affecting an area within 3,000 mm of the center of the fovea or 1,500 mm from the edges of the optic disc. Zone 2: Lesions located outside the boundaries of the zone 1, up to the anterior margins of the vortex veins. Zone 3: Lesions outside the zone 2 up to the ora serrata

and trimethoprim/sulfamethoxazole (28%). The remaining five antiparasitic agents used in current regimens of choice are all used by no more than 10% of responders; they include atovaquone, spiramycin, azithromycin, minocycline, and pyrimethamine/sulfadoxine. Only 17% of respondents used an oral corticosteroid drug for all immunocompetent patients with OT regardless of clinical findings. For those who do not use corticosteroids for all patients, indications for use of corticosteroids include severe vitreous humor inflammatory reactions (71%), decreased vision (59%), proximity of lesions to the fovea or optic disc or zone 1 (Fig. 6.21) (35%), and large lesions (5%) [58].

Some patients are intolerant and allergic or have infections resistant to systemic therapy. Intraocular drug delivery is one option for these patients. Intravitreal injection of clindamycin alone or in combination with dexamethasone has been reported as an alternative for such patients [59]. We often use intravitreal clindamycin and dexamethasone for the treatment of