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Ophthalmic Pearls: Uveitis
Identifying and Treating Toxoplasmosis
Worldwide, toxoplasmosis is the most common cause of uveitis affecting the posterior segment. In the United States, seroprevalence of IgG antibodies against Toxoplasma gondii is 20 to 70 percent. Seroprevalence in other parts of the world is higher, reaching 98 percent among children in certain areas of Brazil. Peripheral chorioretinal scars are the most common ocular finding, but the organism also has a predilection for the macular region. Recurrence is typically characterized by active retinitis adjacent to an old scar with marked vitritis. Reactivation of congenital infection was traditionally thought to be the most common cause of infection, but postnatally acquired infection is now considered to be more common.
Congenital infection occurs in the United States in about 1/1,000 to 1/10,000 live births. The incidence of ocular infection is high with congenital toxoplasmosis (up to 80 percent). Transplacental transmission occurs when the infection is acquired during pregnancy; since cats are the principal vector, it is recommended that pregnant women avoid cats and sandboxes. The risk of transmission is lower in the first trimester, but fetal sequelae are more severe with early infection.
Postnatal infection is most commonly acquired via ingestion of unwashed vegetables contaminated by cat feces or ingestion of poorly cooked meat. Several epidemics of T. gondii infection due to contaminated drinking water have occurred recently, including in 2001 in Brazil, in 1994 in British Columbia, and in 1979 among U.S. soldiers in Panama. Infection may also occur through blood products and organ transplantation. Ocular disease has been estimated to occur in about 2 percent of postnatally infected individuals.
T. gondii is a parasitic protozoan found throughout the environment, although the prevalence of human infection is much higher in tropical areas. It infects many species of animals and birds, but the definitive host is the cat. There are several forms of the parasite, which may reproduce sexually or asexually. Oocysts containing sporozoites are produced during sexual reproduction in the cat intestine. The oocysts are excreted in cat feces and can remain viable for more than a year. Human infection may also occur via ingestion of tissue cysts containing bradyzoites in meat from infected animals. Following human ingestion of either oocysts or tissue cysts, the organism develops into the tachyzoite form which proliferates, infecting host cells and causing their eventual destruction. The tachyzoites may then form cysts that can persist indefinitely in host tissues, with a predilection for central nervous system and muscle tissue. The tissue cysts do not excite an inflammatory response.
Signs and Symptoms
Acute infection in the immunocompetent patient is often asymptomatic, with only mild lymphadenopathy. Some patients may present with fever, myalgia, fatigue, headache, rash, sore throat, hepatosplenomegaly or visual disturbance. Ocular lesions are the most common manifestation in congenital infections, followed by neurologic deficits, CNS calcifications, microcephaly and hydrocephalus. Strabismus, microphthalmia, cataract, optic atrophy, nystagmus and retinal detachment may be associated with congenital cases. Typical symptoms of active ocular disease include blurred vision, floaters and metamorphopsia.
Old retinochoroidal scars, which are usually present, are typically well-defined and variably pigmented. The central portion is atrophic, exposing choroidal vasculature or underlying sclera. Proliferative vitreoretinopathy, retinal gliosis and traction bands may be present. The associated vitritis may be localized or diffuse, with granulomatous anterior segment inflammation.
Active retinitis usually appears as a fluffy white lesion with surrounding edema. It is often circular and rarely bullous in shape. The choroid and sclera may become involved secondarily. Sheathing of retinal vasculature, perivascular exudates and arteriolar plaques (Kyrieleis’ arteriolitis) local or distant to the foci of retinitis may be seen.
Retinal vascular occlusions are also features of the disease. Associated hemorrhage is less common and can be a feature distinguishing toxoplasmosis from viral retinitis. Less common are isolated papillitis or neuroretinitis. Multifocal punctate grayish lesions in the inner or outer retina with or without associated vitritis are less common presentations of T. gondii retinitis and can be difficult to distinguish from other entities.
Many factors can influence the severity of ocular disease. Macular lesions are more common in eyes with congenital disease. Larger lesions are associated with a longer duration of active disease and a higher incidence of complications. Also, more severe disease has been associated with older age, and recurrence of retinochoroiditis has been associated with pregnancy.
Another factor known to influence ocular disease is the T. gondii genotype. Three distinct lineages have been identified. The type I strain is more virulent than type II or type III. Type II is the most common isolate in North America. Route of inoculation can also influence the disease, with oocysts containing sporozoites being more virulent and resistant to digestion than tissue cysts.
The role of diagnostic testing in toxoplasmosis is to confirm the diagnosis so that appropriate treatment can be started. The differential diagnosis includes sarcoidosis, syphilis, viral retinitis, cat scratch disease, lymphoma and tuberculosis. In children, one must consider herpes virus infection, macular coloboma and retinoblastoma. In typical cases, however, many physicians find diagnostic testing unnecessary.
Fluorescein angiography of active lesions shows blockage early followed by leakage. FA may also be helpful for suspected retinal vascular occlusion or choroidal neovascularization. Visual field testing demonstrates defects corresponding to the location of the retinal lesions.
Serologic testing for antitoxoplasma antibodies, usually by enzyme-linked immunoabsorbent assay, can be helpful. IgM titers to the organism indicate recently acquired infection. Although the IgM peak may be transient and therefore missed, in some patients the IgM titer may remain elevated for long periods of time after infection.
Serum IgG antibodies to T. gondii are a reliable indicator of previous infection but their presence does not denote the time of infection. IgG titers can be low in isolated ocular disease, but many physicians accept test positivity in undiluted serum as sufficient evidence of infection. Obviously, this can lead to false positives since there is a high prevalence of seropositivity in the general population. Antibody levels from aqueous humor samples can be measured and compared with those measured from serum as an indicator of local antibody production in response to T. gondii and thus ocular disease. This technique is both sensitive and highly specific for ocular disease, but is in much more widespread use in Europe than in the United States.
Polymerase chain reaction has been used to detect the presence of T. gondii DNA in ocular fluid samples. This method is highly specific, but sensitivity is much lower, probably about 30 to 60 percent. Some investigators have used multiple diagnostic testing modalities with good results.
The type of treatment required for T. gondii retinochoroiditis depends on a number of factors. Acquired disease in an immunocompetent host is often mild and self-limited such that no treatment is necessary, particularly if there is little inflammation, if the lesion is peripheral, and if visual acuity is only minimally affected. In contrast, if the disease is congenital, if the lesion is in or near the macula or optic nerve, if there is a large amount of inflammation, or if vision is significantly affected, then treatment is usually initiated.
Immunocompromised patients are usually treated in any case. A number of antibiotic regimens have been used to treat T. gondii retinochoroiditis. These drugs include sulfadiazine, pyrimethamine, clindamycin, azithromycin, trimethoprim-sulfamethoxazole, atovaquone and spiramycin, which is not available in the United States and is not commonly used. In animal models, these drugs have shown excellent activity against only the tachyzoites, with the exception of azithromycin and atovaquone, which also have some activity against bradyzoites in tissue cysts. This property may be beneficial for decreasing the recurrence of disease, although it has not been proven in clinical trials.
Classic treatment, often referred to as “triple” therapy, uses sulfadiazine (1 g orally four times a day after a 2–4 g loading dose), pyrimethamine (25 mg orally twice daily with a 50 mg loading dose) and prednisone (20–40 mg per day after 24–48 hours on antibiotics). In a survey of uveitis specialists, this remained the most commonly used regimen.1 Pyrimethamine causes bone marrow suppression, so baseline and weekly cell counts should be checked. Also, folinic acid should be administered with pyrimethamine to minimize this side effect.
“Quadruple” therapy using the triple regimen plus clindamycin was the next most common treatment, according to the survey. Clindamycin (300 mg orally four times daily) may also be used alone, given by intravitreal injection or added to another regimen in patients whose disease progresses or where other drugs have contraindications. The data are mixed regarding the efficacy of clindamycin when used as monotherapy, but clindamycin shows good synergism when combined with other drugs. Patients should be monitored for diarrhea. Pseudomembranous colitis is a potentially serious complication of clindamycin therapy, occurring in 1/50,000 to 1/100,000 cases.
Azithromycin (250–1,000 mg/day for three weeks) is synergistic with pyrimethamine and, as compared with classic therapy, showed equivalent results and fewer adverse effects in one small prospective study.2
Trimethoprim-sulfamethoxazole (160/800 mg every 12 hours) is used because of its similar mechanism of action to classic therapy and its better side-effect profile. Several studies have compared it with classic therapy with mixed results, but a recent study at least suggested equivalent efficacy.3
Atovaquone (750 mg every six hours) is active against ocular and CNS toxoplasmosis. Food increases its bioavailability, and atovaquone may be synergistic with the drugs used in triple therapy. Studies to date have not shown a significant decrease in recurrence after short-term therapy in humans.
Also, one must keep in mind that no studies have conclusively shown to what extent antibiotic therapy alters the course of the disease in adult immunocompetent patients as compared with no treatment. Nevertheless, many patients are still treated for the previously mentioned reasons. Treatment is required in newborns, pregnant women and immunosuppressed patients. Most immunocompetent patients are treated with corticosteroids along with antibiotics to control inflammation and minimize secondary damage.
Infection in immunocompromised patients can be more severe and rapidly fatal, with encephalitis developing in up to 50 percent of untreated patients. Toxoplasmic pneumonitis and myocarditis are other serious manifestations in this population. Retinitis may also be more severe, presenting with multiple areas of active retinitis not associated with old scars; it may follow a perivascular distribution or present as a more diffuse necrotizing retinitis.
The inflammatory response in patients with AIDS and toxoplasmosis tends to be much greater than that seen in patients with AIDS and viral retinitis. Treatment is always started in immunocompromised patients, however corticosteroids are usually avoided. Relapse of both CNS and ocular disease is common in patients with AIDS after discontinuation of treatment. For this reason, maintenance therapy is recommended, although no single best regimen has been determined. Management should be coordinated with an infectious disease specialist.
The prognosis for patients with ocular toxoplasmosis depends on a variety of factors, including the location of the lesions, the severity of inflammation and the development of any secondary complications such as cataract, amblyopia, glaucoma, vascular occlusion, optic atrophy or choroidal neovascularization. One study found that about 40 percent of patients with toxoplasmic retinochoroiditis were left with a visual acuity of 20/100 or worse.4
2 Bosch-Driessen, L. T. et al. Am J Ophthalmol 2002;134(1):34–40.
3 Soheilian, M. et al. Ophthalmology 2005; 112(11):1876–1882.
4 Friedmann, C. T. and D. L. Knox. Arch Ophthalmol 1969;81:481–493.
Dr. Gerwin is a fellow with Retina Specialists of Alabama in Birmingham. Dr. Kimble practices there and is associate professor of ophthalmology at Callahan Eye Foundation Hospital of UAB in Birmingham.