AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

The protozoan Toxoplasma gondii is a coccidian, obligate, intracellular parasite responsible for zoonotic infection in humans and other mammals. In addition, it is the most common cause of intraocular inflammation in the world. The cat is the definitive host that becomes infected by eating contaminated raw meat, wild birds, or mice. The 3 forms of the protozoan, all of which are only present in the cat, are tachyzoites, bradyzoites, and sporozoites. Humans and other mammals are infected only by tachyzoites and bradyzoites.

Toxoplasmosis may be congenital or acquired. When a pregnant susceptible woman acquires primary toxoplasmosis, transplacental transmission of the parasite to the fetus may occur. Acquired toxoplasmosis can result from the following:

• Ingestion of tissue cysts from contaminated raw or undercooked beef, lamb, or pork
• Ingestion of oocysts from soil, milk, water, or vegetables
• Inhalation of oocysts
• Contaminated blood transfusions, organ transplants, and accidental inoculation acquired in the laboratory

Pathophysiology

When a cat becomes infected, the organism undergoes sexual reproduction in its intestine. As a consequence, a cat sheds millions of noninfectious unsporulated oocysts in its feces. Sporulation occurs in the next 3-4 days at room temperature. With sporulation, the oocyst becomes infective (sporozoite) for at least a year. Ingestion of the sporulated oocyst results in an acute infection.

The acute infection is typified by tachyzoites that invade and proliferate in almost any type of mammalian cell with the exception of nonnucleated erythrocytes. As the tachyzoites enter the cell, they become vacuolated and undergo reproduction via endodyogeny. In this process, 2 daughter cells are formed within the parent parasite, which becomes destroyed with the host cell as the daughter cells are released. 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. As the host's immune system responds and the tachyzoites convert themselves into bradyzoites, the cyst forms. The cyst is extremely resistant to the host's defenses, and a chronic latent infection ensues.

If a subclinical infection is present, no funduscopic changes are observed. The cyst remains in the normal-appearing retina. Whenever the host's immune function declines for any reason, the cyst wall may rupture, releasing organisms into the retina, and the inflammatory process restarts. If an active clinical lesion is present, healing occurs as a chorioretinal scar. The cyst often remains inactive within or adjacent to the scar.

Frequency

United States

Based upon serologic studies, an estimated one quarter to one half of the US population has been infected by toxoplasmosis. In the United States, 2-6 per 1000 pregnant women acquire toxoplasmosis. The prevalence of congenital toxoplasmosis is 1 in 10,000 live births.

Intraocular toxoplasmosis manifested by necrotizing retinochoroiditis has been reported in 1-21% patients with acquired systemic infections. In a population study, 0.6% residents of Maryland were found to have scars consistent with ocular toxoplasmosis.

International

The prevalence of serum antibodies against toxoplasmosis varies throughout the world and depends on eating habits, hygiene, and climate. Toxoplasmosis appears to be more prevalent in hot humid climates.

The prevalence of congenital toxoplasmosis is 1 in 1000 live births in France. By the fourth decade of life, 90% of the French population, 12.5% of the Japanese population, and 60% of the Dutch population are seropositive for toxoplasmosis.

Mortality/Morbidity

Toxoplasmosis is the most common cause of intraocular inflammation and posterior uveitis in immunocompetent patients throughout the world.

Toxoplasmosis is responsible for approximately 30-50% of all posterior uveitis cases in the United States.

Race

A racial or genetic predilection for this infection is not apparent.

Sex

No sexual predilection exists for this infection.

Age

• The prevalence of positive serologic reaction increases with age. In the United States, 5-30% of individuals in the second decade of life and 10-67% of individuals older than 50 years have antitoxoplasma antibodies.
• Ocular toxoplasmosis has been reported to manifest itself most commonly between the second and fourth decades of life.

CLINICAL

Section 3 of 11  

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History

• Risk factors
• • Immunodeficiency states (eg, AIDS), immunosuppression in patients who have undergone organ transplantation, and malignancies
  • Exposure to cats
  • A history of eating raw or partially cooked meat

• Symptoms
• • Blurred vision
  • Floaters
  • Pain
  • Red eye
  • Metamorphopsia
  • Photophobia

Physical

• Toxoplasmosis is typically classified as follows:
  
  
  • Congenital toxoplasmosis
  • Acquired toxoplasmosis
  • Toxoplasmosis in the immunocompromised host
  • Ocular toxoplasmosis
• Congenital toxoplasmosis
  
  
  • The classic clinical triad of retinochoroiditis, cerebral calcifications, and convulsions defines congenital toxoplasmosis. Other findings include hydrocephalus, microcephaly, organomegaly, jaundice, rash, fever, and psychomotor retardation. It accounts for relatively few cases; however, they tend to account for most acute and fatal infections.
  • When a nonimmune susceptible woman becomes infected during pregnancy, transplacental transmission of T gondii to the fetus may occur, resulting in congenital toxoplasmosis.
  • If the mother acquires the infection during the first trimester, 17% of babies develop congenital toxoplasmosis, but the severity of the disease is greater. If the infection is acquired during the third trimester, 65% of babies develop congenital toxoplasmosis; however, many of them are asymptomatic. Chronic maternal infection is not associated with congenital disease.
  • Antitoxoplasma immunoglobulin M (IgM) antibodies are present in 75% of infants with congenital toxoplasmosis.
  • The most common finding in congenital toxoplasmosis is retinochoroiditis that has a predilection for the posterior pole. It is seen in 75-80% of cases and is bilateral in 85% of cases.
  • Since most patients with active chorioretinitis had preexisting chorioretinal scars, most cases of intraocular toxoplasmosis were previously believed to be secondary to reactivation of a congenital infection.
• Acquired toxoplasmosis
  
  
  • Ingestion of tissue cysts from contaminated beef, lamb, or pork; ingestion of oocysts from soil or vegetables; and contaminated blood transfusions, organ transplants, and accidental inoculation in the laboratory may all result in acquired toxoplasmosis.
  • The acquired infection is usually subclinical and asymptomatic. In 10-20% of cases that become symptomatic, the patient develops a flulike illness characterized by fever, lymphadenopathy, malaise, myalgias, and a maculopapular skin rash that spares the palms and the soles. In individuals who are immunocompetent, the disease is benign and self-limited.
  • Previously, only 1-3% of patients with acquired infection were believed to develop ocular toxoplasmosis. Serologic studies suggest that ocular toxoplasmosis is more commonly associated with acquired infection than previously believed.
• Toxoplasmosis in the immunocompromised host
  
  
  • Host immune function plays an important role in the pathogenicity of toxoplasmosis. Patients who are immunocompromised often develop life-threatening pneumonitis; myocarditis; encephalitis; and an atypical, sight-threatening, severe necrotizing retinochoroiditis.
  • Multifocal, bilateral, and relentlessly progressive lesions characterize the ocular involvement. Because of their immunosuppression, these patients often have problems mounting an inflammatory reaction, which makes the formation of a chorioretinal scar difficult.
  • Often, the serologic diagnosis is also difficult.
  • Only 1-2% of patients with HIV are affected with ocular toxoplasmosis.
  • Elderly patients who acquire toxoplasmosis are at a risk of developing a severe retinochoroiditis, presumably secondary to the waning of cellular immune function that occurs with aging.
• Ocular toxoplasmosis
  
  
  • Earlier studies have shown that up to 75% of patients with congenital toxoplasmosis had chorioretinal scars at birth. In contrast, ocular lesions in patients who acquired toxoplasmosis after birth were not common. Most patients with active chorioretinitis had preexisting chorioretinal scars.
  • Early studies proposed that most cases of ocular toxoplasmosis were secondary to congenital infection and that they tended to occur during the chronic phase of infection. However, later studies have shown the importance of acquired infection in the pathogenesis of ocular toxoplasmosis. Brazilian studies have shown that only 1% of young children with toxoplasmosis had ocular lesions, whereas 21% of persons older than 13 years had ocular lesions.
  • In another study, several members of the same household were affected with ocular toxoplasmosis. In addition, in a Canadian epidemic of toxoplasmosis, up to 21% of those affected developed ocular lesions. Serologic studies suggest that ocular toxoplasmosis is more commonly associated with acquired infection than previously believed.
  • The hallmark of the disease is a necrotizing retinochoroiditis, which may be primary or recurrent. In primary ocular toxoplasmosis, a unilateral focus of necrotizing retinitis is present at the posterior pole in more than 50% of cases. The area of necrosis usually involves the inner layers of the retina and is described as a whitish fluffy lesion surrounded by retinal edema.
  • The retina is the primary site for the multiplying parasites, while the choroid and the sclera may be the sites of contiguous inflammation.
  • When the optic nerve becomes involved by toxoplasmosis, the typical manifestation is optic neuritis or papillitis associated with edema, often called Jensen disease.
  • The sheath of the optic nerve may serve as a conduit for the direct spread of Toxoplasma organisms into the optic nerve from an adjacent cerebral infection. This also results in optic neuritis or papillitis.
  • Punctate outer toxoplasmosis has been described in Japanese and American literature. This form of the disease is unique in that the classic large atrophic posterior lesions are not seen.
  • Inflammatory cells are seen in the vitreous overlying the retinochoroidal or papillary lesion. In many cases, the inflammatory reaction is severe, and the details of the fundus are not visible. This appearance has been termed a "headlight in the fog." Posterior vitreous detachment is commonly seen, and patients may develop precipitates of inflammatory cells on the posterior vitreous face, referred to as vitreous precipitates. Thick vitreous strands and membranes may be present and may require vitrectomy.
  • Toxoplasma antigens are responsible for a hypersensitivity reaction that may result in retinal vasculitis and granulomatous or nongranulomatous anterior uveitis.
  • Posterior synechiae may complicate the course of anterior uveitis, and keratic precipitates (KP) may be seen. The KP may appear in the classic Arlt distribution in milder nongranulomatous configurations and granulomatous morphology. In addition, some patients present with the stellate KP pattern, characterized by a diffuse homogeneous distribution pattern and a stellate fibrillar KP morphology.
  • As the lesion heals, it appears as a punched-out scar, revealing white underlying sclera. This results from extensive retinal and choroidal necrosis surrounded by variable pigment proliferation.
  • With reactivation of live tissue cysts located at the border of the scars (recurrent ocular toxoplasmosis), the areas of newly active necrotizing retinitis are usually adjacent to old scars (so-called satellite lesions).
  • In some patients, multiple grayish white dots at the level of the retinal pigment epithelium (RPE) appear. No associated vitreous reaction occurs with this manifestation.
  • As in other inflammatory conditions, macular edema may be seen.
  • Rarely, ocular inflammation without the necrotizing retinochoroiditis can occur in patients with acquired toxoplasmosis. These patients present with retinal vasculitis, vitreitis, and anterior uveitis. Later, they may develop retinochoroidal scars that suggest that the inflammatory reaction was secondary to T gondii.
  • Rarely, retinal and optic nerve neovascularization may follow. The neovascularization usually regresses with resolution of the inflammation. The exact etiology of neovascularization of the optic nerve and the retina is not well understood. Retinal ischemia associated with severe retinal vasculitis may predispose to neovascularization of the retina. On the other hand, inflammatory reactions alone may cause neovascularization of the retina.

Causes

• Congenital: When a nonimmune susceptible woman becomes infected during pregnancy, transplacental transmission of T gondii to the fetus may occur, resulting in congenital toxoplasmosis.
• Acquired
• • Ingestion of tissue cysts from contaminated beef, lamb, or pork
  • Ingestion of oocysts from soil, water, raw milk, or vegetables
  • Contaminated blood transfusions, organ transplants, and accidental inoculation in the laboratory

DIFFERENTIALS

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Other Problems to be Considered

Toxocariasis
Primary intraocular lymphoma
Pars planitis

WORKUP

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Lab Studies

• Serology
  
  • The diagnosis is usually based on the clinical appearance of the fundus lesion. Serologic evidence of exposure to Toxoplasma organisms serves as supportive evidence.
    
  
  
  • Serum antitoxoplasma antibody titers can be determined by several techniques, to include the following:
    
    • Enzyme-linked immunosorbent assay (ELISA)
      
    
    
    • Indirect fluorescent antibody test
      
    
    
    • Indirect hemagglutination test
      
    
    
    • Complement fixation
      
    
    
    • Sabin-Feldman dye test
      
  
  
  • Serologic findings are important in determining whether acute or chronic systemic infection is present. Acute systemic toxoplasmosis has traditionally been diagnosed by seroconversion. Anti-Toxoplasma immunoglobulin G (IgG) titers present a 4-fold increase that peak 6-8 weeks following infection, then decline over the next 2 years, but remain detectable for life. Anti-Toxoplasma IgM appears in the first week of the infection and then declines in the next few months. The presence of anti-Toxoplasma immunoglobulin A (IgA) has also been shown to be detectable in acute infection; however, since the titers can last for more than 1 year, its value in helping to diagnose an acute phase is limited.
    
  
  
  • Antibody titers do not correlate with ocular disease. Antitoxoplasma antibodies may be very low and should be tested in undiluted (1:1) samples if possible. The absence of antibodies rules out the disease; nevertheless, false-negative results do occur.
    
  
  
  • Invasive techniques are usually reserved for difficult cases, such as patients who are immunocompromised. Ocular fluids can demonstrate the presence of intraocular antibody production. Polymerase chain reaction can detect the causative organism.
    
  
  
  • A fluorescent treponemal antibody absorption (FTA-ABS) test should be obtained to rule out syphilis.

Imaging Studies

• Fluorescein angiography (FA) of active lesions shows hypofluorescence during the early phase of the study, followed by progressive hyperfluorescence secondary to leakage.
• Indocyanine green
  
  
  • Indocyanine green (ICG) of active lesions are mostly hypofluorescent. ICG has imaged hypofluorescent satellite lesions that are not imaged by FA and are not seen during clinical examination.
  • The etiology of such hypofluorescent lesions is unknown but suspected of being a noninfectious, perilesional inflammatory reaction.
• Optical coherence tomography (OCT) is helpful in identifying potential complications, including epiretinal membrane, cystoid macular edema, vitreoretinal traction, and choroidal neovascularization.
• Ultrasound is indicated in the presence of ocular media opacities, especially vitreous opacities. The most common findings include intravitreal punctiform echoes, thickening of the posterior hyaloid, partial or total posterior vitreous detachment, and focal retinochoroidal thickening.

Procedures

• Atypical cases may require either a vitreous sample or an aqueous sample.
• Polymerase chain reaction is capable of detecting T gondii DNA in either an aqueous sample or a vitreous sample in only one third of patients with ocular toxoplasmosis.
• Antitoxoplasma IgG or IgA antibodies may be detected in either an aqueous sample or a vitreous sample. A coefficient is calculated by comparing the concentration of anti-Toxoplasma antibody in the eye and the serum, divided by the concentration of gamma globulin in the aqueous to that in the serum. A coefficient of 8 or higher is consistent with active ocular toxoplasmosis.

Histologic Findings

Histopathology is the criterion standard for diagnosis. Tissue diagnosis is impractical and rarely used clinically. Rarely, a retinal biopsy may be required to elucidate the diagnosis in a highly atypical case. In histologic sections, the tachyzoites appear ovoid or crescent shaped. They measure 6-7 µm in length and 2-3 µm in width.

The tachyzoites stain well with both Giemsa stain and Wright stain. Giemsa-stained smears reveal a bluish cytoplasm and a reddish spherical or ovoid nucleus. In the cyst forms, the wall is eosinophilic, argyrophilic, and weakly periodic acid-Schiff (PAS) positive. The cyst may contain anywhere from 50-3000 bradyzoites. The bradyzoites within the cyst are strongly PAS positive. They form intracellularly within vacuoles. The surrounding membrane is produced by the parasite.

An intense inflammatory reaction is present in the retina, the overlying vitreous, and the underlying choroid. The choroid adjacent to the retinal foci usually shows a granulomatous inflammation. The retina is partially necrotic with a well-defined border between necrotic and unaffected retina. After healing, the retina in the area of infection is destroyed, and chorioretinal adhesions are present.

TREATMENT

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Medical Care

• Because it is a self-limited condition, treatment of systemic acquired toxoplasmosis is usually not recommended.
• In the case of ocular toxoplasmosis, several therapeutic regimens have been recommended. Triple drug therapy refers to pyrimethamine, sulfadiazine, and prednisone. Quadruple therapy refers to pyrimethamine, sulfadiazine, clindamycin, and prednisone. Pyrimethamine should be combined with folinic acid to avoid hematological complications. The duration of treatment varies depending on the patient's response but usually lasts for 4-6 weeks.
• During pregnancy, spiramycin and sulfadiazine can be used in the first trimester. Throughout the second trimester, spiramycin, sulfadiazine, pyrimethamine, and folinic acid are recommended. Spiramycin, pyrimethamine, and folinic acid may be used during the third trimester.
• Corticosteroids
  
  
  • Topical corticosteroids are used depending on the anterior chamber reaction.
  • Depot steroid therapy is absolutely contraindicated in the treatment of ocular toxoplasmosis. The high-dose medication in close proximity to ocular tissues apparently overwhelms the host's immune response, leading to rampant necrosis and the potential for a blind, phthisical globe.
  • Systemic corticosteroids are used as an adjunct to minimize collateral damage from the inflammatory response.
• Topical cycloplegic agents are used depending on the anterior chamber reaction and the degree of pain. They are also used to prevent formation of posterior synechiae.
• Antitoxoplasmic agents include the following:
  
  
  • Sulfadiazine
  • Clindamycin
  • Pyrimethamine
  • Atovaquone
  • Azithromycin

Surgical Care

• Photocoagulation or cryotherapy
• • Caution must be exercised if photocoagulation or cryotherapy is being considered in the treatment of intraocular toxoplasmosis.
  • Intraretinal hemorrhages, vitreous hemorrhage, and retinal detachment have been reported as complications of such treatment. Tissue cysts can exist in a normal-appearing retina.

• Pars plana vitrectomy may be indicated in cases of retinal detachment secondary to vitreous traction or in cases where vitreous opacities persist.

Consultations

Vitreoretinal consultation is desired if pars plana vitrectomy is being considered. Consultations with internal medicine or infectious disease specialists are always recommended.

Activity

No restrictions of activity are necessary.

MEDICATION

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The mere presence of a focus of retinitis is not always an indication for treatment. Generally, small peripheral lesions heal spontaneously and may be followed conservatively. On the other hand, lesions within the vascular arcade, lesions near the optic disc (Jensen papillitis), lesions in the papillomacular bundle, or large lesions irrespective of location are treated. Patients with severe debilitating vitreitis are also treated aggressively.

In a prospective trial, treatment with several regimens failed to shorten the duration of inflammatory activity or to prevent recurrences. However, treatment did reduce the size of the ultimate chorioretinal scar. In addition, experts differ on their preferred initial treatment. In a report, one third of respondents preferred triple therapy (ie, pyrimethamine, sulfadiazine, prednisone), and a little more than one quarter of respondents preferred quadruple therapy (ie, pyrimethamine, sulfadiazine, clindamycin, prednisone).

Drug Category: Antibiotics

Therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Drug Category: Ubiquinone analogs

Inhibit ATP synthesis, which, in turn, causes inhibition of metabolic enzymes, causing the suppression of parasite growth.

Drug Category: Corticosteroids

Have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli. In cases where anterior uveitis is present, topical corticosteroids are used to treat the inflammation.

Drug Category: Folic acid derivatives

Used to counteract toxic effects of folic acid antagonists that act by inhibiting dihydrofolate reductase.

Drug Category: Cycloplegics

As in any eye with uveitis, posterior synechiae often form if a pupil is not mobilized. Anticholinergic agents, such as cyclopentolate, atropine, and homatropine, block the sphincter muscle of the iris and the muscle in the ciliary body that is responsible for accommodation to produce mydriasis and paralysis of accommodation.

FOLLOW-UP

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Further Outpatient Care

• Patients should receive follow-up care as needed.

In/Out Patient Meds

• See Medication.

Deterrence/Prevention

• The principal mode of transmission worldwide is through the ingestion of oocysts shed into the environment in the feces of cats. These organisms remain viable in the soil for at least a year and become a source of infection for mice, rats, birds, and other prey.
• Drinking contaminated water has been reported to cause an outbreak of toxoplasmosis.
• Proper cooking of meat is essential as Toxoplasma species have been isolated from sheep, swine, and cattle. Outbreaks of toxoplasmosis have been reported following ingestion of raw or undercooked meat.
• The tachyzoite is susceptible to heat, freezing, desiccation, and gastric secretions.
• Pregnant women who are seronegative should avoid contact with cats and should continue to have serologic monitoring throughout their pregnancy.

Complications

• Choroidal neovascular membrane
• Branch retinal vein occlusion
• Branch retinal artery occlusion
• Tractional retinal detachment
• Cataract
• Glaucoma
• • Secondary glaucoma may occur with anterior uveitis that is secondary to the obstruction of the outflow channels by the inflammatory cells. This condition may or may not be reversible.

  • Destruction of the trabecula by chronic inflammation and anterior synechiae may also create a chronic pharmacologically nonresponsive glaucoma.

• Posterior synechiae
• Cystoid macular edema
• Retinal perivasculitis

• Optic atrophy

Prognosis

• In one series, 40% of patients had a final visual acuity of 20/100 or worse, and 16% of patients had a visual acuity between 20/40 and 20/80.
• Toxoplasma retinitis frequently reactivates, and recurrence rates approach 50% at 3 years.
• Patients with recurrent disease are more likely to have a permanent visual disability.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Failure to diagnose the infection, thus withholding appropriate treatment
• Treatment with periocular steroid depot injections
• Failure to explain, monitor, or treat the numerous adverse effects of systemic antitoxoplasma medications (Consultations with internal medicine or infectious disease specialists are always recommended.)

MULTIMEDIA

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Media file 1:  Macular scar secondary to congenital toxoplasmosis. Visual acuity of the patient is 20/400.
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Media file 2:  Papillitis secondary to toxoplasmosis, necessitating immediate systemic therapy.
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Media file 3:  Acute macular retinitis associated with primary acquired toxoplasmosis, requiring immediate systemic therapy.
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Media file 4:  Peripapillary scars secondary to toxoplasmosis.
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Media file 5:  Perimacular scars secondary to toxoplasmosis.
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Media file 6:  Inactive chorioretinal scar secondary to toxoplasmosis.
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REFERENCES

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• Holland GN, Muccioli C, Silveira C, Weisz JM, Belfort R Jr, O'Connor GR. Intraocular inflammatory reactions without focal necrotizing retinochoroiditis in patients with acquired systemic toxoplasmosis. Am J Ophthalmol. Oct 1999;128(4):413-20. [Medline].
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Article Last Updated: Jul 27, 2007