TOXOPLASMOSIS

Signs and Symptoms

Toxoplasma gondii is an intracellular obligate protozoan parasite.1-15 In under-developed countries, untreated drinking water is considered a major source of the Toxoplasma organism.9,10 In the developed world, the major sources of the organism are via consumption of raw or undercooked meat (pork, lamb and wild game meat) and raw fruits and vegetables.1-15 The organism can also be acquired through contact with soil contaminated with the feces of the cat or other small game.15 Worldwide exposure to T. gondii has been estimated at 30% in the US and 40-80% in Europe, India, countries in Africa and countries in South America.2,7-12

Congenital cases (newborns with disease) are acquired through seropositive mothers.16 Congenital infection frequently results in systemic complications at birth: fever, jaundice, low birth weight, skin rash, pneumonia and hepatoslenomegaly.4,16 A unique complexity of the disease is that even when infection occurs at the time of birth, signs and symptoms may not become apparent for years.17

In disease acquired later in life, ocular symptoms are known to be variable according to the age when the infection blossoms and the ability to launch a sustained immune response.1-9,14 Affected children (<12 years of age) frequently present with reduced visual acuity and may exhibit an acquired strabismus, nystagmus or evidence of previous or chronic episodes of inflammation.3,18-20 Teenagers and adults also present with decreased vision but may describe floaters secondary to more substantial vitreous reaction along with photophobia, pain, and hyperemia from a uveitic response.3-5 Individuals immunocompromised from either human immunodeficiency virus (HIV) or from iatrogenic suppression (organ transplantation, chemotherapy) are also highly susceptible.14

While the disease has the ability to nest itself in the deeper layers of the retina, active disease doesn’t always present with an aggressive vitreous reaction.1-6,21-25 When the vitritis is heavy, patients may present with the chief complaint that their vision has taken on a red hue. Toxoplasma retinochoroiditis (choroid and retina affected) is most commonly encountered in the posterior pole.3,19,22 The lesions can be solitary, or multiple with satellite lesions.3-6 Active lesions present as gray-white foci of retinal necrosis with adjacent deep choroiditis, retinal vasculitis (sheathing of vessels), intraretinal hemorrhage and varying amounts of vitritis.3-6,8-22 When the optic disc demonstrates involvement, the condition is referred to as toxoplasma neuroretinitis.4-6,23-25

The disease has been recognized as being among the common causes of granulomatous anterior uveitis with mutton-fat keratic precipitates, fibrin, cells, flare, iris nodules and posterior synechiae.3,5,6 Uveitis-based abnormality of intraocular pressure (either low or elevated) often occurs and in cases where inflammation is chronic from recalcitrant or recurrent disease, premature cataract formation is possible.21,26,27

Scar formation occurs as each lesion becomes inactive and is signified by pigmentary hyperplasia.1-6 Old retinal scars connote significant retinal destruction and leave corresponding dense scotomas which may affect vision depending upon location.3-6,28 As in any case of posterior inflammation, cystoid macular edema may develop.4-6 Other associated complications include punctate outer retinitis, papillitis, intraocular inflammation without retinochoroiditis, unilateral pigmentary retinopathy, Fuchs’-like anterior uveitis, scleritis, retinal artery occlusion and multifocal or diffuse necrotizing retinitis.3,29,30

Finally, like any disease involving the subretinal tissues, cytokines and chemoattractants along with the stressor of the inflammation and pathology itself can induce the genesis of choroidal neovascularization, though this is uncommon.31,32

Pathophysiology

Toxoplasmosis was initially identified and described by the team of Nicolle and Manceaux and by Splendore in Brazil in 1908.33-35 They named the organism Ctenodactylus gundi and recognized the source as rodents and rabbits.33-35 Today renamed as Toxoplasma gondii, the organism is among the most successful protozoan parasites, with an innate ability to manipulate the immune system of the host.1-40 The organism can be picked up by any number of mammals and some birds with a renewal lifecycle that is perpetuated in the host’s small intestines. The cat is considered en masse to be the definitive host.1-5,33-40 Congenital transmission occurs from an infected mother to the fetus through the placenta.1-6,33-40 Raw or undercooked meat (lamb, chicken or beef) are also principle vectors.1-6 When not contracted congenitally, the mode of transmission is through direct contact with the organism.

Toxoplasma gondii is an apicomplexan intracellular protozoa (obligate organisms that have evolved complex developmental stages important for pathogenesis and transmission).37-42 It is the most extensively studied organism of the coccidian group.37-42 Cats acquire the organism through kills or by being fed raw meat.38,42 Upon ingestion, T. gondii commences the sexual stage by differentiating into male and female gametes which fuse in the intestinal epithelium of the host, forming a fertilized oocyst.38 The oocyst is then shed in the feces.4,38 This living morphologic form can remain viable in soil for up to one year.4,38,39 The spontaneous process of sporulation (where the oocyst develops sporozoites) creates the infectious form of the organism which can be ingested intentionally or unintentionally by another animal or human.4,5,38,39 Once inside the intestines of the new host, asexual proliferation begins as the organism assumes the form of what is known as the proliferative tachyzoite.4,5,38-40

Tachyzoites disseminate throughout the body via the circulatory and lymphatic systems carried by macrophages.38,39 Tachyzoites can penetrate virtually any nucleated cell.4,5,38,39 Central to the transmission and pathogenesis of the organism is its ability to convert from the proliferative stage (tachyzoite) into latent tissue cysts known as bradyzoites.38,39 Bradyzoites have the ability to accomplish encystment, becoming encapsulated.38,39 This biologic feature permits Toxoplasma to persist in the host and affords the parasite a unique opportunity to spread to new hosts through blood (placenta) or oral contact without proceeding through its sexual stages.39,40

Bradyzoite tissue cysts can survive in brain, heart, skeletal muscle and retinal tissue.38,39,41 They can be reactivated into active toxoplasmosis whenever host immunity becomes impaired.38,39 When the encapsulation breaks down, the organisms transform back into tachyzoites which invade neighboring cells.4,38-40 The resultant inflammatory response of the human immune system in the choroid, retina and nerve create the classic chorioretinal and neuroretinal appearance.1-6,37-40

Management

Laboratory diagnosis of toxoplasmosis is based on isolation of the organism from body fluids and tissues; however, as its presentation is so distinctive, many make the diagnosis based on the observable clinical characteristics.43-45 Detection of T. gondii can be accomplished by direct identification using polymerase chain reaction (PCR) to uncover organism DNA and direct detection of the tachyzoites cysts and bradyzoites from tissues or smears obtained from biopsy of cerebral spinal fluid and blood.43-45 Another approach is indirect detection by checking for antibodies using the antitoxoplasma antibody test, indirect immunofluorescent antibody tests (IFAT), Sabin-Feldman methylene blue dye test (the standard for detecting Toxoplasma antibodies in humans) and complement fixation test.3,4,43-48

Enzyme-linked immunosorbent assay and PCR are laborious, time-consuming, expensive studies.43 Recently, loop-mediated isothermal amplification was developed using isothermal conditions (65°C) for DNA amplification.43 The apparatus requires only a simple incubator and can amplify up to 109 copies in less than an hour, making its use more efficient.43

Toxoplasmosis therapy in immunosuppressed individuals includes specific oral medication for the systemic infection and topical anti-uveitic medications for the ocular inflammatory component. There are several regimens, with different drug combinations.22,24,49-53 Medications include pyrimethamine, sulfadiazine, clindamycin, trimethoprime-sulfamethoxazol, spiramycin, azithromycin, atovaquone and tetracycline.3,4,22,24,49-53 One classic approach includes pyrimethamine in combination with folinic acid to reduce the risk of drug-associated side effects, sulfadiazine and prednisone.24,49-53 A more convenient combination enlists Bactrim DS (trimethoprim 160mg/sulfamethoxazole 800mg, Roche) 1 tab PO BID for 4-6 weeks.53 In patients who are allergic to sulfonamides, atovaquone (750mg, PO Q6H, over 2-6 months) can be substituted as an alternative to the pyrimethamine/sulfadiazine.54

In cases where active disease does not threaten the macula or optic disc in an immunocompetent patient, observation without medical management can be offered.52,53 However, most clinicians continue to prescribe medications despite a lack of Level I evidence to support the efficacy of routine oral antibiotic or oral corticosteroid treatment for acute events in immunocompetent patients.24,55 There is Level II evidence suggesting that long-term prophylactic treatment (one tablet of Bactrim DS every three days) may reduce recurrences in chronic relapsing cases.55,56 In all cases, topical uveitis management includes cycloplegia with atropine 1% or homatropine 5% QD-TID and topical steroids such as prednisolone acetate 1% or difluprednate QID-Q2H in accordance with the level of inflammation.3,4,49-51

The prognosis for ocular toxoplasmosis in immunocompetent individuals is usually good, as long as the optic nerve and macula are not directly involved.3,4,21,22,24,43,52-56 As the disease can play a role in the provocation of other disorders, a full medical work up should be completed.57 Since the infection and inflammation involve the choroid and retina, all lesions have the potential to induce choroidal neovascularization requiring photodynamic therapy and anti-vascular endothelial growth factor injections.37,52-56,59,60 Laser photocoagulation is rarely considered.4,5,59,60

Clinical Pearls

Transmission from an infected pregnant woman to her fetus leading to congenital toxoplasmosis is referred to as vertical transmission.

The risk of vertical transmission increases when infection occurs later in pregnancy. However, the consequences to the fetus are more severe when transmission occurs within the first trimester.

Since acquired infection with T. gondii is currently a more important cause of ocular toxoplasmosis compared to congenital infection, prevention should be directed not only toward pregnant women but toward the general population.

Other causes of granulomatous anterior uveitis with associated posterior inflammation include syphilis, tuberculosis, Lyme disease, Toxocara infection and HIV. Laboratory testing in unconfirmed cases should include these entities.

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