Continuing Education Activity

Toxoplasma retinochoroiditis (TRC) is likely the most common cause of infectious retinochoroiditis worldwide. One-quarter of patients with a history of Toxoplasma retinochoroiditis report worse than 20/200 vision in at least one eye. Patients may become infected in utero or via ingestion of the parasite. This activity describes the evaluation and management of Toxoplasma retinochoroiditis and highlights the role of the interprofessional team in improving care for affected patients.

Objectives:

• Explain the transmission of Toxoplasma retinochoroiditis.
• Explain how to evaluate for Toxoplasma retinochoroiditis.
• Describe treatment modalities for both immunocompetent and immunocompromised patients with primary or recurrent Toxoplasma retinochoroiditis.
• Explain how careful planning and discussion amongst interprofessional team members involved in the management of patients with Toxoplasma retinochoroiditis will improve outcomes.

Introduction

Toxoplasma gondii is likely the most common cause of infectious retinochoroiditis (Toxoplasma retinochoroiditis [TRC]) worldwide[1][2][3]. It typically presents to the eyecare practitioner with quiescent, chorioretinal scars in the inactive phase and a necrotizing chorioretinitis with overlying vitritis in the active phase[4]. While less common, the optic nerve can be affected as well[5]. One-quarter of patients with a history of Toxoplasma retinochoroiditis is reported to have vision worse than 20/200 in at least one eye[6][7].

Etiology

Toxoplasmosis is caused by the obligatory intracellular protozoan parasite T. gondii. Human infection is either by ingestion of oocysts shed in the feces of cats or by consumption of tissue cysts present in raw or undercooked meat[8]. Within several days of exposure, oocysts mature in the human intestine and become infective by liberating sporozoites that in turn differentiate into tachyzoites. When tissue cysts containing bradyzoites are ingested, these will also change into tachyzoites inside the intestine. Tachyzoites then penetrate the intestinal mucosa and reach distant organs such as brain, eyes, liver, spleen, lymph nodes, heart, skeletal muscles and the placenta by blood and lymphatic stream. Dendritic cells and macrophages guide the parasite through the blood-brain barrier allowing infection of the brain and eye[9]. Maternal infection within 6 months of conception may lead to transplacental infection of the fetus resulting in congenital toxoplasmosis[9]. Disseminated tachyzoites can infect a wide variety of human cell types. Inside the host cell, T. gondii forms a parasitophorous vacuole that sequesters the parasite from phagolysosomes and the host immune response[10]. Rapid multiplication results in host cell lysis and infection of new cells. Eventually, tachyzoites will differentiate into the latent bradyzoite and form tissue cysts[11]. Three strains of T. gondii have been identified with strain I the most virulent and strains II and III less virulent[12].

Epidemiology

One-third of the world’s population is estimated to be infected by T. gondii[13]. It is more common in hot and humid climates such as Central America, Asia, and the Caribbean region. However, in more temperate climates such as in Europe, toxoplasmosis is common as well with the highest prevalence rates reported in France. Risk factors are determined by geographical region, meat consumption, personal habits, animal reservoir and climatic conditions[14]. In the United States, seropositivity is between 20% to 70%, while the incidence of Toxoplasma retinochoroiditis is 0.6%[15]. Intrauterine transmission occurs in about one-third of pregnancies of women infected within 6 months of conception. In the United States, congenital toxoplasmosis occurs in about 1/1000 to 10,000 live births[16]. In the majority of cases, bilateral retinal scars are found in the child[17].

Histopathology

While tissue diagnosis is impractical, a retinal biopsy may be required in a highly atypical case[18]. In histologic sections, the tachyzoites are ovoid or crescent-shaped measuring 6 to 7 micrometers in length and 2 to 3 micrometers in width. Giemsa-stained tachyzoites reveal a bluish cytoplasm and a reddish spherical or ovoid nucleus[19]. In the cyst forms, the wall is eosinophilic, argyrophilic, and weakly periodic acid-Schiff (PAS) positive. The cyst may contain anywhere from 50 to 3000 strongly PAS positive bradyzoites within a vacuole. Histological analysis of active TRC reveals an intense inflammatory reaction in the retina, the overlying vitreous, and the underlying choroid with granulomatous inflammation adjacent to the lesion. A well-defined border can be found between the necrotic and unaffected retina. After healing, the infected retina is destroyed, and chorioretinal adhesions are present[20].

History and Physical

TRC is often associated with sudden onset of floaters, vision loss, hazy vision, pain, and/or photophobia. Small, active peripheral lesions, may be asymptomatic. There is often an absence of systemic signs as well.  When present, systemic symptoms mimic an acute flu-like illness, including fever, lymphadenopathy, and malaise. In the immunocompromised patient, toxoplasmic encephalitis may be present and associated with new-onset neurological complaints and/or the diagnosis of a brain abscess. Cerebral toxoplasmosis is found in 10% to 34% of autopsies on patients with HIV/AIDS[21][22].

Toxoplasma causes a necrotizing chorioretinitis that appears as a yellow-white chorioretinal lesion with indistinct margins combined with an overlying focal vitreous infiltrate (described as “a headlight in the fog”) adjacent to an old chorioretinal scar. A localized lobular perivasculitis may occur around arterioles in the area of the active lesion (called Kyrieleis plaques)[23]. Older pigmented lesions may be in clusters or strings. The congenital disease more often appears as a large, atrophic, chorioretinal scar. These scars are unfortunately often in the macula and have been described as a “macular coloboma.”[24] While there is current debate regarding the presentation and prevalence of acquired versus congenital TRC, it is thought that congenital toxoplasmosis is usually present in both eyes while acquired is usually unilateral[25]. In the immunocompromised patient, TRC may be of such severity to mimic acute retinal necrosis (ARN) with multiple coalescing peripheral lesions. When the lesion is adjacent to the optic nerve, a papillitis and neuroretinitis can be present. TRC associated sequelae of intra-ocular inflammation are ERM, persistent vitreous opacities, vitreous bands connecting to the optic nerve, cystoid macular edema, cataract, as well as anterior segment findings that include posterior synechiae, and uveitic glaucoma[26]. In those patients with congenital TRC, microphthalmia, nystagmus, strabismus, can be associated with ophthalmic findings.

Systemic Toxoplasmosis

In congenital toxoplasmosis cases, the mother may have been asymptomatic or have had mild mononucleosis-type symptoms.  In contrast, the newborn may present with prematurity, intrauterine growth restriction, jaundice, hepatosplenomegaly, myocarditis, pneumonitis, various rashes and neurologic findings that include chorioretinitis, hydrocephalus, intracranial calcifications, microcephaly, and seizures. Some of the neurological findings may only become apparent months to years later. The classic triad of neurological findings consists of chorioretinitis, hydrocephalus, and intracranial calcifications.

In immunocompetent patients (as in the case of pregnant mothers), acquired toxoplasmosis generally presents with mild systemic findings that are often not recognized. However, in immunocompromised patients, for example, those with AIDS or those on immunosuppressive therapy, necrotizing chorioretinitis may be so severe as to resemble acute retinal necrosis (necrotizing herpetic retinitis). Neuroimaging is essential in these patients because central nervous system toxoplasmosis has been reported in up to one-third of AIDS patients with retinal findings[27]. These patients require aggressive and often life-long suppressive therapy with pyrimethamine and sulfadiazine[28].

Evaluation

Optical Coherence Tomography (OCT) Scanning

OCT scanning helps detect complications such as an epiretinal membrane, cystoid macular edema, vitreoretinal traction, choroidal neovascularization, and serous retinal detachments. Active TRC displays a highly reflective signal that obscures the underlying choroid. The posterior hyaloid is usually thickened and detached over the lesion[24].

Fluorescein and Indocyanine Green Angiography

An active TRC lesion will be associated with early hyperfluorescence fluorescein angiography (FA) followed by progressive hyperfluorescence. Indocyanine green (ICG) is associated with early hypofluorescence as well. ICG can provide additional information in that it can image hypofluorescent satellite lesions that are not visible with either FA or during clinical examination. These hypofluorescent lesions are thought to be a noninfectious, inflammatory reaction. Acute choroidal ischemia may be visualized with ICG in conjunction with serous retinal detachment[29].

Ultrasonography

Ultrasonography is required when vitreous inflammation obscures a view of the fundus. Findings associated with TRC are punctiform echoes within the vitreous as well as thickening of the posterior hyaloid membrane. A partial or total posterior vitreous detachment and focal retinochoroidal thickening are commonly observed as well[30].

Vitreous or Aqueous Sample

Atypical cases may require either a vitreous or aqueous sample. Anti-Toxoplasma immunoglobulin G or A (IgG or IgA) antibodies may be detected in these samples. A ratio of 8:1 of anti-Toxoplasma antibody in the eye versus serum is consistent with active ocular toxoplasmosis[31].

Treatment / Management

Lesions that are away from the optic nerve or macula and less likely to affect vision are generally not treated. Treatment is usually initiated when a lesion is two disc diameters from the center of the fovea or one disk diameter away from the margins of the optic disc.

A recent meta-analysis of all studies that compared available treatments to observation found no significant difference in the visual outcome in immunocompetent patients with acute Toxoplasma retinochoroiditis (TRC). In patients with chronic relapsing TRC, treatment may reduce recurrences. Despite this, treatment is initiated in patients with lesions that are close to the optic nerve or macula combined with vision significantly restricted in the 20/70 range or worse. Initiation of treatment is never taken lightly as studies reveal that over one-fourth of patients experience an adverse reaction to the drugs commonly used in treatment. Treatment during pregnancy carries the additional consideration of the effect on the fetus.

Treatment of the Immunocompetent Patient with Acute TRC with Oral Medication[32][33].

While there is no consensus on what the best treatment for TRC might be, 3 agents have been used for over 50 years. This “classic therapy” consists of 4 to 8 weeks of oral pyrimethamine, sulfadiazine, and folinic acid combined with high-dose prednisone. Pyrimethamine by mouth twice per day loading dose of 50 mg is followed by 25 mg twice per day.  Sulfadiazine is given as a 2 g orally 4 times a day loading dose, followed by 1 g 4 times a day. Pyrimethamine and sulfadiazine interfere with folic acid metabolism. To avoid developing thrombocytopenia and leucopenia, 3 to 5 mg of oral folinic acid supplementation twice a week.  Sulfadiazine has a significant risk of hepatotoxicity and cannot be prescribed to patients with sulfa allergies. Prednisone can be prescribed at 40-60 mg orally for several weeks to 1 month followed by a taper based on the severity of inflammation.

Several other oral antibiotics including clindamycin (300 mg 4 times a day), spiramycin (1 to 4 g once daily), azithromycin (250 mg), trimethoprim-sulfamethoxazole (800/160 mg), and atovaquone (750 mg 4 times a day) have been tried in combination with a classic therapy or in other combinations. Of these, spiramycin was shown to clearly not be beneficial while clindamycin, trimethoprim-sulfamethoxazole, and atovaquone may be of benefit with a significantly reduced risk of adverse drug reactions[34].

Use of adjuvant steroids, while part of the classic triple therapy, has not definitively been shown to be beneficial and its use varies widely.  In one survey of uveitis specialists, 17% used oral corticosteroids in all immunocompetent patients with TRC. The rest of respondents used corticosteroids only in the presence of severe vitreous inflammatory reaction (71%), decreased vision (59%), the proximity of the lesions to the fovea or optic disc (35%), and for large lesions (5%). Prednisone was the corticosteroid used by 97% of respondents in varying doses and schedules. The most popular regimen for the treatment of TRC was a combination of pyrimethamine, sulfadiazine, and prednisone (29% of respondents). Prednisone is usually started 3 days after the start of antibiotic therapy. While animal studies show the benefit of adjuvant steroid use, several non-randomized studies failed to prove an improved visual outcome convincingly.

Treatment of the Immunocompetent Patient with Acute TRC with Intravitreous Medications.

Treatment with intra-ocular steroids alone is contra-indicated as it typically causes extensive retinitis.  Two clinical trials investigated intravitreous clindamycin (1mg) and dexamethasone (0.4 mg) one injection followed by additional injections every two weeks based on clinical course. These studies indicated that intravitreous injections are a reasonable alternative to classic therapy and could even be used as first-line treatment[35][36].

Treatments to Reduce the Rate of Recurrence of TRC.

Initial treatments in which barrier laser was applied surrounding Toxoplasma chorioretinal scars, did not result in a reduction of recurrence of TRC. Atovaquone and azithromycin treatment for 5 to 6 weeks did not reduce the rate of TRC either. However, long-term use of trimethoprim-sulfamethoxazole (800/160 mg) every 3 days for 20 months in patients with a history of recurrent TRC in one trial, as well as a treatment every other day for one year after a 45-day treatment of active TRC was shown to reduce the rate of recurrence of TRC significantly[37][38].

Treatment of the Immunocompromised Patient with Acute TRC.

Under 2% of patients with the human immunodeficiency virus are affected with TRC. Elderly patients with TRC are at risk of developing a more severe retinochoroiditis, likely due to an age-related reduction in cellular immunity. Local immunosuppression has been associated with TRC as well.  In severely immunocompromised patients, TRC can be much more severe and resemble acute retinal necrosis.  In patients with TRC and AIDS, neuroimaging is indicated because central nervous system (CNS) toxoplasmosis lesions have been reported in up to 29%. These patients are at life-long risk that the latent bradyzoite form of Toxoplasma converts to the active tachyzoite form. Treatment includes ongoing suppressive therapy with pyrimethamine and sulfadiazine[32].

Differential Diagnosis

A large number of infectious and inflammatory diseases that affect the posterior segment should be considered in patients with TRC. These conditions include tuberculosis, HIV retinitis, toxocariasis, sarcoidosis, syphilis, Cytomegalovirus retinitis, Candida endophthalmitis, multifocal choroiditis, serpiginous choroiditis, presumed ocular histoplasmosis, and acute retinal necrosis[39].

Prognosis

Reactivation of TRC from existing chorioretinal scars is more common in children and adolescents and becomes more likely within a few years from the initial infection, with a relatively rapid decline in the incidence of reactivations over the years. One study found a rate of TRC recurrence of about 50% over 3 and 80% over 5 years with an average lifetime recurrence of 2.7 episodes[40].

Deterrence and Patient Education

Areas frequented by cats, especially sand or dirt in gardens or playgrounds, as well as litter boxes, pose a significant risk and should be avoided. Routine cleaning of fruits and vegetables, as well as washing hands after contact with soil and cat litter boxes, is recommended. Toxoplasma cysts are killed at 60 degrees C for 15 minutes or by -20 degrees C for at least 24 hours, and food should be treated accordingly. Water contaminated with oocysts has become a generally accepted method of acquired toxoplasmosis in areas with inadequate water treatment as well[41][42].

Enhancing Healthcare Team Outcomes

TRC is a rare disorder and difficult to manage. It is best managed by an interprofessional team that includes an ophthalmologist, neurologist, infectious disease expert, internist, and specialty trained ophthalmology nurse. Patients who are immunosuppressed usually need long term treatment and follow up. The primary care provider and nurse practitioner should educate the patient on preventive measures such as avoiding areas frequented by cats, especially sand or dirt in gardens or playgrounds, as well as litter boxes. Patients with active disease should routinely clean fruits and vegetables, as well as wash hands after contact with soil and cat litter boxes. The prognosis of patients with TRC is guarded. [41][42].