Ocular toxoplasmosis is a retinochoroiditis caused by infection of the retina with Toxoplasma gondii, an obligate intracellular protozoan. It is the most common cause of infectious uveitis and accounts for more than 50% of all posterior uveitis in some countries7).
T. gondii is a zoonotic infection with felids as definitive hosts and almost all mammals, including humans, as intermediate hosts. Infection occurs through oral ingestion of oocysts excreted in cat feces contaminating soil or water, or by ingestion of tissue cysts in undercooked meat (e.g., pork, lamb, venison). Approximately one-third of the world’s population is infected7), and the seroprevalence in Japanese adults is 20–30%. Ocular toxoplasmosis accounts for about 1% of infectious uveitis cases8).
The protozoan has three morphological forms:
Oocyst: A soil form excreted in cat feces
Tachyzoite: Rapidly multiplying form during active infection
Tissue cyst: Slow-growing form (bradyzoite) that remains dormant in the retina
The proportion of eye diseases caused by ocular toxoplasmosis is estimated at about 2% in the United States, 18% in Brazil, and up to 43% in Africa. Infection rates are highest in tropical regions, reflecting the warm, humid environment favorable for parasite growth.
The population structure of T. gondii is highly clonal, with three main lineages (types I, II, and III) predominant in North America and Europe7). Type II accounts for the majority of acquired ocular disease, while type I is more common in congenital toxoplasmosis. In Brazil, type I and atypical types are involved in acquired infections, and genetic differences may contribute to the diversity of clinical presentations7).
QWhat is the difference between congenital and acquired infection?
A
Congenital infection occurs when the mother is first infected during pregnancy and the parasite is transmitted to the fetus through the placenta, typically resulting in bilateral macular scar lesions. The rate of placental transmission increases during the second and third trimesters, but disease severity tends to be higher with infection in early pregnancy. Acquired infection occurs after birth through ingestion of contaminated food or water, presenting as focal chorioretinitis without old scars in the peripheral fundus. See the “Pathophysiology” section for details.
Fundus photograph of ocular toxoplasmosis. Pigmented chorioretinal scar and satellite lesions near the macula
Miyagaki M, et al. Ocular Toxoplasmosis: Advances in Toxoplasma gondii Biology, Clinical Manifestations, Diagnostics, and Therapy. Pathogens. 2024. Figure 2. PMCID: PMC11509995. License: CC BY.
A chorioretinal scar with pigmentation in the posterior pole of the fundus, with small satellite lesions nearby. This shows typical chorioretinal lesions seen in ocular toxoplasmosis and is suitable for explaining clinical findings.
The clinical findings of ocular toxoplasmosis are broadly divided into typical and atypical findings.
Typical Findings
“Headlight in the fog”: White focal retinitis with vitritis. This finding strongly suggests the disease.
Retinochoroidal scar: Old scar with pigmentation. Recurrent lesions tend to appear at the edge of this scar.
Vitritis: Ranges from mild to severe.
Retinal vasculitis: Seen in vessels near the lesion. Segmental arteritis with Kyrieleis plaques may also be observed.
Anterior uveitis: Secondary non-granulomatous iridocyclitis. Granulomatous and stellate keratic precipitates may also be present.
Atypical Findings
Papillitis / Neuroretinitis: Swelling of the optic disc. May be accompanied by a macular star.
Punctate outer retinitis (PORT): Multiple small lesions in the deep retina. OCT may show huge outer retinal cysts (HORC) 2).
Retinal vascular occlusion: May cause branch artery occlusion or frosted branch angiitis.
Scleritis / Retinal detachment: Complicated in severe cases.
Multifocal diffuse necrotizing retinitis: May present with severe bilateral lesions in immunocompromised patients 7).
In congenital infection, scarred lesions (with a mixture of gray-white fibrous proliferative tissue and dark brown pigmentation in the center, surrounded by a depigmented halo) are seen as main lesions in both maculae. Small pigmented scars called daughter lesions may be present nearby. It is accompanied by anterior chamber inflammation and severe vitreous opacity (“headlight in the fog”), and unlike acquired infection, it is bilateral. Recurrent lesions do not occur simultaneously in both eyes. In acquired infection, localized white to gray-white exudative retinochoroiditis without old scars in the peripheral fundus is observed, accompanied by severe vitreous opacity and retinal vasculitis. With healing, it becomes a well-defined atrophic scar with pigmentation.
Lesions around the optic disc are called Edmund-Jensen juxtapapillary retinochoroiditis. On fluorescein angiography, early phase shows tissue staining around the lesion and a central filling defect, with progressive staining of the defect over time, and marked leakage in the late phase.
In atypical cases, differentiation from acute retinal necrosis (ARN) or intraocular lymphoma can be difficult 5). In a Dutch cohort, 4 of 18 large lesions exceeding 3 disc diameters were initially diagnosed as acute retinal necrosis5).
The main routes of T. gondii infection are as follows:
Oral infection: Ingestion of tissue cysts in undercooked meat (pork, lamb, venison, etc.). Oral ingestion of oocysts from contaminated water or vegetables may also occur.
Infection from felines: Contact with oocysts shed in cat feces.
Transplacental infection: Transmission to the fetus during primary maternal infection in pregnancy. Infection rate is low but disease severity is high in early pregnancy; the rate of placental transmission increases as pregnancy progresses.
Main risk factors are as follows:
Consumption of undercooked meat: Game meat (venison) is particularly high risk. In one case series, systemic symptoms appeared within 1–2 weeks and ocular symptoms at an average of 2.6 months after ingestion of undercooked venison 4).
Contact with cats: Owning three or more cats or kittens.
Immunocompromised state: AIDS, hematologic malignancies, use of immunosuppressive drugs. In CLL patients, it has been reported as an opportunistic infection during ibrutinib use 3).
Elderly: Tendency for higher frequency of ocular lesions due to acquired infection 7).
Kohler et al. (2023) reported four cases of primary infection associated with venison consumption. All were men, mean age 56 years, exposed during the hunting season (October–November), with a clear temporal sequence: systemic symptoms within a few weeks, ocular symptoms 1–3 months later 4).
QIf infected during pregnancy, will the fetus always be affected?
A
Even if primary infection occurs in the mother, it does not always lead to fetal infection; most cases remain subclinical. However, some cases result in severe ocular and neurological symptoms (the tetrad of retinochoroiditis, hydrocephalus, intracranial calcification, and motor nerve disorders) as congenital toxoplasmosis, so antibody screening and early treatment in pregnant women are important.
The diagnosis of ocular toxoplasmosis is primarily based on clinical findings. The combination of a “headlight in the fog” appearance and pigmented retinochoroidal scars is typical, and clinical diagnosis is often possible. The presence of both clinical findings and positive anti-Toxoplasma antibodies strongly supports the diagnosis 8).
If negative, infection can be ruled out. Positivity rate increases with age.
IgM antibody
Suggests recent infection
May remain elevated for over a year. Does not increase during recurrence of congenital infection.
IgG avidity
Estimates whether infection is recent or past
High avidity suggests chronic infection5)
In immunocompetent individuals, if IgG antibody is completely negative, toxoplasmosis can be almost ruled out. However, in immunocompromised patients, active infection is possible even if antibodies are negative3). In CLL patients with hypogammaglobulinemia, attention should be paid to false negatives3).
In acquired infection, serum IgM antibody titers rise and later decrease, which has diagnostic value. IgG antibody titers also rise, but since subclinical infections are common, high antibody titers do not necessarily indicate toxoplasmic chorioretinitis. During recurrence of congenital infection, IgM antibody titers do not increase.
PCR testing of aqueous humor or vitreous fluid is useful in atypical or diagnostically difficult cases.
Sensitivity: approximately 64% for aqueous humor PCR1), 27–75% for vitreous PCR5)
Specificity: 100%5)
In immunocompromised patients, sensitivity increases to 75%3)
The ratio of toxoplasma antibody titer to IgG level in intraocular fluid (Goldmann-Witmer coefficient: Q value) is also useful, with reported sensitivity of 29–81% and specificity of 83–100%5). When combined with immunoblotting, the three methods together achieve sensitivity of 85–97% and specificity of 93%5).
Shakha et al. (2024) reported a 33-year-old man with atypical multifocal retinitis in whom T. gondii was detected by aqueous humor PCR, leading to a definitive diagnosis. The case worsened after sub-Tenon steroid injection, highlighting the danger of depot steroid administration before definitive diagnosis1).
The Standardized Uveitis Nomenclature (SUN) working group published classification criteria for toxoplasmic retinitis in 2021 9). In addition to focal or few necrotizing retinitis, the criteria require either a positive PCR or IgM, or characteristic clinical findings (pigmented scar, round to oval retinitis, recurrent acute course). This criteria, integrating clinical and laboratory findings, is useful for case identification in multicenter studies and clinical trials.
Differential diagnoses requiring special attention: CMV retinitis in immunocompromised patients, acute retinal necrosis, intraocular lymphoma 3)5)
QDoes a positive blood test always indicate ocular toxoplasmosis?
A
A positive IgG antibody only indicates past infection and does not necessarily mean ocular involvement. Since subclinical infection is common, a comprehensive assessment with clinical findings is essential for diagnosing ocular toxoplasmosis. The Uveitis Clinical Practice Guidelines also state that the combination of clinical findings and antibody positivity strongly supports the diagnosis 8).
Not all lesions require treatment. Mild inflammation confined to the peripheral retina tends to heal spontaneously. Treatment is indicated in the following cases:
Lesions threatening the macula, optic disc, or papillomacular bundle
Lesions adjacent to major retinal vessels
Severe vitreous opacity
Significant visual impairment, large lesions (≥1/2 disc diameter)
Immunocompromised state, pregnancy, monocular status
Acetylspiramycin (0.8–1.2 g/day, divided into 3–4 doses) is administered for at least 30 days. It may be continued for 2–3 months until active inflammation resolves. Treatment is discontinued when exudative lesions become scarred and toxoplasma antibody titers decrease.
If vitreous inflammation is severe, oral corticosteroids (starting with prednisone 20–30 mg/day) are used in combination, but it is preferable to wait a few days after starting antimicrobial therapy before adding corticosteroids 8). Combining oral corticosteroids at 0.5 mg/kg/day accelerates improvement in ocular findings. For posterior pole lesions or recurrent foci larger than half a disc diameter, combination therapy with anti-toxoplasma drugs and corticosteroids is necessary.
Clindamycin 1.2 g/day in 4 divided doses for 4–6 weeks as one course is also an option.
The classic treatment is triple therapy with pyrimethamine + sulfadiazine + corticosteroids, and 32% of respondents in a survey by the American Uveitis Society chose it as first-line treatment. Since pyrimethamine is a folate antagonist, folinate (leucovorin) is co-administered to prevent bone marrow suppression. It is usually given for 4–6 weeks.
TMP-SMX (160/800 mg) twice daily is a safe and effective alternative to pyrimethamine + sulfadiazine 7). It has fewer side effects and is readily available.
Kohler et al. (2023) treated all 4 cases of primary infection with TMP-SMZ alone and achieved rapid improvement of retinal lesions. However, at least 3 months of continuous administration was necessary to prevent recurrence of systemic symptoms 4).
Intravitreal injection of clindamycin 1 mg + dexamethasone 0.4 mg shows efficacy comparable to systemic administration, with a recurrence rate of 6–15% after 2 years 5). It is indicated for patients in whom systemic therapy is contraindicated 7). Side effects are almost absent, and the time to resolution is approximately 2.5 ± 1 weeks 5).
Azithromycin 500 mg initially, then 250 mg/day, shows efficacy equivalent to TMP-SMX 5). It can replace sulfadiazine when combined with pyrimethamine, and the frequency of side effects is low 7).
Syed Mohd Khomsah et al. (2023) treated a 35-year-old woman with bilateral ocular toxoplasmosis with azithromycin 500 mg/day and tapering prednisolone for 6 weeks. Vitreitis and optic disc swelling resolved in 4 weeks, but right eye visual acuity was poor due to fibrosis of the papillomacular bundle and macular pucker6).
Atovaquone 750 mg four times daily is used in patients intolerant to first-line agents 5). Response is obtained within 1–3 weeks of starting treatment, and serious adverse effects are reportedly rare.
A prospective randomized trial showed that long-term administration of TMP-SMX (160/800 mg) three times weekly reduced the recurrence rate from 23.8% to 6.6% 7). In another randomized trial, one tablet every other day for 311 days resulted in a recurrence rate of 1.4% at 6 years (placebo group 27.5%) 5).
Toxoplasma infection itself is not an indication for surgery, but vitrectomy is performed for complications such as retinal detachment, epiretinal membrane (ERM), and vitreous hemorrhage5).
In the case series by Kohler et al. (2023), complications occurred in 2 of 4 patients with primary infection: ERM with cystoid macular edema and vitreoretinal traction due to regressed neovascularization4). In the ERM case, visual acuity improved after vitrectomy and membrane peeling.
QShould all recurrences be treated?
A
Small lesions confined to the peripheral retina may heal spontaneously. However, because the number of intraretinal cysts increases with each recurrence, some believe that all recurrences should be treated with antibiotics to minimize future recurrence risk. Treatment is necessary for posterior pole lesions or when visual acuity is affected.
T. gondii primarily infects the retina and can also involve the choroid, vitreous, and anterior chamber7). Choroidal lesions occur secondary to retinal infection and do not appear alone.
Oocysts or tissue cysts ingested orally transform into tachyzoites in the intestine and are disseminated throughout the body via the bloodstream. Proposed routes of reaching the retina include transport by leukocytes and direct passage of tachyzoites through the vascular endothelium 6).
Tachyzoites infect various retinal cells, with Müller glial cells being the most susceptible host cells 6). Infection of the retinal pigment epithelium (RPE) leads to abnormal growth factor production, promoting proliferation of adjacent uninfected RPE cells. This mechanism is thought to contribute to the formation of characteristic pigmented scars.
In necrotizing retinitis, vasculitis and retinal destruction progress. Histologically, extensive granulomatous inflammatory infiltration with necrosis of Bruch’s membrane is observed 7). Scarring progresses from the periphery toward the center, and the degree of pigmentation varies among cases.
Even when transplacental infection occurs, disease onset is rare, and most cases remain subclinical. The main symptoms of congenital toxoplasmosis are the tetrad of retinochoroiditis, hydrocephalus (or microcephaly), intracranial calcification, and psychomotor impairment. Approximately 70% of infants with intrauterine infection have choroidal scar lesions (centered on the macula), of which 1–2% develop severe visual impairment. Recurrence is most common around adolescence, occurring in about one-third of scar lesions.
In an evaluation of 430 patients treated for congenital toxoplasmosis, ocular lesions were found in 30% over a median follow-up of 12 years 7). However, severe bilateral visual impairment occurred in only 2 of 130 cases, and overall functional prognosis was better than predicted in the literature 7).
The cause of recurrence is not fully understood, but rupture of dormant cysts in the retina7) or involvement of circulating toxoplasma in peripheral blood is suspected. Drug-resistant cysts persist in atrophic scarred lesions even after treatment, and recurrence may be triggered by decreased immunity or pregnancy. The risk of recurrence is highest within the first year after the initial episode. The recurrence rate for congenital infection is reported to be approximately 5–30%.
Pidro Miokovic et al. (2024) reported a case of ocular toxoplasmosis in a 16-year-old female with a huge outer retinal cyst-like change (HORC) 2). HORC is a rare finding seen in only 2.5% of all ocular toxoplasmosis cases and is located between the external limiting membrane and the inner border of the RPE. Two weeks after treatment, the HORC resolved and visual acuity improved from 0.5 to 1.0.
Immunocompromised patients often present with atypical clinical features, leading to delayed diagnosis. Since conventional serological tests can yield false-negative results, the role of PCR testing becomes even more important.
Yazdanpanah et al. (2021) reported a case of a 74-year-old woman with CLL in whom ocular toxoplasmosis was difficult to differentiate from intraocular lymphoma 3). Flow cytometry and cytology of vitreous fluid ruled out lymphoma, and PCR using ITS-specific primers detected over 5 million copies of T. gondii DNA. There have also been reports of Toxoplasma DNA detected from intraocular lymphoma cells, suggesting a possible association between the two 3).
Dillon et al. (2022) reported two cases presenting with extensive multifocal retinal lesions 5). Case 1 was hospitalized with a clinical diagnosis of acute retinal necrosis, but vitreous PCR tested positive for Toxoplasma. Case 2 underwent chorioretinal biopsy to differentiate from intraocular lymphoma, and immunohistochemistry revealed numerous tachyzoites. Both cases had large, multifocal lesions exceeding 3 disc diameters in size, markedly different from the typical single lesion of 1–2 disc diameters.
Epidemiology of Primary Infection and Venison Consumption
In Minnesota, USA, the seroprevalence of T. gondii in white-tailed deer reaches 22.5–32.2%, and is even higher in neighboring states 4). A pattern has been reported where ocular symptoms appear in winter after consumption of undercooked venison during the hunting season (autumn) 4). Safe cooking of venison is recommended by heating to an internal temperature of at least 64°C or prior cold storage.
Shakha, Chawla R, Sinha A, Meena S. Atypical acquired toxoplasmosis. Indian J Ophthalmol. 2024;72:772-774.
Pidro Miokovic A, Ratkovic M, Pidro Gadzo A. Toxoplasmosis in the outer retina. Rom J Ophthalmol. 2024;68(2):198-201.
Yazdanpanah O, Monday LM, Surapaneni S, Singh V, Chi J. Ocular toxoplasmosis mimicking lymphoma: exploring the correlation and distinction. Cureus. 2021;13(1):e13014.
Kohler JM, Mammo DA, Bennett SR, Davies JB. Primary ocular toxoplasmosis secondary to venison consumption. Am J Ophthalmol Case Rep. 2023;29:101776.
Dillon AB, Budoff G, McCannel CA, Tsui E, Pullarkat ST, Schwartz SD. Ocular toxoplasmosis: no stranger to the masquerade ball. J Vitreoret Dis. 2022;6(5):391-398.
Syed Mohd Khomsah SN, Muhammed J, Wan Hitam WH. Macular pucker: a devastating complication in ocular toxoplasmosis. Cureus. 2023;15(2):e34617.
Commodaro AG, Belfort RN, Rizzo LV, Muccioli C, Silveira C, Burnier MN Jr, Belfort R Jr. Ocular toxoplasmosis: an update and review of the literature. Mem Inst Oswaldo Cruz. 2009;104(2):345-350.
