Dengyi Zhou

Introduction

Ocular Toxoplasmosis (OT), caused by the parasite Toxoplasma gondii, is considered the most common cause of infectious posterior uveitis (1,2). The infection can affect both congenital and postnatally infected individuals (3). Understanding the pathophysiology, clinical presentation, diagnosis, and management of this condition is essential as it can lead to severe visual impairment if left untreated (4).

Epidemiology

There is large seroprevalence variation, from 10-80% between different countries and even within countries (4). Countries and geographic areas reporting very high seroprevalence of greater than 60% include Brazil, Gabon, Madagascar and South East Asia. High seroprevalence between 40-50% has been reported for large parts of Central and Southern Europe, as well as some African and South American countries (5). The UK has a fairly low seroprevalence of less than 10%, similar to China, Japan, Thailand and Pakistan. The prevalence of OT follows the same distribution and T.gondii accounts for the majority (20-60%) of cases presenting with posterior uveitis (5).

Pathophysiology

T. gondii exists in three forms: tachyzoites, bradyzoites, and oocysts (6). Transmission occurs through ingestion of oocysts (from contaminated sources like cat faeces, soil or water) or tissue cysts (commonly from undercooked meat), or via transplacental transmission in congenital cases (6,7). Following ingestion, T. gondii enters the bloodstream and is transported to various organs, including the eyes, via dendritic cells, monocytes, and macrophages, which act as “Trojan horses” (8). The immune system forms tissue cysts (bradyzoites), leading to a chronic infection state where the host is often asymptomatic (6).

OT can arise after congenital or acquired infection as a result of acute infection or reactivation (9). Immunosuppression of the host as seen in patients with AIDS and after transplantation may lead to the reactivation of latent infection by rupture of tissue cysts and uncontrolled release of bradyzoites, which differentiates into its infectious form: tachyzoites (10,11). The parasite’s interaction with the immune system, particularly T-helper cells and cytokines like IFN-γ and IL-17, results in significant inflammation, contributing to tissue damage and vision loss (4,12).

Clinical Presentation

OT typically presents unilaterally in immunocompetent individuals (13). Common symptoms include blurred vision, reduced visual acuity, floaters, photophobia, pain or ocular redness (14). The hallmark of OT is a fluffy white necrotising retinochoroiditis lesion adjacent to a pigmented scar (13). The classic “headlight in the fog” sign refers to the white lesion seen through the hazy vitreous during fundoscopic examination (13). Immunocompromised individuals may experience more severe, bilateral disease with multiple retinal lesions, and congenital cases tend to present with bilateral disease, increasing the likelihood of blindness (15).

Diagnosis

Diagnosis is largely based on clinical examination with fundoscopic findings being the “gold standard.” However, in ambiguous cases, laboratory tests are used to confirm the presence of T. gondii (4).

Serological Studies

IgM and IgG levels help determine the stage of infection. IgM indicates a recent infection, while IgG persists for life, pointing to chronic infection. Avidity testing of IgG can distinguish between acute and older infections (5).

Intraocular Fluid Analysis

For more definitive diagnosis, especially in immunocompromised patients or atypical cases, intraocular fluid analysis is used (4). Real-time polymerase chain reaction (PCR) amplification of the 35-fold repetitive B1 gene and/or 300-fold repetitive AF146527 gene are used to detect T.gondii DNA in intraocular fluid (16). The Goldmann-Witmer coefficient measures intraocular antibody production, and immunoblotting can further improve diagnostic accuracy, particularly when both IgG and IgA are tested (17). Combining PCR, GWC, and immunoblotting increases sensitivity up to 97% (18). However, limited aqueous sample volumes require prioritisation of tests.

Differential Diagnosis

For uncertain cases, exclusion of other differential diagnoses which share clinical features with OT is important by using PCR or analysis of intraocular antibody synthesis. The most important differential diagnosis of ocular toxoplasmosis is summarised in table 1 (19,20).

	Differential Diagnosis	Overlapping clinical findings
Bacterial	Tuberculosis	Chorioretinal scars, vitritis, vasculitis mainly involving veins and granulomatous anterior uveitis.
	Syphilis	Chorioretinitis, vitritis, vasculitis, serious retinal detachment, papillitis and neuroretinits.
	Endogenous endophthalmitis	Whitish lesions present primarily in choroid going on to involve retina and vitreous body.
Viral	Acute retinal necrosis (Herpes-simplex-Virus)	Rapidly progressing necrotising retinitis initially in peripheral retina with severe intraocular inflammation and occlusive retinal vasculopathy often with anterior segment involvement.
	Cytomegalovirus retinitis	Granular form with multiple lesions may resemble punctate outer retinal toxoplasmosis, whereas oedematous form with larger areas of retinal necrosis and haemorrhage may resemble severe necrotising retinochoroiditis.
Parasitic	Diffuse unilateral subacute neuroretinits	Multifocal grey-white retinal lesions of deep retina or retinal pigment epithelium with mild-to-moderate vitritis which may look like punctate outer retinal toxoplasmosis.
	Ocular toxocariasis	Posterior pole granuloma or peripheral granuloma presenting as focal whitish lesions.
Fungal	Presumed ocular histoplasmosis syndrome	Multiple small atrophic scars present in choroid (‘Histo-Spots’) and choroidal neovascularisation.
Non-infectious	Punctate inner choroidopathy	Multiple small whitish lesions of choroid or retinal pigment epithelium sometimes causing serous retinal detachment.
	Sarcoidosis	Granulomatous anterior, intermediate, posterior or panuveitis. Bilateral retinal lesions with choroidal inflammation.
	Multifocal choroiditis	Multiple peripheral choroidal lesions with vitreal Involvement and chorioretinal scarring.
	Multiple evanescent white dot syndrome	Multiple punctate deep retinal lesions which may resemble punctate outer retinal toxoplasmosis.
	Unilateral acute idiopathic maculopathy	Serous retinal detachment and grey-white lesions of retinal pigment epithelium similar to punctate outer retinal toxoplasmosis.

Treatment

OT is often self-limited in immunocompetent individuals, resolving without intervention in 4-8 weeks (13). Due to this benign natural history, the risk of potential toxicity from anti-parasitic medication may outweigh any benefit gained, so clinicians do not tend to treat small peripheral lesions (13). Treatment is recommended in patients with lesions within vascular arcades, adjacent to the optic disc, larger than 2 optic disk diameters and/or vitreous haze above grade 1+ to reduce loss of vision (21). Active lesions do not tend to heal in immunocompromised patients without treatment, so immediate treatment is required (21).

Classic Triple Therapy

The mainstay of OT treatment includes a combination of pyrimethamine, sulfadiazine, and corticosteroids. This “triple drug therapy” remains widely used and targets parasite replication while controlling inflammation (5).

Alternative Therapies

Newer antibiotics such as of trimethoprim-sulfamethoxazole and azithromycin have been shown to be as effective as classic therapy but with fewer side effects (5). Intravitreal clindamycin combined with corticosteroids offers a promising alternative, delivering high drug concentrations directly into the eye while reducing systemic toxicity (22).

Prophylaxis

For recurrent OT, studies support the use of trimethoprim-sulfamethoxazole to reduce the likelihood of recurrence, especially in high-risk patients. Prophylaxis has been shown to significantly lower recurrence rates (23,24).

Indication	Antibiotic	Mechanism of Action
Ocular Toxoplasmosis (OT)	Pyrimethaminesulfadiazine	Sequential blockade of two steps of folic acid synthesis
	Trimethoprimsulfamethoxazole	Blocks two steps in bacterial folate synthesis
	Intravitreal Clindamycin	Inhibits bacterial protein synthesis by binding to 50s ribosomal subunit
	Azithromycin	Inhibits bacterial protein synthesis by binding to 50s ribosomal subunit
Prophylaxis of recurrence of OT	Trimethoprimsulfamethoxazole	Blocks two steps in bacterial folate synthesis

Complications and Prognosis

The complications of OT include isolated retinal tear, cataract formation, retinal detachment (usually rhegmatogenous and/or tractional), macular oedema, vitreous haemorrhage, secondary glaucoma, choroidal neovascularisation and optic atrophy secondary to optic nerve involvement (13,26).

While OT often resolves with treatment, around 35% of patients develop visual impairment and 20% become legally blind with the most common causes being macular involvement and retinal detachment (26,27). Recurrence is common, with rates ranging between 40-58%, often occurring soon after an initial episode (26).

Conclusion

Ocular toxoplasmosis is a significant cause of vision loss worldwide. Its management relies on prompt diagnosis based on clinical signs, supported by serological and intraocular fluid analyses when necessary. While the standard treatment involves classic triple therapy, alternative options such as trimethoprim-sulfamethoxazole and intravitreal antibiotics offer promising outcomes with fewer side effects. Prophylactic treatments can prevent recurrence, offering hope for improved long-term outcomes.

References

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