Eye Spy With My Little Eye the Three T’s: Ocular Manifestations of Toxocara, Toxoplasma and Tuberculosis in Children

The management of pediatric eye infections can be highly challenging due to a range of clinical (often acute and rapidly deteriorating vision), diagnostic (inability to take appropriate samples from the infected eye) and treatment (limited data to support efficacy and potential toxicity) issues. In the management of infectious uveitis—especially toxocara, toxoplasma and tuberculosis (TB)—empiric treatment is often commenced without microbiological confirmation. These infections are rare in low-endemicity, high-income settings but can be catastrophic, with acute and rapidly deteriorating vision leading to irreversible vision loss. In addition, they may present with only pseudo-inflammatory features and microbiologic or supportive investigations may be negative due to the eye’s immune-privileged status. In this review, we provide up-to-date evidence on the epidemiology, diagnosis and management of ocular toxocara, toxoplasma and TB infection. EPIDEMIOLOGY Toxocara Toxocariasis is a prevalent zoonotic infection caused mostly by the nematodes Toxocara catis or T. canis, with approximately 1.4 billion people infected worldwide.1,2 Seroprevalence varies significantly globally (2%–80%), with lower rates in nontropical settings and higher rates in children.1,2 One study reported 13 cases of toxocara infection per year in the United Kingdom based on reference laboratory reports but the true incidence is unknown as infection is not notifiable and often asymptomatic.3 Risk factors for ocular toxocara include dog or cat contact or ownership (especially juveniles), soil exposure, ingestion of undercooked meat or untreated water and living in poverty.1,2 Age is a significant factor, with median onset at 11.5 years, though it is rarely seen in very young children.2 Toxoplasma Toxoplasma is caused by the protozoan Toxoplasma gondii, and approximately one-third of the global population is thought to be infected.4 Seroprevalence in the United Kingdom is 12%, with up to 90% cases being asymptomatic, and approximately 400 cases reported annually.4,5 Ocular manifestation is frequent in children with congenital infection; in contrast, only 2% of postnatally-acquired infections in a high-income setting were affected by eye disease.6 In the United Kingdom, less than 50 cases are reported annually.5 Risk factors for postnatal infection in high-income settings include ingestion of undercooked meat, contact with cat feces, contaminated soil or water and immunosuppression.7 Those affected early in life are at greater risk of reactivation linked to hormonal changes in childhood and adolescence.7 Tuberculosis Ocular TB (OTB) caused by Mycobacterium tuberculosis is thought to have a prevalence of 2%–10.5% globally, with an incidence in the United Kingdom estimated at 0.73/million/year, accounting for <1% of TB cases.8 It has been estimated that OTB accounts for 1%–4% of uveitis cases in low-endemicity areas,9 though 1 study found 10% of culture-confirmed TB cases had evidence of asymptomatic OTB when examined, suggesting the incidence may be much higher and likely driven by immune-mediated disease.10 Approximately 30% of OTB cases will have no risk factors or exposure history.11 PRESENTATION Ocular pediatric presentations in toxocara, toxoplasmosis and TB can present in otherwise well children with no overt features or risk factors. Presentation may be preceded by a period of latent infection with parasitic or mycobacterial dormancy, or due to harbored infection in the immune-privileged eye after systemic clearance. Given the more prevalent pseudo-inflammatory nature of these infections, presentation is typically due to painless visual changes, which children may report late, if at all. Other signs that prompt assessment include leukocoria, pain, posterior synechiae, photophobia, floaters or squint.1,12 Once reported, there are often suggestive ocular findings that can be diagnosed by an experienced ophthalmologist (Fig. 1).FIGURE 1.: Montage of common ocular phenotypes associated with infection. A: Pseudocolor retinal photograph of the left eye in ocular tuberculosis. This phenotype is called serpiginous-like chorioretinopathy and is the most common manifestation of ocular tuberculosis in the high-income and nonendemic setting. The most obvious abnormality are the white and yellow speckles in the upper part of the image and the central well-demarcated changes at the macula. The red arrow shows old areas of chorioretinitis, the white arrow shows a new area of inflammation. B: Pseudocolor retinal photograph of the right eye in punctate outer retinal toxoplasmosis. This is the most common manifestation of ocular toxoplasmosis in our high-income nonendemic setting outside of congenital ocular toxoplasmosis. The most obvious abnormality is the back and white area at the macular. The red arrow shows the old areas of chorioretinal scarring (classically pigmented in toxoplasmosis) and the white arrow shows a new area of recent activation. C: Pseudocolor retinal photograph of the right eye in ocular toxocariasis. The classical phenotype is a peripheral lesion that forms a tractional band stretching to the optic disc. The vessels can be seen to be “dragged” toward the lesion. The white arrow is the main active lesion and the red arrow is a smaller scarred lesion beneath the white area. This may represent an area of choroidal neovascularization. It is rare for ocular toxocara to present with multiple lesions in the eye.Toxocara Ocular toxocariasis is usually unilateral and mono-parasitic.1 It most commonly presents as a peripheral or posterior-pole granuloma seen as an elevated yellow-white mass which may be surrounded by signs of inflammation (indistinct border due to exudate and hemorrhages).1 Intraocular inflammation is rarely present but involvement of the macula, vitreous bands, retinal traction or neovascularization may lead to visual loss.1 Subretinal granulomatous mass is also highly suggestive of ocular toxocariasis. Other less common and less suggestive presentations include endophthalmitis, anterior uveitis and conjunctivitis.1 Toxoplasma Congenital toxoplasma typically presents bilaterally with circular retinochoroidal scarring involving the macular and posterior pole and is associated with visual impairment despite little active inflammation.7 Postnatal infection often presents with one discrete focus of retinal necrotizing granulomatous inflammation, most commonly at the posterior pole, with surrounding inflammation and vitritis.7 Optic nerve atrophy and retinal detachment can lead to complete vision loss. Tuberculosis Posterior and panuveitis are the most common presentations of OTB, with posterior accounting for half of pediatric cases.13,14 Highly suggestive presentations are tuberculoma, tubercular serpiginous-like choroiditis and peripheral occlusive retinal vasculitis.14 Tuberculoma presents as a large elevated choroidal mass that may be mistaken for a tumor. Tubercular subretinal abscess is a severe form of tuberculoma associated with necrosis. Smaller choroidal granulomas known as tubercular choroiditis may suggest OTB and are more frequently multifocal in immunocompromised.12 Tubercular serpiginous-like choroiditis spreads centrifugally with wave-like progression and central healing and accounts for two-thirds of choroiditis and 38% of OTB in children.13 Occlusive retinal vasculitis is associated with retinal hemorrhagic periphlebitis and neovascularization, and is much less commonly seen in children than adults.12 OTB may also present as granulomatous or non-granulomatous, anterior or intermediate uveitis with vitreous snowball opacities suggestive of granulomatous inflammation.12,14 DIAGNOSIS Despite characteristic ophthalmic features, diagnosis of these 3 infections can be very challenging. This is because of overlapping and subtle phenotypes, lack of associated systemic features or risk factors and atypical presentations in the immunocompromised. In low-endemicity settings, it is essential to rule out more common auto-inflammatory etiologies and mimics. In the systemically well child, with isolated disease, supportive testing may be negative due to ocular immune privilege, and therefore acquiring ocular samples, despite procedural risk, should be considered if safe. Testing should be done in reference laboratories due to the low sensitivity of assays typically available in smaller centers. Supportive Testing In ocular toxocara infection, serum Toxocara Excretion Secretion-enzyme-linked immunosorbent assay sensitivity ranges from 78% to 93% and specificity 92% to 100%.1,15 Increasing titers suggest active infection, and higher titers in aqueous or vitreous samples at a ratio of 3:1 compared with serum are considered diagnostic.1,16 Eosinophilia, isohemagglutinemia and hyperglobulinemia may be present. In ocular toxoplasma, aqueous or vitreous samples paired with serum for serology can help distinguish local infection. The Goldmann-Witmer coefficient calculates the ratio of specific to total IgG across samples with a sensitivity of up to 93% in immunocompetent and 57% in immunocompromised hosts.7,17 The Western blot may be more sensitive in early infection.18 Serum immunoglobulins alone may provide clues to timing, but do not distinguish current infection and may be false-negative if systemic infection has cleared.7,18 High avidity IgG suggests the infection is months old, even if IgM persists.18 Neuroimaging, and particularly an magnetic resonance imaging head with contrast, can identify brain cysts, which may inform the likelihood of developing seizures and reactivation in early adolescence. The interferon gamma release assay sensitivity in OTB ranges from 87.5% to 100% with the lowest rate reported in children.8,13,19 However, children generally present with fewer comorbidities and diagnostic confounders, and therefore interferon gamma release assay positivity may be of greater significance. Higher interferon gamma release assay responses may be associated with improved response to TB treatment.19 These tests are typically negative in low-endemicity settings and should be performed if OTB is suspected.20 Evaluation for pulmonary or extrapulmonary TB infection is helpful to support diagnosis and potentially provide a source for microbiological sampling. A chest radiograph should be conducted first line and high-resolution chest computed tomography considered.12,14 Positron emission tomography computed tomography may be helpful to guide sampling, especially in children where extrapulmonary TB is more common, for example, lymph node biopsy, which has a yield of up to 71%.8,13 Ophthalmic Imaging Fundus photography or ultra-wide field scanning laser ophthalmoscopy provide images of the retina to detect granulomas and retinal folds with indistinct borders suggesting active inflammation. Fundus fluorescein angiography is used to assess active inflammation, vasculitis, neovascularization and areas of nonperfusion.12 Fundus fluorescein angiography may show increased permeability in peripheral veins with leakage in ocular toxocara,21 hypofluorescence in active lesions suggesting atrophy in ocular toxoplasma,7 and occlusive vasculitis highly suggestive of OTB.12 Optical coherence tomography gives a slice of the retina and can identify discrete hyporeflective lesions, the extent of edema and atrophy.12 Ultrasound may be useful where there is significant opacification.21 Microbiologic and Molecular Sampling Acquiring samples from the eye for direct testing for culture, polymerase chain reaction (PCR) or metagenomics is associated with an inherent procedural risk. Metagenomics is an emerging tool, becoming a routine standard of care, but its utility in identifying ocular toxocara, toxoplasmosis or TB is not well-defined. Serologic testing remains gold standard for toxocara diagnosis, with culture and PCR not recommended. In ocular toxoplasma, PCR on ocular samples has poor sensitivity (36%), but is highly specific and can be used in combination with the Goldmann-Witmer coefficient and Western blot to improve sensitivity (up to 97%).7,17 Serum PCR is infrequently positive (4%–25%).17 In OTB in low-endemicity settings, few cases are confirmed microbiologically (5%) and even fewer from ocular samples (2%) due to the paucibacillary nature of the infection.22 PCR and Gene Xpert may be attempted on ocular fluids and though specificity is reported as high as 100%, sensitivity is variable with Gene Xpert and as low as 11%.23 If extra-ocular sites are amenable to biopsy, microbiologic testing should be attempted to exclude mimics, test for antimicrobial resistance and for epidemiologic analysis.12 TREATMENT Treatment of these rare but potentially devastating ocular infections is often commenced based on findings during ophthalmic assessment in the absence of any risk factors, exposures or positive microbiology. The decision to start treatment should be made in close collaboration between ophthalmology and pediatric infectious disease colleagues with careful and regular communication with the child and family. Toxocara Steroids are used to treat active inflammation, topical if anterior, otherwise systemic. Intravitreal dexamethasone implants are effective if systemic steroids are contraindicated.24 The role of anti-helminth treatment is more controversial with concerns regarding efficacy against dormant larvae and the risk of increased inflammation secondary to larval lysis, but potential for antiparasitic activity and reduction in recurrence.25 Albendazole penetrates the cerebrospinal fluid better than mebendazole and has been shown to have some effect, especially if given in conjunction with steroids.26 Laser photocoagulation is recommended if migrating larva are observed. In quiescent disease, the decision may be to monitor only. Unfortunately, 70% of cases present late, and therefore, visual loss may be irreversible.1 Toxoplasma In ocular toxoplasma, the purpose of treatment is to reduce complications and recurrence with most immunocompetent cases resolving without treatment in 4–8 weeks.7 Co-trimoxazole is recommended due to antiparasitic effect, good ocular penetration, tolerance profile and can be used as secondary prophylaxis to prevent disease recurrence.7 Azithromycin is a widely used second choice if toxicities prevent the use of co-trimoxazole. Clindamycin orally or via intravitreal injection with dexamethasone is an alternative, or in combination with co-trimoxazole to shorten the treatment course.7 Steroids may be given concurrently for inflammation, but not alone due to worse outcomes. Tuberculosis Recommendations for presumptive treatment exist from the Collaborative Ocular Tuberculosis Study consensus group and British Thoracic Society and are based on risk stratification due to ocular findings and supportive testing.12,27 Standard TB treatment, using quadruple (isoniazid, rifampicin, pyrazinamide and ethambutol) anti-TB therapy (ATT), is recommended with the possibility of replacing ethambutol with a quinolone (moxifloxacin or levofloxacin) if there are concerns regarding optic neuropathy.12 Minimum treatment length is 6 months, but longer courses of 9–12 months have shown greater efficacy and reduction in treatment failure.12,28 Immunosuppressive treatment is often used in children who typically have a more inflammatory phenotype.13 Some studies report increased treatment failure11,28 and therefore immunosuppression should only be used in selected cases, who should be followed up closely for signs of inflammation and paradoxical worsening after ATT initiation.12,27 When used, immunosuppression should be delayed until 2–4 weeks after the initiation of ATT, unless the paramacular region or optic nerve is involved.12 If sight is threatened, immunosuppression may be started before ATT.12 Immunosuppression may be local, intravitreal or with systemic steroids depending on the region affected; anti-TNF-alpha treatment may also play a role, but has to be used very cautiously.28 Vitrectomy has been used with similar success rates.29 Overall treatment success is high (up to 95% in children) with vision improvement in 65%–75% of cases.13,28 Permanent blindness affects 3.7% with moderate vision loss in 15%.30 Late referral, panuveitis, macula edema and vitreous haze predict worse outcomes.12 CONCLUSIONS Ocular infections in children—whether toxocara, toxoplasmosis or TB—highlight the interface between pediatric infectious diseases and ophthalmology. These conditions are rare in high-income countries, but potentially devastating. They exemplify the challenges of paucibacillary disease, immune privilege, diagnostic uncertainty and reliance on indirect evidence. For pediatric ID clinicians, the key lessons are: 1. If ophthalmic manifestations are convincing, it may be necessary to treat without a microbiological diagnosis. 2. Work in partnership with ophthalmologists. Timely recognition and treatment are essential to preserve vision. The only metric for treatment success or failure may be ophthalmic imaging. 3. If possible, joint clinics are helpful for both patients/parents and physicians. Ultimately, these infections are reminders that the eye is not an isolated organ but part of the systemic infectious disease landscape. Collaborative care ensures that children not only survive, but retain the vision that allows them to thrive.