Asymmetric eye size in an infant

Abstract

Toxoplasmosis is an uncommon congenital infection in Canada, but one with potentially severe clinical manifestations, including fetal death. Neurologic and ocular manifestations are frequent in untreated disease; however, small eye size (microphthalmia) is a rare finding. This finding may be a marker of severe ocular disease. As universal screening does not occur in Canada, clinicians’ early recognition is imperative, particularly given the lack of risk factors in many patients and the benefit that treatment may have even in initially asymptomatic disease. Here, we report a case of congenital toxoplasmosis and review the diagnostics and treatment of the infection.

Case Presentation

A healthy 3-month-old male was referred by his family physician to Ophthalmology for assessment after his parents detected asymmetric eye size and sluggish left eye movement. The ophthalmologist confirmed asymmetric cornea size, and dilated examination showed an indolent scar on the left fovea, suggestive of toxoplasmosis. A plan was made for follow-up for visual acuity monitoring. Two days later, however, the parents brought the boy to the emergency department for expedited assessment due to concerns of increasing head size.

On presentation, the infant had normal vital signs. By report, he looked well. His head circumference measured 43.8 cm (>97th percentile), his weight was 8.5 kg (>97th percentile), and his length was 66.5 cm (>97th percentile). For comparison, his prenatal ultrasound at 19 weeks was normal, including head circumference and brain assessment, and birth measurements at 38 weeks 6 days were head circumference 34.5 cm (50th percentile), weight 3.6 kg (50th–75th percentile), and length was 51 cm (75th percentile).

Investigations revealed a mild thrombocytosis at 441 × 10⁹/L (normal 150–400) and elevated alkaline phosphatase of 457 U/L (normal 40–390 U/L) but otherwise, hematology, electrolytes, and liver enzymes were within normal limits.

As the infant’s growth parameters were all equally greater than the 97th percentile, this may not have raised concern in isolation. However, for the average term infant, the head circumference is typically 34–35 cm at birth, 44 cm at 6 months of age, and 47 cm at 1 year of age (1). While we are unable to confirm, it is believed that computed tomography (CT) of the head was pursued due to the degree of increase in head circumference from birth within the context of concern raised by the abnormal ophthalmologic findings (including sluggish eye movement). The CT demonstrated severe ventriculomegaly, periventricular calcifications, and areas of white matter hypodensity—features that were all consistent with congenital toxoplasmosis. Magnetic resonance imaging (MRI) confirmed this severe obstructive hydrocephalus from cerebral aqueduct stenosis (Figure 1). Ultrasound of the abdomen demonstrated no hepatic/splenic lesions.

Figure 1:

MRI (brain) and CT (head). (a) T2 axial, and (b) T1 sagittal images showing severe obstructive hydrocephalus with aqueduct stenosis and areas of white matter and cortical injury. (c) An axial CT shows ventriculomegaly with periventricular calcifications and white matter hypoattenuation

MRI = magnetic resonance imaging; CT = computed tomography

Subsequent infectious workup demonstrated negative cytomegalovirus IgM/IgG serology and negative toxoplasma polymerase chain reaction (PCR) results on blood and urine, although cerebrospinal fluid (CSF) was not collected at the preference of the attending team. Toxoplasma serology was positive for IgA and IgG antibody, but non-reactive for IgM antibody, compatible with recent infection.

As prior maternal Toxoplasma screening had not been performed, Toxoplasma serology was retrospectively performed on the prenatal samples. The findings demonstrated a negative IgM/IgG/IgA antibody at 8 weeks gestation seroconverting to positive IgM/IgG/IgA by the time of delivery (~39 weeks gestational age).

The pregnancy was uncomplicated with a low risk of exposure to Toxoplasma gondii. Routine prenatal serologies (syphilis, rubella, HIV, hepatitis B, and varicella zoster) were not significant. The family lived in an urban home, drank municipal water, and had no exposure to pets, including cats. In the first month of pregnancy, they visited the United Kingdom; this included a visit to a petting zoo, although the mother recalls thoroughly washing her hands. At approximately 16 weeks gestation, the family travelled to Hawaii and stayed in a vacation home without any recalled exposure to environmental or dietary risk factors. During the pregnancy, the mother recalled gardening occasionally, but always wore gloves and washed her hands thoroughly afterward. She did not recall eating uncooked meat, although 2 months prior to estimated conception, she had ingested uncooked oysters.

Following the above presentation, and supported by serologic results, the infant was diagnosed with congenital toxoplasmosis and was started on pyrimethamine 2 mg/kg/day divided twice a day for 2 days, then 1 mg/kg daily, sulfadiazine 100 mg/kg/day divided twice a day, and folinic acid 10 mg three times weekly. Glucose-6-phosphate dehydrogenase (G6PD) deficiency screen was negative, and hearing assessment was normal. Four months after treatment initiation, the infant is tolerating the medication and has stable hydrocephalus.

Discussion

Toxoplasma gondii, an obligate protozoan parasite, is the etiologic agent of toxoplasmosis. The definitive host is the cat, but several potential intermediate animal hosts exist. Cats acquire the protozoon through ingesting infected animals or soil contaminated with oocysts, and then shed millions of cysts for 1–2 weeks, contaminating their surroundings. Despite this association, cat ownership is not reliably correlated with infection risk (2,3). In one report, under half of the mothers with children diagnosed with congenital toxoplasmosis had any recognized risk factors (3). This finding introduces significant challenges in developing strategies for preventing infection acquisition or in knowing which targeted populations may benefit from screening.

The protozoon is distributed globally as one of the most common parasitic infections. It has a predilection to warm tropical areas with high humidity and low altitude, resulting in optimal cyst survival. Rain is essential for distributing oocysts, whereas sunlight may inactivate them. Reliance on surface water rather than water filtered for drinking is a risk for populations with impaired access to clean water. These factors have traditionally been believed to make Canada a low-incidence region for infection.

Humans may acquire T. gondii through the ingestion of viable cysts in infected tissue that survive in undercooked meat (pork, beef, and lamb) or from contaminated water, fruits, and vegetables. Infection often becomes latent, whereby cysts may persist in brain, muscle, and other organs but are contained by host immunity. Asymptomatic infection is generally the rule in immunocompetent humans, infrequently causing a mild non-specific illness with fever, malaise, rash, and lymphadenopathy.

Historically, toxoplasmosis is of more concern in severely immunocompromised individuals (HIV infection with low CD4+ lymphocytes), in whom infection may cause severe encephalitis.

Rates of infection worldwide have been reported to range from <10% to as high as 80% based on seroprevalence and modified by factors including socioeconomic situation, frequency of raw meat ingestion, tropical climate, cleanliness, and the number of stray cats. Canadian data are sparse, though some northern communities have reported seroprevalence rates of 60%, believed in part to be related to contaminated water sources and undercooked meat ingestion (4). In the United States, approximately 15% of women of childbearing age are infected (5). Meanwhile, rates of congenital toxoplasmosis in developed nations are variable, including the United States at <1, but France at >3/10,000 (2,6).

Of highest concern is the risk of maternal transplacental transmission to a developing fetus, predominantly from primary infection in pregnancy, although reactivation with immunosuppression maintains a low theoretical risk (<1%). Risk of maternal transmission increases with each trimester (2) but is also modified by the inoculum of infection and the maternal immune system. Most infants will have no discernible manifestation of infection at birth.

Unfortunately, the infection can have devastating manifestations, including intrapartum fetal death. The classically described triad of symptomatic congenital toxoplasmosis includes hydrocephalus, intracranial calcifications, and chorioretinitis, although this triad is rare. Other manifestations are wide-ranging, namely, organomegaly, being small for gestational age, and cytopenias. Those with subclinical infections at birth may develop cognitive dysfunction, myocarditis, pneumonitis, motor delay, seizures, hearing loss, or visual abnormalities (7). Hydrocephalus may be symptomatic and chronic, requiring early intervention with ventriculoperitoneal (VP) shunt placement (<25 days), leading to favourable cognitive and motor outcomes (8). Highly suggestive and more frequent ocular findings include chorioretinitis, chorioretinal scars, cataracts, or optic nerve atrophy. Ocular disease may be present at birth. One study found that, of 48 newborns diagnosed with congenital toxoplasmosis by neonatal screening with a normal physical exam, 19% were found to have retinal disease (9). However, in those without detected lesions at birth, up to 80% may develop new and recurrent retinal disease over months to years, even into young adulthood (2,10). Treatment in the first year of life may include either oral pyrimethamine and sulfadiazine or intravitreal clindamycin therapy and may reduce the development of new or recurrent lesions over the coming years (2,7,10–13).

Asymmetric eye size (microphthalmia), as seen in our case, may be reported in 5%–20% of infants with congenital toxoplasmosis (2,14). It is uncommon as the only manifestation of disease, and in the majority of cases, it will be recognized months after the detection of chorioretinitis. Along with other associated ocular pathologies such as strabismus, it may serve as a marker of more severe ocular congenital toxoplasmosis (14). For these reasons, recognition of microphthalmia or strabismus in an infant should prompt expedited ophthalmologic assessment.

Initial diagnostic testing may be prompted in symptomatic infants or where prenatal sonography identifies abnormalities such as hydrocephalus. In our patient, close observation by the parents prompted further investigation. Cranial ultrasound can help identify hydrocephalus, and it may be further characterized by cross-sectional imaging (CT or MRI), which may also demonstrate intracranial (often periventricular) calcifications.

A confirmed diagnosis of toxoplasmosis is based on laboratory findings in the setting of a compatible clinical scenario. Laboratory diagnostics are broad, and we refer the reader to an excellent review on congenital diagnostics (15). Laboratory findings in the infant that are diagnostic of congenital toxoplasmosis include antibody assessment (positive IgM ≥5 days postpartum or IgA ≥10 days postpartum, with positive IgG) or PCR positivity for T. gondii in the blood, urine, and/or CSF. Serology can be negative early in life, particularly if the maternal infection was late in pregnancy, and should be repeated every 2–4 weeks if clinical suspicion is high. Depending on the serologic modality used, combined IgM and IgA testing has an estimated sensitivity of ~70%–75% and specificity >90% (2,15). PCR has lower sensitivity (29%–50%), depending on the sample used (blood, CSF, or urine) likely due to analytic variability and detection limits in various laboratories, but it may be helpful in detecting cases missed by serology (2).

Rarely, a diagnosis can be made if the infant has persistent IgG, despite negative IgM and IgA, supported by serologic evidence of infection in the mother. IgG avidity testing is very useful for women at <16 weeks of gestation to diagnose an acute infection when done as part of prenatal screening. The presence of high avidity immunoglobulins may exclude T. gondii primary infection acquired during pregnancy, indicating that the infection occurred several months previously. It is more complicated for 1) low avidity at <16 weeks gestational age, and 2) high avidity after 16 weeks gestational age. In such situations, a comprehensive serology panel from a reference laboratory (16) should be assessed with clinical presentation and imaging results. The use of IgG avidity testing in newborns has been proposed as an aid to congenital diagnosis (17). Specifically, newborns with low IgG avidity immunoglobulins passed vertically from their mothers may be at higher risk of congenital infection (17,18). Challenges include the fact that low avidity immunoglobulins may persist for long periods while high avidity immunoglobulins may not exclude maternal infection early in the pregnancy, and as such, the clinical utility of this remains to be defined.

Treatment in North America generally consists of pyrimethamine and sulfadiazine, supplemented with folic acid for 1–2 years, depending on the severity of presentation (2). Even in asymptomatic infants, postnatal treatment is imperative as it has been shown to reduce the development of new symptoms and the progression of current ones (11). As such, recognition of congenital infection is crucial. Glucose-6-phosphate dehydrogenase (G6PD) deficiency must be ruled out prior to the use of sulfadiazine, which may precipitate hemolysis.

Pediatric patients should be followed during therapy to monitor for complications of treatment (anemia, kidney/liver injury) as well as for neuro-developmental, hearing, and ophthalmologic assessments. This is best achieved through multidisciplinary collaboration between General Pediatrics, Infectious Diseases, and Ophthalmology.

Universal prenatal maternal screening is currently not adopted in many countries (including Canada) due to low incidence, testing inadequacies, and a lack of proven prevention strategies to justify the cost. It is only recommended for high-risk females (immunosuppressed) or when fetal abnormalities are detected on ultrasound (5). As such, in Canada, emphasis has been placed on preventive strategies to reduce the risk of infection. Risk factors for the acquisition of cysts are outlined in Box 1. Unfortunately, there is limited evidence demonstrating that prenatal education is effective in reducing congenital toxoplasmosis (19).

Box 1: Risk factors for acquiring Toxoplasma gondii (2,5,6).

• Undercooked meat may be a source of T. gondii infection. See Health Canada recommendations for appropriate cooking measures (https://www.canada.ca/en/health-canada/services/general-food-safety-tips/safe-internal-cooking-temperatures.html)

• Thorough cleaning of knives, cutting boards, and counters after contact with raw meat can avoid cross-contamination

• Raw dairy, raw eggs, and unwashed fruit and vegetables can be sources of T. gondii infection

• Freezing, but not refrigeration, can kill T. gondii cysts

• Cat litter boxes may contain T. gondii cysts

When a prenatal maternal infection is detected, spiramycin has been used to prevent fetal transmission with benefits in observational study. A recent open-label randomized controlled trial (RCT) in 131 women suggested the benefit of using pyrimethamine and sulfadiazine to prevent fetal transmission following seroconversion later in pregnancy (20). This joins a host of observational studies indicating that prophylaxis, particularly early after seroconversion, can prevent transmission and may be cost-effective, (2) and it warrants further discussion of screening programs, even in a low-incidence country such as Canada.

In conclusion, although rarely seen in Canada, congenital toxoplasmosis may manifest significant sequelae. Microphthalmia is an uncommon manifestation of congenital toxoplasmosis, but when detected, it should prompt ophthalmologic assessment as a potential manifestation of more severe ocular disease. As universal screening does not occur and prevention education may have limited effectiveness, clinicians must be aware of this congenital infection to recognize and manage it in a timely manner so that complications are minimized or prevented with early and appropriate treatment.

Funding:

No funding was received for this work.

Disclosures:

The authors have nothing to disclose.

Informed Consent:

Informed consent was obtained from the patients.

Peer Review:

This manuscript has been peer reviewed.

Animal Studies:

N/A.