What are the most common congenital infections affecting the central nervous system in a fetus?

Most Common Congenital Infections Affecting the Central Nervous System

Cytomegalovirus (CMV) is the most common congenital infection affecting the central nervous system, followed by toxoplasmosis, syphilis, herpes simplex virus, rubella, and Zika virus. 1, 2

Primary Pathogens in Order of Frequency

Cytomegalovirus (CMV)

• CMV is the leading infectious cause of non-genetic sensorineural hearing loss and neurodevelopmental disability in infants. 3
• The incidence of in utero CMV infection is approximately 2% in the general U.S. population, making it substantially more common than other congenital infections. 1
• CMV accounts for 8-10% of pediatric AIDS-defining illness and causes substantial CNS morbidity including periventricular calcifications, ventriculomegaly, microcephaly, and chorioretinitis. 1, 4
• Approximately 10% of infants with congenital CMV are symptomatic at birth, but 90% of those with symptomatic disease who survive develop late complications including hearing loss, mental retardation, and seizures. 1
• CMV accounts for 12-30% of cases of polymicrogyria when associated with white matter hyperintensities and calcifications. 5

Toxoplasmosis

• The incidence of congenital toxoplasmosis in the United States is estimated at 1 case per 1,000-12,000 live-born infants. 1
• The overall risk for maternal-fetal transmission in women without HIV infection who acquire primary infection during pregnancy is 29%. 1
• CNS manifestations include hydrocephalus, intracerebral calcification, microcephaly, chorioretinitis, and seizures. 1
• The majority of infants (70-90%) are asymptomatic at birth, but most asymptomatic children develop late sequelae including retinitis, visual impairment, and neurologic impairment. 1
• Toxoplasma encephalitis is uncommon among HIV-infected children, reported as an AIDS-indicator condition in <1% of pediatric AIDS cases. 1

Syphilis

• Congenital syphilis incidence has been increasing in the United States over the past decade due to new adult cases and poor access to maternal healthcare. 6
• CNS involvement can present with kidney involvement ranging from mild proteinuria to nephrotic syndrome. 7
• This is a treatable infection when identified early. 6

Herpes Simplex Virus (HSV)

• Unlike other congenital infections transmitted transplacentally, HSV is usually transmitted perinatally during passage through an infected birth canal. 8
• Neonatal herpes infection can lead to lasting neurological deficits and death. 1
• CNS disease presents with seizures, reduced alertness, and focal neurologic deficits. 7
• Treatment options exist, though efficacy varies by population. 6

Rubella

• Rubella directly infects the fetal brain causing aberrant neurodevelopment including neuronal death, gliosis, and disruption of mitosis. 1
• Greater than 20% of subjects from the 1964 rubella epidemic whose mothers tested positive for rubella during pregnancy were diagnosed with schizophrenia spectrum disorders (10-15-fold increased risk). 1
• Rubella is associated with cardiac defects and growth restriction in addition to CNS involvement. 5

Zika Virus

• Zika virus emerged as a significant CNS pathogen following the 2015 South American epidemic. 1
• In utero exposure causes cerebellar atrophy, ventriculomegaly, cerebral calcifications, and microcephaly. 1
• The virus preferentially infects and causes apoptosis of neural progenitor cells, leading to direct CNS tissue destruction. 1, 6
• Microcephaly may be present at birth or develop postnatally within the first year. 7

Key Clinical Pitfalls

A critical pitfall is assuming asymptomatic infants at birth will remain unaffected. The majority of infants with congenital CMV (90%) and toxoplasmosis (70-90%) are asymptomatic at birth but develop late sequelae including hearing loss, visual impairment, and neurodevelopmental delays. 1

Another common error is failing to recognize that sensorineural hearing loss may be absent at birth but develop during the first year of life, requiring ongoing audiologic surveillance. 7

Clinicians must recognize that chorioretinitis and ocular abnormalities can occur even in infants without microcephaly or other obvious brain anomalies, necessitating ophthalmologic evaluation in all suspected cases. 7

Diagnostic Approach

• Systematic evaluation must include neurologic assessment (microcephaly, hydrocephalus, intracranial calcifications, seizures), ophthalmologic examination (chorioretinitis), auditory testing (sensorineural hearing loss), and systemic findings (hepatosplenomegaly, rash, thrombocytopenia). 7
• Neuroimaging with ultrasound, CT, or MRI should be performed 2-4 weeks after onset of maternal illness to allow time for fetal manifestations to develop. 5
• For CMV specifically, amniocentesis with PCR for CMV DNA is most sensitive when performed after 21 weeks gestation and >6 weeks from maternal infection. 1
• Neuroradiologic scoring systems are predictive of developmental outcomes and should guide prognosis discussions. 3