Congenital infections are acquired by the maternal hematogenous-transplacental route or by exposure to organisms during passage through the birth canal. Most fetal bacterial infections are due to the ascent of organisms from the cervix into the amniotic fluid. Congenital infections of the central nervous system (CNS), however, are usually transmitted transplacentally. The TORCH organisms cause most of these CNS infections: Toxoplasma, other (coxsackievirus, syphilis, varicella-zoster, human immunodeficiency virus, and parvovirus B19), rubella, cytomegalovirus, and herpes simplex virus type 2 (HSV). These organisms can cause chorioretinitis, microcephaly, and focal cerebral calcification.

The stage of fetal development at which the infection occurs is a crucial factor in determining the sequelae. In general, CNS infections that occur during the first 2 trimesters tend to cause developmental malformations, whereas those occurring during the third trimester lead to destructive brain lesions. Migration abnormalities are the most common developmental manifestations of congenital CNS infections. Because the fetal brain has limited capacity for astroglial reaction, necrotic tissue caused by a congenital infection is completely removed by the immune response. The resultant defect may persist as a fluid-filled cavity (i.e., porencephaly) or be replaced by expansion of adjacent normal tissue.

Cytomegalovirus

Cytomegalovirus is the most common organism involved in congenital infections. This infection occurs in approximately 40,000 infants in United States per year (approximately 1% of all births). Approximately 10% of infants congenitally infected with cytomegalovirus have clinical manifestations of disease at birth (i.e., cytomegalic inclusion disease). These infants may have hepatosplenomegaly, petechiae, microcephaly, cerebral atrophy, ventriculomegaly, chorioretinitis, or sensorineural hearing loss. Neuronal migration anomalies are common. Approximately 90% of children who survive symptomatic congenital cytomegalovirus infection have long-term neurological sequelae, such as intellectual impairment, seizures, and sensorineural hearing loss. Infants with congenital cytomegalovirus infection born to mothers who have preexisting immunity to the virus are usually asymptomatic at birth, but may go on to exhibit subtle neurodevelopmental sequelae. Up to 20% of these infants have unilateral or bilateral sensorineural hearing loss.^1–3

The major neuroimaging findings of congenital cytomegalovirus infection include generalized periventricular calcifications, cerebral underdevelopment, white matter thinning, porencephaly, cerebellar hypoplasia, cortical dysplasia, and delayed myelination (Figure 16-1). With severe involvement, there is hydranencephaly. Infections occurring early during pregnancy may lead to lissencephaly, cerebellar hypoplasia, delayed myelination, and marked ventriculomegaly. White matter involvement occurs in the form of diffuse thinning or multifocal areas of damage. Cysts may develop in the involved white matter. Infections occurring around the time of the mid-second trimester are usually associated with less severe global brain malformations. Polymicrogyria is common in these children. Schizencephaly can occur. Infections occurring near the end of gestation generally do not result in altered gyral patterns. Periventricular calcifications and white matter changes are common, whereas ventriculomegaly and cortical thinning are relatively mild. White matter involvement in these children tends to spare the periventricular and subcortical regions.^4–8

The presence of periventricular calcifications is an important neuroimaging finding of congenital cytomegalovirus infection, although this is not diagnostically specific. With sonography, there are multiple echogenic periventricular foci (Figure 16-2). Large deposits cause acoustic shadowing. In some instances, there are hypoechoic periventricular ringlike zones. CT shows multiple irregular calcific deposits at the ventricular margins, most prominent along the lateral ventricles. Calcification can also occur elsewhere in the brain, including the basal ganglia. Periventricular calcifications of sufficient size are hypointense on T2-weighted MR images and hyperintense on T1-weighted images. The intracranial calcifications of congenital cytomegalovirus infection are sometimes visible on standard radiographs.

Sonography of newborns with congenital cytomegalovirus infection sometimes shows branching curvilinear hyperechoic bands in the basal ganglia. This appearance is termed “lenticulostriate vasculopathy.” This may be related to a mineralizing vasculopathy or small vessel flow alteration. Although common with cytomegalovirus infections, this finding also occurs with other congenital infections, as well as various noninfectious ischemic or toxic injuries to the developing brain.^9,10

Toxoplasmosis

Congenital toxoplasmosis is an intrauterine infection with the protozoan Toxoplasma gondii. The infection is usually acquired by maternal ingestion of oocysts in uncooked meat. The prevalence of congenital toxoplasmosis in United States is approximately 1 in 2000 livebirths. The clinical spectrum ranges from asymptomatic to fatal. Up to 90% of fetal infections are asymptomatic at birth. Newborns with symptomatic congenital toxoplasmosis have a 10% to 15% mortality rate; substantial long-term sequelae such as intellectual impairment occur in nearly all survivors. More severe manifestations of infection occur when exposure is early during pregnancy. Infection during the first trimester can lead to retinochoroiditis, severe neurological compromise, microcephaly, hepatosplenomegaly, and skin alterations. Infection later during gestation often is clinically silent at birth. These children may later develop seizures, psychomotor disturbances, visual loss, and hearing deficits.^11,12

Congenital toxoplasmosis can produce a granulomatous meningitis or diffuse inflammation of the brain parenchyma. Aqueductal involvement can lead to hydrocephalus. With severe infections occurring during the second trimester, severe brain underdevelopment or hydranencephaly may occur. The parenchymal brain involvement usually predominates in the basal ganglia, deep white matter, and areas adjacent to the cerebral aqueduct. Inflammation and necrosis are often most prominent in the periventricular regions. Foci of brain destruction often undergo calcification. Malformations of cortical development are uncommon in congenital toxoplasmosis, but occasionally occur with early fetal infections.

Neuroimaging studies of infants with severe manifestations of toxoplasmosis acquired early during gestation include extensive cerebral calcifications, ventriculomegaly (due to obstruction or atrophy), generalized cerebral underdevelopment, and regions of porencephaly (due to foci of fetal brain necrosis) (Figure 16-3). Ventriculomegaly is often most prominent in the posterior aspects of the lateral ventricles. Hydranencephaly or polymicrogyria may be present in severe cases. Calcifications within the basal ganglia are common. Microphthalmia and ocular calcifications may also be present. With mild forms of congenital toxoplasmosis, imaging studies show only scattered small periventricular calcifications and minimal ventriculomegaly.^13,14

Herpes Simplex Virus

The newborn with HSV infection can acquire the organism in utero, intrapartum, or postnatally. True congenital HSV infections are uncommon; these occur by the hematogenous-placental pathway. Severe infections occurring during the first trimester may lead to global brain underdevelopment, hydranencephaly, and intracranial calcifications. The major clinical features of intrauterine infection with HSV comprise a triad of findings: (1) skin vesicles and scarring, (2) manifestations of eye infection, and (3) microcephaly or hydranencephaly.^15–17

Acquired herpes simplex infection due to intrapartum or postnatal exposure is much more common (85% to 90% of cases) than the true congenital form. Neonatal herpes simplex infections occur in up to 1 per 2000 deliveries. This is most often due to HSV type 2 exposure during passage through the birth canal. Subsequent viral replication is usually limited to the site of entry, producing infection of the skin, eyes, and/or mouth. These infants present clinically at approximately 10 days of age, usually with clusters of discrete vesicles or with keratoconjunctivitis. If there is progressive viral replication and dissemination, the CNS, lungs, liver, adrenal glands, and other organs can be infected. CNS involvement is usually in the form of meningoencephalitis, with symptoms developing during the first few weeks of life. Neonatal infections with HSV type 1 can also occur. These infections are clinically less severe than those due to type 2, have a slightly later clinical onset, and are most frequently acquired after delivery.

Approximately 30% of infants with neonatally acquired HSV infection have brain involvement. The diagnosis of encephalitis may be difficult, as approximately 40% of these infants do not have skin lesions at the time of presentation. The infant is usually well initially, but eventually develops manifestations such as poor feeding, irritability, jaundice, fever, seizures, and focal neurological abnormalities. CNS involvement can occur as part of disseminated infection or as a localized disorder. The most sensitive and specific diagnostic laboratory technique for HSV encephalitis is the polymerase chain reaction detection of virus DNA in the cerebrospinal fluid. However, false negative results can occur early in the course of the infection. Treatment is with acyclovir.¹⁸

Neonatal herpes virus encephalitis is a necrotizing encephalitis that usually affects the brain in a diffuse manner. In some patients, there is a regional or multifocal pattern of involvement. Initially, there is swelling of the brain, followed by necrosis and inflammatory cell infiltration. Sonography may be normal or show diffuse brain hyperechogenicity in the early stages. In some infants, the ventricles are small due to brain swelling. Potential patterns on diffusion-weighted MR images during this early stage include globally reduced diffusion in the brain, regional involvement, or multifocal lesions (Figure 16-4). Brain signal intensity may be normal on standard spin-echo MR images during this early phase. Proton MR spectroscopy may show accumulation of lactate. After 24 to 48 hours of symptomatic disease, focal patchy parenchymal abnormalities often develop, predominantly in the white matter; these are hypoattenuating on CT and hyperintense on T2-weighted MR. Slight prominence of meningeal contrast enhancement may be present at this stage.

With disease progression over the next few days, the edematous cortical white matter becomes increasingly hyperintense on T2-weighted MR images, hypointense on T1-weighted images, and hypoattenuating on CT. Cortical gray matter may become somewhat hyperattenuating on CT and hyperintense on T1-weighted MR, presumably due to petechial hemorrhage (Figure 16-5). Areas of edema convert from a hypointense to hyperintense character on apparent diffusion coefficient (ADC) MR images (Figure 16-6). As white matter edema in young infants has limited conspicuity on standard T2-weighted images, ADC images are particularly useful. Meningeal enhancement becomes more pronounced; this is a useful characterizing feature of neonatal herpes encephalitis. There is usually rapid progression to diffuse cerebral atrophy, sometimes accompanied by cerebellar volume loss (about half of patients). Multiple foci of encephalomalacia may be present in the white matter. Calcifications often develop along the cortical surface, producing a gyral pattern on imaging studies. Calcification can also occur in the basal ganglia and periventricular white matter.^4,19–21

Rubella

Congenital rubella (congenital rubella syndrome) is a serious fetal infection that is rare in the developed countries because of widespread immunization and screening programs. Fetal exposure during the first 12 gestational weeks leads to a clinically evident infection in approximately 90% of instances. The infection rate drops to 25% to 30% during the second trimester, but increases to 80% to 100% during the last weeks of gestation. Infections acquired during late gestation tend to be clinically benign. The greatest teratogenic effect occurs with early gestational exposure. First-trimester exposures are associated with psychomotor retardation and hearing loss. Potential symptoms of congenital rubella that may be present in the newborn include hypotonia, lethargy, and a bulging fontanelle.^15,22

Rubella infections occurring early during gestation can damage vascular endothelium, potentially resulting in stenotic lesions of the pulmonary artery and aorta. Patent ductus arteriosus and valvular disease can also occur. Both early and late fetal infections can cause hearing loss and ocular abnormalities (microphthalmia, cataracts, and glaucoma). Approximately 10% to 20% of infants with congenital rubella syndrome have an active meningoencephalitis that can persist for months.

With severe early intrauterine rubella infections, neuroimaging studies show generalized brain hypoplasia, microcephaly, and ventriculomegaly. Foci of necrosis and gliosis may be present in the periventricular white matter, basal ganglia, and brainstem due to vasculopathy. These appear on CT as hypoattenuating areas and on MR as multifocal regions of T2 hyperintensity. Dystrophic calcifications and cystic encephalomalacia may also be present in the basal ganglia and cortex. Sonography sometimes demonstrates linear hyperechoic areas in the basal ganglia, that is, lenticulostriate vasculopathy. Generalized edema is the most common imaging finding in symptomatic infants with congenital rubella that was acquired late during gestation.^23,24

Varicella

Symptomatic congenital varicella is rare because maternal infections are uncommon and less than 5% of infants born to mothers who have had varicella during pregnancy have clinical manifestations of the infection. Up to 2% of maternal varicella-zoster virus infections that occur during the first 20 weeks of gestation lead to varicella embryopathy. This is usually a multisystem disorder. Potential manifestations of CNS involvement include microcephaly, cortical hypoplasia, seizures, chorioretinitis, neurological deficits, and microphthalmia. Neuroimaging studies may show cortical atrophy, ventriculomegaly, polymicrogyria, or cerebellar hypoplasia.^25,26

Infants born to mothers who develop clinical manifestations of varicella less than 5 days before delivery or within 2 days after delivery may suffer a severe neonatal varicella infection that can include encephalitis. The initial clinical manifestation typically is a cutaneous exanthem that develops at 5 to 10 days of life. There is progression to pneumonia, hepatitis, and encephalitis. The major clinical manifestations of brain involvement are seizures. Neuroimaging studies show findings of acute encephalomyelitis, with brain swelling and diminished parenchymal attenuation on CT and elevated signal intensity on T2-weighted MR.

Syphilis

Congenital syphilis is due to the transplacental passage of the spirochete Treponema pallidum. These organisms can cross the placenta at any stage of pregnancy, but there is little tissue response prior to the 15th week of gestation. Fetal mortality with congenital syphilis is as high as 25%. The clinical manifestations of congenital syphilis may appear at anytime between birth and 3 months of life. Skin lesions are the most common early manifestations. More than half of infants with congenital syphilis have CNS involvement, but delayed onset of associated clinical manifestations is common. The most frequent intracranial pathology in these patients is inflammatory infiltration of the leptomeninges with mononuclear cells. Secondary involvement of vascular structures can lead to infarction. The most common clinical findings in infants with congenital syphilis are cranial nerve palsies, seizures, and manifestations of elevated intracranial pressure.

CT and MR of infants with congenital syphilis may show prominent enhancement of the leptomeninges. Abnormal enhancement sometimes extends into the parenchyma via the Virchow-Robin spaces. When present, secondary cerebral infarctions typically follow an arterial distribution. Calvarial osteomyelitis occurs in some infants with congenital syphilis. Skull radiography and CT may show ill-defined areas of radiolucency, sometimes with central dense areas (button sequestrum) (Figure 16-7).²⁷

Human Immunodeficiency Virus

Neonatal infections with HIV can occur due to exposure to the virus in utero or during birth. In addition, postnatal transmission can occur with breastfeeding. Overall, between 20% and 40% of children born to untreated HIV infected women become infected. Treatment of the infected mother with antiretroviral drugs and delivery by cesarean section markedly reduce the risk of fetal or neonatal infection.^28,29

Clinical manifestations of neonatal or congenital HIV infection are unusual in the perinatal period. The clinical findings are often nonspecific: failure to thrive, hepatosplenomegaly, lymphadenopathy, interstitial pneumonitis, protracted diarrhea, recurrent infections, and oral candidiasis. Manifestations of CNS involvement may occur during the first several months or first few years of life. Some patients suffer progressive encephalopathy, with dementia, spasticity, and developmental delay. The other major manifestation of CNS involvement is static encephalopathy, with delay in cognitive and motor development. Concomitant involvement of the spinal cord is common.³⁰

Neuroimaging studies of children with CNS pathology due to congenital HIV infection show manifestations of meningoencephalitis, brain atrophy/hypoplasia, and calcific vasculopathy. The subarachnoid spaces are prominent and there is generalized ventriculomegaly. CT and MR may show calcifications in the basal ganglia and subcortical white matter (particularly in the frontal lobes). In young children, MR shows delayed myelination. Children with HIV infection are also at elevated risk for opportunistic infections (e.g., toxoplasmosis) and progressive multifocal leukoencephalopathy (demyelination and white matter necrosis). Infants with or without infections who are born to HIV-infected mothers sometimes have branching echogenic streaks in the basal ganglia on sonography (lenticulostriate vasculopathy).^31–34

Lymphocytic Choriomeningitis Virus

Lymphocytic choriomeningitis virus is a rodent-borne virus that occasionally infects humans in the temperate zones of Europe and North America. Congenital exposure can impede brain development. The most common clinical manifestation at birth is chorioretinitis. There may be bulging of the fontanelle due to obstructive hydrocephalus (caused by necrotizing ependymitis). Other infants are microcephalic. Seizures and psychomotor delay are common.^35,36

The neuroimaging features of congenital lymphocytic choriomeningitis virus infection are similar to those of other congenital viral diseases. Dilation of the lateral and third ventricles is sometimes present. Punctate periventricular dystrophic calcifications are common. Deficient gyral development in the cerebral cortex may occur; MR demonstrates shallow and numerous cortical sulci. There is generalized parenchymal brain thinning.

Viral Meningitis

Viral meningitis is the most common form of CNS infection. The most frequent pathogenic viruses in patients with meningitis are the enteroviruses. Many other viral species, however, can lead to meningitis, including herpes simplex type 2, mumps virus, and lymphocytic choriomeningitis virus. Some viral agents, such as HSV types 1 and 2 and mumps virus, can produce acute encephalitis concomitantly with the meningeal infection.³⁷

Viral meningitis is a form of aseptic (i.e., nonbacterial) meningitis. Noninfectious inflammatory conditions can also evoke a meningeal response, and therefore represent additional etiologies of aseptic meningitis. Examples include collagen vascular diseases, leukemia, CNS tumors, and intrathecal chemotherapy. Aseptic meningitis is usually associated with an abrupt clinical onset, a relatively short duration, and a favorable outcome. Common clinical manifestations include fever, headache, vomiting, and neck stiffness. Cerebrospinal fluid (CSF) analysis shows mild pleocytosis. Typically, there is gradual clinical recovery within days to weeks of the clinical onset.

Neuroimaging studies are generally not required for patients with uncomplicated viral meningitis. CT and MR are usually normal in these patients or show minimal prominence of subarachnoid fluid surrounding the convexities of the brain. There may be subtle prominence of meningeal contrast enhancement on MR. In those patients with associated encephalitis, MR shows T2 hyperintensity in edematous portions of the brain.

Bacterial Meningitis

Acute bacterial meningitis is a relatively common cause of acquired neurological disease in infants and children. In the United States, the incidence of bacterial meningitis for children younger than 5 years is approximately 87 cases per 100,000 children per year. For children older than 5 years, the yearly incidence is approximately 2.2 per 100,000. The peak occurrence is between the ages of 6 and 12 months. About three-quarters of cases occur in children under the age of 3 years. Neonatal bacterial meningitis (i.e., onset during the first month of life) occurs in approximately 0.4% of livebirths. There is substantial variation in the incidence of bacterial meningitis with regard to age, season, geography, ethnicity, and socioeconomic status. There is a high prevalence of bacterial meningitis among Navajo Indians and Alaskan Eskimos. The prevalence among Blacks and Hispanics is 2 to 4 times higher than that of whites.^38–40

The most common mechanism for bacterial access to the meninges is by hematogenous spread and passage through the choroid plexus. Encapsulated bacteria that cause bacterial meningitis usually gain entry into the bloodstream after respiratory colonization. Inflammation of the meninges due to bacterial infection leads to a variety of symptoms, including headache, nausea, vomiting, lethargy, fever, and irritability. Inflammation of sensory nerves can lead to hyperesthesia, photophobia, and nuchal rigidity. Increased intracranial pressure is common, due to disruption of the blood brain barrier, metabolic changes in brain cells, and abnormal cerebral blood flow. Severe infections can lead to seizures, focal neurological signs, and coma.

In older children, the most common organisms to cause bacterial meningitis are Streptococcus pneumoniae and Neisseria meningitidis. Haemophilus influenzae was the major pathogen for bacterial meningitis prior to widespread immunization. Group B streptococcus and E. coli are the most common pathogens in newborns. In trauma patients, the most commonly involved organisms are Streptococcus pneumoniae, Staphylococcus aureus, and group A streptococcus.

Laboratory evaluation of CSF obtained by lumbar puncture provides a definitive diagnosis of meningitis in most instances. Lumbar puncture is contraindicated, however, if there are clinical findings that suggest severely increased intracranial pressure. CT should be performed prior to lumbar puncture if there are clinical indications of a complicating factor such as brain abscess, empyema, hydrocephalus, or intracranial hemorrhage. With uncomplicated meningitis, neuroimaging studies may be normal or show subtle effacement of sulci. On MR, elevated protein in the CSF sometimes leads to alteration in the signal intensity of subarachnoid fluid adjacent to the cerebral convexities. The inflamed meninges may enhance prominently with intravenous contrast (Figure 16-8).

A sterile subdural effusion is a potential complication of bacterial meningitis, particularly in young infants. Effusions are present in about one-quarter of bacterial meningitis patients. Less commonly, a true empyema (i.e., purulent subdural fluid) occurs. Although there is overlap in the imaging appearances of subdural effusion and empyema, the former usually consists of relatively small bilateral convexity collections, whereas empyema more often is localized. Diffusion-weighted MR sequences show reduced ADC values in a pus-filled subdural collection. Diffusion-weighted images are also relatively sensitive for the detection of cerebritis in the subjacent brain parenchyma.

Other potential complications of bacterial meningitis include obstructive hydrocephalus, cerebritis, brain abscess, venous thrombosis, arterial infarction, and ventriculitis (Figure 16-9 and 16-10). The neuroimaging appearance of arterial infarctions in patients with meningitis may reflect a pattern of large vessel involvement or multiple central foci due to involvement of smaller vessels that pass through the basilar cisterns. Infarctions due to venous thrombosis often are relatively small foci within the subcortical white matter. Thrombosis of the superior sagittal sinus causes infarcts in the parasagittal regions of the cerebrum. Straight sinus or vein of Galen occlusion causes thalamic infarcts. Thrombosis of the sigmoid sinus, transverse sinus, or vein of Labbé most often is associated with temporal lobe infarcts.^41,42

Tuberculous Meningitis

Tuberculous meningitis is a life-threatening infection that results in meningeal granulation tissue and exudates. The most common CT and MR manifestations of tuberculous meningitis are thickening and prominent meningeal enhancement of the basal meninges. In about half of patients with tuberculous meningitis, the abnormal basal meninges have increased attenuation on unenhanced CT images; when present, this finding is highly specific for the diagnosis (once subarachnoid hemorrhage is ruled out). Tuberculous meningitis tends to occur with an asymmetric or focal pattern.^43–47

Tuberculous meningitis often leads to vasculitis that can cause brain ischemia and infarction. Infarcts can also occur due to direct extension of meningeal disease into the parenchyma; these are termed “border-zone” infarcts. MR provides improved sensitivity over CT for the prompt detection of meningitis-related infarcts. The status of intracranial arteries in these patients can also be evaluated with MR angiography. Patients with substantial ischemia frequently have evidence of progression to focal or global brain atrophy on followup neuroimaging.

Hydrocephalus is an additional common complication of tuberculous meningitis that tends to occur in the later phases of the disease. Hydrocephalus in these children is usually of the communicating type, due to impaired CSF absorption. Noncommunicating hydrocephalus is suggested when imaging studies show evidence of periventricular CSF migration and other features of elevated intracranial pressure, in addition to ventriculomegaly.⁴⁸

Intracranial suppurative processes can localize within the epidural, subdural, or subarachnoid compartments, within the brain parenchyma, or within the ventricular system. In many instances, bacterial infections involve more than 1 of these sites concurrently. An empyema is a purulent fluid collection in the subdural space. Peripheral extension from bacterial meningitis is a relatively common cause of empyema. However, most subdural fluid collections in children with meningitis are sterile effusions. A localized purulent subarachnoid collection can also occur as a complication of bacterial meningitis. Other potential sources of extraaxial infections include orbital infection, calvarial osteomyelitis, penetrating trauma, hematogenous spread from a distant focus, and seeding via a congenital osseous defect. Most epidural abscesses are due to direct extension from an adjacent source, such as purulent sinusitis or mastoiditis. Common clinical manifestations of an empyema, subarachnoid abscess, or epidural abscess include focal neurological alterations, seizures, and findings of increased intracranial pressure.