Pediatric congenital intracranial infections are a group of different and important entities that constitute a small percentage of all pediatric infections. The causal factors and clinical presentations are different in children compared with adults. They require early recognition because delay diagnosis and initiation of treatment may have catastrophic consequences. Despite improvements in prenatal screening, vaccine safety, and antibiotics, infections of the central nervous system (CNS) remain an important cause of neurological disabilities worldwide. This article reviews the most common congenital infections and their imaging findings.
Infections of the fetal CNS differ from those of older children and adults in that they act on the brain while it is developing. Manifestations and outcomes differ depending on the age of the fetus at the time of infection and on the virulence of the infectious agent. Another feature of prenatal infections is an altered biological response to injury in very young patients.
Congenital fetal brain infections include those in the traditional TORCH, an acronym that denotes toxoplasmosis, rubella, cytomegalovirus (CMV), and herpes simplex viruses (HSVs). In addition to these agents, others have been included such as human immunodeficiency virus (HIV) infection, lymphocytic choriomeningitis virus, parechoviruses, and varicella-zoster virus among others.
Infections of the fetal CNS can occur via 2 main routes. Bacterial infections usually ascend from the cervix to the amniotic fluid from where the fetus is infected, whereas toxoplasmosis, syphilis, and viruses generally cross the placenta from the maternal circulatory system to the fetal circulation.
The placenta is a low-resistant circuit with oxygenated blood flowing to the fetus via the single umbilical vein and deoxygenated blood from the fetus back to the placenta via 2 umbilical arteries.
The umbilical arteries branch radially into the chorionic plate and then down to the placental villi. After exchange of nutrients, oxygen, and waste products with the maternal blood in the intervillous spaces, blood flows back through the villous vessels, which converge at the umbilical cord, and into the umbilical vein. 1 Smooth vessel fibers in stem villi may help to pump blood from the placenta to the fetus. Maternal blood circulates to the intervillous spaces of the placenta via the altered uterine spiral arteries, also called utero placental arteries. Moreover, 20% to 25% of the maternal cardiac output is directed toward the uterus and the placenta. Maternal blood leaves the intervillous spaces via 75 to 175 utero placental veins.
The blood with the highest concentration of oxygen and substrates enters the fetus via the umbilical vein and reaches the liver as the first major organ.
Approximately 50% of umbilical venous blood enters the hepatic circulation, whereas the rest bypasses the liver and joins the inferior cava via the ductus venosus, where it mixes with blood derived from the lower body. The combined lower body plus umbilical venous blood flow enters the right atrium and is directed across the foramen ovale to the left atrium. This blood then flows into the left ventricle and is ejected into the ascending aorta supplying the brain and upper part of the body via the brachiocephalic circulation. A minor proportion of blood from the right ventricle supplies the lungs, whereas the remainder continues through the ductus arteriosus toward the aorta. The major proportion of descending aortic blood is directed to the umbilical arteries to return to the placenta. 2
The immature brain does not respond to injury by astroglial reaction as the adult does; instead, the immune response repairs the damage, removes abnormal cells, and compensates for missing tissue. The immune-mediated inflammatory response, which contributes to the damage produced by viral infection at a later age, is absent or less marked in the fetus. Because the infections happen during brain development, the manifestations differ depending on the age of the fetus. In general, infections during the first 2 trimesters result in congenital malformations such as microcephaly, lissencephaly, and polymicrogyria. The infections that occur during the third trimester result in destructive lesions such as aqueductal stenosis, hydrocephalus, porencephaly, calcifications, demyelination, and atrophy. 3
Suspicion of fetal infection may be raised by the presence of maternal infection or by findings in utero ultrasound including fetal growth restriction, abnormal amniotic fluid volume, intrahepatic or intracranial calcifications, ventricular dilatation, ascite, hydrops fetalis, pericardial or pleural effusions, and hyperechogenic bowel. 4
The CMV is a member of the herpes virus family and is endemic worldwide. It is an ubiquitous virus that usually results in asymptomatic or clinical benign infections in adults. However, during fetal development, the infection is usually severe, resulting in substantial neurodevelopmental sequelae, including cerebral palsy, epilepsy, developmental delay, mental retardation, vision loss, and sensorineural deafness.
Congenital CMV infection is the leading cause of intrauterine infection and brain damage in children. Primary infection occurs in as many as 2.2% of pregnant women. 5 Fetal infection results from transmission of the virus across the placenta and is common in women who experience primary infection during pregnancy.
Infection occurs in approximately 40.000 newborns each year 6 or approximately 1% of all births. Of these, 10% have symptoms and signs that define the disease including hepatosplenomegaly, microcephaly, impaired hearing, and small head size. Cognitive and neurologic impairments are present in approximately 6.5% of infants with CMV congenital infection who were asymptomatic at birth, and the overall prevalence of neurologic deficits among these patients will eventually reach 13.5%.
The CMV is a neurotrophic virus. The mechanism of CNS injury in congenital CMV disease has 2 hypotheses. First, the virus has an affinity for the rapidly growing cells of the germinal matrix, resulting in abnormalities of the cerebral and cerebellar cortices and deposition of calcium in the periventricular regions. Second, there is a primary vascular target by the virus, with hematogenous seeding of the choroid plexus, viral replication in the ependyma, germinal matrix, and capillary endothelium. Fetuses who are infected at a younger gestational age have poorer outcome than those infected at a later stage of development. Infections that occur postnatally are less severe, and such patients may even be asymptomatic. 7 A diagnosis of congenital CMV infection is established within the first 3 weeks of life on the basis of polymerase chain reaction in blood, urine, or saliva.
Neuropathological studies of brains infected prenatally by CMV show evidence of meningoencephalities, microcephaly, calcifications, lissencephaly, polymicrogyria, periventricular leukomalacia, porencephaly, and ventricular dilatation.
The timing of fetal infection is reflected in the imaging manifestations of congenital CMV infection. Infants with early CMV infection (before 18 weeks) tend to have severe clinical sequelae. In them, imaging findings include lissencephaly, cerebellar hypoplasia, and ventriculomegaly. Delayed myelination and calcifications also may be seen. Late second trimester infections (18–24 weeks) are characterized by migrational abnormalities such as polymicrogyria, cerebellar hypoplasia, and occasionally, schizencephaly. After 26 weeks, infections are associated with dysmyelination and white matter disease. Periventricular calcifications are common, and intracranial hemorrhage may be present.
These are the most frequently reported imaging finding, occurring in 34% to 70% of patients. 7 The presence of this finding is associated with developmental delay and mental retardation. Calcifications are easily detected on computed tomography (CT) as foci of high attenuation. In brain sonography (ultrasonography [US]), they appear as echogenic foci with or without acoustic shadowing. In magnetic resonance imaging (MRI), they appear as areas of low signal intensity on T2-weighted imaging and are especially evident on T2* gradient-echo images and susceptibility-weighted images. Calcifications occur especially in the periventricular regions and within the basal ganglia and brain parenchyma. They are more commonly thick and chunky in appearance (Fig. 1).
It is important to recognize that calcifications are not specific by themselves for congenital infections because they can also be present in ischemia and metabolic disorders. Although calcifications are extremely common in CMV infections, absence of this finding does not exclude the diagnosis of CMV.
Migrational abnormalities have been reported in as many as 10% of patients with congenital CMV. Patients infected in the first trimester can have lissencephaly with a thin cortex. Imaging studies show a smooth brain surface with the absence of sulcation. The presence of intracranial calcifications and a diffuse nodular cortical surface is indicative of early fetal infection and not an underlying genetic abnormality.
Patients with injury later in the second trimester tend to have polymicrogyria (Fig. 2). It is best depicted on high-resolution 3-dimensional gradient T1-weighted images. It may resemble an area of thickened cortex, but close inspection shows multiple small abnormal gyri. Schizencephaly is rare but has been described in patients with congenital CMV. 8 In infants younger than 1 year, fluid attenuated inversion recovery (FLAIR) images have poor contrast between gray and white matter; therefore, T2-weighted images are essential to identify cortical malformations.
White Matter Disease
Damage to the white matter is seen in children infected by CMV at any gestational age, occurring as many as 22% of patients. 9 In CT, white matter disease may appear as areas of low attenuation (Fig. 3). The MRI is more sensitive than CT. On T2-weighted images, white matter disease appears as areas of high signal intensity relative to normal white matter. In children older than 1 year, white matter abnormalities are visualized as areas of high intensity on FLAIR images (Fig. 4).
White matter abnormalities may be multifocal or diffuse. In patients with static encephalopathy, an MRI pattern of multifocal lesions predominantly involving parietal white matter, with or without gyral abnormalities, is predictive of congenital CMV infection. 9 Delayed myelination is expected in patients with congenital CMV. However, it is nonspecific and may be seen in a variety of conditions.
Periventricular cysts may appear as cystic areas adjacent to the ventricles on CT, MRI, and US. They are particularly common in the anterior temporal lobes, where they often are associated with adjacent white matter abnormalities (Fig. 5). Cysts have also been reported adjacent to the occipital poles and within frontal and parietal white matter. The presence of anterior temporal cysts with associated white matter disease suggests CMV infection. 9
Atrophy may be manifested as microcephaly, ventriculomegaly, or generalized loss of volume. Microcephaly occurs in as many as 27% of patients with congenital CMV infection and is associated with poor neurologic outcome.
It is the second most common finding in congenital CMV and is often associated with cerebral volume loss. It is a nonspecific finding unless it is associated with basal ganglia and periventricular calcifications (Fig. 6).
This occurs in as many as 27% of patients with congenital CMV infection. Transfontanelle US shows branching curvilinear hyperechogenicities in the basal ganglia and in the walls of the lateral ventricles. Postmortem studies have shown a mineralizing vasculopathy. It is a nonspecific finding because it has also been described in perinatal, acquired, and nonspecific causes. 10
Toxoplasmosis is the second most common congenital CNS infection after CMV in most regions of the world. Toxoplasmosis is caused by Toxoplasma gondii, an intracellular protozoan that is found worldwide. The parasite infects a wide range of birds and mammals. Cats usually serve as primary hosts. Domestic animals such as pigs and cattle serve as intermediate hosts. It is transmitted to humans primarily by ingestion of cysts in undercooked pork or lamb or contaminated vegetables or through direct contact with cat feces. 11
Although the transmission rate from the mother to the fetus increases with each trimester, the severity of infection decreases with each trimester. 3 The incidence of congenital infection is estimated at 1 per 1000 to 3500 live births worldwide. Although the chance of fetal infection is 40% after primary maternal infection, 80% to 90% of infected fetuses are asymptomatic at birth. 12
Symptoms may be present at the time after birth including several days or weeks. Patients exhibit hepatosplenomegaly, jaundice, thrombocytopenia, and petechial or purpuric rash. The principal CNS findings are chorioretinitis (bilateral in 85% of patients), hydrocephalus, and seizures. In contrast to CMV, macrocephaly (a sign of intrauterine hydrocephalus) is much more common in patients with congenital toxoplasmosis. The diagnosis is established by detecting T. gondii-specific immunoglobulin M or immunoglobulin A in the infant serum. Analysis of paired sera from the infant and the infant’s mother can be useful.
Toxoplasmosis can cause meningoencephalities, which may result in hydrocephalus, microcephaly, calcifications, porencephaly, or hydranencephaly. 4 The prognosis is poor in the absence of therapy. Overall mortality ranges from 11% to 14%. Survivors tend to be mentally retarded with seizures and spasticity. Prolonged postnatal therapy started early with pyrimethamine and sulfadiazine, and early shunting of hydrocephalus substantially improves the prognosis.
Findings in imaging studies are similar to those of CMV infections. The severity of brain involvement has been related to the timing of the maternal infection. Infections before 20 weeks of gestation are associated with severe neurological findings on hydrocephalus, areas of porencephaly, and extensive calcifications, especially in the basal ganglia. Infections between 20 and 30 weeks of gestation have a variable outcome with presence of hydrocephalus and periventricular calcifications (Fig. 7). Infections after the 30th gestational week are associated with mild clinical and imaging abnormalities including small periventricular and intracerebral calcifications and are rarely associated with ventricular dilatation. In general, calcifications common and usually involve the basal ganglia, periventricular regions, subcortical white matter, and cerebral cortex. An important feature is the absence of cortical malformations, which are common in CMV (Fig. 8). It has been reported that the brain calcifications can resolve after therapy.
Acquired Immunodeficiency Syndrome
The spread of the HIV in the general population is resulting in an inevitable increase in the number of children affected with acquired immunodeficiency syndrome (AIDS). Approximately 78% of childhood HIV infection is maternally transmitted, and approximately 40% of HIV-positive mothers pass their infection on to their fetus. 3 Mother-to-child transmission can occur in utero, intrapartum, or during breast-feeding.
Children with congenital HIV infections are often asymptomatic at birth. Onset of neurological disease is generally between 2 months and 5 years with a median age of onset of 8 months. Most symptomatic infants present loss of developmental milestones, apathy, failure of brain growth, ataxia, seizures, myoclonus, and spastic paresis. These signs and symptoms indicate a process that mainly affects the white matter, analogous to the subcortical dementia that occurs in adults. 13 Current antiretroviral strategies and specific treatments for infectious or neoplastic complications improve survival and quality of life in these patients.
On pathologic examination, brains of affected children show atrophy, infiltration of microglial nodules, and multinucleated giant cells containing viral particles and calcifications. A characteristic pathologic change has been termed calcific vasculopathy. There are vascular and perivascular inflammatory changes in small- and medium-sized blood vessels of the basal ganglia as well as development of calcified plaques. This finding is associated with atrophy of the basal ganglia and seems to occur secondary to high concentrations of HIV viral protein in this location. 14
The HIV infection in infants can be confirmed by serial serum polymerase chain reaction assays with the first one done in the immediate newborn period, a second test during the first or second months of life, and a third one after 4 months old. If 2 samples are positive for HIV, the patient is considered infected. Two consecutive negative tests make infection unlikely.
The most prominent imaging findings are cerebral atrophy with prominence of the subarachnoid spaces and ventricles, basal ganglia calcifications, and focal white matter lesions 15 (Figs. 9, 10). Calcifications are only seen in patients who were infected in utero and who are already encephalopathic. Subcortical calcifications are more common in the frontal lobes and, in most cases, are bilateral.
Cerebral mass lesions in children with AIDS are usually due to primary lymphoma, reported to occur in less than 5% of affected patients, and usually present with progressive focal neurologic deficits. The CT in these patients shows hyperdense lesions in the basal ganglia and/or thalami that enhance with contrast medium administration. Opportunistic CNS infections are common in adults but occur rarely in children, probably because they are due to reactivation of latent infections that infants and children have not had time to acquire. 13 When they occur, CMV and progressive multifocal leukoencephalopathy are the most common infections in pediatric AIDS.
Cerebrovascular complications have been reported in 4% to 29% of adult patients with AIDS, but only isolated reports in children have described aneurysms, infarctions, and hemorrhage. A retrospective study of 567 children with HIV infection reported a 2.6% incidence of cerebrovascular lesions. Authors found an association with severe immune suppression and vertically acquired HIV. Despite extensive lesions, most children were asymptomatic. 16 Clinical stroke occurs in less than 1% of children with congenital HIV. Formation of fusiform aneurysms of the major vessels of the circle of Willis has also been described. 17
The congenital rubella syndrome was described by Gregg in 1941 and includes congenital heart disease and cataracts as well as deafness, microcephaly, and mental retardation. 18,19 Humans represent the only reservoir of rubella virus, and transmission results from contact with virus-contaminated respiratory secretions. At this moment, congenital rubella is extremely rare in Western countries because of vaccines and screening of pregnant women for the virus.
Placental transmission of rubella occurs at the time of primary maternal infection. If this occurs during the first trimester, the risk of fetal infection approaches 85%. 20 Gestational age at the time of infection is the most important factor in outcome.
Infections in the first 2 months of gestation are associated with cataracts and cardiac abnormalities, typically a patent ductus arteriosus. In 20% of affected infants, an acute meningoencephalitis is present at birth. Deafness is the most common feature of congenital rubella. Infants with rubella differ from those with congenital infections with CMV or T. gondii by lower rates of hepatosplenomegaly and jaundice.
The pathologic appearance of rubella is a generalized vasculitis with cellular necrosis.
On imaging, there are intracranial calcifications in the basal ganglia, periventricular regions, cortex, and ventriculomegaly. Many patients have white matter changes with multifocal T2 hyperintensities and delayed myelination (Fig. 11). Enhanced MRI may show enhancement of the cochlea (cochleitis).
Neonatal Herpes Simplex
The family of the herpes viruses consists of a large group of double-stranded DNA viruses that includes HSV type 1, HSV type 2, CMV, Epstein-Barr viruses, varicella-zoster virus, B virus, herpes virus 6, and herpes virus 7. 21
Most of the HSV infections in neonates result from exposure to maternal type 2 herpetic genital lesions as the child passes through the birth canal. Infrequently, hematogenous transplacental infections in utero can occur.
The incidence of neonatal herpes is estimated to be 1 per 2000 to 5000 deliveries per year. The brain is involved in 30% of infected infants, and almost 80% do not survive the infection. 3 Neonatal HSV infections are considered to be primarily mucocutaneous with compromise of skin, eye, and mouth; without CNS involvement; or disseminated with or without CNS involvement or encephalitis.
Primary herpes virus CNS infection in neonates is typically diffuse. Neuroimaging in neonates reflects the neuropathologic findings of this disorder consisting of acute and chronic parenchymal and leptomeningeal inflammations resulting in necrosis and microcephaly. The HSV destroys much of the brain, with necrosis, cellular debris, macrophages, mononuclear inflammatory cells, calcification, and hypertrophied astrocytes. The ependyma and choroid plexuses are spared, in contrast to CMV and T. gondii infections.
The CT may show hypodense lesions in the periventricular white matter with relative sparing of the basal ganglia and thalami. Cerebellar involvement is seen in one half of the patients. Within the first 3 weeks of presentation, cortical hyperdense areas have been described as characteristic CT findings 21 that persist for weeks to months 22 (Fig. 12).
The MRI is the study of choice in neonates with suspected herpetic encephalitis. Findings are multifocal lesions, temporal lobe involvement, deep gray matter injury, hemorrhages, a watershed pattern of injury, and occasionally, involvement of the brainstem and cerebellum. Early MRI findings in MRI are often absent or seen as loss of gray matter-white matter contrast on T2-weighted images and subtle hyperintensity on T2-weighted images. In this stage, diffusion-weighted imaging depicts early cellular necrosis with reduced diffusion. After the first week, diffusion-weighted imaging becomes less useful, and findings on T2-weighted images are more evident. Contrast enhancement is minimal but can appear as a meningeal pattern. Although the white matter findings are nonspecific, the T1 hyperintensity and T2 hypointensity of the cortical gray matter and the meningeal pattern of enhancement suggest the diagnosis of neonatal herpes simplex encephalitis. As the disease progresses, focal hemorrhagic necrosis, loss of brain substance, cortical thinning, parenchymal calcifications, and cystic encephalomalacia can be seen. Calcifications have a variety of distributions, from punctuate or curvilinear to extensive gyral pattern.
This article reviews the most common congenital brain infections and their clinical presentations. These types of infections differ from those of adults because they affect the developing CNS. For that reason, early diagnosis and treatment are vital to diminish consequences and permanent neurodevelopmental disabilities.
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