Congenital infections are discussed elsewhere.
There are reports of purulent meningitis by mycoplasma (and of course many bacteria), but viral meningitis is not purulent. Best known in neonatal cranial ultrasound is viral encephalitis. Except for CMV and HSV infection, such viral encephalitis is rarely a cause of death, but severe tissue destruction is possible (Muller et al. 2017, Licht-van der Stap et al. 2025). The incidence for enterovirus and human parechovirus (HPeV) meningitis ranges from 0.04 to 0.77/1000 livebirths (de Louvois et al. 2005, Kadambari et al. 2019). Viral meningitis is often self-limiting, treated with supportive therapy. Most common worldwide are HPeV, enterovirus, rotavirus and herpes simplex virus (HSV) infection (Autore et al. 2021). Enteroviral infection typically affects white matter, in a symmetrical pattern and with a predilection for the frontal lobes.
Enterovirus/parechovirus
Infections with enterovirus and HPeV tend to be mild but can also be fulminant. Enterovirus and HPeV are small nonenveloped Picornaviridae. They are subdivided in several serotypes. HPeV type 3 is associated with neonatal encephalitis. Neonates can be admitted with fever, rash, irritability, feeding problems and/or diarrhoea. Group B coxsackie virus and echovirus 11 are often associated with systemic neonatal infection and myocarditis is a well-known complication (Chuang et al. 2019, Zhang et al. 2021). Most acquire the infection in the perinatal period from a symptomatic mother or sibling. Perinatally acquired enterovirus and HPeV infection have their clinical onset between 3 and 7 days of life (Kimberlin et al. 2021). For both enterovirus and HPeV encephalitis CUS can show similar diffuse periventricular hyperechogenicity, resembling non-infectious leukomalacia (Verboon-Maciolek et al. 2006). Involvement of the external capsule and the frontal white matter is seen, especially in HPeV3 (Verboon-Maciolek et al. 2008, Amarnath et al. 2016). Cystic evolution can be detected by serial CUS; cysts more likely develop in the (late) preterm infant (van Zwol et al. 2009), more likely leading to a poor outcome (Britton et al. 2016, de Vries et al. 2019). It is therefore important to perform serial scanning.
Herpes simplex virus
HSV type 1 and 2 are large enveloped double-stranded DNA virions of the herpesviridae family (Kimberlin et al. 2021). About 85 % of the neonates with herpes infection acquire it peripartum. Transplacental infection is rare (5%). Postnatal infection can occur and is almost always caused by HSV type 1 (Volpe et al. 2018). There are three forms of presentation of perinatal HSV infection, which can coexist: skin-eye-mouth, meningoencephalitis and disseminated disease. Neonatal HSV meningoencephalitis usually presents between the second and third week up to the sixth week of life. CUS may show parenchymal changes, but is likely to miss small cortical lesions. It is therefore recommended to document lesions with MRI (Vossough et al. 2018). In adults, herpes encephalitis follows a retrograde axonal pathway from the oropharyngeal mucosa, and typically affects the medial temporal lobes, frontal lobes, and the limbic system sparing the basal ganglia. Neonatal HSV encephalitis is presumed haematogenous, and has a more variable imaging appearance. It can be multifocal or only limited to the thalamic region, the corticospinal tract, the frontal lobes or the cerebellum, perhaps with a not-haematogenous entry port (Kidokoro et al. 2017). Lesions can be both ischaemic and haemorrhagic. Near total cerebral mantle destruction has been reported.
Two possibilities for HSV to enter the brainstem via a cranial nerve and to ascend to thalamus.
Rotavirus
Rotavirus is a nonenveloped double stranded Reovirida (Kimberlin et al. 2021). Gastro-enteritis only occurs in 20% of infected neonates (Verboon-Maciolek et al. 2012, Yeom et al. 2016, Oh et al. 2021). Rotavirus can be detected in stool, even in the absence of diarrhaea. CSF is usually normal, without pleocytosis or positive culture, and only in a few reports PCR for rotavirus was weakly positive (Verboon-Maciolek et al. 2012). In recent years rotavirus "encephalitis" has been reported as a cause of neonatal seizures. It is typically presenting on day 4-6 and can mimic the so-called 'fifth day seizures' (Oh et al. 2021). CUS demonstrates hyperechogenicity of the white matter from 24-48 hours after onset of symptoms (de Vries et al. 2019). This may evolve into cysts, more likely in the late preterm infant. There is a predilection for the frontal lobes. MRI shows the extent of injury, especially with early diffusion weighted imaging. There are multiple studies that reported symmetrical diffusion restriction in white matter. Although the appearance is similar to cystic leukomalacia, the white matter abnormalities may extend more into subcortical white matter (Ku et al. 2018, de Vries et al. 2019).
First description by Komrower in 1955 was of maternal fever 12 days before and infant fever 8 days after delivery. This child died early after onset of illness. Mice at home were the probable source. Experimental infection of mice results in viral replication in germinal matrix and ependyma. This arenavirus infects humans via rodents by direct contact with contagious fomites (mice or hamsters). Congenital infection has resulted in (Barton and Mets 2001): microcephaly (38 %), hydrocephalus, calcification (periventricular like CMV, rubella)(in > 50 %), disturbance of neuronal migration and chorioretinitis (93 %).
Noticeably absent are deafness (2/40), hepatosplenomegaly (2/40) and thrombocytopenia. The calcifications are in periventricular white matter, striatum and thalamus and are perfectly symmetrical, unlike the calcifications in congenital CMV infection. The latter can be unilateral and are asymmetrical if bilateral. The diagnosis is based on serological evidence (ELISA antibodies) or on PCR positivity in blood or CSF. Although virus isolation is possible, human LCMV infections are generally diagnosed by means of serologic testing.
Clinical differential diagnosis of LCMV fetopathy. Symptomatic neonatal CMV and enterovirus infections are associated with hepatosplenomegaly, which is rarely noted in patients with congenital LCMV infections. Hearing deficits, which are not common in both symptomatic and asymptomatic infants who were infected with CMV, are unusual in infants with congenital LCMV infection. Congenital rubella syndrome, an entity that has decreased in prevalence but that has not been eliminated after the institution of universal immunization, is associated with cataracts, heart disease, and deafness, all of which have been extremely uncommon in patients with congenital LCMV infection. Both congenital rubella syndrome and congenital syphilis are also associated with a salt-and-pepper retinopathy not found in LCMV-infected infants. In addition, the osseous and hepatic abnormalities that are characteristic of congenital syphilis have been virtually absent in infants with congenital LCMV infection. LCMV, like human parvovirus B19, should be considered a cause of nonimmune hydrops fetalis. Congenital toxoplasmosis remains the most problematic differential diagnosis. As is the case in patients with congenital CMV and LCMV infections, chorioretinitis with macular scarring may occur. Congenital toxoplasmosis, however, tends to be associated with diffuse intracerebral calcifications, in contrast to congenital LCMV infection, which has been associated with periventricular calcifications.
Enterovirus / Coxsackie / Parechovirus — clinical and pathological detail
Tens of of non-polio enteroviruses cause abortion, stillbirth, prematurity and neonatal sepsis. They include enterovirus, coxsackie A and B. Infections peak in summer and fall in temperate climates. Both transplacental (symptoms within the first three days of life), intrapartum and postpartum transmission can occur. The mother (or nursing personnel) may have (i) a blank history, (ii) fever and abdominal pain (pseudo-appendicitis), (iii) pleurodynia (fever, thoracic pain), (iv) aseptic meningitis, (v) hand-foot-mouth disease. Mortality rates are high in recent (within one week) antepartum and low in postnatal infection. Humoral immune response in the mother is protective as in varicella infection in the perinatal period. Generalized infection in the newborn may be mild (reluctance to feed, fever, diarrhoea with echo and cox A, meningitis, apnoea) or severe [temperature instability, hepatitis, abdominal distension, coagulopathy with long PT and aPTT, pneumonitis, myocarditis - disturbed rhytm or conduction, rarely infarction -, adrenal haemorrhage, nephritis with medullary haemorrhage]. The septicaemic variant has been reported with echovirus types 2, 4, 5, 6, 9, 11, 14, 16, 18, 19, 21, and 22. A maculopapular rash is often noticed. Tonsillar vesicles have been seen with cox B2 meninigitis. Myocarditis can be the main problem in some children. More than 90 % of viral neonatal meningitides are due to enterovirus. Recent observations emerged of parechovirus encephalitis (Boivin et al. 2005). Our small cohort illustrated the range of effects of HPeV-3 on the neonatal brain (van Zwol et al. 2008). Though parechovirus infections are common, cases of severe life threatening disease in the newborn are not. This might be explained by the fact that discovery of HPeV-3 is relatively recent and the virus is not regularly tested for. Two of our patients died in status epilepticus. In two patients primary white matter injury was the presenting sign, together with seizures and a rash. Death due to HPeV-1 has been described before but to our knowledge not due to HPeV-3.
HSV — detailed clinical course
Neonatal HSV infection affects 1 per 2000 to 50,000 newborns; at least half have brain infection. Two thirds are due to HSV type 2. Most (80 %) infections occur during birth, but a proportion of around 10 % is either of antepartum or postpartum origin. Exacerbation during delivery is common following gestational primo-infection, less so following pre-pregnancy infection and during recurrence near the time of delivery. Most neonates with HSV infection have a mother who never presented with signs of HSV infection. Relatives and hospital personnel can be sources of postnatal infection. Typically, onset of clinical problems is rarely in the first week, mean age of onset is around day 16. Children are lethargic and irritable, feed poorly and may have fever. They become lethargic, develop apnoea and have seizures in up to 50 %, both general and focal. Primary pneumonitis with fever but without vesicles carries a high mortality rate as does anicteric fulminant liver failure. The prognosis is worse for preterms, facing ascending prenatal infection with rupture of the membranes, for infants with DIC or pneumonitis, and of course if treatment is started too late. Skin lesions are not obligatory, not even in the disseminated form. They are seen in about half of newborns with HSV encephalitis. Encephalitis may follow skin infection with merely a couple of vesicles. Facing seizures and vesicular eruption one must differentiate from incontinentia pigmenti, where vesicles arrange in a linear fashion, tend to develop bullae and eosinophilic spongiosis is seen on histology. Eye inflammation may smolder as suspected by increasing prevalence of chorioretinal scars over time. Cataract can be one of the end stage findings, together with 'retinal dysplasia'. In early postnatal encephalitis due to HSV (with preferential temporal and cingular involvement) the EEG will become epileptic and may be quasiperiodic (repititive sharp-slow wave complexes). The diagnosis of perinatal HSV infection can be based on: viral cultures, positive PCR in CSF (75 % if CNS clinically affected, in 24% if SEM disease even with normal CSF in some). PCR amplified DNA-positivity of CSF is very common (for a few weeks) but may be absent for up to 20 % of affected brains. CSF glucose can be low (around 30 mg/dL) for several weeks, the cellular reaction in CSF is limited (usually < 200 WBC/mm3, mainly mononuclear and with erythrocytes added), CSF protein can be very high (> 500 mg/dL). Convalescent serum may show specific IgM positivity.
Treatment with acyclovir must be intravenous, prompt and for 3 weeks (2 weeks for SEM disease). Skin/eye/mouth disease requires systemic treatment to prevent systemic or cerebral progression (reduction from 70 to < 20 %), as subclinical encephalitis in those infants may lead to sequelae. Recurrent cures may be indicated in infancy, perhaps on the basis of PCR presence in CSF, as recurrence is common (around 10%). Higher dosage to 20 mg/kg/8h has been recommended especially for systemic and cerebral involvement. During postnatal relapses of brain inflammation the portal of entry may be axonal inflow from cranial nerves or alternatively the virus may reactivate from brain itself.
HSV antenatal brain infection. In utero antepartum infection is rare and presents with prematurity (3/4), microcephaly (only if infected early), keratoconjunctivitis and /or chorioretinitis (if severe with microphtalmia), skin lesions (vesicles, bullae and/or scars, may have healed in case of early infection) and all stages of brain damage between multicystic encephalopathy and hydranencephaly. Cystic germinolysis has been described, proof of inflammation or cell death in germinal matrix. Isolated chorioretinitis is a possibility. The earlier the infection in utero the higher the risk of brain injury (84 % for infection in first or second, 29 % for infection in third trimester). On rare occasions infection may lead to non-immune hydrops. The placenta may harbor foci of necrotizing villitis with limited inflammatory reaction. The agent is virtually always HSV type 2. Recent antepartum infection after PROM may be the cause of skin/eye infection from birth without disseminatation (if treated promptly). Seizures on the first day may be the presenting sign. Additional findings can be: hepatomegaly, calcified adrenal glands.
HSV perinatal brain infection. In perinatal encephalitis due to HSV acquired just before (viral amnionitis) or during (cervical infection) delivery, a marked neuropathologic evolution can be seen: after an interval of a few days the affected, especially parietal and temporal parenchyma (not temporofrontal as in later life) becomes hyperechoic, thus producing pictures resembling MCA stroke or asphyxia, with brain swelling (Singer 1980, Matsumoto et al. 1983, Cleveland et al. 1987, Bale and Murphy 1997). The basal ganglia, if affected by this process, are hit on both sides and thalamus is not spared. White matter and brainstem/cerebellum can be affected as well. Lesions are bilateral, not necessarily symmetrical. HSV injures neurons as well as vessels, axons and glia. Inclusions can be found in neurons and oligodendroglia. Microglial reaction may be extensive and cause widespread appearance of microglial micronodules and chronic histiocytic infiltrates called malakoplakia (Mirra et al. 1971, Chang et al. 1980). The viral entry with the disseminated type and encephalitis is through inflammation of microvessels. Striatal vasculopathy may thus be one of the sonographic findings. The inflammatory process may become haemorrhagic. Mononuclear meningitis is associated. Focal necrosis can be seen in cerebellar folia, in dentate nucleus, in basis pontis and in medulla. Damage may be progressive after birth for several weeks. Finally hydrocephalus ex vacuo follows, bilateral temporal necrosis with gyriform calcifications in the subcortex and periventricular calcification. In the worst cases, moving through a stage of multicystic encephalopathy one eventually ends with postnatal hydranencephaly (Smith et al. 1977, Lyen et al. 1981). Early full lesion description may best be done with FLAIR or diffusion-weighted MRI (Kato et al. 1998). Cortical highlighting is probably not due to haemorrhage but to vessel dilatation and cell death. Most survivors have both severe motor and cognitive problems, although on occasion this may be limited to behavioural problems and mild cognitive dysfunction, in case of isolated periventricular calcification.
Parvovirus B19
The DNA virus parvo B19 needs species-specific P receptors to infect erythroid precursor cells, megakaryocytes, endothelial cells, cardiac myocytes, neutrophils and hepatocytes. Individuals lacking P antigen are not susceptible to infection with this virus. Viral replication exhausts marrow precursors and shortens the lifespan of red blood cells (fetal red cells already have a normal short life of 45 to 70 days), in part due to hemolysis. Anaemia, myocarditis and liver failure due to extramedullary haematopoiesis and secondary haemochromatosis all contribute to non-immune fetal hydrops. Hydrops develops between 1 to 3 months after maternal exposure, peak time being 4 to 6 weeks later. Fetal death peaks a few weeks after clinical onset of infection in the mother but intervals up to 12 weeks have been reported. Around 10 % of all cases of NIFH are due to parvovirus infection. NIFH occurs in about 3 % of fetuses when the mother has a parvo B19 infection between 9 and 20 weeks of gestation. NIFH of infectious nature is rarely seen with other agents: CMV, HSV, rubella, coxsackie, adenovirus, toxoplasmosis, syphilis, myocarditis with agent not specified. "Transient" hydrops has been reported, with a favorable outcome in infants found to be viremic after birth.
The diagnosis of recent fetal parvoviral infection can be made by finding: elevated specific IgM (day 3-60), a rise in specific IgG (persistently high throughout the first year from about day seven of disease onwards), viral DNA in fetal or neonatal blood (PCR amplified sequences), the virus in placenta or tissue with immunohistochemistry or LM/EM (inclusions). Routine viral culture is not feasible. Fetal sonographic examination should alarm by detecting NIFH and carditis. The affected fetus may be of transparent pallor. (S)he will have a hypoplastic erythroid series, severe extramedullary haematopoiesis in liver and spleen and possibly the blueberry muffin rash (∆∆ CMV, rubella, toxo, parvo, twin to twin transfusion syndrome, fetomaternal transfusion). Giant cell hepatitis, cholestasis and hemosiderin deposition are found in liver, without obvious necrosis as in herpes infection. Inflammation is limited. Inclusions of two types (early basophilic, later typically eosinophilic) in the nucleus of erythroid precursors (pronormoblast and normoblast) are seen in marrow and in vessels (also in placenta, lungs and renal glomerular capillaries). In liver, e.g. in sinusoids, giant pronormoblasts are readily seen. The placenta is thick, edematous and pale, with an excess of erythroblasts, villous fibrosis and limited necrosis (with calcification). Inclusions are seen in villous normoblasts. Heart findings can be myocarditis, myocyte hypertrophy and possibly fibroelastosis.
The evidence for an embryonic (first trimester) infection with survival and malformation is scanty: a few reports mention a rubella-like syndrome with eye lesions (microphtalmia, lens necrosis and retinal folds) and anencephaly (Hartwig et al. 1989). Fetal encephaloclastic lesions were described in the sense of necrosis, calcification and disturbed neuronal migration (polymicrogyria and ventriculomegaly). These mothers were infected between the 21th and 24th week of gestation. Presenting symptoms were hypotonia, infantile spasms, delayed development and arthrogryposis. Anencephaly and cerebellar hypoplasia were induced in animal models with other parvoviruses. More detailed reports of brain infection are needed.
Severe neonatal systemic disease caused by parvovirus has been reported in isolated cases (Vogel et al. 1997). Congenital parvovirus infection was diagnosed in two liveborn premature infants born at 24 and 35 weeks of gestational age. The illnesses were associated with placentomegaly, petechial rash, edema, hepatomegaly, anemia and thrombocytopenia, respiratory insufficiency, and death at 5 and 6 days of age. The syndromes exhibited by these cases shared common but nonspecific features with other life-threatening congenital infections. Serological studies in one case supported the diagnosis of parvoviral infection. Postmortem examination of both revealed nuclear inclusions in erythroid precursor cells characteristic of parvovirus infection. Use of PCR confirmed the presence of parvovirus DNA in one of the cases.
Mumps
Mumps pneumonia can cause severe neonatal respiratory distress. Aqueduct atresia, inseparable from malformative atresia, has been induced with mumps virus in experimental young animals. The association was reported in a human newborn with unilateral hydrocephalus. This finding was not corroborated by cohort studies of mumps in pregnancy. Loosened vaccination habits may redirect attention toward mumps in pregnancy. In isolated congenital hydrocephalus one should have an eye and hearing exam. Besides mumps, isolated hydrocephalus without calcification may be due to infection in utero with VZV, HSV, CMV, LCM.
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Johnson RT (1975) Hydrocephalus and viral infections. Dev Med Child Neurol 17:807-816.
Adenovirus
Adenovirus is one of the agents of neonatal viral pneumonia (ranking third after RSV and enterovirus), often with fatal outcome. Fever, lethargy, hepatosplenomegaly and coagulopathy all mimick enteroviral sepsis in its severe form. The neonate's liver is usually enlarged and liver enzymes are elevated. Adenoviral infection, like parvovirus B19, has been linked with fetal pleural effusion. Culturing the virus in conjunctival or bronchial secretions is the preferable method of diagnosis. The virus has been isolated from brains with perivascular inflammation and reactive astrocytosis. Encephalitis may be heralded by seizures and lowered consciousness. Often the mother will mention upper respiratory tract symptoms or a flu in the antepartum period.
Abzug MJ, Levin MJ (1991) Neonatal adenovirus infection: four patients and a review of the literature. Pediatrics 87:890-896.
Meyer K, Girgis N, Garey V (1985) Adenovirus associated with congenital pleural effusion. J Pediatr 107:433-435.
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EBV
Proof of the possibility of in utero EBV came from descriptions by Brown and Stenchever 1978 and Goldberg and Fulginiti 1981. Possible patterns of injury include growth retardation, microphtalmia, cataracts, metaphyseal osteitis, thrombocytopenia and congenital heart disease. Atypical lymphocytes and a high total serum IgM may point to the viral infectious nature. Specific early (anti EA) and late (anti EBNA) antigens may elicit detectable and diagnostic antibody responses. In utero infection is rare because primo-infection in pregnancy is rare (low prevalence of seronegative women of childbearing age). Intracranial calcification was reported in a congenital CMV-EBV tandem infection. In children EBV encephalitis can cause low T1 and high T2 signals in striatum, resolving after the acute stage. Other neurological patterns of injury may be meningitis, cerebellar ataxia, myelitis transversa, neuritis optica, Guillain-Barré syndrome, Bell's palsy and brainstem encephalitis (often fatal)(Ono et al. 1998).
Brown ZA, Stenchever MA (1978) Infectious mononucleosis and congenital anomalies. Am J Obstetr Gynecol 131:108-109.
Goldberg GN, Fulginiti VA, Roy G (1981) In utero Epstein-Barr virus (infectious mononucleosis) infection. JAMA 246:1579.
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Imaging findings
The typical enterovirus encephalitis images are well reported. Lethargy, fever, rash and seizures can be part of a systemic illness or be the main problem.
Low intensity areas on T1W MRI correspond with hyperintense foci on T2W and hyperechoic areas of inflamed white matter in some infants; these lesions resemble leukomalacia but differ in their more erratic (frontal as much as parieto-occipital) location and sometimes in their asymmetry (Haddad et al. 1990, Verboon-Maciolek et al. 2005). Hyperechoic initial stages are due to microglial and astroglial response to perivascular inflammation, cystic destruction may follow frank infarction of these areas after 1 tot 3 weeks.
Callosal white matter may be affected with striking swelling and hypointensity. In the acute stage injury really stands out in diffusion weighted sequences. The end result can be multicystic white matter destruction.
CSF may carry viral agents even in the absence of pleiocytosis.
Diagnosis is by culture of serum, stools (longest persistence) or CSF or by presence of RNA in PCR tested specimens.
Specific IgM may be documented for the Coxsackie infections.
Not only white matter, but also brainstem, cerebral and cerebellar cortex may be affected at postmortem. Intraventricular bleeding can complicate severe infection. Bilateral striatal inflammation, not necessarily ending in necrosis, can be one of the postnatal features of echovirus encephalitis (Freund et al. 1998).
Friede 1989: a glial nodule in coxsackie encephalitis affecting the tegmentumColour representation of affected areas (in red) (based on DWMRI in an instance of parechovirus encephalitis): bilateral but asymmetrical changes in cerebral and cerebellar white matter
Viral encephalitis: ultrasound findings
Bilateral non-congenital extensive hyperechoic change in white matter (not haemorrhagic) can occur: in preterm leukomalacia, in bacterial encephalitis, by acute intrapartum asphyxia, due to progressive leukodystrophy and some inborn errors of metabolism, by genetic brain inflammation (pseudo-Torch) and due to hypoglycaemia.
Other
Hemophagocytic lymphohistiocytosis (HLH) is a rare immune hyperactivation syndrome which may be primary (genetic) or secondary to various immune-related conditions including infection, immunodeficiency and malignancies. It can be associated with significant morbidity and mortality. Epstein-Barr virus (EBV) is a known infectious cause of acquired HLH, but EBV-associated HLH involving the central nervous system is rare and not well characterized neuropathologically (Magaki et al. 2017). We observed an infant of 2 months with seizures and fever, preceding fatal EBV-associated HLH with severe involvement of the central nervous system showing florid hemophagocytosis in the choroid plexus, with extensive neuron loss and gliosis in the cerebrum, cerebellum and brainstem. This inflammatory process celarly differs from viral white matter infection.
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