Neuroimaging of Pediatric Intracranial Infection

Views and Reviews

Neuroimaging of Pediatric Intracranial InfectionPart 2: TORCH,Viral, Fungal, and Parasitic InfectionsJoshua P. Nickerson, MD, Beat Richner, MD, Ky Santy, MD, Maarten H. Lequin, MD, Andrea Poretti, MD,Christopher G. Filippi, MD, Thierry A.G.M. Huisman, MDFrom the Divisions of Neuroradiology (JPN) and Pediatric Radiology (AP, TAGMH), Russell H. Morgan Department of Radiology and Radiological Science, The Johns HopkinsHospital, Baltimore, MD; Divisions of Pediatrics (BR) and Pediatric Imaging (KS), Jayavarman VII Kantha Bopha Hospitals, Siem Reap, Cambodia; Division of Pediatric Radiology,Sophia Childrens Hospital, Erasmus University Rotterdam, the Netherlands (MHL); Division of Pediatric Neurology, University Childrens Hospital, Zurich, Switzerland (AP);and Department of Neuroradiology, The University of Vermont/Fletcher Allen Healthcare, Burlington, VT (CGF).

Keywords: Pediatric intracranial infec-tions, children, ultrasound, magnetic res-onance imaging, susceptibility-weightedimaging, diffusion-weighted imaging, dif-fusion tensor imaging, magnetic reso-nance spectroscopy.

Acceptance: Received August 20, 2011,and in revised form October 27, 2011.Accepted for publication December 15,2011.

Correspondence: Thierry A.G.M.Huisman, MD, EQNR, FICIS, Division ofPediatric Radiology, Russell H. MorganDepartment of Radiology and Radiologi-cal Science, Johns Hopkins Hospital, 600North Wolfe Street, Nelson BasementB-173, Baltimore, MD 21287-0842.E-mail: [email protected] Neuroimaging 2012;XX:113.DOI: 10.1111/j.1552-6569.2011.00699.x

A B S T R A C TIn the second half of this 2-part review, the neuroimaging features of the most commonviral, fungal, and parasitic infections of the pediatric central nervous system are discussed.Brief discussions of epidemiology and pathophysiology will be followed by a review ofthe imaging findings and potential differential considerations.

IntroductionAs discussed in the first part of this review on pediatric centralnervous system (CNS) infections, the pediatric radiologist orneuroradiologist who routinely reads pediatric studies must befamiliar with the variable appearance of pediatric CNS infec-tions. Having discussed the various imaging modalities avail-able and the manifestations of bacterial infections (part 1), at-tention is turned to the viral infections and their sequelae, aswell as fungal and parasitic infections.

Before individual infectious agents are presented, a brief dis-cussion of imaging patterns and manifestations of broad diseaseclassifications is warranted. Certain classes of pathogens havea predilection for particular anatomic regions, and the imag-ing findings subsequently may be predictive of the infectiousagent. For example, herpes simplex virus (HSV) is well knownto preferentially affect the temporal and frontal lobes, fungalinfections often involve the central gray matter, Haemophilus in-fluenzae is seen to predominantly affect the subcortical regions,and cytomegalovirus (CMV) typically spares the subcorticalU-fibers while affecting the remainder of the cerebral white

matter. These preferential tissue involvements are helpful whenfaced with an imaging study in which many of the findings maybe nonspecific. Frequently, the imaging patterns associated withthe infectious agents are a result of the method through whichthat agent gains access to the CNS. Aside from the obviousdifferences between direct invasion from adjacent structuresand delivery via the bloodstream, the antigens presented bydifferent agents may result in their preferential deposition invarious brain regions. Tissue damage is in many cases duenot only to the endotoxins associated with the pathogen butto the associated inflammatory response of the host immunesystem.

Congenital Viral InfectionsPrenatal, intrauterine viral infections of the CNS are uniquebecause the fetal immune system is immature and the brainis rapidly developing. Interference with the various devel-opmental processes, for example, myelination, migration, orcortical organization may result in various presentations on

Copyright C 2012 by the American Society of Neuroimaging 1

Fig 1. Axial contrast enhanced CT image of a 10-year-old child withconfirmed congenital toxoplasmosis shows bilateral microophthalmiaand chorionic calcifications as well as deformity of the lenses (whitearrows).

neuroimaging depending on the gestational age at the timeof initial infection and the selective affinity of the infec-tious agents for the different brain structures. The prototypi-cal viruses to involve the fetus are summarized in the well-known mnemonic: TORCH (Toxoplasmosis, Other (Syphilis),Rubella, Cytomegalovirus, and Herpes Simplex Virus).

In utero infection with Toxoplasma gondii (Torch) is re-ported to occur in between one and six births per 1,000.1

Transplancental infection rates increases during progressingpregnancy from less than 20% in the first trimester to morethan 60% in the third trimester.1 The incidence of fetal infec-tion inversely correlates with severity of fetal damage at differ-ent pregnancy stages. The degree of damage to the fetal CNSdepends on the gestational date of infection. If the fetus is in-fected before 20 weeks of gestation, findings may be severeincluding the presence of microcephaly, hydrocephalus, tetra-paresis, seizures, cognitive impairment, migrational disorders,microophthalmia (Fig 1) and blindness due to chorioretinitis.Infection after 20 weeks of gestation results in more variableoutcomes with variable severity of the complications of ear-lier infection.2 The toxoplasma parasite may cause areas ofnecrosis within all parts of the neuroaxis including cerebrum,cerebellum, brain stem, and spinal cord. As a result of the im-mature immune system and impaired phagocytic ability of themacrophages, the areas of necrosis often undergo calcification,the hallmark finding of congenital toxoplasmosis.3 In congeni-tal toxoplasmosis, calcifications are typically located within thebasal ganglia, periventricularly, or in the cerebral cortex (Fig 2).The size of the calcifications has been correlated with the du-ration of infection with larger calcifications being seen in thesetting of first and second trimester infection. Traditionally,detection is been accomplished using computer tomography(CT) to search for areas of increased density reflecting calcifi-cation. However, a recent study by Lago and colleagues com-pared the utility of ultrasound (US) with CT for detection oftoxoplasmosis-associated calcifications and found a similar sen-sitivity and a high-intermodality agreement of 94%.3 Given the

Fig 2. Axial noncontrast CT images (A, B) of a 5-year-old childwith confirmed congenital toxoplasmosis show the typical multifo-cal periventricular and cortical/subcortical punctuate calcifications aswell as a moderate ventriculomegaly as complication of the infection.The overlying cortex and cerebellum (not shown) were unremarkableindicating that infection occurred late in pregnancy.

absence of ionizing radiation and the ease of obtaining trans-fontanellar US in the neonate, this technique should be the firstline examination if infection is suspected.

Congenital syphilis (tOrch) is caused by the Treponema pal-lidum spirochete and may cause infection via the transplacentalroute or may be acquired at the time of birth.4 The incidenceof neonatal syphilis varies widely by geographic region. One ofthe highest reported incidences is in South Africa where a highrate of maternal infection results in congenital infection in up to0.45% of infants.1 The incidence in theUnited States of America(USA) is significantly lower. In contrast to the other TORCHinfections, involvement of the CNS by syphilis is often asymp-tomatic at birth. Neurosyphilis may however present in the firstmonths of life with leptomeningitis and a nonspecific imagingpattern.4 There is often an associated hydrocephalus. Typically,the manifestations are more dramatic in the gastrointestinal (in-testinal obstruction) and musculoskeletal systems (periostitis,osteitis, osteochondritis and pseudoparalysis).

Rubella (toRch) is caused by a togavirus of the genus Ru-bivirus which can infect and replicate within the placenta.5 His-torically, rubella occurred in epidemics with the most recent inthe USA between 1964 and 1965. Since then, a systematic vac-cination program has resulted in the near-complete eradicationof this entity. Recently less than 50 cases of congenital rubellaare reported per year in the United States.5 The rubella virusshows a predilection for the CNS, and infected infants may typ-ically demonstrate cataracts, glaucoma, cardiac malformations,cochlear dysfunction, and central hearing loss.6 Involvement ofthe CNS is characterized by encephalitis resulting in muscularhypotonia, bulging anterior fontanelle, irritability, vasomotorinstability, lethargy, and seizures. Imaging findings reported inthe setting of congenital infection may include the presenceof subcortical hypodensities on CT corresponding to areas ofT2 hyperintensity on magnetic resonance imaging (MRI) andthe presence of periventricular and basal ganglia calcifications(Fig 3).7 Cerebellar hypoplasia and neuronal migration anoma-lies have also been reported.8

CMV (torCh) is the most commonly encountered TORCHinfection with incidence rates between 30,000 and 40,000 cases

2 Journal of Neuroimaging Vol XX No X 2012

Fig 3. Axial noncontrast CT (A) and T2-weighted MRI (B, C) im-ages of a 6-month-old child with confirmed congenital rubella infec-tion show small calcifications within the basal ganglia, along the in-tramedullary veins within both frontal lobes and within the deep layersof the overlying cerebral cortex and adjacent subcortical white matter(white arrows on A). MRI shows ill-defined, multifocal regions of dys-myelination within the periventricular white matter of both cerebralhemispheres (white arrows on B, C). No migrational abnormalitieswere noted.

Fig 4. Axial T2-(A, B) and parasagittal T1-weighted (C) MR imagesof a newborn with confirmed, early congenital CMV-infection. An ex-tensive developmental disorder is noted with a severe migrational andorganizational disorder (lissencephaly), periventricular white mattersignal abnormalities, moderate ventriculomegaly and mild micro-cephaly. Discrete T2-hypointense, subependymal calcifications arenoted along the lateral ventricles.

per year in the United States.1 Congenital CMV is the mostcommon cause for infectious hearing loss.8 As with toxoplas-mosis, the timing of infection during pregnancy correlates withthe severity of findings on imaging. Early infections around 16-18 weeks of gestation result in lissencephaly (Fig 4), whereaslater infections around 1824 weeks of gestation may causepolymicrogyria (Fig 5).9 Finally, later infection may result in ananatomically, normal appearing brain. Additional neuroimag-ing findings in congenital CMV infection include ventricu-lomegaly (Fig 5), abnormal white matter signal intensity (Figs 4,5), which is particularly located in the temporal lobes and repre-sents delayed or deficient myelination, cysts in the anterior por-tion of the temporal lobes, intracranial calcifications (Fig 5), andcerebellar hypoplasia (Fig 5).9-11 The severity of the cerebellarabnormalities correlates also with the timing of the infectionduring the pregnancy.12 The sensitivity of US, CT, and MRIwith regard to complications of CMV infection has extensivelybeen evaluated. In one series, US detected abnormalities in 56%of cases, CT in 71%, and MRI in 89%.13 In addition, althoughUS has been shown effective in the detection of periventricu-lar calcifications, lentriculostriate vasculopathy and pseudo-cystformation, MRI demonstrated to be of additional clinical utilityin revealing sonographically occult polymicrogyria, hippocam-pal dysplasia, and cerebellar hypoplasia.9 In addition, MRI

Fig 5. Axial CT-images (A-C), axial (D), coronal (E), and sagittal (F)T2-weighted MR images of a 2-year-old child with confirmed con-genital CMV-infection show multifocal, predominantly periventricu-lar located calcifications within the supra- and infratentorial brain aswell as a thickened, smooth dysplastic cortex, moderate ventricu-lomegaly, a small cerebellum and a CT-hypodense, T2-hyperintensedysmyelination of the periventricular white matter. In addition, a mildmicrocephaly is noted. The extension and degree of brain affectionindicates that infection occurred early during pregnancy.

may demonstrate the presence of abnormalities as early as with24 weeks of gestation.14 SWI is particularly helpful to de-tect calcifications based on its high susceptibility for cal-cium depositions that distort the magnetic field with resul-tant focal signal loss (Fig 6).15 A negative imaging workupalso has prognostic value as a favorable long-term neuro-logic outcome has been associated with absence of US orMRI abnormalities.16 In a study by Van der Voorn andcolleagues, imaging of congenital CMV infection was corre-lated with changes associated with periventricular leukoma-lacia. The similar neuropathologic changes associated withthese conditions suggest a final common pathway in theseentities.17

The most common viral encephalitis in adults, HSV (torcH)is the second most common TORCH infection with an inci-dence of up to one in 5000 children reported in the USA.1

In contrast to the other TORCH infections, most of the HSVinfections in neonates are not strictly congenital, but occur inthe perinatal/neonatal period and result from exposure to ma-ternal HSV type 2 genital lesions at the time of vaginal birth.The HSV-2 virus is associated with a greater degree of morbid-ity than the HSV-1 strain. Unlike the adult manifestations ofHSV infection, in the neonate the frontal and temporal lobesmay not be as preferentially involved and rather the deep andperiventricular white matter may be affected.18 In addition,hemorrhage is rarely seen in the setting of congenital HSV in-fection. Although diffuse cortical involvement is often present,there have been reported cases of involvement limited to thebrain stem and cerebellum.19 Findings on US and CT are non-specific and include the presence of both focal (often cytotoxic)edema and brain swelling.20 CT has been shown to correlatepoorly with the neurodevelopmental outcome of neonatal HSV

Nickerson et al: Clinical Imaging of Pediatric Intracranial Infection Part 2 3

Fig 6. Axial CT-images (A, D), T2-weighted images (B, E), and SWIimages (C, F) of an 8-month-old boy with congenital cytomegalovirusinfection presenting with microcephaly, developmental delay, andepileptic seizures. Moderate hydrocephalus and white matter volumeloss as well as subtle subependymal calcifications are seen on the CTstudy (white arrow on D). The extent of calcium depositions is how-ever much better appreciated on the SWI images as SWI-hypointensesignal abnormalities (C, F). In addition, cerebellar hypoplasia (A, B)and high-grade loss of the hemispheric white matter (E), including amore focal subcortical defect in the right parieto-occipital region arenoted (E).

infection.21 MRI is the most sensitive modality for the detec-tion of HSV in the CNS. Diffusion-weighted imaging (DWI) hasbeen reported to be more sensitive than T2 or FLAIR imaging.HSV infections of the CNS typically show a pattern of cortical

restricted diffusion early in the course of the illness (Fig 7).22,23

Sequelae of infection may be devastating with development ofdiffuse cystic encephalomalacia in addition to the possibility ofmortality (Fig 7).

Although not included in the traditional TORCH infections,intrauterine infections by varicella virus, Parvovirus B19, andhuman immunodeficiency virus (HIV) may result in a similarpattern of cerebral injury. Congenital varicella infection is rare,and occurs as a result of maternal infection after the 20th weekof gestation.24 Findings on imaging may include microcephaly,hydrocephalus, polymicrogyria, cerebellar hypoplasia, calcifi-cations, and global atrophy. Patients may clinically present withdevelopmental delay and seizures. One case reported by Di-mova and Karparov demonstrated unilateral volume loss andsignificant subcortical calcifications mimicking Sturge-Weber-Dimitri syndrome.24 Maternal infection early in gestation hasbeen reported to result in abnormalities of neuronal migrationincluding the presence of polymicrogyria and heterotopia.25 Incongenital HIV infection, calcifications of the basal ganglia andsubcortical white matter may be present (Fig 8).

Of note, when faced with imaging findings suggestiveof TORCH infection, some inherited disorders such as theAicardi-Goutie`res syndrome (AGS), the pseudo-TORCH orBaraitser-Reardon syndrome, and the cystic leukoencephalopa-thy due to mutation in the gene encoding the RNASET2glycoprotein should be considered. In contrast to congenitalviral infections, inherited disorders have typically a progres-sive clinical course. AGS typically presents in infancy with ir-ritability, poor feeding, progressive microcephaly, spasticity,and dystonia and death often occurs in early childhood.26

Multiple punctuate calcifications within the basal ganglia (the

Fig 7. Axial T2-weighted (A), postcontrast T1-weighted (B), DWI (C) images, and ADC maps (D) of a 4-week-old newborn whopresented with seizures and progressive lethargy. MRI shows a moderate T2-hyperintense swelling of the cortex within both tempo-ral lobes (right > left) with reduced cortico-medullary differentiation. On the contrast-enhanced T1-weighted image a mildly increasedleptomeningeal enhancement is noted (white arrows). Significantly restricted diffusion (DWI-hyperintense, ADC-hypointense) is seenwithin the cortex and immediate subcortical white matter of both temporal lobes and hippocampi. The restricted diffusion also extendsalong the hippocampal commissure. Findings are highly suggestive of herpes simplex infection, which was subsequently confirmed.Follow-up MRI including axial T2-weighted (E), T1-weighted (F), DWI (G) MR images, and ADC maps (H) 4 months later show exten-sive, severe cystic encephalomalacia involving both temporal lobes. The areas of tissue loss match the regions with restricted diffusion on theinitial MRI.


Fig 8. Axial CT images (A, B) of a 1-year-old child with confirmedcongenital HIV infection show bilateral, ill defined, dense calcifica-tions within the lentiform nuclei as well as within the subcortical frontaland parietal white matter bilaterally. No ventriculomegaly.

putamina are predominantly involved), lobar white matter, anddentate nuclei, diffuse or with an antero-posterior gradient T2-hyperintense signal abnormality of the subcortical and deepwhite matter, and diffuse, cortical and white matter atrophywith subsequent ventriculomegaly are the typical neuroimagingfindings in AGS.27 The pseudo-TORCH or BaraitserReardonis characterized by imaging findings suggestive of neonatalTORCH infection but negative serology for any of these in-fectious agents.28 The etiology is presumed to be genetic andin some cases a homozygous mutation in the tight-junction pro-tein gene JAM3 has been reported.29 In addition, mutationin the gene encoding the RNASET2 glycoprotein may resultin a cystic leukoencephalopathy resembling congenital CMVinfection.30

Viral InfectionsMost commonly, viral infections of the pediatric CNS mani-fest in the form of a meningitis. Progression to viral encephali-tis can be usually distinguished clinically by the presence offocal neurologic deficits or global neurologic deterioration.20

The involvement of the gray matter in viral encephalitis hastypically been reported to account for changes in neurologicstatus.31 In many causes of viral encephalitis the imaging pat-terns are nonspecific. US and CT may only show areas of cor-tical and subcortical edema, whereas findings on MRI mayalso be limited to areas of parenchymal T2 prolongation.23

T2-hyperintense signal abnormalities and swelling involvingthe cortical gray matter, subcortical white matter, and/or hip-pocampi may be found periictally in the context of generalizedtonic-clonic seizures and/or status epilepticus.32 These MR sig-nal changes are transient and may be associated with restricteddiffusion (hyperintensity on DWI and matching reduced valueson ADC maps).33 Because seizures are a common clinical pre-sentation/complication of encephalitis, transient periictal signalchanges are a differential diagnosis of encephalitis and corre-lation to the medical history and clinical presentation as wellas laboratory findings is important for correct diagnosis. In-terestingly, periictal T2-hyperintense signal abnormalities with

Fig 9. Axial T2- (A-C), FLAIR- (D-F), and postcontrast T1- (G-I)weighted MR images of an 11-year-old boy with a 6 weeks course ofprogressively worsening dysarthria, weakness and ataxia show T2-and FLAIR-hyperintense signal abnormalities within the pons, cere-bellar peduncles, midbrain, and cortical-subcortical frontal and oc-cipital white matter consistent with ADEM. Note the matching patchyenhancement (GI) due to the subacute phase of the disease.

restricted diffusion have been found to be an effect rather thanthe cause of status epilepticus.34

Acute disseminated encephalomyelitis (ADEM) is animmune-mediated inflammatory disease which typically occursas a late complication of a viral infection.35 ADEM is usuallya monophasic disease with sudden onset and rapidly, progress-ing impairment of consciousness and focal neurologic deficits.In the majority of the patients a complete recovery is seenwithin 2-3 months.36 Recurrent and multiphasic courses are,however, also described. ADEM presents with large, patchy,ill-defined regions of T2- and FLAIR-hyperintensity in thecontext of a viral infection and is therefore another differ-ential diagnosis to acute encephalitis (Fig 9).37 In ADEM,however, the lesions affect predominantly the subcortical andperiventricular white matter, while acute viral encephalitis ischaracterized by predominant cortical lesions. In ADEM var-ious patterns of postcontrast enhancement may be seen in thesubacute phase (Fig 9).

Some of the viral agents may, however, demonstrate a char-acteristic pattern of brain involvement (Table 1) and that alongwith the clinical history and laboratory findings may narrow thedifferential diagnosis.


Table 1. Characteristic Imaging Features of Selected Intracranial ViralInfections

Viral Infection Characteristic Neuroimaging Findings

Neonatal HSV encephalitis Multiple T2-hyperintese lesions,involvement of basal ganglia andthalami, rarely hemorrhagic lesions

Childhood HSVencephalitis

Involvement of the limbicsystem/temporal lobe, usuallybilaterally, asymmetric,hemorrhagic lesions common, basalganglia and thalami spared

West Nile virus encephalitis T2-hyperintense lesions involvingbilaterally basal ganglia and thalami

Japanese encephalitis T2-hyperintense lesions involvingbilaterally the thalami, restricteddiffusion intralesionally

Enteroviruses T2-hyperintense lesions involvingbrainstem and cerebellum(rhombencephalitis)

EBV encephalitis Involvement of basal ganglia andthalami

HSV = herpes simplex virus; EBV = EpsteinBarr virus.

EpsteinBarr virus (EBV) is a ubiquitous gamma herpesvirus which typically causes infectious mononucleosis and se-roconversion in up to 90% of the children.38 Neurologic man-ifestations of EBV infections include meningoencephalitis, theAlice in Wonderland syndrome, cerebellitis, aseptic menin-gitis, transverse myelitis, Guillain-Barre syndrome, and cranialneuritis mostly affecting the seventh cranial nerve.39,40 EBV hasa tropism for the deep gray matter nuclei. Therefore, the pres-ence of hyperintense signal abnormalities in the basal ganglia,and thalami on T2- and FLAIR-weighted MR images suggestsEBV encephalitis.41 These lesions typically do not enhance af-ter contrast injection and may also involve the cerebral cortex,subcortical white matter, and less often, the brain stem andcerebellum.

Parvovirus B19 is a ubiquitous agent which causes ery-thema infectiosum in children. As many as 60% of adultsare seropositive for parvovirus B19.42 The incidence ofmeningoencephalitis in the setting of systemic viral infection inchildren has been estimated to be between 4-5%.43 Up to 31%of patients with CNS involvement may suffer from long-termsequelae.42 Imaging studies in these patients may be normal,or may demonstrate the presence of nonspecific white mat-ter hyperintensities on T2-weighted MRI and mild ventricu-lomegaly.42,43 Patients with sickle cell disease are at particularrisk of stroke in the setting of parvovirus B19 infection associ-ated with aplastic crisis.42

In the last 10 years, the West Nile virus has emerged asthe most common viral agent implicated in encephalitis in thewestern hemisphere.44 The virus is a member of the flavivirusfamily and is an arbovirus, spread bymosquitos.Most infectionsare subclinical, and the true incidence of this infection may infact be much greater than reported. However, there are rarecases of severe forms of disease including encephalitis, menin-gitis, meningoencephalitis, and acute flaccid paralysis, whichresults from anterior horn cell involvement similar to that seen

Fig 10. Axial T2-weighted (A), coronal FLAIR (B), axial DWI (C) MRimages, and axial ADC map (D) of a 5-year-old Cambodian girl withconfirmed Japanese encephalitis (JEV-PCR positive in the CSF).She presented with seizures and progressive coma; MRI showssymmetrical, ill defined T2- and FLAIR-hyperintense signal abnor-malities in both thalami with matching regions of restricted diffusion(DWI-hyperintense, ADC-hypointense) on diffusion weighted imaging(white arrows on A-D) compatible with Japanese encephalitis.

in polio infection.44 The imaging findings in West Nile virus in-fection are nonspecific. CT imaging is most frequently normal,and on MRI, DWI has been reported to be the most sensitivesequence with identification of cortical and subcortical lesionswith restricted diffusion in early infection.23

Two additional members of the flavivirus family should beconsidered in the setting of pediatric CNS infections. Japaneseencephalitis is rare in the west, but has been estimated to af-fect up to 50,000 patients per year and result in up to 10,000deaths per year. Children and young adults are most frequentlyinfected. Imaging has been reported to be significantly moresensitive in the setting of Japanese encephalitis than in WestNile virus with CT studies demonstrating abnormalities in 38%and MRI in up to 90% of patients.23 Mixed intensity abnor-malities predominantly within the thalami but also involvingthe basal ganglia, brain stem, and cortical areas are character-istic (Figs 10, 11). Murray Valley encephalitis is a member ofthe same group of viral infections as Japanese encephalitis, andhas been reported to demonstrate similar imaging findings.23

Dengue fever is caused by another flavivirus with a mosquitovector. Dengue is primarily endemic in Southeast Asia andAfrica, but has also been reported in Australia andNorth Amer-ica.45 A study of nine patients by Misra et al showed no CTabnormalities and only one of nine patients had signal abnor-malities in the globus pallidus characterized by T2 prolongation


Fig 11. Long-echo time (TE = 144 ms) water-suppressed 1H-MRSspectrum with voxel positioned within the signal abnormality of leftthalamus (same patient of Fig 7) shows an inverted double lactatepeak at 1.3 ppm as well as an increased Choline/Creatine ratio,and a decreased N-acetyl aspartate/Creatine ratio confirming tissuenecrosis/injury.

bilaterally.45 Another study of patients with confirmed Dengueinfection of the CNS reported no focal CT imaging findings.46

As such, imaging is likely of limited value in the setting of thisflavivirus infection.

The Nipah virus is a paramyxovirus that was first reportedin the late 1990s in southeast Asia.47 Imaging findings in this in-fection have been reported to include the presence of multiplesmall nonspecific white matter T2-hyperintensities on MRI.23

Pathologic correlation suggests that these findings may be sec-ondary to the presence of small and medium vessel vasculitis.47

In patients with long-term deficits following infection, areas ofconfluent subcortical and cortical signal change as well as globalcerebral or cerebellar atrophy have been reported.47

Influenza A and B viruses are common respiratorypathogens from the Orthomyxoviridae family. Neurologiccomplications have been observed in both InfluenzaA andB in-fections and include mostly febrile seizures, whereas influenza-associated encephalopathy/encephalitis is less common andmay show transient lesions with T2-hyperintense signal abnor-mality and restricted diffusion affecting the splenium of the cor-pus callosum.48 Acute necrotizing encephalopathy (ANE) is arare fulminant encephalopathy of early childhood and is mostlytriggered by viral infections such as Influenza A and B, parain-fluenza, varicella, and Human Herpes Virus type 6 (HHV6),but may also result from Mycoplasma pneumoniae and vaccina-tions.49 The initial presentation begins with signs and symp-toms of a viral childhood infection followed by a progressiveand rapid deterioration culminating in coma. CT-hypodenselesions affecting the thalami and brain stem with matching T2-and FLAIR-hyperintense, edematous lesions on MRI are themain neuroimaging findings (Fig 12).50 The internal and ex-ternal capsulae, putamen, claustrum, hippocampus, amygdala,mammillary bodies, cerebellum, periventricular white matter,and medial temporal lobes may also be involved. Involvementof the pons is a poor prognostic factor. Early recognition of ANEis important because early treatment with steroids is essential. Afamilial genetic predisposition (point mutations in the RANBP2gene) has been found and allows identification of additional,at-risk individuals in an affected family.51

Another arbovirus transmitted by mosquitos that may causesignificant morbidity as a result of CNS infection in children

is the Chikungunya virus. Robin and colleagues described aseries of children with confirmed infection by this alphavirusendemic to tropical Africa and southeast Asia who presentedwith altered levels of consciousness, hallucinations, nuchalrigidity, seizures, headache, and focal neurologic deficits.52 USdemonstrated the presence of edema and lenticulostriate vas-culopathy. CT imaging may show generalized edema, and inone case cerebellar hemorrhage was reported. In older chil-dren, MRI was frequently normal, but all infants less than onemonth of age demonstrated regions of restricted diffusion inthe centrum semiovale and corpus callosum without associatedenhancement.52

Several members of the Picornaviridae family that includeparechovirus, coxackievirus, poliovirus, and echovirus, havebeen reported to result in encephalitis in children. Infectionsby these agents are associated with severe neurologic damageand poor outcome.18 Most children are infected before the ageof 5 years with coxackievirus and echovirus, infections are of-ten seen in the late summer or fall.31,53 Infection may predomi-nantly affect thewhitematter, and brain injury or edemamay bevisible on US, though more detailed information is yielded byMRI, and DWI in particular.54 Multifocal areas of restricted dif-fusion within the white matter are reported, in addition small ar-eas of susceptibility artifact have been seen suggesting that theseencephalitides may become hemorrhagic.54 Coxackievirus andpoliovirus show a predilection for the anterior horn cells withinthe spinal cord as well as the medulla, pons, and cerebellumaccounting for the propensity to cause motor disturbances.18

The manifestations of HIV in neonates and children differsignificantly from those encountered in the adult population. Atleast 50% of infected children will develop neurologic signs andsymptoms during the course of their disease.55 HIV transmis-sion may occur in a vertical fashion during pregnancy, at thetime of delivery, or via breastfeeding.55 Although in adults themost common clinical presentation of primary HIV involve-ment of the CNS is that of subacute encephalitis and progres-sive dementia, children more commonly manifest with diffuseencephalopathy.20 Three forms have been described in the liter-ature. The most severe form presents with subacute progressiveencephalopathy characterized by progressive global deteriora-tion with loss of acquired skills. This form is most frequentlyseen in infants and young children who have not undergoneany form of antiretroviral therapy. In the less severe form, aprogressive encephalopathy of the plateau subtype is seen inwhich acquisition of new skills is significantly slowed or evenarrested. Static encephalopathy is the mildest form in whichnew skills are gained but at a significantly slower rate.55 Georgeet al reviewed the imaging findings in HIV infected children in-cluding the appearance of primaryHIV encephalopathy as wellas the opportunistic infections seen in these patients.55 In sum-mary, the most common imaging findings are those of globalparenchymal atrophy and ventriculomegaly (Fig 13). Later inthe course of infection, white matter lesions similar to thosedescribed in varicella and CMV may be present. Secondarysuperinfections differ from those seen in adult patients. For ex-ample, although toxoplasmosis is seen with some frequency inadults, only a few cases have been reported in HIV-infectedchildren. The most common pediatric secondary infection is


Fig 12. Axial (A, E) and coronal (B, F) T2-weighted MR images, axial ADC maps (C, G), axial SWI image (D), and midsagittal T2-weightedimage (H) of an 8-year-old child with acute necrotizing encephalopathy in the context of Influenza A infection show marked T2-hyperintensesignal abnormalities of the pons, thalami, and capsulae externae with matching restricted diffusion (ADC hypointense). The pons appearsswollen and SWI shows multiple small hypointense signal abnormalities consistent with petechial hemorrhages.

Fig 13. Axial (A) and coronal (B) T2-weighted MR images of a 4-month-old child with perinatally acquired HIV-infection show severeglobal brain atrophy and delayed myelination.

CMV, which presents with periventricular foci of T2 prolonga-tion onMRI accompanied by enhancement on postgadoliniumimaging. Tuberculosis infection may be seen, but the typicalbasal enhancement described in the first part of this reviewis often absent given lack of an inflammatory response. Fun-gal infections such as Aspergillus and Cryptococcus may beseen, and manifestations are similar to the immunocompetentpatient as will be discussed subsequently. Progressive multi-focal leukoencephalopathy (PML) as a result of JC virus (JCare the initials of the index patient) infection is seen less fre-quently than in adults, though cases have been reported.56,57 Inchildren, the neuroimaging appearance of PML is the samethan in adults and includes T2-hyperintense signal abnor-malities within the (mostly frontal or parieto-occipital) whitematter without mass effect or postcontrast enhancement (Fig14).40 Finally, there are reports of CNS infection with Epstein-Barr virus, HSV, and candidiasis in children with HIV aswell.38

Fig 14. Axial T2- (A-C) and postcontrast T1-weighted (DF) MRimages of a 15-year-old girl with perinatally acquired HIV-infectionshow T2-hyperintense confluent areas of demyelination predomi-nantly within the right parietooccipital white matter with extensioninto the right cingulate gyrus compatible with progressive multifocalleukoencephalopathy (PML). The overlying cortex is typically sparedin the early phases. In addition, multiple punctuate T2-hyperintenselesions are seen throughout the entire right hemisphere. The area ofT2-hyperintensity typically does not enhance and no significant masseffect is noted.

Fungal InfectionsFungal infection of the pediatric CNS are most frequently seenin the extremely premature neonate or in immunocompro-mised children.18 In the case of the premature neonate, fungalinfection ranks third behind TORCH infection and bacterialmeningitis as a cause of infectious encephalopathy.8 In additionto childrenwithHIV, patients with immunocompromission dueto systemic chemotherapy or stem cell transplantation have alsobeen reported at increased risk for fungal CNS infection with


mortalities reported as high as 36%.5,58 The imaging findingsin fungal encephalitis are nonspecific and may mimic other in-fections as well as intracranial metastatic disease.59 Althoughit has been reported that DWI is the most sensitive sequencewith respect to the presence of fungal abscess within the brain,it is worth noting that the pattern of diffusion restriction maydiffer or may not be present in certain organisms. A study byLuthra et al described a pattern of restricted diffusion withinthe periphery of fungal collections in the brain correspond-ing to crenated projections as identified on the conventionalMR sequences rather than the typical restricted diffusion seenwithin the center of pyogenic abscesses.60 These authors re-port that fungal abscesses are most frequently located withinthe deep white matter and basal ganglia and only infrequentlydemonstratematching contrast enhancement. Another group ofauthors reported an increased incidence within the deep graynuclei and the presence of heterogeneous signal on both T2-weighted sequences and DWI.61 However, others report thegreatest frequency of fungal cerebral abscesses to occur at thegray-white matter junctions and to be associated with ring en-hancement following gadolinium administration.62 It is likelythat the age of the patient and the immune status play a rolein the distribution of lesions and their imaging characteristics(e.g., contrast enhancement) that has not been fully understoodat this point.

Candida albicans is a diploid fungus which may cause dis-seminated fungemia in up to 5% of very low birth weightneonates.8 In these neonates, CNS involvement which may in-clude meningitis, ependymitis, and microabscess formation hasbeen reported to occur in up to 64% of children.8 These patientstypically have poor clinical outcomes.63 Imaging findings mayinclude the presence of diffuse parenchymal lesions throughoutthe supratentorial and infratentorial brain as well as occasion-ally within the ventricles with a varying degree of associatedenhancement depending on the ability of the host to mount animmune response.18 Under appropriate treatment, the imagingchanges may regress over a time course of up to 6 months. Onestudy comparing the effectiveness of US and MRI found nodifference in the sensitivity to microabscess formation.63

Aspergillus infection may involve the CNS in severelyimmunocompromised patients and has been reported to bethe most common fungal infection in children undergoingchemotherapy or having received hematopoietic stem celltransplantation.58 Invasive aspergillus infection of the CNSmaybe associated with a very high mortality, greater than 85%.18

The imaging appearance may be subtle with minimal mass ef-fect on CT and nonspecific MRI findings, though associatedsinus disease may suggest inclusion of aspergillus in the dif-ferential diagnosis in these patients (Fig 15).20 Although rarein the setting of HIV infection, aspergillus has been reportedto present with edematous, ring-enhancing hemorrhagic le-sions. Infarctions and aneurysm formation is believed to re-sult of fungus-induced vasculitis.55 Susceptibility artifact maysurround aspergillus collections as a result of the paramag-netic effect of elements within the hyphae.55 These artifactsmay mimic calcifications or hemorrhages. If the degree ofimmune compromise is severe, absence of enhancement hasbeen reported in the setting of autopsy proven angioinvasiveaspergillosis.64

Additional fungal infections in children reported in the liter-ature include Cryptococcus in immunocompromised patients(HIV disease, oncologic patients, children after bone marrowtransplantation, and teenagers with rheumatologic disordersreceiving immunosuppression) with imaging features rangingfrom minimal nonspecific changes to pseudocyst formationwithin the basal ganglia and thalami.55 Unusual opportunisticinfections with fungus Pseudallescheria boydii , that may presentwith imaging characteristics similar to invasive aspergillo-sis, have been described in the setting of near-drowning.65

Although mucor mycosis may also be seen in the setting ofsevere immunocompromised children and is also associatedwith concomitant sinus disease, progression of this infectionis so rapid that imaging usually offers little support to changeclinical outcomes.20

Parasitic InfectionsParasitic infections of the CNS are rare. The most commonparasite to involve the pediatric brain is Taenia solium, the porktapeworm responsible for neurocysticercosis. The findings inchildren are similar to those in adults and are clinically char-acterized by an initial asymptomatic stage followed by seizuresand focal neurologic signs. An elevated intracranial pressuremay develop due to inflammatory responses related to thedeath of the larva within the brain parenchyma.20 The imagingfindings vary depending on the life stage of the parasite withmarked ring enhancement and surrounding edema manifestedby T2 prolongation within the adjacent white matter associatedwith spontaneous or treatment-related larval death (Fig 16).20,23

Following these acute changes, the parasite undergoes involu-tion and may calcify resulting in the characteristic CT findingsseen in the setting of prior infection.20 Calcifications in neu-rocysticercosis or other parasitic infections are typically, easilydepicted by SWI (Fig 16).

Turget reported on a large number of children and adoles-cents in Turkey with hydatidosis of the CNS.66 Hydatid disease,caused by infection with Echinococcus granulosus involves theCNS in less than 3% of cases. However, the majority of thosecases are seen in pediatric patients.63 Imaging findings includethe presence of unilocular cysts seen on both CT and MRIsimilar to the appearance of this infection elsewhere in thebody.

Cerebral malaria caused by the mosquito-borne parasitePlasmodium falciparum is endemic to Africa and SoutheastAsia. This infection may involve patients of all ages and maybe fatal in 20-50% of cases.67 Cerebral malaria typically resultsin diffuse petechial hemorrhagingwithin the brain parenchyma.Conventional MRI may underestimate the degree of cerebralmicro-hemorrhages, susceptibility-weighted sequences (SWI)have been shown to reveal the extent of injury with highersensitivity and in much better detail.67

Another rare parasitic cause of encephalitis reported in chil-dren is Balisascaris procyonis, also known as the raccoon round-worm. This parasite is acquired due to ingestion of soil withfeces of infected raccoons. Infection may cause severe mor-bidity and mortality. Imaging findings include diffuse T2 pro-longation throughout the white matter predominantly in the


Fig 15. Axial T2- (A, E), axial contrast enhanced T1-weighted (B, F), axial DWI (C, G) MR images, and axial ADC maps (D, H) of a 2.5-year-oldchild with acute lymphoblastic leukemia and confirmed, multiple intracerebral aspergillus abscesses (developed under ongoing chemotherapytreatment) show multiple T2-hyperintense lesions with mildly enhancing capsule and characteristic restricted diffusion (hyperintense on DWIand hypointense on ADC maps) throughout both hemispheres. The lesions are located within the central gray matter as well as at thecortical/subcortical junction. Despite the size of the lesions, the mass effect is minimal.

Fig 16. Axial (A) and coronal (B) T2-weighted, axial (C) and coronal (D) FLAIR, axial DWI (E) and axial SWI (F) images of a 5-year-old Indiangirl presenting with fever and new focal seizures show a T2- and FLAIR-hypointense round lesion within the subcortical white matter of theright parietal lobe with minimal surrounding edema. DWI (E) shows the lesion as hypointense, indicating increased diffusion and differentiatingit from a bacterial abscess. The hypointense susceptibility artifact on SWI (F) represents intralesional calcifications.

periventricular locations followed by the development of pro-found cerebral atrophy.68

ConclusionsAlthough relatively uncommon, infections of the CNS inneonates and children may result in catastrophic brain injurywith poor outcome if untreated. However, in many cases ap-propriate treatmentmay limit morbidity andmortality. As such,early and correct recognition of the imaging findings is of cru-

cial importance to guide treatment. Although many findingsmay be nonspecific, an understanding of the patterns of ab-normality in conjunction with the clinical presentation and de-mographic characteristics of the child may help establish ornarrow the differential diagnosis and be of outmost impor-tance to the clinicians caring for these patients. Familiaritywith infectious diseases that were believed defeated or havebecome rare is important. High-end multimodality imaging in-cluding DWI and 1H-MRS are essential to narrow differentialdiagnosis.


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Neuroimaging of Pediatric Intracranial Infection