Neuroimaging of herpesvirus infections in children

There are two serotypes of HSV: HSV-1 and HSV-2. For practical purposes, HSV-1 typically involves the skin and mucosa of the face while HSV-2 is associated with genital infection. Because neonates usually acquire the infection during birth, neonatal herpes, which can cause CNS complications, is usually secondary to HSV-2. In contradistinction, the most common etiology of HSE in non-neonatal children is reactivation of HSV-1 [14]. Both serotypes are capable of causing congenital infection [5, 15].

True congenital HSV infection, i.e. transplacental transmission of the virus by the mother to the fetus, accounts for only 5–10% of “neonatal herpes.” Congenital infection is usually caused by HSV-2 [16, 17] and is apparent within the first days of life. In these cases, the virus has crossed the placenta to infect the newborn and can be found in amniotic fluid and placental tissue [18, 19]. Affected neonates present with a combination of skin lesions, chorioretinitis, microcephaly, and/or hydranencephaly [5, 15]. This congenital presentation differs from neonatal herpes, and because it is outside the scope of this review, will not be discussed in further detail.

The incidence of neonatal herpes is difficult to track because it is not a reportable disease, and HSV-1 and HSV-2 seroprevalence varies regionally. Most sources quote an incidence of one per 3,000 to 20,000 live births [20]. In contradistinction to congenital infection, which presents within the first few days of life, neonatal herpes results from contact with infected lesions or secretions during or shortly after birth [5, 15, 16, 21], and presentation is delayed for 2–4 weeks [5]. Children can contract the virus from an asymptomatic mother or even from close contact with caregivers during the perinatal period [15]. Neonatal HSV infection is divided into three categories: skin-eye-mouth (SEM) disease, CNS disease, and disseminated infection [15, 22], although there is clinical overlap, particularly of the latter two manifestations. Animal models have shown that cutaneous contraction of the virus results in SEM or mild disseminated disease, both with a relatively benign course. Individuals infected through the mucous membranes, respiratory tract, or eyes develop disseminated and/or CNS disease and have increased morbidity and mortality [23, 24]. Approximately 30% of all infected neonates develop CNS manifestations, presenting with seizures, irritability, lethargy, and/or fever [5, 15, 22]. Approximately two-thirds of neonatal herpes encephalitis is caused by infection with HSV-2 [15] and the prognosis is worse for these patients. In a study comparing the long-term outcome of treated neonatal herpes encephalitis, infants infected with HSV-2 had higher morbidity. Whereas children with HSV-1 CNS disease (n = 9) were normal at follow-up, those with HSV-2 infection (n = 15) had increased rates of microcephaly, seizures, cerebral palsy, and mental retardation [25]. It is recommended that neonates with herpes encephalitis be treated at higher doses than adults and children with HSE [26].

Non-neonatal HSV is yet another entity, with unique clinical and imaging features compared to neonatal HSV infection [27]. To differentiate these two patient groups, throughout this article CNS manifestations in non-neonatal herpes will be referred to as HSE. HSE is the most common cause of non-epidemic focal encephalitis in children older than 6 months [14, 28, 29], and 25–30% of cases occur in children [30]. HSE is usually caused by HSV-1 and is the manifestation of reactivated disease. HSV-1 is a ubiquitous virus that rarely causes neurologic complications. Children usually become infected with the virus early in life from direct contact with the secretions or lesions of infected individuals (who may or may not be symptomatic). The primary infection is more often asymptomatic, and likewise, the virus is typically shed from an asymptomatic individual. Gingivostomatitis is the second most common presentation of the primary viremia and is self-limiting. After primary infection, the virus persists in a latent form within the trigeminal sensory ganglion [6]. By unclear mechanisms, the virus occasionally reactivates and can travel retrograde along branches of the trigeminal nerve, along the ventral leptomeninges, and infect the brain, particularly the frontal and temporal lobes [5, 6]. This mechanism of entry, perhaps in concert with cellular tropism [2], accounts for the typical involvement of the limbic system in HSE discussed below. Patients with reactivation of HSV-1 typically present with antecedent fever and headache. Those with encephalitis have a combination of seizures, personality changes, acute mental status changes, and focal neurologic deficits [30], whereas those with meningitis typically lack focal neurologic abnormalities [29]. Early detection and diagnosis of HSV-1 encephalitis is crucial, as prompt administration of acyclovir can dramatically reduce morbidity and mortality [30]. Excellent recent reviews of pediatric [31] HSE [14] are available.

HSV-1 and HSV-2 infections represent the archetype for herpesvirus CNS disease. The protean nature of the virus family is reflected in the spectrum of clinical presentations and imaging findings seen with CNS HSV infection. The differing mechanisms of CNS entry lead to the varied presentations and to the different neuroimaging appearances. The differential diagnosis of any given case will vary depending on the type of herpes encephalitis. In the older child with HSE, there is a pattern of non-enhancing cortical and subcortical signal abnormalities. The differential considerations in this setting would include other viral encephalitides, acute demyelinating encephalomyelitis (ADEM) and, especially in a seizing child, tubers of tuberous sclerosis. Diffusion abnormalities seen in HSV infection can lessen the suspicion for ADEM, while a lack of other stigmata of tuberous sclerosis would exclude that entity. Older children with HSE have signal abnormalities in the medial temporal and inferior frontal lobes, insula, and cingulate gyrus that distinguish HSV among other causes of encephalitis. Further specificity derives from the fact that HSV infection often causes hemorrhage, which is seen as increased signal on T1-W images or decreased signal on GRE sequences because of deoxyhemoglobin. DWI is also an excellent adjunct when there is suspicion of HSE because this aggressive cytotoxic encephalitis can cause brain necrosis, which, when imaged early, manifests as diffusion restriction [45, 46]. Of course, with diffusion abnormalities, stroke (both venous and arterial) and mitochondrial cytopathy enters into the differential diagnosis. In the case of HSV, the hypothesized mechanism of spread along the meningeal nerves in an older child is helpful. One would not expect ischemia to center along the insular cortex but rather to have a more classic vascular territory pattern. Magnetic resonance arteriography (MRA) and venography would be of benefit when trying to differentiate HSE from stroke. When the MRI findings raise the suspicion of HSV infection, it is important to impress upon referring clinicians the likelihood of HSE, as some authors advocate starting acyclovir even in cases of a negative initial PCR when the imaging findings are compelling [12].

The natural history of VZV infection has been well described [47, 48]. VZV enters the body through the respiratory tract or conjunctiva. The primary viremia occurs within 4–6 days and is followed about 10 days later by a mild, self-limiting viral exanthema. Like other herpes viruses, VZV remains latent within the trigeminal ganglion [49]. CNS complications are the most common cause of VZV-associated hospitalization in otherwise healthy children [50] and occur with an incidence of 1% [51]. Although the incidence of chickenpox has decreased in the 10 years since use of the VZV vaccine became widespread [52], the increasing use of PCR has increased awareness of VZV as an important etiologic agent of acute CNS symptoms [53, 54]. CNS complications of VZV infection include acute cerebellar ataxia, encephalitis, and vasculitis [3, 50, 55‐58]. As elucidated below, these complications are each sequelae of vascular involvement by the virus rather than the result of completely separate disease pathways.

Cerebellar ataxia is a clinical syndrome of headache, vomiting, irritability, and gait abnormalities that is usually self-limiting. Acute cerebellar ataxia occurs in the days or weeks following primary VZV infection and was previously considered an immune-mediated process. It is now known that acute cerebellar ataxia results from varicella’s cerebellar neurotropism and corresponds to VZV cerebellitis pathologically and radiographically [3, 31, 57, 59].

The term VZV encephalitis is really a misnomer. VZV does not cause a primary encephalitis [56] but rather directly infects cerebral vessels, resulting in a small-vessel arteriopathy, which is more properly referred to as VZV multifocal vasculopathy or leukoencephalopathy [3, 53, 56, 60]. We prefer the latter term because it better reflects the imaging findings that help the radiologist form a useful differential diagnosis. VZV multifocal leukoencephalopathy is the most common CNS complication of chickenpox. In a study of 38 patients (mean age 8.6 years) with VZV infection and acute neurologic symptoms, it was the most common presentation, occurring in 79% of patients [58]. Clinically, the presentation of leukoencephalopathy varies. Signs and symptoms are non-specific and resemble those seen in other viral encephalitides. Children can present with headache, confusion, and/or fever [3, 60], or present with more profound CNS complications such as mental status changes, seizure, stroke, or focal deficits [56]. Focal neurologic deficits are caused by ischemia and are usually subacute symptoms of hemiplegia, aphasia, and/or visual deficits. Patients are commonly immunocompromised from transplantation or HIV infection [60].

Throughout the literature, large-vessel VZV vasculopathy is referred to as herpes zoster ophthalmicus, granulomatous angiitis, VZV vasculitis, and VZV-associated stroke. Pathologically, the spectrum ranges from necrotizing arteritis with aneurysms to vascular occlusion with or without inflammatory changes [3]. Globally, we refer to this spectrum as VZV vasculitis. Varicella is a well-documented risk factor for ischemic stroke in children and is responsible for approximately one-third of childhood strokes. Children with stroke from VZV vasculitis tend to be healthier than children with stroke from other causes [55], and, in contrast to children with multifocal leukoencephalopathy, they tend to be immunocompetent. The vasculitis presents weeks to months after the rash has resolved and presents as an acute focal deficit [60, 61]. VZV-associated stroke often causes acute hemiparesis in the setting of basal ganglia infarction, a fairly characteristic presentation in pediatric stroke [55, 61‐63].

Whenever a child with recent chickenpox or a VZV-exposed non-immunized or immunosuppressed child presents with acute neurologic symptoms, the diagnosis of VZV infection should be considered. Likewise, a history of chickenpox should be sought and VZV vasculitis considered when an otherwise healthy child presents with stroke and MRI abnormalities in the basal ganglia and/or hemispheric white matter [55, 62, 63]. In these days of widespread immunization, the pediatrician might not consider VZV infection in the differential of acute neurologic deficits.

There are numerous examples of pre-eruptive chickenpox causing neurologic complications [31, 67]. In one study [54, 58], 44% of patients with primary VZV infection, documented by PCR or elevated IgM, had no rash in the 4 weeks surrounding acute neurologic changes. The differential of childhood stroke includes metabolic and mitochondrial disorders, progressive multifocal leukoencephalopathy (PML), trauma (arterial dissection), and hemolytic uremic syndrome (HUS). Imaging can be very helpful in narrowing these considerations. In the setting of diffuse white matter changes, spectroscopy will show elevated lactate and decreased NAA. Diffuse white matter signal abnormalities in children with HIV infection can represent either PML or VZV infection. The white matter abnormalities of these two entities differ in that those in VZV vasculitis are usually smaller and less confluent than seen in PML [60], and in PML the high signal white matter has a strikingly sharp interface with the subcortical U-fibers. Trauma is also a major cause of pediatric stroke. MRA is particularly helpful in this setting because it can help differentiate the arteriopathic changes of VZV vasculitis described above from the tapering associated with dissection. (Fat-suppressed T1-W axial source images also nicely show the crescentic bright T1-W signal of a dissection hematoma.)

We have shown that the range of CNS imaging manifestations in VZV infection extends from mild cerebellitis to multifocal parenchymal edema to overt stroke. These different patterns should be familiar to the radiologist reading pediatric neuroimaging studies. It is also helpful to understand that these protean manifestations all result from VZV vasculitis and that patients have different clinical presentations depending on their pattern of vascular involvement. Imaging can be the first clue to a diagnosis of VZV infection and help lead toward PCR confirmation. This is of particular importance because most experts recommend treating severe VZV vasculopathy with a combination of prednisone (60–80 mg/day for 3–5 days) and intravenous acyclovir (500 mg/m² body surface area for a total of 7 days [60]).

Like the other herpesviruses, EBV is a ubiquitous pathogen found in almost all people by the end of their second decade. The virus infects the nasopharyngeal epithelium and circulating peripheral B lymphocytes. The virus remains dormant within circulating B-cells but occasionally activates in the presence of mucosal epithelium, then sheds silently into infectious saliva. Primary EBV infection is typically asymptomatic in younger children but causes the syndrome of high fever, tonsillopharyngitis, hepatosplenomegaly, and lymphadenopathy characteristic of infectious mononucleosis in adolescents [68]. About 20% of patients with primary EBV infection have various complications, and neurologic involvement occurs in about 5% [7, 69]. Cerebral involvement of EBV infection can range from encephalitis and meningoencephalitis to optic neuritis [70, 71]. Current evidence supports an immunologic mechanism rather than direct viral invasion as the cause of EBV-related CNS disease [68, 72].

EBV encephalitis is more common than often appreciated and in the NIAD Collaborative Antiviral Study Group series was the most common agent to mimic HSE [8]. One unusual feature of children with EBV encephalitis is that other than headache and fever, typical symptoms of infectious mononucleosis are conspicuously absent [68, 70, 71]. Common symptoms include altered consciousness, visual hallucinations, psychosis, and/or fever [70, 71]. Seizures are present in almost half of patients with EBV encephalitis [68]. Most children have a benign clinical course without neurologic sequelae, but about 10% have residual persistent deficits, and several deaths have been reported [53, 68, 70, 71]. Some have advocated treatment with acyclovir and steroids, and although there is little to support this approach, this may augment supportive care in some patients [68, 69, 73].

Optic neuritis is an unusual complication of acute EBV infection and can occur outside of, or after the onset of, infectious mononucleosis [74‐76]. Like EBV encephalitis, it is thought that the process is immune-mediated. Involvement can be unilateral or bilateral and is usually retrobulbar but can extend to the optic chiasm [74]. Antiviral or steroid treatment has been given, but complete recovery can occur without treatment [75].

CNS involvement as a result of EBV infection is associated with diverse neurologic manifestations including meningitis, meningoencephalitis, cerebellitis, cranial neuritis (optic nerves and optic chiasm), and occasionally brain stem encephalitis and myelitis. Reported cerebral sites of involvement include the striatal body (putamen and caudate nucleus), thalami, subcortical cerebral white matter, insular cortex, cerebellar gray matter and white matter, optic nerves and chiasm, and rarely the brain stem. Fortunately, most cases are associated with an excellent clinical outcome.

MRI findings of EBV are typically those of T1-W hypointensity, T2-W hyperintensity, lack of diffusion restriction, and an intact blood–brain barrier. Liberal use of MRS, particularly in the investigation of basal ganglia involvement, can sometimes help distinguish between infection, ischemia, and other toxic/metabolic derangements in many cases.

Like HSV infection, CMV infection can be congenital or present later in life, either as primary or recurrent infection. Although outside the scope of this review, a brief discussion of congenital CMV infection is appropriate. Congenital CMV infection is the most common congenital viral infection worldwide and occurs in about 1 per 100 births [83]. Vertical transmission across the placenta results in fetal infection, and the earlier the transmission occurs during gestation, the poorer the outcome [84]. The vast majority of infected neonates are asymptomatic, but about 10% present have low birth weight, hepatitis, pneumonitis, and/or neurologic and hematologic abnormalities [83, 84]. Congenitally infected infants can later have failure to thrive and progressive hearing deficits. Neuroimaging features of congenital CMV infection include periventricular calcifications, ventriculomegaly, delayed myelination, hippocampal dysplasia, periventricular occipital cysts, lissencephaly, and cortical migration abnormalities [5, 83, 85, 86]. Neuroimaging abnormalities are an excellent predictor of poor neurologic outcome [86, 87].

Outside the context of congenital disease, pediatric CMV infection occurs most commonly in immunosuppressed patients such as those with HIV infection or after solid organ or bone marrow transplantation. Immunocompetent children are rarely affected [88]. If a patient has a normal immune system, meningoencephalitis is usually the only CNS manifestation of CMV and is typically self-limiting [89, 90]. In the immunocompromised, CNS CMV infection can manifest as meningoencephalitis, ventriculoencephalitis, and/or cerebral mass lesions. Diffuse encephalitis is the most common of these and presents with fever, headache, and non-specific non-focal neurologic signs such as confusion and memory loss. Immunosuppressed patients are more likely to have focal neurologic signs [88, 91, 92]. Ventriculoencephalitis is particularly associated with a positive HIV status [88, 91] and typically has a rapid onset with quick neurologic decline, usually to coma and death [88]. Accompanying cranial neuropathies are often seen in these patients and are a clue to the diagnosis [93]. The rarest form of acute cerebral CMV infection is that of mass lesions, a very rare presentation only reported in AIDS patients [94‐96].

The MRI findings of CMV meningoencephalitis are non-specific and similar to those of other viral encephalitides. Most investigators describe cortical and/or subcortical areas of decreased T1-W and increased T2-W signal, usually in the frontal and parietal lobes [5]. Pathologically, CMV infection often involves the ependyma and subependyma [97]. Imaging typically shows meningeal enhancement after administration of gadolinium contrast agent (Fig. 8). In patients with ventriculoencephalitis, there is also periventricular enhancement [88, 91, 98, 99]. In 1990, Balakrishnan et al. [97] documented decreased T1-W signal in these patients and explained that increased T2-W signal was obscured by adjacent CSF signal. Presumably, with increased use of FLAIR imaging today, the ventriculitis and periventricular necrosis would be better visualized as increased ependymal FLAIR signal against dark CSF that has been suppressed. In cases of ventriculitis, some authors have also reported ventriculomegaly [99]. The cerebral masses caused by CMV in AIDS patients manifest as solitary enhancing or ring-enhancing parenchymal lesions [94, 95, 100].

CMV infection should be considered in the immunosuppressed child with encephalopathy and non-focal neurologic signs. The ultimate diagnosis relies on PCR to demonstrate CMV DNA in the CSF, but imaging has been shown to be useful in the diagnosis of CMV infection [11]. When the radiologist sees encephalitis or ventriculoencephalitis in an immunosuppressed child with non-specific neurologic signs, the possibility of CMV should be raised and CSF tested. Prompt treatment of CMV with intravenous antiviral agents such as ganciclovir or foscarnet has been shown to improve outcome [101]. Because CMV infections are largely seen in HIV-positive patients who may have concomitant HIV encephalitis, differentiation of these two entities can be difficult. Two things may help: the clinical deterioration of patients with CMV encephalitis is more rapid than of those with HIV encephalitis alone, and MRI can demonstrate ependymal enhancement of the ventricles and/or parenchymal masses associated with CMV [92]. In patients with HIV infection and possible lymphoma, CMV ventriculoencephalitis needs to be differentiated from lymphoma. Imaging can be helpful in that the periventricular enhancement of infection is usually more thin than the mass-like enhancement seen in lymphoma [102].

HHV-6 was discovered in 1986 and has two variants, HHV-6A and HHV-6B [103]. The latter is associated with childhood disease and infects almost all children worldwide. Antibodies to this ubiquitous virus are found in 95% of the population; most children are infected with the B variant before the age of 2 years [103]. Primary infection causes a febrile exanthem known as roseola infantum (sixth disease) [104], but some patients remain asymptomatic [105]. The virus enters the body through the salivary glands, where it replicates and sheds further particles via infectious saliva. The virus remains latent throughout the body, including the salivary glands, white blood cells, and the brain [103, 106‐108]. It is well-accepted that the virus is quite neurotropic [103, 109, 110] and HHV-6 can result in prolonged, recurrent seizures in a minority of children. Acute HHV-6B infection is associated with seizures in 13% of children [107] and causes almost 30% of first-time febrile seizures in infants. Although the causality of this relationship is somewhat controversial [111], HHV-6 infection should be considered in children younger than 2 years with first-time febrile seizures [107, 112]. Primary HHV-6 infection has also been implicated in encephalitis [113, 114], but more commonly, HHV-6 encephalitis is encountered in immunosuppressed patients as reactivation. Reactivation of HHV-6 is seen in 50% of bone marrow transplant patients [106], usually 2–4 weeks after transplantation [115, 116], but only affects the CNS in a minority of patients. Patients with reactivation HHV-6 encephalitis present with mental status changes, fever, seizures, and headache [115]. Care should be taken that true HHV-6 reactivation is documented in such patients so as to exclude incidental latent infection coincident with encephalitis of another etiology. PCR detection of HHV-6 DNA in the CSF of immunocompromised patients with CNS symptoms has been shown to have a high specificity [117]. Mortality of HHV-6 encephalitis is more than 50%, but can be reduced dramatically by prompt treatment with ganciclovir or foscarnet [115].

CT findings in patients with HHV-6 encephalitis are usually negative [115, 118]. MRI is also occasionally negative but characteristically reveals non-enhancing areas of abnormal signal in the medial temporal lobes and limbic system, reflecting edema [115, 118, 119]. In particular, bilateral or unilateral increased T2/FLAIR signal is found in the hippocampi, amygdala and/or parahippocampal gyrus, usually without diffusion restriction [118, 120‐122]. In patients without initial MR abnormalities, delayed imaging usually demonstrates signal abnormalities as described above [118]. Months after the encephalitis, patients have resolution of signal abnormalities but persistent volume loss in the medial temporal lobes [118, 121, 122]. A more unusual but catastrophic CNS complication of HHV-6 is basal ganglia involvement with acute necrotizing encephalopathy. This has been reported in multiple infants or very young children with primary HHV-6 infection. These children had basal ganglia lesions that were low density on CT and high T2-W signal on MR. Findings are usually bilateral and symmetric and involve the striatum [123], thalami [124], cerebellum, and/or brainstem [125] (Fig. 9).

HHV-6 infection is clinically under-appreciated. Fortunately, it almost always has a benign course and, other than associated febrile seizures, CNS complications are rare in immunocompetent children. On the other hand, HHV-6 can reactivate in immunosuppressed children and present with encephalopathy. When these patients have medial temporal signal changes without enhancement or diffusion restriction (which are typically seen in HSE), HHV-6 should be considered.