Handbook of Clinical Neurology, Vol.

112 (3rd series)

Pediatric Neurology Part II
O. Dulac, M. Lassonde, and H.B. Sarnat, Editors
2013 Elsevier B.V. All rights reserved

Chapter 122

Acute viral encephalitis

F. ROZENBERG*
Universit Paris Descartes & Department of Virology, Hopital Cochin, France

INTRODUCTION to skin and mucosa in the vast majority, and devastating

More than 100 viruses belonging to various families
may cause encephalitis in humans (Johnson, 1996).
Fortunately, encephalitis is a rare consequence of mostly
benign viral diseases. Viruses are involved in encephalitis
in two ways: acute primary (or infectious) viral enceph-
alitis is caused by viral invasion followed by virus repli-
cation in the brain, whereas postinfectious encephalitis is
viewed as the consequence of immune-mediated patho-
genesis, since virus components are not detectable in the
brain, but an abnormal immune reaction directed against
brain parenchyma is observed. It is crucial to distinguish
between acute primary and postinfectious encephalitis,
since their management and prognosis are quite differ-
ent. In this chapter, we will mainly review acute primary
viral encephalitis, focusing on herpes simplex virus
(HSV) encephalitis (HSE).
PATHOGENESIS OFACUTE PRIMARY
VIRAL ENCEPHALITIS
Viruses take two main routes to reach the brain. Most
viruses enter the central nervous system (CNS) via hema-
togenous spread. Mumps-infected monocytes cross the
fenestrated endothelium of the choroid plexus and reach
the choroidal epithelium; there, viral replication results in
release of infectious particles into the cerebrospinal fluid
(CSF) and dissemination through ventricular pathways.
Most arboviruses enter the brain after a step of viremia
by crossing the bloodbrain barrier, constituted by the
tight junctions of capillary endothelial cells of the brain
parenchyma. In contrast, rabies virus and HSV reach
the brain strictly through transneuronal spread from a
peripheral portal of entry. The potential of viruses to cause
encephalitis greatly varies and clearly depends both on
host (age, sex, immunity, genetic background) and viral
factors; for instance, HSV causes mild disease restricted
HSE in rare cases, whereas rabies virus causes deadly
CNS disease in almost all infected patients. Mumps neu-
rological manifestations are three times more prevalent in
males than in females. Japanese encephalitis virus (JEV), a
flavivirus, mostly invades and injures the CNS of children
whereas West Nile virus (WNV), another member of the
same family, causes more severe neurological disease in
old and immune-depressed patients. Although much pro-
gress has been achieved recently in the understanding of
factors leading to brain invasion and pathogenesis in
experimental models, most mechanisms of human viral
encephalitis are incompletely understood. Defects in the
innate immune response have been associated with severe
viral infections in humans as in animal models (reviewed
in Sancho-Shimizu et al., 2007). Conversely, other data
underline the deleterious role of the host inflammatory
response. Crossing of the bloodbrain barrier by WNV
may be facilitated by tumor necrosis factor alpha
(TNF-a)-induced changes in endothelial permeability,
and mice that lack Toll-like receptor (TLR)-3 show
reduced WNV entry into the brain (Wang et al., 2004). Sim-
ilarly, pathogenesis of HSV is increased by brain destruc-
tive inflammatory responses, suggesting that virulence is
not restricted to the ability of the virus to reach and repli-
cate in the CNS (Lellouch-Tubiana et al., 2000; Lundberg
et al., 2008; Marques et al., 2008). Altogether, the outcome
of viral infection seems to depend on a subtle balance
between the host immune response and viral factors able
to counteract it.
PRINCIPLES OF VIROLOGICAL
DIAGNOSIS
The virological diagnosis of acute viral primary encepha-
litis relies principally on CSF analysis, which shows
lymphocytic pleocytosis, moderately elevated protein,

*Correspondence to: Flore Rozenberg, M.D., Ph.D., Department of Virology, Hopital Cochin, Assistance Publique-Hopitaux de
Paris, France. E-mail: flore.rozenberg@svp.aphp.fr
1172 F. ROZENBERG
and normal glucose. However, CSF content does not
differentiate acute infectious from postinfectious enceph-
alitis. To do so, markers of the host immune response may
be used. Type I (alpha/beta) interferons (IFNs) are cyto-
kines of the innate immune response induced by cell rec-
ognition of viral nucleic acids by members of the TLRs.
IFN-a is produced in large amounts by plasmacytoid den-
dritic cells, but virtually any nucleated cell can produce
low levels of this cytokine including astrocytes, microglial
cells, and neurons (Delhaye et al., 2006; Paul et al., 2007).
In vivo, IFN-a can be detected in various biological fluids
using biochemical or biological tests, and its dosage has
been routinely used in the French pediatric setting as a
marker of viral infection. Indeed, the production of
IFN-a in the CSF is rapidly induced in viral acute enceph-
alitis, whereas it is not produced in postinfectious enceph-
alitis (Lebon et al., 1979). IFN-a is undetectable in
physiological conditions (<2 international units/mL).
However, evidence of intrathecal production of IFN-a
requires a comparison of serum to CSF levels, to ensure
that elevated CSF levels are not due to bloodbrain barrier
damage. Specific laboratory confirmation of an increas-
ing number of viral infections of the CNS is obtained
by PCR-derived molecular tools: viral nucleic acids are
detected in early CSF, and are cleared concomitantly with
the appearance of specific antibodies, as first demon-
strated for HSE (Rozenberg and Lebon, 1991; Aurelius
et al., 1993b; Lakeman and Whitley, 1995; Whitley and
Lakeman, 1995). Serology is not useful for immediate
therapeutic guidance, but is used retrospectively to con-
firm or invalidate a presumed diagnosis. Serology per-
formed on two successive serum samples may show
seroconversion or a significant four-fold elevation of
virus-specific IgG titers. In the CSF, virus-specific IgM
has a high diagnostic value indicative of acute infectious
encephalitis. Finally, intrathecal synthesis of specific IgG
is constant after acute viral CNS infection, appearing at
least 710 days after onset, whereas it is absent in post-
infectious encephalitis (Linde et al., 1997). Evidence of
specific intrathecal antibody production is demonstrated
by comparing the ratio between serum and CSF IgG levels
with a reference antibody, in order to discriminate
high CSF IgG levels due to bloodbrain barrier leakage
(Hjalmarsson et al., 2009). In addition, intrathecal immune
activation persists for months to years after the acute
encephalitis episode, thus allowing a delayed restrospec-
tive diagnosis (Aurelius et al., 1993a).
HERPES SIMPLEX ENCEPHALITIS
Pathogenesis
Herpes simplex encephalitis is the commonest cause of
sporadic focal encephalitis in the Western world, occur-
ring in 24/million/year. In children, as in adults, HSE is
due to HSV-1 in virtually all cases. HSV-1 infections are
widespread worldwide. A recent European seroepide-
miology study showed a steady increase in the propor-
tion of HSV-1 seropositive with age, the median age of
acquisition varying from > 25 to 59 years along a
northsouth/east gradient, which probably reflects
sociodemographic status (Pebody et al., 2004). Primary
infections, acquired through close contact from an
infected individual excreting the virus, are mostly
asymptomatic or mild in adults, but may result in
gingivostomatitis in 10% of infected children. After ini-
tial replication in the skin and mucosa, the virus infects
the sensory nerve endings innervating the infected
territory, and migrates by retrograde axonal flow
toward the nucleus of neurons, located in the trigeminal
ganglia. There, the virus establishes latency, from which
it may reactivate to cause limited mucocutaneous
recurrences.
The pathogenesis of HSE is largely unknown.
Experimentally HSV reaches the CNS through neuronal
spread, following neuro-anatomical pathways (Ugolini
et al., 1989; Boerman et al., 1992). In human brain, HSV
preferentially infects the limbic and temporal region, as
a consequence of either infection of meningeal trigeminal
fibers or infection of olfactory bulbs secondary to inocu-
lation of olfactory mucosa, as suggested by human obser-
vations and animal experimental data (Dinn, 1980).
Surprisingly, HSE may occur either during primary
HSV infection, a situation most often encountered in chil-
dren or adolescents, or in previously HSV-seropositive
patients, as seen in 2 out of 3 adults with HSE. Interest-
ingly, only 10% of patients present symptoms of cutane-
ous or mucous HSV infection at the time of encephalitis.
Moreover, a study performed in the early 1980s showed
that the viral strain recovered from the brain differed
from the strain recovered from the lip or pharynx of
the same patient with HSE in 3 out of 8 cases, suggesting
that HSE could occur after reinfection as well as after pri-
mary infection or reactivation (Whitley et al., 1982). Mac-
roscopically, the brain displays necrotic bilateral
asymmetrical lesions of the temporal and orbital cortex.
Microscopically, necrosis is associated with diffuse
inflammation and perivascular lymphocytic infiltration
(Sobel et al., 1986). Viral intranuclear inclusions are in-
constant; viral antigens are detectable only at the early
stage of the disease (Esiri, 1982). Later, gliosis and
microglia proliferation develop. It is noteworthy that viral
DNA remains detectable in brain tissue (Schmidbauer
et al., 1988; Lellouch-Tubiana et al., 2000), which suggests
that viral latency in the CNS might be the source of
resumption of viral replication and of HSE relapses,
which are frequently observed in children (Spiegel et al.,
2008), and may be triggered by neurosurgery
(Bourgeois et al., 1999).
 ACUTE VIRAL ENCEPHALITIS
In neonates who acquire infection during delivery
through their mothers genital tract, HSV-2 and HSV-1
are equally involved. In the newborn, pathogenesis of
encephalitis may be secondary to hematogenous spread
of the virus, resulting in multiorgan involvement and
diffuse necrosis of the brain. Symptoms of disseminated
infection usually manifest during the first week of life.
However, encephalitis is the only manifestation of about
25% of neonatal HSV infections; these cases develop
after the second week of life and present focal cerebral
involvement, probably reflecting transneuronal spread
of the virus as in older patients (Kimberlin, 2004).
Clinical presentation, EEG, and imaging
Large pediatric series have shown that, although HSE
may occur at all ages, most cases occur under the age
of 3, and in particular in infants aged 312 months
(Lahat et al., 1999; De Tiege et al., 2003b; Elbers et al.,
2007). Several series have shown a slightly higher
male-to-female ratio (Ito et al., 1998; De Tiege et al.,
2008). The classical clinical presentation of HSE, which
consists of fever (> 38.5 C), altered level of conscious-
ness, and focal seizures, is observed in the majority of
cases. Focal febrile seizures in the context of a nonspe-
cific febrile disease and soon turning to status epilepti-
cus are the first neurological symptoms in most
children under 3 years of age. Other symptoms include
personality changes, hemiparesis, dysphasia, ataxia,
headache and emesis, an opercular syndrome, or gener-
alized febrile seizures (Delong et al., 1981). Atypical,
Fig. 122.1. Herpetic encephalitis. FLAIR, left temporal pole, hippocampus and thalamus hypersignal. (C) Cingular contrast
enhancement.
1173
subacute, or mild forms of HSE have repeatedly been
reported, accounting for frequent failure of diagnosis.
If absent upon initial presentation, specific neurological
manifestations generally appear during the following
days, and careful follow-up is therefore required.
The initial EEG is abnormal in most patients with
HSE. Focal or diffuse slowing, focal sharp waves, or
spikes have been described. Periodic lateralized epilepti-
form discharges have been associated with HSE, but are
delayed and not specific for this etiology. While CT scan-
ning usually shows suggestive focal lesions, scans may
be normal the first days of disease. Magnetic resonance
imaging (MRI) is more sensitive, showing earlier anom-
alies associated with necrosis and edema (Fig. 122.1).
Brain lesions in HSE typically involve the medial tempo-
ral lobes, the insula, and the orbital region of the frontal
lobes. However, in children, extratemporal (parietal,
occipital, frontal) regions and thalamic lesions are fre-
quently observed (reviewed in De Tiege et al., 2008).
Virological diagnosis
Despite major advances, the diagnosis of pediatric HSE
remains considerably complex. Classically, the CSF con-
tains lymphocytic pleocytosis (10500 cells/mL), some-
times red blood cells, and moderately elevated protein
(0.51.5 g/L). Most pediatric series have reported, how-
ever, that CSF drawn in the earliest stage of the disease
may be strictly normal or contain a predominance of
polymorphonuclear blood cells. In addition, IFN-a level
was elevated in the CSF of only 26 of 31 children with
1174 F. ROZENBERG
HSE during the first 3 days of disease (De Tiege et al.,
2003b), compared with 43 of 43 adults (Raschilas
et al., 2002). PCR is the gold standard for HSE diagnosis
(Lipkin, 1997), with an estimated sensitivity of 96% and
99% specificity in the general population. However, in
pediatric HSE, sensitivity averages 75% (De Tiege
et al., 2008). Negative HSV PCR results have been statis-
tically associated with CSF containing < 10 cells/mm3, a
situation that is more frequent in the pediatric than the
adult setting (De Tiege et al., 2003b). Indeed, virus
replication in brain parenchyma precedes meningitis
and release of the virus into the CSF (Boerman et al.,
1992). Repeated PCR testing on a subsequent lumbar
puncture is therefore recommended in case of a negative
initial result. Viral DNA is detected in most cases in the
first week of disease, in 3050% in the second week, and
in less than 25% after day 15 (Rozenberg and Lebon,
1991; Linde et al., 1997; Schloss et al., 2009). Quantifica-
tion of viral load in HSE has been estimated at between
102 to 107 HSV genomes/mL CSF, with no apparent cor-
relation between the amount of HSV DNA in the initial
samples and prognosis (Schloss et al., 2009). Viral load
declines after treatment in all patients, and prolonged
detection correlates with poor outcome (Hjalmarsson
et al., 2009).
Although HSV PCR is the gold standard, intrathecal
synthesis of anti-HSV IgG has high diagnostic value
(Nahmias et al., 1982). This method is of particular inter-
est in patients seen at late stages of HSE, in atypical
forms of the disease and may still be used months to
years after the initial infectious episode (Aurelius
et al., 1993a).
Treatment and evolution
The prognosis of HSE has been transformed by acyclovir
therapy (Whitley et al., 1986). Acyclovir is generally
administered intravenously at a dosage of 30 mg/kg/
day for a period of 14 days. Although observations of
persistently PCR-positive CSF after a full-course acyclo-
vir regimen have occasionally suggested that the dura-
tion of therapy should be lengthened (Cinque et al.,
1996), longer duration or higher dosages have not been
evaluated, except in neonates, in whom a significant
reduction in relapse was obtained with prolonged and
double-dosed antiviral therapy (Kimberlin, 2004). Over-
all, recent pediatric series show that the current outcome
of HSE remains unsatisfactory with unacceptably high
mortality and morbidity rates, although evaluation cri-
teria and duration of follow-up differ between studies
(Lahat et al., 1999; Elbers et al., 2007; Hsieh et al.,
2007). Sequelae include mostly epileptic seizures, devel-
opmental delay, and residual hemiplegia. To date, the
only parameter that can be modified to improve the
prognosis of patients with HSE is the delay from disease
onset to the start of drug administration (Raschilas et al.,
2002). Among other factors, CNS penetration of acyclo-
vir and deleterious host inflammatory responses might
account for failure of therapy. Proven virological resis-
tance of HSV to antiviral drugs has never been reported
in immunocompetent patients with HSE.
Up to 30% of reported pediatric HSE cases presented
with acute clinical relapses. Relapse may be secondary to
resumption of viral replication in the brain, as suggested
by new necrotico-hemorrhagic lesions distant from the
initial site of HSE, positive PCR and/or elevated IFN-a
in the CSF, and clinical improvement under acyclovir.
However, some episodes of neurological deterioration
occur after HSE without evidence of virus replication,
such as choreo-athetoid movements, which have a poor
prognosis and might be due to an immune-mediated
process (De Tiege et al., 2005). Thalamic lesions are
often observed in such relapses (Fig. 122.2) (Barthez-
Carpentier et al., 1995; De Tiege et al., 2003a).
Perspectives
Numerous experimental models have supported the pro-
tective role of IFN pathways in HSV neuroinvasion (Leib
et al., 1999; Luker et al., 2003). In rare pediatric cases, a
genetic defect of the innate immune response has been
linked to recurrent episodes of HSE (Sancho-Shimizu
et al., 2007). These data suggested that an initial innate
immune response is crucial to restrict virus replication
and led to the proposal to reinforce this response in order
to attenuate neuronal damage (Wintergerst et al., 1999).
Induction of innate immunity by TLR-3 agonist pretreat-
ment indeed protected mice challenged with HSV, by
enhancing the expression of proinflammatory genes in
the infected brain and by suppressing viral replication
(Wintergerst et al., 1999; Boivin et al., 2008). However,
this study did not test the effects of IFN induction after
onset of viral replication. In addition, other results have
favored the role of inflammation as a major determinant
of mortality (Lundberg et al., 2008), and some clinical
observations support the beneficial use of steroids
alongside antiviral therapy in patients with HSE (Fitch
and van de Beek, 2008; Martinez-Torres et al., 2008),
suggesting that the immune response has to be sup-
pressed to avoid irreversible brain damage. In an exper-
imental model, a TLR2-mediated cytokine response to
HSV-1 was shown to contribute to lethal encephalitis
(Kurt-Jones et al., 2004), and in neonatal HSV-1 infec-
tion the sepsis syndrome was associated with a TLR2-
linked exuberant cytokine production, suggesting that
blocking TLR proteins might be considered in the treat-
ment of the disease (Kurt-Jones et al., 2005). Strikingly,
prolonged immune activation without viral replication
 ACUTE VIRAL ENCEPHALITIS
Fig. 122.2. Same patient as in Fig. 122.1. Three months later T1 and FLAIR sequences (2) show perisylvian and temporal atrophy
with hypersignal in the ipsilateral orbitofrontal and contralateral insular areas.
was evidenced by microglial activation and T lympho-
cyte retention in the brain of experimentally infected
mice, as in human HSE cases (Lellouch-Tubiana et al.,
2000; Marques et al., 2008), and associated with
increased morbidity or mortality. A more precise under-
standing of the respective role of the multiple path-
ways of the immune response is mandatory before any
immunomodulatory therapy is set up.
ENTEROVIRUS ENCEPHALITIS
Human enteroviruses are small nonenveloped RNA
viruses, which comprise more than 80 serotypes. These
ubiquitous viruses are mainly transmitted by the feco-oral
route, and cause a wide spectrum of mostly self-limited
diseases; in particular, they are the commonest agents
of mild viral meningitis across the world. However, cer-
tain serotypes of enterovirus also cause acute myocardi-
tis, hepatitis, or more severe CNS infection. The prototype
member of the enterovirus family, poliovirus (PV), which
gains access to the CNS through viremia and possibly ret-
rograde axonal flow, has a selective tropism for motor
neurons of the spinal cord, accounting for the symptoms
of poliomyelitis. Overall, encephalitis is a relatively rare
complication of enterovirus infections: a recent study
demonstrated that enterovirus represented less than 5%
of diagnosed causes of encephalitis, with milder clinical
illness than encephalitis due to other causes (Fowlkes
et al., 2008). In newborns, Coxsackie virus and echovi-
ruses have been associated with severe infections of the
heart, liver, or brain (Verboon-Maciolek et al., 2008),
1175
and in congenital immunodeficiencies such as X-linked
agammaglobulinemia enteroviruses may provoke chronic
meningoencephalitis (Rotbart et al., 1990). After the neo-
natal period, enterovirus 71 caused an unusual rate of neu-
rological complications in children, during a Taiwanese
epidemic. Involvement of the midbrain was notable,
and rhombencephalitis resulted in high mortality in chil-
dren under the age of 5 years, and heavy sequelae
(Wong et al., 2000). An Australian outbreak caused by
the same virus caused a variety of CNS symptoms such
as cerebellar ataxia, acute transverse myelitis, and febrile
convulsions the following year (Gilbert et al., 1988).
Again, the molecular and cellular basis of increased viru-
lence of enterovirus 71 is unsolved. Diagnosis of
enterovirus-linked neurological complications is easily
performed by PCR detection of viral RNA in the CSF. Iso-
lation of the virus is possible from CSF at the acute stage
of disease. Detection of the virus outside the CNS (throat,
stool) is possible for longer periods but may not be asso-
ciated with the neurological illness, since enteroviruses
are widespread and cause mostly asymptomatic
infections.
ARBOVIRUS ENCEPHALITIS
Arboviruses (arthropod-borne viruses) are RNA envel-
oped viruses that belong to different virus families
(Togaviridae, Flaviviridae, Bunyaviridae, Reoviridae).
In arthropod vectors (mosquitoes, ticks), they replicate
and spread to salivary glands, and are transmitted to ver-
tebrates through inoculation by vector bite. Humans
1176 F. ROZENBERG
are accidental hosts, while small mammals and birds con-
stitute the natural reservoir amplifying the virus. The
prevalence of arbovirus infections depends on geogra-
phy and season. Although most arbovirus infections
are mild or asymptomatic, they represent the most fre-
quent cause of epidemic encephalitis worldwide. The fre-
quency and severity of neuro-meningeal manifestations
depend on virus and host (Johnson, 1996). Japanese
encephalitis virus, a member of the Flaviviridae, has a
wide distribution in Asia. At least 50 000 cases are
reported annually, with 10 000 deaths. Children between
3 and 15 years are mostly affected, and have the highest
risk for severe neurological manifestations, fatality, and
disabling sequelae. In contrast, other flaviviruses, i.e.,
tick-borne encephalitis virus (TBEV), which predomi-
nates in Europe and far Eastern Europe, and WNV, which
recently spread from Mediterranean countries to the
American continent, produce milder symptoms in chil-
dren than in the elderly. In the Togaviridae family, sev-
eral alphaviruses cause encephalitis, the most severe
being eastern equine encephalitis (EEV) virus, which is
enzootic along the eastern coast of America. In children
under 10 years, the frequency of encephalitis is three-fold
higher than in adults, and mortality due to encephalitis
has been estimated at around 3040%. Western equine
encephalitis (WEE) virus, which prevails in western parts
of the American continent, has also a higher case-to-
infection and encephalitis rate in children than in adults,
but its overall incidence is lower than that of EEV.
Most encephalitis manifestations are nonspecific, but
some reflect the virus tropism for CNS targets; for
instance, WNV preferentially infects neurons of the
brainstem, thalami, and spinal cord, but the molecular
basis of such specificity is unknown (Davis et al.,
2006). Diagnosis is based on epidemiological features
and confirmed by serology and evidence of intrathecal
IgM production. PCR assays have been developed for
several arboviruses (Huang et al., 1999). No specific
treatment exists, and prevention consists of vector con-
trol and avoiding vector bites. Vaccines have been devel-
oped for JEV and TBEV.
RABIES
Rabies is a zoonotic disease caused by a highly neuro-
tropic rhabdovirus, whose natural hosts are vertebrates
(dogs, fox, and bats). Rabies is mostly transmitted
through the bite of a rabid animal, but infection through
inhalation has been occasionally reported in caves inhab-
ited by infected bats. Humans are accidental hosts and
dead-ends for the virus. In Asia and Africa, where
50 000100 000 deaths are reported annually, the dis-
ease is transmitted by street dogs. In Europe and North
America, rabies has become exceptional since potential
exposure cases due to wildlife (small mammals or bats)
receive prophylaxis. However, cases imported from
endemic areas may occur. The virus infects peripheral
neurons of the site of entry and then migrates retro-
gradely along neuronal tracts to reach the CNS. From
there, the virus travels anterogradely to several organs,
salivary glands, and skin. The delay of appearance of
neurological symptoms (usually 2060 days) depends
on the anatomical site of virus inoculation: the more dis-
tant the lesion from the brain, the longer the incubation.
This delay corresponds to the time of neuronal transport
added to rounds of virus replication in neurons of the
tracts. However, in several cases, incubation periods
greater than 6 months have raised the issue of silent viral
persistence in the organism. Brain lesions include viral
inclusions (Negri bodies), which were recognized a cen-
tury ago, perivascular inflammatory infiltrates, and
microglial proliferation. The high mortality of rabies is
thought to result from virus-induced neuron dysfunction
and death, but more precise mechanisms are unknown
and no specific treatment exists once the virus has
reached the CNS. Diagnosis is performed in specialized
centers and presently relies on viral RNA detection in
CSF and saliva (Crepin et al., 1998). Immediate post-
exposure prophylactic sero-vaccination is the only means
of reducing morbidity and mortality (Plotkin, 2000).
POSTINFECTIOUS ENCEPHALITIS
These conditions were recognized and characterized by
neuropathological and virological studies which showed
inflammation of the brain parenchyma associated with
demyelination, without any evidence of direct viral inva-
sion. The pathogenesis of postinfectious encephalitis is
still incompletely understood, but several arguments
favor an inappropriate immune response directed toward
brain cells, induced by infection by a variety of pathogens
including viruses. Indeed, most cases were historically
associated with eruptive febrile diseases of childhood,
and their incidence has been drastically reduced by mea-
sles, mumps, rubella (MMR) vaccination. Since no path-
ogen can be detected in the CSF/brain, the virological
diagnosis is most often performed by showing either sero-
conversion toward a specific virus or persistent viral
excretion/viremia, which is evidence that a recent viral
infection shortly preceded encephalitis.
Measles, mumps, rubella
Acute measles encephalomyelitis occurs in 1/1000
infected subjects, and may affect school-aged children,
within the week following the rash, rarely before it. MRI
performed 14 days after the first neurological symp-
toms shows widely distributed, multifocal high signal
in cerebral hemispheres and swelling of the cortex with
 ACUTE VIRAL ENCEPHALITIS
bilateral involvement of basal ganglia on T2, with
decreased apparent diffusion coefficient (ADC) (Lee
et al., 2003). Absence of viral detection in the brain
parenchyma, absence of intrathecal synthesis of anti-
bodies against the virus, and presence of lympho-
proliferative responses to myelin basic protein all
suggest that the disease is immune-mediated and similar
to experimental allergic encephalomyelitis (Johnson
et al., 1984). However, infection of brain endothelial cells
was evidenced by in situ hybridization in children after
acute fatal measles (Esolen et al., 1995).
Neurological complications following rubella are
similar to those following measles, although less frequent,
estimated at between 1/6000 and 1/24 000 infections.
Weakness with neurophysiological signs of multifocal
conduction blocks associated with encephalitis was
reported in an adolescent (Chang et al., 1997). In children,
convulsions with coma lasting several days are usually fol-
lowed by complete recovery (Konior et al., 1995). Carotid
artery thrombosis, optic neuritis, peripheral neuritis, and
myelitis have also rarely been reported (Paret et al., 1993).
Finally, GuillainBarre syndrome, myelitis, and
meningitis have been reported following mumps
(Anand et al., 1997). Although rare, encephalitis may
affect basal ganglia with severe epilepsy sequelae
(Leheup et al., 1987).
HHV-6
Although neurological complications of human herpesvi-
rus 6 (HHV-6) are usually considered benign, the most
frequent being febrile seizures in infancy, rare cases of
encephalitis/encephalopathy mainly comprising severe
seizures with or without major sequelae are also on record
(Yoshikawa and Asano, 2000), and HHE syndrome has
been observed (Kawada et al., 2004). Involvement of
HHV-6 in temporal lobe epilepsy in adults has been sus-
pected (Fotheringham et al., 2007).
Varicella-zoster
Acute cerebellar ataxia is the most frequent neurological
complication of varicella, which occurs in 1/4000
infected children aged below 15 years. Its mechanism
is thought to be immune-mediated, although weak levels
of VZV (varicella-zoster virus) DNA are inconstantly
detected in patients CSF.
It is usually benign, although mild sequelae may persist,
and acyclovir does not improve outcome (Camacho-
Badilla et al., 2008). Although complications usually
appear after the rash, they may precede it or be delayed
(Wagner et al., 1998). Rare neurological complications,
including encephalitis, meningitis, and myelitis, have been
described. The virus is not detected in the brain in
immunocompetent patients but in brain vessels, and these
1177
complications are presumably secondary to VZV vasculo-
pathy. In addition, varicella is with HIV the main viral
cause of stroke, which may occur several months/years
after chickenpox in children, and is diagnosed by intrathe-
cal synthesis of specific antibodies (Ueno et al., 2002).
EpsteinBarr
A large range of neurological manifestations have been
reported as complications of EpsteinBarr virus (EBV)
infection, such as acute disseminated encephalomyelitis,
acute hemorrhagic encephalitis, cerebellitis, cranial neu-
ritis, and polyradiculoneuritis (Gavin et al., 1997; Meyer
et al., 2010), but their pathogenesis is not well under-
stood. The detection of EBV DNA in the CSF is helpful
for diagnosis but must be interpreted cautiously in
patients presenting EBV primo-infection and a high
blood viral load (Bathoorn et al., 2011).
Rotavirus
Rotavirus, one of the most common causes of gastro-
enteritis in infants, may cause neurological disorders,
including encephalitis, encephalopathy, seizures, and
cerebellitis, which is followed by prolonged mutism possi-
bly related to dentate nucleus damage (Takanashi et al.,
2010; Kubota et al., 2011). Reversible diffusion anomalies
of the callosal splenium (Fig. 122.3) are frequent in case of
brief or transient neurological symptoms, whereas diffu-
sion anomalies in the cerebellar cortex and dentate nuclei
may be followed by cerebellar atrophy. Rare cases of stria-
tal necrosis (Mordekar et al., 2005) and rhabdomyolysis
(Minami et al., 2007) are also on record. Viral RNA has
exceptionally been detected in the CSF. High levels of
IFN-a are, however, constantly detected in the serum of
infected children, suggesting a cytokine-mediated patho-
genesis of CNS involvement (unpublished data).
Influenza
Neurological complications of influenza are rare (1.5% in
all age ranges), affect generally young children (80%
under 5 years), and have mostly been described in Asia,
suggesting a genetic susceptibility to infection. Variable
neurological involvement has been described, including
Reye syndrome, myelitis, GuillainBarre syndrome, and
encephalitis manifesting as status epilepticus with focal
diffusion anomalies on MRI, or extrapyramidal signs
with diffusion anomalies in the thalami or putamen.
Supratentorial white matter and infratentorial anomalies
can be combined. There is no evidence of the presence of
the virus in the CNS by CSF PCR or protein electrophore-
sis, but high levels of systemic cytokines are detected sug-
gesting an explosive systemic immune response. At the
other extreme of the range of severity, severe but
1178 F. ROZENBERG
Fig. 122.3. Axial diffusion-weighted magnetic resonance image (left) and apparent diffusion coefficient map (right) demonstrate
linear high signal intensities on the splenium of the corpus callosum on the day of admission. From Yang and Lee (2010) (Creative
Commons Attribution Non-Commercial License).
transient encephalopathy lasting a few days before full
recovery with transient hypersignal of the splenium,
which could be hemorrhagic, has been reported
(Goenka et al., 2010). However, as for rotavirus, the com-
bination with ataxia may comprise mutism during the
recovery phase (Fluss et al., 2010). Although the few pedi-
atric patients with H1N1 encephalitis had mild seizures
and/or altered mental status, and all recovered fully with-
out any neurological sequelae at discharge (Centers for
Disease Control and Prevention, 2009), one lethal case
of acute necrotizing encephalitis is on record with
rapid-onset deep coma and diffuse swelling of the white
matter on CT and MRI (Martin and Reade, 2010). Pulses
of steroid therapy may be useful in these cases (Webster
et al., 2010). Acute necrotizing encephalopathy rarely
occurs (Lyon et al., 2010); rare cases have been associated
with mutations in a component of the nuclear pore,
RANBP2 (Neilson et al., 2009).
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