++
The terms encephalitis, meningoencephalitis, and encephalomyelitis are
generally used interchangeably to denote inflammation of the brain, brain
stem, and/or spinal cord. National Hospital Discharge Survey
data reveal that children under 12 months of age have the highest
rate of encephalitis and that males have a slightly higher risk
than females.9 There is a general presumption that
most acute encephalitis cases are caused by viral infections, although
active surveillance studies are able to identify a specific viral
etiology for only 9% to 22% of cases, and the
cause of approximately 60% of cases cannot be determined.9-11 The
list of viruses proven or suspected to cause acute encephalitis
is extensive and prominently represented by herpesviruses, enteroviruses,
flaviviruses, togaviruses, bunyaviruses, adenoviruses, mumps virus,
lymphocytic choriomeningitis virus, human immunodeficiency virus,
and rabies virus that all replicate in neural cells causing neuronal
destruction and inflammation, primarily in gray matter (Table 232-1).
++
The terms postinfectious encephalitis and acute
demyelinating encephalomyelitis (ADEM)
are interchangeably applied to acute central nervous system (CNS)
disease that rarely complicates infection with some common viruses,
including measles virus, rubella virus, influenza viruses, and other
respiratory viruses. Evidence for CNS viral replication is generally lacking,
and immunopathologic mechanisms are considered to be responsible
for the characteristic perivascular inflammation and demyelination associated
with postinfectious encephalitis.
+++
Herpes Simplex
Virus Encephalitis
++
Herpes simplex virus (HSV) causes only 8% to 12% of
encephalitis cases of known etiology9-11 but deserves
special consideration because HSV is identified in population-based
studies as the most common cause of viral encephalitis.9 Unlike
other viral infections, the outcome of HSV encephalitis can be improved
with prompt and safe antiviral therapy. HSV type 1 (HSV 1) and HSV
type 2 (HSV 2) are closely related alpha herpesviruses that share
a tropism for mucocutaneous sites, the ability to establish latency
in neural tissues, and the ability to reactivate repeatedly, causing
recurrent disease. HSV encephalitis is characterized by inflammation
with perivascular lymphocytic cuffing, edema, and hemorrhagic necrosis
of affected areas of the CNS.
++
In neonates, HSV encephalitis may occur as isolated CNS disease
or may develop in the course of disseminated HSV disease; altogether
about half of infants with neonatal HSV infection develop encephalitis.
Viremia probably represents the major route of transmission to the
CNS during disseminated neonatal HSV infection resulting in diffuse,
patchy CNS involvement. In contrast, transport to the brain is likely
to occur via peripheral sensory neurons in neonates who present
with localized CNS disease. In either case, the absence of preexisting
immunity and immature T cell responses permits a high level of virus
replication and spread within the immature brain. Both HSV 1 and
HSV 2 can be transmitted to the newborn in the perinatal period,
but encephalitis occurs more commonly and is more severe with HSV
2 infection. Overall, infants less than 4 weeks of age are at risk,
although disseminated HSV infection typically begins within the first
10 days of life, and infants with disease limited to the CNS are
more likely to have onset of disease in the second or third week
of life.12 Neonates with HSV encephalitis typically present
with lethargy, poor feeding, and focal and/or generalized
seizures. Motor abnormalities in the form of tremors, paresis, and
hypo- or hyperreflexia may be noted on exam.
++
About one third of HSV encephalitis cases beyond the newborn
period occur in children and adolescents with an approximate annual
incidence of 2 to 4 per 1,000,000.12 Virtually
all are a consequence of sporadic HSV 1 disease that may occur as
either primary or recurrent infection. Unlike other herpesviruses,
HSV is not associated with a propensity to cause encephalitis in
immunocompromised patients. The hallmark of HSV encephalitis is
focal neurological disease that may affect any part of the brain,
brain stem, or spinal cord13,14 but most commonly
involves one or both temporal lobes. More than 90% of patients
present with fever and altered consciousness, and more than two
thirds exhibit headache, personality change, dysphagia, and focal
or generalized seizure activity. Other common early findings are
hemiparesis, memory loss, ataxia, and cranial nerve palsies.
+++
Diagnostic Evaluation
++
The initial evaluation of suspected HSV encephalitis includes
brain imaging, electroencephalography (EEG), and CSF examination. Magnetic
resonance imaging (MRI) is reported to be more sensitive than computerized
tomography (CT) for detection of focal brain lesions. The periodic
lateralized epileptiform discharges (PLEDs) demonstrated by EEG represent
sensitive but relatively nonspecific evidence of HSV encephalitis.
At least 90% of patients will have an abnormal CSF examination
with an elevated CSF WBC and elevated protein concentration on presentation.
++
Confirmation of HSV encephalitis depends on detection of HSV
virus in CSF or CNS tissue. Polymerase chain reaction (PCR) detection
of viral DNA in CSF is highly sensitive and specific when compared
with virus isolation from brain biopsy specimens.15 PCR
testing early in the course of HSV encephalitis may produce a false-negative
result, but HSV DNA has been shown to persist in CSF in virtually
all patients who have repeat lumbar punctures up to 7 days, even
when on effective antiviral therapy.15 Infectious
virus can also be isolated when brain biopsy is performed 4 or more
days after the start of antiviral therapy. HSV is rarely isolated
in cell culture from CSF from patients with encephalitis.
+++
Treatment and Outcome
++
Untreated HSV encephalitis is fatal for more than two thirds
of cases, and only about 10% of survivors recover with
normal neurological function. Intravenous acyclovir therapy given at
a dose of 10 mg/kg q8h for 10 days reduces mortality to
approximately 25% and improves the prognosis for survivors.16 A
higher acyclovir dose of 20 mg/kg qh8 for 21 days may improve
survival for neonates when compared with the standard dose, although
this has not been studied in a direct comparative trial.17
++
Relapse of central nervous system disease with recurrent fever,
focal neurologic symptoms, and CSF pleocytosis is reported in 10% to
25% of patients with acute herpes simplex virus (HSV) encephalitis.
Relapse occurs within days to months of discontinuation of antiviral
therapy and is associated with similar signs and symptoms compared
with the initial episode. Although HSV can be recovered from some
cases of recurrent disease, the inability to demonstrate the presence
of HSV by virus isolation or PCR in many others suggests a second
mechanism that may be immunologically mediated.
++
In addition, long-term studies of infants who have onset of encephalitis
in the neonatal period find a high risk of periodically reactive
CNS disease with severe adverse neurological sequelae (especially
among infants experiencing recurrent herpetic skin lesions) in the
first year of life. It is uncertain whether these infants benefit
from long-term antiviral prophylaxis beyond the neonatal period
(see Chapter 309).
+++
Arthropod-Borne Encephalitis
++
Several families of positive-strand RNA viruses cause acute encephalitis
in humans and other mammals following the bite of an infected mosquito
or tick, including certain flaviviruses, togaviruses, and bunyaviruses.
These taxonomically distinct viruses are often collectively referred
to as “arboviruses” due to the common requirement
for an arthropod vector, and all exist within diverse ecologic systems
that include animal reservoirs in nature. More than 20 arboviruses
cause acute encephalitis worldwide; among the most prevalent are
Japanese encephalitis virus that is responsible for widespread disease throughout
East and Southeast Asia and West Nile virus that has been the predominant
cause of arthropod-borne encephalitis in North America during the
past decade.
+++
Japanese Encephalitis Virus
++
Japanese encephalitis virus, a flavivirus, is responsible for
thousands of human encephalitis cases throughout South and Southeast
Asia. Culex mosquitoes that breed in marshy environments including
rice patties serve to maintain a sylvatic cycle involving water fowl
and domestic pigs. The ratio of symptomatic to asymptomatic infections
is approximately 1:250 and most illness is mild and self-limited.
However, encephalitis cases, which occur mainly among children less
than 15 years old, are severe with an estimated mortality of 25% and
significant neurological and cognitive sequelae in 30% of
survivors. The spectrum of CNS manifestations includes meningismus,
altered consciousness, seizures, extrapyramidal signs, and acute
motor neuron disease.18
++
The laboratory diagnosis of Japanese encephalitis virus infection
is based on demonstration of specific antibodies in serum or CSF which
appear by 7 to 10 days after onset of symptoms. There is no available
specific antiviral therapy. Approximately 30% of hospitalized
patients die from Japanese encephalitis, and up to 50% of
survivors have neurological sequelae.
++
Although the risk of Japanese encephalitis is low for most travelers
to endemic areas, immunization is recommended when there is a high
risk of exposure, such as with travel to rural areas during the
rainy season when mosquito activity is high. An inactivated vaccine produced
in mouse brains (Biken) was licensed in the United States in 1992
for travelers and military personnel. A new cell-culture-grown inactivated
vaccine is expected to be available soon.
++
West Nile virus (WNV) is a member of the same flavivirus complex
as Japanese encephalitis virus and St. Louis encephalitis virus.
Human infections with WNV occur widely in Africa, Europe, South
Asia, and Australia, but were unknown in the Americas until 1999 when
an outbreak occurred in the New York City metropolitan area caused
by a virus with close genetic identity to WNV circulating in Israel
and elsewhere the Middle East.19 The virus has
since spread across the North American continent causing hundreds
to thousands of cases each year. In most locations, human disease
coincides with a summer–fall sylvatic cycle that includes
viral amplification in birds and transmission via Culex species
mosquito vectors. Person-to-person spread may occur via transfusion
of blood and blood products, organ transplantation, transplacental
transmission, and breastfeeding.
++
Introduction of WNV following a mosquito bite is followed by
migration of WNV to regional lymph nodes where viral replication
leads to a viremia that seeds many organs including the central
nervous system. Approximately 20% of infected persons develop
illness that in the majority of patients is limited to fever, malaise,
arthralgias, and rash that last for 3 to 10 days. Neurologic disease
occurs in a smaller proportion of laboratory-confirmed infections,
perhaps 1 in 150, but in a higher percentage of reported cases due
to the propensity to test and report cases with serious disease.
Children are at lower risk of developing CNS disease than adults,
and risk is increased among persons with chronic disease and immunodeficiency,
including patients with solid organ transplants and patients with
hematological malignancies. West Nile encephalitis may coincide
with a number of manifestations indicating different levels of CNS
involvement, including seizures, movement disorders (tremor, myoclonus,
parkinsonism), optic neuritis, chorioretinitis, cranial nerve palsy,
cerebellar ataxia, acute motor neuron disease, radiculopathy, Guillain-Barré syndrome,
and demyelinating peripheral neuropathy.
++
A specific laboratory diagnosis depends on demonstration of either
WNV IgM antibodies or RNA in serum or CSF. There is no specific antiviral
therapy for WNV infection, and no vaccine is yet available. Full
recovery from WNV neuroinvasive disease occurs in less than half
of survivors. Long-term sequelae include alterations in cognition,
inability to concentrate, and residual muscle weakness.
++
Recovery from infection is thought to be associated with long-term
immunity. As with many other acute viral infections, humoral antibody
correlates with protection from disease, and T cell responses are
important in the host’s response to infection.
+++
Other North
American Arthropod-Borne Virus Diseases
++
California encephalitis virus (CE), eastern equine encephalitis
(EEE) virus, western equine encephalitis (WEE) virus, and St. Louis
encephalitis (SLE) virus are mosquito-borne viruses that are also
important causes of CNS infection. Each of these viruses has a distinct
sylvatic cycle, geographic distribution, and spectrum of disease,
and each is associated with a high ratio of inapparent infections
compared with clinical disease. CE, EEE, and WEE have higher clinical
attack rates among children, and SLE virus, like its close relative
West Nile virus, is more often observed in adults.
++
CE virus is a bunyavirus that causes a reported 50 to 100 cases
of encephalitis each year in the United States. The La Crosse strain of
CE virus which is transmitted from small mammals by tree hole mosquitoes
is endemic in Midwest states. In contrast, EEE and WEE viruses are
members of the alphavirus genus (family: Togaviridae) which cause
sporadic and unpredictable regional outbreaks of human encephalitis
when conditions are optimal for breeding of mosquitoes that maintain
these viruses in a natural cycle that includes migratory birds.
Compared with other causes of arthropod-borne encephalitis, disease
due to CE virus is relatively mild, and most children recover from
infection with minimal or no neurologic sequelae. In contrast, disease
caused by both EEE and WEE viruses is more severe in children with
high rates of death and disability among survivors.
++
Virus-specific IgM antibody is present in the serum and cerebrospinal
fluid at the time of presentation for most arthropod-borne virus
encephalitis cases. Serologic testing for regionally prevalent arthropod-borne
virus diseases is generally available in state and provincial public
health laboratories in the United States and Canada. Treatment is
limited to supportive measures because no antiviral therapy is available.
+++
Postinfectious Encephalitis
++
Postinfectious encephalitis (or acute disseminated encephalomyelitis)
is an acute, inflammatory brain disease that occurs as a complication
of certain respiratory and systemic viral infections and is observed
following administration of several vaccines, including smallpox
(vaccinia virus) vaccine, rabies vaccine, pertussis vaccine, tetanus
toxoid, and influenza vaccine. The pathological features of postinfectious
encephalitis are accurately replicated in the experimental allergic
encephalomyelitis animal model in which an immune-mediated reaction
against myelin protein can be demonstrated.20 Antimyelin
basic protein antibodies can be demonstrated in some patients with
postinfectious encephalitis, but evidence of viral replication within
the CNS is virtually never demonstrated.
++
Postinfectious encephalitis is estimated to represent about 10% to
15% of acute encephalitis cases in the United States. The
current incidence is probably lower than in the past when smallpox
vaccines were universally administered and measles, rubella, and
varicella infections still affected most children. Abrupt onset of
fever, altered mental status, seizures, or focal neurologic signs
may occur before, during, or, more commonly, within 3 weeks after
a respiratory, gastrointestinal, or rash illness. The inflammatory
changes in cerebrospinal fluid do not distinguish postinfectious
encephalitis from other causes of acute encephalitis, but contrast-enhanced
MRI examination often reveals characteristic white matter abnormalities
on T2 and fluid-attenuated inversion recovery (FLAIR) images in
white matter, cerebellum, basal ganglia, and brain stem. Although
widely used, there is no evidence that steroid treatment is effective.
Recovery may occur very slowly, but most patients survive without
severe disability. Patients who develop recurrent episodes may ultimately
receive a diagnosis of multiple sclerosis.
+++
Acute Hemorrhagic Leukoencephalitis
++
Acute hemorrhagic leukoencephalitis is a rare form of acute encephalitis
of unknown etiology characterized by abrupt onset, a rapid course, and
often a fatal outcome. The pathological changes reflect those of
postinfectious encephalitis with edema, demyelination, and perivascular
inflammation but also include extensive hemorrhagic lesions within
white matter. Compared with postinfectious encephalitis, the cerebrospinal
fluid findings in acute hemorrhagic encephalitis include a relatively
higher white blood cells, predominance of polymorphic leukocytes,
and the characteristic presence of red blood cells (RBCs). Because
patients with acute hemorrhagic encephalitis are usually treated with
high-dose steroid therapy based on anecdotal experience, it is important
to rule out herpes simplex virus encephalitis that has many similar clinical
features.
+++
Acute Cerebellar Ataxia
++
Acute cerebellar ataxia is a common, distinct clinical entity
of young children usually caused by acute cerebellitis without evidence
of other serious central nervous system disease. Both direct infection
and postinfectious, immunopathologic mechanisms are postulated to
occur.21 Acute varicella infection is a prominent
cause; other reported coincident infections include enterovirus
infection, measles, mumps, rubella, parvovirus, and Epstein-Barr
virus.
++
The typical patient is a toddler or young child who develops
a truncal ataxia and a wobbly gait 5 to 10 days after onset of the
inciting infectious episode, which may have resolved. More severe cases
may be accompanied by nausea, vomiting, nystagmus, dysarthria, or
dysmetria, but fever and other signs of CNS disease are rare. Disability
is often maximal at onset. Even though symptoms resolve slowly over
days to weeks, most children recover completely without residual deficits. The
most important task of the pediatrician is to rule out a more serious
cause for ataxia.
+++
Brain Stem Encephalitis
++
Enterovirus 71 possesses a unique ability to invade the ventral
brain stem, cerebellum, and spinal cord, producing a spectrum of
serious neuromotor syndromes including acute flaccid paralysis of
one or more extremities, cranial nerve paresis, tremors, myoclonus,
ataxia, and a devastating, often fatal syndrome of acute neurogenic
pulmonary edema that may result from destruction of medullary vasomotor
and respiratory centers. Although enterovirus 71 infections have
occurred worldwide, most cases of brain stem encephalitis have occurred
among infants and young children during large outbreaks of enterovirus
71 hand-foot-mouth syndrome in Southeast Asia since 1997.22