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602.2 Viral Meningoencephalitis from Kliegman: Nelson Textbook of Pediatrics on M...

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Kliegman: Nelson Textbook of Pediatrics, 18th ed.


Copyright 2007 Saunders, An Imprint of Elsevier

602.2 Viral Meningoencephalitis

Viral meningoencephalitis is an acute inflammatory process involving the meninges and, to a variable
degree, brain tissue. These infections are relatively common and may be caused by a number of
different agents (see Table 602-3 ). The CSF is characterized by pleocytosis and the absence of
microorganisms on Gram stain and routine bacterial culture. In most instances, the infections are self-
limited. In some cases, substantial morbidity and mortality occur.

ETIOLOGY.

Enteroviruses are the most common cause of viral meningoencephalitis. To date, more than 80
serotypes of these small RNA viruses have been identified. The severity of infection caused by
enteroviruses ranges from mild, self-limited illness with primarily meningeal involvement to severe
encephalitis resulting in death or significant sequelae.

Arboviruses are arthropod-borne agents, responsible for some cases of meningoencephalitis during
summer months. Mosquitoes and ticks are the most common vectors, spreading disease to humans and
other vertebrates, such as horses, after biting infected birds or small animals. Encephalitis in horses
(blind staggers) may be the 1st indication of an incipient epidemic. Although rural exposure is most
common, urban and suburban outbreaks also are frequent. The most common arboviruses responsible
for CNS infection in the United States are West Nile virus (WNV) and St. Louis and California
encephalitis viruses (see Chapter 264 ). West Nile virus made its appearance in the Western hemisphere
in 1999. It has gradually made its way from the east to the west coast over successive summers. In
2002, WNV caused the largest epidemic of arboviral encephalitis ever described in North America, with
transmission reported in 44 states and the District of Columbia. Cumulatively, from 1999 through 2005, a
total of 46 states reported ~19,000 human infections caused by WNV. WNV may also be transmitted by
blood transfusion, organ transplantation, or vertically across the placenta. Most children with WNV are
either asymptomatic or have a nonspecific viral-like illness. Approximately 1% develop CNS disease;
adults are more severely affected than children.

Several members of the herpes family of viruses can cause meningoencephalitis. Herpes simplex
virus type 1 (HSV-1) is an important cause of severe, sporadic encephalitis in children and adults.
Brain involvement usually is focal; progression to coma and death occurs in 70% of cases without
antiviral therapy. Severe encephalitis with diffuse brain involvement is caused by herpes simplex
virus type 2 (HSV-2) in neonates who usually contract the virus from their mothers at delivery. A mild
transient form of meningoencephalitis may accompany genital herpes infection in sexually active
adolescents; most of these infections are caused by HSV-2. Varicella-zoster virus (VZV) may cause
CNS infection in close temporal relationship with chickenpox. The most common manifestation of
CNS involvement is cerebellar ataxia, and the most severe is an acute encephalitis. After primary
infection, VZV becomes latent in spinal and cranial nerve roots and ganglia, expressing itself later
as herpes zoster, sometimes with accompanying mild meningoencephalitis. Cytomegalovirus (CMV)
infection of the CNS may be part of congenital infection or disseminated disease in
immunocompromised hosts, but it does not cause meningoencephalitis in normal infants and
children. Epstein-Barr virus (EBV) has been associated with myriad CNS syndromes (see Chapter
251 ). Human herpes virus 6 (HHV-6) can cause encephalitis, especially among
immunocompromised hosts.

Mumps is a common pathogen in regions where mumps vaccine is not widely used. Mumps
meningoencephalitis is mild, but deafness due to damage of the 8th cranial nerve may be a
sequela. Meningoencephalitis is caused occasionally by respiratory viruses (adenovirus, influenza
virus, parainfluenza virus), rubeola, rubella, or rabies; it may follow live virus vaccinations against
polio, measles, mumps, or rubella.

EPIDEMIOLOGY.

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The epidemiologic pattern of viral meningoencephalitis is primarily determined by the prevalence of


enteroviruses, the most common etiology. Infection with enteroviruses is spread directly from person
to person, with a usual incubation period of 46 days. Most cases in temperate climates occur in the
summer and fall. Epidemiologic considerations in aseptic meningitis due to agents other than
enteroviruses also include season, geography, climatic conditions, animal exposures, and factors
related to the specific pathogen.

PATHOGENESIS AND PATHOLOGY.

Neurologic damage is caused by direct invasion and destruction of neural tissues by actively multiplying
viruses or by a host reaction to viral antigens. Tissue sections of the brain generally are characterized by
meningeal congestion and mononuclear infiltration, perivascular cuffs of lymphocytes and plasma cells,
some perivascular tissue necrosis with myelin breakdown, and neuronal disruption in various stages,
including, ultimately, neuronophagia and endothelial proliferation or necrosis. A marked degree of
demyelination with preservation of neurons and their axons is considered to represent predominantly
postinfectious or allergic encephalitis.

The cerebral cortex, especially the temporal lobe, is often severely affected by HSV; the arboviruses
tend to affect the entire brain; rabies has a predilection for the basal structures. Involvement of the
spinal cord, nerve roots, and peripheral nerves is variable.

CLINICAL MANIFESTATIONS.

The progression and severity of disease are determined by the relative degree of meningeal and
parenchymal involvement, which, in part, is determined by the specific etiology. The clinical course
resulting from infection with the same pathogen varies widely. Some children may appear to be mildly
affected initially, only to lapse into coma and die suddenly. In others, the illness may be ushered in by
high fever, violent convulsions interspersed with bizarre movements, and hallucinations alternating with
brief periods of clarity, followed by complete recovery.

The onset of illness is generally acute, although CNS signs and symptoms are often preceded by a
nonspecific febrile illness of a few days' duration. The presenting manifestations in older children
are headache and hyperesthesia, and in infants, irritability and lethargy. Headache is most often
frontal or generalized; adolescents frequently complain of retrobulbar pain. Fever, nausea and
vomiting, photophobia, and pain in the neck, back, and legs are common. As body temperature
increases, there may be mental dullness, progressing to stupor in combination with bizarre
movements and convulsions. Focal neurologic signs may be stationary, progressive, or fluctuating.
West Nile virus and nonpolio enteroviruses may cause anterior horn cell injury and a flaccid
paralysis. Loss of bowel and bladder control and unprovoked emotional outbursts may occur.

Exanthems often precede or accompany the CNS signs, especially with echoviruses, coxsackieviruses,
VZV, measles, rubella, and, occasionally, West Nile virus. Examination often reveals nuchal rigidity
without significant localizing neurologic changes, at least at the onset.

Specific forms or complicating manifestations of CNS viral infection include Guillain-Barr


syndrome, transverse myelitis, hemiplegia, and cerebellar ataxia.

DIAGNOSIS.

The diagnosis of viral encephalitis is usually made on the basis of the clinical presentation of nonspecific
prodrome followed by progressive CNS symptoms. The diagnosis is supported by examination of the
CSF, which usually shows a mild mononuclear predominance (see Table 602-1 ). Other tests of potential
value in the evaluation of patients with suspected viral meningoencephalitis include an
electroencephalogram (EEG) and neuroimaging studies. The EEG typically shows diffuse slow-wave
activity, usually without focal changes. Neuroimaging studies (CT or MRI) may show swelling of the brain
parenchyma. Focal seizures or focal findings on EEG, CT, or MRI, especially involving the temporal
lobes, suggest HSV encephalitis.

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Differential Diagnosis.

A number of clinical conditions that cause CNS inflammation mimic viral meningoencephalitis (see Table
602-2 ). The most important group of alternative infectious agents to consider is bacteria. Most children
with acute bacterial meningitis appear more critically ill than those with CNS viral infection.
Parameningeal bacterial infections, such as brain abscess or subdural or epidural empyema, may have
features similar to viral CNS infections. Infections caused by M. tuberculosis, T. pallidum (syphilis), B.
burgdorferi (Lyme disease), and Bartonella henselae, the bacillus associated with cat scratch disease,
tend to result in indolent courses. Analysis of CSF and appropriate serologic tests are necessary to
differentiate these various pathogens.

Infections due to fungi, rickettsiae, mycoplasma, protozoa, and other parasites may also need to be
included in the differential diagnosis. Consideration of these agents usually arises as a result of
accompanying symptoms, geographic locality of infection, or host immune factors.

Various noninfectious disorders may be associated with CNS inflammation and have manifestations
overlapping with those associated with viral meningoencephalitis. Some of these disorders include
malignancy, collagen vascular diseases, intracranial hemorrhage, and exposure to certain drugs or
toxins. Attention to history and other organ involvement usually allows elimination of these
diagnostic possibilities.

Laboratory Findings.

The CSF contains from a few to several thousand cells per cubic mm. Early in the disease, the cells
are often polymorphonuclear; later, mononuclear cells predominate. This change in cellular type is
often demonstrated in CSF samples obtained as little as 812 hr apart. The protein concentration in
CSF tends to be normal or slightly elevated, but concentrations may be very high if brain destruction
is extensive, such as that accompanying HSV encephalitis. The glucose level is usually normal,
although with certain viruses, for example, mumps, a substantial depression of CSF glucose
concentrations may be observed.

The CSF should be cultured for viruses, bacteria, fungi, and mycobacteria; in some instances,
special examinations are indicated for protozoa, mycoplasma, and other pathogens. The success of
isolating viruses from the CSF of children with viral meningoencephalitis is determined by the time in
the clinical course that the specimen is obtained, the specific etiologic agent, whether the infection
is a meningitic as opposed to a localized encephalitic process, and the skill of the diagnostic
laboratory staff. Isolating a virus is most likely early in the illness, and the enteroviruses tend to be
the easiest to isolate, although recovery of these agents from the CSF rarely exceeds 70%. To
increase the likelihood of identifying the putative viral pathogen, specimens for culture should also
be obtained from nasopharyngeal swabs, feces, and urine. Although isolating a virus from one or
more of these sites does not prove causality, it is highly suggestive. Detection of viral DNA or RNA
by polymerase chain reaction may be useful in the diagnosis of CNS infection caused by HSV and
enteroviruses, respectively. CSF serology is the diagnostic test of choice for WNV.

A serum specimen should be obtained early in the course of illness and, if viral cultures are not
diagnostic, again 23 wk later for serologic studies. Serologic methods are not practical for
diagnosing CNS infections caused by the enteroviruses because there are too many serotypes. This
approach may be useful in confirming that a case is caused by a known circulating serotype.
Serologic tests may also be of value in determining the etiology of nonenteroviral CNS infection,
such as arboviral infection.

TREATMENT.

With the exception of the use of acyclovir for HSV encephalitis (see Chapter 249 ), treatment of viral
meningoencephalitis is supportive. Treatment of mild disease may require only symptomatic relief.
Headache and hyperesthesia are treated with rest, nonaspirin-containing analgesics, and a reduction in
room light, noise, and visitors. Acetaminophen is recommended for fever. Codeine,

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morphine, and the phenothiazine derivatives may be necessary for pain and vomiting, but if
possible, their use in children should be minimized because they may induce misleading signs and
symptoms. Intravenous fluids are occasionally necessary because of poor oral intake. More severe
disease may require hospitalization and intensive care.

It is important to anticipate and be prepared to manage convulsions, cerebral edema, inadequate


respiratory exchange, disturbed fluid and electrolyte balance, aspiration and asphyxia, and cardiac or
respiratory arrest of central origin. Therefore, patients with severe encephalitis should be monitored
closely. In patients with evidence of increased ICP, placement of a pressure transducer in the epidural
space may be indicated. The risks of cardiac and respiratory failure or arrest are high with severe
disease. All fluids, electrolytes, and medications are initially given parenterally. In prolonged states of
coma, parenteral alimentation is indicated. SIADH is common in acute CNS disorders; monitoring of
serum sodium concentrations is required for early detection (see Chapter 560 ). Normal blood levels of
glucose, magnesium, and calcium must be maintained to minimize the likelihood of convulsions. If
cerebral edema or seizures become evident, vigorous treatment should be instituted.

PROGNOSIS.

Supportive and rehabilitative efforts are very important after patients recover. Motor incoordination,
convulsive disorders, total or partial deafness, and behavioral disturbances may follow viral CNS
infections. Visual disturbances due to chorioretinopathy and perceptual amblyopia may also occur.
Special facilities and, at times, institutional placement may become necessary. Some sequelae of
infection may be very subtle. Therefore, neurodevelopmental and audiologic evaluations should be
part of the routine follow-up of children who have recovered from viral meningoencephalitis.

Most children completely recover from viral infections of the CNS, although the prognosis depends
on the severity of the clinical illness, the specific cause, and the age of the child. If the clinical illness
is severe and substantial parenchymal involvement is evident, the prognosis is poor, with potential
deficits being intellectual, motor, psychiatric, epileptic, visual, or auditory in nature. Severe sequelae
should also be anticipated in those with infection caused by HSV. Although some literature suggests
that infants who contract viral meningoencephalitis have a poorer long-term outcome than older
children, most other data refute this observation. Approximately 10% of children younger than 2 yr
with enteroviral CNS infections suffer an acute complication such as seizures, increased ICP, or
coma. Almost all have favorable long-term neurologic outcomes.

PREVENTION.

Widespread use of effective viral vaccines for polio, measles, mumps, rubella, and varicella has
almost eliminated CNS complications from these diseases in the United States. The availability of
domestic animal vaccine programs against rabies has reduced the frequency of rabies encephalitis.
Control of encephalitis due to arboviruses has been less successful because specific vaccines for
the arboviral diseases that occur in North America are not available. Control of insect vectors by
suitable spraying methods and eradication of insect breeding sites, however, reduces the incidence
of these infections. Furthermore, minimizing mosquito bites through the application of DEET-
containing insect repellents on exposed skin and wearing long-sleeved shirts, long pants, and socks
when outdoors, especially at dawn and dusk, reduces the risk of arboviral infection.

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