Background

Encephalitis, an inflammation of the brain parenchyma, presents as diffuse and/or focal

neuropsychological dysfunction. Although it primarily involves the brain, the meninges are
frequently involved (meningoencephalitis).
From an epidemiologic and pathophysiologic perspective, encephalitis is distinct from
meningitis, though on clinical evaluation both can be present, with signs and symptoms of
meningeal inflammation, such as photophobia, headache, or stiff neck. It is also distinct
from cerebritis. Cerebritis describes the stage preceding abscess formation and implies a highly
destructive bacterial infection of brain tissue, whereas acute encephalitis is most commonly a
viral infection with parenchymal damage varying from mild to profound.
Although bacterial, fungal, and autoimmune disorders can produce encephalitis, most cases are
viral in origin. The incidence of encephalitis is 1 case per 200,000 population in the United
States, with herpes simplex virus (HSV) being the most common cause. Considering the
subacute and chronic encephalopathies, the emergency department (ED) physician is most
likely to encounter toxoplasmosis in an immune-compromised host.
The relatively common acute arboviral encephalitides vary widely in epidemiology, mortality,
morbidity, and clinical presentation, and no satisfactory treatment exists for these infections.
However, attempts to distinguish these acute arboviral encephalitides from the treatable acute
viral encephalitides due to herpes simplex or varicella are important.
Herpes simplex encephalitis (HSE), which occurs sporadically in healthy and immunecompromised adults is also encountered in neonates infected at birth during vaginal delivery
and is potentially lethal if not treated. Varicella-zoster virus encephalitis (VZVE) is life
threatening in immune-compromised patients. Swift identification and immediate treatment of
HSE or VZVE can be lifesaving. From a risk-benefit standpoint, most authorities recommend
initiating ED treatment with acyclovir in any patient whose central nervous system (CNS)
presentation is suggestive of viral encephalitis, especially in the presence of fever,
encephalopathy, or focal findings, and in all neonates who appear ill for whom a CNS infection
is being considered.
See the following for more information:

California Encephalitis
CBRNE--Venezuelan Equine Encephalitis
Eastern Equine Encephalitis
Encephalitis
Herpes Simplex Encephalitis
HIV-Associated Cytomegalovirus Encephalitis
Japanese Encephalitis
St. Louis Encephalitis
Venezuelan Equine Encephalitis
Viral Encephalitis
West Nile Encephalitis
Western Equine Encephalitis

Pathophysiology

Portals of entry are virus specific. Many viruses are transmitted by humans, though most cases
of HSE are thought to be reactivation of HSV lying dormant in the trigeminal ganglia.
Mosquitoes or ticks inoculate arbovirus, and rabies virus is transferred via an infected animal
bite or exposure to animal secretions. With some viruses, such as varicella-zoster virus (VZV)
and cytomegalovirus (CMV), an immune-compromised state is usually necessary to develop
clinically apparent encephalitis.
In general, the virus replicates outside the CNS and gains entry to the CNS either by
hematogenous spread or by travel along neural pathways (eg, rabies virus, HSV, VZV). The
etiology of slow virus infections, such as those implicated in the measles-related subacute
sclerosing panencephalitis (SSPE) and progressive multifocal leukoencephalopathy (PML), is
poorly understood.
Once across the blood-brain barrier, the virus enters neural cells, with resultant disruption in cell
functioning, perivascular congestion, hemorrhage, and a diffuse inflammatory response that
disproportionately affects gray matter over white matter. Regional tropism associated with
certain viruses is due to neuron cell membrane receptors found only in specific portions of the
brain, with more intense focal pathology in these areas. A classic example is the HSV
predilection for the inferior and medial temporal lobes.
In contrast to viruses that invade gray matter directly, acute disseminated encephalitis and
postinfectious encephalomyelitis (PIE), most commonly due to measles infection and associated
with Epstein-Barr virus (EBV) and CMV infections, are immune-mediated processes that result
in multifocal demyelination of perivenous white matter.

Etiology
The cause of encephalitis is usually infectious in nature. Viral agents, such as HSV types 1 and
2 (the latter much more common in neonates than adults), VZV, EBV, measles virus (PIE and
SSPE), mumps virus, and rubella virus, are spread through person-to-person contact. Human
herpesvirus 6 may also be a causative agent.[3] The CDC has confirmed that WNV can be
transmitted by means of organ transplantation and via blood transfusions.
Important animal vectors include mosquitoes and ticks, which spread the arbovirus group, and
warm-blooded mammals, which are vectors for rabies and lymphocytic choriomeningitis (LCM).
Bacterial pathogens, such as Mycoplasma species and those causing rickettsial disease or
catscratch disease, are rare and invariably involve inflammation of the meninges out of
proportion to their encephalitic components. Encephalitis due to parasites and fungi other
than Toxoplasma gondii are covered elsewhere.
Noninfectious causes include the demyelinating process in acute disseminated encephalitis.

Epidemiology

United States statistics

Determining the true incidence of encephalitis is impossible, because reporting policies are
neither standardized nor rigorously enforced. In the United States, several thousand cases
of viral encephalitis are reported to the CDC each year, with an additional 100 cases a year
attributed to PIE. These figures probably represent a fraction of the actual number of cases.
HSE, the most common cause of sporadic encephalitis in Western countries, is relatively rare;
the overall incidence is 0.2 per 100,000, with neonatal HSV infection occurring in 2-3 per 10,000
live births.
The arbovirus group is the most common cause of episodic encephalitis, with a reported
incidence similar to that of HSV. These statistics may be misleading in that most people bitten
by arbovirus-infected insects do not develop clinically apparent illness and, of those who do,
less than 10% develop overt encephalitis.
Arboviruses require an insect vector, which is generally present between June and October. The
2 most common arboviruses result in (1) St Louis encephalitis, found throughout the United
States but principally in urban areas around the Mississippi River, and (2) the geographically
misnamed California virus encephalitis (CE)in particular, LaCross encephalitis (LAC)which
affects children in rural areas in states of the upper Midwest and North East.
Among the other arbovirus-caused encephalitides, the deadliest (and, fortunately, rarest)
is eastern equine encephalitis (EEE), which is encountered in New England and surrounding
areas; western equine encephalitis (WEE), a milder disease, is most common in rural
communities west of the Mississippi River. Powassan virus is the only well-documented
arbovirus transmitted by ticks.
Less common causes of viral encephalitis include VZV encephalitis, with an incidence of
roughly 1 in 2000 infected persons. Measles produces 2 devastating forms of encephalitis: PIE,
which occurs in about 1 in 1000 infected persons, and SSPE, occurring in about 1 in 100,000
infected patients. Rarest in the United States are the 0-3 unrelated annual cases of rabies
encephalitis, typically a consequence of the immigration of an infected person from Mexico or
Central America during the long incubation period of the rabies virus but prior to the onset of
clinically apparent disease.

International statistics
Japanese virus encephalitis (JE), occurring principally in Japan, Southeast Asia, China, and
India, is the most common viral encephalitis outside the United States.

Age-related differences in incidence

Individuals at the extremes of age are at highest risk, particularly for HSE. Neonatal HSE is a
manifestation of disseminated infection type 1 or 2, whereas older infants, children, and adults
are much more likely to have localizing CNS infection almost exclusively due to type 1, in a
bimodal distribution of patients aged 5-30 years or older than 50 years.
St Louis encephalitis and WNE are more common and are most severe in patients older than 60
years; conversely, LAC is more common and is most severe in children younger than 16 years.
EEE and WEE disproportionately affect infants while EEE disproportionately affects children and
elderly persons.

Prognosis
The prognosis is dependent on the virulence of the virus and the patients health status.
Extremes of age (< 1 y or >55 y), immune-compromised status, and preexisting neurologic
conditions are associated with poorer outcomes.
Untreated HSE has a mortality of 50-75%, and virtually all untreated or late-treatment survivors
have long-term motor and mental disabilities. The mortality in treated HSE averages 20%, and
the neurologic outcome correlates with the neurological disability present at the time of the first
dose of acyclovir or comparable antiviral agents. Approximately 40% of survivors have minor-tomajor learning disabilities, memory impairment, neuropsychiatric abnormalities, epilepsy, finemotor-control deficits, and dysarthria.
Outcomes in arboviral JE and EEE are catastrophic, similar to untreated HSE, with high
mortality and severe morbidity, including mental retardation, hemiplegia, and seizures. Other
arboviruses cause substantially less morbidity and mortality. For example, St Louis encephalitis
and WNE have a mortality rate of 2-20%, the higher rates found in patients older than 60 years.
Long-term sequelae with St Louis encephalitis include behavioral disorders, memory loss, and
seizures.
WEE is associated with few deaths and much less morbidity, although developmental delay,
seizure disorder, and paralysis occasionally occur in children, and postencephalitic
parkinsonism may occur in adults. CE is typically associated with mild illness, and most patients
make a full recovery; however, the minority of patients with severe disease have a 25% chance
of focal neurologic dysfunction. Death rates from WEE and LAC are less than 5%.
PIE secondary to measles is associated with a mortality rate approaching 40% of cases, with a
high rate of neurologic sequelae in survivors. SSPE is uniformly fatal, although the disease
course may last anywhere from several weeks to 10 years.

VZVE has a mortality of 15% in immune-competent patients and virtually 100% in immunesuppressed patients. The mortality for EBV encephalitis is 8%, with substantial morbidity found
in approximately 12% of survivors.
Rabies encephalitis and acute disseminated encephalitis are virtually 100% fatal, although there
are rare survivors reported in the medical literature.

History
The clinical presentation and course can be markedly variable. The acuity and severity of the
presentation correlate with the prognosis. A history of mosquito or tick bites or exposure to
mouse/rat droppings should be sought. Recognizing certain mammalian animal bite(s)
associated with rabies or exposure to a bat in an enclosed space for which antirabies treatment
was not obtained is very important.
The viral prodrome is typically several days and consists of fever, headache, nausea and
vomiting, lethargy, and myalgias. The specific prodrome in encephalitis caused by varicellazoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), measles virus, or mumps
virus includes rash, lymphadenopathy, hepatosplenomegaly, and parotid enlargement. Dysuria
and pyuria are reported with St Louis encephalitis. Extreme lethargy has been noted with West
Nile encephalitis (WNE).
The classic presentation is encephalopathy with diffuse or focal neurologic symptoms, including
the following:

Behavioral and personality changes, with decreased level of consciousness

Neck pain, stiffness
Photophobia
Lethargy
Generalized or focal seizures (60% of children with CE)
Acute confusion or amnestic states
Flaccid paralysis (10% of patients with WNE)
Of note, severe headache is not always found. Less common is the complaint of paraspinal
backache.
Symptoms of herpes simplex virus (HSV) infection in neonates (aged 1-45 d) may include
localized skin, eye, or mouth lesions in the early phase of illness with encephalitis. Diminished
alertness, irritability, seizures, and poor feeding develop later in the course of illness, and
disseminated disease and shock are late findings.
Herpes simplex encephalitis (HSE) in older children and adults is not typically associated with
active herpetic eruptions and is characterized by the acute onset of more severe symptoms of
encephalitis early in the course of illness.
Toxoplasma encephalopathy accounts for as many as 40% of HIV-positive patients with
neurologic disease who present with a subacute headache, findings of subtle to remarkable
encephalopathy, and, often, focal neurological complaints/findings. Rarely, this may be the
presenting symptom complex of profound immune suppression due to HIV infection.

Physical Examination

Look for supporting evidence of viral infection. The signs of encephalitis may be diffuse or focal.
At the extremes, 80% of patients with HSE present with focal findings. Typical findings include
the following:

Altered mental status

Personality changes are very common
Focal findings, such as hemiparesis, focal seizures, and autonomic dysfunction
Movement disorders (St Louis encephalitis, eastern equine encephalitis [EEE], western
equine encephalitis [WEE])
Ataxia
Cranial nerve defects
Dysphagia, particularly in rabies
Meningismus (less common and less pronounced than in meningitis)
Unilateral sensorimotor dysfunction (postinfectious encephalomyelitis [PIE])
Findings of HSV infection in neonates (aged 1-45 d) may include the following:
Herpetic skin lesions over the presenting surface from birth or with breaks in the skin,
such as those resulting from fetal scalp monitors
Keratoconjunctivitis
Oropharyngeal involvement, particularly buccal mucosa and tongue
Encephalitis symptoms, such as seizures, irritability, change in level of attentiveness,
bulging fontanelles
Additional signs of disseminated, severe HSV include jaundice, hepatomegaly, and
shock
As noted above, Toxoplasma infection causing encephalitis is found in immune-suppressed
patients. They exhibit significant encephalopathy with lethargy or personality changes, and 75%
present may present with focal neuropathology.

Complications
Encephalitis may be associated with a number of complications, including the following:

Seizures
Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)
Increased intracranial pressure (ICP)
Coma

Differential Diagnoses

Brain Abscess
Catscratch Disease
Herpes Simplex
Herpes Simplex Encephalitis
Hypoglycemia
Leptospirosis in Humans
Meningitis
Pediatrics, Meningitis and Encephalitis
Status Epilepticus
Subarachnoid Hemorrhage
Systemic Lupus Erythematosus
Tick-Borne Diseases, Lyme
Tick-Borne Diseases, Rocky Mountain Spotted Fever

Toxoplasmosis
Tuberculosis

Approach Considerations
Although bacterial, fungal, and autoimmune disorders can produce encephalitis, most cases are
viral in origin. Accordingly, in addition to standard blood and urine tests, studies may be
performed to identify the infectious agent causing the encephalitis.[4] It is important, when
possible, to distinguish acute arboviral encephalitides from potentially treatable acute viral
encephalitides, especiallyherpes simplex encephalitis (HSE) and varicella-zoster encephalitis,
as a high suspicion for these disorders and prompt treatment can reduce the severity of
neurological sequelae and can be lifesaving.

Blood and Urine Tests

A complete blood count (CBC) with differential should be performed, although findings are often
within the normal range.
Serum electrolyte levels are usually normal unless dehydration is present; the syndrome of
inappropriate secretion of antidiuretic hormone (SIADH) occurs in 25% of patients with St Louis
encephalitis.
The serum glucose level should be determined to rule out confusion due to treatable
hypoglycemia and to compare with the cerebrospinal fluid (CSF) glucose value. Low serum
results are found in nutritionally deprived patients, while diabetic patients may present with
elevated glucose levels compatible with complicating hyperosmolar state or diabetic
ketoacidosis.
Blood urea nitrogen (BUN) and creatinine levels are helpful to assess hydration status, and liver
function tests should be performed to assess for end-organ dysfunction or the need to adjust
antimicrobial therapy dosing regimens.
A lumbar puncture (LP) should be performed on all patients suspected of having a viral
encephalitis. A platelet count and coagulation profile are indicated in patients who are chronic
alcohol users, have liver disease, and those in whom disseminated intravascular coagulation
(DIC) is suspected. The patient may require platelets or fresh frozen plasma (FFP) before LP.
A urinary electrolyte test should be performed if SIADH is suspected. Urine or serum toxicology
screening may be indicated in selected patients presenting with a toxic delirium or confusional
state.

Studies to Identify Infectious Agent

Herpes simplex virus (HSV) cultures of suspicious lesions and a Tzanck smear should be
obtained. Viral cultures of CSF, including HSV, should be performed, although the incidence of
the latter being positive is rare. Blood cultures for bacterial pathogens should be obtained.
Complement fixation antibodies are useful in identifying arbovirus. Cross-reactivity exists among
a subgroup of arboviruses, the flaviviruses (eg, viruses that cause St Louis encephalitis,
Japanese virus encephalitis [JE], and West Nile encephalitis [WNE]), and the antibodies found
in persons inoculated with yellow fever vaccine.
Heterophile antibody and cold agglutinin testing for Epstein-Barr virus (EBV) may be helpful.
Serologic tests for toxoplasmosis can be helpful in light of an abnormal computed tomography
(CT) scan, particularly in the case of single lesions. However, the overlap in titer levels between
exposed but currently uninfected and reactivated groups may complicate interpretation.

Computed Tomography, Magnetic Resonance Imaging, and

Electroencephalography
Performance of a head CT scan with and without contrast agent should be performed in virtually
all patients with encephalitis. This should be done prior to LP if there are focal complaints or
findings, signs to search for evidence of elevated intracranial pressure (ICP), obstructive
hydrocephalus, or mass effect due to focal brain infection. Head CT scanning also helps
exclude brain hemorrhage or infarction as a cause of an encephalopathic state. Magnetic
resonance imaging (MRI) is more sensitive than CT scanning in demonstrating brain
abnormalities earlier in the disease course.
In HSE, MRI may show several foci of increased T2 signal intensity in medial temporal lobes
and inferior frontal gray matter. Head CT commonly shows areas of edema or petechial
hemorrhage in the same areas. EEE and tick-borne encephalitis may show similar increased
MRI signal intensity in the basal ganglia and thalamus.
In toxoplasmosis, contrast-enhanced head CT typically reveals several nodular or ringenhancing lesions. Because lesions may be missed without contrast, MRI should be performed
in patients for whom use of contrast material is contraindicated.
In HSE, electroencephalography (EEG) often documents characteristic paroxysmal lateral
epileptiform discharges (PLEDs), even before neuroradiography changes. Eventually, PLEDs
are positive in 80% of cases; however, the presence of PLEDs is not pathognomonic for HSE.

Analysis of Cerebrospinal Fluid

The most important diagnostic test in the emergency department (ED) to rule out bacterial
meningitis is prompt Gram staining and, if available, polymerase chain reaction (PCR) of the
CSF in patients with suspected HSV encephalitis. PCR for HSV DNA is 100% specific and 75-

98% sensitive within the first 25-45 hours. Types 1 and 2 cross-react, but no cross-reactivity
with other herpes viruses occurs. Arguably, a series of quantitative PCRs documenting the
decline of viral load with acyclovir treatment is strongly supportive of the diagnosis of HSV, and
selected patients my avoid need for brain biopsy.

Brain Biopsy
Although most histologic features are nonspecific, brain biopsy is the criterion standard because
of its 96% sensitivity and 100% specificity.
The presence of Negri bodies in the hippocampus and cerebellum are pathognomonic of rabies,
as are HSV Cowdry type A inclusions with hemorrhagic necrosis in the temporal and
orbitofrontal lobes.

Emergency Department Care

With the important exceptions of HSE and varicella-zoster encephalitis, the viral encephalitides
are not treatable beyond supportive care. Treatments for T gondiiand cytomegalovirus (CMV)
encephalitis are available but generally not initiated in the ED.
The goal of treatment for acutely ill patients is administration of the first dose or doses of
acyclovir, with or without antibiotics or steroids, as quickly as possible. The standard for acute
bacterial meningitis is the initiation of treatment within 30 minutes of arrival. Consider instituting
an ED triage protocol to identify patients at risk for HSE.
Collect laboratory samples and blood cultures before the start of IV therapy. Even in
uncomplicated cases of encephalitis, most authorities recommend a neuroimaging study (eg,
magnetic resonance imaging [MRI] or, if that is not available, a contrast-enhanced head
computed tomography [CT] scan) beforelumbar puncture (LP).

Management of hydrocephalus and increased intracranial pressure

In patients with hydrocephalus and increased intracranial pressure (ICP), general measures
include management of fever and pain, control of straining and coughing, and prevention of
seizures and systemic hypotension.
In otherwise stable patients, elevating the head and monitoring neurologic status usually are
sufficient. When more aggressive maneuvers are indicated, early use of diuresis (eg,
furosemide 20 mg IV, mannitol 1 g/kg IV) may be helpful, provided that circulatory volume is
protected. Dexamethasone 10 mg IV q6h helps in managing edema surrounding spaceoccupying lesions. Hyperventilation (arterial CO2 tension [PaCO2] 30 mm Hg) may cause a
disproportional decrease in cerebral blood flow (CBF), but it is used to control increasing ICP on
an emergency basis.

Intraventricular ICP monitoring is controversial. Some authorities believe that dangerous focal
edema with a pressure gradient between the temporal lobe and the subtentorial space usually is
not detected by the monitor and that this failure of detection can lead to a false sense of
security. In fact, monitor placement may potentially aggravate a pressure gradient.

Treatment of systemic complications

Look for and treat systemic complications (eg, hypotension or shock, hypoxemia, hyponatremia,
and exacerbation of chronic diseases), particularly in herpes simplex encephalitis (HSE),
eastern equine encephalitis (EEE), Japanese virus encephalitis (JE).

Empiric treatment of HSV meningoencephalitis and VZV encephalitis

Empiric adult emergency treatment for herpes simplex virus (HSV) meningoencephalitis and
varicella-zoster virus (VZV) encephalitis consists of acyclovir 10 mg/kg (infused over 1 h) q8h
for 14-21 days. Give acyclovir 10-15 mg/kg IV q8h for neonatal HSV; for HSV encephalitis in the
pediatric population, give acyclovir 10 mg/kg IV q8h.
In HIV-positive patients, consider foscarnet, given the increased incidence of acyclovir-resistant
HSV and herpes zoster virus (HZV).

Approach Considerations
Prehospital care
In the prehospital setting, evaluate and treat for shock or hypotension. Administer crystalloid
infusion in patients with evidence of circulatory compromise. Consider airway protection in
patients with an altered mental status. Seizure precautions are indicated. Treat seizures
according to usual protocols (ie, lorazepam 0.1 mg/kg given intravenously [IV]). All patients
should receive oxygen and have intravenous access secured en route to the emergency
department (ED).

Pediatric Meningitis and Encephalitis

Background
Despite advances in antimicrobial and general supportive therapies, central nervous system
(CNS) infections remain a significant cause of morbidity and mortality in children. As classical
signs and symptoms often are not present, especially in the younger children, diagnosing CNS
infections is a challenge to the emergency department. Also, even for children who have had
prompt diagnosis and treatment, a high frequency of neurologic sequelae remains. This often
leads to legal action. The emergency clinician is faced with the daunting task of separating out
those few children with CNS infections from the vast majority of children who come to the ED
with less serious infections.

Pathophysiology
To develop bacterial meningitis, the invading organism must gain access to the subarachnoid
space. This is usually via hematogenous spread from the upper respiratory tract where the initial
colonization has occurred. Less frequently, there is direct spread from a contiguous focus (eg,
sinusitis, mastoiditis, otitis media) or through an injury, such as a skull fracture.
The most common causative organisms in the first month of life are Escherichia coli and group
B streptococci. Listeria monocytogenes infection also occurs in patients in this age range and
accounts for 5-10% of cases. Neisseria meningitidisinfections occurring in the first month of life
have been reported. From 30-60 days, group B streptococcal infection occurs frequently, and
the gram-negative enterics decline in frequency. Streptococcus pneumoniae, Haemophilus
influenzae, and N meningitidis occur rarely in this age group. In those older than 2 months, S
pneumoniae and N meningitidis currently cause the majority of the cases of bacterial
meningitis. H influenzae may still occur, especially in children who have not received the Hib
vaccine.
The most common causative organisms (eg, N meningitidis, S pneumoniae, H influenzae)
contain a polysaccharide capsule that allows them to colonize the nasopharynx of healthy
children without any systemic or local reaction. A concurrent viral infection may facilitate the
penetration of the nasopharyngeal epithelium by the bacteria. Once in the bloodstream, the
polysaccharide capsule allows the bacteria to resist opsonization by the classical complement
pathway and, thus, inhibit phagocytosis.
Unusual bacteria occasionally cause meningitis. Pasteurella multocida is known to cause skin
infections from cat or dog bites. A recent case described a 7-week-old infant with P
multocida meningitis after exposure to dog saliva with no wound, emphasizing the need to
protect young children from this pathogen. This infection, while rare, is associated with
significant morbidity and mortality.

Salmonella meningitis should be suspected in any child with this organism grown at any other
site in an unwell child or one younger than 6 months. Mothers known to be infected
with Salmonella during pregnancy may put their child at risk. As therapy is different
for Salmonella meningitis, while rare, it must be considered in the above situations.
The bacteremic phase allows penetration of the cerebrospinal fluid (CSF) through the choroid
plexus. The CSF is poorly equipped to control infection because type-specific antibodies do not
penetrate the blood brain barrier well and complement components are absent or in low
concentrations.
The cell walls of both gram-positive and gram-negative bacteria contain potent triggers of the
inflammatory response. In the gram-positive bacteria, teichoic acid is considered the major
pathogenic component. In gram-negative bacteria, lipopolysaccharide or endotoxin is the major
pathogenic component. These components are released in the CSF during bacterial growth and
especially with the lysis of bacterial cells. Antibiotic therapy causes a significant release of the
mediators of the inflammatory response.
The mediators of the inflammatory response include cytokines (tumor necrosis factor, interleukin
1, 6, 8, 10), platelet activating factor, nitric oxide, prostaglandins, and leukotrienes. These
mediators cause disruption of the blood brain barrier, vasodilation, neuronal toxicity, meningeal
inflammation, platelet aggregation, and activation of leukocytes. The capillary endothelial cell is
the main site of injury in bacterial meningitis; thus, it is a vasculitis, which results in destruction
of vascular integrity. The ultimate consequences are damage to the blood brain barrier, brain
edema, impaired cerebral blood flow, and neuronal injury.
Because of the damage done by the body's response to the infection, various anti-inflammatory
agents have been used in an attempt to decrease the morbidity and mortality of bacterial
meningitis. Only dexamethasone occasionally has been proven effective.
Viral meningitis or aseptic meningitis is the most common infection of the CNS. It most
frequently occurs in children younger than 1 year. Enterovirus is the most common causative
agent and is a frequent cause of febrile illnesses in children. Other viral pathogens include
paramyxoviruses, herpes, influenza, rubella, and adenovirus. Meningitis may occur in up to half
of children younger than 3 months with enteroviral infection. Enteroviral infection can occur any
time during the year but is associated with epidemics in the summer and fall. Viral infection
causes an inflammatory response but to a lesser degree than bacterial infection. Damage from
viral meningitis may be due to an associated encephalitis and increased intracranial pressure.
Fungal meningitis is rare but may occur in immunocompromised patients; children with cancer,
previous neurosurgery, or cranial trauma; or premature infants with low birth rates. Most cases
are in children who are receiving antibiotic therapy and, thus, usually are inpatients.
The etiology of aseptic meningitis caused by drugs is not well understood. This form of
meningitis is infrequent in the pediatric population.

Encephalitis is a similar disease of the central nervous system. This disease is an inflammation
of brain parenchyma. Often, a viral agent is responsible. Viral entry occurs through
hematogenous or neuronal routes.
The more common form of encephalitis is transmitted by bites of mosquitoes and ticks, infected
with the virus. The virus comes from the Togavirus, Flavivirus, and Bunyavirus families.
The more common types of encephalitis in the United States are La Crosse virus, eastern
equine encephalitis virus, and St Louis virus. Often, these causes of encephalitis cause similar
signs and symptoms. Confirmation and differentiation come from laboratory testing. However, its
utility is limited to a number of identifiable pathogens.
West Nile virus is becoming a leading cause of encephalitis, caused by the arbovirus from the
Flaviviridae family. Mosquitoes, spreading virus between its natural hosts, migrating birds,
transmit it. Mosquitoes bite humans, who become infected with the virus. However, human
hosts are dead-end hosts for the virus.
Most humans do not develop the disease. Approximately 1 symptomatic infection develops for
every 120-160 asymptomatic ones. The young and old are at risk of developing symptomatic
disease.
It has become a greater public health issue, given that spread occurs with migratory birds. The
first cases were identified in New York City in 1999, with additional cases being identified in the
following years across the United States.
Encephalitis can be transmitted by other means. Herpetic encephalitis and rabies are two
examples, where transmission occurs by direct contact and mammalian bites, respectively. In
the case of herpetic encephalitis, there is evidence of virus reactivation and subsequent
intraneuronal transmission, leading to encephalitis.

Epidemiology
Frequency
United States
The advent of vaccine has changed the incidence of disease. The incidence of disease caused
by H influenzae, S pneumoniae, and N meningitidis has decreased.
The advent of universal Hib vaccination in developed countries has lead to the reduction of
more than 99% of invasive disease. The vaccine is directed against the H influenzae type b
strain. This protection continues even when Hib is coadministered with other vaccines. Just as
important, the vaccine continues to confer immunity into later childhood.

A similar effect occurs with the advent of pneumonococcal vaccine. This is true for the
pneumococcal polysaccharide vaccines conjugated to various proteins. Given at ages 2, 4, and
6 months, this vaccine has reduced invasive disease more than 90%. Age groups most affected
are those younger than age 2 years and those aged 2-5 years. This was proven in a
surveillance study in Louisville, Kentucky.[1]Nearly half of those with pneumococcal disease are
caused by nonvaccine serotypes.[2, 3]
However, vaccine for Neisseria has not been efficacious in younger children. This is due to poor
immunogenic response. Current recommendation targets immunization for children older than
age 2 years and high-risk patients with asplenic and terminal complement deficiencies. In
addition, young adults living in close quarters, such as dormitories or military barracks, will
benefit.
The incidence of neonatal meningitis has shown no significant change in the last 25 years. Viral
meningitis is the most common form of aseptic meningitis and, since the introduction of mumps
vaccine, is caused by enteroviruses in up to 85% of cases. Incidence of encephalitis is more
difficult to estimate because of difficulty in establishing the diagnosis. One report estimates an
incidence of 1 in 500-1000 in the first 6 months of life.
International
In a survey by the Hib and Pneumococcal Working Group, the incidence of meningitis in 2000
varied from regions across the world. The overall incidence of pneumococcal meningitis was 17
cases per 100,000, with the highest incidence in Africa at 38 cases per 100,000 and the lowest
incidence in Europe at 6 cases per 100,000. The overall death rate was 10 cases per 100,000.
The highest death rate was 28 cases per 100,000 in Africa, and the lowest death rates were 3
cases per 100,000 in Europe and Western Pacific regions.[4]
A similar trend was identified for Hib meningitis. The overall incidence of Hib meningitis in 2000
was 31 cases per 100,000. The African region had the highest rate at 46 cases per 100,000,
and Europe had the lowest rate at 13 cases per 100,000. The death rate was 13 cases per
100,000. The highest death rate was 31 cases per 100,000 in Africa, and the lowest death rate
was 4 cases per 100,000 in Europe.[5]

Mortality/Morbidity
Morbidity and mortality rates depend on the infectious agent, age of the child, general health,
and prompt diagnosis and treatment. Despite improvement in antibiotic and supportive therapy,
a significant mortality and morbidity rate remains.

The overall mortality for bacterial meningitis is 5-10% and varies with causative
organism and age. Neonatal meningitis has a mortality rate of 15-20%. In older children, the
mortality rate is 3-10%. Meningitis from S pneumoniae has the highest mortality rate (26.330%); H influenzae type B has a 7.7-10.3% mortality rate; N meningitidis has the lowest
mortality rate of the most common organisms, at 3.5-10.3%.

Up to 30% of children have neurological sequelae. This varies by organism,

with S pneumoniae having the highest rate of complications.
o
One study indicates that the complication rate from S pneumoniaemeningitis did
not vary if the infection was from a penicillin sensitive or resistant strain. This study showed
that dexamethasone did not improve outcomes.[6]
o
Some studies have shown the incidence of profound bilateral hearing loss, up to
4% in all bacterial meningitis cases.[7] Sensorineural hearing loss is one of the most frequent
problems. Children at greatest risk for hearing loss include those with evidence of increased
intracranial pressure, abnormal findings on CT scan, male sex, low glucose levels in CSF,
infection by S pneumoniae, and nuchal rigidity.
o
As many of the children affected are very young and cognitive and motor skills
are immature, some of the sequelae may not be recognized for years. A recent study
followed children who recovered from meningitis for 5-10 years. They found 1 in 4 schoolaged meningitis survivors had either serious and disabling sequelae or a functionally
important behavior disorder or neuropsychiatric or auditory dysfunction that impaired their
performance in school.

Viral meningoencephalitis: Enteroviral infection usually has few complications. Herpes

simplex and arbovirus infections, in addition to viral infections in AIDS patients, can result in
severe neurological disease.

Tuberculous meningitis: Morbidity and mortality rates are related to the stage of the
disease. Stage I has a 30% significant morbidity, stage II 56%, and stage III 94%.
Race
o

Bacterial meningitis more frequently occurs in black and Hispanic children. This is thought to be
related to socioeconomic rather than racial factors.

Sex
Prevalence of bacterial meningitis is higher in males. A recent report from Finland showed
males more often had mumps and varicella encephalitis, whereas females had adenoviral
and Mycoplasma encephalitis more often.

Age
For both meningitis and encephalitis, the greatest occurrence is in children younger than 4
years with a peak incidence in those aged 3-8 months.

History

Bacterial meningitis
The younger the child, the less likely he or she is to exhibit the classic symptoms
of fever, headache, and meningeal signs.
Meningitis in the neonatal period is associated with maternal infection or pyrexia
at delivery. The child younger than 3 months may have very nonspecific symptoms, including
hyperthermia or hypothermia, change in sleeping or eating habits, irritability or lethargy,
vomiting, high-pitched cry, or seizures.

Meningismus and a bulging fontanel may be observed but are not needed for
diagnosis.

A child who is quiet at rest but who cries when moved or comforted may have
meningeal irritation (paradoxical irritability).
After age 3 months, the child may display symptoms more often associated with
bacterial meningitis, with fever, vomiting, irritability, lethargy, or any change in behavior.
After age 2-3 years, children may complain of headache, stiff neck, and
photophobia.
The clinical course may be brief and fulminant with rapid progression of
symptoms or may follow a more gradual course with several days of upper respiratory
infection progressing to more severe symptoms. The fulminant course is more often
associated with N meningitidis infection.
Viral meningitis
In areas with widespread vaccination of children, enteroviruses are the most
common causes of viral meningitis. The onset is variable and may have several days of fever,
anorexia, and general malaise. It also may present as a rather abrupt onset of fever, nausea,
vomiting, and headache.
Additional symptoms are shared with enteroviral infections, such as pharyngitis,
conjunctivitis, and myositis.
Other causes of viral meningitis also may be associated with encephalitis.
Arboviral infections frequently have associated encephalitis and seizures.
Adenoviral, mumps, and varicella-zoster infections tend to be more severe than
enteroviral infections, and often evidence of encephalitis is present.
In areas with low vaccination rates, mumps virus is often the most frequent cause
of meningitis.
Fungal meningitis occurs in immunocompromised patients and has a variable
presentation.
Aseptic meningitis may be caused by drugs, usually nonsteroidal anti-inflammatory
drugs (NSAIDs), IVIG, and antibiotics. A recent report was of a pediatric patient with a
trimethoprim-sulfamethoxazoleinduced meningitis. Symptoms were similar to those of viral
meningitis. Symptoms may occur within minutes of ingestion of the drug.
Encephalitis
Diagnosis for the causative viral agent is aided by historical facts. Information
such as season of year, travel, activities, and exposure to animals helps with diagnosis.
A distinction between viral encephalitis and postinfectious encephalomyelitis is
important because management and prognosis are different. With postinfectious
encephalomyelitis, the usual presentation is a nonspecific respiratory viral syndrome.

Physical
Physical examination findings are widely variable based on age and infecting organism. It is
important to remember that the younger the child, the less specific the symptoms.

o
o

In the young infant findings that definitely point to meningitis are rare.
The infant may be febrile or hypothermic.
Bulging of the fontanel, diastasis of the sutures, and nuchal rigidity point to
meningitis but are usually late findings.
As the child grows older, the physical examination becomes more reliable.
Meningeal signs (eg, headache, nuchal rigidity, positive Kernig and Brudzinski
signs) should be sought, and their presence or absence recorded.

o
o
o
o

o
o

A definitive diagnosis of meningitis requires examination of CSF vialumbar

puncture. Presence or absence of classic meningeal signs and symptoms should not be
used as the sole criteria for referring patients for further diagnostic testing.[8]
Focal neurological signs may be present in up to 15% of patients and are
associated with a worse prognosis.
Seizures occur in up to 30% of children with bacterial meningitis.
Obtundation and coma occur in 15-20% of patients and are more frequent with
pneumococcal meningitis.
Encephalitis may present like meningitis or the symptoms of the systemic viral
infection may predominate.
Encephalitis
Physical findings for encephalitis are fever, headache, and decreased
neurological function. Decreased neurological functions include altered mental status, focal
neurological function, and seizure activities. These findings can help identify the virus type
and prognosis.
In West Nile virus, the signs and symptoms are nonspecific and include fever,
malaise, periocular pain, lymphadenopathy, and myalgia.
West Nile virus has some unique physical findings including fine, maculopapular,
erythematous rash; proximal muscle weakness; and flaccid paralysis. This rash is commonly
found in children.
Critically ill patients have neurological dysfunction, such as altered mental status
and cranial nerve dysfunction, as the major physical finding.

Herpes Simplex Encephalitis

Background
Despite advances in antiviral therapy over the past 2 decades, herpes simplex
encephalitis (HSE) remains a serious illness with significant risks of morbidity and
death.[1, 2, 3] Herpes simplex encephalitis occurs as 2 distinct entities:

In children older than 3 months and in adults, HSE is usually localized to the
temporal and frontal lobes and is caused by herpes simplex virus type 1 (HSV-1).

In neonates, however, brain involvement is generalized, and the usual cause is

herpes simplex virus type 2 (HSV-2), which is acquired at the time of delivery.
Except where otherwise specified, this article describes HSE as it occurs in older
children and adults (as opposed to neonatal HSE). HSE must be distinguished from
herpes simplex meningitis, which is more commonly caused by HSV-2 than by HSV-1
and which often occurs in association with a concurrent herpetic genital infection. Like
other forms of viral meningitis, herpes simplex meningitis usually has a benign course
and is not discussed in this article.
Patients with HSV may require long-term antiviral treatment if they have recurrent
lesions or if other organ systems are involved (as in herpes simplex keratitis). HSV
remains dormant in the nervous system; rarely, it presents as encephalitis, possibly by
direct transmission through peripheral nerves to the central nervous system (CNS). This
encephalitis is a neurologic emergency and the most important neurologic sequela of
HSV.

Pathophysiology
The pathogenesis of HSE in humans is poorly understood. Neurons are quickly
overwhelmed by a lytic and hemorrhagic process distributed in an asymmetric fashion
throughout the medial temporal and inferior frontal lobes. Wasay et al reported temporal
lobe involvement in 60% of patients.[4] Fifty-five percent of patients demonstrated
temporal and extratemporal pathology, and 15% of patients demonstrated extratemporal
pathology exclusively. Involvement of the basal ganglia, cerebellum, and brainstem is
uncommon.
The exact mechanism of cellular damage is unclear, but it may involve both direct virusmediated and indirect immune-mediated processes. The ability of HSV-1 to induce
apoptosis (programmed cell death, or cellular suicide) in neuronal cells, a property not
shared by HSV-2, might explain why the former causes virtually all cases of herpes
simplex encephalitis in immunocompetent older children and adults. [5, 6]
A vivid description of the temporal course of tissue destruction is given in an
immunohistologic autopsy study of patients succumbing to HSE over periods of days to

weeks in the era prior to acyclovir: The impression is of a rapidly spreading wave of viral
infection within limbic structures, probably starting on one side of the brain and
spreading within it and to the other side, lasting about 3 weeks and resulting in severe
necrosis and inflammation in infected parts of the brain. [7]
Brain infection is thought to occur by means of direct neuronal transmission of the virus
from a peripheral site to the brain via the trigeminal or olfactory nerve. Factors that
precipitate HSE are unknown. The prevalence of HSE is not increased in
immunocompromised hosts, but the presentation may be subacute or atypical in these
patients. HSV-2 may cause HSE in patients with HIV-AIDS. [8, 9, 10]
HSE represents a primary HSV infection in about one third of cases; the remaining
cases occur in patients with serologic evidence of preexisting HSV infection and are due
to reactivation of a latent peripheral infection in the olfactory bulb or trigeminal ganglion
or to reactivation of a latent infection in the brain itself. A substantial number of
neurologically asymptomatic individuals may have latent HSV in the brain. In a
postmortem study, HSV was present in the brains of 35% of patients with no evidence
of neurologic disease at the time of death. [11]
Neonatal HSE may occur as an isolated CNS infection or as part of disseminated
multiorgan disease.

Etiology
As noted (see Pathophysiology), HSE is caused by HSV, an enveloped, doublestranded DNA virus. HSV-1 and HSV-2 are both members of the larger human
herpesvirus (HHV) family, which also includes varicella-zoster virus (VZV, or HHV-3)
and cytomegalovirus (CMV, or HHV-5). HSV-1, or HHV-1, is the more common cause of
adult encephalitis; it is responsible for virtually all cases in persons older than 3 months.
HSV-2, or HHV-2, is responsible for a small number of cases, particularly in
immunocompromised hosts.
HSV-1 causes oral lesions (so-called fever blisters); these are common and may
respond to antiviral medications, though they spontaneously remit in most cases. HSV-2
causes genital lesions. It was previously thought to appear within 1-2 weeks of primary
infection, then to recur with lessening severity. That lesions may appear clinically at any
interval after primary infection is now known. HSV-2 may be treated with antiviral
medications.
In adults, the host immune response, combined with viral factors, determines
invasiveness and virulence. Mitchell et al showed that the invasiveness of HSV-1

glycoprotein variants is controlled by the host response. [12] Geiger et al used interferongammaknockout mice to show how interferon-gamma protected against HSV-1
mediated neuronal death.[13] These data suggested that the presentation and severity of
encephalitis vary.
Evidence from a European study suggested that socioeconomic status and geography
might affect levels of virus seropositivity. However, clinical correlation is difficult,
because HSE can occur at any time, regardless of the patients socioeconomic status,
age, race, or sex.
In children, encephalitis often results from primary infection with HSV. Approximately
80% of children with HSE do not have a history of labial herpes.
Cathomas et al report a case of HSE as a complication of chemotherapy for breast
cancer.[14]

Neonatal herpes simplex encephalitis

The predominant pathogen is HSV-2 (75% of cases), which is usually acquired by
maternal shedding (frequently asymptomatic) during delivery. A preexisting but recurrent
maternal genital herpes infection results in 8% risk of symptomatic infection, usually
transmitted at the second stage of labor via direct contact. Should the mother acquire
genital herpes during pregnancy, the risk increases to 40%.
The absence of a maternal history of prior genital herpes does not exclude risk; in 80%
of cases of neonatal HSE, no maternal history of prior HSV infection is present.
Prolonged rupture of the membranes (>6 h) and intrauterine monitoring (eg, attachment
of scalp electrodes) are risk factors.
In about 10% of cases, HSV (often type 1) is acquired post partum by contact with an
individual who is shedding HSV from a fever blister, finger infection, or other cutaneous
lesion.[15, 16]

Epidemiology
In the United States, HSE is the most common nonepidemic encephalitis and the most
common cause of sporadic lethal encephalitis. Incidence is 2 cases per million
population per year. HSE may occur year-round. HSV-1 is ubiquitous, and HSV-2 is also
common. International incidence is similar to that in the United States.

Age-, sex-, and race-related demographics

HSE has a bimodal distribution by age, with the first peak occurring in those younger
than 20 years and a second occurring in those older than 50 years. HSE in younger
patients usually represents primary infection, whereas HSE in older persons typically
reflects reactivation of latent infection. One third of HSE cases occur in children.
Herpes affects both sexes equally, though genital herpes may be more apparent in the
male because of anatomy. No racial predilection exists.

Prognosis
Untreated HSE is progressive and often fatal in 7-14 days. A landmark study by Whitley
et al in 1977 revealed a 70% mortality in untreated patients and severe neurologic
deficits in most of the survivors.[17]
Mortality in patients treated with acyclovir was 19% in the trials that established its
superiority to vidarabine. Subsequent trials reported lower mortalities (6-11%), perhaps
because they included patients who were diagnosed by polymerase chain reaction
(PCR) rather than brain biopsy and who thus may have been identified earlier with
milder disease.[1, 3]
The mortality of neonatal HSE is substantial, even with treatment; 6% in patients with
isolated HSE and 31% in those with disseminated infection.
Sequelae among survivors are significant and depend on the patients age and
neurologic status at the time of diagnosis. Patients who are comatose at diagnosis have
a poor prognosis regardless of their age. In noncomatose patients, the prognosis is age
related, with better outcomes occurring in patients younger than 30 years.
Significant morbidity exists among those treated. Neurologic outcomes in survivors
treated with acyclovir are as follows:

No deficits or mild deficits - 38%

Moderate deficits - 9%
Severe deficits - 53%
Anterograde memory often is impaired even with successful treatment of HSE.
Retrograde memory, executive function, and language ability also may be impaired. A
study by Utley et al showed that patients who had a shorter delay (< 5 d) between
presentation and treatment had better cognitive outcomes. [18]
Elbers and colleagues followed properly treated children for 12 years after the HSE.
They found seizures in 44% of the children and developmental delay in 25% of the
children. They concluded that HSE continues to be associated with poor long-term
neurologic outcomes despite appropriate therapy.[19]

Shelley and colleagues reported a case of intracerebral hematoma occurring in a

patient successfully treated with a full course of acyclovir after apparent eradication of
the virus. The hematoma occurred in the region of the encephalitis. [20]
Marschitz and colleagues reported a case of chorea after HSE. [21]
Relapses after HSE have been reported to occur in 5-26% of patients, with most
relapses occurring within the first 3 months after completion of treatment. Relapses are
more frequent in children than adults. It is unclear whether such relapses represent
recurrence of viral infection or an immune-mediated inflammatory process. Some of the
relapses reported in earlier studies may have been due to inadequate duration of
treatment rather than true recurrences of HSE.
A long-term follow-up study of patients with HSE suggested that the pathogenic
mechanisms present during relapses differ from those present during the initial
infection.[22] Serial measurements of inflammatory markers as well as HSV viral load in
the CSF of relapsing patients demonstrated increased inflammatory markers without
detectable HSV during relapses. These findings suggest that immune-mediated events,
rather than direct viral-mediated neuronal toxicity, may predominate in relapses.

History
Herpes simplex encephalitis (HSE) is an acute or subacute illness that causes both
general and focal signs of cerebral dysfunction. It is sporadic and occurs without a
seasonal pattern. Although the presence of fever, headache, behavioral changes,
confusion, focal neurologic findings, and abnormal cerebrospinal fluid (CSF) findings
are suggestive of HSE, no pathognomonic clinical findings reliably distinguish HSE from
other neurologic disorders with similar presentations (see Workup). [23]
Patients may have a prodrome of malaise, fever, headache, and nausea, followed by
acute or subacute onset of an encephalopathy whose symptoms include lethargy,
confusion, and delirium. The following are typically the most common symptoms of
HSE[24] :

Fever (90%)
Headache (81%)
Psychiatric symptoms (71%)
Seizures (67%)
Vomiting (46%)
Focal weakness (33%)
Memory loss (24%)
Signs and symptoms of neonatal HSE develop about 6-12 days after delivery, at which
time lethargy, poor feeding, irritability, tremors, or seizures may be noted. Those with
disseminated disease also have abnormal liver function test results and
thrombocytopenia. In contrast to older patients, neonates often have herpetic skin
lesions.

The initial presentation may be mild or atypical in immunocompromised patients (eg,

those with HIV infection or those receiving steroid therapy).

Physical Examination
The most frequent findings on physical examination are fever and mental status
abnormalities. Meningeal signs may be present, but meningismus is uncommon.
Typical findings on presentation include the following [24] :

Alteration of consciousness (97%)

Fever (92%)
Dysphasia (76%)
Ataxia (40%)
Seizures (38%) - Focal (28%); generalized (10%)
Hemiparesis (38%)
Cranial nerve defects (32%)
Visual field loss (14%)
Papilledema (14%)
A causal or temporal relationship between peripheral lesions (eg, herpes labialis) and
HSE does not exist. In addition, many febrile diseases may precipitate herpes labialis.
Therefore, the presence or absence of such lesions neither confirms nor excludes the
diagnosis.
Unusual presentations occur. Both herpes simplex virus type 1 (HSV-1) and herpes
simplex virus type 2 (HSV-2) may produce a more subacute encephalitis, apparent
psychiatric syndromes, and benign recurrent meningitis. Less commonly, HSV-1 may
produce a brain stem encephalitis, and HSV-2 may produce a myelitis.
Ku et al discussed the unique presentation of HSE in a bilingual patient, who developed
global aphasia for 1 language (his most recently learned language) but retained most of
his birth language ability.[25]
McGrath et al reported on 4 patients with confirmed HSE, each with an anterior
opercular syndrome, and observed that the syndrome (ie, paralysis of the masticatory,
facial, pharyngeal, and lingual muscles) occurred as the primary manifestation of HSE
in 2 patients and as part of the encephalitis picture in the other 2 patients. [26] The authors
suggested that unique presentations (eg, anterior opercular syndrome), should alert the
clinician to the possibility of HSE.
Mondal et al reported basal ganglia involvement in a child with HSE, demonstrating
extrapyramidal symptoms.[27] Li and Sax reported HSE-associated cerebral hemorrhage
in an HIV-positive person.[28]

Complications

Even in treated cases of HSE, complications and sequelae (both focal and global) are
not uncommon. If treatment of HSE is delayed, permanent neurologic deficits may
develop in survivors.
Common sequelae among survivors include motor deficits, seizure disorders, and
changes in mental status. Cognitive and memory deficits are particularly common. So
too are recurrent seizures; some authorities recommend prophylactic treatment with
anticonvulsant drugs in patients with severe HSE.
In addition, patients with HSE are subject to the same complications as any other
seriously ill and immobilized patients with depressed levels of consciousness (eg,
aspiration, deep venous thrombosis, decubitus ulcers).

Diagnostic Considerations

Myoclonus
Management of increased intracranial pressure (ICP) in the neuro intensive care
unit (ICU)
Management of intracranial hemorrhage (ICH) in the neuro ICU
Electroencephalography (EEG) in coma
Increased ICP
Neuro-Behet disease

Differential Diagnoses

Acute Disseminated Encephalomyelitis

Aphasia
Aseptic Meningitis
Benign Childhood Epilepsy
Benign Neonatal Convulsions
Childhood Migraine Variants
Complex Partial Seizures
Confusional States and Acute Memory Disorders
Dissection Syndromes
Early Myoclonic Encephalopathy
EEG in Common Epilepsy Syndromes
EEG in Dementia and Encephalopathy
EEG in Status Epilepticus
Epileptiform Discharges
Frontal Lobe Epilepsy
Frontal Lobe Syndromes
Generalized EEG Waveform Abnormalities
Haemophilus Meningitis

HIV-1 Associated CNS Complications (Overview)

Intracranial Epidural Abscess
Intracranial Hemorrhage
Lennox-Gastaut Syndrome
Leptomeningeal Carcinomatosis
Migraine Headache
Migraine Headache: Pediatric Perspective
Migraine Variants
Neurosyphilis
Paraneoplastic Encephalomyelitis
Seizures and Epilepsy: Overview and Classification
Simple Partial Seizures
Status Epilepticus
Temporal Lobe Epilepsy

Approach Considerations
In suspected herpes simplex encephalitis (HSE), the workup must be initiated rapidly
and should not delay treatment. General laboratory studies are not helpful in diagnosis
but may show evidence of infection or detect renal disease (in which case treatment
must be adjusted). A high index of suspicion is required in all immunocompromised
patients with febrile encephalopathy.
No pathognomonic clinical findings are associated with HSE. Focal neurologic deficits,
cerebrospinal fluid (CSF) pleocytosis, and abnormalities on computed tomography (CT)
scanning may be absent initially. The diagnosis can be confirmed only by means of
polymerase chain reaction (PCR) or brain biopsy.
Diagnostic modalities for neonatal HSE are similar to those for HSE in older children
and adults.

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) of the brain is the preferred imaging study. Protondensity and T2 images may be more helpful than T1 images. MRI can noninvasively
establish many of the potential alternative diagnoses of HSE.
Abnormalities are found in 90% of patients with HSE; MRI may be normal early in the
course of illness. Temporal lobe involvement (see the images below), sometimes
hemorrhagic, and early involvement of white matter are typical. The inferomedial portion
of the temporal lobe is most commonly affected on MRI, sometimes in association with
abnormalities of the cingulate gyrus.

Axial proton density-weighted image in 62-year-old woman with confusion

and herpes encephalitis shows T2 hyperintensity involving right temporal lobe.

Axial gadolinium-enhanced T1-weighted image reveals enhancement of

right anterior temporal lobe and parahippocampal gyrus. At right anterior temporal tip is hypointense,
crescentic region surrounded by enhancement consistent with small epidural abscess.

Axial diffusion-weighted image reveals restricted diffusion in left medial

temporal lobe consistent with herpes encephalitis. This patient also had positive result on
polymerase chain reaction assay for herpes simplex virus, which is both sensitive and specific. In
addition, patient had periodic lateralized epileptiform discharges on electroencephalography, which
supports diagnosis of herpes encephalitis.

Findings of localized temporal abnormalities are highly suggestive of HSE, but again,
confirmation of the diagnosis depends on the identification of herpes simplex virus
(HSV) by means of PCR or brain biopsy.

Computed Tomography

Approximately one third of patients with HSE have normal CT findings on presentation.
Head CT may show changes in the temporal and/or frontal lobe, but CT is less sensitive
than MRI.
Low-density lesions may be found in two thirds of cases, especially in the temporal
lobes, but they may not appear until 3-4 days after onset. Edema and hemorrhages may
be present. After 1 week, contrast enhancement may be detectable.

Electroencephalography
Electroencephalography (EEG), though lacking in specificity (32%), has 84% sensitivity
to abnormal patterns in HSE. Focal abnormalities (eg, spike and slow- or periodic
sharp-wave patterns over the involved temporal lobes) or diffuse slowing may be
observed.
Periodic complexes and periodic lateralizing epileptiform discharges (PLEDs), in the
proper clinical context, are strongly suggestive of HSE. However, Beneto et al reported
9 patients with confirmed HSE who had no PLED activity or had other EEG patterns. [29]

Analysis of Cerebrospinal Fluid

Once a space-occupying lesion has been excluded by imaging, lumbar puncture always
should be performed in suspected HSE. In general, CSF yield is proportional to the
volume analyzed; an adequate volume of CSF should be obtained (>10 mL).
Acutely, a typical viral profile is identified. Red blood cells (RBCs) and xanthochromia
may be seen. Patients typically have mononuclear pleocytosis of 10-500 white blood
cells (WBCs)/L (average, 100 WBCs/L). As a result of the hemorrhagic nature of the
underlying pathologic process, the RBC count may be elevated (10-500/L). Protein
levels are elevated to the range of 60-700 mg/dL (average, 100 mg/dL). Glucose values
may be normal or mildly decreased (30-40 mg/dL).
In about 5-10% of patients, especially children, initial CSF results may be normal.
[30]
However, on serial examinations, the cell counts and protein values increase.
Viral cultures of CSF are rarely positive and should not be relied on to confirm the
diagnosis. However, HSV can be cultured from the CSF in about one third of affected
neonates.

Polymerase chain reaction

CSF should be sent for HSV-1 and HSV-2 polymerase chain reaction (PCR) study. PCR
analysis of CSF for the detection of HSV DNA has virtually replaced brain biopsy as the
criterion standard for diagnosis.[31, 32] Schloss and colleagues report that whereas
quantitative PCR is more rational than a nested PCR, the former has little prognostic
use.[33]
PCR is highly sensitive (94-98%) and specific (98-100%). Results become positive
within 24 hours of the onset of symptoms and remain positive for at least 5-7 days after
the start of antiviral therapy.
Clinical severity and outcome appear to correlate with viral load as assessed by
quantitative PCR techniques,[34] but not all investigators have confirmed this correlation.
[35]

False-negative findings may occur early in the course of the disease when viral DNA
levels are low (within 72 hours of the onset of symptoms) or when blood is present in
the CSF, because hemoglobin may interfere with PCR. [36]
Pretest probability should be considered in interpretation of results. A negative result
obtained less than 72 hours after the onset of symptoms in a patient with a high pretest
probability (on the basis of fever, focal neurologic abnormalities, or CSF pleocytosis)
should be repeated.
False-positive test results are rare and usually reflect accidental contamination of the
specimen in the laboratory.

Brain Biopsy
Brain biopsy was once considered the only definitive means of diagnosing HSE. The
results of brain biopsy can also establish alternative diagnoses, both treatable (eg, brain
tumor) and nontreatable (eg, non-HSV viral encephalitis). Currently, with the advent of
PCR technology, the role of brain biopsy is diminishing. Studies have demonstrated that
PCR testing of CSF is as accurate as brain biopsy in confirming the diagnosis of HSE.
When the diagnosis of HSE cannot be established by other means (eg, when lumbar
puncture is precluded or nondiagnostic), brain biopsy can yield a definitive diagnosis
and may be considered. However, with the availability of nontoxic and effective antiviral
medications, brain biopsy is rarely used today. The procedure carries a complication
rate of about 3%.

Orbitofrontal or limbic encephalitis may be seen. One hallmark of the condition is

significant hemorrhage in these locations. On pathology specimens, Cowdry A
inclusions are seen.

Other Tests
Serologic analysis
Serologic evaluation of blood or CSF may be useful for retrospective diagnosis, but it
has no role in the acute diagnosis and treatment of patients.
Strategies based on increases in antibody levels and on the ratio of antibody levels in
serum and CSF have not proven to be clinically useful.

Tzanck preparations
HSV can sometimes be confirmed by Tzanck preparations taken from vesicular lesions
in neonates with herpes simplex encephalitis.

Quantification of intrathecal antibodies

Intrathecal antibodies can be quantified, thus giving evidence for a central nervous
system (CNS) antibody response.

Approach Considerations
A high index of suspicion is required to make the diagnosis of herpes simplex
encephalitis (HSE), and expeditious evaluation is indicated after the diagnosis is
considered. In the absence of any other identifiable cause, consider HSE in any febrile
patient with encephalopathy and CSF pleocytosis. Start empiric acyclovir therapy
promptly in patients with suspected HSE pending confirmation of the diagnosis because
acyclovir, the drug of choice, is relatively nontoxic and because the prognosis for
untreated HSE is poor.
Failure to consider the possibility of HSE can result in delayed diagnosis and treatment,
with subsequent increased risks of mortality and morbidity. A single-center study from a
high-volume academic emergency department (ED) reported that only 29% of patients
with a presentation suggestive of viral encephalitis (fever, neuropsychiatric
abnormalities, cerebrospinal fluid [CSF] pleocytosis, and a negative CSF Gram stain)
received acyclovir in the ED.[37]

Initial Management
Prehospital care consists of supportive management of the patients airway, breathing,
and circulation (ABCs). General nutritional and fluid support is important. Universal
precautions are appropriate. Monitor for increased intracranial pressure (ICP) and
seizures.
Intensive care unit (ICU) care may be required, especially if seizure activity or increased
ICP is present. Depending on the availability of local expertise (eg, infectious disease,
neurology, neurosurgery specialists), transfer to a tertiary care facility may be
appropriate. Hospitalization is not routine for uncomplicated herpes simplex virus type 1
(HSV-1) or herpes simplex virus type 2 (HSV-2) infection.

Management of increased intracranial pressure

Treatment of brain edema ranges from simple measures (eg, elevating head of bed,
gentle diuresis with medication such as furosemide) to more complex measures (eg,
mannitol and steroids, intubation with hyperventilation).

Management of seizures
Behavioral manifestations of HSE may resemble seizures, which are also common.
Should seizure activity become apparent or should electroencephalography (EEG)
show evidence of nonconvulsive seizures, begin anticonvulsant therapy.
Benzodiazepines may be useful for aborting status epilepticus but, because of their
short duration, are ineffective at preventing further seizures. A longer-acting agent is
preferable.

Antiviral Therapy
Pharmacotherapy for HSE is available in the form of acyclovir. Patient outcome is
improved after treatment with this agent. Acyclovir is the treatment of choice for HSE. [1, 3,
38]
When the diagnosis of HSE is suspected or has been established, acyclovir (typically
30 mg/kg/d intravenously [IV] in adults) should be initiated immediately.
Through a series of in vivo reactions catalyzed by viral and host cellular enzymes,
acyclovir is converted to acyclovir triphosphate, a potent inhibitor of HSV DNA
polymerase, without which viral replication cannot occur. Human cells are not affected.

Acyclovir has relatively few serious adverse effects. Because of its high pH, IV acyclovir
may cause phlebitis and local inflammation if extravasation occurs. Gastrointestinal (GI)
disturbances, headache, and rash are among the more frequent adverse reactions.
The drug is excreted by the kidney, and the dose should be reduced in patients with
renal dysfunction. Crystal-induced nephropathy may occur if the maximum solubility of
free drug is exceeded. Risk factors for this are IV administration, rapid infusion,
dehydration, concurrent use of nephrotoxic drugs, underlying renal disease, and high
doses. The risk of renal toxicity is reduced by adequately hydrating the patient (eg, 1
mL/d of fluid for each 1 mg/d of acyclovir).
Acyclovir is considered appropriate for serious infections during pregnancy. The
manufacturer cautions that it should be used in pregnancy only when the potential
benefits outweigh the potential risks. However, a prospective registry of acyclovir use in
pregnancy between 1984 and 1999, including 756 first-trimester exposures,
demonstrated a 3.2% rate of birth defects, similar to that expected in the general
population.[39]
In immunocompetent patients, viral resistance to acyclovir has been clinically
insignificant, with a reported prevalence of less than 1%. [40] However, in
immunocompromised patients, this figure rises to 6%. Degree of immunosuppression
and duration of exposure to acyclovir appear to be the most important risk factors for
the development of resistant strains.
Since most relapses occur within 3 months of completing an initial course of IV
acyclovir, a prolonged course of an oral antiviral agent (eg, valacyclovir) has been
suggested after initial treatment. An ongoing clinical trial is currently evaluating a 90-day
course of valacyclovir versus placebo after treatment with acyclovir in patients with
HSE.[41]
A 2009 Cochrane database review of data from 17 trials that compared interventions
used for the prevention and treatment of HSV in patients being treated for cancer
concluded that acyclovir is effective in preventing and treating HSV infections.
Valacyclovir was not found to be more effective than acyclovir, nor did a higher dose of
valacyclovir make a difference. Some evidence indicated that placebo, as a prophylaxis,
is more effective than prostaglandin E, but the risk of bias was unclear in all trials. [42]
If long-term suppressive therapy is needed, acyclovir or famciclovir can be used orally.

Neonatal herpes simplex encephalitis

Acyclovir in doses of 20 mg/kg IV every 8 hours (60 mg/kg/d) is currently recommended
for neonatal HSE. This dosage is higher than that used in older children and adults (30
mg/kg/d), but, in neonates, it has been shown to improve mortality and morbidity when
compared with the lower dosage. Because the higher dosage is associated with
neutropenia, the white blood cell (WBC) count should be monitored closely.

Steroid Therapy
The role of steroids in the treatment of HSE remains uncertain. To the extent that
cellular damage in HSE is the result of immune-mediated inflammatory processes
triggered by the viral infection, the anti-inflammatory effects of steroids may be
beneficial. However, there is also concern that steroids might suppress immune
responses of the host that are necessary to limit viral replication.
Animal studies have demonstrated a beneficial effect of steroids on outcome, without
evidence of increased viral replication or dissemination. [43, 44] Steroids have been used to
reduce cerebral edema in patients with severe HSE.
One nonrandomized, retrospective human study compared the outcomes of patients
with HSE who received steroids in addition to acyclovir with the outcomes of those who
received acyclovir alone.[45] The steroid group had improved outcomes at 3 months.
Although these results suggest a possible role for steroids in HSE, definitive
recommendations must await the results of larger prospective studies.
The German trial of Acyclovir and Corticosteroids in Herpes-simplex-virus-Encephalitis
(GACHE), a multicenter, randomized, placebo-controlled trial, is currently enrolling
patients with HSE in a study designed to assess the outcomes of treatment with
acyclovir against the outcomes of treatment with acyclovir plus dexamethasone. [46]

Prevention
No measures are known to be effective for preventing HSE in adults and older children.
Person-to-person transmission does not occur. Prophylactic treatment of close contacts
and special isolation precautions are unnecessary.
Preventive measures for neonatal HSE include cesarean delivery in women with active
herpetic genital infections at the time of delivery and protection of neonates from
persons with active herpetic infections. Some authorities recommend a course of

suppressive acyclovir therapy near the time of delivery in mothers with a history of
genital herpes.

Medication Summary
The goals of therapy are to reduce morbidity, to shorten the clinical course of the
disease, to prevent complications, and to prevent recurrences. Pharmacotherapy for
herpes simplex encephalitis (HSE) is available in the form of acyclovir. Patient outcome
is improved when this agent is used for treatment.

Antivirals
Class Summary
The goals of using antivirals are to shorten the clinical course, prevent complications,
prevent development of latency and subsequent recurrences, decrease transmission,
and eliminate established latency.
View full drug information

Acyclovir (Zovirax)
Acyclovir is the drug of choice for HSE. It has demonstrated inhibitory activity against
both herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) and
is taken up selectively by infected cells. Mortality from HSE before use of acyclovir was
60-70%; since acyclovir, it is approximately 30%.

Anticonvulsants
Class Summary
Anticonvulsants are used to terminate clinical and electrical seizure activity as rapidly as
possible and to prevent seizure recurrence.
View full drug information

Carbamazepine (Tegretol)
Carbamazepine is effective in treatment of complex partial seizures; it appears to act by
reducing polysynaptic responses and blocking posttetanic potentiation.

View full drug information

Phenytoin (Dilantin, Phenytek)

Phenytoin is a hydantoin. Its primary site of action appears to be the motor cortex,
where it may inhibit spread of seizure activity; it may reduce maximal activity of the
brain stem centers responsible for the tonic phase of grand mal seizures.
The dose should be individualized; if daily dosage cannot be divided equally, larger
dose should be given before bedtime. A phosphorylated formulation, fosphenytoin, is
available for parenteral use.

Diuretics
Class Summary
These agents are used for the management of increased intracranial pressure in
complications resulting from herpes simplex encephalitis.
View full drug information

Furosemide (Lasix)
Furosemide is a loop diuretic that increases the excretion of water by interfering with the
chloride-binding co-transport system, which, in turn, inhibits sodium and chloride
reabsorption in the ascending loop of Henle and distal renal tubule. It increases renal
blood flow without increasing the filtration rate. The onset of action generally is within 1
hour. It increases potassium, sodium, calcium, and magnesium excretion.
Furosemide is used in the acute setting for reduction of increased ICP. The proposed
mechanisms in lowering ICP include following: (1) suppression of cerebral sodium
uptake, (2) carbonic anhydrase inhibition resulting in decreased CSF production, and
(3) inhibition of cellular membrane cation-chloride pump, thereby affecting the transport
of water into astroglial cells.
The dose must be individualized to the patient. Depending on the response, administer
at increments of 20-40 mg, no sooner than 6-8 hours after the previous dose, until
desired diuresis occurs. When treating infants, titrate with 1-mg/kg/dose increments until
a satisfactory effect is achieved.
View full drug information

Mannitol (Osmitrol)
Mannitol reduces cerebral edema with the help of osmotic forces, and it decreases
blood viscosity, resulting in reflex vasoconstriction and lowering of ICP.