Encephalitis

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 the 2 often coexist with signs and symptoms of meningeal inflammation, such as photophobia, headache, or
a 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.
Of the subacute and chronic encephalopathies, the emergency department (ED) physician is most likely to encounter
toxoplasmosis in immunocompromised patients.
No satisfactory treatment exists for the relatively common acute arboviral encephalitides, which vary in epidemiology,
mortality, and morbidity, if not clinical presentation. Clinically distinguishing these acute arboviral encephalitides
from the 2 potentially treatable acute viral encephalitides is important. These potentially treatable viral encephalitides
are herpes simplex encephalitis (HSE), which is a sporadic and lethal disease of neonates and the general population,
and the less common varicella-zoster encephalitis, which is deadly in immunocompromised patients.
Swift identification and immediate treatment can be lifesaving. Most authorities advocate initiating ED treatment with
the relatively safe agent acyclovir in any patient whose central nervous system (CNS) presentations (particularly
encephalopathy and focal findings) have no apparent explanation and in all neonates who appear ill and are without a
final diagnosis.
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
West Nile encephalitis
In 1999, a late summer outbreak of West Nile encephalitis (WNE), an arbovirus not previously found in the United
States, was implicated in several deaths in New York. By late summer 2002, West Nile virus had been identified
throughout the eastern and southeastern United States. Following bird migration, the virus began to extend westward,
and by April 2003, virus activity had been detected in 46 states and the District of Columbia.
An updated Centers for Disease Control and Prevention (CDC) report for 2007 (West Nile Virus Update) included
information regarding viremic blood donors. Throughout the world, outbreaks of WNE have been associated with
severe neurologic disease, though, in general, only 1 in 150 affected patients develop symptomatic WNE. In 2008, the
number of cases reported to the CDC dropped.[1]
For more information, see the CDC fact sheet on West Nile virus, links to state and local government web sites on
West Nile virus, and the Environmental Protection Agency (EPA)/CDC article on mosquito control.
For clinical information on the Internet, see West Nile Virus: A Primer for the Clinician, from the August 6, 2002,
issue of Annals of Internal Medicine. The Canadian equivalent, West Nile Virus: Primer for Family Physicians, was
published on June 10, 2005, in Canadian Family Physician.[2]
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 animal bite. With some viruses, such as varicella-zoster virus (VZV) and cytomegalovirus
(CMV), an immunocompromised host is a key risk factor.
In general, the virus replicates outside the CNS and gains entry either by hematogenous spread or by traveling along
neural (rabies virus, HSV, VZV) and olfactory (HSV) pathways. 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 inflammatory response diffusely affecting gray matter disproportionately to
white matter. Focal pathology is the result of neuron cell membrane receptors found only in specific portions of the
brain and accounts for the regional tropism found with some viruses. For example, HSV has a predilection for the
inferior and medial temporal lobes.
In contrast to viruses that invade gray matter directly, acute disseminated encephalitis and postinfectious
encephalomyelitis (PIE), secondary to measles (most common), Epstein-Barr virus (EBV), and CMV, are immune-
mediated processes that result in multifocal demyelination of perivenous white matter.
Etiology
The cause of encephalitis is usually infectious but may be noninfectious (eg, the demyelinating process in acute
disseminated encephalitis).
Viral agents, such as HSV type 1 and 2 (almost exclusively in neonates), 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 West Nile virus can be transmitted by means of an organ transplant and
via blood transfusions.
Important animal vectors include mosquitoes, ticks (arbovirus), and warm-blooded mammals (rabies, lymphocytic
choriomeningitis).
Bacterial pathogens, such as Mycoplasma species and those causing rickettsial 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 is beyond the scope of this article.
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 only 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 (neonatal HSV infection occurs in 2-3 per 10,000 live births).
Arboviruses are the most common causes 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 clinical
disease, and only 10% develop overt encephalitis.
All 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 northern Midwest and 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.
Among less common causes of viral encephalitis, varicella-zoster encephalitis has an incidence of 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. Typically, 0-3 unrelated cases of rabies encephalitis are
identified yearly.
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). Older infants, children, and adults succumb to localized CNS infection (almost
exclusively type 1) according to a bimodal pattern of 5-30 years and 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; EEE disproportionately affects children and elderly persons.
Prognosis
The prognosis depends the virulence of the virus and on variables associated with the patients health status, such as
extremes of age, immune status, and preexisting neurologic conditions. Poor outcomes can be anticipated in infants
younger than 1 year and adults older than 55 years.
Untreated HSE has a mortality of 50-75%, and virtually 100% of survivors have long-term motor and mental
disabilities. The mortality in treated HSE averages 20% and is correlated with mental status changes at time of first
dose of acyclovir. Approximately 40% of survivors have minor-to-major learning disabilities, memory impairment,
neuropsychiatric abnormalities, epilepsy, fine-motor-control deficits, and dysarthria.
Arboviral JE and EEE are as catastrophic as untreated HSE, with high mortality and severe morbidity, including
mental retardation, hemiplegia, and seizures. Other arboviruses, however, are associated with a somewhat more benign
clinical course. For example, St Louis encephalitis and WNE have a mortality of 2-20%. Increased mortality and
morbidity are found in patients who are older than 60 years and have St Louis encephalitis or WNE. Long-term
sequelae with St Louis encephalitis include behavioral disorders, memory loss, and seizures.
WEE is associated with relatively low mortality and morbidity, although developmental delay, seizure disorder, and
paralysis occur in children, and postencephalitic parkinsonism occurs in adults. CE usually is a milder disease, with
most patients making a full recovery, though 25% of those with severe disease continue to have focal neurologic
dysfunction. Death rates from WEE and LAC are less than 5%.
The mortality associated with PIE secondary to measles approaches 40%, with a high rate of neurologic sequelae in
survivors. SSPE is universally fatal, although the disease course may last anywhere from several weeks to 10 years.
VZV encephalitis has a mortality of 15% in immunocompetent patients and virtually 100% in immunosuppressed
patients. The mortality for EBV encephalitis is 8%, and the morbidity is 12%.
Rabies encephalitis and acute disseminated encephalitis are virtually 100% fatal, though the medical literature includes
reports of survivors.
Patient Education
For patient education resources, see the Brain and Nervous System Center and the Bacterial and Viral Infections
Center, as well as Brain Infection, West Nile Virus, Encephalitis, and Ticks.
Proceed to Clinical Presentation

]
Table. Cerebrospinal
Fluid Findings by
Type of Organism Bacterial Meningitis Viral Meningitis* Fungal Meningitis
CSF Finding
(Normal)
Pressure (5-15 cm Increased Normal or mildly Normal or mildly
water) increased increased in tuberculosis (TB)
May be increased
Patients with AIDS
and cryptococcal meningitis
at increased risk of blindness
and death unless pressure
maintained at < 30 cm
Cell counts, No cell count excludes Usually < 500, nearly 100s of mononuclear
mononuclear bacterial meningitis 100% mononuclear cells
cells/L Typically thousands of < 48 hours, clinically
polymorphonuclear cells, but significant
 counts may not change dramatically polymorphonuclear
or even be normal (classically in pleocytosis may be
Preterm (0-25) very early meningococcal indistinguishable from early
meningitis or in extremely ill bacterial meningitis,
neonates) particularly with EEE
Lymphocytosis with normal Nontraumatic RBCs in
Term (0-22) CSF chemistry results observed in 80% of patients with HSV
15-25% of patients, especially if meningoencephalitis, though
counts < 1000 or if patient is 10% have normal CSF results
partially treated
6 mo+ (0-5) About < 90% of patients
with ventriculoperitoneal shunts
and CSF WBC count >100 cells/L
are infected; CSF glucose level
usually normal, and these patients
pathogens are less pathogenic than
others
Cell count and chemistry
levels normalize slowly (days) with
antibiotics
Microorganisms Gram stain 80% effective No organism India ink 80-90%
(none) Inadequate decolorization effective for detecting fungi
may cause Haemophilus influenzae AFB stain 40%
to be mistaken for gram-positive effective for TB; increase
cocci yield by staining supernatant
Pretreatment with from at least 5 mL of CSF
antibiotics may affect stain uptake,
causing gram-positive species to
appear to be gram-negative and
decrease culture yield by an
average of 20
Glucose
Decreased Normal Sometimes decreased
Aside from fulminant
bacterial meningitis, TB,
primary amebic
Euglycemia (>50% meningoencephalitis, and
serum) neurocysticercosis cause
lowest glucose levels

Hyperglycemia
(>30% serum)

Protein Usually >150 mg/dL Mildly increased Increased >1000

May be >1000 mg/dL mg/dL, with relatively benign
clinical presentation
suggestive of fungal disease
Preterm (65-150
mg/dL)

Term (20-170 mg/dL

6 mo+ (15-45
mg/dL)

*Some bacteria (eg, Mycoplasma, Listeria, Leptospira, Borrelia burgdorferi [Lyme disease]) cause alterations in spinal
fluid that resemble the viral profile. An aseptic profile is also typical of partially treated bacterial infections (>33%,
especially those in children, are treated with antimicrobials) and of the 2 most common causes of encephalitisthe
arboviruses and the potentially curable HSV.

Wait 4 hours after glucose load.

AFBacid-fast bacillus; CSFcerebrospinal fluid; EEE-eastern equine encephalitis; HSVherpes simplex virus;
RBCred blood cell; TBtuberculosis; WBCwhite blood cell.

Viral Encephalitis
Background
Clinically relevant involvement of the central nervous system (CNS) by viruses is an uncommon event, considering
the overwhelming number of individuals affected by the different human viral infections. Most commonly, clinically
relevant viral encephalitis affects children, young adults, or elderly patients, but the spectrum of involvement depends
on the specific viral agent, host immune status, and genetic and environmental factors.[1, 2]
The term acute viral encephalitis (from Greek enkephalos + -itis, meaning brain inflammation) is used to describe
restricted CNS involvement (ie, involvement of the brain, sparing the meninges); however, most CNS viral infections
involve the meninges to a greater or lesser extent, leading to aseptic meningitis or causing mild meningoencephalitis
rather than pure encephalitis.
In addition to acute viral encephalitis, other less established and more unusual manifestations of viral infections
include progressive neurologic disorders, such as postinfectious encephalomyelitis (such as may occur after measles or
Nipah virus encephalitis) and conditions such as postpoliomyelitis syndrome, which has been considered by some to
be as a persistent manifestation of poliovirus infection.
This article is a general overview of the most common viral encephalitides and provides details about general workup
and treatment for these important conditions. More detailed descriptions of each viral family are provided elsewhere.
See the following:
Herpes Simplex Encephalitis
California Encephalitis
Eastern Equine Encephalitis
Japanese Encephalitis
St Louis Encephalitis
Venezuelan Encephalitis
Western Equine Encephalitis
West Nile Encephalitis
Pathophysiology
The initial event in the replicative cycle of a virus is its interaction with receptors present on the surface of a cell.
Knowledge of this interaction is important in understanding viral spread, tropism, and pathogenesis. The following
cellular receptors have been described for these viruses (see Table 1, below):

Measles virus - CD46


Poliovirus - CD155

Herpes simplex virus (HSV) - Heparan sulfate; Hve A, B, and C; tumor necrosis factor receptor superfamily 14
(TNFSF14); HVEM; Prr1 and Prr2; and nectin-1 and nectin-2

Rabies virus - AChR, NCAM, and NGFR

Human immunodeficiency virus-1 (HIV-1) - CD4, CCR5/3, and CXCR4

JC virus - N-linked glycoprotein and alpha 2-6 sialic acid

West Nile virus - Cholesterol-rich membrane microdomains[3]

Table 1. Physiologic Roles of Known Viral Receptors (Open Table in a new window)
Virus Receptor Abbreviation/Synonym Function
Measles virus Membrane cofactor protein CD46 Regulates complement and prevents
activation of complement on autologous
cells
Poliovirus CD155 hPVR/CD155 Expressed on primary human monocytes;
supports poliovirus replication in vivo
HSV Heparan sulfate None Cell surface proteoglycans
Herpesvirus entry mediator Hve A, HVEM TNF receptor superfamily
A
Herpesvirus entry mediator Hve B, Human nectin-2, or Participate in organization of epithelial and
B Prr2alpha-Hve B endothelial junctions
Herpesvirus entry mediator Hve C, nectin1delta, or Prr1-Hve Immunoglobulin superfamily
C C
TNFSF14 hTNFSF14/HVEM-L TNF receptor superfamily
Rabies virus Nicotinic AChR (a- AChR Nicotinic AChR
bungarotoxin binding site)
NCAM NCAM, CD56, D2CAM, Leu19, Cell adhesion glycoprotein of
or NKH-1 immunoglobulin superfamily
NGFR NGFR NGFR
p75 neurotrophin receptor p75NTR
(p75NTR)
HIV-1 CD4 CD4 T lymphocyte protein with helper or
inducer function in immune system
CCR3 CCR3 Chemotactic activity
CCR5 CCR5 Coreceptor for macrophage-tropic strain
CCR6 CCR65 Chemotactic activity
CXCR4 CXCR4 Coreceptor for CD4
JC virus N-linked glycoprotein with N-linked glycoprotein Unknown
alpha 2-6 sialic acid
Japanese B Protein GRP78 --- ER-stress response protein
virus [4]

AChRacetylcetylcholine receptor; CCRchemokine receptor; HSVherpes simplex virus; NCAMneural cell

adhesion molecule; NGFRnerve growth factor receptor; TNFtumor necrosis factor.
Despite viral tropism, the pattern of distribution of lesions in the brain is rarely specific enough to permit identification
of the infecting virus.
The pathophysiology of viral encephalitis varies according to the viral family. Viruses enter the CNS through 2 distinct
routes: (1) hematogenous dissemination and (2) retrograde neuronal dissemination.
Hematogenous dissemination is the more common path. Humans are usually incidental terminal hosts of many viral
encephalitides. Arbovirus encephalitides are zoonoses, with the virus surviving in infection cycles involving biting
arthropods and various vertebrates, especially birds and rodents. The virus can be transmitted by an insect bite and
then undergoes local replication in the skin.
Transient viremia leads to seeding of the reticuloendothelial system and muscles. After continuous replication,
secondary viremia leads to seeding of other sites, including the CNS. In fatal cases, little histopathologic change is
noted outside the nervous system. St. Louis encephalitis is an exception, in that renal involvement is occasionally
present.
On gross examination, variable degrees of meningitis, cerebral edema, congestion, and hemorrhage are observed in the
brain. Microscopic examination confirms a leptomeningitis with round-cell infiltration, small hemorrhages with
perivascular cuffing, and nodules of leukocytes or microglial cells. Demyelination may follow the destruction of
oligodendroglias, and involvement of ependymal cells may lead to hydranencephaly. Neuronal damage is seen as
chromatolysis and neuronophagia.
Areas of necrosis may be extensive, especially in eastern equine encephalitis (EEE) and Japanese encephalitis (JE).
Recent experimental evidence has shown that arboviruses can induce apoptotic cell death in neurons in the brains of
their hosts. Patients who survive the initial illness associated with viral encephalitis feature varying degrees of repair,
which may include calcification in children.
Retrograde neural dissemination is the main route of spread for several important viral pathogens. Rabies virus usually
spreads to the CNS through retrograde peripheral nerve dissemination. This virus tends to exhibit tropism for the
temporal lobes, affecting the Ammon horns. One of the possible routes of CNS spread for herpes simplex virus (HSV)
is through the olfactory tracts. Herpesviruses have tropism for the temporal cortex and pons, but the lesions may be
widespread.
Herpes simplex encephalitis (HSE) in infants is usually part of a widespread infection that produces focal necrotic
lesions with typical intranuclear inclusions in many organs. In adults and in some children, lesions are confined to the
brain. Necrotic foci may be macroscopically evident as softening. Inclusion bodies are found readily in the margins of
areas of necrosis; focal perivascular infiltration and neuronal damage are evident.
In addition to the direct effect of the viral pathogen, acute encephalopathy may be associated with viral infections and
increased plasma concentrations of chemokine (CXC motif) ligand 8 (CXCL8; interleukin [IL]-8), chemokine (C-C
motif) ligand 2 (CCL2; monocyte chemotactic protein-1 [MCP - 1]), IL-6, and CXCL10 (interferon gammainduced
protein 10 kd [IP-10], without viral neuroinvasion (hyperactivated cytokine response).[5]
Accordingly, it is important to differentiate encephalitis from encephalopathy as a disruption of brain function that is
not related to a direct structural or inflammatory process. To illustrate the difficulty of making this distinction in daily
clinical practice, until recently it was not clear whether encephalopathy after dengue fever infection was due to direct
CNS invasion or to viremia. Studies have now documented the presence of IgM and IgG for dengue virus in the
cerebrospinal fluid (CSF) of patients with dengue fever and neurologic manifestations.
Etiology
HSE is the most common form of encephalitis in the United States (see Herpes Simplex Encephalitis). Human
herpesvirus (HHV)-6, the causative agent of exanthema subitum, has been associated with a wide spectrum of
neurologic complications, including viral (focal) encephalitis. Numerous other viruses are known to cause encephalitis
(see Tables 2 and 3 below). The viruses most commonly associated with acute childhood encephalitis are mumps
virus, measles virus, and varicella-zoster virus (VZV).
Table 2. Common Viral Encephalitides: Part 1 (Open Table in a new window)
Viral Specific Clinical
Virus (Family) Transmission Mortality Sequelae Season
Structure Patterns
HSV (herpesvirus) ds DNA Unknown 70% if Rare forms: subacute, Common All year
untreated psychiatric, opercular,
recurrent meningitis

HSV-1: brainstem; HSV-

2: myelitis

VZV (herpesvirus) ds DNA Direct contact Variable; low Rash, encephalitis in 0.1- Adults worse; Late winter,
(air), highly in children 0.2% of children with cerebellitis good spring
contagious chickenpox; cerebellar
ataxia (cerebellitis)
Influenza virus ss RNA Direct contact Unknown Reversible frontal Parkinsonism Usually
(orthomyxovirus) (air), highly syndrome in children; (encephalitis winter
 contagious Guillain-Barr, myelitis lethargica)
Enteroviruses ss RNA Fecal-oral route Low; high Herpangina; hand, foot, Mild, except for Summer,
(picornavirus) for mouth disease; enterovirus 71 fall;
enterovirus enterovirus 71 causes tropics: no
71 rhombencephalitis season
Rabies virus ss RNA Dogs, wild Virtually Paresthesias; confusion, Mortality All year
(rhabdovirus) animals (eg, fox, 100% spasms, hydrophobia; virtually 100%
wolf, skunk) brainstem features
dsdouble strand; HSVherpes simplex virus; sssingle strand; VZVvaricella-zoster virus.
Table 3. Common Viral Encephalitides: Part 2 (Open Table in a new window)
Viral
Virus (Family) Transmission Mortality Specific Clinical Patterns Sequelae Season
Structure
Lymphocytic ss RNA Rodents Low (< Progressive fever and Rare More in
choriomeningitis 1%) myalgia; orchitis; aseptic winter
virus (arenavirus) meningitis; leukopenia,
thrombocytopenia
Lassa virus ss RNA Rodents 15% Multisystem disease; Deafness (one All year
(arenavirus) proteinuria third)
Mumps virus ss RNA Direct contact Low Parotitis, pancreatitis, Frequent Winter
(paramyxovirus) (air), highly orchitis, aseptic meningitis sequelae and
contagious spring
Measles virus ss RNA Direct contact 10% Characteristic rash; frequent Frequent: Winter
(paramyxovirus) (air), highly EEG changes; myelitis mental and
contagious retardation, spring
seizures, SSPE
Nipah virus ss RNA Pigs; bats 40% Brainstem or cerebellar SSPE-like All year
(paramyxovirus) signs; segmental myoclonus, syndrome?
dysautonomia
dsdouble strand; EEGelectroencephalographic; sssingle strand; SSPEsubacute sclerosing panencephalitis.
Arthropod-borne viruses (arboviruses) are important causes of encephalitis worldwide. More than 20 arboviruses that
can cause encephalitis have been identified. These arboviruses are enveloped RNA viruses from different families:
Togaviridae (genus Alphavirus), Flaviviridae (genus Flavivirus), Bunyaviridae (genus Bunyavirus), and Reoviridae
(see Table 4 below).
Table 4. Common Arboviral Encephalitides (Open Table in a new window)
Specific Clinical
Virus (Family) Vector Reservoir Mortality Sequelae Season
Patterns
Eastern equine Aedes sollicitans Birds 35% Severe, rapid Common, June to
virus (alphavirus) progression especially in
children

October

Western equine Culex tarsalis Birds 10% Classic encephalitis Moderate in July to
virus (alphavirus) infants; low in
others

October

Venezuelan Mosquito species Horses, small ~ 0.4 % Low rate (4%) of Mild Rainy
equine mammals CNS involvement season
encephalitis virus
(alphavirus)
St Louis Culex pipiens,C Birds 2% in young SIADH More in elderly August to
encephalitis virus tarsalis people; 20% in people October
(flavivirus) elderly people
Japanese Culex Birds 33% (50% in Extrapyramidal 50% neuro Summer
encephalitis virus taeniorhynchus elderly people) features psychiatric;
(flavivirus) parkinsonism
West Nile virus Culex,Aedes spp Birds In US: 12% Motor or brainstem Usually not Summer
(flavivirus) (elderly people involvement prominent
only)
Far East Ixodes Small 20% Epilepsia partialis Frequent; Spring to
encephalitis virus persulcatus (tick) mammals, continua residual early
(flavivirus) birds weakness summer
Central European Ixodes ricinus Small Less common Limb-girdle Less common April to
encephalitis virus (tick) mammals, than in Far East paralysis than in Far East October
(flavivirus) birds (spine/medulla)
Powassan virus Ixodes cookei Small High Severe encephalitis Common (50%) May to
(flavivirus) (tick) mammals, December
birds
Dengue virus Aedes spp Mosquitoes Low, except Flulike syndrome; Mild, except for Rainy
(flavivirus) hemorrhagic rare CNS hemorrhagic season
involvement
La Crosse virus Aedes triseriatus Small Low (< 1%) Mild, primarily in Mild; seizures Summer
(bunyavirus) mammals children
Colorado tick Dermacentor Small Low Mild
fever virus andersoni (tick) mammals
(orbivirus)
CNScentral nervous system; SIADHsyndrome of inappropriate antidiuretic hormone secretion.
Important encephalitides caused by alphaviruses include EEE, western equine encephalitis (WEE), and Venezuelan
equine encephalitis (VEE). EEE is endemic along the eastern and Gulf coasts of the United States, in the Caribbean
region, and in South America. North American strains produce a fulminant disease (50-75% mortality) with a high
incidence of neurologic sequelae.
WEE is most common in the western and midwestern United States but has a lower mortality rate (10%) than EEE.
VEE occurs in South America and Central America as well as in the southwestern United States, typically causing
mild disease and, rarely, neurologic impairment.
Flaviviruses are transmitted by ticks and mosquitoes and are found worldwide. The most common form of flavivirus is
the Japanese B encephalitis virus. This flavivirus is one of the most important causes of viral encephalitis worldwide,
with 50,000 new cases and 15,000 deaths annually. It has been found in China, Southeast Asia, the Indian
subcontinent, the Philippines, New Guinea, Guam, and Australia.
West Nile virus is a flavivirus similar to the Japanese B virus. Its life cycle occurs between birds and mosquitoes.
Culex mosquitoes, Anopheles mosquitoes, and Aedes mosquitoes are the primary vectors to humans. West Nile virus is
endemic in Africa, the Middle East, Russia, India, Indonesia, and parts of Europe. It was detected for the first time in
the Western hemisphere during an outbreak of encephalitis in the summer of 1999 in New York City (see West Nile
Encephalitis).[6, 7]
Dengue fever is the most important arboviral infection of humans, with 100 million cases per year. It can now be seen
in any country between the tropics of Capricorn and Cancer (placing an estimated 2.5 billion people at risk). Until
recently, dengue fever was considered to be uncommonly associated with neurologic manifestations (except when
dengue hemorrhagic fever is present). However, this view has changed; in endemic areas, dengue fever may be one of
the most common forms of viral encephalitis.[8, 9]
Before the 1999 outbreak of West Nile encephalitis (WNE), St Louis encephalitis was the most common disease
caused by a flavivirus in the United States. Outbreaks of St Louis encephalitis occur from August to October
throughout the country. Individual susceptibility to the St Louis virus increases with age, and encephalitis can be
accompanied by hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Mortality is age related, ranging from 2-20%, and sequelae are present in 20% of survivors.
Other important flaviviral diseases include Far East tick-borne encephalitis (former eastern Russia), Central European
tick-borne encephalitis (Central Europe),[10] and Powassan encephalitis (Canada and northern United States).
Bunyaviruses are the largest group of arboviruses and include the viruses that cause La Crosse encephalitis,
Jamestown Canyon encephalitis, and California encephalitis (CE). La Crosse virus is the most common cause of
arboviral encephalitis in the United States and produces seizures and focal neurologic signs, manifested primarily in
children, with a mortality of less than 1% and rare sequelae.[11]
Orbivirus is transmitted by the tick Dermacentor andersoni and is seen in the Rocky Mountains of the United States.
Retroviruses are also a cause of encephalitis. Human T-cell lymphotrophic virus type 1 (HTLV-I) is associated
predominantly with spastic paraparesis, not with causing encephalitis. Certain forms of encephalitis are observed
almost exclusively in patients with HIV. Among those, cytomegalovirus (CMV) ventriculoencephalitis has emerged as
a unique entity in patients with advanced HIV infection.
Measles and mumps viruses (paramyxoviruses) can also cause neurologic disease. Measles typically does not cause
encephalitis in the acute phase, but 1 in 1000 cases can give rise to postinfectious autoimmune syndrome (ie, SSPE).
Nipah virus (Paramyxoviridae family) was first detected after an outbreak of encephalitis in pig farmers in Malaysia.
Nipah virus is a zoonosis and infects pigs. Subsequent outbreaks occurred in several countries in South Asia, including
Bangladesh (2001 and 2003).[12]
Arenaviruses usually infect rodents. Thus, lymphocytic choriomeningitis most commonly occurs during the winter,
when mice are indoors and humans have contact with their excreta. Meningitis or meningoencephalitis follows a 5- to
10-day incubation period. Recovery can be prolonged but is usually complete. Lassa fever is a West African disease
that starts with gastrointestinal (GI) and respiratory complaints and progresses to hemorrhagic shock. Unilateral or
bilateral deafness may follow the period of encephalitis. Mortality is in the range of 8-52%.
Enteroviruses are picornaviruses. The Picornaviridae family includes coxsackievirus A and B, poliovirus, echovirus,
enterovirus 68 and 71, and hepatitis A virus (HAV). Enteroviruses are transmitted by the fecal-oral route, and CNS
spread is through the hematogenous route. Infection is most common in summer and early fall. Outbreaks of
enterovirus 71 have occurred in Japan, Malaysia, and Taiwan.
Rabies is an important pathogen in developing countries, where endemic canine infection still exists. In Europe and
the United States, rabies is present in wild animals (eg, skunks, foxes, raccoons, bats); however, it is controlled in
domestic animals with vaccination. Rabies usually incubates for 20-60 days but can incubate for years.
In a 2007 outbreak of Chikungunya virus infection in Italy, 1 elderly patient developed encephalitis and died.[13] This
reinforces the risk of new outbreaks of newer forms of encephalitis in Europe and other parts of the world.[14]
Epidemiology
United States statistics
Epidemiologic studies estimate the incidence of viral encephalitis at 3.5-7.4 per 100,000 persons per year. Overall,
viruses are the most common cause of encephalitis. The Centers for Disease Control and Prevention (CDC) estimates
an annual incidence of approximately 20,000 new cases of encephalitis in the United States; most are mild in nature.
(See the CDC Division of Vector-Borne Infectious Diseases, Arboviral Encephalitides.)
The 2 most common nonendemic causes of viral encephalitis in the United States are HSV and rabies virus. HSV
encephalitis is the most common form of viral encephalitis and has an incidence of 2-4 cases per 1 million population
per year and accounts for 10% of all cases of encephalitis in the United States.
Arboviral encephalitis affects 150-3000 persons per year, depending on occurrence and intensity of epidemic
transmission. WNE affected 373 individuals in 2009, with 32 deaths. St. Louis encephalitis affected 3000 individuals
in 1975; an outbreak with 24 confirmed or possible cases occurred in the state of Arkansas in 1991. La Crosse
encephalitis usually affects 80-100 individuals per year. EEE was confirmed in 257 cases since 1964, and WEE was
confirmed in 639 cases.
International statistics
The annual incidence of viral encephalitis is most likely underestimated, especially in developing countries, because of
problems with pathogen detection.[15] JE affects at least 50,000 individuals per year.
In a study from Finland, the incidence of viral encephalitis in adults was 1.4 cases per 100,000 persons per year.[16]
HSV was the organism most frequently identified as the cause (16%), followed by VZV (5%), mumps virus (4%), and
influenza A virus (4%).
Age-, sex-, and race-related demographics
Children and young adults are typically the groups that are most often affected. However, severity is usually more
pronounced in infants and elderly patients. The clinical course in children may be considerably different from that seen
in adults. HSE may be associated with a relapse in 25% of the cases, which may present as a movement disorder, most
often choreoathetosis.[17]
Mumps meningoencephalitis affects men more often than women. Men working in areas infested by infected
mosquitoes have a higher incidence of arboviral infections.
No racial predilection exists, although different genetic factors may predispose individuals to more severe forms of
CNS involvement.
Prognosis
The mortality depends largely on the etiologic agent of the encephalitis. The severity of sequelae apparently varies
according to the causative virus as well.[18] The average lifetime cost of the sequelae of encephalitis approaches US$3
million.
HSE carries a mortality of 70% in untreated patients, with severe sequelae among survivors.
After WEE, sequelae are uncommon in adults but are frequent in children. Recurring convulsions with motor or
behavioral changes affect more than half of children who are infected when younger than 1 month.
With EEE, most adults older than 40 years who survive (10% mortality) do so unscathed; children younger than 5
years have crippling sequelae consisting of mental retardation, convulsions, and paralysis.
Permanent sequelae after St. Louis encephalitis are uncommon, except for elderly individuals; the mortality rate is 2%
in young adults and 20% in elderly patients.
La Crosse virus causes a relatively mild encephalitis with a low fatality rate.
Mortality is low in VEE, CE, and encephalitis due to Colorado tick fever virus. Neurologic sequelae in these
conditions are not frequent and are usually mild.
JE has a mortality of almost 50% in patients older than 50 years and a mortality rate of less than 20% in children.
The Far East form of tick-borne encephalitis is more severe than the Central European form of tick-borne encephalitis,
with mortalities as high as 20% and frequent sequelae. Epilepsia partialis continua may develop during the
convalescent period or later. Residual weakness may also be present.
The 20-year risk of developing an unprovoked seizure is 22% for patients with viral encephalitis associated with early
seizures and 10% for viral encephalitis without early seizures. Of patients with CNS infection, 18-80% develop
epilepsy, which is usually refractory to medical treatment. A considerable number of such patients develop unilateral
mesial temporal lobe epilepsy and can have a good outcome after surgery.[19]
Patient Education
Education helps in the early diagnosis of encephalitis, especially in areas of endemic disease. Control of the mosquito
vector has been effective in several recent epidemics.
The belief that HSV-2 lesions initially appear 2 weeks after primary infection can lead to false accusations of
infidelity. The physician should emphasize that the initial outbreak of lesions may occur at any time, possibly years,
after infection.
For patient education resources, see the Brain and Nervous System Center, the Bacterial and Viral Infections Center,
and the Bites and Stings Center, as well as Meningitis in Adults, Mumps, and Encephalitis.
Proceed to Clinical Presentation

]
Table 1. Physiologic Roles
of Known Viral Receptors Receptor Abbreviation/Synonym Function
Virus
Measles virus Membrane cofactor CD46 Regulates complement and prevents
protein activation of complement on
autologous cells
Poliovirus CD155 hPVR/CD155 Expressed on primary human
monocytes; supports poliovirus
replication in vivo
HSV Heparan sulfate None Cell surface proteoglycans
 Herpesvirus entry Hve A, HVEM TNF receptor superfamily
mediator A
Herpesvirus entry Hve B, Human nectin-2, or Participate in organization of
mediator B Prr2alpha-Hve B epithelial and endothelial junctions
Herpesvirus entry Hve C, nectin1delta, or Prr1- Immunoglobulin superfamily
mediator C Hve C
TNFSF14 hTNFSF14/HVEM-L TNF receptor superfamily
Rabies virus Nicotinic AChR (a- AChR Nicotinic AChR
bungarotoxin binding
site)
NCAM NCAM, CD56, D2CAM, Cell adhesion glycoprotein of
Leu19, or NKH-1 immunoglobulin superfamily
NGFR NGFR NGFR
p75 neurotrophin p75NTR
receptor (p75NTR)
HIV-1 CD4 CD4 T lymphocyte protein with helper or
inducer function in immune system
CCR3 CCR3 Chemotactic activity
CCR5 CCR5 Coreceptor for macrophage-tropic
strain
CCR6 CCR65 Chemotactic activity
CXCR4 CXCR4 Coreceptor for CD4
JC virus N-linked glycoprotein N-linked glycoprotein Unknown
with alpha 2-6 sialic
acid
Japanese B virus[4] Protein GRP78 --- ER-stress response protein
AChRacetylcetylcholine receptor; CCRchemokine receptor; HSVherpes simplex virus; NCAMneural cell
adhesion molecule; NGFRnerve growth factor receptor; TNFtumor necrosis factor.
]
Table 2. Common
Viral Specific Clinical
Viral Encephalitides: Transmission Mortality Sequelae Season
Structure Patterns
Part 1 Virus (Family)
HSV (herpesvirus) ds DNA Unknown 70% if Rare forms: subacute, Common All year
untreated psychiatric, opercular,
recurrent meningitis

HSV-1: brainstem; HSV-

2: myelitis

VZV (herpesvirus) ds DNA Direct contact Variable; Rash, encephalitis in 0.1- Adults worse; Late
(air), highly low in 0.2% of children with cerebellitis winter,
contagious children chickenpox; cerebellar good spring
ataxia (cerebellitis)
Influenza virus ss RNA Direct contact Unknown Reversible frontal Parkinsonism Usually
(orthomyxovirus) (air), highly syndrome in children; (encephalitis winter
contagious Guillain-Barr, myelitis lethargica)
Enteroviruses ss RNA Fecal-oral route Low; high Herpangina; hand, foot, Mild, except for Summer,
(picornavirus) for mouth disease; enterovirus 71 fall;
enterovirus enterovirus 71 causes tropics: no
 71 rhombencephalitis season
Rabies virus ss RNA Dogs, wild Virtually Paresthesias; confusion, Mortality All year
(rhabdovirus) animals (eg, fox, 100% spasms, hydrophobia; virtually 100%
wolf, skunk) brainstem features
dsdouble strand; HSVherpes simplex virus; sssingle strand; VZVvaricella-zoster virus.
]
Table 3. Common Viral
Viral
Encephalitides: Part 2 Transmission Mortality Specific Clinical Patterns Sequelae Season
Structure
Virus (Family)
Lymphocytic ss RNA Rodents Low (< Progressive fever and Rare More in
choriomeningitis virus 1%) myalgia; orchitis; aseptic winter
(arenavirus) meningitis; leukopenia,
thrombocytopenia
Lassa virus ss RNA Rodents 15% Multisystem disease; Deafness (one All year
(arenavirus) proteinuria third)
Mumps virus ss RNA Direct contact Low Parotitis, pancreatitis, Frequent Winter
(paramyxovirus) (air), highly orchitis, aseptic meningitis sequelae and
contagious spring
Measles virus ss RNA Direct contact 10% Characteristic rash; Frequent: Winter
(paramyxovirus) (air), highly frequent EEG changes; mental and
contagious myelitis retardation, spring
seizures, SSPE
Nipah virus ss RNA Pigs; bats 40% Brainstem or cerebellar SSPE-like All year
(paramyxovirus) signs; segmental syndrome?
myoclonus, dysautonomia
dsdouble strand; EEGelectroencephalographic; sssingle strand; SSPEsubacute sclerosing panencephalitis.
]
Table 4. Common
Arboviral Specific Clinical
Vector Reservoir Mortality Sequelae Season
Encephalitides Patterns
Virus (Family)
Eastern equine virus Aedes sollicitans Birds 35% Severe, rapid Common, June to
(alphavirus) progression especially in
children

October

Western equine virus Culex tarsalis Birds 10% Classic Moderate in July to
(alphavirus) encephalitis infants; low in
others

October

Venezuelan equine Mosquito species Horses, ~ 0.4 % Low rate (4%) of Mild Rainy
encephalitis virus small CNS involvement season
(alphavirus) mammals
St Louis encephalitis Culex pipiens,C Birds 2% in young SIADH More in elderly August to
virus (flavivirus) tarsalis people; 20% in people October
elderly people
Japanese Culex Birds 33% (50% in Extrapyramidal 50% neuro Summer
encephalitis virus taeniorhynchus elderly people) features psychiatric;
(flavivirus) parkinsonism
West Nile virus Culex,Aedes spp Birds In US: 12% Motor or Usually not Summer
(flavivirus) (elderly people brainstem prominent
only) involvement
Far East encephalitis Ixodes Small 20% Epilepsia partialis Frequent; Spring to
virus (flavivirus) persulcatus (tick) mammals, continua residual early
birds weakness summer
Central European Ixodes ricinus Small Less common Limb-girdle Less common April to
encephalitis virus (tick) mammals, than in Far East paralysis than in Far East October
(flavivirus) birds (spine/medulla)
Powassan virus Ixodes cookei Small High Severe Common (50%) May to
(flavivirus) (tick) mammals, encephalitis December
birds
Dengue virus Aedes spp Mosquitoes Low, except Flulike syndrome; Mild, except for Rainy
(flavivirus) hemorrhagic rare CNS hemorrhagic season
involvement
La Crosse virus Aedes triseriatus Small Low (< 1%) Mild, primarily in Mild; seizures Summer
(bunyavirus) mammals children
Colorado tick fever Dermacentor Small Low Mild
virus (orbivirus) andersoni (tick) mammals
CNScentral nervous system; SIADHsyndrome of inappropriate antidiuretic hormone secretion.