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.
More recently, provocative studies have found high antibody seroprevalence to viruses such as Ebola, Marburg, and Lyssa viruses in multiple African countries, indicating the presence of a high number of undiagnosed cases every year, including high neutralizing titers of antibodies to rabies virus in 11% of a small cohort of asymptomatic Peruvians living in the Amazon with prior exposure to bats. These studies raise the possibility that in some populations, those conditions may be more common than previously recognized.  The emergence of new types of viral infections, such as the Toscana virus (in the Western European countries located on the northern border of the Mediterranean sea, Cyprus and Turkey) where seropositivity in the population is not matched by clinical symptoms (indicating that most infections are mild) also highlight the fact that we need to be alert about the possible threats from unknown pathogens, even in areas that are not necessarily tropical or surrounded by rain forests.
An unusual CNS involvement leading to microcephaly due to infection of pregnant women by Zika virus has also been recently reported and highlights the constant need to look for new types of neurological manifestations of viral infections in humans. 
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:
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
Rabies virus - AChR, NCAM, and NGFR
JC virus - N-linked glycoprotein and alpha 2-6 sialic acid
Table 1. Examples of Physiologic Roles of Known Viral Receptors (Open Table in a new window)
|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 A||Hve A, HVEM||TNF receptor superfamily|
|Herpesvirus entry mediator B||Hve B, Human nectin-2, or Prr2alpha-Hve B||Participate in organization of epithelial and endothelial junctions|
|Herpesvirus entry mediator C||Hve C, nectin1delta, or Prr1-Hve C||Immunoglobulin superfamily|
|TNFSF14||hTNFSF14/HVEM-L||TNF receptor superfamily|
|Rabies virus||Nicotinic AChR (a-bungarotoxin binding site)||AChR||Nicotinic AChR|
|NCAM||NCAM, CD56, D2CAM, Leu19, or NKH-1||Cell adhesion glycoprotein of immunoglobulin superfamily|
|p75 neurotrophin receptor (p75NTR)||p75NTR|
|HIV-1||CD4||CD4||T lymphocyte protein with helper or inducer function in immune system|
|CCR5||CCR5||Coreceptor for macrophage-tropic strain|
|CXCR4||CXCR4||Coreceptor for CD4|
|JC virus||N-linked glycoprotein with alpha 2-6 sialic acid||N-linked glycoprotein||Unknown|
|Japanese B virus ||Protein GRP78||---||ER-stress response protein|
|AChR—acetylcetylcholine receptor; CCR—chemokine receptor; HSV—herpes simplex virus; NCAM—neural cell adhesion molecule; NGFR—nerve growth factor receptor; TNF—tumor 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.
Recent studies have reported a Mendelian predisposition to some forms of encephalitis (especially herpes simplex encephalitis) due to defects in the following pathways: TLR-3 interferon, autosomal recessive STAT-1 deficiency and X-linked NEMO deficiency, UNC-93B deficiency, and autosomal dominant TLR3 deficiency.  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 gamma–induced protein 10 kd [IP-10], without viral neuroinvasion (hyperactivated cytokine response).
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.
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)
|Virus (Family)||Viral Structure||Transmission||Mortality||Specific Clinical Patterns||Sequelae||Season|
|HSV (herpesvirus)||ds DNA||Unknown||70% if untreated||
Rare forms: subacute, psychiatric, opercular, recurrent meningitis
HSV-1: brainstem; HSV-2: myelitis
|VZV (herpesvirus)||ds DNA||Direct contact (air), highly contagious||Variable; low in children||Rash, encephalitis in 0.1-0.2% of children with chickenpox; cerebellar ataxia (cerebellitis)||Adults worse; cerebellitis good||Late winter, spring|
|Influenza virus (orthomyxovirus)||ss RNA||Direct contact (air), highly contagious||Unknown||Reversible frontal syndrome in children; Guillain-Barré, myelitis||Parkinsonism (encephalitis lethargica)||Usually winter|
|Enteroviruses (picornavirus)||ss RNA||Fecal-oral route||Low; high for enterovirus 71||Herpangina; hand, foot, mouth disease; enterovirus 71 causes rhombencephalitis||Mild, except for enterovirus 71||Summer, fall; tropics: no season|
|Rabies virus (rhabdovirus)||ss RNA||Dogs, wild animals (eg, fox, wolf, skunk)||Virtually 100%||Paresthesias; confusion, spasms, hydrophobia; brainstem features||Mortality virtually 100%||All year|
|ds—double strand; HSV—herpes simplex virus; ss—single strand; VZV—varicella-zoster virus.|
Table 3. Common Viral Encephalitides: Part 2 (Open Table in a new window)
|Virus (Family)||Viral Structure||Transmission||Mortality||Specific Clinical Patterns||Sequelae||Season|
|Lymphocytic choriomeningitis virus (arenavirus)||ss RNA||Rodents||Low (< 1%)||Progressive fever and myalgia; orchitis; aseptic meningitis; leukopenia, thrombocytopenia||Rare||More in winter|
|Lassa virus (arenavirus)||ss RNA||Rodents||15%||Multisystem disease; proteinuria||Deafness (one third)||All year|
|Mumps virus (paramyxovirus)||ss RNA||Direct contact (air), highly contagious||Low||Parotitis, pancreatitis, orchitis, aseptic meningitis||Frequent sequelae||Winter and spring|
|Measles virus (paramyxovirus)||ss RNA||Direct contact (air), highly contagious||10%||Characteristic rash; frequent EEG changes; myelitis||Frequent: mental retardation, seizures, SSPE||Winter and spring|
|Nipah virus (paramyxovirus)||ss RNA||Pigs; bats||40-75%||Brainstem or cerebellar signs; segmental myoclonus, dysautonomia||SSPE-like syndrome?||All year|
|ds—double strand; EEG—electroencephalographic; ss—single strand; SSPE—subacute 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)
|Virus (Family)||Vector||Reservoir||Mortality||Specific Clinical Patterns||Sequelae||Season|
|Eastern equine virus (alphavirus)||Aedes sollicitans||Birds||35%||Severe, rapid progression||Common, especially in children||
|Western equine virus (alphavirus)||Culex tarsalis||Birds||10%||Classic encephalitis||Moderate in infants; low in others||
|Venezuelan equine encephalitis virus (alphavirus)||Mosquito species||Horses, small mammals||~ 0.4 %||Low rate (4%) of CNS involvement||Mild||Rainy season|
|St Louis encephalitis virus (flavivirus)||Culex pipiens,C tarsalis||Birds||2% in young people; 20% in elderly people||SIADH||More in elderly people||August to October|
|Japanese encephalitis virus (flavivirus)||Culex taeniorhynchus||Birds||33% (50% in elderly people)||Extrapyramidal features||50% neuro psychiatric; parkinsonism||Summer|
|West Nile virus (flavivirus)||Culex,Aedes spp||Birds||In US: 12% (elderly people only)||Motor or brainstem involvement||Usually not prominent||Summer|
|Far East encephalitis virus (flavivirus)||Ixodes persulcatus (tick)||Small mammals, birds||20%||Epilepsia partialis continua||Frequent; residual weakness||Spring to early summer|
|Central European encephalitis virus (flavivirus)||Ixodes ricinus (tick)||Small mammals, birds||Less common than in Far East||Limb-girdle paralysis (spine/medulla)||Less common than in Far East||April to October|
|Powassan virus (flavivirus)||Ixodes cookei (tick)||Small mammals, birds||High||Severe encephalitis||Common (50%)||May to December|
|Dengue virus (flavivirus)||Aedes spp||Mosquitoes||Low, except hemorrhagic||Flulike syndrome; possible CNS involvement||Mild, except for hemorrhagic||Rainy season|
|La Crosse virus (bunyavirus)||Aedes triseriatus||Small mammals||Low (< 1%)||Mild, primarily in children||Mild; seizures||Summer|
|Colorado tick fever virus (orbivirus)||Dermacentor andersoni (tick)||Small mammals||Low||Mild|
|CNS—central nervous system; SIADH—syndrome 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). [8, 9]
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. [10, 11, 12] It is important to emphasize that the geographic distribution of dengue virus has increased. In 2009, locally acquired disease was diagnosed in New York City and subsequently in Key West in Florida (no locally acquired disease had been reported in the US since 1945).
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),  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.  Toscana virus was identified in Central Italy in 1971. It has a larger geographic distribution over the northern border of the Mediterranean Sea, including Cyprus and Turkey. Most affected individuals are not symptomatic or mildly symptomatic, although severe cases of meningitis and meningo-encephalitis have been reported.
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). 
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 (EV) 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. In 2014, the United States experienced a nationwide outbreak of EV-D68 associated with severe respiratory illness. From mid-August 2014 to January 15, 2015, CDC or state public health laboratories confirmed a total of 1,153 people in 49 states and the District of Columbia with respiratory illness caused by EV-D68. Almost all of the confirmed cases were among children, many whom had asthma or a history of wheezing.  One study reports that EV-D68 inhibits innate antiviral immunity by downregulation of interferon regulatory factor 7 (IRF7).  Outbreaks of enterovirus 71 have occurred in Japan, Malaysia, and Taiwan. Enterovirus 71 is typically associated with hand-foot-and-mouth disease, but up to 30% may develop neurological manifestations. In 2012, a severe encephalitis outbreak in Cambodia, with a 69% mortality rate in children, was secondary to enterovirus 71 serotype C4. The disease mainly affected children aged 3 years and younger.
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.  This reinforces the risk of new outbreaks of newer forms of encephalitis in Europe and other parts of the world.  Recent outbreaks of Zika virus in Brazil led to the development of CNS malformations in newborns of infected pregnant women, especially due to microcephaly. 
Epidemiologic studies estimate the incidence of viral encephalitis at 3.5-7.4 per 100,000 persons per year.
The annual incidence of viral encephalitis is most likely underestimated, especially in developing countries, because of problems with pathogen detection.  In a study from Finland, the incidence of viral encephalitis in adults was 1.4 cases per 100,000 persons per year. 
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.
The annual incidence of viral encephalitis is most likely underestimated, especially in developing countries, because of problems with pathogen detection.  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.  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. 
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.
The mortality depends largely on the etiologic agent of the encephalitis. The severity of sequelae apparently varies according to the causative virus as well.  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.
A large number of cases of newborns with microcephaly has been reported in pregnant women infected by Zika virus. 
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. 
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.
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