(See also Introduction to Brain Infections Introduction to Brain Infections Brain infections can be caused by viruses, bacteria, fungi, or, occasionally, protozoa or parasites. Encephalitis is most commonly due to viruses, such as herpes simplex, herpes zoster, cytomegalovirus... read more .)
Etiology of Encephalitis
Encephalitis is usually a primary manifestation or a secondary (postinfectious) immunologic complication of viral infection.
Primary viral infection
Viruses causing primary encephalitis directly invade the brain. These infections may be
Epidemic (eg, due to arbovirus, echovirus, coxsackievirus, or poliovirus Poliomyelitis Poliomyelitis is an acute infection caused by a poliovirus (an enterovirus). Manifestations include a nonspecific minor illness (abortive poliomyelitis), sometimes aseptic meningitis without... read more [in some underdeveloped countries])
Sporadic (eg, due to cytomegalovirus Cytomegalovirus (CMV) Infection Cytomegalovirus (CMV, human herpesvirus type 5) can cause infections that have a wide range of severity. A syndrome of infectious mononucleosis that lacks severe pharyngitis is common. Severe... read more or to herpes simplex Herpes Simplex Virus (HSV) Infections Herpes simplex viruses (human herpesviruses types 1 and 2) commonly cause recurrent infection affecting the skin, mouth, lips, eyes, and genitals. Common severe infections include encephalitis... read more
, varicella-zoster Herpes Zoster Herpes zoster is infection that results when varicella-zoster virus reactivates from its latent state in a posterior dorsal root ganglion. Symptoms usually begin with pain along the affected... read more 
, lymphocytic choriomeningitis Lymphocytic Choriomeningitis Lymphocytic choriomeningitis is caused by an arenavirus. It usually causes a flu-like illness or aseptic meningitis, sometimes with rash, arthritis, orchitis, parotitis, or encephalitis. Diagnosis... read more , rabies Rabies Rabies is a viral encephalitis transmitted by the saliva of infected bats and certain other infected mammals. Symptoms include depression and fever, followed by agitation, excessive salivation... read more , or mumps virus Mumps Mumps is an acute, contagious, systemic viral disease, usually causing painful enlargement of the salivary glands, most commonly the parotids. Complications may include orchitis, meningoencephalitis... read more 
)
Mosquito-borne arboviral encephalitides infect people during the spring, summer, and early fall when the weather is warm (see table Some Arboviral Encephalitides Some Arboviral Encephalitides Encephalitis is inflammation of the parenchyma of the brain, resulting from direct viral invasion. Acute disseminated encephalomyelitis is brain and spinal cord inflammation caused by a hypersensitivity... read more ). Incidence in the US varies from 150 to > 4000 cases yearly, mostly in children. Most cases occur during epidemics.
In the US, the most common sporadic encephalitis is caused by herpes simplex virus Herpes Simplex Virus (HSV) Infections Herpes simplex viruses (human herpesviruses types 1 and 2) commonly cause recurrent infection affecting the skin, mouth, lips, eyes, and genitals. Common severe infections include encephalitis... read more (HSV); hundreds to several thousand cases occur yearly. Most are due to HSV-1, but HSV-2 may be more common among immunocompromised patients. HSV encephalitis occurs at any time of the year, tends to affect patients < 20 or > 40 years, and is often fatal if untreated.
Rabies Rabies Rabies is a viral encephalitis transmitted by the saliva of infected bats and certain other infected mammals. Symptoms include depression and fever, followed by agitation, excessive salivation... read more remains a significant cause of encephalitis in developing countries and still causes a few cases of encephalitis in the US.
Encephalitis can also occur as a late reactivation of latent or subclinical viral infection. The best known types are
Subacute sclerosing panencephalitis Subacute Sclerosing Panencephalitis (SSPE) Subacute sclerosing panencephalitis is a progressive, usually fatal brain disorder occurring months to usually years after an attack of measles. It causes mental deterioration, myoclonic jerks... read more (which occurs years after a measles infection and is thought to represent reactivation of the original infection; it is now rare in Western countries)
Progressive multifocal leukoencephalopathy Progressive Multifocal Leukoencephalopathy (PML) Progressive multifocal leukoencephalopathy (PML) is caused by reactivation of the JC virus. The disease usually occurs in patients with impaired cell-mediated immunity, particularly patients... read more
(which is caused by reactivation of JC virus; particularly in AIDS or immunosuppressed patients)Herpes simplex type 1 and herpes zoster encephalitis
Immunologic reaction
Encephalitis can occur as a secondary immunologic complication of certain viral infections or vaccinations. Inflammatory demyelination of the brain and spinal cord can occur 1 to 3 weeks later (as acute disseminated encephalomyelitis); the immune system attacks one or more central nervous system (CNS) antigens that resemble proteins of the infectious agent. The most common causes of this complication used to be measles, rubella, chickenpox, and mumps (all now uncommon because childhood vaccination is widespread); smallpox vaccine; and live-virus vaccines (eg, the older rabies vaccines prepared from sheep or goat brain). In the US, most cases now result from influenza Influenza Influenza is a viral respiratory infection causing fever, coryza, cough, headache, and malaise. Mortality is possible during seasonal epidemics, particularly among high-risk patients (eg, those... read more A or B virus, enteroviruses Overview of Enterovirus Infections Enteroviruses, along with rhinoviruses (see Common Cold) and human parechoviruses, are a genus of picornaviruses (pico, or small, RNA viruses). All enteroviruses are antigenically heterogeneous... read more , Epstein-Barr virus Infectious Mononucleosis Infectious mononucleosis is caused by Epstein-Barr virus (EBV, human herpesvirus type 4) and is characterized by fatigue, fever, pharyngitis, and lymphadenopathy. Fatigue may persist weeks or... read more 
, hepatitis A Hepatitis A Hepatitis A is caused by an enterically transmitted RNA virus that, in older children and adults, causes typical symptoms of viral hepatitis, including anorexia, malaise, and jaundice. Young... read more or hepatitis B Hepatitis B, Acute Hepatitis B is caused by a DNA virus that is often parenterally transmitted. It causes typical symptoms of viral hepatitis, including anorexia, malaise, and jaundice. Fulminant hepatitis and... read more virus, or HIV Human Immunodeficiency Virus (HIV) Infection Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more 
. Immunologically mediated encephalitis also occurs in patients with cancer and other autoimmune disorders.
Rarely, apparent encephalitis has developed in patients with COVID COVID-19 COVID-19 is an acute, sometimes severe, respiratory illness caused by a novel coronavirus SARS-CoV-2. COVID-19 was first reported in late 2019 in Wuhan, China and has since spread extensively... read more -19 COVID-19 COVID-19 is an acute, sometimes severe, respiratory illness caused by a novel coronavirus SARS-CoV-2. COVID-19 was first reported in late 2019 in Wuhan, China and has since spread extensively... read more , caused by the novel pandemic severe acute respiratory syndrome coronavirus (SARS-CoV2); the mechanism is not clear, but an immunologic contribution to the mechanism of apparent encephalitis is possible, as is direct viral invasion of the brain.
Encephalopathies caused by autoantibodies to neuronal membrane proteins (eg, N-methyl-d-aspartate [NMDA] receptors) may mimic viral encephalitis. Some evidence suggests that anti-NMDA receptor encephalitis is a more common type of encephalitis than was previously thought. It occasionally develops after encephalitis due to herpes simplex virus, even when the encephalitis was successfully treated.
Pathophysiology of Encephalitis
In acute encephalitis, inflammation and edema occur in infected areas throughout the cerebral hemispheres, brain stem, cerebellum, and, occasionally, spinal cord. Petechial hemorrhages may be present in severe infections. Direct viral invasion of the brain usually damages neurons, sometimes producing microscopically visible inclusion bodies. Severe infection, particularly untreated herpes simplex virus (HSV) encephalitis, can cause brain hemorrhagic necrosis.
Acute disseminated encephalomyelitis is characterized by multifocal areas of perivenous demyelination and absence of virus in the brain.
Symptoms and Signs of Encephalitis
Symptoms of encephalitis include fever, headache, and altered mental status, often accompanied by seizures and focal neurologic deficits. A gastrointestinal (GI) or respiratory prodrome may precede these symptoms. Meningeal signs are typically mild and less prominent than other manifestations.
Status epilepticus Status epilepticus A seizure is an abnormal, unregulated electrical discharge that occurs within the brain’s cortical gray matter and transiently interrupts normal brain function. A seizure typically causes altered... read more , particularly convulsive status epilepticus, or coma suggests severe brain inflammation and a poor prognosis.
Olfactory seizures, manifested as an aura of foul smells (rotten eggs, burnt meat), indicate temporal lobe involvement and suggest HSV encephalitis.
Diagnosis of Encephalitis
MRI
Cerebrospinal fluid (CSF) testing
Encephalitis is suspected in patients with unexplained alterations in mental status. Clinical presentation and differential diagnoses may suggest certain diagnostic tests, but MRI and CSF analysis (including polymerase chain reaction [PCR] for HSV and other viruses) are usually done, typically with other tests (eg, serologic tests) to identify the causative virus. Despite extensive testing, the cause of many cases of encephalitis remains unknown.
MRI
Contrast-enhanced MRI is sensitive for early HSV encephalitis, showing edema in the orbitofrontal and temporal areas, which HSV typically infects. MRI shows demyelination in progressive multifocal leukoencephalopathy and may show basal ganglia and thalamic abnormalities in West Nile and eastern equine encephalitis. MRI can also exclude lesions that mimic viral encephalitis (eg, brain abscess Brain Abscess A brain abscess is an intracerebral collection of pus. Symptoms may include headache, lethargy, fever, and focal neurologic deficits. Diagnosis is by contrast-enhanced MRI or CT. Treatment is... read more 
, sagittal sinus thrombosis).
CT is much less sensitive than MRI for HSV encephalitis but can help because it is rapidly available and can exclude disorders that make lumbar puncture risky (eg, mass lesions, hydrocephalus, cerebral edema).
CSF testing
Lumbar puncture Lumbar Puncture (Spinal Tap) Lumbar puncture is used to do the following: Evaluate intracranial pressure and cerebrospinal fluid (CSF) composition (see table Cerebrospinal Fluid Abnormalities in Various Disorders) Therapeutically... read more (spinal tap) is done. If encephalitis is present, CSF is characterized by lymphocytic pleocytosis, normal glucose, mildly elevated protein, and an absence of pathogens after Gram staining and culture (similar to CSF in aseptic meningitis). Pleocytosis may be polymorphonuclear in severe infections. CSF abnormalities may not develop until 8 to 24 hours after onset of symptoms. Hemorrhagic necrosis can introduce red blood cells (RBCs) into CSF and elevate protein. CSF glucose levels may be low when the cause is varicella-zoster virus, mumps, or lymphocytic choriomeningitis virus.
PCR testing of CSF is the diagnostic test of choice for HSV-1, HSV-2, varicella-zoster virus, cytomegalovirus, enteroviruses, and JC virus. PCR for HSV in CSF is particularly sensitive and specific. However, results may not be available rapidly, and despite advances in technology, false-negative and false-positive results may still occur because of a variety of conditions; not all are technical failures (eg, the blood in a mildly traumatic CSF tap may inhibit the PCR amplification step). False-negative results can occur early in HSV-1 encephalitis; in such cases, testing should be repeated in 48 to 72 hours. A new technique, next-generation sequencing is becoming more widely available and may identify nucleic acids of agents that otherwise escape detection.
CSF viral cultures grow enteroviruses but not most other viruses. For this reason, CSF viral cultures have been superseded by PCR and are rarely used in diagnosis.
CSF viral IgM titers are often useful for diagnosing acute infection, especially West Nile encephalitis, for which they are more reliable than PCR. CSF IgG and IgM titers may be more sensitive than PCR for varicella-zoster virus encephalitis. Paired acute and convalescent serologic tests of CSF and blood must be drawn several weeks apart; they can detect an increase in viral titers specific for certain viral infections.
Brain biopsy
Brain biopsy may be indicated for patients who
Are worsening
Are responding poorly to treatment with acyclovir or another antimicrobial
Have a lesion that is still undiagnosed
However, brain biopsy has a low yield unless it targets an abnormality seen on MRI or CT.
Prognosis for Encephalitis
Recovery from viral encephalitis may take a very long time. Mortality rate varies with cause, but severity of epidemics due to the same virus varies during different years. Permanent neurologic deficits are common among patients who survive severe infection.
Treatment of Encephalitis
Supportive care
Acyclovir for HSV or varicella-zoster virus encephalitis
Supportive therapy for encephalitis includes treatment of fever, dehydration, electrolyte disorders, and seizures. Euvolemia should be maintained.
Because prompt identification of HSV or varicella-zoster virus by PCR is difficult, treatment should not be withheld pending confirmation by testing. Until HSV encephalitis and varicella-zoster virus encephalitis are excluded, acyclovir 10 mg/kg IV every 8 hours should be started promptly and continued usually for 14 days or until infection with these viruses is excluded. Acyclovir is relatively nontoxic but can cause liver function abnormalities, bone marrow suppression, and transient renal failure. Giving acyclovir IV slowly over 1 hour with adequate hydration helps prevent nephrotoxicity. Cytomegalovirus encephalitis can be treated with ganciclovir and/or other antiviral drugs.
Because a bacterial central nervous system (CNS) infection is often difficult to exclude when patients who appear seriously ill present, empiric antibiotics are often given until bacterial meningitis is excluded.
If encephalitis is due to an immunologic reaction (eg, acute disseminated encephalomyelitis [postinfectious encephalomyelitis]), treatment should be begun immediately; it may include corticosteroids (prednisone or methylprednisolone) and plasma exchange or IV immune globulin.
Key Points
Viruses that cause epidemic or sporadic infections can invade and infect brain parenchyma (causing encephalitis) and/or trigger postinfectious inflammatory demyelination (acute disseminated encephalomyelitis).
Encephalitis causes fever, headache, and altered mental status, often accompanied by seizures and focal neurologic deficits.
Do contrast-enhanced MRI and CSF testing.
Until HSV encephalitis and varicella-zoster virus encephalitis are excluded, promptly treat with acyclovir and continue, usually for 14 days or until infection with these viruses is excluded.
Treat encephalitis due to an immunologic reaction with corticosteroids and plasma exchange or IV immune globulin.
