Encephalitis

Cause

Etiology 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 [in some underdeveloped countries]) Sporadic (eg, due to herpes simplex, rabies, varicella-zoster, or mumps virus) Mosquito-borne arboviral encephalitides infect people during the spring, summer, and early fall when the weather is warm. 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 (HSV); hundreds to several thousand cases occur yearly. Most are due to HSV-1, but HSV-2 may be more common among immuno- compromised patients. HSV encephalitis occurs at any time of the year, tends to affect patients <20 or > 40 yr, and is often fatal if untreated. Primary encephalitis can occur as a late consequence of a viral infection. The best known types are HIV infection with encephalopathy and dementia (see page HIV-Associated Dementia) Subacute sclerosing panencephalitis (which occurs years after a measles infection and is thought to represent reactivation of the original infection; it is now rare in Western countries—see page Subacute Sclerosing Panencephalitis (SSPE)) Progressive multifocal leukoencephalopathy (which is caused by reactivation of JC virus—see page Progressive Multifocal Leukoencephalopathy (PML)) 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 wk later (as acute disseminated encephalomyelitis); the immune system attacks one or more CNS antigens that resemble proteins of the infectious agent. The most common causes 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 A or B virus, enteroviruses, Epstein-Barr virus, hepatitis A or B virus, or HIV. Encephalopathies caused by autoantibodies to neuronal membrane proteins (eg, N -methyl-d-aspartate receptors) may mimic viral encephalitis.

Pathophysiology

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 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.

Diagnosis

MRI 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 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, 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 If encephalitis is present, CSF (see page Neurologic Diagnostic Procedures : Lumbar puncture (spinal tap)) 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 h after onset of symptoms. Hemorrhagic necrosis can introduce RBCs into CSF and elevate protein. CSF glucose levels may be low when the cause is varicella-zoster virus 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 h. CSF viral cultures grow enteroviruses but not most other viruses. For this reason, CSF viral cultures 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, who are responding poorly to treatment with acyclovir or another antimicrobial, or who 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 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

Supportive care Acyclovir for HSV or varicella-zoster virus encephalitis Supportive therapy includes treatment of fever, dehydration, electrolyte disorders, and seizures. Euvolemia should be maintained. Until HSV encephalitis and varicella-zoster virus encephalitis are excluded, acyclovir 10 mg/kg IV q 8 h 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 h with adequate hydration helps prevent nephrotoxicity. Because a bacterial 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, treatment may include corticosteroids (prednisone or methylprednisolone) and plasma exchange or IV immune globulin.

Symptoms and Signs

Symptoms include fever, headache, and altered mental status, often accompanied by seizures and focal neurologic deficits. A GI or respiratory prodrome may precede these symptoms. Meningeal signs are typically mild and less prominent than other manifestations. Status epilepticus, 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.

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.