Introduction
Background
Encephalitis, an inflammation of the brain parenchyma, presents as diffuse and/or focal neuropsychological dysfunction. 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.
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.
Of the subacute and chronic encephalopathies, the 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. The latter encephalitides include 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 acyclovir in any patient whose CNS presentations (particularly encephalopathy and focal findings) have no apparent explanation and in all neonates who appear ill and are without a final diagnosis.
In 1999, a late summer outbreak of West Nile encephalitis (WNE), an arbovirus not found previously in the United States, was implicated in several deaths in New York. By late summer 2002, West Nile virus has been identified throughout the eastern and southeastern United States. Following bird migration, the virus is presently extending 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) includes 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.
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 resources for physicians and interested laypersons provided by Cornell's Environmental Risk Analysis Program. Finally, West Nile Virus: A Primer for the Clinician from the August 6, 2002, issue of the Annals of Internal Medicine is available online in Adobe PDF format. The Canadian equivalent, West Nile Virus: Primer for Family Physicians, was published June 10, 2005 in Canadian Family Physician.
Pathophysiology
Portals of entry are virus specific. Many viruses are transmitted by humans, although most cases of HSE are thought to be reactivation of the herpes simplex virus (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, 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 regional tropism found with some viruses. For example, HSV has a predilection for the inferior and medial temporal lobes.
Although most histologic features are nonspecific, brain biopsies are the diagnostic criterion standard for rabies. Presence of Negri bodies in the hippocampus and cerebellum are pathognomonic of rabies, as are HSV Cowdry type A inclusions with hemorrhagic necrosis in the temporal and orbitofrontal lobes.
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, which result in multifocal demyelination of perivenous white matter.
Frequency
United States
Determining the true incidence is impossible because reporting policies are neither standardized nor rigorously enforced. In the United States, several thousand cases of viral encephalitis are reported yearly to the CDC, with an additional 100 cases a year attributed to PIE. This is probably 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 reported incidence similar to that of HSV. These statistics may be even more misleading because 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 (in particular, the strain that causes LaCross encephalitis [LAC]), which affects children in rural areas in states of the northern Midwest and East.
Among the other arboviruses causing encephalitis, the deadliest and, fortunately, most uncommon, eastern equine encephalitis (EEE), is encountered in New England and surrounding areas; the milder western equine encephalitis (WEE) 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: postinfectious, 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
Japanese virus encephalitis (JE), occurring principally in Japan, Southeast Asia, China, and India, is the most common viral encephalitis outside the United States.
Mortality/Morbidity
Mortality and morbidity are related to host factors, such as preexisting CNS injury and the virulence of infecting organism. Poor outcomes can be anticipated in infants younger than 1 year and adults older than 55 years.
- Untreated HSE has a mortality rate of 50-75%, virtually 100% of survivors have long-term motor and mental disabilities. Treated HSE correlates strongly with severity of illness at the time of medical intervention, and morbidity is usually quoted at approximately 20%.
- Arboviral JE and EEE are equally as catastrophic as untreated HSE, but other arboviruses are associated with a more benign clinical course. For example, St Louis encephalitis and WNE have a mortality rate of 2-20%, and death rates from WEE and LAC are less than 5%. The incidence of neurologic sequelae is around 25% but highly variable.
- The mortality rate 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 rate of 15% in immunocompetent patients and virtually 100% in immunosuppressed patients. The mortality rate for EBV encephalitis is 8%, and the morbidity rate is 12%. Rabies encephalitis and acute disseminated encephalitis are virtually 100% fatal, though the medical literature includes reports of survivors.
Sex
Individuals at the extremes of age are at highest risk, particularly for HSE.
Age
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.
Clinical
History
- Clinical presentation and course can be markedly variable. Acuity and severity of presentation correlates with prognosis.
- The patient may have history of animal bite for which antirabies treatment may not have been obtained.
- The general viral prodrome is several days long and consists of fever, headache, nausea and vomiting, lethargy, and myalgias.
- The specific prodrome in VZV, EBV, CMV, measles, and mumps includes rash, lymphadenopathy, hepatosplenomegaly, and parotid enlargement.
- Dysuria and pyuria are reported with St Louis encephalitis.
- Extreme lethargy has been noted with WNE
- The classic presentation is encephalopathy with diffuse or focal neurologic symptoms, including the following:
- Behavioral and personality changes, decreased level of consciousness
- Stiff neck, photophobia, and lethargy
- Generalized or localized seizures (60% of children with California encephalitis [CE])
- Acute confusion or amnestic states
- Flaccid paralysis (10% with WNE)
- Less common symptoms include headache and other complaints of meningismus.
- Neonatal HSV infection symptoms (1-45 d) may occur in any combination.
- Skin, eye, and mouth lesions (early presentation)
- Encephalitis - Change in level of alertness, irritability, seizures, poor feeding
- Evidence of widespread, disseminated disease, such as rash or shock
- HSE in older children and adults
- Unrelated to history of oral lesions in infants
- Acute onset of severe symptoms of encephalitis
- Toxoplasma encephalopathy accounts for as many as 40% of patients who are HIV positive with neurologic disease who present with a subacute headache, encephalopathy, and, often, a focal neurological complaint. This may be the presenting symptom of immunosuppression/HIV infection.
Physical
Look for supporting evidence of viral infection.
- The signs of encephalitis may be diffuse or focal (80% of patients with HSE present with focal findings) as follows:
- Altered mental status and/or personality changes (most common)
- Focal findings, such as hemiparesis, focal seizures, and autonomic dysfunction
- Movement disorders (St Louis encephalitis, EEE, WEE)
- Ataxia
- Cranial nerve defects
- Dysphagia (Rabies may account for foaming at the mouth and hydrophobia.)
- Meningismus (less common and less pronounced than in meningitis)
- Unilateral sensorimotor dysfunction (PIE)
- HSV infection in the neonate (aged 1-45 d)
- Herpetic skin lesions over the presenting surface from birth or with breaks in the skin, such as those resulting from fetal scalp monitors
- Keratoconjunctivitis
- Oropharyngeal involvement, particularly buccal mucosa and tongue
- Encephalitis symptoms, such as seizures, irritability, change in level of attentiveness, bulging fontanels
- Additional signs of disseminated HSV, such as shock, jaundice, and hepatomegaly
- Toxoplasma encephalopathy: In immunosuppressed patients, 75% present with a focal neuropathology, about one half with encephalopathic changes.
Causes
- The etiology of encephalitis is usually infectious, but may be noninfectious, such as the demyelinating process in acute disseminated encephalitis.
- Infectious etiologies: Viral agents, such as HSV type 1 and 2 (almost exclusively in neonates), VZV, EBV, measles virus (PIE and SSPE), mumps, and rubella are spread through person-to-person contact.
- 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.
- The CDC confirmed that West Nile virus can be transmitted by means of an organ transplant and via blood transfusions.
More on Encephalitis |
 Overview: Encephalitis |
| Differential Diagnoses & Workup: Encephalitis |
| Treatment & Medication: Encephalitis |
| Follow-up: Encephalitis |
| References |
| Next Page » |
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Further Reading
Keywords
cephalitis, cerebritis, acute encephalitis, herpes simplex encephalitis, HSE, varicella-zoster encephalitis, VZ encephalitis, West Nile encephalitis, WNE, WestNilevirus,West Nile virus encephalitis, St Louis encephalitis, SLE, California virus encephalitis, LaCross encephalitis, LAC, eastern equine encephalitis, EEE, western equine encephalitis, WEE, Powassan virus, POW virus, Japanese virus encephalitis, JE, arboviralJE, subacute encephalopathies, chronic encephalopathies, acute arboviral encephalitides, acute viral encephalitides, cytomegalovirus encephalitis, CMV encephalitis, sclerosing panencephalitis, SSPE, progressive multifocal leukoencephalopathy, PML, HSV Cowdry type A inclusions, acute disseminated encephalitis, postinfectious encephalomyelitis, PIE, Epstein-Barr virus, EBV encephalitis, subacute sclerosing panencephalitis, SSPE, rabiesencephalitis, acutedisseminated encephalitis, stiff neck, photophobia, lethargy, toxoplasma encephalopathy, meningismus
