AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Acute viral encephalitis (enkephalos + -itis, meaning brain inflammation) is often an unusual manifestation of common viral infections and most commonly affects children and young adults. Most viral infections of the CNS either involve the meninges, leading to aseptic meningitis, or cause mild meningoencephalitis rather than encephalitis.

In general, viral encephalitides can be divided into 4 separate categories based on the cause and pathogenesis of the following complications: acute viral encephalitis; postinfectious encephalomyelitis; slow viral infections of the CNS; and chronic degenerative diseases of the CNS, which are presumed to be of viral origin. This article focuses on acute viral encephalitis. For a more detailed description of each viral family, refer to the Infectious Diseases section of eMedicine and the articles Herpes Simplex Encephalitis and 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 for more information):

• 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

Despite viral tropism, the pattern of distribution of lesions in the brain is rarely sufficiently specific to enable identification of the infecting virus.

Table 1. Physiological Role of Known Viral Receptors

*Abbreviations: PV – Poliovirus; TNF – Tumor necrosis factor; AChR – Acetylcholine receptor; NCAM – Neural cell adhesion molecule; NGFR – Nerve growth factor receptor; CCR – Chemokine receptor

The pathophysiology of viral encephalitis varies according to the viral family. Viruses enter the CNS through 2 distinct routes: hematogenous dissemination or neuronal retrograde dissemination. Hematogenous spread is the most 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, as 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 and Japanese B encephalitis. 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.

Another form of CNS spread is through retrograde neural dissemination. Rabies usually spreads to the CNS through retrograde peripheral nerve dissemination. Rabies virus tends to exhibit tropism for the temporal lobes, affecting the Ammon horns. One of the possible routes of CNS spread for HSV is through the olfactory tracts. Herpesvirus encephalitis 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. Herpesviruses have tropism for the temporal cortex and pons, but the lesions may be widespread.

Frequency

United States

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. Epidemiological data follow; for additional updated epidemiologic data, see the CDC Division of Vector-Borne Infectious Diseases, Arboviral Encephalitides.

• The 2 endemic causes of viral encephalitis in the United States are HSV and rabies. HSV encephalitis is the most common form of viral encephalitis and has an incidence of 2 cases per 1 million population per year and accounts for 10% of all cases of encephalitis in the United States.
• Arboviral encephalitis comprises 150-3000 cases per year, depending on occurrence and intensity of epidemic transmission.
• West Nile encephalitis had affected 480 individuals, with 24 deaths, as of August 28, 2002.
• St. Louis encephalitis affected 3000 individuals in 1975.
• La Crosse encephalitis usually affects 70 individuals per year.
• Eastern equine encephalitis was confirmed in 153 cases since 1964, and western equine encephalitis was confirmed in 639 cases.

International

The annual incidence of viral encephalitis is most likely underestimated, especially in developing countries, because of problems with pathogen detection. Japanese B encephalitis affects at least 50,000 individuals per year.

In a recent study from Finland, the incidence of viral encephalitis in adults was 1.4 cases per 100,000 persons per year. HSV was identified most often as the cause (16%), followed by varicella-zoster (5%), mumps (4%), and influenza A viruses (4%).

Mortality/Morbidity

The mortality rate depends largely on the etiologic agent of the encephalitis. Herpesvirus encephalitis carries a mortality rate of 70% in untreated patients, with severe sequelae among survivors. For details on the incidence of sequelae in survivors, see Complications and Prognosis as well as Tables 2-4.

Sex

Mumps meningoencephalitis affects men more often than women. Men working in areas infested by infected mosquitoes have a higher incidence of arboviral infections.

Age

Children and young adults are usually the most often affected groups. However, severity is usually more pronounced in infants and elderly patients.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Viral encephalitis is marked by acute onset of a febrile illness.
• Patients with viral encephalitis generally experience signs and symptoms of leptomeningeal irritation (eg, headache, fever, neck stiffness).
• Patients with viral encephalitis also develop focal neurological signs; seizures; and alteration of consciousness, starting with lethargy and progressing to confusion, stupor, and coma.
• Behavioral and speech disturbances are common.
• Abnormal movements can be seen but are rare.
• Involvement of the hypothalamic/pituitary axis can lead to hyperthermia or poikilothermia.
• Specific clues taken from the patient's history depend on the viral etiology. Clinical findings reflect disease progression according to viral tropism for different CNS cell types. Particular clinical manifestations of different encephalitides can be reviewed in Tables 2-4. Some important clinical presentations are as follows:
• • Atypical presentations include a reversible frontal lobe and limbic syndrome without disturbances of consciousness or motor function. These presentations have been described in children with influenza virus infection.
  • HSV-1 encephalitis and HSV-2 encephalitis have subacute forms, presenting with psychiatric syndrome and anterior opercular syndrome, known as benign recurrent meningitis. HSV-1 encephalitis may produce a brainstem encephalitis, and HSV-2 encephalitis may produce a myelitis.
  • West Nile virus infection is usually asymptomatic in areas of endemic disease. In symptomatic individuals, an influenzalike illness occurs after incubation of 3-15 days; CNS involvement occurs in fewer than 15% of cases. Severe neurological infection is more common when the virus is introduced in an area of nonendemic disease. In 1999, during the New York City outbreak, 62 patients developed encephalitis, and 7 died (a case fatality rate of 12%, with all deaths occurring in older patients). Axonal neuropathy, demyelinating polyneuropathy similar to that in Guillain-Barré syndrome, encephalitis with and without muscle weakness, and aseptic meningitis were described.
  • Japanese B encephalitis typically affects children and young adults. Older adults are affected in epidemics. The clinical presentation includes a nonspecific prodrome and frequent seizures.
  • Dengue fever classically presents with a severe influenzalike illness or dengue hemorrhagic fever. Less commonly, dengue fever can lead to encephalitis or encephalopathy, transverse myelitis, and mononeuropathy or polyneuropathy similar to that in Guillain-Barré syndrome. The hemorrhagic form may also cause hepatic failure leading to a Reye syndrome–like illness.
  • Enteroviral encephalitis is usually associated with a good prognosis. However, enterovirus 71 has a high mortality rate and can present with herpangina or enteroviral hand, foot, and mouth disease. Complications include myocarditis and acute flaccid paralysis. Enterovirus 71 can cause a chronic meningoencephalitis in patients who are immunocompromised.
  • Mumps encephalitis typically starts 3-10 days after parotitis and usually resolves without sequelae, except for occasional hydrocephalus due to ependymal cell involvement. Measles does not usually cause acute encephalitis.
  • Rabies usually incubates 20-60 days but is capable of incubating for years. Infection does not occur in all humans bitten by an infected animal but is uniformly fatal when clinical disease develops. After a prodrome of fever, headache, malaise, seizures, and behavioral abnormalities, hydrophobia and aerophobia supervene. Coma and death occur in one to several weeks. Once symptoms start, treatment is ineffective.
  • Recently in southern Vietnam, a viral encephalitis caused by avian influenza A (H5N1) and not involving the respiratory tract was diagnosed in 2 siblings: a 4-year-old boy, who presented with severe diarrhea, seizures, coma, and death and his sister. His CSF only revealed high protein, but H5N1 was isolated from CSF, fecal, throat, and serum specimens.

Physical

Findings from physical examination are not usually diagnostic. Focal neurological deficits (eg, opisthotonos, pareses, tremors, ataxia, hypotonia, diplopia), accentuated reflexes, and extensor plantar responses may be observed. Abnormal movements and, rarely, tremor may be seen. Increased intracranial pressure can also lead to papilledema and cranial nerve VI palsy. Particular clinical manifestations of different types of encephalitis can be reviewed in Tables 2-4.

• A minority of patients with arbovirus develop acute encephalitis (or encephalomyelitis), meningitis, or a combination of both. Focal signs are only occasionally prominent in arboviral encephalitis. Patients may also have evidence of spinal cord involvement.
• Japanese B encephalitis can cause marked extrapyramidal manifestations, such as dull masklike face with wide staring eyes, tremor, choreoathetosis, head nodding, and rigidity. Flaccid paralysis, especially involving the lower extremities, has been described as being due to damage to the anterior horn cells.
• Parkinsonism can be a sequela of Japanese B encephalitis, and von Economo encephalitis (encephalitis lethargica) is considered to be a sequela of influenza encephalitis.
• Enterovirus 71 can cause rhombencephalitis with myoclonus, tremor, ataxia, cranial nerve involvement, neurogenic pulmonary edema, and coma.
• Nipah virus, in addition to the classical encephalitis presentation, produces cerebellar and brainstem signs, as well as segmental myoclonus, significant hypertension, and tachycardia. Encephalitis delayed 4 months after exposure to the virus has been described, suggesting similarities to the subacute sclerosing panencephalitis (SSPE) phenotype.

Causes

For further information, explanatory text follows Tables 2-4.

Table 2. Common Viral Encephalitides I

*Abbreviations: ds - Double strand; ss - Single strand

Table 3. Common Viral Encephalitides II

*Abbreviations: ds - Double strand; ss - Single strand; SSPE - Subacute sclerosing panencephalitis

Table 4. Common Arboviral Encephalitides

*Abbreviations: SIADH – Syndrome of inappropriate antidiuretic hormone secretion

• Herpesvirus encephalitis is the most common form of encephalitis in the United States and has been reviewed in a different eMedicine article (see Herpes Simplex Encephalitis). Human herpesvirus 6, causative agent of exanthema subitum, has been associated with a wide spectrum of neurological complications, including viral (focal) encephalitis. Arboviral encephalitides are transmitted by mosquitoes and include eastern equine encephalitis, western equine encephalitis, Venezuelan equine encephalitis, St. Louis encephalitis, Japanese B encephalitis, Murray Valley encephalitis, and California encephalitis. The most common viruses associated with acute childhood encephalitis are mumps, measles, and varicella-zoster virus (VZV).
• Arthropod-born 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.
• • Important alphaviruses include eastern equine encephalitis, western equine encephalitis, and Venezuelan equine encephalitis.
    • Eastern equine encephalitis 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 rate) with a high incidence of neurological sequelae.
    • Western equine encephalitis is most common in the western and midwestern United States but has a lower mortality rate (10%) than eastern equine encephalitis.
    • Venezuelan equine encephalitis occurs in South America and Central America as well as in the southwestern United States, typically causing mild disease and, rarely, neurological 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. The Japanese B virus has been described 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. The life cycle of the West Nile virus 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. West Nile virus was detected for the first time in the western hemisphere during an outbreak of encephalitis in the summer of 1999 in New York City. For more details, see the eMedicine article West Nile Encephalitis.
• Dengue fever is the most important arboviral infection of humans, with 100 million cases per year. Dengue fever can now be seen in any country between the tropics of Capricorn and Cancer (placing an estimated 2.5 billion people at risk). Dengue fever does not commonly cause neurological manifestations except when dengue hemorrhagic fever is present.
• Prior to the recent outbreaks of West Nile virus, 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 release. Mortality rate 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 viruses that cause La Crosse encephalitis, Jamestown Canyon encephalitis, and California encephalitides. La Crosse virus is the most common cause of arboviral encephalitis in the United States and produces seizures and focal neurological signs, manifested primarily in children, with a mortality rate of less than 1% and rare sequelae.
• 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. (For more details, see the various eMedicine articles on the neurological complications of HIV infection.)
• Measles and mumps viruses (paramyxoviruses) commonly cause neurological 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 and respiratory complaints and progresses to hemorrhagic shock. Unilateral or bilateral deafness may follow the period of encephalitis. The mortality rate can range from 8-52%.
• Enteroviruses are picornaviruses. This family includes coxsackie A, coxsackie B, poliovirus, echovirus, enterovirus 68, and enterovirus 71, as well as hepatitis A virus. 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. Recent outbreaks of enterovirus 71 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 20-60 days but can incubate for years.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Complex partial status epilepticus
Myoclonus
Partial seizures with secondary generalization
Seizure, partial (focal)
Benign epilepsy syndromes

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Usually, general laboratory studies are not helpful except to identify a viral infectious process (eg, lymphocytic predominance in the CBC count rather than polymorphonuclear cells indicative of bacterial infection). During epidemics, viral encephalitis is diagnosed readily on clinical grounds. However, sporadic cases of viral encephalitis are often difficult to distinguish from other febrile illnesses (eg, a child with gastroenteritis, dehydration, and convulsions) or from intoxications.
• In most instances, the currently available specific laboratory tests only help provide a retrospective diagnosis. Serologic tests depend on the occurrence of a rise in antibody titer. However, the early detection of specific immunoglobulin M (IgM) antibody may assist early diagnosis.
• Anti-West Nile virus IgM is detectable in the cerebrospinal fluid (CSF) and serum 10 days after infection onset. A polymerase chain reaction (PCR)–based test for rapid detection of West Nile virus has recently been developed in California. A diagnosis of Japanese B encephalitis can be confirmed serologically with demonstration of IgM in the CSF (sensitivity and specificity >95%). The PCR test may detect the virus within 2 days, but the test's reliability is uncertain. Enzyme-linked immunosorbent assays (ELISA) for detection of IgM and immunoglobulin G (IgG) of dengue fever are available for serum and CSF.

Imaging Studies

• CT scan
• • In HSV encephalitis, CT scan may show low-density lesions in the temporal lobes, which may not be present until 3-4 days after onset.
  • Edema and hemorrhages may be found, and, after 1 week, contrast enhancement may be observed.
  • CT findings are usually not helpful in differentiating the different viral encephalitides. However, given the low cost and ready availability in most institutions, CT scan can be used to evaluate acute disease progression and to follow up on complications.
  • CT scan can readily reveal important complications, such as hemorrhage, hydrocephalus, and herniation, and can help guide neurosurgical interventions.
• MRI
• • MRI is more sensitive than CT scan in identifying viral encephalitides.
  • In herpesvirus encephalitis, MRI typically shows temporal lobe lesions, which may be hemorrhagic and unilateral or bilateral. Inferomedial temporal lobe and cingulate gyrus are the areas most commonly detected by MRI. In children and infants, a more widespread pattern may be observed.
  • MRI may help in differentiating Japanese B encephalitis from Nipah virus encephalitis. Japanese B encephalitis is characterized by gray matter involvement. Nipah virus encephalitis is associated with multiple, small, white matter lesions.
  • The rhombencephalitis caused by enterovirus 71 can be visualized by T2-weighted MRI, which shows hyperintense signals in the brainstem.
  • A peculiar MRI pattern on diffusion-weighted imaging and magnetic resonance spectroscopy has been described in an acute and rapid form of subacute sclerosing panencephalitis.
• Relying on MRI findings to make the diagnosis of encephalitis or to distinguish among the different viral etiologies is usually not advisable.

Other Tests

• Electroencephalography
• • In herpesvirus encephalitis, electroencephalography (EEG) shows abnormalities in four fifths of biopsy-proven cases. Focal temporal changes, diffuse slowing, and periodic complexes and periodic lateralizing epileptiform discharges (PLEDs) are commonly described. Frontal slowing and occasional frontal spikes have been described in encephalitis associated with influenza virus.
  • Japanese B encephalitis is commonly associated with 3 EEG patterns: diffuse continuous delta activity, diffuse delta activity with spikes, and alpha coma pattern. In one study, EEG pattern did not correlate with the Glasgow coma scale score and outcome.
  • In St. Louis encephalitis, EEG is characterized by diffuse delta activity, and spike and waves are not prominent in the acute stage.

Procedures

• Spinal tap should be performed immediately once a space-occupying lesion is ruled out.
• • CSF examination is critical to establish the diagnosis and reveals, acutely, a typical viral profile: mildly elevated protein (60-80 mg/dL), normal glucose, and a moderate pleocytosis, up to 1000 leukocytes/µL. Mononuclear cells usually predominate, although early in fulminant encephalitis, polymorphonuclear leukocytes predominate, glucose and chloride concentrations in the CSF are normal, and protein is increased. Viral cultures are rarely helpful for acute management. Findings from CSF cultures for enteroviruses, mumps, and certain arboviruses may be positive.
  • Herpesvirus encephalitis may be associated with increased red blood cells and xanthochromia in the CSF. The fluid should be sent for HSV-1 and HSV-2 PCR to detect HSV DNA. PCR is highly specific and remains positive for as long as 5 days after initiation of treatment. Intrathecal antibodies can also be quantified.

Histologic Findings

• In acute viral encephalitis, capillary and endothelial inflammation of cortical vessels is a pathologic hallmark occurring in the gray matter or at the junction of the gray matter and white matter. Lymphocytic infiltration of the gray matter and neuronophagia may also occur. Astrocytosis and gliosis become prominent with disease progression.
• Some histopathologic features, such as Cowdry type A inclusion bodies in HSV and Negri bodies in rabies, are unique to viral infections. Arboviruses cause little histopathologic change outside the nervous system, with the possible exception of renal involvement in St. Louis encephalitis.
• Gross examination reveals varying degrees of meningitis, cerebral edema, congestion, and hemorrhage 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, Japanese B encephalitis, and the Far East form of tick-borne encephalitis.
• In patients who survive the initial illness, varying degrees of repair are observed, which may include calcification. The pattern of distribution of lesions in the brain is rarely sufficiently specific to enable identification of the infecting virus. However, the lesions in eastern equine encephalitis are concentrated in the cortex. In western equine encephalitis, lesions are concentrated in the basal nuclei. In St. Louis encephalitis, lesions are concentrated in substantia nigra, thalamus, pons, cerebellum, cortex, bulb, and anterior horn cells.
• Herpesvirus encephalitis 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. Hemorrhage and Cowdry type A inclusions bodies are found readily in the margins of areas of necrosis.
• Herpesvirus has tropism for the temporal cortex and pons, but the lesions may be widespread. Rabies virus tends to exhibit a tropism for the temporal lobes, affecting the Ammon horns. Autopsy studies in individuals with West Nile virus have shown particular brainstem involvement, especially the medulla, with endoneural mononuclear inflammation of cranial nerve roots.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Medical care should be devoted to appropriate management of the airway; bladder function; fluid and electrolyte balance; nutrition; and prevention of bedsores, secondary pulmonary infection, and hyperpyrexia.

• Increased intracranial pressure should be managed in the ICU setting with head elevation, gentle diuresis, mannitol, and hyperventilation.
• Seizures
• • Encephalitis causes a wide range of behavioral manifestations with limbic and frontal syndromes that can be difficult to distinguish from partial seizures.
  • Seizure activity can be closely observed using EEG monitoring, and the threshold for administering temporary anticonvulsant therapy should be low.
  • Phenytoin and valproic acid can be administered intravenously. Phenytoin and carbamazepine can be administered when oral or intragastric drug administration is possible. Benzodiazepines are also important when used to abort status epilepticus.

Surgical Care

Brain biopsy can yield definitive diagnosis. A biopsy may be considered when a lumbar puncture is precluded or when the diagnosis is uncertain (eg, to rule out other conditions such as vasculitis). Caution should be exercised before requesting a brain biopsy. PCR for HSV has significantly decreased the need for brain biopsy in herpesvirus encephalitis.

Consultations

Encephalitis is a neurological emergency. Consultation with a neurologist is recommended. Consultation with a neurosurgeon is helpful if a brain biopsy is considered.

• Consultation with an infectious disease specialist is also appropriate.
• Given the high likelihood of long-term need for cognitive rehabilitation and physical rehabilitation, especially in moderately severe and severe forms of encephalitis, establishing a multidisciplinary approach early in the disease course is appropriate. A multidisciplinary approach includes consultations with physical, occupational, and speech therapists, as well as consultation with a dietitian.

Diet

No dietary restrictions are necessary. The infectious process, especially with the presence of fever, increases nutritional requirements. Early assessment by a speech therapist and a dietitian helps prevent further body wasting and detects early behavioral manifestations that prevent adequate nutritional intake such as placidity, apraxia, dysphagia, or agitation.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

No specific treatment is available for the arbovirus encephalitides. Ribavirin seems to be effective for Lassa fever. The efficacy of ribavirin in other viral infections is being evaluated.

Pharmacotherapy for herpesvirus encephalitis consists of acyclovir and vidarabine. Outcome is improved with either agent, but acyclovir is more effective and less toxic. Even if the final diagnosis of HSV encephalitis has not been established, IV acyclovir should be initiated immediately.

After promising results were demonstrated by a small series, recombinant interferon alpha is currently being assessed in a trial for Japanese B encephalitis.

At some centers, antibacterial treatment of bacterial meningitis is administered until the diagnosis of bacterial meningitis is excluded.

Drug Category: Antiviral agents

These agents shorten the clinical course, prevent complications, prevent development of latency and subsequent recurrences, decrease transmission, and eliminate established latency.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• A multidisciplinary approach must be instituted as early as possible to start physical and cognitive rehabilitation and to minimize cognitive problems and long-term sequelae.
• Care in an ICU setting may be required, especially if seizure activity or increased intracranial pressure is present.

Further Outpatient Care

• Outpatient care should be focused on improvement of physical and neurological sequelae.

In/Out Patient Meds

• Patients may need long-term anticonvulsant therapy if seizure activity persists after the acute phase. Accordingly, additional therapy may be necessary for extrapyramidal, motor, and behavioral complications.

Deterrence/Prevention

• Surveillance is important to predict outbreaks of arboviral infections. Mosquitoes can be sampled to estimate infection rates in mosquito pools. Protective clothing and repellents are useful in the prevention of arthropod bites. Avoidance of outdoor activities is also useful. Prompt removal of ticks may decrease the risk of transmission of a tick-borne virus. Effective preventive measures include removing water-holding containers and discarded tires. Insecticides may be useful in the emergency control of infected mosquitoes. Control of the mosquito vector has been used with apparently good results in several recent epidemics.
• Vaccines are available for eastern equine encephalitis, western equine encephalitis, and Venezuelan equine encephalitis in horses. A live attenuated vaccine (TC-83) has been used to protect laboratory and field workers from the virus that causes Venezuelan equine encephalitis. Vaccines have also been developed for Japanese B encephalitis and tick-borne encephalitis.
• Killed virus vaccines have been produced experimentally for several arboviruses. A live-attenuated Japanese B vaccine (SA 14-14-2) has been used widely in Asia. Since 1989, 120 million children have been immunized, and a recent report has demonstrated the efficacy of a single dose in preventing Japanese B encephalitis when administered only days or weeks before exposure to infection. The only internationally licensed Japanese B encephalitis virus vaccine is a formalin-inactivated vaccine. Limited use (eg, in exposed laboratory workers) has been made of vaccines for Venezuelan equine encephalitis and tick-borne viral encephalitis. Passive immunization of laboratory workers exposed to a known virus in a laboratory accident has been accomplished with immune (human) serum or gamma globulin.
• Despite control efforts and disease surveillance, the 1999 outbreak of West Nile virus in New York, with subsequent spread to other states in the United States, showed that different viruses may be spread in the western hemisphere because of increased international travel and trade. Massive culling of pigs in Malaysia decreased the incidence of Nipah virus infection.

Complications

• Secondary bacterial infections of the respiratory and urinary tracts are major complications of encephalitis. Complications depend on the severity of the encephalitis and generally decline in importance as the acute illness passes.
• With recovery from acute viral encephalitis, evidence of neuronal injury and death becomes apparent as residual neurological defects, impairment of intelligence, and psychiatric disturbances. The severity of these sequelae varies according to the causative virus.
• Sequelae occur in 30-40% of patients aged 5-40 years and include extrapyramidal features (especially dystonia and occasionally parkinsonism), weakness, and seizure disorders. Sequelae are reported in only 3-10% of cases of Japanese B encephalitis in Japan. Yet, 25-30% of young adult males serving in the armed forces of the United States during World War II had sequelae (including neuroses) 6 months after infection. In addition, 10 of 25 individuals who had Japanese B encephalitis in Guam in 1948 had neurological or intellectual defects 10 years later.
• Hyponatremia due to inappropriate secretion of antidiuretic hormone may be frequent in St. Louis encephalitis. Dehydration, respiratory complications, nosocomial infections, and decubitus ulcers may also occur.
• See Tables 2-4 for further details on the complications of each viral group.

Prognosis

• The severity of sequelae apparently varies according to the causative virus.
• • After western equine encephalitis, 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 eastern equine encephalitis, most adults older than 40 years who survive (10% mortality rate) 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 rates are low in Venezuelan equine encephalitis, California encephalitis, and encephalitis due to Colorado tick fever virus. Neurological sequelae in these conditions are not frequent and are usually mild.
  • Japanese B encephalitis has a mortality rate 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 mortality rates 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 proportion of such patients develops unilateral mesial temporal lobe epilepsy and can have a good outcome after surgery.
• The average lifetime cost of the sequelae of encephalitis approaches US $3 million.
• See Tables 2-4 for further details on the prognosis of each viral group.

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.
• For excellent patient education resources, visit eMedicine's Brain and Nervous System Center, Bacterial and Viral Infections Center, and Bites and Stings Center.

  Also, see eMedicine's patient education articles Meningitis in Adults, Mumps, Encephalitis, West Nile Virus, Ticks, Spinal Tap, and Measles.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Delayed diagnosis of HSV encephalitis increases morbidity and mortality rates; failure to diagnose and treat early could result in litigation. With the wide availability of effective therapy, initiating treatment before a definitive diagnosis of HSV encephalitis (ie, during the workup) is now common practice.
• 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.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Jan 11, 2007