eMedicine Specialties > Neurology > Neurological Infections

Viral Encephalitis

Author: Francisco de Assis Aquino Gondim, MD, MSc, PhD, Professor Adjunto III, Departments of Physiology and Pharmacology, Neurology Residency Program Director, Faculdade de Medicina, Universidade Federal do Ceará, Brazil
Coauthor(s): Gisele Oliveira, MD, Staff Physician, Department of Neurology, Saint Louis University School of Medicine; Florian P Thomas, MD, MA, PhD, Drmed, Director, Spinal Cord Injury Unit, St Louis Veterans Affairs Medical Center; Director, National MS Society Multiple Sclerosis Center; Professor, Department of Neurology and Psychiatry, Associate Professor, Institute for Molecular Virology, and Department of Molecular Microbiology and Immunology, St Louis University
Contributor Information and Disclosures

Updated: Oct 4, 2008

Introduction

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
• West Nile virus - Cholesterol-rich membrane microdomains¹

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

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*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. Herpes viruses 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. The clinical course in children may be considerably different from the adult forms. Herpes simplex encephalitis may be associated with a relapse in 25% of the cases, which may present as a movement disorder, most often choreoathetosis.²

Clinical

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; seizures³ ; 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.³
  • Dengue fever⁴ 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

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

Table 3. Common Viral Encephalitides II

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

Table 4. Common Arboviral Encephalitides

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*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.
• In a 2007 outbreak of Chikungunya virus infection in Italy, 1 elderly patient developed encephalitis and died.⁵ This reinforces the risk of new outbreaks of newer forms of encephalitis in Europe and other parts of the world.

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