Encephalitis, Viral

ENCEPHALITIS refers to inflammation of the brain. The term includes both viral infections of the brain with predominately gray matter disease and acute disseminated encephalomyelitis (ADEM), an immune-mediated demyelinating disease. Clinically, both forms of encephalitis usually manifest fever, nuchal rigidity, alterations of consciousness, focal neurological signs, and often seizures. The pathology of acute viral encephalitis is characterized by mononuclear inflammatory cells in a perivascular distribution in the gray matter and meninges and neural cell destruction with neuronophagia. The pathology of ADEM or postinfectious encephalomyelitis is characterized by perivenular mononuclear cell inflammation and demyelination predominately in the white matter of the brain and spinal cord. Both forms of encephalitis are linked primarily with viral infections, but both are associated with some bacterial infections. Rarely, acute encephalitis may be due to fungal and parasitic infection, and ADEM may be associated with vaccines. The two forms of encephalitis tend to be due to different spectra of viruses and involve different mechanisms of pathogenesis. Following some general comments on viral pathogenesis, the two forms of encephalitis are discussed separately.

Pathogenesis

Viruses can be released by infected humans or animals in saliva, respiratory droplets, breast milk, feces, urine, semen, vaginal secretions, blood, or tissue. Viruses have no mobility but must penetrate formidable barriers to enter the body of a susceptible human host. The skin is covered by a layer of keratinized cells that will not sustain virus replication, but arthropods and animal bites, needles, and tissue transplantation can breach this barrier directly (Table 1 ). The mucous membranes of the respiratory, gastrointestinal, and genitourinary tract are protected by secretory immunoglobulins, and all are monitored by macrophages that phagocytize viruses and other particles. In addition, the respiratory tract has a mucous coating and cilia that beat the film containing inhaled particles outward and away from the epithelial cells of the lower respiratory tract, and the gastrointestinal and genitourinary tracts have extremes of acidity. A few nonenveloped, acid-resistant viruses (adenoviruses, enteroviruses, parvoviruses, and reoviruses) can survive passage through the acidity and solvents of the gastrointestinal tract.

Table 1.

ENTRY FOR VIRUSES CAUSING HUMAN VIRAL ENCEPHALITIS^a

Route of entry in natural infection	Viruses
Inoculation
Arthropod bite	Arboviruses
Animal bite	Rabies virus
	Herpesvirus simiae
Blood transfusion	Cytomegalovirus
	Hepatitis B virus
	Human immunodeficiency virus
	Human T cell lymphotropic virus
Transplantation	Rabies virus
	Creutzfeldt–Jakob disease
Intentional	Vaccine viruses
Respiratory
Droplet	Mumps virus
	Parainfluenza virus
	Measles virus
	Influenza virus
	Lymphocytic choriomeningitis virus
	Other arenaviruses
	Adenoviruses
	Varicella-zoster virus
Saliva	Herpes simplex virus type 1
	Cytomegalovirus
	Epstein–Barr virus
Enteric	Enteroviruses (poliovirus, coxsackievirus, and echoviruses)
	Adenoviruses
	Hepatitis A virus
Venereal	Herpes simplex virus type 2
	Cytomegalovirus
	Hepatitis B virus
	Human immunodeficiency virus
	Human T cell lymphotropic virus
Transplacental	Rubella virus
	Cytomegalovirus
	Human immunodeficiency virus
	Other viruses

^aModified from Johnson (1998).

Once permissive host cells are infected in the subcutaneous tissue, the mucous membranes, or the hematopoietic system (particularly macrophages), cycles of replication usually occur locally before there is invasion of the central nervous system (CNS). Pathways of spread into the CNS are along nerves or via the blood (Table 2 ). For many years, the nerves, both peripheral and olfactory, were regarded as the sole portals into the CNS, and early experimental studies documented the neural transmission of rabies virus, herpes simplex virus, and polioviruses. Nerve endings have receptors for some viruses, and the viruses are transported by the retrograde axon transport system to the cell bodies, where replication is possible. This transport occurs in the peripheral nervous system along motor and sensory fibers and also within the CNS, exemplified by the movement of polioviruses between spinal cord motor neurons and corresponding cortical neurons. The olfactory pathway is a unique venue for neural spread since the olfactory rods extend out from the olfactory mucosa and the central processes of the olfactory neurons synapse within the CNS. Thus, a single neuron can provide transport from the ambient environment to the CNS. Despite this direct connection, few aerosol or respiratory infections have been found to invade through the olfactory route.

Table 2.

PATHWAYS FOR VIRUS SPREAD TO THE CNS^a

Pathway	Experimental hosts	Natural disease of humans
Neural	Herpes simplex virus	Rabies virus
	B virus	Herpes simplex viruses
	Rabies virus	Varicella-zoster virus
	Polioviruses	Herpes simiae (B virus)
	Reovirus, type 3	?Polioviruses
	Borna virus
	Scrapie agent
	Creutzfeldt–Jakob disease agent
Olfactory	Herpes simplex virus	?Herpes simplex virus, type 1
	Polioviruses	Aerosol infections with rabies and arboviruses
	Arboviruses
	Coronavirus
Hematogenous	Herpes simplex virus	Enteroviruses (poliovirus, coxsackievirus, and echoviruses)
	Cytomegalovirus	Cytomegalovirus
	Polioviruses	Epstein–Barr virus
	Coxsackieviruses	Mumps virus
	Mumps virus	Measles virus
	Lymphocytic choriomeningitis virus	Adenovirus
	Most arboviruses	Filoviruses
	Parvoviruses	Lymphocytic chorimeningitis virus
	Reovirus, type 1	Other arenaviruses
	Simian immunodeficiency virus	Arboviruses
	Other lentiviruses and oncoviruses	Human immunodeficiency virus
		Human T cell lymphotropic virus

^aFrom Johnson (1998).

Although early studies concluded that the blood–brain barrier was impenetrable by viruses, most viruses do invade the CNS from the blood. Some viruses infect cerebral endothelial cells or choroid plexus epithelial cells and “grow” into the CNS. Others cross uninfected vascular endothelial cells into the brain in endocytotic vesicles or within infected mononuclear cells. Invasion from blood depends on the magnitude and duration of the viremia. Viruses in the blood are promptly removed by the reticuloendothelial system and, like other particles, speed of clearance is size dependent. Small viruses are removed more slowly, and many larger viruses avoid clearance by growth in leukocytes or adhesion to red cells.

Within the CNS, specific cell populations may be vulnerable to specific viruses. For example, rabies virus infects only neurons, and early in infection neurons that modify behavior are selectively affected. This explains the unique clinical syndrome of vigilance and agitation. Similarly, polioviruses selectively infect and destroy motor neurons causing the syndrome of flaccid paralysis. Arboviruses infect primarily neurons, and herpes simplex virus infects neurons, glia, and endothelial cells. JC virus selectively lyses oligodendrocytes causing demyelinating disease. Enteroviruses and mumps virus infect primarily meningeal and ependymal cells; therefore, they usually cause benign meningitis and only rarely are associated with encephalitis.

Neuroinvasiveness, neurotropism, and neurovirulence are features of viruses that need to be differentiated. Neuroinvasiveness is the ability to penetrate the CNS. Neurotropism is the ability to infect neural cells other than neurons and is distinct from neuronotropism, which indicates the ability to infect neurons. Neurovirulence relates to the ability to cause disease. Thus, mumps virus that can often be recovered from spinal fluid during uncomplicated parotitis is highly neuroinvasive, is neurotropic in ependymal cells but not neuronotropic, and has a low level of neurovirulence. In contrast, most arbovirus infections are asymptomatic or cause only fever, malaise, and minor systemic symptoms. On rare occasions when arboviruses infect the brain, they usually cause encephalitis with a significant death rate; thus, these viruses are not highly neuroinvasive but are highly neurotropic (and neuronotropic) and neurovirulent. It must be noted that neuroinvasiveness and neurovirulence are also dependent on a myriad of host factors, such as age, immune responses, and genetic constitution.

Acute Viral Encephalitis

Epidemiology

The incidence of acute encephalitis is estimated between 3.5 and 7.4 per 100,000 persons per year (which is approximately one-third the incidence of viral meningitis). Encephalitis has been associated with approximately 100 different viruses that cause disease of variable severity (Table 3 ). Encephalitis is more common in children than in adults and varies by gender, season, and geographic location. For example, CNS complications of mumps virus infections are three times more common in males than females. Seasonally, enterovirus infections are more common in summer and early fall, lymphocytic choriomeningitis virus infections are more common in winter, and arbovirus infections are more common during the feeding season of the transmitting arthropod. Regionally, rabies causes more than 25,000 deaths per year in India but only 1–5 deaths in the United States. Each year a variety of arboviruses cause 200–2000 cases of encephalitis in the United States, tick-borne encephalitis virus causes several thousand cases in Europe, and Japanese encephalitis virus causes approximately 30,000 cases in Asia.

Table 3.

SEVERITY OF ACUTE ENCEPHALITIS WITH DIFFERENT VIRUSES^a

Virus(es)	Severity of encephalitis
Rabies virus	>99% of cases are fatal
Herpes simplex viruses	>70% of cases are fatal (if untreated)
Arboviruses	1–50% of cases are fatal (dependent on virus and age of host)b
Lymphocytic choriomeningitis virus	Common mild encephalitis; rare deaths
Mumps virusc	Common mild encephalitis; rare deaths
Cytomegalovirus	Occasional encephalitis with infectious mononucleosis
Epstein–Barr virusc	Occasional encephalitis with infectious mononucleosis
Adenoviruses	Rare cases of serious encephalitis in children
HIV	Rare acute encephalitis at the time of primary infection
Human herpesvirus 6	Mild encephalitis in children
Coxsackieviruses and echoviruses	Rare fatal encephalitis in neonates

^aModified from Johnson (1996).

^bCalifornia encephalitis is fatal in <1% of children, western encephalitis in 10% of infants, St. Louis encephalitis in 20% of elderly persons, and eastern encephalitis in 50% of individuals of all ages.

^cSome fatal cases have the pathology of postinfectious encephalomyelitis. Some viruses may cause acute encephalitis and ADEM.

Clinical Findings

Clues to the causative agent may be found in a history of travel, family illnesses, recreational activities, animal exposures, and past immunization. General examination may show a rash in enterovirus, herpesvirus 6 and 7, and West Nile virus infections; herpangina in coxsackievirus infections; adenopathy in HIV, Epstein–Barr virus, and cytomegalovirus infections; parotitis in mumps or lymphocytic choriomeningitis virus infections; or pneumonitis in adenovirus, lymphocytic choriomeningitis, or Nipah virus infections.

The classic clinical symptoms and signs of encephalitis are fever, headache, nuchal rigidity, depression of consciousness, focal neurological signs, and often seizures. Occasionally, fever is not present at the time of presentation, stupor may obscure a complaint of headache, or nuchal rigidity may be absent; thus, no finding is absolute. Spinal fluid examination is critical for diagnosis. Typically, a mononuclear cell pleocytosis, modest elevation of protein, normal sugar content, and often increased pressure are found. Early in disease, polymorphonuclear cells may predominate or fluid may be acellular, but within 24 hr a mononuclear cell response usually evolves. In some infections mild depressions of sugar content are present. The presence of red cells may suggest herpetic encephalitis, but the finding is neither consistent nor specific.

Rabies and herpes simplex virus encephalitis usually present with characteristic syndromes. Rabies may present as either an ascending paralysis simulating the Guillian–Barré syndrome or an altered mental status with periods of confusion with bizarre behavior and autonomic signs progressing to intense agitation with aerophobia and hydrophobia. Herpes simplex virus encephalitis usually localizes to one or both temporal lobes, which may cause bizarre behavior, hallucinations, aphasia, and quadratic visual field defects. Imaging studies typically show low-density lesions in one or both temporal lobes with enhancement and mass effect. Only approximately one-half of patients with encephalitis with temporal lobe signs prove to have herpes simplex virus encephalitis. More than 90% of patients with herpetic encephalitis have these findings, but herpes simplex virus causes only 10% of cases of encephalitis and other agents may occasionally mimic these symptoms and signs.

Diagnosis

Diagnosis of herpes simplex virus encephalitis is important since it is the most common cause of fatal nonepidemic encephalitis worldwide, and there is specific treatment that can reduce the fatality rate from approximately 70 to 20%. The second diagnostic imperative is to rule out nonviral disease that can masquerade as viral encephalitis and that requires specific therapies (Table 4 ).

Table 4.

DISEASES THAT CAN MASQUERADE AS VIRAL ENCEPHALITIS^a

Infectious agents
Rickettsia	Rocky Mountain spotted fever
	Typhus
	Q fever
Bacteria	Spirochetes
	Syphilis (secondary or meningovascular)
	Leptospirosis
	Borrelia burgdorferi (Lyme disease)
	Mycoplasma pneumoniae infection
	Cat scratch fever
	Listeriosis
	Brucellosis (particularly B. melatensis)
	Tuberculosis
	Typhoid fever
	Whipple disease
	Parameningeal infections (epidural, petrositis)
	Partially treated bacterial meningitis
	Subacute bacterial endocarditis
	Brain abscess
Fungi	Cryptococcosis
	Coccidioidomycosis
	Histoplasmosis
	North American blastomycosis
	Candidiasis
Parasites	Toxoplasmosis
	Cysticercosis
	Echinococcosis
	Trichinosis
	Trypanosomiasis
	Plasmodium falciparum infection
	Amoebiasis (Nagleria and Acanthamoeba)
Noninfectious conditions
Tumors	Gliomatosis cerebri
	Carcinomatous meningitis
	Ruptured intracerebral cysts
Collagen vascular	Systemic lupus erythematosis
	Rheumatoid meningitis
	Vasculitis
Other inflammatory diseases	Sarcoidosis
	Bechet's disease
	Uveoencephalitis syndromes
	Hashimoto's encephalopathy
Drug-induced meningitis (NSAIDS)

^aModified from Johnson (1998).

Diagnosis is dependent on identifying virus in spinal fluid or brain tissue or on serological tests that often require a convalescent serum too late to aid in acute management. In herpes simplex and other herpesvirus infections, polymerase chain reactions can identify specific viral DNA in spinal fluid. In many arbovirus infections, IgM capture enzyme-linked immunoassays on spinal fluid can quickly identify specific viral infections.

Acute Disseminated Encephalomyelitis

Epidemiology

Historically, ADEM accounted for one-third of cases of acute encephalitis. Vaccine practices have reduced or eliminated the major causes (Table 5 ). Cessation of vaccinia infections to prevent smallpox and institution of immunizations for measles, mumps, rubella, and varicella viruses have eliminated the majority of cases of ADEM. Indeed, in nations with successful immunization policies, the majority of cases are now related to nonspecific upper respiratory infections.

Table 5.

VIRUSES ASSOCIATED WITH ACUTE DISSEMINATED ENCEPHALOMYELITIS^a

Virus(es)	Frequency	Comment
Vaccinia virusb	1:60 to 1:100,000	Eliminated by discontinuation of vaccination
Measles virus	1:1,000	Almost eliminated by introduction of vaccine
Varicella-zoster virus	1:4,000	Largely associated with acute cerebellar ataxia
Rubella virus	<1:20,000	Reduced 99% in the United States by vaccine
Epstein–Barr virus	Rare	In early weeks of infectious mononucleosis
Mumps virusc	Rare	Reduced 99% in the United States by vaccine
Influenza viruses	Rare
Nonspecific respiratory disease	Rare

^aModified from Johnson (1996).

^bOccurred with variola virus infection (smallpox), but the frequency was never accurately determined.

^cAlthough acute demyelination has been reported in a few fatal cases, mumps virus meningitis and/or encephalitis usually represent direct infection of neural cells.

Clinical Findings

A history is often obtained that an exanthem or a nonspecific respiratory or gastrointestinal illness preceded the encephalitis symptoms by 5 days to 3 weeks. For example, postmeasles encephalomyelitis typically begins 4–8 days after the rash when the child has defervesced and is returning to normal activities. Headache, fever, and depressed consciousness develop abruptly, often with focal neurological signs and seizures. Postvaricella encephalitis is commonly limited to acute cerebellar ataxia.

The spinal fluid may show a mild pleocytosis and protein elevation, but in one-third of patients these analyses remain normal. Assays for myelin basic protein are often positive, consistent with the demyelinating nature of the disease. Magnetic resonance imaging is the more definitive test, often showing multifocal white matter lesions with enhancement suggesting inflammatory lesions of similar age.

Diagnosis

In ADEM, virus isolation or serological studies are of little aid in diagnosis. A similar clinical–pathological syndrome follows immunization with rabies and Japanese encephalitis vaccines prepared in neural tissues and, in the case of rabies vaccines, has been shown to be associated with an immune response to myelin basic protein. Similar lymphoproliferative responses to myelin basic protein have been shown in postmeasles encephalomyelitis and in postvaricella cerebellar ataxia, indicating an analogous autoimmune mechanism. Indeed, in ADEM, after measles the virus cannot be found in the brain by virus isolation, immunocytochemical staining, or in situ hybridization; in this disease encephalitis occurs without evidence of neuroinvasion.

Slow Infections of the CNS

Chronic inflammatory diseases of the CNS include subacute sclerosing panencephalitis with measles virus, progressive multifocal leukoencephalopathy with JC virus, HIV-associated encephalitis, and myelopathy with HTLV-1 virus. These diseases represent distinct syndromes with unique mechanisms of pathogenesis.

Treatment and Prevention

Specific drug treatments are available only for herpesvirus infections. The incidence of HIV-associated encephalitis has been reduced by antiviral therapy, but whether this represents only a postponement of CNS disease is yet to be determined. Rabies is unique in that postexposure treatment with vaccine and immune globulin can reduce the hazard of disease, but once clinical symptoms have developed no treatment is effective.

Vaccines can prevent measles, mumps, rubella, chickenpox, Japanese encephalitis, and tick-borne virus infections. An unanticipated bonus of measles immunization has been the virtual elimination of subacute sclerosing panencephalitis.

See also–

Acute Disseminated Encephalomyelitis (ADEM); Acute Hemorrhagic Encephalitis; Arboviruses, Encephalitis Caused by; Central Nervous System Infections, Overview; Human Herpes viruses; Measles Virus, Central Nervous System Complications of; Meningitis, Viral; Rabies Virus