ViralViral EncephalitisEncephalitis

IntroductionIntroduction Encephalitis is an acute inflammatory process affecting the Encephalitis is an acute inflammatory process affecting the

brainbrain

Encephalitis can be caused by bacterial infection and, most Encephalitis can be caused by bacterial infection and, most often, by viral infection with over 100 viruses implicated often, by viral infection with over 100 viruses implicated worldwide. worldwide.

Encephalitis is the most serious manifestation of viral CNS Encephalitis is the most serious manifestation of viral CNS infection. infection.

Encephalitis is distinguished from aseptic meningitis by the Encephalitis is distinguished from aseptic meningitis by the extent and severity of cerebral dysfunction, independent of extent and severity of cerebral dysfunction, independent of signs of meningeal inflammation.signs of meningeal inflammation.

IntroductionIntroduction Many more cases of encephalitis actually occur each Many more cases of encephalitis actually occur each

year than those reported.year than those reported.

Incidence of 3.5-7.4 per 100,000 persons per yearIncidence of 3.5-7.4 per 100,000 persons per year

Symptoms Symptoms FeverFever HeadacheHeadache Behavioral changesBehavioral changes Altered level of consciousnessAltered level of consciousness Focal neurologic deficitsFocal neurologic deficits SeizuresSeizures

Causes of Viral EncephalitisCauses of Viral Encephalitis Herpes viruses: HSV-1, HSV-2, VZV, CMV, EBV, Herpes viruses: HSV-1, HSV-2, VZV, CMV, EBV,

HHV-6 HHV-6 AdenovirusesAdenoviruses Influenza Influenza Enteroviruses including poliovirusesEnteroviruses including polioviruses Measles, mumps, and rubella virusesMeasles, mumps, and rubella viruses Rabies virusRabies virus Arboviruses: Japanese encephalitis, St. Louis Arboviruses: Japanese encephalitis, St. Louis

encephalitis, West Nile encephalitis, Eastern and encephalitis, West Nile encephalitis, Eastern and Western equine encephalitis, Venezuelan equine Western equine encephalitis, Venezuelan equine encephalitis, Lacrosse encephalitis, Colorado tick encephalitis, Lacrosse encephalitis, Colorado tick fever, and lymphocytic choriomeningitis viruses fever, and lymphocytic choriomeningitis viruses

Etiology and PathologyEtiology and Pathology There are two types of encephalitis, There are two types of encephalitis, primaryprimary which which

is caused by direct viral infection, and is caused by direct viral infection, and secondarysecondary which results from complication of a current or a which results from complication of a current or a recent viral infection.recent viral infection.

Primary infection can be focal or diffuse and Primary infection can be focal or diffuse and secondary encephalitis is acute and disseminated secondary encephalitis is acute and disseminated that often occurs 2 to 3 weeks following the initial that often occurs 2 to 3 weeks following the initial infectioninfection

Most cases of primary encephalitis are caused by Most cases of primary encephalitis are caused by enteroviruse, herpes viruses, arboviruses and enteroviruse, herpes viruses, arboviruses and rabies virusrabies virus

Secondary encephalitis, usually a complication of viral Secondary encephalitis, usually a complication of viral infection, is considered to have an immunologic infection, is considered to have an immunologic mechanism. mechanism.

Examples are encephalitides secondary to measles, Examples are encephalitides secondary to measles, chickenpox, influenza, rubella, vaccinia, and many chickenpox, influenza, rubella, vaccinia, and many other less well defined viral infections. other less well defined viral infections.

These parainfectious or postinfectious encephalitides These parainfectious or postinfectious encephalitides typically develop 5 to 20 days after onset of illness typically develop 5 to 20 days after onset of illness and are characterized by perivascular demyelination and are characterized by perivascular demyelination seen at autopsy; a virus is rarely isolated from the seen at autopsy; a virus is rarely isolated from the brain. brain.

Very rarely, encephalitis or other encephalopathies Very rarely, encephalitis or other encephalopathies occur as a late consequence of viral infections. occur as a late consequence of viral infections.

The best known is subacute sclerosing The best known is subacute sclerosing panencephalitis and progressive rubella panencephalitis and progressive rubella panencephalitis, associated with measles and panencephalitis, associated with measles and rubella viruses respectively.rubella viruses respectively.

Direct viral invasion of the brain is likely to result in Direct viral invasion of the brain is likely to result in neuronal necrosis, frequently with visible inclusion neuronal necrosis, frequently with visible inclusion bodies. bodies.

In parainfectious and postinfectious In parainfectious and postinfectious encephalomyelitis, perivenous demyelinating encephalomyelitis, perivenous demyelinating lesions are characteristic.lesions are characteristic.

Epidemiology Viruses causing primary encephalitis may Viruses causing primary encephalitis may

spread in epidemics (arboviruses, polioviruses, spread in epidemics (arboviruses, polioviruses, echoviruses, and coxsackieviruses) or echoviruses, and coxsackieviruses) or sporadically (herpes simplex, varicella -zoster, sporadically (herpes simplex, varicella -zoster, and mumps viruses). and mumps viruses).

Mosquito-borne arboviral encephalitides (St. Mosquito-borne arboviral encephalitides (St. Louis, eastern and western equine, and Louis, eastern and western equine, and Lacrosse) infect humans only during warm Lacrosse) infect humans only during warm weather.weather.

PathogenesisPathogenesis The pathogenesis of encephalitis due to herpes The pathogenesis of encephalitis due to herpes

simplex virus, arboviruses, and rabies virus is different simplex virus, arboviruses, and rabies virus is different for each virus. for each virus.

In neonates, herpetic encephalitis is predominantly In neonates, herpetic encephalitis is predominantly due to HSV-2, and irrespective of serotype, the acute due to HSV-2, and irrespective of serotype, the acute generalized necrotizing encephalitis is often generalized necrotizing encephalitis is often accompanied by evidence of systemic infection of the accompanied by evidence of systemic infection of the liver, adrenals, and other organs. liver, adrenals, and other organs.

In children and adults, herpetic encephalitis is caused In children and adults, herpetic encephalitis is caused by HSV-1 and is usually localized. by HSV-1 and is usually localized.

HSV Encephalitis in an immune host results either HSV Encephalitis in an immune host results either from the entry of a new virus, possibly across the from the entry of a new virus, possibly across the olfactory mucosa, or from reactivation of latent virus in olfactory mucosa, or from reactivation of latent virus in the trigeminal ganglia, which spread along sensory the trigeminal ganglia, which spread along sensory nerve fibers to the base of the anterior and middle nerve fibers to the base of the anterior and middle fossa.fossa.

In either case, infection is localized to the orbital, In either case, infection is localized to the orbital,

frontal, and medial temporal lobes. frontal, and medial temporal lobes.

Because the host is immune, virus presumably Because the host is immune, virus presumably spreads from cell to cell over a contiguous localized spreads from cell to cell over a contiguous localized area, infecting neurons and glial cells. area, infecting neurons and glial cells.

In contrast, arboviruses (mainly togaviruses, In contrast, arboviruses (mainly togaviruses, flaviviruses, and bunyaviruses) spread to the flaviviruses, and bunyaviruses) spread to the brain from the blood. brain from the blood.

The systemic infection causes few, if any, The systemic infection causes few, if any, symptoms. symptoms.

Depending on the virus, between 1 in 20 and 1 in Depending on the virus, between 1 in 20 and 1 in 1000 infections are complicated by CNS infection. 1000 infections are complicated by CNS infection.

The encephalitis is diffuse, but is localized largely The encephalitis is diffuse, but is localized largely to neurons.to neurons.

Clinical Course of EncephalitisClinical Course of Encephalitis Encephalitis may produce fever and malaise Encephalitis may produce fever and malaise

without meningeal signs, or it may cause without meningeal signs, or it may cause meningeal signs with cerebral dysfunction. meningeal signs with cerebral dysfunction.

As brain parenchyma becomes involved, there As brain parenchyma becomes involved, there is an alteration of consciousness; personality is an alteration of consciousness; personality changes, ataxia, seizures, cranial nerve changes, ataxia, seizures, cranial nerve abnormalities, and paralysis followed by coma.abnormalities, and paralysis followed by coma.

In addition to headache and fever, In addition to headache and fever, hallucinations and bizarre behavior are hallucinations and bizarre behavior are common, and these are sometimes confused common, and these are sometimes confused with psychiatric illness.with psychiatric illness.

Focal seizures and hemiparesis are frequent, Focal seizures and hemiparesis are frequent,

and aphasia develops if the disease is localized and aphasia develops if the disease is localized to the dominant temporal lobe.to the dominant temporal lobe.

Herpes simplex virus-1 encephalitis in the non-Herpes simplex virus-1 encephalitis in the non-neonate typically causes focal signs that may neonate typically causes focal signs that may evolve over a period of up to 1 or 2 weeks.evolve over a period of up to 1 or 2 weeks.

Herpes simplex encephalitis is clinically similar Herpes simplex encephalitis is clinically similar to other viral encephalitides but is strongly to other viral encephalitides but is strongly suggested by repeated seizures occurring early suggested by repeated seizures occurring early in the course of disease and by signs indicating in the course of disease and by signs indicating temporal or frontal lobe involvement. temporal or frontal lobe involvement.

Arbovirus infections cause a more diffuse and Arbovirus infections cause a more diffuse and acute disease, with a rapid depression of acute disease, with a rapid depression of consciousness, greater frequency of consciousness, greater frequency of generalized seizures, and multifocal signs. generalized seizures, and multifocal signs.

At times, however, arbovirus or any other form At times, however, arbovirus or any other form of encephalitis may localize to the temporal of encephalitis may localize to the temporal areas, producing signs very similar to those of areas, producing signs very similar to those of herpes simplex virus encephalitis.herpes simplex virus encephalitis.

DiagnosisDiagnosis Viral infections must be differentiated from other Viral infections must be differentiated from other

infections (bacterial, rickettsial, spirochetal, and infections (bacterial, rickettsial, spirochetal, and parasitic) and noninfectious disordersparasitic) and noninfectious disorders

The major problem is to distinguish viral The major problem is to distinguish viral

encephalitis from acute or partially treated encephalitis from acute or partially treated bacterial meningitisbacterial meningitis

Diagnosis is usually based on CSF changes, Diagnosis is usually based on CSF changes, including normal glucose and absence of including normal glucose and absence of bacteria on culture.bacteria on culture.

Cultures (eg, from the nasopharynx or stool) and Cultures (eg, from the nasopharynx or stool) and attention to epidemic agents in the community may attention to epidemic agents in the community may help. help.

Because of public health implications, serum should Because of public health implications, serum should be drawn and preserved whenever the diagnosis of be drawn and preserved whenever the diagnosis of encephalitis or aseptic meningitis of uncertain encephalitis or aseptic meningitis of uncertain etiology is first suspected.etiology is first suspected.

The CSF examination in acute encephalitis may or The CSF examination in acute encephalitis may or may not show an increase in pressure, but usually may not show an increase in pressure, but usually reveals an inflammatory response of mononuclear reveals an inflammatory response of mononuclear cells.cells.

RBCs in CSF after an atraumatic spinal tap RBCs in CSF after an atraumatic spinal tap suggest herpes simplex infection because of the suggest herpes simplex infection because of the necrotizing pathology of the disease, but they are necrotizing pathology of the disease, but they are not universally present nor are they specific to not universally present nor are they specific to the disease.the disease.

Viruses are occasionally isolated directly from Viruses are occasionally isolated directly from CSF or from other tissues but are identified in CSF or from other tissues but are identified in fewer than half of the cases.fewer than half of the cases.

Herpes simplex virus is rarely isolated from CSF Herpes simplex virus is rarely isolated from CSF but it can be precisely identified by polymerase but it can be precisely identified by polymerase chain reaction in CSF. chain reaction in CSF.

A prompt, definitive diagnosis of HSV-1 A prompt, definitive diagnosis of HSV-1 encephalitis requires brain biopsy of the area encephalitis requires brain biopsy of the area where typical encephalitis with inclusion bodies where typical encephalitis with inclusion bodies is seen.is seen.

The diagnosis is confirmed by either The diagnosis is confirmed by either immunocytochemical staining of herpes simplex immunocytochemical staining of herpes simplex virus antigens in brain cells or virus isolation.virus antigens in brain cells or virus isolation.

Biopsy is, however, rarely indicated and should Biopsy is, however, rarely indicated and should be reserved for patients who are worsening, be reserved for patients who are worsening, have an undiagnosed lesion after CT or MRI, or have an undiagnosed lesion after CT or MRI, or have a poor response to acyclovir.have a poor response to acyclovir.

The electroencephalogram (EEG) is helpful in The electroencephalogram (EEG) is helpful in the diagnosis of herpes simplex virus the diagnosis of herpes simplex virus encephalitis because periodic spikes and slow encephalitis because periodic spikes and slow waves often localize to the infected temporal waves often localize to the infected temporal lobe. In other forms of encephalitis slowing is lobe. In other forms of encephalitis slowing is more diffuse.more diffuse.

Computerized tomography (CT) in cases of Computerized tomography (CT) in cases of herpes simplex virus encephalitis usually shows herpes simplex virus encephalitis usually shows an attenuated area in the medial temporal lobes an attenuated area in the medial temporal lobes and sometimes a mass effect, but these and sometimes a mass effect, but these findings, like the CSF and EEG changes, are findings, like the CSF and EEG changes, are not diagnostic. not diagnostic.

MRI may detect inferior-frontal and medial-MRI may detect inferior-frontal and medial-

temporal lobe inflammation earlier than EEG, temporal lobe inflammation earlier than EEG, CT, or radionuclide brain scanning, prompting CT, or radionuclide brain scanning, prompting antiviral therapy before neurological antiviral therapy before neurological deterioration occurs.deterioration occurs.

MRI can exclude brain abscess, subdural MRI can exclude brain abscess, subdural

empyema, subdural hematoma, tumor, and empyema, subdural hematoma, tumor, and sagittal sinus thrombosis, which can clinically sagittal sinus thrombosis, which can clinically mimic encephalitis.mimic encephalitis.

Prognosis and TreatmentPrognosis and Treatment The only treatable cause of viral encephalitis is The only treatable cause of viral encephalitis is

Herpes viruses.Herpes viruses. Therefore, until HSV encephalitis is Therefore, until HSV encephalitis is ruled out by PCR, the patient must be treated with ruled out by PCR, the patient must be treated with acyclovir.acyclovir.

The mortality rate varies with etiology, and epidemics The mortality rate varies with etiology, and epidemics due to the same virus vary in severity in different due to the same virus vary in severity in different years. years.

Permanent cerebral sequelae are more likely to occur Permanent cerebral sequelae are more likely to occur in infants and young children improve in a shorter time in infants and young children improve in a shorter time than adults with similar infections.than adults with similar infections.

Permanent sequelae include mental retardation, Permanent sequelae include mental retardation, epilepsy, blindness and deafness. epilepsy, blindness and deafness.

Post-infectious Viral Syndromes of the CNSPost-infectious Viral Syndromes of the CNS Post infectious encephalitis is seen in Post infectious encephalitis is seen in

approximately 1:1000 cases of measles, mumps, approximately 1:1000 cases of measles, mumps, vaccinia, etc., and is immunologically mediated. vaccinia, etc., and is immunologically mediated.

Reye’s syndromeReye’s syndrome follow infections with influenza, follow infections with influenza, varicella, adenovirus and other viruses. It chiefly varicella, adenovirus and other viruses. It chiefly affects children between the ages of 2 and 16. affects children between the ages of 2 and 16.

Guillain-Barré syndromeGuillain-Barré syndrome is an acute is an acute inflammatory demyelinating polyneuropathy often inflammatory demyelinating polyneuropathy often following one of many antecedent viral and non-following one of many antecedent viral and non-viral illness. viral illness.