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 brain flaviviruses, and bunyaviruses) spread to the brain from the blood. 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 generalized consciousness, greater frequency of generalized seizures, and multifocal signs. seizures, and multifocal signs.

At times, however, arbovirus or any other form of At times, however, arbovirus or any other form of encephalitis may localize to the temporal areas, encephalitis may localize to the temporal areas, producing signs very similar to those of herpes producing signs very similar to those of herpes simplex virus encephalitis.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 etiology encephalitis or aseptic meningitis of uncertain etiology is first suspected.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 the not universally present nor are they specific to the disease.disease.

Viruses are occasionally isolated directly from CSF Viruses are occasionally isolated directly from CSF or from other tissues but are identified in fewer than or from other tissues but are identified in fewer than half of the cases.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 findings, and sometimes a mass effect, but these findings, like the CSF and EEG changes, are not like the CSF and EEG changes, are not diagnostic. 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.

Viruses that Cause EncephalitisViruses that Cause Encephalitis

Herpes Simplex VirusesHerpes Simplex Viruses Herpes encephalitis is rare. However, it is the most Herpes encephalitis is rare. However, it is the most

common sporadic (non-epidemic), acute, focal common sporadic (non-epidemic), acute, focal hemorrhagic, necrotizing encephalitis. hemorrhagic, necrotizing encephalitis.

The incidence of herpes simplex encephalitis is The incidence of herpes simplex encephalitis is about 1 in 250,000 to 1 in 500,000 per year. about 1 in 250,000 to 1 in 500,000 per year. Neonatal HSV infection occurs more frequently with Neonatal HSV infection occurs more frequently with an incidence of 1/3000 to 1/10,000 deliveries. an incidence of 1/3000 to 1/10,000 deliveries.

The infection of neonates may occur intrauterine, The infection of neonates may occur intrauterine, during parturition, or postnatally by breast- feeding, during parturition, or postnatally by breast- feeding, from father to child and by nosocomial transmission. from father to child and by nosocomial transmission.

Herpes encephalitis can occur during the Herpes encephalitis can occur during the primary infection or during recurrent infection. primary infection or during recurrent infection.

The disease affects all ages and all sexes The disease affects all ages and all sexes equally and it has no seasonal variation.equally and it has no seasonal variation.

There is preponderance in Caucasians who There is preponderance in Caucasians who

account for up to 95 percent of proven cases. account for up to 95 percent of proven cases.

Prognosis Prognosis

• 70% die if untreated 70% die if untreated • Prognosis is very bad if consciousness is >6 on Prognosis is very bad if consciousness is >6 on

the Glasgow Coma Score. the Glasgow Coma Score. • Permanent neurological sequelae develop Permanent neurological sequelae develop

among survivors. among survivors. • Only 2.5% get normal function back Only 2.5% get normal function back

After recovery, most patients develop severe After recovery, most patients develop severe memory disorder, olfactory hallucinations or memory disorder, olfactory hallucinations or loss of smell, and extreme alterations of loss of smell, and extreme alterations of personality.personality.

EBVEBV

Infectious mononucleosis may produceInfectious mononucleosis may produce- meningoencephalitismeningoencephalitis- acute cerebellar ataxiaacute cerebellar ataxia- transverse myelitistransverse myelitis- ascending myelitis ascending myelitis - psychosis.psychosis.

CytomegalovirusCytomegalovirus Congenital CMV infection is associated with a variety of Congenital CMV infection is associated with a variety of

neurological disorders including microcephaly, neurological disorders including microcephaly, hydrocephalus, seizures, optic atrophy, deafness and motor hydrocephalus, seizures, optic atrophy, deafness and motor deficits. deficits.

Acquired CMV infections have been associated with Acquired CMV infections have been associated with transverse myelitis, brachial plexitis, Guillain-Barré syndrome transverse myelitis, brachial plexitis, Guillain-Barré syndrome and adult encephalitis.and adult encephalitis.

CMV causes polyradiculopathy and myelitis in AIDS patientsCMV causes polyradiculopathy and myelitis in AIDS patients

Neurologic Complications Neurologic Complications of Varicella -Zoster Virus of Varicella -Zoster Virus

InfectionInfection

Varicella in the Varicella in the Immunocompetent HostImmunocompetent Host

Serious neurologic complications occur in <1% Serious neurologic complications occur in <1% of cases:of cases: Aseptic meningitisAseptic meningitis Cerebellar ataxiaCerebellar ataxia Transverse myelitisTransverse myelitis EncephalitisEncephalitis Guillain-Barré syndromeGuillain-Barré syndrome Arterial ischemic strokesArterial ischemic strokes Optic neuritisOptic neuritis

Varicella Encephalitis - 1Varicella Encephalitis - 1 IncidenceIncidence

1-2/10,000 cases of varicella1-2/10,000 cases of varicella Incidence is highest in adults and infantsIncidence is highest in adults and infants

PresentationPresentation Symptoms usually appear about one week after Symptoms usually appear about one week after

rash (though may be earlier or later). rash (though may be earlier or later). Acute or gradual onset.Acute or gradual onset. Fever, headache, vomiting, altered mental statusFever, headache, vomiting, altered mental status Focal neurologic findings, hyper/ hyporeflexia, Focal neurologic findings, hyper/ hyporeflexia,

hemiparesis, and sensory changeshemiparesis, and sensory changes Seizures 29-52% of casesSeizures 29-52% of cases

Varicella Encephalitis - 2Varicella Encephalitis - 2 PathogenesisPathogenesis

Role of active viral replication in CNS?Role of active viral replication in CNS? Pathologic findings are more consistent with a post-Pathologic findings are more consistent with a post-

infectious demyelinating process. Inclusion bodies infectious demyelinating process. Inclusion bodies are rarely seen.are rarely seen.

PrognosisPrognosis Mortality of about 5-10% (higher mortality in older Mortality of about 5-10% (higher mortality in older

literature probably due to Reye’s syndrome)literature probably due to Reye’s syndrome) 10-20% of survivors will have neurologic sequelae10-20% of survivors will have neurologic sequelae

TherapyTherapy IV acyclovir recommended, but no prospective dataIV acyclovir recommended, but no prospective data

Varicella with Cerebellar AtaxiaVaricella with Cerebellar Ataxia Incidence Incidence - 1/4000 cases of varicella- 1/4000 cases of varicella PresentationPresentation

Ataxia usually develops simultaneously with rash (can Ataxia usually develops simultaneously with rash (can precede the rash)precede the rash)

Ataxia is accompanied by headache, vomiting and Ataxia is accompanied by headache, vomiting and lethargylethargy

25% have fever, nuchal rigidity, and nystagmus25% have fever, nuchal rigidity, and nystagmus Seizures are rareSeizures are rare

Prognosis Prognosis Self-limited disease, most patients improve in 1-3 weeksSelf-limited disease, most patients improve in 1-3 weeks Virtually all recover without sequelaeVirtually all recover without sequelae

DiagnosisDiagnosis Clinical diagnosis is sufficient in typical casesClinical diagnosis is sufficient in typical cases

Pediatric Arterial Ischemic Pediatric Arterial Ischemic Stroke SyndromesStroke Syndromes

Immunocompetent children (median age of 5 Immunocompetent children (median age of 5 years) present with acute hemiplegiayears) present with acute hemiplegia

Median interval between varicella and onset of Median interval between varicella and onset of neurologic deficits is about 2 monthsneurologic deficits is about 2 months

CT/MRI show unilateral infarcts of deep structures CT/MRI show unilateral infarcts of deep structures (e.g., basal ganglia, internal capsule)(e.g., basal ganglia, internal capsule)

Angiography demonstrates vasculopathy of the Angiography demonstrates vasculopathy of the branches of the middle cerebral arterybranches of the middle cerebral artery

Outcome is frequently good (better than adults)Outcome is frequently good (better than adults)

Neurologic Complications of Herpes ZosterNeurologic Complications of Herpes Zoster Postherpetic neuralgia – pathology in the Postherpetic neuralgia – pathology in the

central and peripheral nervous systemcentral and peripheral nervous system Cranial nerve syndromes (e.g., Ramsay-Hunt, Cranial nerve syndromes (e.g., Ramsay-Hunt,

Bell’s palsy)Bell’s palsy) Motor neuropathiesMotor neuropathies Retinal necrosisRetinal necrosis Large-vessel encephalitis (granulomatous Large-vessel encephalitis (granulomatous

arteritis)arteritis)- Delayed contralateral hemiplegia- Delayed contralateral hemiplegia

Chronic small-vessel encephalitis (immuno -Chronic small-vessel encephalitis (immuno -compromised host)compromised host)

Herpes Zoster Ophthalmicus with Delayed Herpes Zoster Ophthalmicus with Delayed Contralateral HemiparesisContralateral Hemiparesis

Reported in normal and immunocompromised Reported in normal and immunocompromised patientspatients

Usual onset is at about seven weeks (up to 6 Usual onset is at about seven weeks (up to 6 months) after ophthalmic zostermonths) after ophthalmic zoster

Presents as a stroke with headache and Presents as a stroke with headache and hemiplegia (contralateral to the zoster)hemiplegia (contralateral to the zoster)

Mortality of 20-25% Mortality of 20-25% High probability of neurologic sequelaeHigh probability of neurologic sequelae

Zoster Sine HerpeteZoster Sine Herpete Radicular neuropathic pain in a dermatomal Radicular neuropathic pain in a dermatomal

distribution distribution without without cutaneous eruptioncutaneous eruption Pathogenesis – VZV reactivation in ganglion, Pathogenesis – VZV reactivation in ganglion,

but transaxonal spread of virus to skin halted but transaxonal spread of virus to skin halted by host immune response?by host immune response?

Prevalence unknownPrevalence unknown Difficult to diagnose and a few cases have Difficult to diagnose and a few cases have

been linked to VZV by 4-fold antibody rises or been linked to VZV by 4-fold antibody rises or positive CSF PCR for VZV DNApositive CSF PCR for VZV DNA

Cercopithecine Herpes Virus 1 Cercopithecine Herpes Virus 1

( B virus)( B virus) The only monkey virus pathogenic to humansThe only monkey virus pathogenic to humans Most human cases are associated with Rhesus Most human cases are associated with Rhesus

monkey bitesmonkey bites Unusual biological properties, particularly the Unusual biological properties, particularly the

high propensity to cause neurological diseasehigh propensity to cause neurological disease Following an animal bite by 3-5 days local Following an animal bite by 3-5 days local

inflammation and lymhangitis developinflammation and lymhangitis develop Transverse myelitis is a prominent neurological Transverse myelitis is a prominent neurological

findingfinding

The disease ultimately progresses to the brain The disease ultimately progresses to the brain where all regions of the brain can be involved where all regions of the brain can be involved without of evidence of localization to any particular without of evidence of localization to any particular regionregion

Hemorrhagic foci, necrosis, and inflammatory Hemorrhagic foci, necrosis, and inflammatory changes with edema and degeneration of motor changes with edema and degeneration of motor neuronsneurons

There can be evidence of myelitis, encephalitis, or There can be evidence of myelitis, encephalitis, or encephalomyelitisencephalomyelitis

Other organs like the liver and the lung can be Other organs like the liver and the lung can be involved as a result of transient viremiainvolved as a result of transient viremia

Clinically, early stage of vesicular eruption is Clinically, early stage of vesicular eruption is accompanied by fever, myalgia, vomiting, cramping, accompanied by fever, myalgia, vomiting, cramping, meningeal irritation and cranial nerve signs such as meningeal irritation and cranial nerve signs such as nystagmus and diplopianystagmus and diplopia

Neurological symptoms develop very rapidly with Neurological symptoms develop very rapidly with altered sensation, hyperesthesia, and /or parasthesia altered sensation, hyperesthesia, and /or parasthesia of the limbs usually preceding weakness, areflexia, of the limbs usually preceding weakness, areflexia, and flaccid paralysisand flaccid paralysis

Progression to decreased levels of consciousness, Progression to decreased levels of consciousness, altered mentation, respiratory depression, seizures, altered mentation, respiratory depression, seizures, and ultimately neurological death. Most survivors have and ultimately neurological death. Most survivors have serious brain damageserious brain damage

Measles EncephalitisMeasles Encephalitis Rare Rare Encephalitis is an infrequent complication of Encephalitis is an infrequent complication of

measles occurring in approximately 1 in 1000 measles occurring in approximately 1 in 1000 in natural infections. in natural infections.

Season: winter and spring Season: winter and spring Measles encephalitis has a mortality rate of Measles encephalitis has a mortality rate of

10%. 10%. Approximately 60 percent of survivors are left Approximately 60 percent of survivors are left

with permanent neurological damage. with permanent neurological damage.

Subacute Sclerosing Panencephalitis (SSPE)Subacute Sclerosing Panencephalitis (SSPE)

- A rare (7 x 10- A rare (7 x 10-6-6), late complication of measles.), late complication of measles. - It has been associated with a defective or - It has been associated with a defective or

absent M protein. absent M protein.

- Both white matter and gray matter are affected.- Both white matter and gray matter are affected. - Virus replication is defective, and virus can be - Virus replication is defective, and virus can be

recovered only by co-cultivation of brain tissue.recovered only by co-cultivation of brain tissue.

- Virus spreads from cell-to-cell (no budding). - Virus spreads from cell-to-cell (no budding).

SSPE ManifestationsSSPE Manifestations

- Mental deterioration - Mental deterioration - Alternations in personality - Alternations in personality - Clumsiness and poor school performance - Clumsiness and poor school performance - Progressive spasticity.- Progressive spasticity. - Myoclonic episodes and salaam-like seizures. - Myoclonic episodes and salaam-like seizures. - Optic atrophy and akinetic mutism.- Optic atrophy and akinetic mutism. - Inevitably fatal- Inevitably fatal

Progressive Rubella PanencephalitisProgressive Rubella Panencephalitis ((PRPPRP))

An unusual late-onset rubella encephalitis following An unusual late-onset rubella encephalitis following congenital rubella congenital rubella

a prolonged asymptomatic period, followed by neural a prolonged asymptomatic period, followed by neural deterioration during the second decade of life. deterioration during the second decade of life.

These include behavioral changes, intellectual decline, These include behavioral changes, intellectual decline, ataxia, spasticity, and sometimes seizures. ataxia, spasticity, and sometimes seizures.

It is inevitably fatal within 8 years.It is inevitably fatal within 8 years.

PRP may also be a very rare late complication of PRP may also be a very rare late complication of natural childhood rubella.natural childhood rubella.

Mumps EncephalitisMumps Encephalitis Rare Rare Season: winter and spring Season: winter and spring Most patients with mumps encephalitis make Most patients with mumps encephalitis make

a complete recovery. a complete recovery. Deafness, epilepsy, and/or mental retardation Deafness, epilepsy, and/or mental retardation

may occur. may occur. In mumps, CNS involvement may be primary In mumps, CNS involvement may be primary

or post infectious.or post infectious.

Major Arboviruses That Cause Major Arboviruses That Cause EncephalitisEncephalitis

FlaviviridaeFlaviviridae Japanese encephalitis virusJapanese encephalitis virus St. Louis encephalitis virusSt. Louis encephalitis virus West NileWest Nile

TogaviridaeTogaviridae Eastern equine encephalitis virusEastern equine encephalitis virus Western equine encephalitis virusWestern equine encephalitis virus Venezuelan equine encephalitis virusVenezuelan equine encephalitis virus

BunyaviridaeBunyaviridae La Crosse encephalitis virusLa Crosse encephalitis virus

Arbovirus Clinical Picture: Initial SignsArbovirus Clinical Picture: Initial Signs

HeadacheHeadache Malaise Malaise Anorexia Anorexia Nausea and VomitingNausea and Vomiting Abdominal painAbdominal pain

Developing CNS SignsDeveloping CNS Signs Altered LOC – mild lethargy to deep coma.Altered LOC – mild lethargy to deep coma. AMS – confused, delirious, disoriented.AMS – confused, delirious, disoriented. Mental aberrations: Mental aberrations:

hallucinationshallucinations agitationagitation personality change personality change behavioral disorders behavioral disorders occasionally frank psychosisoccasionally frank psychosis

Focal or general seizures in >50% of severe Focal or general seizures in >50% of severe cases.cases.

Severe neurological deficits.Severe neurological deficits.

Neurological SignsNeurological Signs Virtually every possible focal neurological Virtually every possible focal neurological

disturbance has been reported.disturbance has been reported. Most CommonMost Common

AphasiaAphasia Ataxia Ataxia Hemiparesis with hyperactive tendon reflexesHemiparesis with hyperactive tendon reflexes Involuntary movementsInvoluntary movements Cranial nerve deficits (ocular palsies, facial Cranial nerve deficits (ocular palsies, facial

weakness)weakness)

Japanese EncephalitisJapanese Encephalitis FlavivirusFlavivirus Rural Asia, rice paddiesRural Asia, rice paddies Vector- Culex mosquitoesVector- Culex mosquitoes Reservoir: birds, pigs, other animalsReservoir: birds, pigs, other animals Ache, behavioral and mental status changesAche, behavioral and mental status changes Seizures, paralysis, cranial nerves, tremor, Seizures, paralysis, cranial nerves, tremor,

ataxiaataxia Mortality- 25%, sequelae - 75%,Mortality- 25%, sequelae - 75%, Vaccine- 2-3 doses, 85-98% effective- Vaccine- 2-3 doses, 85-98% effective-

travelers?travelers?

St. Louis EncephalitisSt. Louis Encephalitis FlavivirusFlavivirus Most common Most common mosquito-transmitted mosquito-transmitted

human pathogen in the human pathogen in the US and CanadaUS and Canada

Leading cause of Leading cause of epidemic flaviviral epidemic flaviviral encephalitisencephalitis

Fever, headache, Fever, headache, meningitis, encephalitismeningitis, encephalitis

Tremor, ataxia, cranial Tremor, ataxia, cranial nervesnerves

Mortality 7%, >60 years Mortality 7%, >60 years old 20%, sequelaeold 20%, sequelae

West Nile VirusWest Nile Virus FlavivirusFlavivirus Primary host – wild birdsPrimary host – wild birds Principal arthropod vector Principal arthropod vector

– mosquitoes– mosquitoes Geographic distribution - Geographic distribution -

Africa, Middle East, Africa, Middle East, Western Asia, Europe, Western Asia, Europe, Australia, North America, Australia, North America, Central AmericaCentral America

Clinical Features of WNV Clinical Features of WNV InfectionInfection 5-15 day incubation period post mosquito

bite Typical case is mild: fever, headache, myalgia/ arthralgia, and anorexia (symptoms last 3-6 days) Sore throat and GI complaints (N/V/D) may occur Occasional maculopapular rash (trunk>extremities) In elderly or patients with co-morbidities, it may progress to aseptic meningitis or encephalitis Rare complications include myocarditis and pancreatitis

Neurological involvement in severe cases• Encephalitis• Meningitis• Meningoencephalitis• Anterior myelitis• Encephalopolyradiculitis

Clinical Features of WNV Clinical Features of WNV InfectionInfection

WNV Encephalitis: PrognosisWNV Encephalitis: Prognosis• Recovery is usually complete in non-Recovery is usually complete in non-

hospitalized patientshospitalized patients

• Less rapid recovery in adults compared to Less rapid recovery in adults compared to children, occasionally with residual deficitschildren, occasionally with residual deficits

• Of hospitalized patients, 50% recovered Of hospitalized patients, 50% recovered

but not to full functional level whereas 40% but not to full functional level whereas 40% recovered fullyrecovered fully

• Most fatalities in patients > 50 y.o.Most fatalities in patients > 50 y.o.

Eastern Equine EncephalitisEastern Equine Encephalitis Genus Alphavirus, family Genus Alphavirus, family

TogavirusTogavirus Eastern and Gulf coasts, summer, Eastern and Gulf coasts, summer,

fallfall Vector- Culiseta melanuriaVector- Culiseta melanuria Birds, horses, humans of all ages; Birds, horses, humans of all ages;

high case rateshigh case rates Fever, headache, mental status, Fever, headache, mental status,

seizures, comaseizures, coma CSF Leukocytosis, hyponatremiaCSF Leukocytosis, hyponatremia MRI- basal ganglia, thalamus, MRI- basal ganglia, thalamus,

brainstembrainstem High mortality >50%, sequelaeHigh mortality >50%, sequelae

Western Equine EncephalitisWestern Equine Encephalitis Genus Alphavirus, family Genus Alphavirus, family

togavirustogavirus US, Canada, summer, fallUS, Canada, summer, fall Vector- Culex tarsalis, rural, Vector- Culex tarsalis, rural,

irrigationirrigation Birds, horses, humansBirds, horses, humans Case rates- adults- 1:1000, Case rates- adults- 1:1000,

infants 1:1infants 1:1 Fever, sore throat, vertigoFever, sore throat, vertigo CSF WBC 50-500, increased CSF WBC 50-500, increased

proteinprotein Mortality 2-5%, sequelae in Mortality 2-5%, sequelae in

infantsinfants

Venezuelan Equine EncephalitisVenezuelan Equine Encephalitis Similar to EEE and WEESimilar to EEE and WEE Family: Togaviridae, Genus: AlphavirusFamily: Togaviridae, Genus: Alphavirus Vector; MosquitoesVector; Mosquitoes Reservoir: bats, birds, rodents, equine and Reservoir: bats, birds, rodents, equine and

small tropical mammals.small tropical mammals. Aerosol TransmissionAerosol Transmission, person to person , person to person

transmission is possibletransmission is possible Prognosis:Prognosis: Less than 1% death rate in humansLess than 1% death rate in humans High death rate reported in horsesHigh death rate reported in horses

La Crosse Virus (LCV)La Crosse Virus (LCV) Bunyaviridae, transmitted by an Bunyaviridae, transmitted by an

AedesAedes species. species. The majority of infections are The majority of infections are

subclinical or result in mild subclinical or result in mild illness. illness. 

Most cases occur in children Most cases occur in children under 16 years of ageunder 16 years of age

Frank encephalitis, progressing to Frank encephalitis, progressing to seizures and coma, is seen during seizures and coma, is seen during severe illness. severe illness.

TheThe mortality rate is <1%. mortality rate is <1%.  Neurological sequelae resolve Neurological sequelae resolve

within several years. within several years.

Nipah Virus EncephalitisNipah Virus Encephalitis ParamyxovirusParamyxovirus Malaysia and Singapore; pig contactMalaysia and Singapore; pig contact Adult males- pig farmers and abattoirsAdult males- pig farmers and abattoirs Pathology: necrotizing vasculitis, syncytiaPathology: necrotizing vasculitis, syncytia MRI- focal white matter lesionsMRI- focal white matter lesions Leukopenia, lymphopenia, hyponatremiaLeukopenia, lymphopenia, hyponatremia Mortality 40%Mortality 40%

Summary – Confirmed and Probable Summary – Confirmed and Probable Human Cases in the USHuman Cases in the US

VirusVirus YearsYears Total casesTotal cases

Eastern EquineEastern Equine 1964-20001964-2000 182182

Western EquineWestern Equine 1964-20001964-2000 649649

La CrosseLa Crosse 1964-20001964-2000 2,7762,776

St. LouisSt. Louis 1964-20001964-2000 4,4824,482

West NileWest Nile 1999-20101999-2010 > 10.000> 10.000

Progressive MultifocalProgressive Multifocal Leukoencephalopathy (PML)Leukoencephalopathy (PML)

An end-stage complication of HIV, caused by An end-stage complication of HIV, caused by the JC virusthe JC virus

   PML is rare in the general community, but PML is rare in the general community, but

relatively common in HIV infection (affecting relatively common in HIV infection (affecting 4% of all AIDS patients). 4% of all AIDS patients).

Routine testing for HIV should be considered Routine testing for HIV should be considered for any patient with PMLfor any patient with PML

   Evolution occurs over weeks to monthsEvolution occurs over weeks to months

Initially, afebrile, alert, no headacheInitially, afebrile, alert, no headache

Progressively impaired speech, vision, motor Progressively impaired speech, vision, motor functionfunction

Cranial nerve deficit and cortical blindnessCranial nerve deficit and cortical blindness

Cognition affected relatively lateCognition affected relatively late Coma and death within a year of diagnosisComa and death within a year of diagnosis

CT brain scan may be normal or remarkable for CT brain scan may be normal or remarkable for areas of diminished density or demyelinationareas of diminished density or demyelination

PCR of CSF for detection of JC virus: positive in PCR of CSF for detection of JC virus: positive in about 60% of the casesabout 60% of the cases

Differential diagnosis:Differential diagnosis: ToxoplasmosisToxoplasmosis Primary CNS lymphomaPrimary CNS lymphoma  

Definitive diagnosis is by brain biopsyDefinitive diagnosis is by brain biopsy

DiagnosticsDiagnostics

HIV-associated dementia (HAD)HIV-associated dementia (HAD) It is the first manifestation of HIV disease in It is the first manifestation of HIV disease in

up to 10% of patientsup to 10% of patients Afebrile; general lethargyAfebrile; general lethargy Triad of cognitive, motor and behavioral Triad of cognitive, motor and behavioral

dysfunctiondysfunction EarlyEarly - concentration and memory deficits, - concentration and memory deficits,

inattention, motor- uncoordination, ataxia, inattention, motor- uncoordination, ataxia, depression, emotional labilitydepression, emotional lability

LateLate - global dementia, paraplegia, mutism - global dementia, paraplegia, mutism