Transcript Viral Encephalitis

Viral Encephalitis
Introduction

Encephalitis is an acute inflammatory process
affecting the brain

Encephalitis can be caused by bacterial infection and,
most often, by viral infection with over 100 viruses
implicated worldwide.
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Encephalitis is the most serious manifestation of viral
CNS infection.
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Encephalitis is distinguished from aseptic meningitis
by the extent and severity of cerebral dysfunction,
independent of signs of meningeal inflammation.
Introduction
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Many more cases of encephalitis actually occur each
year than those reported.
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Incidence of 3.5-7.4 per 100,000 persons per year
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Symptoms
 Fever
 Headache
 Behavioral changes
 Altered level of consciousness
 Focal neurologic deficits
 Seizures
Causes of Viral Encephalitis
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Herpes viruses: HSV-1, HSV-2, VZV, CMV, EBV,
HHV-6
Adenoviruses
Influenza
Enteroviruses including polioviruses
Measles, mumps, and rubella viruses
Rabies virus
Arboviruses: Japanese encephalitis, St. Louis
encephalitis, West Nile encephalitis, Eastern and
Western equine encephalitis, Venezuelan equine
encephalitis, Lacrosse encephalitis, Colorado tick
fever, and lymphocytic choriomeningitis viruses
Etiology and Pathology

There are two types of encephalitis, primary which
is caused by direct viral infection, and secondary
which results from complication of a current or a
recent viral infection.
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Primary infection can be focal or diffuse and
secondary encephalitis is acute and disseminated
that often occurs 2 to 3 weeks following the initial
infection
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Most cases of primary encephalitis are caused by
enteroviruse, herpes viruses, arboviruses and
rabies virus
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Secondary encephalitis, usually a complication of viral
infection, is considered to have an immunologic
mechanism.
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Examples are encephalitides secondary to measles,
chickenpox, influenza, rubella, vaccinia, and many
other less well defined viral infections.
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These parainfectious or postinfectious encephalitides
typically develop 5 to 20 days after onset of illness and
are characterized by perivascular demyelination seen
at autopsy; a virus is rarely isolated from the brain.
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Very rarely, encephalitis or other encephalopathies
occur as a late consequence of viral infections.
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The best known is subacute sclerosing
panencephalitis and progressive rubella
panencephalitis, associated with measles and
rubella viruses respectively.
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Direct viral invasion of the brain is likely to result in
neuronal necrosis, frequently with visible inclusion
bodies.
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In parainfectious and postinfectious
encephalomyelitis, perivenous demyelinating
lesions are characteristic.
Epidemiology
 Viruses
causing primary encephalitis may
spread in epidemics (arboviruses, polioviruses,
echoviruses, and coxsackieviruses) or
sporadically (herpes simplex, varicella -zoster,
and mumps viruses).
 Mosquito-borne
arboviral encephalitides (St.
Louis, eastern and western equine, and
Lacrosse) infect humans only during warm
weather.
Pathogenesis
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The pathogenesis of encephalitis due to herpes
simplex virus, arboviruses, and rabies virus is different
for each virus.
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In neonates, herpetic encephalitis is predominantly
due to HSV-2, and irrespective of serotype, the acute
generalized necrotizing encephalitis is often
accompanied by evidence of systemic infection of the
liver, adrenals, and other organs.
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In children and adults, herpetic encephalitis is caused
by HSV-1 and is usually localized.
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HSV Encephalitis in an immune host results either
from the entry of a new virus, possibly across the
olfactory mucosa, or from reactivation of latent virus in
the trigeminal ganglia, which spread along sensory
nerve fibers to the base of the anterior and middle
fossa.
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In either case, infection is localized to the orbital,
frontal, and medial temporal lobes.
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Because the host is immune, virus presumably
spreads from cell to cell over a contiguous localized
area, infecting neurons and glial cells.
 In
contrast, arboviruses (mainly togaviruses,
flaviviruses, and bunyaviruses) spread to the
brain from the blood.
 The
systemic infection causes few, if any,
symptoms.
 Depending
on the virus, between 1 in 20 and 1 in
1000 infections are complicated by CNS
infection.
 The
encephalitis is diffuse, but is localized largely
to neurons.
Clinical Course of Encephalitis
 Encephalitis
may produce fever and malaise
without meningeal signs, or it may cause
meningeal signs with cerebral dysfunction.
 As
brain parenchyma becomes involved, there
is an alteration of consciousness; personality
changes, ataxia, seizures, cranial nerve
abnormalities, and paralysis followed by coma.
 In
addition to headache and fever,
hallucinations and bizarre behavior are
common, and these are sometimes confused
with psychiatric illness.
 Focal
seizures and hemiparesis are frequent,
and aphasia develops if the disease is localized
to the dominant temporal lobe.
 Herpes
simplex virus-1 encephalitis in the nonneonate typically causes focal signs that may
evolve over a period of up to 1 or 2 weeks.
 Herpes
simplex encephalitis is clinically similar
to other viral encephalitides but is strongly
suggested by repeated seizures occurring early
in the course of disease and by signs indicating
temporal or frontal lobe involvement.
 Arbovirus
infections cause a more diffuse and
acute disease, with a rapid depression of
consciousness, greater frequency of
generalized seizures, and multifocal signs.
 At
times, however, arbovirus or any other form
of encephalitis may localize to the temporal
areas, producing signs very similar to those of
herpes simplex virus encephalitis.
Diagnosis
 Viral
infections must be differentiated from other
infections (bacterial, rickettsial, spirochetal, and
parasitic) and noninfectious disorders
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major problem is to distinguish viral
encephalitis from acute or partially treated
bacterial meningitis
 Diagnosis
is usually based on CSF changes,
including normal glucose and absence of
bacteria on culture.
 Cultures
(eg, from the nasopharynx or stool)
and attention to epidemic agents in the
community may help.
 Because
of public health implications, serum
should be drawn and preserved whenever the
diagnosis of encephalitis or aseptic meningitis
of uncertain etiology is first suspected.
 The
CSF examination in acute encephalitis may
or may not show an increase in pressure, but
usually reveals an inflammatory response of
mononuclear cells.
 RBCs
in CSF after an atraumatic spinal tap
suggest herpes simplex infection because of
the necrotizing pathology of the disease, but
they are not universally present nor are they
specific to the disease.
 Viruses
are occasionally isolated directly from
CSF or from other tissues but are identified in
fewer than half of the cases.
 Herpes
simplex virus is rarely isolated from
CSF but it can be precisely identified by
polymerase chain reaction in CSF.
A
prompt, definitive diagnosis of HSV-1
encephalitis requires brain biopsy of the area
where typical encephalitis with inclusion bodies
is seen.
 The
diagnosis is confirmed by either
immunocytochemical staining of herpes simplex
virus antigens in brain cells or virus isolation.
 Biopsy
is, however, rarely indicated and should
be reserved for patients who are worsening,
have an undiagnosed lesion after CT or MRI, or
have a poor response to acyclovir.
 The
electroencephalogram (EEG) is helpful in
the diagnosis of herpes simplex virus
encephalitis because periodic spikes and slow
waves often localize to the infected temporal
lobe. In other forms of encephalitis slowing is
more diffuse.
 Computerized
tomography (CT) in cases of
herpes simplex virus encephalitis usually shows
an attenuated area in the medial temporal lobes
and sometimes a mass effect, but these
findings, like the CSF and EEG changes, are
not diagnostic.
 MRI
may detect inferior-frontal and medialtemporal lobe inflammation earlier than EEG,
CT, or radionuclide brain scanning, prompting
antiviral therapy before neurological
deterioration occurs.
 MRI
can exclude brain abscess, subdural
empyema, subdural hematoma, tumor, and
sagittal sinus thrombosis, which can clinically
mimic encephalitis.
Prognosis and Treatment
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The only treatable cause of viral encephalitis is
Herpes viruses. Therefore, until HSV encephalitis is
ruled out by PCR, the patient must be treated with
acyclovir.
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The mortality rate varies with etiology, and epidemics
due to the same virus vary in severity in different
years.
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Permanent cerebral sequelae are more likely to occur
in infants and young children improve in a shorter time
than adults with similar infections.
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Permanent sequelae include mental retardation,
epilepsy, blindness and deafness.
Post-infectious Viral Syndromes of the CNS
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Post infectious encephalitis is seen in
approximately 1:1000 cases of measles, mumps,
vaccinia, etc., and is immunologically mediated.
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Reye’s syndrome follow infections with influenza,
varicella, adenovirus and other viruses. It chiefly
affects children between the ages of 2 and 16.
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Guillain-Barré syndrome is an acute
inflammatory demyelinating polyneuropathy often
following one of many antecedent viral and nonviral illness.
Viruses that Cause Encephalitis
Herpes Simplex Viruses
 Herpes
encephalitis is rare. However, it is the
most common sporadic (non-epidemic), acute,
focal hemorrhagic, necrotizing encephalitis.
 The
incidence of herpes simplex encephalitis is
about 1 in 250,000 to 1 in 500,000 per year.
Neonatal HSV infection occurs more frequently
with an incidence of 1/3000 to 1/10,000
deliveries.
 The
infection of neonates may occur
intrauterine, during parturition, or postnatally by
breast- feeding, from father to child and by
nosocomial transmission.
 Herpes
encephalitis can occur during the
primary infection or during recurrent infection.
 The
disease affects all ages and all sexes
equally and it has no seasonal variation.
 There
is preponderance in Caucasians who
account for up to 95 percent of proven cases.
Prognosis
• 70% die if untreated
• Prognosis is very bad if consciousness is >6 on
the Glasgow Coma Score.
• Permanent neurological sequelae develop
among survivors.
• Only 2.5% get normal function back
 After
recovery, most patients develop severe
memory disorder, olfactory hallucinations or
loss of smell, and extreme alterations of
personality.
EBV
Infectious mononucleosis may produce
- meningoencephalitis
- acute cerebellar ataxia
- transverse myelitis
- ascending myelitis
- psychosis.
Cytomegalovirus
 Congenital
CMV infection is associated with a
variety of neurological disorders including
microcephaly, hydrocephalus, seizures, optic
atrophy, deafness and motor deficits.
 Acquired
CMV infections have been associated
with transverse myelitis, brachial plexitis,
Guillain-Barré syndrome and adult encephalitis.
 CMV
causes polyradiculopathy and myelitis in
AIDS patients
Neurologic Complications
of Varicella -Zoster Virus
Infection
Varicella in the
Immunocompetent Host
 Serious
neurologic complications occur in <1%
of cases:
 Aseptic meningitis
 Cerebellar ataxia
 Transverse myelitis
 Encephalitis
 Guillain-Barré syndrome
 Arterial ischemic strokes
 Optic neuritis
Varicella Encephalitis - 1
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Incidence
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1-2/10,000 cases of varicella
Incidence is highest in adults and infants
Presentation
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Symptoms usually appear about one week after
rash (though may be earlier or later).
Acute or gradual onset.
Fever, headache, vomiting, altered mental status
Focal neurologic findings, hyper/ hyporeflexia,
hemiparesis, and sensory changes
Seizures 29-52% of cases
Varicella Encephalitis - 2
 Pathogenesis
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Role of active viral replication in CNS?
Pathologic findings are more consistent with a postinfectious demyelinating process. Inclusion bodies
are rarely seen.
 Prognosis
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Mortality of about 5-10% (higher mortality in older
literature probably due to Reye’s syndrome)
10-20% of survivors will have neurologic sequelae
 Therapy
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IV acyclovir recommended, but no prospective data
Varicella with Cerebellar Ataxia
 Incidence - 1/4000 cases of varicella
 Presentation
 Ataxia usually develops simultaneously with rash (can
precede the rash)
 Ataxia is accompanied by headache, vomiting and
lethargy
 25% have fever, nuchal rigidity, and nystagmus
 Seizures are rare
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Prognosis
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Self-limited disease, most patients improve in 1-3 weeks
Virtually all recover without sequelae
 Diagnosis
 Clinical diagnosis is sufficient in typical cases
Pediatric Arterial Ischemic
Stroke Syndromes
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Immunocompetent children (median age of 5
years) present with acute hemiplegia
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Median interval between varicella and onset of
neurologic deficits is about 2 months
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CT/MRI show unilateral infarcts of deep structures
(e.g., basal ganglia, internal capsule)
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Angiography demonstrates vasculopathy of the
branches of the middle cerebral artery
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Outcome is frequently good (better than adults)
Neurologic Complications of Herpes Zoster
neuralgia – pathology in the
central and peripheral nervous system
 Cranial nerve syndromes (e.g., Ramsay-Hunt,
Bell’s palsy)
 Motor neuropathies
 Retinal necrosis
 Large-vessel encephalitis (granulomatous
arteritis)
 Postherpetic
- Delayed contralateral hemiplegia
 Chronic
small-vessel encephalitis (immuno compromised host)
Herpes Zoster Ophthalmicus with Delayed
Contralateral Hemiparesis
 Reported
in normal and immunocompromised
patients
 Usual onset is at about seven weeks (up to 6
months) after ophthalmic zoster
 Presents as a stroke with headache and
hemiplegia (contralateral to the zoster)
 Mortality of 20-25%
 High probability of neurologic sequelae
Zoster Sine Herpete
 Radicular
neuropathic pain in a dermatomal
distribution without cutaneous eruption
– VZV reactivation in ganglion,
but transaxonal spread of virus to skin halted
by host immune response?
 Pathogenesis
 Prevalence
 Difficult
unknown
to diagnose and a few cases have
been linked to VZV by 4-fold antibody rises or
positive CSF PCR for VZV DNA
Cercopithecine Herpes Virus 1
( B virus)
 The
only monkey virus pathogenic to humans
 Most human cases are associated with Rhesus
monkey bites
 Unusual biological properties, particularly the
high propensity to cause neurological disease
 Following an animal bite by 3-5 days local
inflammation and lymhangitis develop
 Transverse myelitis is a prominent neurological
finding
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The disease ultimately progresses to the brain
where all regions of the brain can be involved
without of evidence of localization to any particular
region
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Hemorrhagic foci, necrosis, and inflammatory
changes with edema and degeneration of motor
neurons
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There can be evidence of myelitis, encephalitis, or
encephalomyelitis
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Other organs like the liver and the lung can be
involved as a result of transient viremia
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Clinically, early stage of vesicular eruption is
accompanied by fever, myalgia, vomiting, cramping,
meningeal irritation and cranial nerve signs such as
nystagmus and diplopia
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Neurological symptoms develop very rapidly with
altered sensation, hyperesthesia, and /or parasthesia
of the limbs usually preceding weakness, areflexia,
and flaccid paralysis
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Progression to decreased levels of consciousness,
altered mentation, respiratory depression, seizures,
and ultimately neurological death. Most survivors have
serious brain damage
Measles Encephalitis
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Rare
Encephalitis is an infrequent complication of
measles occurring in approximately 1 in 1000
in natural infections.
Season: winter and spring
Measles encephalitis has a mortality rate of
10%.
Approximately 60 percent of survivors are left
with permanent neurological damage.
Subacute Sclerosing Panencephalitis (SSPE)
- A rare (7 x 10-6), late complication of measles.
- It has been associated with a defective or
absent M protein.
- Both white matter and gray matter are affected.
- Virus replication is defective, and virus can be
recovered only by co-cultivation of brain tissue.
- Virus spreads from cell-to-cell (no budding).
 SSPE
Manifestations
- Mental deterioration
- Alternations in personality
- Clumsiness and poor school performance
- Progressive spasticity.
- Myoclonic episodes and salaam-like seizures.
- Optic atrophy and akinetic mutism.
- Inevitably fatal
Progressive Rubella Panencephalitis
(PRP)
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An unusual late-onset rubella encephalitis following
congenital rubella
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a prolonged asymptomatic period, followed by neural
deterioration during the second decade of life.
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These include behavioral changes, intellectual
decline, ataxia, spasticity, and sometimes seizures.
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It is inevitably fatal within 8 years.
PRP may also be a very rare late complication of
natural childhood rubella.
Mumps Encephalitis
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Rare
Season: winter and spring
Most patients with mumps encephalitis make
a complete recovery.
Deafness, epilepsy, and/or mental retardation
may occur.
In mumps, CNS involvement may be primary
or post infectious.
Major Arboviruses That Cause
Encephalitis
 Flaviviridae
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Japanese encephalitis virus
St. Louis encephalitis virus
West Nile
 Togaviridae
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Eastern equine encephalitis virus
Western equine encephalitis virus
Venezuelan equine encephalitis virus
 Bunyaviridae
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La Crosse encephalitis virus
Arbovirus Clinical Picture: Initial Signs
 Headache
 Malaise
 Anorexia
 Nausea
and Vomiting
 Abdominal pain
Developing CNS Signs
LOC – mild lethargy to deep coma.
 AMS – confused, delirious, disoriented.
 Mental aberrations:
 Altered
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hallucinations
agitation
personality change
behavioral disorders
occasionally frank psychosis
 Focal
or general seizures in >50% of severe
cases.
 Severe neurological deficits.
Neurological Signs
 Virtually
every possible focal neurological
disturbance has been reported.
 Most Common
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Aphasia
Ataxia
Hemiparesis with hyperactive tendon reflexes
Involuntary movements
Cranial nerve deficits (ocular palsies, facial
weakness)
Japanese Encephalitis
 Flavivirus
 Rural
Asia, rice paddies
 Vector- Culex mosquitoes
 Reservoir: birds, pigs, other animals
 Ache, behavioral and mental status changes
 Seizures, paralysis, cranial nerves, tremor,
ataxia
 Mortality- 25%, sequelae - 75%,
 Vaccine- 2-3 doses, 85-98% effectivetravelers?
St. Louis Encephalitis
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Flavivirus
 Most common
mosquito-transmitted
human pathogen in the
US and Canada
 Leading cause of
epidemic flaviviral
encephalitis
 Fever, headache,
meningitis, encephalitis
 Tremor, ataxia, cranial
nerves
 Mortality 7%, >60 years
old 20%, sequelae
West Nile Virus
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Flavivirus
 Primary host – wild birds
 Principal arthropod vector
– mosquitoes
 Geographic distribution Africa, Middle East,
Western Asia, Europe,
Australia, North America,
Central America
Clinical Features of WNV Infection
 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
Clinical Features of WNV Infection
Neurological
involvement in severe cases
• Encephalitis
• Meningitis
• Meningoencephalitis
• Anterior myelitis
• Encephalopolyradiculitis
WNV Encephalitis: Prognosis
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Recovery is usually complete in non-hospitalized
patients
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Less rapid recovery in adults compared to
children, occasionally with residual deficits
•
Of hospitalized patients, 50% recovered but not
to full functional level whereas 40% recovered
fully
•
Most fatalities in patients > 50 y.o.
Eastern Equine Encephalitis
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Genus Alphavirus, family
Togavirus
Eastern and Gulf coasts, summer,
fall
Vector- Culiseta melanuria
Birds, horses, humans of all ages;
high case rates
Fever, headache, mental status,
seizures, coma
CSF Leukocytosis, hyponatremia
MRI- basal ganglia, thalamus,
brainstem
High mortality >50%, sequelae
Western Equine Encephalitis
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Genus Alphavirus, family
togavirus
US, Canada, summer, fall
Vector- Culex tarsalis, rural,
irrigation
Birds, horses, humans
Case rates- adults- 1:1000,
infants 1:1
Fever, sore throat, vertigo
CSF WBC 50-500, increased
protein
Mortality 2-5%, sequelae in
infants
Venezuelan Equine Encephalitis
 Similar
to EEE and WEE
 Family: Togaviridae, Genus: Alphavirus
 Vector; Mosquitoes
 Reservoir: bats, birds, rodents, equine and
small tropical mammals.
 Aerosol Transmission, person to person
transmission is possible
 Prognosis:
 Less than 1% death rate in humans
 High death rate reported in horses
La Crosse Virus (LCV)
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Bunyaviridae, transmitted by an
Aedes species.
The majority of infections are
subclinical or result in mild
illness.
Most cases occur in children
under 16 years of age
Frank encephalitis, progressing to
seizures and coma, is seen during
severe illness.
The mortality rate is <1%.
Neurological sequelae resolve
within several years.
Nipah Virus Encephalitis
 Paramyxovirus
 Malaysia
and Singapore; pig contact
 Adult males- pig farmers and abattoirs
 Pathology: necrotizing vasculitis, syncytia
 MRI- focal white matter lesions
 Leukopenia, lymphopenia, hyponatremia
 Mortality 40%
Summary – Confirmed and Probable
Human Cases in the US
Virus
Years
Total cases
Eastern Equine
1964-2000
182
Western Equine
1964-2000
649
La Crosse
1964-2000
2,776
St. Louis
1964-2000
4,482
West Nile
1999-2010
> 10.000
Progressive Multifocal
Leukoencephalopathy (PML)
An end-stage complication of HIV, caused by
the JC virus
PML is rare in the general community, but
relatively common in HIV infection (affecting
4% of all AIDS patients).
Routine testing for HIV should be considered
for any patient with PML
Evolution occurs over weeks to months
 Initially,
afebrile, alert, no headache
 Progressively
impaired speech, vision, motor
function
 Cranial
nerve deficit and cortical blindness
 Cognition
 Coma
affected relatively late
and death within a year of diagnosis
Diagnostics
 CT brain scan may be normal or remarkable for
areas of diminished density or demyelination
 PCR of CSF for detection of JC virus: positive in
about 60% of the cases
 Differential diagnosis:
 Toxoplasmosis
 Primary CNS lymphoma
 Definitive diagnosis is by brain biopsy
HIV-associated dementia (HAD)

It is the first manifestation of HIV disease in
up to 10% of patients

Afebrile; general lethargy
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Triad of cognitive, motor and behavioral
dysfunction
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Early - concentration and memory deficits,
inattention, motor- uncoordination, ataxia,
depression, emotional lability
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Late - global dementia, paraplegia, mutism