Transcript No Slide Title - Division of Infectious Diseases

VIRAL ENCEPHALITIS
Irv Salit
November 2009
OBJECTIVES
To know……
• The causes of viral encephalitis in
Canada
• The causes of viral encephalitis
world-wide
• General aspects of Arboviruses
• Important aspects of Herpes, West
Nile infections
• Differential Diagnosis of viral
encephalitis
Meningitis vs. Encephalitis
• The clinical distinction between
meningitis and encephalitis is based
upon the state of brain function and
presence of meningismus
• Seizures and postictal states can be
seen with meningitis alone and
should not be construed as definitive
evidence of encephalitis
RATES
ENCEPHALITIS
Rate per 100,000
EUROPE
?
MENINGITIS
Rate per 100,000
?
BOTH
Sporadic 0.1- 0.5
Endemic 5-15
USA
Endemic 20-30
?
?
Death rate 0.1 – 0.3
?
?
CANADA
AUSTRALIA
Data more available on numbers of cases for specific causes
30-80% have unknown etiology
Ratio of 1 : 2: 0.5 for Encephalitis : Meningitis : Encephalomyelitis
ENCEPHALITIS
MICROBIAL
Post-infectious
Infectious
DIFFERENTIAL
Allergic
Rasmussen’s: unilateral, kids, seizures
Lupus
MS
Vascular
Toxic
ENCEPHALITIS
Infectious Causes
BACTERIAL
• Bartonella
• Mycoplasma
• Listeria
• Subacute bacterial endocarditis
• Whipple’s
PARASITIC
• Malaria
• Toxoplasmosis
• Acanthameba
• Naegleria
• Bayliascaris procyonis
VIRAL
•
•
•
•
•
•
•
* Herpes simplex
* Arboviruses
* Enteroviruses
Mumps
Measles
Influenza
VZV
VIRAL
•
•
•
•
•
•
•
•
•
•
•
HIV
EBV
HHV-6
CMV
Rabies, Lyssavirus
LCM
Henipahviruses (Hendra: Australian horse
handlers; Nipah: swine contact)
JC virus (PML)
Herpes B (monkey handlers)
Chikungunya (Africa)
Hepatitis C
DIAGNOSIS
Suspected diagnosis is based on:
• Season
• Geography
• Animal contacts
• Clinical features
SEASONAL VARIATION IN ENCEPHALITIS
West Nile
CANADA
SURVEILLANCE FOR VIRAL
ENCEPHALITIS
• 188 patients were tested
• 60 patients (32%) met suspect case
definition
• 34 (57%) had discharge diagnosis of
encephalitis
• agents: herpes simplex (n = 8), varicella
(n = 2), Powassan (n = 1), echovirus 30 (n
= 1) group B Streptococcus (n = 1); WNV
(=0)
CMAJ 166(1):29-35, 2002 Jan 8
ENCEPHALITIS
• 145 patients admitted to HSC with
encephalitis-like illness
• death, 2% (1)
• motor difficulties, 26% (13)
• global neurological deficits, 16% (8)
• mental status changes, 14% (7)
Clinical Infectious Diseases. 26(2):398-409, 1998
ENCEPHALITIS
Confirmed or probable etiology
identified in 20 (40%):
• Mycoplasma pneumoniae (9 cases)
• M. pneumoniae and enterovirus (2)
• Herpes simplex virus (4)
• Epstein-Barr virus (1)
• HHV-6 (1)
• HHV-6 and influenza type A (1)
• influenza virus type A (1)
• Powassan virus (1)
ENCEPHALITIS
• possible pathogen: was identified in
13 (26%) including M. pneumoniae in
nine
• Mycoplasma pneumoniae in 50/159
(31%) children
(Bitnun. CID 32(12):1674, 2001)
Mycoplasma Encephalitis
• 58 cases (22 female, 36 male; median age
10 years) from 38 reports
• 76% had respiratory symptoms prior to
neurologic disease
• 40% presented with pulmonary infiltrates
• Thirty-three (57%) recovered without
sequelae, 20 (34%) had minor to major
sequelae and 5 (9%) died
Journal of Child Neurology. 19(11):865-71,
2004
NEWER INFORMATION on
ENCEPHALITIDES
Enterovirus 71 (EV71)
• Hand, foot and mouth disease
• High mortality in brainstem encephalitis
complicated by pulmonary edema,
particularly in children <5
• autonomic nervous system dysregulation
• intravenous IgG and milrinone
(phosphodiesterase III inhibitor)
associated with significantly decreased
mortality by attenuating sympathetic
activity and cytokine production
Expert Review of Antiinfective Therapy. 7(6):735-42, 2009 Aug
INFLUENZA
Encephalopathic Syndromes
•
•
•
•
Spanish flu: encephalitis
Post-encephalitic Parkinson’s
Reye syndrome
MERS: mild encephalopathy with promptly
reversible splenial lesions
• Other syndromes: Acute necrotising
encephalitis, ADEM, AESD, etc.
Amin et al. PIDJ 2008; 27 (5): 390
Tada et al. Neuropediatrics 2008; 39(2): 134
American Journal of Neuroradiology. 25(5):798-802, 2004
Biological Chemistry. 385(6):487-92, 2004 Jun.
Nisha Thampi, ID Rounds, Nov 12, 2009
EPIDEMIOLOGY
• Japan 1:100,000 in children <15 yo
• HSC: 4% of encephalitis
– Abnormal MRI
– Age <2yo
Amin et al. 2008. PIDJ; 27 (5): 390
INFLUENZA
Encephalopathy -Mechanisms
• Direct virus infection of ependymal cells,
vascular endothelium, neurons (rarely
found in CSF)
• Mini-plasmin modifies the brain capillaries
to create permissive state in some
• Cytokine-mediated destruction of bloodbrain barrier
• Autoantibody production
Frankova et al. 1977. Arch Virol; 53: 265
Studahl 2003. J Clin Virol 28: 225
Toplak, Avcin 2009. Ann NY Acad Sci; 1173: 619
NEUROANATOMIC LOCALIZATION OF
EPSTEIN-BARR VIRUS ENCEPHALITIS
1. Cerebral hemisphere
2. Cerebellum and basal ganglia
• If isolated hemispheric gray or white
matter: good recovery
• Thalamus: ~ 50% have sequelae
• Brainstem: highest mortality
Journal of Child Neurology. 24(6):720-6, 2009 Jun.
HEPATITIS C VIRUS INFECTION
AND THE BRAIN
• Significant neurocognitive impairment in
HCV infection
• Reports of HCV-associated cerebral
vasculitis
• HCV in brain samples or CSF
• Viral sequences in the brain often differed
from those in the liver
• Trojan horse hypothesis: HCV-infected
mononuclear blood cells enter the brain
Metabolic Brain Disease. 24(1):197-210, 2009
Metabolic Brain Disease. 19(3-4):383-91, 2004
NIPAH VIRUS
• Henipavirus (Hendra + Nipah) - a
Paramyxovirus
• Emerged in Malaysia and Singapore in
1998-99
• close contact with infected pigs
• Some person-to-person spread
• Contamination of pig swill by bat
excretions
• mortality rate: 40% - 70%
• relapses and long-term neurological
defects.
• vasculitis-induced thrombosis and direct
neuronal involvement
HERPES SIMPLEX
HERPES SIMPLEX
• Most common cause of encephalitis
at any time of the year
• HSV-1 causes more than 95% of
cases
• age distribution is biphasic: peaks at
5 to 30 and > 50 years of age
HERPES SIMPLEX ENCEPHALITIS
Signs
• personality change, hallucinations,
and aphasia
• Suggests temporal lobe localization
typical of that infection
HERPES SIMPLEX
• The most helpful finding on standard tests
is CSF red blood cells in the absence of a
traumatic lumbar puncture
• CSF PCR for viral DNA is highly accurate:
98% sensitive and 100% specific. May be
negative in first 72h
• Untreated cases: mortality= 70%; 2.5%
overall (11% of survivors) regain normal
brain function
• Acyclovir has lowered the mortality rate to
19% with 38% of treated patients returning
to normal function
• significantly poorer outcome:
 Glasgow coma score of less than 6
 Age greater than 30 years
 Duration of encephalitis greater than four days
MRI
• Diffusion-weighted MRI is most sensitive
test
• May be diagnostic when PCR is negative
(<72 hours)
• Typical findings in 86% of PCR+ subjects
ARBOVIRUSES
ARBOVIRUSES
(AR=arthropod and
BO=borne)
• clinical manifestations are
indistinguishable
• Signs of encephalitis appear on day
2-3
• minimal alterations in mental status
to coma
• The majority of human infections are
asymptomatic or flu-like syndrome
• insidious or sudden onset
• fever, headache, myalgias, malaise
and occasionally prostration.
• may lead to encephalitis with a fatal
outcome or permanent neurologic
sequelae.
• only a small proportion progress to
frank encephalitis
• Viral transfer from the blood to the
CNS through the olfactory tract has
been suggested
CYCLE
•
•
•
•
Arthropod (mosquitoes or ticks)
Virus
Birds
Mammals
WNV
SURVEILLANCE
• dead birds
• sentinel chickens
• mosquito pools
• human infection
• human disease
ARBOVIRAL ENCEPHALITIS
UNITED STATES
Cumulative : 1964-2005
• *** St. Louis encephalitis (SLE) (4600)
• ** California Group (La Crosse) (3200)
• ** West Nile (2800)
• Western equine encephalitis (640)
• Eastern equine encephalitis (215)
• Powasssan (2)
• most transmitted by mosquitoes
• only ~150 cases/year in U.S.
• Have been uncommon in Canada
although outbreaks have occurred
(including WNV in 2002-2003)
CANADA
ARBOVIRUSES IN CANADA THAT HAVE
CAUSED HUMAN DISEASE
Virus
Family
Occurrence
Vertebrate
Arthropod
WEE
Togaviridae
BC,AB,SK,MB,ON
Wild birds
Mosquitoes
EEE
Togaviridae
ON,QC
Wild birds
Mosquitoes
SLE
Flaviviridae
SK, ON,QC
Wild birds
Mosquitoes
WNV
Flaviviridae
ON,NS,QC,MB,SK
Wild birds
Mosquitoes
POW
Flaviviridae
BC,AB,ON,QC, NS
Wild mammals
SSH
Bunyaviridae
ALL provinces, YT,NWT
Wild mammals
Mosquitoes
JC
Bunyaviridae
NWT,SK,MB,ON,QC,NF
Wild mammals
Mosquitoes
CTF
Reoviridae
BC, AB
Wild mammals
Ticks
Ticks
WEE
• Pre-WNV had been the most
important cause of human disease
• outbreaks in Canada each decade
since the 1930's
• in the Prairies in 1941: 1094 human
cases (= most of the cases until
1990)
• U.S. : 15 / year
• mortality rate = 8 to 15%
• Children more likely to get disease
than adults
• Horses can suffer severe, often fatal
disease
“CALIFORNIA
SEROGROUP" VIRUSES
• *La Crosse , *Snowshoe Hare Virus and
Jamestown Canyon Virus
• Bunyavirus
• SSH virus has been reported from all 10
provinces: hare and other animals
• mosquitoes
• School-age children
• Eastern and Central U.S. (70-150 cases/yr)
• 12 % - short-term neurologic deficits
• cognitive or behavioral sequelae
present at 10 to 18 months followup
ST. LOUIS ENCEPHALITIS
• Flavivirus
• wild bird reservoir
• Culex mosquitoes
• most frequent in persons over age 50
• U.S. : 100 / year but very variable
year to year
• no commercially available human
vaccines for these U.S./Canadian
diseases
• Japanese encephalitis vaccine and
tick-borne encephalitis vaccine
available
• An equine vaccine is available for
WNV, EEE, WEE and Venezuelan
equine encephalitis (VEE).
• Rapid serologic assays such as IgMcapture ELISA (MAC-ELISA) and IgG
ELISA may be positive soon after
infection.
• Early in infection, IgM antibody
• Later in infection, IgG antibody is
more reactive.
• Inclusion of monoclonal antibodies
(MAbs) with defined virus
specificities in these solid phase
assays has allowed for a level of
standardization
• PCR
POWASSAN (POW) VIRUS
• Flavivirus (enveloped, singlestranded RNA virus).
• only well documented tick-borne
encephalitis in the United States and
Canada
• first isolated from the brain of a 5year-old child who died in
Powasssan Ontario in 1958
• may have residual neurological
problems.
POWASSAN
• Rare: Canada - 12 cases from 1958 to
1999. U.S. – 1 case / year
• Seven in children < 10 years of age
• At least four cases were fatal
• Four surviving patients: persistent
debility.
• Most infections do not result in
disease
• 1-3% in northern Ontario are Ab+
• several species of small wild
mammals and several species of
ticks
• can pass through winter in dormant
ticks
• Infection of wild mammals very
common, but disease is unusual
WEST NILE VIRUS
Crows, ravens, jays and magpies
WEST NILE VIRUS
•
•
•
•
Flavivirus (JE, SLE, Murray Valley)
1937: West Nile Province of Uganda
1999: NYC - 61 cases, 7 deaths
2000: 0.5%-2.6% have WNV Ab in
NYC
• 2001: USA - 57 cases, 4 deaths
• 2001: Ontario - 128 + dead birds in 12
health units (SW and CE Ontario). No
human cases.
• 2002: over 14,000 horses in N.A. with
clinical illness due to WN were
reported
• 2002-2003: outbreaks in Canada
• 80% of people infected with the virus
suffer no disease or illness of any
kind
• 20% of infected people may develop
some form of mild illness
WNV HUMAN CASES in
CANADA in 2003
•
•
•
•
851 probable
466 confirmed
10 deaths
Mainly Saskatchewan and Manitoba
WNV in CANADA in 2006
HUMAN:
• 123 cases
• Neurological (34), Non-Neurological (78),
Unclassified (11)
• Alberta 24, Manitoba 50, Saskatchewan 11
• Ontario 38
DEAD BIRDS:
• Ontario 257 positives / 972 tested
• Canada : 273/2461
• 75% were Crows and 25% were Blue Jays
• Almost no ravens, magpies.
DOMESTIC ANIMALS:
• Horses
WNV in CANADA in 2006
2003
2005
• Virus first active in the spring because dormant
adult infected mosquitoes become active or
because infected migratory birds bring the virus
•
mosquitoes begin to transmit virus from bird to
bird
• Spring and summer: only birds and bird-feeding
mosquitoes are infected
• late in the summer, species of mosquito that feed
on birds and mammals reach their peak of annual
activity
CLINICAL WNV
• extremes of age
• hospitalized patients: 85% > age 50
• case fatality = 12%
• the most frequent cause of death is
cerebral edema
• 3-6 days of fever, headache,
backache, myalgia, and anorexia
• roseolar or maculopapular rash
occurs in about half of the patients
and lasts up to a week
• Generalized lymphadenopathy
• CT normal
• MRI: a third showed acute meningeal
enhancement
• Preliminary studies of ribavirin in cell
culture systems suggest a potential
benefit
• in vivo studies with other flaviviruses
suggest no effect
TORONTO AREA OUTBREAK
(2002)
Neurologic Disease
• 64 patients : 57 had encephalitis or
neuromuscular weakness or both, 5
had aseptic meningitis
• mean age was 61 years (range 26-87).
• febrile prodromal illness
• Rash (25%)
• decreased level of consciousness
often evolved to severe lower motor
neuron neuromuscular weakness
TORONTO AREA OUTBREAK
(2002)
Neurologic Disease
• Neuromuscular weakness in 26 (46%) of
the 57 patients with neurological
manifestations was documented days to
weeks after the onset of illness.
• Weakness consisted of flaccid
quadriparesis in 17 patients
• Ataxia and swallowing disorders
• 16 (25%) required intubation and
ventilation
• 10 deaths
Pepperell. CMAJ 2003, 168: 1399
• IgM capture enzyme-linked
immunosorbent assay (ELISA)
• confirmed by plaque reduction
neutralization test (PRNT)
• PCR
• Serology : cross-reacts with JE and
Yellow fever
• Middle East: 3-8% Ab+ (up to 90% in one
Egyptian survey)
TICK-BORNE
ENCEPHALITIS (TBE)
• caused by two closely related
flaviviruses
• eastern subtype causes Russian
spring-summer encephalitis (RSSE)
and is transmitted by Ixodes
persulcatus
TICK-BORNE
ENCEPHALITIS (TBE)
• the western subtype is transmitted
by Ixodes ricinus and causes Central
European encephalitis
• mortality of up to 25% in some
outbreaks
• Fever is often biphasic
• severe headache and neck rigidity
• transient paralysis of the limbs,
shoulders or less commonly the
respiratory musculature
• A few patients are left with residual
paralysis.
• TBE vaccine
JAPANESE ENCEPHALITIS
• flavivirus
• endemic from India to Japan
• major public health problem in Asia
(estimated 50,000 cases annually)
• related to SLE
• rice fields and pigs
• usual tourist to southeast Asia: risk
is very low
• Clinical disease: case-fatality
rate=10-30%
REFERENCES
• Sampathkumar P.
West Nile virus: epidemiology, clinical presentation,
diagnosis, and prevention. Mayo Clinic Proceedings.
78(9):1137-43; 2003
• Bitnun A. Ford-Jones E. Blaser S. Richardson S.
Mycoplasma pneumoniae ecephalitis. Seminars in
Pediatric Infectious Diseases. 14(2):96-107, 2003
• Romero JR. Newland JG.
Viral meningitis and encephalitis: traditional and emerging
viral agents. Seminars in Pediatric Infectious Diseases.
14(2):72-82, 2003
• McCarthy M.
Newer viral encephalitides. Neurologist. 9(4):189-99, 2003
• Gritsun TS. Lashkevich VA. Gould EA.
Tick-borne encephalitis. Antiviral Research. 57(1-2):12946, 2003
• Johnson RT.
Emerging viral infections of the nervous system. Journal of
Neurovirology. 9(2):140-7, 2003
• Bonthius DJ. Karacay B.
Meningitis and encephalitis in children. An update.
Neurologic Clinics. 20(4):1013-38, vi-vii, 2002
• Shoji H. Azuma K. Nishimura Y. Fujimoto H. Sugita Y.
Eizuru Y.
Acute viral encephalitis: the recent progress. Internal
Medicine. 41(6):420-8, 2002
• CDC Arboviral Webpage. Maps, numbers of cases over 20
years.
http://www.cdc.gov/ncidod/dvbid/arbor/arbocase.htm
• Arboviruses in Canada
http://wildlife1.usask.ca/
THE END
• Oxidative stress, primarily due to reactive
oxygen species (ROS) and reactive
nitrogen species (RNS) is a feature of
many viral infections
• ROS and RNS cause oxidative damage to
both host tissue and progeny virus
• The lipid-rich nervous system is
particularly susceptible to lipid
peroxidation