VIRAL ENCEPHALITIS

Irv Salit

November 2009

OBJECTIVESTo 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

ENCEPHALITISRate per 100,000

MENINGITIS Rate per 100,000

BOTH

EUROPE ? ? Sporadic 0.1- 0.5

Endemic 5-15

USA Endemic 20-30 ? ?

CANADA

AUSTRALIA Death rate 0.1 – 0.3 ? ?

Data more available on numbers of cases for specific causes30-80% have unknown etiologyRatio 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

ENCEPHALITISInfectious 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

INFLUENZAEncephalopathic 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): 134American Journal of Neuroradiology. 25(5):798-802, 2004Biological 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

INFLUENZAEncephalopathy -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 blood-brain barrier

• Autoantibody production

Frankova et al. 1977. Arch Virol; 53: 265Studahl 2003. J Clin Virol 28: 225Toplak, 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 Ticks

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

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 IgM-capture 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, single-stranded

RNA virus).

• only well documented tick-borne encephalitis in the United States and Canada

• first isolated from the brain of a 5-year-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

Crows, ravens, jays and magpies

WEST NILE VIRUS

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 2006HUMAN:• 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):129-46, 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