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CNS Infections I-V

MICRO570/AQ/F12 36-40

CENTRAL NERVOUSSYSTEM INFECTIONS

Ateef A. Qureshi, PhD

Professor of Microbiology

Fall 2012

Body Systems Exposed to the Environment

MouthRespiratory Tract

GI Tract

Skin

Uro-Genital Tract

Anus ©A.Qureshi S12

UNEXPOSED:Bones & Joints

Circulatory SystemCentral Nervous System

Central Nervous System (CNS)

Infections

•Three organ systems are closed systems

– Bone and Joints

– Vascular (Circulatory)

– The Central Nervous System.

•Infections of these are associated withan increased morbidity and mortality

•These systems are normally sterile andhave no normal biota


Infections

• No direct communication with the external

environment (Blood Brain Barrier)

• Pathogens reach CNS either by directextension from a contiguous structure orby hematogenous dissemination from adistant site or through neural tissue

• In order to institute appropriate empiric

therapy, it is critical to know the normalbiota and most common pathogensassociated with each of these distantsites



CNS Infections I-V

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Fenestratedendothelium

B-CSF-B

Thin BasementMembrane

B-B-B B-CSF-B

Blood VesselTight (ICAM)Junctions

ThickBasementMembrane

Brain-CSF-B

Choroid plexus

epithelium

©A.Qureshi, S10

Comparison ofBlood-Brain, Blood-CSF and Brain-CSF Barriers

*Low antibody, little/no phagocytes and complement

B-B-B

CSF*Brain

Gap Junctions


Infections

•CNS structures protected from external injury-No room for expansion = closed-space infections

•Diagnosis and identification of pathogensoften requires invasive procedures•-multidisciplinary approach

•CSF lacks normal immunologic host defenses-No circulating antibodies in CSF

•Delay in instituting appropriate therapy

increases both morbidity and mortality

Terminology Meningitis- infection of the CNS coverings

Encephalitis- infection of brain parenchyma

Myelitis- infection of spinal cord

Meningoencephalomyelitis- infection of manyareas of brain

Abscess- localized pockets of infection in spinal

cord or brain Empyema- epidural or subepidural abscess

UniversalEpidemiologic Considerations

Patient demographics- age, immune status

Disease pattern- acute or chronic

Exposure history- exposure, bites etc

Epidemiology- geographic location, season,outbreaks

Etiology of infection- bacterial, viral, fungal or

protozoan



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Encephalitides of Viral Etiology

Virus GeographicDistribution

Age Group PredominantSeason

Herpes Virus 1&2 All All None

West Nile Virus All Older adults Summer-Fall

EEE Virus Atlantic & GulfCoast and GreatLakes

Children Summer-Fall

WEE Virus Western US &Canada

Infants & Older adults Summer-Fall

CaliforniaEncephalitis Virus

Midwest & NE US;S. Canada

Older children Summer-Fall

Enteroviruses All Infants & children Summer

Varicella-ZosterVirus

All Children &Immunocompromised

Winter

Modified from Table 61-3, page 593, Schaecter’s Mechanisms of Microbial Diseases, 4th. Edition,2007 ©A. Qureshi, S2010

Entry, Replication and Spread

Hematogenous (Important forabscesses)

Meningococci from respiratory epithelium

West Nile virus through insect bite

Rubella virus through Transplacentaltransmission


Neural

Rabies peripheral nerves to nerve axons toganglia and spinal cord to brain

Human Herpes viruses 1-3 through nerves


Direct inoculation through trauma orinjury

Penetrating head trauma and surgery Most common- Staph. aureus Immunodeficient or HIV infections- Nocardia,

Aspergillus, Candida



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Most likely through Choroid plexus as it ishighly vascularized; inflammation mayincrease entry into CNS

Direct extension Infections of teeth, middle ear or mastoids or

sinuses


Most common bacterial etiology Aerobic and anaerobic streptococci,

Bacteroides

Enterobacteriaceae

Psudomads

Fusibacterium

Peptococcus

Etiology depends upon location of thesource of infection Mouth- mixed biota Lungs- Streptococci, Fusibaterium,

Corynebacterium, Peptococcus sp. Heart- Strep. viridans, Staph. aureus Urinary tract- Enterobacteriaceae,

Pseudomonas

Wounds- Staph. aureus

Entry, Replication and Spread CNS Syndromes

Meningitis Acute Meningitis- viral or bacterial

Chronic Meningitis- fungi and tubercle bacilli

Encephalitis- viral

Myelitis- viral

Brain Abscesses

Acute Brain Abscess- generally poly microbial Chronic Brain Abscess- tubercle bacilli, fungi and

protozoa



CNS Infections I-V

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MENINGITIS

Meningitis and Meningism

Meningitis Infection of the membranes and fluid surrounding

the brain and spinal cord (spinal meningitis)causing inflammation of the meninges

Meningism Group of Symptoms and signs associated with the

inflammation

Headache

Nuchal rigidity

Nausea and vomiting

Photophobia

Tests for Meningism

Demonstrate inability to flex the neck and touchthe chin to the chest

Demonstrate inability to oppose the nose withthe knees

Tripod sign- inability to sit without making a tripodwith hands

Kernig’s sign- patient’s leg can not bestraightened because of hamstring spasm

Brudzinski’s neck sign- patient retracts the legswhen neck is lifted

Symptoms associated withMeningitis

Depend upon age , microorganism and theroute to meninges

Early symptoms (nonspecific) Fever* Malaise Aches and pains Nausea Vomiting

Headache*

* HALL MARKS of Meningitis



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Symptoms associated withMeningitis

More specific to meningitisPhotophobiaNuchal rigidity * DrowsinessConvulsions, fitsInconsolable crying (infants/toddlers)

* HALL MARKS of Meningitis

Diagnosis of CNS infections

Cerebrospinal Fluid Chemical and cellular analysis

Culture

PCR

Features of CSFEtiology Leukocytes

(mm3)

Neutrophils%

Glucose

(mg/dL)

Protein

(mg/dL)

Normal 0-6 0 40-80 20-50

Meningitis:

Acute Bacteria l

>1000 >50 0-10 >100

Viral 10-1000Usually <300

High for 24hrs, then <50

40-80 50-100

Chronic Mycobact.

& Fungal

100-500 <10 ≤40 >100

(Mycobact.)

50-100(Fungal)

Encephali tis *Viral 10-500 High for 24

hrs, then <50

40-80 50-100

BrainAbscess

Bacterial

Fungal

10-100 <50 40-80 50-100

* 10-500 RBCs in HHV-1 Infection ©A Qureshi, S2010

Diagnosis of CNS infections

Neuroimaging Helpful in partial differentiation of viral

encephalitis

Japanese B virus: grey matter involvement

Nipah virus: multiple, small, white matter lesions

Human herpes virus-1: hemorrhages

Abscesses and Empyema differentiation



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Meningitis

Inflammation of the meninges due to viralor bacterial infections.

Aseptic

Over 50% of the cases are due to a variety ofviruses

Rest of the cases are due to bacteria withspecial growth requirements or slow growers

Causes of Aseptic Meningitis

Viruses Bacteria

Common Enteroviruses

Arboviruses*

HHV-2

Borrelia burgdorferi*

Inadequately treated bacterialmeningitis

Uncommon Mumps

HHV-5 (CMV)

HHV-6

HIV

Mycobacterium tuberculosis

Leptospira sp*

Micoplasma pneumoniae

*Incidence varies with the region

Modified from :Neurol. Clin.2008, 26:635

©A. Qureshi S10

Viral Infections of CNS

Viruses use at least two pathways to enterthe CNS

Hematogenous (most common)

Neural Through Olfactory nerve- HHV-1&2

Intra-axonal through neuron route- Rabies

Direct injury

Viral infections range from meningitis tomyelitis

Viral MeningitisCommon causes of Aseptic meningitis

Enteroviruses ( ECHO), coxsackie and poliovirus

Herpes virus and other viruses are less common

Mumps virus meningitis is a complication ofinfection

CSF findings Glucose –normal

Protein- moderately high

WBC count- increased, predominantlylymphocytes

Gram stain- NO BACTERIA



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Enteroviruses Enteroviruses belong to family Picornaviridea Naked, small (25-30 nm), icoshedral viruses Resistant to pH 3-9, detergents and heat Contain single-stranded positive polarity RNA

Transfecting viruses

Baltimore Class IVa, RNA replication incytoplasm

Most Enteroviruses are Cytolytic Over 63 serotypes involved in meningitis Poliovirus has only 3 serotypes and may cause

meningitis to myelitis Eradicated from the Western Hemisphere through

OPV

Enteroviruses

More than 90% of viral meningitis cases aredue to Enteroviruses

Other syndromes caused by Enterovirusesinclude;

Hand-foot and mouth disease

Herpangina

Myocarditis

Pleurodynia

Acute hemorrhagic conjunctivitis

Enteroviruses

Clinical syndromes are determined by

Virus class and serotype

Tissue tropism

Infectious dose

Portal of entry

Patient: age, sex, Immune competence

EnterovirusesEpidemiology

Worldwide distribution

Humans are the only reservoir

Asymptomatic infections are common

Show seasonality;

Temperate climates- Summer to Fall (water)

Tropical climates- year-round (fecal-oral)

Infants and children MOST susceptiblePlease refer to Murray et al (6 th .Ed);Box 56-4 p 556



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Polioviruses

Member of family Picornaviridae Same viral characters as that of

Enteroviruses

Spreads through fecal-oral route byconsuming contaminated food and water Through direct contact with infected stool or

throat secretions

Polioviruses

Symptoms common to those of meningealirritationHeadache, fever, nuchal rigidity, followed by

weakness in one or more extremities

Clinical syndrome:Acute Flaccid Paralysis , due to infection of

anterior horn of grey matter

Polioviruses

Pathogenesis Infects enterocytes of the GI tract

Transverses intestinal wall through basementmembrane

Moves into gut-associated lymphoid tissue,e.g. Peyer’s patches (site of primaryreplication)

Resulting viremia seeds peripheral tissue,virus enters the neurons of the peripheral

nervous system that innervates the peripheraltissues , and the virus traffics to the CNS usingretrograde axonal transport.(Lancaster and Pfeiffer, 2010)

Polioviruses

Outcomes of infection

Inapparent infections

95% asymptomatic, virus in RES

Diagnosis: by virus isolation from feces andoropharynx, and by specific serum antibodies

Abortive polio (minor illness)- flu likesymptoms

Similar to any systemic viral infection

Polio encephalitis- RARE

Non-paralytic polio (aseptic meningitis)

Similar to other enteroviral meningitis



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Polioviruses

Outcomes of Infection (cont’d)

Paralytic polio (<2% of cases)

Viral spread is normally restricted* due to;

Limited replication of virus in peripheral neurons

Insufficient retrograde axonal transport inperipheral neurons

Innate resistance through IFN α / β production

* Lancaster KZ, Pfeiffer JK (2010)

Polioviruses

Outcomes of Infection (cont’d)

When these barriers are breeched the outcome will be paralytic polio: Spinal - flaccid paralysis due to lysis of the

anterior horn cells

Bulbar - paralysis of cranial nerve IX and X,medullar/respiratory centers

* Lancaster KZ, Pfeiffer JK (2010)

PoliovirusesLive oral vaccine

Sabin vaccine is stable at room temperaturewith MgCl2

Produces secretory antibodies

Virus can spread to contacts and enhanceherd immunity and may cause paralytic polio(~1 in 4 million)

Please see Table 56-2 in Murray et al 6 th .Ed, p 561

Polioviruses

Prevention

Inactivated vaccine

Formalized Salk vaccine injected i.m.

Local antibody is not produced

Mostly used in Western Hemisphere ( wherepolio is considered eradicated)

Please see Table 56-2 in Murray et al 6 th .Ed, p 561



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Meningitis

Septic (as opposed to viral Aseptic)

Caused by bacteria only

Associated with high Mortality and Severity

Etiology is AGE dependent

Causes of Septic Meningitis

AGE Most common Others

Birth to 3 months Streptococcus agalactiae Escherichia coli

L. monocytogenes

3 to 60 months Streptococcus pneumoniae

Neisseria meningitidis

H. influenzae type b

> 60 months Streptococcus pneumoniae


L. monocytogenes

Other Gram negative organisms

Any age (cranial

surgery)

Staphylococcus aureus

Any age(immunosuppressed)

L. monocytogenes

Other Gram negatives

(including P. aeruginosa)

Features of CSFEtiology Leukocytes

(mm3)

Neutrophils%

Glucose

(mg/dL)

Protein

(mg/dL)

Normal 0-6 0 40-80 20-50

Meningitis:

Acute Bacterial

>1000 >50 0-10 >100

Viral 10-1000Usually <300

High for 24hrs, then <50

40-80 50-100

Chronic Mycobact.

& Fungal

100-500 <10 ≤40 >100

(Mycobact.)

50-100(Fungal)

Encephalitis *Viral 10-500 High for 24

hrs, then <50

40-80 50-100

BrainAbscess

Bacterial

Fungal

10-100 <50 40-80 50-100

* 10-500 RBCs in HHV-1 Infection ©A Qureshi, S2010

Bacterial Infections of CNS

Over 25 infectious agents involved

Severe, life threatening infections requiring prompt diagnosis and treatment

Septic meningitis (Bacterial meningitis)



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Bacterial Infections of CNSBacterial invasion into CNS

Invasion from nearby site Middle ear or chronic sinusitis

Spread from a distant site Hematogenous invasion

Direct introduction RARE, sometimes the source can not be identified

Bacterial Meningitis

Neonates- Strep agalactiae , Coliforms and Listeria monocytogenes

Infants- Streptococcus pneumoniae, Neisseria meningitidis, and H. influenzae

Children- Strep. pneumoniae , N. meningitidis and Listeria monocytogenes

Streptococcus pneumoniae most commonexcept neonates

More than 75% of total cases are caused by N.meningitidis, Strep. pneumoniae and H.

influenzae, combined

Causes of Septic Meningitis

AGE Most common Others

Birth to 3 months Streptococcus agalactiae Escherichia coli

L. monocytogenes

3 to 60 months Streptococcus pneumoniae


H. influenzae type b

> 60 months Streptococcus pneumoniae


L. monocytogenes

Other Gram negative organisms

Any age (cranial

surgery)

Staphylococcus aureus

Any age(immunosuppressed)

L. monocytogenes

Other Gram negatives (including P. aeroginosa)

Bacterial Virulence Factors


Capsule, IgA protease, pili, and endotoxin

Haemophilus influenzae

Capsule, IgA protease, pili, and endotoxin

Streptococcus pneumoniae

Capsule, and IgA protease only



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Gram negative, coffee bean shaped,intracellular (PMNs) exclusively human pathogen

Many members of the genus arecommensals of upper respiratory tract

About 30% of the population maytransiently carry N. meningitidis


Transmission is via droplet inhalationMore than 1/3 of the cases occur in the first

five years of ageHigh morbidity and mortality, ~50% survivors

have neurologic or other sequelae


Diagnosis Clinical signs- rash (Tumbler test), sepsis , fever,

nuchal rigidity CSF tap- protein, glucose and WBC count Culture- fastidious organism requires 5-10%

CO2

Blood or CSF sample- plate on chocolate agar Nasopharyngeal swab- plate on to Modified Martin-

Thayer agar

Contains antibiotics to inhibit normal biota Rapid techniques

Latex agglutination PCR


Prevention

Tetravalent vaccine composed of Groups A, C, Y,and W135 (Group B is weakly immunogenic)

Protection is group specific

Protection is limited to ~3 years

Vaccination does not protect from carriage of the organism

Vaccine is poorly immunogenic for infants under 2

years of age



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Streptococcus agalactiae

Beta hemolytic, Taxos A resistant, Group Bstreptococcus

Normal female genital organism (~40%colonized))

60% mortality for babies who developmeningitis during the first week of life

Premature birth is an important risk factor

Streptococcus agalactiae

Neonates

Lethargy, fever, sepsis and respiratory distress

Children and adults

Puerperal fever at delivery and other skin andsoft tissue infections


Gram positive lancet shaped, alphahemolytic, Taxos P sensitive cocci(Optochin)

Part of normal biota of 20% adults and>75% healthy children

MOST COMMON cause of bacterial

meningitis

Streptococcus pneumoniae Highest cause of infantile meningitis

Mortality rate for pneumococcal meningitisis ~25%

Neurological sequelae is ~50% In elderly, it may follow pneumonia

Middle ear infections

Sinusitis



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• Pathogenesis (Braun et al.2002; J. Clin. Invest., 109:19-27)

• Hydrogen peroxide- due to absence ofcatalase large amounts accumulate andenhance apoptosis

• Pneumolysin

• pore forming toxin

• Potent neurotoxin; can trigger cellular apoptosis


Pathogenesis (Guikel et al.,2003, PNAS,100:14363-14367)

In mouse models, invasion can occur throughnasopharynx (not hematogenous)

Teichoic and lipoteichoic acids of cell wallmediate binding to the gangliosides expressedon the neurons (confused as normal cargo)

Subsequent travel is then via retrogradeaxonal transport along olfactory neurons

Haemophilus influenzae

Gram negative fastidious encapsulatedpleomorphic organisms

Spread via blood from respiratory tract to thebrain

Infection opportunity between 4 months to 3years

Greater risk of permanent neurologicdamage than any other bacterial meningitis

Vaccines made with type B capsularpolysaccharide

Enterobacteriaceae

Escherichia coli K1

Gram negative, facultative anaerobes

During pregnancy increased colonization ofK1 strain with 8% mortality

Spreads from nasopharynx to the meninges



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Enterobacteriaceae Symptoms

<1 month old- irritability, lethargy, vomiting, lackof appetite and seizures

4-18 months- nuchal rigidity, tense fontanels,and fever

Older children & adults- headache, vomiting,confusion, lethargy, seizures and fever

Interactions during meningitis

Escherichia coli GI, respiratory orgenitourinary tract

bloodstream

Slide kindly provided by Dr J. Rayner

Enterobacteriaceae

Klebsiella pneumoniae Gram negative rods High incidence in cockroach infested areas Early onset- <3 days- 2nd only to GBS

(leukopenia and neutropenia)

Late onset- 8-28 days-2nd only to Staphylococcus

(leukocytosis and neutrophilia)



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Enterobacteriaceae

Klebsiella pneumoniae Symptoms

Lethargy, poor feeding, little cry, fever, sclerema

Culture from blood, CSF, urine C-reactive protein positive

Listeria monocytogenes

Gram positive non spore forming aerobicmotile rods

Epidemiology Food-borne (dairy and deli)

Soil, water, decaying vegetation

Human intestines may be reservoir, 2-12% humans carry the organism

Can be transmitted to the baby duringdelivery (may cause spontaneous

abortions)


Pathogenesis Grows in macrophages Releases “Internalin A & B”- as a cell

attachment molecule which trigger entry

Hemolysins- pore-forming toxin. Allowsescape from phagosome to the phagosol. Listeriolysin O- protein that helps in movement

within the cell

2 Phospholypase Cs- which help break the cellmembrane

ActA- Uses host cell actin to move to the newcells


Diagnosis Intracellular gram positive rods in macrophages

and neutrophils CSF culture- looks like β-Strep , but catalase + ,

and “tumble”



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Slide is kindly provided by Dr Rayner

Spirochetes Infections of CNS

Treponema pallidum Early stages are infectious with no CNS

involvement Takes about 10 year or longer for non treated

cases Neurosyphilis is the Tertiary stage of the disease

and no longer infectious Delayed hypersensitivity is part of the pathologic

mechanism of tissue damage Commonly found in different tissues of the body

as “Gummas” Infection of CNS is via meningovascular route

Spirochetes Infections of CNSTreponema pallidum

SymptomsCNS degenerative changes resulting in mental

changes

May have frank psychosis

Shuffling gait “tabes dorsalis”

DiagnosisSpinal fluid may be helpful

Elevated WBCs and protein

VDRL positive


Leptospira interrogans Animals are reservoirs

Spreads through animal urine contaminatedwater and food (survives weeks in water)

No body of water in the US is free from it

Sensitive to Acid pH, drying and soap

~100 cases/year

Sewer workers, miners, veterinarians and meatpackers are at risk



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Leptospira interrogans

Symptoms Incubation 7-13 days (range 5 days - 4 weeks)

Bacteremic phase- influenza like symptomsand fever (bacteria NOW enter the CNS)

2 nd Phase - ~3+weeks

Headache with “aseptic” meningitis

Sometimes hemodynamic collapse


Leptospira interrogans

Diagnosis Blood culture

CSF analysis and culture

Rise in antibody between acute and convalescentstages

LeptospirosisFollowing countries report activity;

Sri Lanka

Denmark (2 cases, basement cleaning)

Philippines, 37 cases

France, swimmers are reported to have

been infected


Borrelia burgdorferi

~15% Neurologic abnormalities, rarely fatal

Starts with a tick bite

Large spirochetes- 0.2x10-30 µm



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Symptoms Classic “bull’s eye” rash, fever, joint pain,

meningeal irritation 2nd Stage- dissemination system wide 3rd Stage- mild neurologic or frank encephalitis



Diagnosis Loose irregular spirals, Silver or immuno-

flourescent stain

Difficult to cultureCDC recommends antibody screen using ELISA

Fungal Infections of CNSDisseminate hematogenously from a remote

site of infection (oropharynx or lung)

Create multiple areas of infection within brainand other organs

Can cause abscesses

Meningoencephalitis occurs early throughvascular invasion by the fungus

Can see secondary thrombosis, cerebralinfarction and hemorrhages

Fungal Infections of CNS

Common fungiCandida albicans Cryptococcus neoformans Cryptococcus gattii

Histoplasma capsulatum Aspergillus fumigatus



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Fungal Infections of CNS

Diagnosis Antibody studies CXR Candida- forms granulomatus reaction. Yeast forms

seen with silver stain Cryptococcus- fungi appear like encapsulated

spheres. Capsules can be seen by mucicarminestain

Histoplasma- CT scan Aspergillus- branching hyphae; classical

appearance

Please revisit your notes on Respiratory fungal infections by Dr. Lennon

Crytococcus

Cryptococcus neoformans

Disease of the immunocompromized

After Pneumocytis it is the most importantinfection in AIDS patients

Found in pigeon excreta, soil and folliage,

Spreads through aerosols

Mainly a disease of respiratory tract

Cryptococcus

Cryptococcus gattii

A new variety or species?

First report in N. America in 1999 in BC, Canada

Associated with Eucalyptus trees and/or seeds,soil, foliage

Not associated with pigeons

Inflicts immunocompetent people

Children and elders killed in a matter of a week

Mainly a pulmonary disease (75%) but causesmeningitis in ~9-10% of the cases

Blindness through optic neuropathy

Protozoan Meningitis

Amoebic meningitis (Naegleria fowleri )

Fresh water amoeba

Currently reported cases in Kansas,Virginia and Florida

I death last week in Florida



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ENCEPHALITIS

Encephalitis

Etiology Viral

Herpes viruses, enteroviruses,arboviruses , rabiesvirus, HIV, HTLV-1, Paramyxoviruses (Nipah virus,mumps, rubeolavirus) and arenaviruses

Bacterial (RARE) Exceptions : Legionella pneumophilia, Borrelia

burgdorferi, Treponema pallidum

Fungal Cryptococcus neoformans and C. gattii

Parasitic

Plasmodium falciparum, Trypanosomes

EncephalitisDefined as inflammation of brain parenchyma

Encephalitis is considered clinically a moresevere syndrome than viral meningitis

SymptomsHeadache

Fever

Altered consciousness-lethargy to confusion andcoma

Behavioral and speech disturbance

Seizures

EncephalitisArboviruses

Arthropod-borne viral infections

Distributed worldwide

Transmitted by mosquitoes and ticks

Sporadic and epidemic encephalitis

Seizures are generally the complications in

children.



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Arboviruses

All arboviruses are enveloped viruses withicosahedral nucleocapsid and contain atransfecting RNA

Major families of arboviruses (Togaviridae and Flaviviridae ) Togaviridae

Belongs to Baltimore Class IVb

Early and late proteins made

Virus buds at the plasma membrane

TogaviridaeVenezuelan Equine Encephalitis (VEE)

Togaviridae (alphavirus) Spread through Culex and Aedes mosquitoes

Symptoms Prodrome- fever, chills, weakness, headache,

myalgia (due to viral replication )

Rapid progression- nuchal rigidity, confusion,somnolence, seizure in 50% of cases and coma(due to spread through microvascular permeability of brain, then cell-to-cell occurs via axon and dendrites )

NO DEATHS in humans , 80% mortality in horses

Togaviridae

Eastern Equine Encephalitis (EEE)

Common in North America

Spreads through Aedes and Culiseta sp

Humans are dead-end hosts but Aedes mayspread from horse to human

Clinical symptoms similar to that of VEE

HIGH MORTALITY in humans

Togaviridae

Western Equine Encephalitis (WEE)

Spreads through Culex and Culiseta

Common in rural areas of US in summermonths

Fatality rate 3-4%, death in 1-2 days. Childrenhave a 30% chance of CNS sequelae



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Pathophysiology of EquineEncephalitides

Defuse CNS involvementNeutrophils and macrophages infiltrate brain

parenchyma causing focal necrosis andspotty demyelination

Vascular inflammation with endothelialproliferation and small vessel thrombosis

Pathophysiology of EquineEncephalitides

EEE Large number of active virus entering in

brain parenchyma Effects the perikaryon and dendrites of

neurons with minimal glial cell infiltration

WEE Damage mediated by large number of

immunologically active cells that enter brain Cell death by apoptosis primarily in the glial

and inflammatory cells

ArbovirusesAll arboviruses are enveloped viruses with

icosahedral nucleocapsid and contain atransfecting RNA

Major families of arboviruses Togaviridae

Belongs to Baltimore Class IVb

Early and late proteins made Virus buds at the plasma membrane

Flaviviridae Belongs to Baltimore class IVa

Polyprotein is translated first which cleaves into manyindividual proteins

Virus buds inside cytoplasmic vesicles and the virus isreleased through exocytosis

FlaviviridaeSt. Louis Encephalitis virus (SLE)

Epidemiology Transmitted by culex mosquitoes

Argentina: Mar. 2011, 5 confirmed/7 suspected

Overt infection depends upon Efficiency of replication at extra neural sites

Degree of viremia

Age of the host

Pathophysiology Virus enters through BBB (astrocyte complex)

Or cross fenestrated endothelium (choroidplexus)



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FlaviviridaeSymptoms

Mortality 2-20% (higher in elderly)

Malaise and fever only 20% develop sequelae(irritability, memory loss, movement disorders,motor deficits)

Seizures and coma COMMON

No chronic illness

FlaviviridaeJapanese B Encephalitis virus (JBE)

Epidemiology Spread through Culex mosquitoes

Incubation 4-14 days

Rural areas of Asia

September 2011: India; 319 deaths and Nepal; 5deaths.

Symptoms

Viral prodrome- fever by 2nd week

Encephalitis syndrome with tremors NOT seizures

Low CSF IgG/IgM ratio= higher death rate

FlaviviridaeWest Nile Encephalitis virus (WNV)

Epidemiology Wild birds are reservoir, spreads through

Aedes mosquitoes

3-15% fatal

Very RARE person to person transmission

Symptoms Viral prodrome with maculopapular rash on

trunk and extremities Headache, HIGH fever, nuchal rigidity, stupor,

tremor and seizures, paralysis

BunyaviridaeAt least 200 different viruses included in

this group

Enveloped viruses containing single-stranded negative polarity, segmented (3)RNA

Spreads through mosquitoes, ticks andflies California Encephalitis virus

La Crosse virus



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Rhabdoviridae

Lyssavirus: Rabies

Structure Bullet shaped virus

Single-stranded, negative polarity RNA

Helical nucleocapsid in an envelope

5 proteins- N,P,M,G and L Surface glycoprotein attaches to cell receptors

including Acetylcholine receptor at neuromuscular junctions

RhabdoviridaeLyssavirus: Rabies

Pathophysiology Viral entry into the cell is via endocytosis

Virus has a preference for nerve and salivarygland cells (travels via axons to CNS)

Spreads from brain to salivary glands, kidneysand conjunctival cells (virus in tears )

RhabdoviridaeEpidemiology

Estimated 35000-50,000 cases worldwide

Highest in Asia ~90% cases

Endozoonotic: all warm blooded animals aresusceptible

Urban- dogs and cats

Sylvatic- wildlife

Rhabdoviridae

Symptoms Incubation 20-90 days, may extend to a year

Nonspecific – general malaise, fever, headache(tingling pain and weakness at the bit site)

Progressive - neurologic symptoms includinginsomnia, confusion, slight or partial paralysis,agitation, hypersalivation, dysphagia(hydrophobia)

Paralytic –disorientation, stupor

Death within days after symptoms (~7 days)



CNS Infections I-V

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Rhabdoviridae

Diagnosis Saliva- virus isolation, RT-PCR Serum and CSF for rabies antibodies (FA and

ELISA) Brain tissue- Negri bodies , Babes nodules

consisting of glial cells

RHABDOVIRIDAE

TreatmentPrevention Wash all wounds with soap and water 1 dose of immune globulin and 4 doses of

vaccine on days; 1,3,7 &14, days + 2 boosterson days 0 and 3*

* New recommendations by CDC published on Mar 18, 2010

Rabies postexposure prophylaxis (PEP) schedule - US, 2010(MMWR Vol.59/RR2; Mar 18, 2010)

Not previously vaccinated

Intervention Regimen*

(for ALL age groups including children)

Wound cleansing All PEP should begin with immediate thoroughcleansing of all wounds with soap and water. Ifavailable, a virucidal agent (e.g., povidine-iodinesolution) should be used to irrigate t he wounds.

Human rabiesimmune globulin(HRIG)

Administer 20 IU/kg body weight. If anatomicallyfeasible, the full dose should be infiltrated around andinto the wound(s), and any remaining volume should

be administered at an anatomical site (intramuscular[IM]) distant from vaccine administration.

Vaccine Human diploid cell vaccine (HDCV) or purified chic kembryo cell vaccine (PCECV) 1.0 mL, IM (deltoid butnever in the gluteal region), 1 each on days 0, 3, 7 and14.

(For immunocompromised; 5 shots)

Rabies postexposure prophylaxis (PEP) schedule - US, 2010(MMWR Vol.59/RR2; Mar 18, 2010)

Previously vaccinated

Intervention Regimen*

(for ALL age groups including children)

Wound cleansing All PEP should begin with immediate thoroughcleansing of all wounds with soap and water. Ifavailable, a virucidal agent such as povidine-iodinesolution should be used to irrigate the wounds.

HRIG HRIG should not be administered.

Vaccine HDCV or PCECV 1.0 mL, IM (deltoid but never in thegluteal area), 1 each on days 0 and 3.

For persons with immunosuppression, rabies PEPshould be administered using all 5 doses of vaccine ondays 0, 3, 7, 14, and 28.



CNS Infections I-V

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Papovaviridae

Polyoma virus (JC virus)-PML (ProgressiveMultifocal Leuko-encephalopathy)

Viral DNA in majority of healthy humans

Multifocal signs including; hemiparesis, visualloss, seizures, dementia, personality changesand gait problems

Characteristic white matter lesions common inposterior occipital area

Paramyxoviridae

Class V, single-strand, linear, negativepolarity RNA viruses

Hendra virus; affecting horses

Nipah virus (Barking pig syndrome)

Mumps virus

Rubeola virus

Paramyxoviridiae

Nipah virus: Belongs to genus Henipavirus.

Recognized in 1999 in pig farmers in Malaysia.Now endemic in Malaysia, Singapore andBangladesh.

Bangladesh: more than 200 deaths since 2001

2011: 35 deaths by Mar.31., no current cases

Spreads through bats feces/urine /salivacontaminated fruit juices.

Paramyxoviridiae

Rubeola virus- SSPE (Subacute Sclerosing Pan Encephalitis)

Slow fatal condition after more than 10 years ofmeasles

Worldwide, more common in boys (3:1) than girls

Behavior changes in school age children

Fulminant course- 10% of cases death in 3months

Chronic course- death in 4-10 years



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Other virus infections of theCNS

Arenaviridae - Lymphocytic Choriomeningitis

Togaviridae- Rubella virus

Herpesviridae - Human Herpes virus 1-8

Retroviridae - HIV-1

MyelitisAcute inflammation of the spinal cordDepending upon virus, this can lead to flaccid

paralysisSymptoms

Headache

Fever Irritation followed by

Weakness of one or more extremities

Etiology Poliovirus was the leading cause before vaccination West Nile virus is the most signif icant after 2000

BRAIN ABSCESSAND

EMPYEMA

Brain Abscess and Empyema

Abscess

Fixed boundaries

Empyema

Lack of definable shape or size



CNS Infections I-V

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Localized bacterial infection of brainparenchyma and subdural or epiduralspaces

Pressure from accumulation of exudatesmay permanently damage the brain tissue

May be fatal if not treated properly

Polymicrobial in nature


Symptoms

Usually are rapid and associated with theirlocation

Headache

Changes in mental status- drowsiness to coma

Generalized seizure

Etiology of Brain AbscessesAccording to Anatomical Location

SITE PREDISPOSINGFACTOR

ORGANISM (S)

Frontal SinusitisDental sepsis

Streptococci,Bacteroides,Staph. aureus Hemophilus spp.

Temporal Otitis mediaMastoiditis

Streptococci,Bacteroides,

Enterobacteriaceae

Frontal,Temporal,Parietaletc

TraumaPenetratingwound

Staph. aureus Clostridia

Multiple Infective endocarditisCongenital heartDiseaseLung abscess

Staph. aureus,Streptococci (viridans gp)Fusibacteria, Nocardia


Fungal brain abscess

Disseminated hematogenously from remotesite ( lungs or oropharynx)

Create multiple areas of infection within brain

Meningoencephalitis occurs early throughvascular invasion

Etiology Aspergillus, Cryptococcus, Candida



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Prion Infectionsof CNS

Transmissible SpongiformEncephalopathies

Prion is an abnormal isomer of normal hostprotein

NO NUCLEIC ACID present

Replicate without provoking antibody orinflammatory response

Are resistant to some inactivation methodsused for bacteria and viruses (70% alcohol,X-rays and UV light etc)


Sensitive to autoclaving and bleach

Disease confined to the CNS and may takedecades to manifest

Can be inherited (~15%) of cases)


Pathogenesis Normal PrPc- glycoprotein with secondary

structures dominated by Alpha helix

Prion protein PrPSc- glycoprotein withsecondary structures dominated by Beta- pleats

When P

r

P

Sc

molecules comes in contact withthe normal PrPc molecule, the normal PrPc

changes into the abnormal PrPSc



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Pathogenesis (Cont’d) Modified protein aggregates in neurons as

myeloid plaques

Spongy appearance of cerebrum is due to theformation of vacuoles in the cortex andcerebellum


Spread of Prions Sporadic- no apparent cause

Inherited - through autosomal dominant trait

Ingestion - infected food, cannibalism Kuru-

incubation ~20 years

Involves progressive trunchal shaking andunsteady gait. Death within 3-24 months

Medical events- (Iatrogenic) through surgery,

organs etc


Creutzfeld Jekob Disease (CJD)

Most common prion human disease

Peak incidence 55-65 years, but can affect

teenagersNo treatment


Symptoms Insidious mental deterioration

Early cerebellar and visual problems

Severe dementia in 6 months Brain and lower motor neuron involvement



CNS Infections I-V


Cases of CJD have been due to Infected corneal transplants

Reused, improperly sterilized brain surgeryequipment

Pituitary hormone injections derived fromcadavers

Accidental cuts during autopsies or surgeries


Bovine Variant of CJDBSE re-emerged in 1996 with progressive

neurodegenerative disease resulting inpatient death

Normally bovine but crossed to humans asMad Cow Disease

Diagnosis Biopsy of Brain

Spongiform encephalopathy Accumulation of abnormally folded protein

Sporadic disease

CSF- no cells

CNS Infections

This was by no means a completeinventory of infectious agents involved

There are many more; however, wediscussed ONLY the very common andfrequent infections

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