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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
Central Nervous System (CNS)
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
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CNS Infections I-V
MICRO570/AQ/F12 36-40
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
Central Nervous System (CNS)
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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CNS Infections I-V
MICRO570/AQ/F12 36-40
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
Entry, Replication and Spread
Neural
Rabies peripheral nerves to nerve axons toganglia and spinal cord to brain
Human Herpes viruses 1-3 through nerves
Entry, Replication and Spread
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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CNS Infections I-V
MICRO570/AQ/F12 36-40
Entry, Replication and Spread
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
Entry, Replication and Spread
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
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CNS Infections I-V
MICRO570/AQ/F12 36-40
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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CNS Infections I-V
MICRO570/AQ/F12 36-40
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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CNS Infections I-V
MICRO570/AQ/F12 36-40
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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CNS Infections I-V
MICRO570/AQ/F12 36-40
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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CNS Infections I-V
MICRO570/AQ/F12 36-40
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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CNS Infections I-V
MICRO570/AQ/F12 36-40/
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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CNS Infections I-V
MICRO570/AQ/F12 36-40/
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
Neisseria meningitidis
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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CNS Infections I-V
MICRO570/AQ/F12 36-40/
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
Neisseria meningitidis
H. influenzae type b
> 60 months Streptococcus pneumoniae
Neisseria meningitidis
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
Neisseria meningitidis
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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CNS Infections I-V
MICRO570/AQ/F12 36-40/
Neisseria meningitidis
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
Neisseria 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
Neisseria meningitidis
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
Neisseria meningitidis
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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CNS Infections I-V
MICRO570/AQ/F12 36-40/
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
Streptococcus pneumoniae
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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CNS Infections I-V
MICRO570/AQ/F12 36-40/
Streptococcus pneumoniae
• 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
Streptococcus pneumoniae
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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CNS Infections I-V
MICRO570/AQ/F12 36-40/
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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CNS Infections I-V
MICRO570/AQ/F12 36-40/
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)
Listeria monocytogenes
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
Listeria monocytogenes
Diagnosis Intracellular gram positive rods in macrophages
and neutrophils CSF culture- looks like β-Strep , but catalase + ,
and “tumble”
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CNS Infections I-V
MICRO570/AQ/F12 36-40/
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
Spirochetes Infections of CNS
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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CNS Infections I-V
MICRO570/AQ/F12 36-40/
Spirochetes Infections of CNS
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
Spirochetes Infections of CNS
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
Spirochetes Infections of CNS
Borrelia burgdorferi
~15% Neurologic abnormalities, rarely fatal
Starts with a tick bite
Large spirochetes- 0.2x10-30 µm
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CNS Infections I-V
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Spirochetes Infections of CNS
Borrelia burgdorferi
Symptoms Classic “bull’s eye” rash, fever, joint pain,
meningeal irritation 2nd Stage- dissemination system wide 3rd Stage- mild neurologic or frank encephalitis
Spirochetes Infections of CNS
Borrelia burgdorferi
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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CNS Infections I-V
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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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CNS Infections I-V
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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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CNS Infections I-V
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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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CNS Infections I-V
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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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CNS Infections I-V
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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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CNS Infections I-V
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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)
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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.
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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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CNS Infections I-V
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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
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CNS Infections I-V
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Brain Abscess and Empyema
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
Brain Abscess and Empyema
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
Brain Abscess and Empyema
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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CNS Infections I-V
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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)
Transmissible SpongiformEncephalopathies
Sensitive to autoclaving and bleach
Disease confined to the CNS and may takedecades to manifest
Can be inherited (~15%) of cases)
Transmissible SpongiformEncephalopathies
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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CNS Infections I-V
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Transmissible SpongiformEncephalopathies
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
Transmissible SpongiformEncephalopathies
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
Transmissible SpongiformEncephalopathies
Creutzfeld Jekob Disease (CJD)
Most common prion human disease
Peak incidence 55-65 years, but can affect
teenagersNo treatment
Transmissible SpongiformEncephalopathies
Symptoms Insidious mental deterioration
Early cerebellar and visual problems
Severe dementia in 6 months Brain and lower motor neuron involvement
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CNS Infections I-V
Transmissible SpongiformEncephalopathies
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
Transmissible SpongiformEncephalopathies
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