Download CNS Infections I

Microbiology: CNS Infections- Bacterial, Fungal and Parasitic (Neely)
CNS ARCHITECTURE:

Basics:
CNS: brain and spinal cord
Should be sterile: no normal flora
Protection: skull and vertebral column (protect from mechanical pressure and act as barriers to infection)
Main routes of infection: blood vessels and nerves that traverse the walls of the skull and vertebral column
o Blood Borne Invasion: most common route of infection

Types of Infections: all lead to inflammation
Meningitis: inflammation of the meninges
Encephalitis: inflammation of the brain tissue
Abscesses: suppurative infection of the brain tissue
Meningoencephalitis: inflammation of the brain and meninges
Encephalomyelitis: inflammation of the spinal cord

Invasion of the CNS:
Blood borne invasion occurs across the BBB (encephalitis and abscesses) or the BCB
o Blood Brain Barrier (BBB): tightly joined endothelial cells surrounded by glial processes
o Blood-CSF Barrier (BCB): endothelium with fenestrations and tightly joined choroid plexus epithelial
cells
Function: inhibit passage of microbes, antibodies and some antimicrobial drugs
Mechanism: tight junctions (zonula occludens) between endothelial (BBB) and epithelial cells (BCB)
However, microbes may traverse these barriers:
o Infect cells that compromise the barrier
o Passive transport across in intracellular vacuoles
o Carried across by white blood cells (ie. macrophages)
MECHANISMS OF BACTERIAL INFECTION OF THE CNS:

Mucosal Colonization: many CNS infection causing bacteria are members of normal mucosal flora; infection usually
requires immunocompromised or overgrowth of microbe

Invasion of the bloodstream: with survival and multiplication, leading to high levels of bacteremia

Crossing the BBB: via one of the methods listed above

Survival and multiplication: must occur in the meninges and/or brain parenchyma

Bacterial products are proinflammatory (LPS, TA, PG): cause edema and increased pressure via recruitment of WBC
and release of pro-inflammatory cytokines

Cytokine action: recruit more WBCs and promote edema (increasing intracranial pressure), which leads to increased
permeability of the BBB

Increased permeability leads to diapedesis: infiltration of neutrophils and lymphocytes into the CNS

Neuronal injury and edema: due to production of more cytokines by WBC (can lead to neuronal death)
ACQUISITION OF BACTERIAL CNS PATHOGENS:

Many bacterial are normal mucosal flora: as mentioned above, CNS infection with these microbes usually requires
immunocompromise or overgrowth

Carriage Rates:
Streptococcus pneumoniae:
o Significant carriage in pharynx and mouth
o Small amount of carriage in nose and UG tract
Neisseria meningitidis:
o Heavy carriage in pharynx
o Significant carriage in nose, mouth and UG tract
Haemophilus influenza:
o Significant carriage in nose, pharynx and mouth
Group B Streptococcus:
o Heavy carriage in GI tract
o Significant carriage in UG tract
E.coli K1:
o Heavy carriage in GI tract
o Significant carriage in mouth and UG tract
o Small amount of carriage in nose and pharynx
QUANTIFICATION OF CSF INFLAMMATION:

Response to Viruses/Fungal Infections:
o Increase in lymphocytes (mostly T cells)
o Increase in monocytes
o Slight increase in protein

Response to Bacteria: rapid and dramatic
o Increase in PMNs
o Increase in proteins (CSF visibly turbid; due to cytokine release and release of protein by bacteria)
o Decrease in glucose (because bacteria are using it as food source)
Indicator
Normal
Acute Bacterial
Fungal or Viral
WBCs (per uL)
0-5
>1,000 (PMNs)
100-500 (lymphocytes)
%PMNs
0
>50
<10
RBCs (per uL)
0-2
0-10
0-2
Glucose (mg/dL)
45-85
<30
≤40
Protein (mg/dL)
15-45
>100
50-100
ACUTE BACTERIAL MENINGITIS:

Basics: may be caused by viral or bacterial infection, or by disease that can cause inflammation of tissues without
infection (viral are most common cause)

Symptoms: may appear suddenly
Common: high fever, severe/persistent headache, stiff neck, N/V
Important (may require emergency treatment: changes in behavior (confusion), sleepiness, and difficulty
waking up
Infants: irritability, tiredness, poor feeding, fever (hard to diagnose)

Onset:
Acute: onset of symptoms within hours or days (bacterial or viral infection)
Chronic: symptoms fluctuate over the course of weeks, months or years (viruses)
Post-Neonatal Infections:

Streptococcus pneumoniae (pneumococcus):
Basics: primary cause of bacterial meningitis in the US
Virulence Factors:
o Adhesins: PspA and CpbA (bind choline on cell surfaces)
o IgA protease
o Pneumolysin: cytotoxin released when the bacteria lyses (also inhibits Ab binding to bacteria)
o Autolysin: release causes bacteria to release intracellular contents (including pneumolysin)

Bacteria able to detect number of bacteria present and turn on these genes if necessary

Lyse (die) to increase survival of cells that don’t lyse
o Capsule: over 90 serotypes
o Outer wall components (PG, TA): pro-inflammatory (results in tissue damage)
Etiology/Pathogenesis:
o Acquisition: aerosols or direct contact with oral secretions (carried asymptomatically in nasopharynx;
carriage rate DECREASES with age)
o Distribution: ubiquitous
o Risk Factors:

Immunosuppression

Distant foci of infection

Low levels of circulating Abs to capsular polysaccharide
Clinical ID:
o Structure: Gram (+) diplococci (lancet shaped)
o Biochemical Tests:

Catalase (-)

Alpha hemolytic

Optochin sensitive (distinguish from other alpha hemolytic strep)

Bile sensitive (distinguish from GDS)

Quelling Reaction (+)
 Swelling of the capsule caused by contact with serum containing serotype-specific
Abs
-
Vaccines:
o 23 Valent: capsular polysaccharides to 23 serotypes that are responsible for ~90% of infections

60-70% efficacy

Not effective in kids under 2
o 7 valent (PCV7): 7 capsular polysaccharides that cause disease most commonly in children,
immunocompromised and elderly patients

100% effective for serotypes it protects against

Conjugated to diphtheria proteins

Neisseria menigitidis (meningococcus):
Basics: second leading cause of acute bacterial meningitis; human specific
Virulence Factors:
o IgA protease
o Pili (Pil proteins): adherence to epithelium
o LOS: similar to LPS (toxic/pro-inflammatory)
o Capsule: several serogroups

A: 5%

B: 50%

C: 20%

Y: 10%

W135: 10%
Pathogenesis/Etiology:
o Acquisition: aerosols or direct contact with oral secretions (carried asymptomatically in nasopharynx;
carriage rate INCREASES with age)

Invasion of blood and CNS is rare and poorly understood
o Distribution: ubiquitous (causes sporadic outbreaks and epidemics)
o Risk Factors: close contact with infected people or areas of outbreak
o Symptoms: same as previously mentioned, PLUS

Hemorrhagic rash with petechiae (reflects associated septicemia)

May lead to eccymosis and necrosis of fingertips and toes that could require amputation

In ~1/3 of patients the rash is fulminating with complications due to DIC, endotoxemia, shock
and renal failure
Vaccines:
o Basics: protect against groups A, C, Y and W135

Do NOT protect against B (which causes the majority of disease) because of sialic acid that
can lead to autoimmunity
o Meningococcal polysaccharide vaccine (MPSV4): <10 and >55
o Meningococcal conjugate vaccine (MCV4): 11-55
Clinical ID:
o Shape: Gram (-) cocci (generally diplococci)
o Fastidious: requires CAP to grow (needs heme from lysed RBCs)
o Biochemical Tests:

Oxidase (+)

Ferments glucose and maltose

Haemophilus influenza type B (Hib):
Basics: used to be the leading cause of meningitis in ages 5 mo-5 years, but now rare where Hib vaccine used
Virulence Factors:
o IgA protease
o LPS
o Capsule: 6 serotypes (A-F; B responsible for most cases of meningitis)
o Pili
o OMPs
Pathogenesis/Etiology:
o Acquisition: aerosols or direct contact with oral secretions (carried asymptomatically in nasopharynx)
o Distribution: ubiquitous
o Risk Factors: close contact with infected people or areas of outbreak
-


Clinical ID:
o Shape: Gram (-) pleiomorphic coccobacilli
o Facultative anaerobe
o Capsule: can be encapsulated (typeable) and non-encapsulated (nontypeable)
o Fastidious growth: requires CAP

Factor V: NAD

Factor X: hemin
Vaccine:
o Protective Ab would develop naturally by age 5, but also develops following vaccination
College Outbreaks:
Cause: meningococcus and pneumococcus
Risk Factors: lifestyle changes (poor eating habits, alcohol use, smoking, pulmonary infections) result in change
in immune function and microbiota composition
Summary:
Major sequelae from all 3 types of infection is deafness
Pathogen
Host
Clinical Features
Mortality (% of
Sequelae (% of
treated cases)
treated cases)
N. meningitidis
Children and
Acute onset (6-24 hours)
7-10
<1
adolescents
skin rash
H.influenzae
Children <5
Onset less acute (1-2 days)
5
9
S.pneumoniae
All ages
Acute onset
20-30
15-20
Esp. <2 and elderly
May follow pneumonia or
septicemia in elderly
Common Virulence Factors:
N.meningitidis
H.influenzae
S.pneumoniae
Capsule
+
+
+
IgA Protease
+
+
+
Pili
+
+
Endotoxin
+
+
OMPs
?
+
-
Neonatal Infections:

Basics:
Fatal in 1/3 of cases
Often lead to permanent sequelae (cerebral palsy, epilepsy, mental retardation, hydrocephalus)
Clinical diagnosis in infant is difficult (non-specific signs such as fever, poor feeding, V/D, respiratory distress)

Causative agents:
Listeria monocytogenes: G(+) rod
E.coli K1: G(-) rod
Group B Streptococcus: G(+) cocci in chains
Toxoplasma gondii: parasite
CHRONIC BACTERIAL MENINGITIS:

Mycobacterium tuberculosis:
Basics: relatively rare
Pathogenesis: 2 step process
o Enter host by droplet inhalation: infect lung macrophages, forming a granuloma (primary lesion)
o Dissemination to LNs as lung infection progresses: results in a short, but significant bacteremia, which
can lead to dissemination to CNS

Tubercle forms at meninges (initial CNS lesion)

Caseating exudate  meningitis  blockage of CSF fluid  nerve/blood vessel damage
Etiology:
o Acquisition: aerosol spread or reactivation of latent disease
o Distribution: highest in urban and endemic areas
o Risk Factors:

Previous TB infection

Immunosuppression

Travel to endemic areas
BACTERIAL ENCEPHALITIS:

Basics:
Most often caused by viral infection of the brain
o Can also occur as result of fungal infection of the brain OR dissemination of a systemic bacterial
infection
Symptoms:
o Common: sudden fever, headache, vomiting, abnormal visual sensitivity to light, stiff neck and back,
confusion, drowsiness, clumsiness, unsteady gait, irritability
o Require Emergency Treatment: LOC, poor responsiveness, seizures, muscle weakness, sudden severe
dementia, memory loss, withdrawal from social interaction, impaired judgment

Borrelia burgdorferi (Lyme Disease):
Pathogenesis:
o Dissemination after initial infection: inflammatory response and characteristic skin lesion at site of
insect bite

Bacteria spread hematogenously within days, causing systemic inflammatory response

Can localize in CNS, joints and skin after several months
o Encephalitis is usually aseptic: due to inflammatory response and not pathogen itself
Etiology:
o Acquisition: tick bite
o Distribution: most common in NE US (now in Midwest)
o Symptoms: initial skin lesion leading to possible arthritis and neurological problems
o Risk Factors: residence/travel to endemic areas
Clinical ID:
o Shape: spirochete (difficult to Gram stain)
o Microaerophilic
o Difficult to culture: requires BSK-II media
o Diagnosis requires use of serological tests: have variable reliability

Treponema pallidum (Tertiary Syphilis):
Basics: late stage CNS infection that is rare in the US because of ability to easily treat syphilis
Pathogenesis: 3 stages of disease
o Primary: multiplication of bacteria at site of entry, producing localized infection
o Secondary: follows asymptomatic period; dissemination of bacteria to other tissues (ie. CNS)
o Tertiary: can occur after 20-30 years
Etiology:
o Acquisition: STI
o Symptoms:

Initial genital chancre (primary)

If untreated, leads to skin rash (secondary)

If untreated, lead to dissemination to CNS (neurosyphilis)
 Difficulty controlling muscle movements, paralysis, numbness, gradual blindness,
dementia
Clinical ID:
o Shape: Gram (-) spirochete
o Immunological testing
POST-INFECTIOUS SYNDROMES:

Campylobacter jejuni (Guillain Barre Syndrome):
Virulence Factors:
o Low Infectious Dose: as few as 800 organisms required
o Chemotaxis, motility and flagella: allows for attachment and colonization of gut epithelium
o Virulence determinants after colonization:

Iron acquisition

Host cell invasion

Toxin production

Epithelial disruption
-
-
Pathogenesis/Etiology:
o Acquisition: contaminated food (usually chicken)
o Symptoms: food poisoning, acute paralysis
o Guillan Barre Syndrome: occurs in 1/100 infections

Demyelinating disorder characterized by immunologic attack on peripheral nerve myelin

Due to cross reactivity between microbial LPS and human gangliosides
Clinical ID:
o Shape: Gram (-) curved rods
o Microaerophilic
o Motile: darting motility
POLYMICROBIAL ABSCESSES:

Basics: localized suppurative infection within the brain

Pathogenesis: leads to space occupying region that compresses normal structures
Symptoms: headache, drowsiness, confusion, hemiparesis, seizures, speech difficulties, fever, NO stiff neck

Etiology:
Most are polymicrobial: often anaerobic organisms
o Gram (+): Streptococcus, Peptostreptococcus, Staphylococcus, Nocardia, Actinomyces
o Gram (-): Bacteroides, Prevotella, Fusobacterium, E.coli, Citrobacter koseri, Proteus mirabilis
Most common cause is Streptococcus:
o S.anginosus (US)
o S.milleri (Europe)
o Infect synergistically with anaerobic organisms
Brain abscesses in AIDS patients:
o Toxoplasma gondii
o Cryptococcus

Diagnosis:
CT scan: prior to lumbar puncture (due to risk of brain herniation)
o After 4-5 days, abscess surrounded by fibrous capsule that results in ring-enhancing appearance on CT
with contrast

Clinical Parameters:
Acquisition: usually normal flora (usually sequelae of local/remote infections; do not arise de novo)
o Treat primary infection
Risk Factors:
o Immunocompromise
o Head injury (skull fracture)
o Congenital heart disease in kids
o Distal infection (infections of heart, lungs, kidneys etc.)
o Local infection (otitis media, dental abscess, sinusitis)
FUNGAL INFECTIONS (CHRONIC MENINGOENCEPHALITIS):

Cryptococcus neoformans:
Virulence Factors:
o Latent Infection: most primary pulmonary infections usually asymptomatic and lead to latent infection
that can be reactivated in immunocompromised patients (may remain localized or disseminate through
the body to CNS)
o Capsule: antiphagocytic; prevents complement and Ab deposition
o Melanin: pigment that protects against oxidative defenses of macrophages
o Phospholipase B: degrades host phospholipids and aids in tissue destruction/cellular escape
o Urease
Pathogenesis/Etiology:
o Acquisition: inhalation
o Distribution: pigeon excreta and rotting wood are natural reservoirs
o Risk Factors: immunosuppression (common cause of meningitis in HIV+ patients)
Clinical ID:
o Staining:

Gram (+) yeast

India Ink (+): stain for capsule
o
o

Calcofluor White (+): fungal stain
Biochemical: urease (+)
Detection of capsular Ag in CSF or serum

Coccidiodes imitis (Valley Fever):
Pathogenesis:
o Formation of spherules in the lungs: from arthroconidia
o Acute Respiratory Infection: 7-21 days after exposure (resolves rapidly under most conditions)

May lead to chronic pulmonary condition

May disseminate to meninges, bones, joints, subcutaneous and cutaneous tissues
o Meningitis: fatal if not treated
o Symptoms: initial flu-like symptoms, then possible spread to CNS (1% of cases)
Etiology:
o Acquisition: inhalation (no person to person spread)
o Distribution: endemic to SW US
o Risk Factors: outbreaks occur in dust storms, earthquakes, and earth excavations (due to dispersion of
arthroconidia)
Clinical ID:
o Mold at 25 degrees; spherules at 37 degrees
o Endospores seen in tissues

Histoplasma capsulatum (North America Histoplasmosis):
Pathogenesis:
o Acquisition: inhalation of macroconidia from the soil
o Distribution: central and southern US (bird and bat guano)
o Risk Factors:

Immunosuppresion

Age (<2, elderly)

Exposure to large inoculum
o Majority of infections follow subclinical and benign course: in normal hosts
o Dissemation: typically amongst imunosuppressed; can lead to chronic meningitis or encephalitis, which
can be potentially fatal
CAPSULE: THE UBIQUITOUS VIRULENCE FACTOR

Present on bacteria and fungi:
Streptococcus pneumoniae
Neisseria meningitidis
Haemophilus influenza
GBS
Cryptococcus neoformans
E.coli K1

Used for identification:
Serogroups/serotypes
Quelling reaction
India ink stain

Functions:
Prevent complement and Ab deposition
Antiphagocytic
Intracellular protection
Toxic to host cells
PARASITIC INFECTIONS:

Trypanosoma cruzi (Chagas Disease):
Acquisition: bite from infected Triatome bug
Distribution: southern US to southern Argentina
Risk Factors: infants and travel to endemic areas
Symptoms: initial sore where bite occurred; fever, acute encephalitis; possible chronic disease affected heart,
colon or CNS


Plasmodium falciparum (Malaria):
Acquisition: bite from infected mosquito
Site of infection: liver and RBCs
Risk Factors: age (<10) and exposure to endemic areas
Symptoms: acute
o Widespread disease of the brain accompanied by recurrent episodes of malarial fever (fever, chills,
anemia)
o If cerebral malaria (CM) not treated, it is fatal in 24-72 hours
Life Cycle:
o Two hosts: humans and female Anopheles mosquitos
o Humans: sporozoites injected by mosquito; grow and multiply in liver cells first, then in RBCs

RBCs: growth destroys cell, releasing merozoites (daughter cells) that continue the cycle by
invading other RBCs)
o Mosquito: gametocytes are picked up by mosquito when they bite humans, undergo a different cycle

Sporozoites: found in mosquito’s salivary glands after 10-18 days; inject into humans when
they bite them

Therefore, mosquito carries disease form human to human (vector): does not suffer from
infection with parasite
Toxoplasma gondii: covered in another lecture
Primary infection: flu-like symptoms
Progression: can progress to encephalitis and psychotic symptoms (similar to schizophrenia)