Introduction: Infections of the Central Nervous System

1
Introduction Infections of the Central Nervous
System

• A.S. Oglesby, Ph.D.
• College of Osteopathic Medicine
• Western University

2
Central Nervous System Structure

• Compartments and membranes
• Brain
• Pia Mater
• Subarachnoid space (CSF)
• Arachnoid mater
• Subdural potential space
• Dura mater
• Epidural potential space
• Skull
• Three locations where infection may occur
• Subarachnoid Space
• Subdural Space
• Epidural Space

3
Blood Supply

• Endothelial cells (tunica intima) of the
  capillaries have continuous tight junctions, with
  no gaps creating the blood brain barrier (BBB)
• Endothelial cells surrounded by the processes of
  astrocytes, with a continuous basement
• Many molecules do not cross this BBB

4
Cerebral Spinal Fluid (CSF)

• Located in the ventricles and subarachnoid space
• Continuous with the extracellular fluid of the
  brain
• Produced by secretion
• Reabsorption by vesicular transport
• Complete exchange every 3-4 hours
• CSF should be sterile

5
Differences between CSF Plasma
Relative Concentration, CSF and Plasma (mg/dl),
Normal Values
CSF glucose is normally 2/3 of blood glucose
6
Inmmune Responses of the CNS

• Normal
• Antibody titer low in CSF, Serum/CSF antibody
  ratio normally above 200. Little IgG and IgA is
  derived from blood.
• Cells in CSF are small numbers of lymphocytes,
  with no plasma cells. There are no
  polymorphonuclear leukocytes. WBCs shoud be less
  than 4/mm3.

7
Immune Response of the CNS

• Infected with inflammation, the BBB is
  breached, with the primary site in the
  microvascular endothelium.
• Bacterial components may cause secretion by local
  macrophages of cytokines in the subarachnoid
  space, with causes a breach in the BBB.
• Transudate of serum proteins my get in.
• Polymorphonuclear leukocytes may enter,
• Subacute and chronic inflammatory infiltrates
  often contain plasma cells and antibody
  production may occur at the site
• T lymphocytes of cell-mediated immunity come in,
  or intracellular parasites, such as viruses
• Mycobacterium tuberculosis, Listeria
  monocytogenes, Toxoplasma gondii
• Antibiotics ordinarily do not cross the BBB,
  although antibiotics may cross during
  inflammatory reactions

8
Definitions

• Meningitis inflammation of the meninges of the
  brain or spinal cord
• Encephalitis inflammation of the brain
• Myelitis inflammation of the spinal cord
• Neuritis inflammation of the peripheral nerves
• Brain abscess focal intracranial suppuration in
  the brain substances
• Subdural empyema infection between dura mater
  and subarachnoid space
• Epidural abscess focal suppuration between
  skull and dura mater

9
Routes of Infection of the CNS

• Hematogenous spread with most infectious agents
  from extracranial foci, retrograde propagation of
  infected thrombi within emissary veins
• Neurotrophic spread in the case of some viruses
• Spread of organisms through bone
• Injury includes inoculation of extradural
  bacteria
• Congenital problems, including congenital dermal
  sinus and myelomeningocele

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Bacterial Infections Acute Bacterial Meningitis

• Manifestations General, fever, headache,
  irritability, convulsions, drowsiness, coma,
  stiff neck, bulging fontanelles
• Largely independent of the cause
• Too some extent dependent upon age
• CSF gram stain and/or bacterial culture usually
  positive, unless it has been partially treated
  with antibiotics

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Bacterial Infections Acute Bacterial Meningitis

• Bacteria include
• Haemophilus influenzae
• Neisseria meningitidis
• Streptococcus pneumoniae
• Gram (-) rods

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Etiology and Epidemiology in Adults and Children
in Postnatal Period

• Haemophilus influenzae (70 lt 5 yrs of age)
• Gram (-) rod, requires X and V factors
• Respiratory transmission
• Virulence associated with antiphagocytic capsule
• 6 antigenic types (a-f capsular antigens
  serotypes)
• Type b accounts for more than 90 of human cases
  of H. influenzae meningitis before the vaccine
  (Hib). Now it is less common than non-type b.
• Capsules provide virulence, can become invasive.
• 1/3 of survivors have neurological morbidity,
  especially deafness (35).
• Mental retardation 11
• Cerebral palsy 7
• Seizures 5
• 50 Judges o be functioning normally

13
Etiology and Epidemiology in Adults and Children
in Postnatal Period

• Haemophilus influenzae (70 lt 5 yrs of age before
  advent of conjugated vaccines)
• Predisposing factors include the presence of
  pharyngitis or otitis media, but spread is
  hematogenous
• Nasopharengeal carriers common but poorly
  correlated with risk of disease, because some
  biotypes are more virulent than others
• Carraige rates have decreased markedly, but the
  organism does still circulate in the population
• Prophylaxis includes immunization with one of the
  H. influenzae b conjugate vaccines starting at
  two months of age.

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Acute Bacterial Meningitis Etiology
Epidemiology in Adults Children in Postnatal
Period

• Neisseria meningitidis (meningococcal meningitis,
  epidemic cerebrospinal fever)
• Gram () coccus, oxidase positive
• Respiratory transmission
• Virulence associated with antiphagocytic capsule
• At least 13 serotypes based on polysaccaride
  capsule
• 98 of meningococcal meningitis is caused by A,
  B, C, Y or W-135. In the US, 30 is due to type
  B, 30 to type C and 30 to type Y.
• A is most associated with epidemics
• Others usually cause sporadic cases

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Acute Bacterial Meningitis Etiology
Epidemiology in Adults Children in Postnatal
Period

• Neisseria meningitidis (meningococcal meningitis,
  epidemic cerebrospinal fever)
• Causes disease mainly in children and young
  adults
• Epidemics late in winter and early in spring
• Overcrowding and fatigue are predisposing
  factors, as seen in military recruits and
  institutionalized children
• Nasopharengeal carriers may be important in
  transmission, but some biotypes are more virulent
  than others
• Meningococcemia is another manifestation of
  meninggococcal disease, and may occur with or
  wothout meningitis

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Acute Bacterial Meningitis Etiology
Epidemiology in Adults Children in Postnatal
Period

• Neisseria meningitidis (meningococcal meningitis,
  epidemic cerebrospinal fever)
• Fulminant disease with death within 24 hours due
  to widespread vasculitis
• PROBABLY, NO OTHER ORGANISM RIVALS THE CAPACITY
  OF NEISSERIA MENINGITIDIS TO PRODUCE FULMINANT
  ILLNESS AND DEATH WITHIN A FEW HOURS. THE CASE
  FATALITY RATE IS AROUND 10 FOR MENINGOCOCCEMIA
  EVEN WITH THERAPY. THE CAUSE OF DEATH IS OFTEN
  DISSEMINATED INTRAVASCULAR COAGULATION (DIC).
• The classical findings at necropsy is extensive
  hemorrhage into both adrenal glands the
  Waterhouse-Friderichsen Syndrome.
• 11-20 of survivors have sequelae such as
  neurological disability, limb loss and hearing
  loss.

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Acute Bacterial Meningitis Etiology
Epidemiology in Adults Children in Postnatal
Period

• Neisseria meningitidis (meningococcal meningitis,
  epidemic cerebrospinal fever)
• Prophylaxis
• Chemoprophylaxis of very close contacts such as
  family members can help prevent transmission
• A vaccine is available containing capsular
  antigenic types A, C, Y and W-135. (Type B
  capsular material is poorly antigenic). It is
  not recommended for routine use in the general
  population, but is recommended for military
  recruits, for controlling outbreaks, and should
  be suggesting for incoming college Freshmen.

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Acute Bacterial Meningitis Etiology
Epidemiology in Adults Children in Postnatal
Period

• Streptococcus pneumoniae
• Gram () diplococcus, optochin ()
• Virulence associated with antiphagocytic capsule
• 84 serotypes based on capsule
• Diseases
• Pneumonia is most important
• Otitis media is most common
• Meningitis is most frequent in adults and
  children lt 5 years of age
• 5 die
• 20 learning disabilities and deafness
• Associated with meningitis after a head wound.
• Other complications include bacteremia,
  pneumonia, mastoiditis, endocarditis, or
  sinusitis

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Acute Bacterial Meningitis Etiology
Epidemiology in Adults Children in Postnatal
Period

• Streptococcus pneumoniae
• High normal carrier rate
• Pnemumovax
• Prepared from 23 capsular serotypes, recommended
  for all people over the age of 65 years
• Prevnar
• Protein conjugated vaccine containing 7 capsular
  serotypes most likely to cause meningitis and
  bacteremia in young children, now recommended for
  all infants

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Acute Bacterial Meningitis Etiology
Epidemiology in Adults Children in Postnatal
Period

• Gram (-) Rods
• Usually hospital acquired
• Occurs in conjunction with head trauma,
  neurosurgical procedures or sepsis
• Genera involved Klebsiella, E. coli, Pseudomonas

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Acute Meningitis of the Newborn

• Etiology and Causative Agents
• Group B Streptococcus, S. agalactiae
• Escherichia coli
• Listeria monocytogenes
• Ureaplasma urealyticum

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Acute Meningitis of the Newborn

• Etiology
• Group B Strep (BGS), Streptococcus agalactiae,
  can be found in the vaginal and rectal areas of
  20 of normal women
• Now considered the most common bacterial cause of
  sepsis, meningitis, pneumonia and death among
  newborns in the US.
• Survivors have permanent hearing and vision loss,
  as well as learning disabilities. Untreated
  carriers have a 1/200 chance of delivering an
  infected baby.
• Treatable with intrapartum antibiotics.

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Acute Meningitis of the Newborn

• Escherichia coli, capsular type K-1, gram (-) rod
  that is an enteric organism, found in the
  perineal flora of the mother

24
Acute Meningitis of the Newborn

• Listeria monocytogenes, gram () motile rod, that
  is usually food born, may cause fetal death and
  maternal death in infected pregnant women as well
  as immunocompromised

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Acute Meningitis of the Newborn

• Etiology
• GBS, E. coli, L. monocytogenes, U. urealyticum
• Most cases occur in the first week postpartum,
  represent spread from sites colonized in the
  hospital, such as the gut, throat and umbilicus
• Factors that facilitate include
• Maternal illness, carraige of the organism and
  premature rupture of the membranes
• Fetal prematurity and low birth weight
• Environmental carriers or contaminated
  equiptment, such as humidifiers

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Acute Meningitis of the Newborn

• Entry of organism into subarachnoid space
• Portals of entry include
• Nasopharengeal colonization
• Blood-born (bacteremia, septicemia) enters
  subarachnoid space
• Between the tight junctions of the endothelial
  cells
• Within circulating phagocytic cells such as
  monocytes
• Transcellular transport within endothelial cell
  vacoules
• Extension from one anatomical location to another
• Otitis media ? mastoiditis ? meningitis
• Paranasal sinuses ? meningitis
• Trauma, such as a skull fracture, coupled with
  CSF otorrhea or rhinorrhea
• Anatomical defects, such as congenital dural
  defects
• Shunt-associated (10-30 of people with shunts
  will come down with meningitis.

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Acute Meningitis of the Newborn

• Pathogenesis
• Once into the subarachnoid space
• organism multiples
• In-migration of neutrophils
• Loosening of the BBB, with inflow of proteins and
  fluids
• Cerebral edema due to release of toxic factors
• Obstruction of CSF flow, increased intracranial
  pressure

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Age Specific Incidence of Bacterial Meningitis in
1995
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Correlation of Cause of Acute Bacterial
Meningitis with Age Group and Direct Innoculation
30
Correlation of Cause of Acute Bacterial
Meningitis with Age Group and Direct Innoculation
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Acute Bacterial Meningitis

• History
• Physical Examination
• Laboratory Diagnosis
• CSF
• Blood
• Feces
• Prognosis

This is a case of acute meningitis. It is
important to make the diagnosis and begin
antibiotic treatment as soon as possible.
Clinical signs may include headache, neck
stiffness (from irritation of spinal nerve
roots), fever, and clouded consciousness.
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Acute Bacterial Meningitis

• WBC Count, with normal values lt 4/mm3 and
  bacterial meningitis gt 1200/mm3
• Polys
• Glucose below 30 mg/dl suggests bacterial
  meningitis
• Protein, have increased break in BBB
• Eosinophils
• Tumor cytology
• C reactive protien

• History
• 70 of diagnoses can be made from history
• Physical Examination
• 90 of diagnoses can be made from history and
  physical examination
• Laboratory Diagnosis
• Stat gram stain of centrifuged sediment
• Culture, including chocolate agar

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Acute Bacterial Meningitis

• Examination of blood and other samples
• CSF requires at least three tubes
• Microbiology ? gram stain culture of spun CSF
• Chemistry ? glucose and protein
• Cytology ? cell count and differential, with a
  wet mount of uncentrifuged CSF also
• Blood and other samples
• Granulocyte count ? polys eosinophils, basophils
  have greater than gt 10,000 granulocytes/mm3
• Serum sodium lt135mEq/L suggests inappropriate ADH
  and TB meningitis
• Culture may yield agent causing meningitis when
  CSF cultures are sterile
• Acute and convalescent serum shows a four-fold
  rise in titer
• Sputum and bone marrow shows TB or fungal
  etiology
• Fecal samples may show enterovirus

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Intracranial Abscesses
CT scan with contrast revealed a 2.0 cm diameter
ring enhancing mass in the right occipital lobe
with edema extending into the posterior temporal
and parietal lobes. Partial opacification of the
right maxillary sinus also noted.

• Brain abscess
• Epidural abscess
• Subdural Empyema

36
Intracranial Abscesses

• Types of intracranial abscesses
• Brain abscesses focal suppurative process
  within the brain, result of mixed infections,
  etiology depends on organisms
• Etiology
• Aerobic and anaerobic strep, 60-70
• Bacteroides, 20-40
• Staph ssp 10-15
• Gram (-) rods, 23-33
• Fungi 10-15
• Toxoplasma gondii, in HIV ()
• Epidemiology
• Most commonly from contiguous sources, such as
  otitis media, mastoiditis, sinusitis, dental
  sepsis or penetrating trauma
• Less commonly from distant site, via hematogenous
  seeding, such as from the heart and lung

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Intracranial AbscessesTypes of Intracranial
Abscesses

• Epidemiology - portals of entry to CNS include
• Paranasal sinuses gt 50
• Otitis media, mastoiditis 10-20
• Metastatis from lung 5
• Skull trauma. Surgical procedures, infection from
  subdural hematoma variable

• Both are nearly identical in etiology.
• Epidural Abscess - Lesion has created a space
  between the dura mater and the skull
• Subdural Empyema - Lesion has created a space
  between the dura mater and the arachnoid
• Etiology
• Aerobic and anaerobic strep ssp are most common
• Staphlococcus aureus
• Other anaerobes
• Facultative gram (-) rods
• In young children, subdural empyema may be
  extension of meningitis

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Intracranial abscesses

• Suppurative Intracranial phlebitis
• lesion spreads centrally along the emissary
  veins, or it may propagate to cortocal vein
  thrombosis or venous sinus thrombosis
• Etiology
• Staph aureus
• Staph epidermitis, strep, gram (-), anarobes
• Epidemiology
• Most commonly follows infection of paranasal
  sinuses, middle ear, face or oropharnyx
• May occur in association with epidural abscess,
  subdural empyema or meningitis
• Occasionally occurs from distant sites, such as
  the lungs

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Manifestations of Intracranial Abscesses

• Manifestations
• Severe headaches ? most common symptoms
• Focal neurological signs
• Leukocytes
• Diagnosis
• History
• Skull films
• CSF
• Leukocyte count
• Glucose and protein
• Culture
• Blood culture
• Prognosis
• Mortality rate high, especially with subdural
  empyema
• Neurological deficits

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Spinal Epidural Abscess Subdural Empyema

• Organisms
• Staph aureus
• Aerobic and anaerobic strep ssp
• Organisms from a distant source
• Source
• Extension of osteomyelitis or paravetrebral
  infection
• Hematogenous spread

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Bacterial Toxicoses

• Tetanus
• Botulism

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Tetanus

• Etiology
• Clostridium tetani, gram (), anaerobic
  spore-former
• Spores ubiquitous in the soil
• Vegitative form present in guts of humans and
  animals
• Wounds are portals of entry
• Umbilical stump in underdeveloped countries
• IV heroin users, popping black tar heroin

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Tetanus

• Pathogenesis
• Anaerobic conditions needed for germination of
  spores
• No suppuration, gangrene or inflammation
• Tetanospasmis, an exotoxin responsible for the
  symptoms
• An A-B toxin, A causes toxic effect, B allows for
  binding
• Toxin enters motor neuron at myoneural junction
  by retrograde transport to alpha motor neuron
  synapse
• Impairs NT release from inhibitory neurons
• Effects may last days to weeks

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Tetanus

• Manifestations uncontrolled motor input to
  skeletal muscle, patient remains alert
• Local earliest, may affect only areas where the
  Clostridium containing wound in located
• Generalized (80 progression rate)
• Trismus lock jaw
• Risus sardonicus grimace of mouth
• Rigidity
• Spasms
• Death, due to respiratory failure
• Diagnosis
• Clinical signs
• No history of immunization
• History of a wound within the last two weeks

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Tetanus

• Prognosis
• With proper supportive care, 10-15 morality
• Without proper care, 60
• After recovery, no sequelae
• Prevention
• Preexposure immunization with toxoid
• Postexposure with tetanus prone wounds
• Immediate surgery to remove dead tissue
• Toxoid
• Human tetanus hyperimmune globulin (TIG)

46
Tetanus

• Other comments
• Antibiotics kill vegetative forms, but are not
  helpful because they do not get to the site well
• A patient who gets tetanus is not immune to the
  subsequent attack. The lethal dose is smaller
  than the antigenic dose.
• Elderly people are especially at risk in the US,
  should be immunized when they interact with the
  healthcare system