Infections of the Central Nervous System

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Infections of the Central Nervous System

• Charles S. Bryan, M.D.
• December 3, 2007

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Some terms

• Pleocytosis increased WBCs in the CSF
• Hypoglycorrhachia low CSF glucose
• Meningitis inflammation of meninges
• Encephalitis inflammation of the brain
• Meningoencephalitis both of the above
• Myelitis inflammation of the spinal cord
• Encephalomyelitis encephalitis myelitis

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Some terms (2)

• Parameningeal infection localized infection
  beside the meninges, e.g.
  
  
  
  
  brain abscess
  
  
  
  
  subdural empyema
  
  
  
  
  epidural abscess
  
  
  
  
  suppurative intracranial
  thrombophlebitis
  
  
  
  mycotic aneurysm
  

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The CSF formula

• Red cells (normally 0)
• WBCs (normally
• Differential (normally all mononuclear cells)
• Protein (normally 15 to 45 mg/dL)
• Glucose (normally 40 to 70 mg/dL or about 2/3 of
  simultaneous blood glucose)

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Some pointers on the LP

• If you think of it, its generally best to do it!
• In chronic problems, rule out localized
  intracranial pathology for acute problems, dont
  delay if there are no localizing signs!
• Save an extra tube (the Golden Rule)!

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Acute bacterial meningitis

• A MEDICAL EMERGENCY
• Consider in every patient with a history of URI
  interrupted by one of the meningeal symptoms
  vomiting, headache, lethargy, confusion, stiff
  neck
• Clinical picture is often unimpressive when the
  patient is first seen

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Triad of acute bacterial meningitis

• Fever (bacterial invasion of blood CSF)
• Stiff neck (nuchal rigidity due to protective
  reflexes from inflammation of the subarachnoid
  space)
• Brain dysfunction (nausea/vomiting, headache,
  irritability/excitability obtundation)

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Kernig sign(Vladimir Kernig, 1840-1917, Russian
physician)

• Limitation in passive extension at the knee due
  to spasm of the hamstrings
• Basis A protective reaction to prevent the pain
  of stretching inflamed sciatic nerve roots
• Kernigs method Done with patient sitting (now
  usually done with patient supine)

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Brudzinskis sign(Josef Brudzinski, 1874-1917,
Polish pediatrician)

• Flexion at the knees and hips in response to
  passive flexion of the neck
• Basis Protective reaction to prevent stretch of
  inflamed sciatic roots (similar to Kernigs sign)
• May be more sensitive if done in the sitting
  position

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LP in acute bacterial meningitis

• Purulent CSF with 1000 cells (mainly PMNs)
  EQUALS acute bacterial meningitis
• Increased intracranial pressure due to localized
  pathology is the sole absolute contraindication
  to LP
• Indications for repeat LP Initial tap
  non-diagnostic failure to improve on
  appropriate antibiotic therapy vague residual
  symptoms with relapse

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Grams stain of CSF in meningitis

• Sensitivity is 70 to 80, but false-positives
  reduce the overall usefulness by about one-half
• Beware of decolorization artifacts!
• In meningococcal meningitis, there may be only a
  few microorganisms, easily missed among the red
  background debris

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Pathogenesis of meningitis

• Mucosal colonization
• Mucosal invasion
• Bacteremia
• Meningeal invasion
• Bacterial replication in CSF
• Host response to bacterial antigens
• Subarachnoid space inflammation

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Pathogen offensive strategies in acute bacterial
meningitis

• IgA protease secretion
• Ciliostasis
• Adhesive pili
• Evasion of alternative complement pathway by
  polysaccharide capsule

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Host defensive strategies in acute bacterial
meningitis

• Secretory IgA
• Ciliary activity
• Mucosal epithelium
• Complement (serum bactericidal system)
• Cerebral endothelium Blood-brain barrier

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The blood-brain barrier in meningitis

• 99 of bacteremic adults do not develop
  meningitis
• However, 1/3 of bacteremic infants develop
  meningitis suggesting immaturity of blood-brain
  barrier
• Barrier seems to function unidirectionally
  (inoculation of subarachnoid space causes
  bacteremia 1/3 of the time)

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The blood-brain barrier in meningitis (2)

• Normal functions active transport, facilitated
  diffusion, aqueous secretion of CSF, homeostasis
• Major sites arachnoid membrane, choroid plexus,
  and endothelial cells of cerebral microvascular
• Meningitis cytokines (especially interleukin-1)
  increase permeability

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Cytokines in meningitis

• Interleukin-1, tumor necrosis factor,
  prostaglandins, other
• Presence of tumor necrosis factor in CSF may be
  specific for bacterial meningitis (as opposed to
  viral meningitis)

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Why is bacterial meningitis so devastating?

• Increased permeability of blood-brain barrier
  resulting in inflammatory response
• Brain edema from three mechanisms vasogenic from
  increased blood-brain-barrier permeability
  cytotoxic from toxic products from inflammatory
  cells or bacterial products interstitial from
  obstruction of CSF flow

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Complications of meningitis

• Acute complications requiring supportive care
  Seizures, aspiration, hyperthermia,
  hyponatremia/hyponatremia hypotension from
  septicemia
• Other organ systems Pulmonary GI bleeding
  pericardial tamponade (from pericarditis)
• Chronic Hydrocephalus subdural effusion

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Causes of bacterial meningitis by age

• Neonates E. coli, group B streptococci, Listeria
  monocytogenes, other bacteria
• 2 months to 5 years (1) H. influenzae (2) N.
  meningitidis (3) S. pneumoniae
• 5 to 30 (1) N. meningitidis (2) S. pneumoniae
• 30 to 65 (1) S. pneumoniae (2) Gram-negative
  bacteria including N. meningitidis
• 65 as above, but more cases due to Listeria
  monocytogenes and aerobic gram-neg rods

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The big three of bacterial meningitis

• Streptococcus pneumoniae Numerous serotypes of
  which about 20 cause about 80 of cases of
  invasive disease
• Haemophilus influenzae Of the 6 encapsulated
  types (a through f), only type b regularly causes
  meningitis
• Neisseria meningitidis 80 of isolates from
  nasopharynx or CSF have fimbriae

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Haemophilus influenzae meningitis

• Peak susceptibility between 7 and 12 months 93
  of cases under age 5
• Frequency increased in 2nd half of 20th century
  prior to the vaccine
• Complications subdural effusions, cerebral
  anoxia, cortical vein thrombophlebitis,
  blindness, hearing loss, spasticity, hemiplegia,
  convulsions, low IQ

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H. influenzae meningitis current issues

• Case-fatality rate is only 3 to 8, but 30 to
  50 of survivors have some mental deficits.
• Drug resistance (by plasmid-mediated
  beta-lactamase production)
• Epidemiology in day-care centers
• Preventability by vaccination

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Invasive meningococcal disease

• Can have meningitis, meningococcemia, or both
• About 30 to 40 of patients have meningococcemia
  without meningitis
• About 10 to 20 of patients have fulminant
  meningococcemia (50-60 die)
• About 1 to 2 of patients have chronic
  meningococcemia

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Invasive meningococcal disease (2)

• Most infections are acquired from asymptomatic
  carriers
• In families, as many as 5 develop secondary
  cases
• Age incidence of cases is almost exactly the
  inverse of antibody prevalence
• Encephalitis, myocarditis, and widespread
  hemorrhages can be seen in fatal cases

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Epidemiology of meningococcal disease

• About 1 to 2 cases/100,000 in temperate areas
  occurs especially in the winter and spring
• Serogroups A and C are known as epidemic
  strains group B is major cause of sporadic
  disease in the U.S. group Y is also a case of
  sporadic disease (also 29-E W-135 Z)

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Meningococcal disease indications for preventive
therapy

• Household contact Someone who frequently eats
  and sleeps in the same dwelling
• Intimate contact Someone with direct contact
  with oropharyngeal secretions (e.g., kissing
  mouth-to-mouth CPR)
• Small children in day-care centers

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Pneumococcal meningitis

• The major cause of acute meningitis in adults
  20 to 60 mortality and 1/2 of survivors have
  residua
• Most patients have predisposing causes otitis
  sinusitis pneumonia skull trauma with CSF leak
  endocarditis alcoholism impaired host defenses
• Diagnosis often delayed due to comorbidity

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Neonatal meningitis due to gram-negative bacilli

• Especially susceptible infants with
  myelomeningocele, marasmus, or middle ear disease
• Pathogens E. coli (61) Proteus (11)
• 81 of E. coli have K1 capsular antigen versus
  20-40 of E. coli in normal stools

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Meningitis in adults due to gram-negative bacilli

• Prior neurosurgery in 50 of patients
• Prior head trauma in another 30 of patients
• Associated medical problems in about 20 of
  patients, including severe underlying disease
  ruptured brain abscess strongyloidiasis

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Listeria monocytogenes meningitis

• 2 of cases of meningitis in the U.S.
• Disproportionately affects the very young, the
  old, and the debilitated
• CSF Grams stains may be misleading
• Bacteremia is common
• Neonates syndromes of intra-uterine acquisition
  versus late-onset listeriosis

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Epidemiology of bacterial meningitis some
associations

• Lower socioeconomic status increased risk of H.
  influenzae, S. pneumoniae
• Immunosuppression, lymphoma, or leukemia
  Listeria monocytogenes
• Skull fracture S. pneumoniae
• Congenital dermal sinuses E. coli, S.
  epidermidis, diphtheroids, Pseudomonas

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Aseptic meningitis etiology of the term

• Wallgren, 1925 A disease characterized by acute
  onset, meningeal symptoms, CSF pleocytosis,
  generally mononuclear, with sterile cultures, a
  relatively benign clinical course, of short
  duration, with recovery
• Wallgren, 1951 A syndrome of multiple causes
  and not a specific etiologic illness.

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Aseptic meningitis current operational definition

• A characteristic syndrome with meningeal
  irritation, CSF pleocytosis, and absence of
  microorganisms by direct examination or culture.
  The term viral meningitis is permissible if the
  illness is typical of an acute viral process
  with mononuclear pleocytosis and a short,
  uncomplicated course. However, it should be noted
  that many other processes can mimic viral
  meningitis. . . .

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Causes of viral meningitis

• Enteroviruses cause 1/2 of proven cases,
  typically in the summer in persons
• Others Flaviviruses, mumps viruses lymphocytic
  choriomeningitis herpesviruses (HSV-1, HSV-2,
  VZV, CMV) measles Epstein-Barr virus
  alpha-virus bunyavirus hepatitis virus

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Pearls on viral meningitis

• Enteroviruses Rash is typically maculopapular
  but can be petechial (mainly ECHO and Coxsackie)
• Mumps low CSF glucose is common
• Lymphocytic choriomeningitis intense pleocytosis
  is common
• If picture looks like aseptic meningitis but CSF
  formula is confusing, repeat LP in about 6 hours

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Other causes of aseptic meningitis syndrome

• Partially-treated bacterial meningitis
• Tuberculous or fungal meningitis
• Parameningeal infection
• Syphilis or leptospirosis
• Toxoplasmosis, amebiasis
• Sarcoidosis
• Drug reactions

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The syndrome of chronic meningitis

• Some combination of fever, headache, lethargy,
  confusion, nausea, vomiting, and stiff neck
• Frequent elevation of CSF protein, predominantly
  lymphocytic pleocytosis, low CSF glucose
• Process fails to improve or progresses during at
  least 4 weeks of observation.

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Causes of chronic meningitis

• Infections Tuberculosis, cryptococcosis and
  other fungal infections, syphilis, brucellosis,
  and miscellaneous agents that more commonly cause
  brain abscess
• Other tumors, sarcoidosis, granulomatous
  angiitis, uveomeningoencephalitis, Behcets
  disease, chronic benign lymphocytic meningitis

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Tuberculous meningitis

• Sometimes associated with miliary tuberculosis
• Patients are older today compared to
  pre-chemotherapy era
• Normal CSF in up to 50 non-reactive PPD in a
  bout 20
• At least 24 neurologic syndromes

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Cryptococcal meningitis

• Prior to HIV, up to 50 of patients had no
  underlying disease
• HIV disease points out strong association with
  impaired T-cell function
• Over 85 have demonstrable cryptococcal antigen
  in CSF
• Papilledema in 50 cranial nerve palsies in 20

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Syphilitic meningitis

• Rare
• 50 have focal signs 1/3 have cranial nerve
  palsies
• Usually subacute
• Negative serum serology in 35 negative CSF
  serology in 14
• Specificity of CSF FTA-ABS in doubt

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Herpes simplex encephalitis

• The most important cause of sporadic viral
  encephalitis
• Necrotizing. One may find RBCs in CSF
• Prominent temporal lobe involvement (aphasia,
  bizarre behavior, hallucinations)

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Herpes simplex encephalitis (2)

• High mortality, with high frequency of residua
  among survivors
• Many disease entities can mimic this process
• Historically, diagnosable with certainty only by
  brain biopsy
• However PCR of CSF now available

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Brain abscess

• Classic triad Fever, headache, focal neurologic
  deficit (all three of these features are present
  in less than 1/2 of cases)
• Focal neurologic deficits correlate well with
  anatomic location frontal, temporal, parietal,
  occipital, cerebellar

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Brain abscess (2)

• Presentation is often that of a non-specific mass
  lesion tumor is a frequent preoperative
  diagnosis
• Ring-enhancing lesion on CT scan
• 20 are cryptogenic remainder are secondary to
  contiguous or distant infection or to trauma
  including neurosurgery

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Brain abscess (3)

• Predisposing contiguous infections otitis media
  mastoiditis sinusitis (frontal, ethmoidal,
  sphenoid) dental sepsis
• Predisposing distant infections lung abscess,
  empyema, bronchiectasis endocarditis infection
  anywhere in the face of a right-to-left shunt
  from congenital heart defect

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Brain abscess (4)

• Streptococci in 60 to 70 (especially
  peptostreptococci and S. anginosus)
• Bacteroides species 20 to 40
• Enterobacteriaceae 23 to 33
• Fungi 10 to 15
• Pneumococci, H. influenzae, protozoa, helminths
  

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Subdural empyema

• Sinusitis (especially frontal) is the
  predisposing factor in 50 of cases
• Otitis media or mastoiditis predisposes in 10 to
  20 of cases
• High prevalence of anaerobic organisms

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Cavernous sinus thrombosis

• Often from paranasal sinusitis or infection of
  face or mouth
• Unilateral periorbital edema exophthalmos
  chemosis
• Papilledema fixed eye with involvement of
  nerves III, IV, V, and VI
• S. aureus the most common pathogen

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Spinal epidural abscess

• Fever, back pain, motor/sensory/sphincteric
  defects, paralysis
• Consider in any febrile patient with localized
  back pain
• S. aureus in 60 to 90
• MRI now diagnostic procedure of choice (dont do
  LP first if this diagnosis is suspected!)