Infections of the Central Nervous System

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Infections of the Central Nervous System

• Helmut Albrecht, M.D.
• November 2008

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CNS Infections

• Meningitis
• Bacterial, viral, fungal (cave chemical, cancer)
• Encephalitis
• Bacterial, viral
• Meningoencephalitis
• Abscess
• Parenchymal, subdural, epidural

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Terminology

• 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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Terminology (2)

• Parameningeal infection localized infection
  next to the meninges, e.g.
• brain abscess
• subdural empyema
• suppurative thrombophlebitis
• mycotic aneurysm

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Case

• A 35 yo man is brought to the ER
• h/o 5 days fever and chills
• His wife relates that he has been very confused
  today and she called 911 after a seizure
• PMHx is unremarkable except for a splenectomy at
  age 14 after a MVA
• Meds prn tylenol in the last week
• NKDA
• Vaccinations are up to date

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Case

• Exam
• Ill appearing man
• Temp 39 C
• Lethargic and can answer simple questions but can
  give no meaningful history.
• Neck is stiff to flexion and extension
• Fine petecchial rash on chest and upper arms

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Exam in suspected CNS Infection

• Mental Status
• Cranial nerve and fundoscopic exam
• Meningeal Signs
• General exam rashes, lymphadenpathy
• Labs CBCD, BMP, PT/PTT, bHCG, blood cultures,
  UA CS
• Radiology CT head - uncontrasted if no focal
  signs, contrast if mass suspected (not needed in
  gt90 of patients with meningitis)

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Lumbar Puncture

• No need to obtaining CT before LP
• Age lt60
• Immunocompetent
• No h/o CNS disease
• No recent seizure (lt1week)
• Normal sensorium cognitition
• No papilledema
• No focal neuro deficits

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Initial Management of Patients with Signs of
Meningitis
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Some pointers on the LP

• If you think of it, do it!
• In chronic problems, rule out localized
  intracranial pathology for acute problems, dont
  delay if there are no localizing signs!
• Save extra fluid!

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LP

• Increased intracranial pressure is expected but
  LP contraindicated if a mass is present or if
  epidural spinal abscess is suspected
• Left lateral decubitus position
• L3-L4 interspace or L4-L5 interspace
• Think about your studies before the LP

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LP

• Tube 1 cell count and differential (2 cc)
• Tube 2 glucose and protein (2 cc)
• Tube 3 gram stain and routine culture,
• cryptococcal antigen, AFB stain and culture,
• cytology, special studies (VDRL, viral studies,
• PCRs), keep the rest (fill er up)
• Tube 4 cell count and differential (2 cc)

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Key CSF Features

• CSF is not liquid gold get enough to get your
  answer
• CSF Glucose is 2/3 of serum glucose (cave DM)
• Red cells (normally 0), WBCs (normally lt 5/mm3)
• Differential (normally all mononuclear cells)
• Protein (normally 15 to 45 mg/dL)
• Traumatic LPs
• CSF pro increases by 1 for every 1000 RBCs
• Tube 1 and Tube4 for RBCs when SAH is in the
  differential or tap is traumatic
• Very high CSF protein levels will make CSF yellow
• Send a full tube of CSF for cytology not just a
  few ccs

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Lumbar Puncture

• Contraindications
• Infection in overlying skin
• Increased ICP with focal lesion
• Relative
• Coagulopathy
• Thrombocytopenia
• If delay is anticipated obtain blood cultures and
  GIVE antibiotics
• You have 2 hours after Abx before sensitivity is
  affected

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Acute bacterial meningitis

• A MEDICAL EMERGENCY
• Consider in every patient with a history of URI
  evolving into meningeal symptoms vomiting,
  headache, lethargy, confusion, stiff neck
• Clinical picture may be unimpressive when patient
  is first seen

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Epidemiology

• 400 per 100,000 in neonates
• 1-2 per 100,000 in adults
• Strep pneumoniae Neisseria meningitidis
• HIB vaccine has been very effective
• Mortality
• 5 in children beyond infancy
• 25 in neonates and in adults

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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 (intracranial pressure plus
  inflammation resulting in nausea/vomiting,
  headache, irritability/excitability, altered
  mental status, obtundation)

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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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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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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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Bacterial Menigitis

• Age less than 3 months
• Group B strep
• L. monocytogenes
• E. coli
• Strep pneumoniae

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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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Bacterial Meningitis

• 3 Months to 18 years
• N. meningitidis
• S. pneumoniae
• H. influenzae

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Bacterial Meningitis

• Age 18 to 50 years
• S. pneumoniae
• N. meningitidis
• H. influenzae

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Bacterial Meningitis

• Over age 50 years
• S. pneumoniae
• L. monocytogenes
• Gram (-) bacilli

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Clinical Features

• History
• Living conditions
• College dorm/barracks?N meningitidis
• Trauma
• Recent neurosurgery?Staph/gram(-) rod
• Immunocompetence
• Immunization hx
• None?HiB
• Antibiotic use

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Epidemiology of bacterial meningitis some other
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
• Splenectomy S. pneumo, H. flu, N. meningitidis,
  listeria

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Acute Bacterial Meningitis (nosocomial)

• 40 of cases associated with
• head trauma
• neurosurgery
• shunts
• Mortality 35
• Trauma, surgery SA, gram negatives
• Shunts SA, CNS, Propionibacteria

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OUTBREAK!

• Setting Pig farms in Sichuan, China
• 3 farm workers died with meningitis
• Spreading infection
• 215 infected, 50 with meningitis
• 24 with SSTI, 26 with sepsis
• Chinese health authorities send physicians,
  epidemiologists, and microbiologists
• New human adopted strain of Strep. suis

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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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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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Vaccine

• There are 12 known serogroups of Neisseria
  meningitides
• In US 60 of all cases of meningococcal disease
  and 80-90 of all cases in adolescents, are
  caused by serogroups C, Y, and W-135.
• Both the polysaccharide vaccine (PSV4) and the
  MCV4 vaccine provide protection against these
  three strains as well as serogroup A.
• Unfortunately, neither vaccine provides
  protection against serogroup B. This serogroup
  causes nearly one third of all cases of
  meningococcal disease in the United States and is
  the most frequent cause of meningococcal disease
  in infants.

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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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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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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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Other causes of aseptic meningitis syndrome

• Partially-treated bacterial meningitis
• Tuberculous or fungal meningitis
• Parameningeal infection
• Syphilis or leptospirosis
• Toxoplasmosis, amebiasis
• Sarcoidosis
• Drugs (Sulfa, IVIG, NSAIDS)

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Viral Meningitis

• 85 secondary to
• Echo-
• Coxsackie
• Entero-
• Also consider HSV, and EBV
• Neutrophils may predominate in the CSF in the
  first 24 hours
• Consider starting ATBs until cultures come back
  (-)

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Causes of viral meningitis

• Enteroviruses cause gt 1/2 of proven cases,
  typically in the summer in persons lt 40
• 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 petecchial (mainly ECHO and Coxsackie)
• Mumps low CSF glucose is common
• Lymphocytic choriomeningitis virus 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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Diagnosis
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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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Chronic Meningitis

• Myriad infectious causes,
• most common TB
• spirochetes (syphillis, Lyme)
• bacteria (Brucella)
• fungi (Cryptococcus, Candida, Sporothrix,
  Coccidiodes, Histoplasma)
• Many non infectious causes
• (Behçets, neoplasm, sarcoid)

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Chronic Meningitis (cont.)

• Important diagnostic considerations
• Cell count in CSF may not be diagnostic/specific
  
• (1/3 patients with TB have PMN predominance,
  normal
• CSF in up to 50
• Large volumes of CSF, repeat taps may increase
  yield
• PCR available for TB, more sensitive than
  culture
• Skin testing (including repeats) useful for TB
  but
• non-reactive PPD in about 20
• If all else fails, may try empiric trials (TB,
  fungi)

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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

• Very 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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Encephalitis

• Myriad causes
• Viruses HSV, VZV, Herpes B, arboviruses
• Bacteria Rickettsia, Ehrlichia, Listeria,
• Syphilis, Lyme, Leptospira
• Fungi Crypto, histo,etc.
• Protozoa Naegleria, Acanthamoeba, malaria,
• toxoplasma, trypanosoma
• Most with available treatment or public health
• implications, so specific diagnosis important

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Herpes simplex encephalitis

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

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Encephalitis (cont.)

• HSV
• PCR available, accurate, precludes need for brain
  bx if pos
• Very acute, acyclovir/valacyclovir highly
  effective
• Herpes B
• Simian herpes virus related to HSV (asymptomatic)
• Devastating (usually fatal) illness in humans
• Transmission bite/mucous membrane contact
• Prompt treatment essential
• p.o. valaciclovir for postexposure
• iv acyclovir for symptomatic persons

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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

• Presentation often that of a non-specific mass
  lesion
• tumor is a frequent preoperative diagnosis
• Ring-enhancing lesion on CT scan
• 20 cryptogenic, 80 with distant
  infection/trauma
• Classic triad Fever, headache, focal neurologic
  deficit
• (all three present in less than 50 of cases)
• Focal neurologic deficits correlate well with
  anatomic
• location frontal, temporal, parietal,
  occipital,
• cerebellar

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Brain Abscess

• Focal brain infection related to
• penetrating trauma
• infection of paranasal sinuses
• infection of middle ear
• extension of dental abscess
• infectious emboli
• hematogenous spread (often in the
• setting of immune suppression)

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Bacterial Brain Abscess--Microbiology

• Predisposing Condition Microbiology
• Otitis, mastoiditis Strep, anaerobes,
  Enterobacteriaceae
• Sinusitis Streptococci, Bacteroides, Staph,
• Hemophilus, Enterobacteriaceae
• Dental Fusobacterium, Prevotella,
• Bacteroides, Streptococci
• Penetrating trauma Staph, Strep,
  Enterobacteriaceae
• (including surgery)
• Bacterial endocarditis Staphylococci,
  Streptococci

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Other Bacteria Causing Focal Brain Lesions

• Nocardia
• Patients with defects in cell-mediated immunity
• (esp. steroids, organ transplants, HIV,
  neoplasm)
• Listeria
• Mycobacteria

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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
  lt 1

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Management of Brain Abscess

• Imaging to confirm suspicion
• Aspiration or surgery if large lesions
• and/or microbiology unclear
• (e.g. pos. blood cx in patient with SBE).
• Long-term abx (such as 3rd gen. ceph.
• or high dose PCN metronidazole)

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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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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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