1. Infections of the Central Nervous System:
Meningitis and Brain Abscesses
Robyn S. Klein, M.D., Ph.D.
Washington University School of Medicine
2. Case Presentation
60 year old woman presents to ER in NC during the summer with
new onset seizures. She had been well until four days prior when
she developed a URI. One day ago she developed a fever and HA.
Last evening the HA worsened and she appeared confused at times.
This morning she entered her kitchen, poured a box of cereal on the
table, then drove her car through the closed garage door.
There is no history of travel and she has no other significant medical
history.
PE reveals an acutely ill, irritable patient. She is oriented to place
and year but cannot calculate. Temp is 101.6 F (38.7 C), pulse is
100/min, RR 24/min and BP 110/60 mm Hg. There is no rash. Pupils
are equal and reactive, neck is moderately stiff to passive motion.
There are no localizing neurologic findings.
3. Laboratory Studies
Hematocrit 36%
WBC 11 (85% PMNs, 12% lymphs, 3% monos)
BUN 12
Plasma glucose 105
Elecrolytes normal
Head CT+contrast: nonenhancing, low-density temporal lobe lesion
CSF: normal OP, cell count 200 (65% lymphs, 35% PMNs), 2 RBCs
glucose and protein are normal.
Gram stain: negative for bacteria
Which antimicrobials would you start?
a. Ampicillin and ceftriaxone
b. Ampicillin, vancomycin and ceftriaxone
c. Ampicillin, ceftriaxone and acyclovir
d. Ampicillin and metronidazole
4. Approach to the Diagnosis of CNS Infections
Assess risk for infection
Exposures
Season
Concomitant illnesses
Physical Examination
Assess safety of LP
Identify other findings
Diagnostic Evaluation
Pathogen specific vs. nonspecific
CSF and neuroimaging
liklihood of herniation
viral meningitis
encephalitis
subarachnoid hemorrhage
most bact. meningitis
liklihood of herniation
severe bact. Meningitis
subdural empyema
brain abscess
severe HSV
rickettsial encephalitis
Reye syndrome
5. Pathogenesis
1. Nasopharyngeal acquisition
2. Bloodstream invasion
3. Bacterial entry into CSF
4. Multiplication within CSF
5. Subarachnoid space inflammation
6. Increased BBB permeability and vasogenic,
cytotoxic and interstitial edema
7. Increased intracranial pressure
6. Immune surveillance/activation in the CNS
• CNS devoid of classical APCs
•dendritic cells localized to
meninges, vessels and choroid
plexus
• CNS without lymphatics
• CNS lacks constitutive MHC
•MHC II expression restricted to
recruited APCs
• Blood-brain/CSF barrier
Flugel, Nature, 2009; 462, 94-98
11. Imaging of Intracranial Infections
CT
• Rapid (~10 min)
• High density=white (bone
and blood)
• Low density=gray (brain,
CSF, air)
• Iodinated contrast
evaluates BBB
MRI
• Takes time
• Images in 3 planes
• Can assess
– Morphology/pathology
– Blood flow
– BBB (Gadolinium)
• Contrast resolution
• Technological advantages
– FLAIR
– MTI
– DWI
12. MRI Imaging in Meningitis
Axial FLAIR: cerebritis Post-contrast T1WI: area of
enhancement
13. Pyogenic Meningitis
• Leptomeningitis
Inflammation of arachnoid
tissue/space
Dura
Arachnoid
Space
Pia
Parenchym
a
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and the University of Iowa’s Virtual Hospital, www.vh.org
14. Clinical Clues to Etiology
• Age
• Predispositions
– URIs
– smoking
– pregnancy
• Immune status
• Epidemiologic considerations
– Meningococcal outbreaks
– H. flu. Infections in family
– Season
• Rashes
– Petechial-purpuric vs. Maculo-petechial
• Atypical presentations
– Think: brain/parameningeal abscess
– Think: BE
– Think: tumor-related CSF leak
15. General Management of Suspected Meningitis
• Early recognition often difficult
• Initial clinical survey
– Secure airway, vascular access
– Provide oxygen
– Evaluated for altered MS
– Administer mannitol
• Empiric antibiotics!
• THEN LP
• Treatment delay increases morbidity/mortality
• Vaccination: Hib type 2, MCV-4 (serogroups A,
C, Y and W-135)
16. Determination of Etiologic Agent
• CSF gram stain
– Past: used to guide initial Rx; now thought to be misleading
– In pneumococcal meningitis, gram stain positive in 70-90%
• CSF/blood cultures positive in 77% of episodes in adults
– Positive in 60-80% of untreated patients (yield is 20%
lower with prior antibiotic therapy)
– Sensitive, but this varies with offending organism:
• 90%: pneumococci or staphylococci
• 86%: H. influenzae (now eradicated by Hib vaccine)
• 75%: N. meningitidis A,C,Y,W135
• 50%: gram negs. Listeria or anaerobes, fungi (nonAIDS)
• 37%: mTB (requires large volumes)
17.
18. Incidence of Bacterial Meningitis in USA
Percentage Incidence
(per 100K)
Fatality Rate
(%)
S. pneumo.* 71 1.1 21
N. mening. 12 0.6 3
Gp B Strep. 7 0.3 7
L. monocyt. 4 0.2 15
H. Influ. 6 0.2 6
Others: Staph/Stre
p,
Gram negs
*44% intermediate or high level resistance to penicillin
19.
20. Pneumococcal conjugate vaccine (PCV7):
• Added in 2000
• Effective in preventing IPD
• Provides herd immunity
• 2003: drop in 30K cases
• Overall 33% decrease in cases, esp
<5yo
21. Petechial/Ecchymotic Rash:
Meningococcemia
• Other causes of erythematous or petechial rash:
– Enterovirus
– ECHO virus type 9
– H. influenzae
– S. pneumoniae
– RMSF
– S. aureus endocarditis
22. Meningococcal Disease
Invasive meningococcal disease occurs in three common clinical
forms: meningitis (50% of cases), blood infection (30%) and
pneumonia (10%); other forms account for the remainder (10%)
of the cases.
Onset can be abrupt and course of disease rapid.
Case fatality rate is 10%-14%; 11%-19% of survivors suffer
serious sequelae (a condition caused by previous disease)
including deafness, neurologic deficit, or limb loss.
23. Causative Bacteria
Meningococci are carried only by humans in the nasopharynx—their only
reservoir
Overall 5%-10% of the population carries the bacteria
Adolescents and young adults have the highest carriage rates
Few carriers develop disease
Transmission occurs when close, face-to-face contact permits the exchange
of salivary secretions from people who are ill or are carriers
Worldwide, the vast majority of disease is caused by 5 serogroups (A, B, C,
Y, W-135) of the bacterium
In the United States, almost all cases are caused by serogroups B, C and Y;
there is currently no licensed vaccine that protects against serogroup B in
the U.S.
24.
25. Meningococcal Conjugate Vaccine (MCV4)
Licensed in the United States for persons 2–55 years of age
Covers Serogroups A, C, Y and W-135
Included in the Vaccines for Children (VFC) Program
Cost to private sector per dose: $100.00-$110.00
Indications:
college freshmen living in a dormitory
military recruits
Splenectomy
Complement deficiency
Occupational exposure
Travel to endemic countries (Sub-Saharan Africa)
Meningococcal Polysaccharide Vaccine (MPSV4)
Licensed in 1981
Recommendations for use: MPSV4 is recommended for
individuals who are at elevated risk aged over 55
26. Complications of Meningitis
• Brain swelling with increased IC pressure/herniation
• Cortical vein phlebitis/cerebral arteritis and infarction
• Subdural effusions/empyema
• Hydrocephalus
• Ventricular empyema
• Sagittal sinus thrombosis
• Focal cortical necrosis
• 10% still die
• 40% survivors: mental retardation, paralysis, blindness
27. Meningitis in Tropical Areas
• Hib, S. pneumo. with >30% resistance
• Unusual pathogens
– Nontyphoidal Salmonella spp.
– S. Aureus
– S. Suis
– mTB (especially elderly, IC)
– Angiostrongylus cantonensis (rat lung
worm)
Paralysed and in agony: How one
man's dream trip became a
holiday from hell after he was
struck by crippling 'rat lungworm'
parasite
By HANNAH ROBERTS UPDATED:
08:19 EST, 21 January 2012
28. Initial Therapy for Community
Acquired Purulent Meningitis
Age Pathogens Drugs
3mo-50y S. pneumo. Vanco + Ceftriax
N. mening. 500mg q6hr 2g q12hr
>50y L. monocyt. Above + Ampicillin
2g q4hr
Skull fx S. pneumo. Vanco + Cefepime or Mero
CSF leak various Strep. 2g q8hr
Corticosteroids: 0.15 mg/kg, q6hr, starting with first dose of antibx
29. Antibiotic Penetration into the CSF
Class Antibiotic Comments
Standard dose
adequate
Chloramphenicol,
Sulphonamides,
trimethoprim,
fluoroquinolones,
metronidazole,
rifampicin, isoniazid,
pyrazinamide
Good oral availability
Require high dose Penicillins,
cephalosporins
Penetration enhanced
by inflamed meninges
Standard dose only
when meninges
inflamed
Vancomycin,
clindamycin,
ethambutol
Toxicity prevents high
dose
Do not penetrate CNS Aminoglycosides Requires intrathecal
administration
30. Chemoprophylaxis for contacts of index case
• Neisseria meningitidis
– Household contacts including pupils in same dormitory or
sharing a kitchen
– Any mouth-to-mouth contact
– Unprotected ET intubation during 7 days prior
– Immunize contacts as well
– Agents: rifampin, cipro
• Hemophilus influenzae type b
– Household contacts if one is <4 and unimmunized
– Household contacts of IC child regardless of immunization
status
– All school contacts regardless of age when 2 or more cases
occur in <120 days
– Index case <2 yrs or member of household with a susceptible
contact treated with regimen other than ceftriaxone, cefotaxime
– Agents: rifampin
31. An audit of acute bacterial meningitis in a large teaching hospital 2005-10.
Stockdale AJ, Weekes MP, Aliyu SH.
QJM. 2011 Aug 11.
35. Granulomatous Meningitis: Subacute
or Chronic Syndromes
• Course runs weeks to years
• Symptoms and signs may fluctuate
• Fever, HA, stiff neck, photophobia, MS
--time course gradual, lethargy common
36. Granulomatous Meningitis: TB
• Primarily in patients from underdeveloped
countries; <10% of all meningitis in USA
• Occurs secondary to hematogenous spread
• Tuberculomas form in or near arachnoid
layer--> rupture and induce intense
inflammatory response
• Diagnosis requires large volumes CSF
37. TB Meningitis
A. CT: tuberculomas
B. Fourth Ventricle
www.vh.org
C. caseating granuloma
www.vh.org
A. MRI: Basilar meningitis
38. Treatment of TB Meningitis
• Required anti-TB
chemotherapy
– INH, RIF, PZA, ETH
• Duration of therapy
– 4 drugs x 3 mos
– 3 drugs x 6 mos
• Corticosteroids: improves
survival not disability
– IV Dexamethasone 4 wks
– Oral Dexamethasone 4 wks
• Clinical & diagnositic
follow-up
39. Granulomatous Meningitis: Fungi
• Cryptococcus
– CSF Ag: positive in 83-98% of patients
• Candida
– IVDU, trauma, surgery
• Coccidioides immitis
– Complement fixing Abs in up to 95%
• Histoplasma (rare)
– CSF vs. urine Ag
Copyright protected material used with permission of the authors and the University of Iowa’s Virtual Hospital, www.vh.org
40. Treatment of Fungal Meningitis
• Cryptococcal
– Ampho B + Flucytosine (pk 70-80; tr 30-40 mg/L)
– Fluconazole
– Suppression: Fluconazole or Itraconazole
• Candidal
– Ampho B + Flucytosine or + Fluconazole
• Coccidioidomycosis
– Fluconazole indefinitely
– Ampho B
• Histo/blasto
– Ampho B
41. Fungal Cerebritis/Abscess
• Opportunistic invaders
• Granulomatous
inflammation with
hemorrhagic necrosis
• Most common
pathogens:
– Candida
– Aspergillus
– Zygomycetes
• Differential Diagnoses
• Treatment
– Ampho B
– Azoles
– Flucytosine
– Extensive drainage
Copyright protected material used with permission of the authors and the University of Iowa’s Virtual Hospital, www.vh.org
42. Lymphocytic (Aseptic) Meningitis
• Usually of viral etiology
• Produces minimal changes grossly
• Negative CSF cultures and stains
Common Less common Rare
Enteroviruses HSV-1 Adenovirus
Arboviruses Mumps EBV
HSV-2 LCMV Influenza A, B
HIV-1 ?VZV Measles
Parainfluenza
Rubella
Copyright protected material used with permission of the authors and the University of Iowa’s Virtual Hospital, www.vh.org
43. Approach to the Patient with Aseptic
Meningitis
History:
history of travel, organ transplant
exposures to HIV, TB, STDs, rodents, insects, drugs
systemic signs; season
PE:
skin: exanthem, enanthem, vesicles
Parotitis: mumps, LCMV, coxsackievirus
Orchitis: mumps, LCMV
LAD: EBV, HIV, CMV
Lab eval:
CSF studies (PCR, cultures)
PPD, VDRL, HIV Ab
acute and convalescent serologies
44. Amplification of Viral Nucleic Acids
PCR, NAS-BA, BC-DNA
Single most important method for diagnosis of:
Herpesviruses
Enterovirus 71
45. Treatment of Viral Meningitis
• Enteroviruses: Pleconaril (VP 63843) 400 mg tid
• Herpesviruses: Acyclovir 10mg/kg IV with hydration
• LaCrosse Virus or HF viruses: Oral Ribavirin
– Loading dose 30 mg/kg
– then 15 mg/kg q6 x 6 dys; 7.5 mg/kg q6 x 6 dys
• WNV: High titer IVIG has had variable results
• Corticosteroids
• Airway protection/Mannitol
46. Brain Abscesses
• Relatively uncommon: 1/100,000 persons/yr
• 75% are associated with peripheral infections
– Pre-antibiotic era: mastoiditis, otitis media or paranasal sinusitis
– Current era: pulmonary infections and endocarditis
• Opportunistic infections
• Parasites
• Course of primary infection: months to years
• Presents with HA (>75%), focal neurologic deficit (>60%),
seizure (25-30%)
• HA, N/V often begin intermittently, progress to crisis
• Mortality: 33-50%
47. Stages of Abscess Development
1
2
3
Cerebritis: inflamed area
with discoloration and
softening.
Formation of capsule
with soft center.
Formation of fibro-gliotic
capsular wall with
pus-filled center.
(Tung and Rogg, 2003, AJNR, 24:1110)
48. Bacterial Abscesses
• Most Common Organisms
(80%):
– Anaerobic streptococci
– Pneumococcus sp
– Staphylococcus sp.
• Less Common Organisms
(15%):
– Coliforms
– Actinomyces
• Occasional Findings (5%):
– Multiple organisms
– No organisms
• Differential Diagnoses
– CNS infections
– CNS neoplasms
– Cerebrovascular disease
• Treatment
– PCN
– Metronidazole
– 3rd gen Ceph
– Nafcillin or Vanco
– Drainage
– Anticonvulsants
