cns infections 2013 -mk.pptx
TRANSCRIPT
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Mahen Kothalawala
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CNS infections Meningitis,
Encephalitis,
Parameningeal abscesses (subdural empyema andepidural abscess),
Brain abscesses,
&
CSF shunt infections.
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Meningitis
is an inflammatory response to bacterial infection of thepia-arachnoid and CSF of the subarachnoid space
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Epidemiology
Incidence is between 3-5 per 100,000
More than 2,000 deaths annually in the U.S.
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Bacterial meningitis and other CNS infections areconsidered infectious disease emergencies that can causesignificant patient morbidity and mortality.
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Mortality/Morbidity Bacterial meningitis -uniformly fatal before the antimicrobial
era.
overall mortality rate has decreased, but remains alarminglyhigh - - Higher in developing countries
Varies with the specific etiologic agent
S pneumoniae 19-26%
H influenzae - 3-6%
N meningitidis 3-13%,
L monocytogenes 15-29%
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Survivors end up with complications
Children suffers mostly with complications
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Morbidity associated with
complications
in children In adults
sensorineural hearing loss / Cranial nervepalsies
brain infarction,,
epilepsy hydrocephalus,
diffuse brain swelling
hydrocephalus,
cerebral vein thrombosis,
cerebral palsy
More with H.influenzae meningitis
**** Severe morbidity is associated with H.influenzae meningitis and TB
meningitis due to fibrinous exudates
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Viral meningitis
Viral meningitis (without encephalitis) is less than 1%.
In patients with deficient humoral immunity (eg,agammaglobulinemia), enterovirus meningitis mayhave a fatal outcome.
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Meningococcal
Meningitis belt - Faso, Chad, Ethiopia and Niger; in2002, the outbreaks occurring in
Burkina Faso, Ethiopia and Nigeraccounted for about 65% of cases
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Crossing of the
BBB and entryinto the CSF
Bloodstreaminvasion
Nasopharyngealepithelial cell
invasion
Bacteremia with
intravascularsurvival
Nasopharyngealcolonization
Neisseria meningitides (meningococcus)and nasopharyngeal colonization with S
pneumoniae (pneumococcus).
Survival andMultiplication in
the subarachnoidspace
Pathogenesis of Meningitis
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Retrograde flowto meningesthrough the
olfactory bulb
Nasopharyngealepithelial cell
invasion
MeningitisFree living
amoeba in naturalresovoires
Pathogenesis of Meningitis
eg,Naegleria fowleri,
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Meningitis
Spread along the
CSF fistuloustract
Colonizing bacteria insinuses/auditorycanal otitismedia, congenital
malformations, trauma, directinoculation during intracranial
manipulation
Pathogenesis of Post traumatic/Neurosutgery Meningitis
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Pathogenesis cont.With in the CNS, the infectious agents likely survive as
immunoglobulins, neutrophils, complement components
absent or activity limited
replication of infectious agents remain uncontrolled triggersthe cascade of meningeal inf lammation
Increased CSF concentrations of TNF-alpha, IL-1, IL-6, andIL-8 are characteristic findings in patients with bacterial
meningitis
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Treatment using rapidly bactericidal agents maytransiently worsen the patients condition due to rapidrelease of pyrogenic substances in to CSF
Increase of proinflammatory mediators
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Specific Pathogens
A P d i P h
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Age group Predominant Pathogen
Age 0-4 weeks S agalactiae (group B streptococci)E coli K1L monocytogenes
Age 4-12 weeks S agalactiaeE coliH influenzaeS pneumoniae
N meningitidis
Age 3 months to 18
years
N meningitidis (worldwide epidemic strains A,B,C W135)
S .pneumoniaeH influenzae
Age 18-50 years S pneumoniaeN meningitidisH influenzae
Age older than 50 years S pneumoniaeN meningitidisL monocytogenesAerobic gram-negative bacilli
Immunocompromisedstate
S pneumoniaeN meningitidis
L monocytogenesAerobic ram-ne ative bacilli
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***Direct extension from the throat or nasal or ear colonization an give rise to post
traumatic meningitis
Intracranial manipulation, includingneurosurgery
Staphylococcus aureusCoagulase-negative staphylococciAerobic gram-negative bacilli,includingPseudomonas aeruginosa
Basilar skull fracture S pneumoniae
H influenzaeGroup A streptococci
CSF shunts Coagulase-negative staphylococciS aureusAerobic gram-negative bacilli
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Other causes
Bacteraemic infectionof Salmonella, Brucella andStaphylococcus aureus can cuase meningitis
Gram Negative meningitis in overwhelming infectionsdue to Strogyloides / Hyper infection due toStrongyloides stercorhalis
Leptospira and Treponema
Protozoa Acanthomoeba and Naeglaria fowleri Fungi Histoplasma and
Nematodes Angyostrogilus cantonensis
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Clinical diagnosis unreliable- symptoms unreliable specially extremesof age
The efficacy of treatment (CNS) infections -depends on the accuracy ofthe etiologic diagnosis.
requires the best specimen at the appropriate time,
transporting it to the laboratory under optimum conditions,
processing the specimen efficiently and timely manner,
and selecting the tests necessary to identify the spectrum of possibleetiologies
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Clinical signKernig's sign sensitivity, 5%; likelihood ratio for a positive test result
[LR(+)], 0.97)
Brudzinski's sign (sensitivity, 5%; LR(+), 0.97),
Nuchal rigidity (sensitivity, 30%; LR(+), 0.94)
Degree of meningealinflamation
6 up to 100 Clinical signs are unreliable
Inbetween Unreliable(>/=1000 WBCs/mL of CSF Nuchal rigidity shows diagnostic value- sensitivity
100% and negative predictive value 100%
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Diagnosis
Should not be delayed
Inform laboratory
Initial report based on Cell count and Direct smear Cytospin method gives more positive yield than
traditional overlaying
Gram stain can be considered as the gold standard
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Diagnosis Is established by investigation of CSF obtained from
lumbar puncture,
Cysternal puncture or ventricular puncture orfontanelle taps possible not done routinely
Exclude raised intracranial pressure before performingthe procedure due to possibility of herniation
Place of CT/ MRI to exclude SOL
When, contraindication +, diagnosis established usingother means Blood culture, WBC/DC, CRP togetherwith symptoms
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Additional factors for success Communication between the clinician and laboratory-
about clinical notes, Patient condition, antibiotictherapy, Patient delay and Doctor delay
Seasonal prevalence of infectious diseases, forenteroviruses and arboviruses,
the epidemiology of emerging diseases such as West
Nile virus, and the immune status of the patient canbeis helpful.
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Specimen collection and
transportationtimingAll specimens should be collected prior to the
initiation of antimicrobials
If therapy initiated action to nullify it-Innoculating itto broth media 1:5 ratio< specially for cerebral abcess
Specimens for diagnosis of CNS
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Specimens for diagnosis of CNS
infections
Disease Specimen Quantity Note
Meningitis Cerebrospinal fluid
(CSF)
Mininmum of 1 mL/culture 1 to 2 mL [PCR]), 1 mL \antibody test
For M. tuberculosis, anddimorphic and filamentous fungirequire repeat CSF or largevolumes (10 to 20 mL) of
ventricular CSF.Blood 5 to 10ml as for bloodculture
Encephalitis or brainabscess
Abscessmaterial orirrigation
fluid
0.5 to 1.0 mL per culturerequest preferred
1 to 10 mL can be added to bloodculture medium antimicrobial
effect- dilution of 1 :5 or 1:10
Tissue 0.5 cc preferred minced /gently ground. Minceonly if filamentous fungi
expected.
Subdural
empyemaor epidural
Abscess
material /irrigation
0.51.0 mL per culture
request preferred
Small volumes of pus diluted
(ratio of 1:2) with sterile saline toallow washing of material from
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Collection and transportationSpecimen Container Transport/Storage Conditions
Cerebrospinalfluid (CSF)
Sterile tube. Room temperature. Ice/Refrigeration aredetrimental to some bacteria and
anaerobes. For PCR 4 Cfor
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Collection of CSF
Cerebrospinal fluid collected by lumbar puncture is theroutine specimen for diagnosis of meningitis
Strict aseptic techniques
Three or four containers depending on tests requested
But should have separate tubes for Gram stain/culture,
Biochemistry and glucose level- accompanied by bloodsample for RBS
Never to keep it in refrigerator
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Which tube for microbiology?Any tube possible
First tube- Theoretically risk of contamination -epithelium or blood from skin and soft tissuecapillaries ruptured during the punctur
In practice, total volume of fluid is more importantthan the tube cultured.
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CSF Examinations
Macroscopy color,clotting etc
Complete count
Differential count Gram stain of direct smear
Culture
Biochemistry sugar difference and proteins
PCR when indicated
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CSF Macroscopy
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Color of CSF supernatant Conditions or causes
Purulent Pyogenic meningitis
Yellow Blood breakdown productsHyperbilirubinemiaCSF protein >=150 mg per dL (1.5 g per L)>100,000 red blood cells per mm3
Orange Blood breakdown productsHigh carotenoid ingestion
Pink Blood breakdown products
Green HyperbilirubinemiaPurulent CSF
Brown Meningeal melanomatosis
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Normal CSF values
Cell component Age Category Normal Value
Leukocytes Neonates 0 30 cells X 10 / L
1 to 4 yr old 0 20 X 10 / L
5 to puberty 0 10 X 10 / L
Erythrocytes Newborn 0 675 X10 / LAdults 0 10 X10 / L
Protein Neonates 0.7 g/l
Adults 0.2 0.4 g/l
Glucose > 60% of RBS value is considerednormal
Bacterial or viral counts should be considered where leukocyte counts arenear the upper normal value5 WBCs per mm3 (normal value)
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differential diagnosis of various
forms of meningitisDiagnosis Pressure Cells
(10 / l)PMN Glucose
ratioProtein(g/ l)
Lactate(mmol/l)
normal < 20 cm 1-2 < 1 > .5 < 0.45 (1545mg/dl) < 2
Acutepyogenic
>20 cm >1000 > 50% < .4(>.2)
> 1(100 mg) > 4
Chronic variable > 1000 Vary < .4 > 0.45 > 2
Aseptic(Viral)
< 20 cm < 1000 .4 Vary < 2
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As CSF is hypotonic, WBCs lyse with the time.
Process, immediately
87% of Patients with meningitis 1000 /mm WBCs
99% of Patients with meningitis 100 per mm3
More likely to have viral meningitis 100 per mm3
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Lymphocytes : PMN
CSF, PMN:L ratio is unreliable for diagnosis ofmeningitis
Viral meningitis may show lymphocytosis butinitially PMN predominates
Neutropaenics no or less PMN response
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Presence of RBCs Indicates intra cerebral ,SAH or traumatic tap
Presence of RBCs make interpretation of CSF analysisdifficult
But, rarely obscures it
Inspecting first and third lumbar puncture samples if RBC count different - Traumatic tap
WBC:RBC ratio of 1:500 to 1:1000 is considered normal CSF obtain > 12 hrs post ICH may have WBC counts up
to 500 X 10 /l - due to inflammation
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Direct smear Gram stain
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a Gram stain of the cytospin CSF has a sensitivity of90% if the LP is carried out before the administrationof antibiotics.
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Effects of antibiotics in CSF culture
and Direct smears In a retrospective review of 128 children with bacterial
meningitis, Kanegaye et al. (2001)
compared 39 patients who received empiricantimicrobial therapy before LP with 55 whounderwent LP before receiving antimicrobial therapy
Treatment Group - Bacterialsterilization
Treatment group
Meningococcus sterilization occurredwithin 2 hrs
Up to 24 to 48 hrs CSF cellular andbiocheical parameters remained unchained
Pneumococcus sterilization occurredwithin 4 hours
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Condition Diagnostic test Sensitivity (%) Specificity(%)
Bacterial meningitis Cytospin Gram stain 6090 100
Culture 90 100
Antigen detectionassays * 50100 100
Tuberculous meningitis Acid-fast stain 1022 100
Culture3888 100
PCR 2785 95100
Effect of antibiotic treatment oncerebrospinal fluid. Am J ClinPathol 1983; 80:386-387.
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Blood cultures 50 to 80% patients with meningitis has accompanied
bacteremias - blood cultures would be useful to isolationof organisms more than CSF growth
Specially where LP is contraindicated
Blood culturesVolume 20ml or as
recommended by themanufactures
Collected before antibiotic therapy> 2 cultures taken from different sites or three cultures with
in 24 hrsInnoculate into broth medium at a ratio of >1:5
When suspecting Dimorphic fungi or cryptococcus blodshould be colected to tube containing lysis solution for lysiscentrifugation
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Utilityof Gram stain for diagnosis of Pyogenic
meningitis
Etiology Sensitivity
All common etiologiesno previous antibiotics 75% to 90%
All common etiologiesantimicrobial therapyprior to lumbar puncture
40% to 60%
Streptococcus pneumoniae without antibiotics 90%
Neisseria meningitidis - 75%
Haemophilus influenzae 86%
Listeria monocytogenes
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Unfortunately the positivity rate of gram staining andcultures remain low between 25- 40% as against therate of 80-85% from the developed world
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Partially treated meningitis
As the early symptoms and signs - non-specific, up to 50% receiveoralantibiotics.
This delay the presentation to hospital &
CSF findings altered; - Gram stain and growth of organism
may benegative
Antibiotics rarely interfere with CSFprotein/glucose andmolecular diagnosis (PCR).
In partially treated meningitis request for PCR and bacterialantigens - not affectedby prior antibiotic administration.
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Tuberculuos meningitisAFB positive only in 3%
Cobweb formation is seen 2/3 cases
Ratio of albumin to globulin changes can be used asscreening method(Nl ratio 6:1)Abnormal in TBMchanges can be predicted with eletrophoresis(Modified Levinsons test
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Use of Bacterial Antigen Testing The use of rapid bacterial antigen detection in CSF and other body
fluids has come under question. Rarely does a positive result alter therapy, and test performance is
similar to that of the Gram's stain.
Two contemporary approaches are advocated for bacterial antigentesting. The first recommends testing only those specimens with abnormal CSF
parameters (cell count, protein, glucose).[35] This approach results in a68% reduction in the number of antigen tests performed.
Although positive CSF cultures occur when white blood cell count,glucose, and protein values are within normal ranges, this is unusual
and does not justify testing all CSF for bacterial antigen. Another approach eliminates antigen testing, except in a few limited,
specific cases, such as prior antimicrobial therapy when culture resultsare negative after 24 to 48 hours of incubation.
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latex particle agglutination tests , have similarsensitivities to Gram stain or culture
of doubtful benefit when used routinely,
but sometimes identify organisms in patients withpartially treated bacterial meningitis and negativeGram stain and culture.
Cultures for bacteria and fungi should always beperformed, even in patients already treated withantibiotics.
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Use of Culture
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Culture media Incubation
For routinely encountering pathogens Good quality Blood A,chocolate Agar eithersheep or HBA -
24 to 48 hrs in 3-5% CO
Facultative anaerobes Broth media
Anaerobes from cerebral abscesses thioglycollate or choppedmeat broth,
Extendedincubation- onlywhen requested
Yeast and fungi Use of lysiscentrifugation method
Only whenrequested
********Culturing technique and media hardly ever changed over the years
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Emerging issues
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Methods of rapid diagnosis
Emergence of antibiotic resistant Pathogens
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PCR
Broad range of PCRs N.meningitidis,
H.influenzae,Streptococcus pneumoniae
PCR of blood Buffy coat provide higher yield for N.meningitidis
Agents of Aseptic meningitis Rapid RealTime PCRfor entero viruses available results in 60 min
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Antibiotic resistance
worldwide increase in infection withpenicillin andcephalosporin resistant strains ofS pneumoniae,
caused by either alteration in the penicillinbinding
proteins (Mosaic PBP)
Incidence increasing Europe, South Africa, Asia, and theUnited States.
American Academy of Pediatrics recommended
combination therapy, initially with vancomycin and either
cefotaximeor ceftriaxone for all children 1 month of age orolder withdefinite or probable bacterial meningitis.
N. meningitis less susceptible strains