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CNS INFECTIONS
Overview
• Life-threatening problems with high associated
mortality and morbidity
• Presentation may be acute, subacute, or chronic
• Clinical findings determined by anatomic site(s) of
involvement, infecting pathogen, and host
response
• Vulnerability of CNS to effects of inflammation &
edema mandates prompt diagnosis with
appropriate therapy if consequences to be
minimized
THE PATIENT WITH ACUTE CNS
INFECTION
Overall Goals in Management
1. To promptly recognize the patient with an acute
CNS infection syndrome
2. To rapidly initiate appropriate empiric therapy
3. To rapidly and specifically identify the etiologic
agent, adjusting therapies as indicated
4. To optimize management of complicating
features
CNS Infections
• Signs and symptoms
–
–
–
–
–
Fever
Headache
Altered mental status -lethargy to coma
Neck stiffness – meningismus – flex/ext
Increased intracranial pressure – papilledema,
nausea/vomiting, abducens palsies, bulging
fontanelle in infants
Exam in suspected CNS Infection
•
•
•
•
•
•
Mental Status
Cranial nerve and fundiscopic exam
Meningeal Signs
General exam – rashes, lymphadenpathy
Labs
Radiology – CT head - uncontrasted if no
focal signs, contrast if mass suspected
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
LP
• Tube #1 – glucose and protein
• Tube #2 – cell count and differential
• Tube #3 – gram stain and rountine culture,
cryptococcal antigen, stain and culture,
VDRL, viral studies (PCR)
CSF Characteristics
Bacterial
Viral
Fungal
TB
Opening
Pressure
Elevated
Slightly Normal Ususally
elevated or High high
Gluc
Low
Normal Low
Low
Pro
Very high Normal High
High
Rbcs
Few
None
None
None
Wbcs
(c/mm3)
>200
<200
<50
20-30
Diff
PMNs
Mono
Mono
Mono
Key CSF Features
• CSF is not liquid gold – get enough to get your answer
• CSF Glucose is 2/3 of serum glucose
– Important in diabetic patients
• Traumatic LPs –
– CSF pro increases by 1 for every 1000 rbcs
• Very high CSF Protein levels will make CSF yellow
• Send a full tube of CSF for cytology not just a few cc’s
Bacterial Meningitis
•
•
•
•
•
Streptococcus pneumoniae
Hemophilus influenzae
Listeria moncytogenes
Group B streptococcus
Niesseria meningitidis
Chronic Meningitis
• Immunocompromised patients
–
–
–
–
Cryptococcus neoformans
HIV
M. tuberculosis
M. avium
• Carcinomatous meningitis
– Lung, breast
ACUTE CNS INFECTIONS
1.
2.
3.
4.
5.
6.
Bacterial meningitis***
Meningoencephalitis
Brain abscess
Subdural empyema
Epidural abscess
Septic venous sinus
thrombophlebitis
Diagnostic Accuracy of Signs of
Meningeal Irritation in Pts with
Suspected Meningitis
Sign
Nuchal
rigidity
Kernig’s
Brudzinsk.
Sens Spec PPV NPV +LR -LR
30%
5%
5%
68%
26%
73%
0.94 1.02
95%
95%
27%
27%
72% 0.97 1.0
72% 0.97 1.0
From:Thomas KE et al, CID 2002, 35:46-52
APPROACH TO THE PATIENT WITH
POSSIBLE CNS INFECTION
If the patient has a CNS infection syndrome, is it antimicrobial
or non-antimicrobial requiring?
Crucial and recurring question addressed sequentially over time
Points in DecisionMaking Process
Within the 1st 30 mins
of patient contact
Available Data Base
For Decision-Making
Clinical assessment
After 1-2 hours
CSF analysis
At 24-48 hours
CSF cultures
Thereafter as clinically indicated
APPROACH TO THE PATIENT WITH SUSPECTED
MENINGITIS
Decision-Making Within the First 30 Minutes
Clinical Assessment
Mode of presentation
Acute (< 24 hrs)
Subacute (< 7 days)
Chronic (> 4 wks)
Historical/physical exam clues
Clinical status of the patient
Integrity of host defenses
CSF STUDIES
•
•
•
•
•
•
Color/Clarity
Cell counts/WBC diff
Chemistries (protein, glucose)
Stains/Smears (Gram)
Cultures (routine)
+/- Antigen screens
CSF SMEARS & STAINS
• GmS + in 60-90% of pts with
untreated bacterial meningitis
• With prior ATB Rx, positivity of GmS
decreases to 40-60%
• REMEMBER: + GmS = Heavy
organism burden & worse prognosis
CEREBROSPINAL FLUID PROFILES*
Neutrophilic/Low glucose (purulent)
Lymphocytic/Normal glucose
Lymphocytic/Low glucose
*Profile designation based on WBC differential
and glucose concentration.
NE Hyslop, Jr and MN Swartz, Postgrad Med 58:120,
1975.
BACTERIAL VS VIRAL MENINGITIS
Predictors of bacterial etiology:
• CSF glucose < 34
• CSF: Serum glucose ratio < 0.23
• CSF protein > 220
• CSF WBC count > 2000
• CSF neutrophil count > 1180
[Presence of any ONE of the above findings
predicts bacterial etiology with > 99%
certainty]
APPROACH TO THE PATIENT
WITH SUSPECTED MENINGITIS
Decision-Making at 24-48 hours
CSF Culture Results
Culture positive  Adjust therapy based upon
specific organism and sensitivities
Culture negative  Evaluate for “aseptic”
meningitis syndrome
TO LP OR NOT TO LP
• Single most impt diagnostic test
• Mandatory, esp if bacterial
meningitis suspected
• If LP contraindicated, obtain BCs
(+ in 50-60%), then begin
empirical Rx
THE PATIENT WITH SUSPECTED
CNS INFECTION
Contraindications to LP
Absolute:
Skin infection over site
Papilledema, focal neuro signs,
Relative:
Increased ICP without
papilledema
Suspicion of mass lesion
Spinal cord tumor
Spinal epidural abscess
Bleeding diathesis or ↓ plts
CNS INFECTIONS
CCT
• Over-employed diagnostic modality  Leads to
unnecessary delays in Rx & added cost (?)
• Rarely indicated in pt with suspected acute
meningitis (?)
• Mandatory in pt with possible focal infection
• Increased sensitivity with contrast enhancement
CCT Before LP in Patients with
Suspected Meningitis
• 301 pts with suspected meningitis; 235
(78%) had CCT prior to LP
• CCT abnormal in 56/235 (24%); 11 pts (5%)
had evidence of mass effect
• Features associated with abnl CCT were age
>60, immunocompromise,
Hasbun, NEJM 2001;345:1727
CNS INFECTIONS
MRI
• Not generally useful in acute diagnosis
(Pt cooperation; logistics)
• Very helpful in investigating potential
complications developing later in
clinical course such as venous sinus
thrombosis or subdural empyema
THE PATIENT WITH SUSPECTED CNS
INFECTION
Role of Repetitive LP’s
1.
Rarely indicated in proven bacterial meningitis unless
clinical response not optimal or as expected, fever
recurs, or infection is due to ATB resistant
pathogen
2. Essential in pts with “aseptic meningitis” syndromes to
monitor course &/or response to empiric therapies
3. Essential in pts with subacute/chronic meningitis of
proven etiology to assess response to Rx
4. Not routinely indicated at end-of-therapy for bacterial
meningitis
BACTERIAL MENINGITIS
• Incidence of 3 cases/100,000 population/yr
(~25,000 total cases)
• Fever, meningismus, & altered mentation
present in > 85% of pts
• Other clinical findings
– Cranial nerve palsies/focal signs 10-20%
– Seizures 25-30%
– Papilledema < 1%
BACTERIAL MENINGITIS
Caveats re: Antimicrobial Rx
• Therapy is gen’ly IV, high dose, &
bolus
• Dosing intervals should be appropriate
for drug being administered
• Utilize “cidal” therapy whenever
possible
• Initiate therapy promptly (ie, within 30
mins)
THE THERAPY OF MENINGITIS
Desirable Antimicrobic Properties
1.
2.
3.
Activity vs suspected pathogen(s)
[preferably cidal]
Adequate CSF diffusion
Acceptable risk of toxicity
THE THERAPY OF MENINGITIS
CNS Penetration
Good Diffusion
Penicillins
3rd & 4th Gen Cephs
Chloramphenicol
Rifampin
TSX
Poor Diffusion
Early Gen Cephs
Clindamycin
AMGs
Tetracyclines
Macrolides
Bacterial Meningitis
Important Changes in Epidemiology
• Marked decline in the occurrence of Hib
• ↑’ing incidence of S. pneumo (50+% of
cases in US)
• Shift from peds disease to adult disease
• ↑’ing incidence of ATB-resistant organisms,
esp. S. pneumo
– PCN resistance ~ 35% (15-20% high level)
– Ceph resistance 15-20% (5-10% high level)
COMMON BACTERIAL PATHOGENS BASED ON
PREDISPOSING FACTOR IN PATIENTS WITH
MENINGITIS
Predisposing Factor
Age
0-4 wk
4-12 wk
3 mo to 18 yr
18-50 yr
>50 yr
Common Bacterial Pathogens
Streptococcus agalactiae, Escherichia coli,
Listeria monocytogenes, Klebsiella
pneumoniae, Enterococcus spp., Salmonella
spp.
S. agalactiae, E. coli, L. monocytogenes,
Haemophilus influenzae, Streptococcus
pneumoniae, Neisseria meningitidis
H. influenzae, N. meningitidis, S. pneumoniae
S. pneumoniae, N. meningitidis
S. pneumoniae, N. meningitidis, L.
monocytogenes, aerobic gram-negative bacilli
COMMON BACTERIAL PATHOGENS BASED ON
PREDISPOSING FACTOR IN PATIENTS WITH
MENINGITIS
Predisposing Factor
Immunocompromised state
Basilar skull fracture
Head trauma; postneurosurgery
Cerebrospinal fluid shunt
Common Bacterial Pathogens
S. pneumoniae, N. meningitidis, L.
monocytogenes, aerobic gramnegative bacilli (including P.
aeruginosa)
S. pneumoniae, H. influenzae, group A
β-hemolytic streptococci
Staphylococcus aureus, Staphylococcus
epidermidis, aerobic gram-negative
bacilli (including P. aeruginosa)
S. epidermidis, S. aureus, aerobic gramnegative bacilli (including P.
aeruginosa)
EMPIRIC THERAPY OF MENINGITIS IN THE
ADULT
Clinical Setting
Likely Pathogens
Therapy
Community-acquired
S. pneumoniae
N. meningitidis
[Listeria]
[H. influenzae]
Ceftriaxone
2 g q12h
+
Vanco 1-2 g 12h
+/Ampi 2 g q4h
Closed head trauma
Streptococci
S. pneu
+
Pen G 3-4 mu q4h
Vancomycin 1-2 g q12h
EMPIRIC THERAPY OF MENINGITIS IN THE
ADULT
Clinical Setting
Likely Pathogens
Therapy
High risk patients
Compromised hosts
Neurosurgical
or
Open head injury
Nosocomial
Elderly
S. aureus
Gram negative
bacilli
Vancomycin 2-3 gm/d
+
Ceftazidime 2 gm q8h
Listeria
Cefepime 2 gm q8h
[Ceftriaxone 2 gm q12h]
[Cefotaxime 2 gm q4h]
+/Ampicillin 2 gm q4h
SPECIFIC THERAPY FOR KNOWN PATHOGENS
Pathogen
Recommended Therapy
S. pneumoniae*
N. meningitidis
Streptococci
Pen G 18-24 mu/d
or
Ampicillin 12 gm/d
[Chloro 75-100 mg/kg/d]
[Ceftriaxone 2-4 gm/d]
H. influenzae
Cefotaxime 12 gm/d
[Ceftriaxone 2-4 gm/d]
Group B strep
Pen G 18-24 mu/dor
Ampicillin 12 gm/d
[plus aminogl]
[Ceftriax 2-4 gm/d]
SPECIFIC THERAPY FOR KNOWN PATHOGENS
(continued)
S. aureus
Nafcillin 12 gm/d
[Vancomycin 2-3 gm/d]
Listeria
Ampicillin 12 gm/d
or
Pen G 18-24 mu/d
[plus aminoglycoside]
Gram negative
bacilli
Cefotaxime 12 gm/d
[Ceftriaxone 2-4 gm/d]
Pseudomonas
Ceftazidime 6-8 gm/d or
Cefepime 6 gm/d
[plus aminoglycoside]
Meningite batterica
Terapia empirica
Fattori predisponenti
Ampicillina
+ Cefotaxime
Patogeni batterici
comuni
Ampicillina + aminoglicosidi
0-4 settimane
S. agalactiae, E. coli,
L. monocytogenes,
K. Pneumoniae,
Vancomicina+
Cefalosporine
1-23 mesi
di III gen
S. pneumoniae, N. meningitidis, S. agalactiae, H. influenzae
Vancomicina+ Cefalosporine
E. coli.
di III gen
2-50 anni
N. meningitidis, S. pneumoniae
> 50 anni
Vancomicina+Ampicillina
S. pneumoniae, N.
meningitidis, L. monocytogenes,+ aerobi
Cefal. III gen.
gram neg.
Frattura base cranica
Vancomicina + Ampicillina +
S. pneumoniae, N. meningitidis,
L. monocytogenes, aerobi
Ceftazidime
gram neg. (inclusa P. aeruginosa)
Vancomicina +
S. pneumoniae, H. influenzae,
group A, III
β-hemolytic
Cefalosporina
gen
Neurochirurgia
Vancomicina +
S. aureus, S. epidermidis,
aerobi gram neg.
Cefalosporina
III gen
Ospite
immunocompromesso
Shunt liquorale
streptococci
(inclusa P. aeruginosa)
Vancomicina +
S. epidermidis,
S. aureus, aerobi gram neg.
Cefepime/ceftazidime/meropenem
(inclusa P. aeruginosa)
CORTICOSTEROIDS AND MENINGITIS
• Role of steroids still somewhat uncertain
• Recent European study in adults suggested that Rx
with dexa associated with ↓ in risk of unfavorable
outcome (25%→15%, RR 0.59) & in mortality
(15%→7%, RR for death 0.48)
• Benefit primarily ltd to pts w/S. pneumo
• Dose of dex was 10mg IV q6h X 4d; per protocol,
dex given concurrent with or 15-20 mins before 1st
dose of ATBs
Original Article
Dexamethasone in Vietnamese Adolescents and
Adults with Bacterial Meningitis
Nguyen Thi Hoang Mai, M.D., Tran Thi Hong Chau, M.D., Guy Thwaites, M.D., Ly Van
Chuong, M.D., Dinh Xuan Sinh, M.D., Ho Dang Trung Nghia, M.D., Phung Quoc Tuan,
M.D., Nguyen Duy Phong, M.D., Nguyen Hoan Phu, M.D., To Song Diep, M.D.,
Nguyen van Vinh Chau, M.D., Nguyen Minh Duong, M.D., James Campbell,
Constance Schultsz, M.D., Chris Parry, M.D., M. Estee Torok, M.D., Nicholas White,
F.R.C.P., Nguyen Tran Chinh, M.D., Tran Tinh Hien, M.D., Kasia Stepniewska, Ph.D.,
and Jeremy J. Farrar, F.R.C.P.
N Engl J Med
Volume 357(24):2431-2440
December 13, 2007
Study Overview
• In this randomized, placebo-controlled
trial involving 435 adolescents and
adults with meningitis in Vietnam, the
use of adjunctive dexamethasone did not
reduce the rate of death or disability at 6
months
• In subgroup analyses, a benefit of
treatment was seen in patients with
confirmed bacterial meningitis, whereas
harm was identified in those with
probable bacterial meningitis
Enrollment and Outcomes
Mai NTH et al. N Engl J Med 2007;357:2431-2440
Kaplan-Meier Survival Estimates According to Study Group
Mai NTH et al. N Engl J Med 2007;357:2431-2440
Rates of Death and Disability 6 Months after Randomization
Mai NTH et al. N Engl J Med 2007;357:2431-2440
Conclusion
• Dexamethasone does not improve the
outcome in all adolescents and adults
with suspected bacterial meningitis; a
beneficial effect appears to be confined
to patients with microbiologically proven
disease, including those who have
received prior treatment with antibiotics
PREDICTORS OF ADVERSE CLINICAL OUTCOMES
IN PTS WITH COMMUNITY-ACQUIRED
BACTERIAL MENINGITIS
• Retrospecitve study; 269 pts (84% culture +)
• Adverse clinical outcome in 36% of pts (Death 27%, neuro
deficit 9%)
• altered MS, and seizures on presentation all
independently associated with adverse clinical outcome
• Delay in administration of appropriate ATB Rx also
associated with adverse clinical outcome
Aronin et al, AIM1998;129:862
BACTERIAL MENINGITIS
Duration of ATB Rx
Pathogen
Duration of Rx (d)
H. influenzae
7
N. meningitidis
7
S. pneumoniae
10-14
L. monocytogenes
14-21
Group B strep
14-21
GNRs
21
NEJM 1997;336:708
Tabella 4 – soggetti deceduti per agente eziologico
decessi
totale
isolati
n.
(%)
Haemophilus influenzae
7
--
(0,0)
Listeria spp
1
--
(0,0)
Neisseria meningitidis
12
2
(16,7)
Streptococco agalactiae
2
--
(0,0)
Streptococco pneumoniae
53
5
(9,4)
Altro
2
2
(100,0)
Totale
77
9
(11,7)
Microrganismo
Tutti i soggetti sono stati sottoposti a ricovero;
dei 77 casi in cui è stato identificato il microrganismo
responsabile 9 (11,7%) sono deceduti.
Il quadro clinico di 4 pazienti è stato correlato con la
meningite, mentre quello dei restanti 4 con la sepsi.
Due decessi si sono verificati in bambini al di sotto dei 2
anni di età (entrambi da Neisseria meningitidis).
Tabella 3 - Distribuzione assoluta e percentuale dei 76 microrganismi isolati, per quadro clinico e microrganismo
Meningite
Sepsi
Altro quadro
Totale
Microrganismo
n
Haemophilus influenzae
4
Listeria spp.
1
Neisseria meningitidis
7
Streptococco agalactiae
1
Streptococco pneumoniae
16
Altro
--
Totale
29
(%)
(13,8)
(3,4)
(24,1)
(3,4)
(55,2)
--
n
(%)
n
(%)
n
3
(7,1)
--
--
7
--
(0,0)
--
--
1
5
(11,9)
--
--
12
1
(2,4)
--
--
2
31
(73,8)
6
(100,0)
53
2
(4,8)
--
--
2
42
6
77
(%)
(9,1)
(1,3)
(15,6)
(2,6)
(68,8)
(2,6)
Grafico 5
- Incidenza delle forme invasive batteriche identificate,
per classe di età (al 30/06/2007)
12
10,9
10
per 100,000 abitanti
8
6
4,5
3,3
4
2,9
2
0,9
1,1
0
< 1 anno
1-2 anni
3-4 anni
5-14 anni
15-64 anni
65+ anni
tipizzazione
sierogruppo molecolare
C
B
C
C
B
W135
B
B
A
B
C
C
B
C
C
C
C
C
C
B
C
B
sequenziameto/
taglio virtuale
sequenza
C
Y/ W135
Y
Y/ W135
B
Y
C
C
ABCZ ADK AROE FUMC GDH PDHC PGM
46
29
186
176
67
175
96
4
10
5
4
6
3
8
9
6
73
133
26
6
9
2
3
7
2
8
5
2
3
6
9
5
9
9
10
5
18
9
11
9
17
7
5
1
3
36
53
15
10
6
63
5
9
6
12
10
5
18
9
11
9
17
10
6
63
5
9
6
12
2
3
4
3
8
4
6
46
5
2
7
26
20
2
7
5
1
13
36
53
15
2
3
4
3
8
4
6
2
3
4
3
8
4
6
2
3
4
3
8
4
6
2
3
4
3
8
4
6
2
3
4
3
8
4
6
2
3
4
3
8
4
6
4
10
15
9
8
11
9
2
3
4
3
8
4
6
12
6
9
35
9
15
9
C
8
10
5
4
6
6
8
B
10
6
63
5
9
6
21
ST
1975
32
833
8
23
3496
1403
23
1403
11
2888
213
11
11
11
11
11
11
269
11
3478
il ceppo è simile ad altri 14 ST tutti
appartenenti al clonal complex ST-32
complex/ET-5complex (sequenziati i 7
geni 2 volte) si veda foglio 1337692
il ceppo è simile ad altri 3 ST tutti
appartenenti al clonal complex ST41/44 complex/Lineage 3 si veda
foglio 1343091
ST
1975
32
833
8
sierogruppo
POR A VR1
POR A VR2
C
B
C
C
B
W135
B
B
A
B
C
C
B
C
C
C
C
C
C
B
C
B
12-1
7
18
5
13-1
16-2
34-2
2
P1.12-1,13-1
P1.7,16-2
P1.18,34-2
P1.5,2
07-feb
5-2
22
7-2
5-2
4
10-14
14
4
10-2
P1.7-2,4
P1.5-2,10-14
P1.22,14
P1.7-2,4
P1.5-2,10-2
7-2
5-1
19-1
22
4
10-8
15
14
P1.7-2,4
P1.5-1,10-8
P1.19-1,15
P1.22,14
5-1
5-1
5-1
5-1
5-1
10-8
10-8
10-8
10-8
10-8
P1.5-1,10-8
P1.5-1,10-8
P1.5-1,10-8
P1.5-1,10-8
P1.5-1,10-8
5-1
19-1
5-1
18
10-8
15-11
10-8
25,25-7
23
21
16
P1.21,16
24
7-2
4
P1.7-2,4
CLONAL COMPLEX
-
1
ST-32 complex/ET-5complex
2
ST-41/44 complex/LINEAGE 3
3
ST-8 complex/CLUSTER A4
4
5
23
3496
1403
23
1403
11
2888
213
11
11
11
11
11
11
269
11
ST-23 complex/CLUSTER A3
6
ST-213 complex
7
ST-41/44 complex/LINEAGE 3
8
ST-23 complex/CLUSTER A3
9
ST-41/44 complex/LINEAGE 3
10
ST-11
11
-
12
ST-213 complex
13
ST-11 complex/ET-37 complex
14
ST-11 complex/ET-37 complex
15
ST-11 complex/ET-37 complex
16
ST-11 complex/ET-37 complex
17
ST-11 complex/ET-37 complex
18
ST-11 complex/ET-37 complex
19
ST-269complex
20
ST-11 complex/ET-37 complex
21
3478
ST/41/44 complex/LINEAGE 3
22
il ceppo è simile ad altri 14 ST tutti
appartenenti al clonal complex ST-32
complex/ET-5complex (sequenziati i 7
geni 2 volte) si veda foglio 1337692 ST-32 complex/ET-5complex
il ceppo è simile ad altri 3 ST tutti
appartenenti al clonal complex ST41/44 complex/Lineage 3 si veda
foglio 1343091
ST-41/44 complex/LIineage 3
P1.5-1,10-8
P1.19-1,15-11
P1.5-1,10-8
P1.18,25-7
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Attenzione