Infezioni del sistema nervoso

centrale

Clinica di Malattie Infettive

Policlinico S. Orsola – Malpighi
Scenari Clinici

Caso 1: una donna di 70 anni con ipertensione in

terapia ben controllata arriva al PS per febbre da 3
giorni, stato confusionale e rallentata
Incapace di cooperare all’esame obiettivo
Rigidità nucale alla flessione del collo
Scenari Clinici
Case 2: Uomo di 30 anni si presenta al PS con una
storia da 24 ore di cefalea, dolore retronucale e scolo
nasale
EO. Non febbre, vigile ed orientato, cefalea, ma non
rigidità nucale anche se accentuazione del dolore alla
flessione del collo, Kerning e Brudzinski assenti
RICHIAMO ANATOMICO PATOLOGIE

TECA
CRANICA
SPAZIO EPI-DURALE ASCESSO EPIDURALE
DURA MADRE

SPAZIO SUB-DURALE EMPIEMA SOTTODURALE

ARACNOIDE

SPAZIO SUB- MENINGITI

ARACNOIDEO

PIA MADRE

ENCEFALITI
ENCEFALO ASCESSI CEREBRALI
 Meningite

Processo infiammatorio a carico delle

leptomeningi (pia madre e aracnoide)
provocato dall’invasione dello spazio
sub-aracnoideo da parte di un agente
patogeno (batterio, virus, micete,
protozoo od elminta).
 Vie di ingresso nel liquor

Ematogena: superamento barriere, a livello dei seni

della dura madre e dei plessi coroidei

Contiguità: da infezioni adiacenti, sinusiti, otiti,

mastoiditi, infezioni cuoio capelluto,

Diretta: da soluzioni di continuo parete ossea: traumi,

frattura, intervento chirurgico, meningocele
 Classificazione delle meningiti
in base al liquor cefalo-rachidiano (LCR)

A liquor torbido (decorso acuto):

batteri

A liquor limpido (decorso acuto, subacuto, cronico):

virus
batteri (tubercolosi, sifilide, Malattia di Lyme e
borreliosi, leptospirosi, brucellosi, rickettsiosi,
infezione da Mycoplasma pneumoniae)
miceti
elminti
 MENINGITI INFETTIVE a LIQUOR LIMPIDO - AGENTI
ETIOLOGICI

BATTERI
- Leptospira
- Brucella
VIRUS
- Borrelia burgdorferi - Enterovirus
- T. pallidum - Adenovirus
- Rickettsiosi - Coxsackie
- Virus della parotite
- Mycoplasma P. - HIV
-Mycobacterium T - Virus influenzali
- Virus parainfluenzali
- Virus della coriomengite linfocitaria
- Virus del morbillo
- Rotavirus
- WNF virus
- TOSV
 CNS infections
Incidence Morbidity Mortality
Bacterial 0.6-4 cases per 30-50% 3-37%
meningitis 100,000 permanent
adults/year neurological
sequelae
Encephalitis “Rare” If due to HSV 0-70%
HSV: 0.2-0.4 >50% ~ 10%
cases per neurological
100,000 sequelae
adults/year
Cerebral Rare 20-70% 8-25%
abscess
Bacterial meningitis in United States,
1998-2007 Thigpen MC NEJM 2011; 21: 2016-25

1670 cases reported in 2003-2007 (deaths 215 cases 13%)

S. pneumoniae 58%, GBS 18%, N. meningitidis 14%, H. influenzae 7%, L.
monocytogenes 4%

587pts

Case rate fatality 6.9%

Bacterial meningitis in United States,
1998-2007 Thigpen MC NEJM 2011; 21: 2016-25

1670 cases reported in 2003-2007

S. pneumoniae 58%, GBS 18%, N. meningitidis 14%, H. influenzae 7%, L.
monocytogenes 4%

1083 pts

Case rate fatality 16.4%

ESCMID guideline: diagnosis and treatment of
acute bacterial meningitis
Clin Microbiol Infect. 2016 May;22 Suppl 3:S37-62
Causative organisms of neonatal meningitis
Country United France Spain Netherlands Total
Kingdom
Observation period 2010–2011 2001–2007 1997–1998 2006–2012

Streptococcus 150 258 69 88 565 (58%)

agalactiae

Escherichia coli 41 123 12 27 203 (21%)

Listeria 11 7 0 1 19 (2%)
monocytogenes

Streptococcus 28 8 0 3 39 (4%)
pneumoniae

Other 72 43 22 14 156 (16%)

ESCMID guideline: diagnosis and treatment of
acute bacterial meningitis
Clin Microbiol Infect. 2016 May;22 Suppl 3:S37-62
Causative organisms of paediatric meningitis
Country France Denmark France Netherlands Total

Observation 2001–2007 1997–2006 1995–2004 2006–2012

period
Neisseria 1303 159 35 308 1805 (50%)
meningitidis

Streptococcus 802 195 35 310 1342 (37%)

pneumoniae

Haemophilus 78 8 11 73 170 (5%)

influenzae

Other 137 56 8 101 302 (8%)

ESCMID guideline: diagnosis and treatment of
acute bacterial meningitis
Clin Microbiol Infect. 2016 May;22 Suppl 3:S37-62
Causative organisms of adult bacterial meningitis
Country Denmark Turkey United Czech Netherlands Total
Kingdom Republic
Observation 1998–2012 1994–2003 1997–2002 1997–2004 2006–2012
period
Neisseria 42 251 550 75 171 1089
meningitidis (27%)
Streptococcus 92 457 525 82 1001 2157
pneumoniae (53%)

Haemophilus 3 2 48 3 56 112 (3%)

influenzae
Listeria 5 6 48 21 74 154 (4%)
monocytogenes
ESCMID guideline: diagnosis and treatment of
acute bacterial meningitis
Clin Microbiol Infect. 2016 May;22 Suppl 3:S37-62

Conclusions

Level 2 Most common causative pathogens in neonatal

meningitis are Streptococcus agalactiae and
Escherichia coli.
Level 2 Most common causative pathogens in children
beyond the neonatal age are Neisseria meningitidis
and Streptococcus pneumoniae.
Level 2 Most common causative pathogens in adults are
Streptococcus pneumoniae and Neisseria
meningitidis. Another important causative
microorganism in adults is Listeria monocytogenes.
Incidence of various pathogens in different age groups and
with specific risk factors for bacterial meningitis
 Meningite - patogenesi colonizzazione mucosa

diffusione ematogena
replicazione batterica esponenziale

Passaggio barriera emato-encefalica

aumentata permeabilità BEE

pleiocitosi
edema e > pressione endocranica
invasione dello spazio sub-aracnoideo

danno neuronale
rilascio di citochine pro-infiammatorie
MENINGITI
INFETTIVE
patogenesi
Does this patient have an acute CNS infection?
Case 1
-A previously healthy 70-year-old
woman presents to the emergency
department with a 3-day history of
fever, confusion, and lethargy.
-She is unable to cooperate with a
full physical examination, but she has
neck stiffness upon neck flexion.
-The findings from a chest
radiograph and urinanalysis are
normal
Case 2
-A 30 year old man presents to the
emergency department with a few
days history of “bad flu” with fever
and headache.
-On clinical examination, he is febrile
and quite confused. He can fully flex
his neck Kerning and Brudzinski
singns are absent
 MENINGITI INFETTIVE - MANIFESTAZIONI
CLINICHE

Stato FEBBRE
settico
CEFALEA
Ipert. endocranica ALTERAZIONI SENSORIO

Irritazione meningea RIGOR NUCALIS

Sindrome MENINGEA
FOTOFOBIA
Ipert. endocranica VOMITO

Mod. vasc. Cerebrale CONVULSIONI

SEGNI FOCALI
Danno nervi cranici
PARALISI SELETTIVE

MODALITA’ di ESORDIO VARIABILI, da quadri IPERACUTI a SUB-ACUTI

 SINDROME MENINGEA - semeiotica
Posizione a cane di fucile
paziente in decubito laterale con cosce flesse sull’addome e
gambe flesse sulle cosce
Segno di Kernig
dolore oppositivo all’estensione della coscia flessa sull’addome
e del ginocchio flesso sulla coscia
Segno di Brudzinski
la flessione passiva del collo provoca flessione riflessa della
coscia e del ginocchio
Segno di Amoss
impossibilità a sedere senza impiegare il sostegno
posteriore degli arti superiori
Segno di Binda
Alla torsione del collo consegue torsione consensuale delle
spalle
 Tempo di insorgenza dei sintomi
Sintomatologia

S. pneumoniae,
H. influenzae

N. meningitidis

0 24 2 3 4 5 6
ORE GIORNI
Sepsi da Meningococco
Sepsi da Meningococco
 MENINGITI INFETTIVE
PECULIARITA’ DELLE MANIFESTAZIONI CLINICHE IN ETA’
PEDIATRICA

NEONATO
- MAI RIGOR
- AGITAZIONE / SONNOLENZA
- SUZIONE RIDOTTA
- CONVULSIONI MOLTO FREQUENTI

LATTANTE
- NUCA CIONDOLANTE
- TENSIONE delle FONTANELLE
ESCMID guideline: diagnosis and treatment of
acute bacterial meningitis
Clin Microbiol Infect. 2016 May;22 Suppl 3:S37-62
ESCMID guideline: diagnosis and treatment of
acute bacterial meningitis
Clin Microbiol Infect. 2016 May;22 Suppl 3:S37-62
Does this patient have an acute CNS infection?
Metanalysis of 845 patient-episodes, in adult patients with meningitis confrmed
by LP or autopsy Attia J et al. JAMA 1999;281:175-181
Sens Spec PPV NPV
 Fever, neck stiffness and
Jolt accentuation 97% 60% NA NA
altered mental status: of headache
sens 46%, spec 100% Fever 85% 45% NA NA
Altered mental 67% More common in
 The absence of all 3 signs status bacterial than viral
meningitis
of the classic triad
Neck stiffness 30-70% 71% 41% 61%
reduces the probability of
Kernig’s sign 11% 95% 60% 60%
meningitis
Brudzinski’s 9% 95% 50% 62%
Focal neurologic 23% Not useful in ruling out
 95% of pts with ABM findings meningitis
have ≥ 2: F, NS, AMS and Rash 22% More common in
headache meningococcemia
Van de Beek D et al. NEJM 2004;351:1849-59
Brouwer MC Lancet 2012;380:1684-1692
 Diagnosi
Esame del liquor microscopico e
colturale
La diagnosi precoce ed il trattamento
precoce della meningite batterica sono
imperativi per ridurre la mortalità e la
morbilità.
I medici devono praticare la puntura
lombare ad ogni paziente in cui sospettino
tale diagnosi a meno che non vi siano
specifiche controindicazioni a questa
procedura.
 Le infezioni del SNC causano
alterazioni liquorali

La diagnosi di meningite si fonda

sull’esame del liquor per mezzo di
puntura lombare o rachicentesi nello
spazio tra la 4^ e la 5^ vertebra
lombare.
Differential diagnosis

Virus Batteri Funghi Parassiti

Patient history Immunocompromised External factors
state
Duration of symptoms Type of Season
immunosuppression
Infection at other sites Length of Recent travels
immunosuppression
Prior CNS disease Vaccination status Domestic animals,
mosquito or tick bite
Patients behavior Prophylaxis Camping, spelunking,
bathing in fresh water
Classical CSF Features of the different causes of
meningitis

• Classic abnormalities of CSF composition in bacterial meningitis are:

 pleocytosis of mainly polymorphic leukocytes

 low glucose concentration
 low CSF to blood glucose ratio
 elevated protein levels

• Both in adults and children that characteristics are present in 90% of patients. A completely normal
CSF occurs but is very rare.

•In neonatal meningitis, CSF leukocyte count, glucose and total protein levels are frequently
within normal range or only slightly elevated.

The UK joint specialist societies guideline on the diagnosis and management of acute meningitis and
meningococcal sepsis in immunocompetent adults
McGill et al. J.Infect 2016
 Guidelines on routine cerebrospinal fluid
CSF glucose concentration, CSF/serum analysis. Report from an EFNS task
Force
glucose ratio Deisenhammer et al. Eur J Neurology 2006;13:913

• Glucose is actively transported across the blood–brain barrier the CSF glucose levels
are directly proportional to the plasma levels and therefore simultaneous measurement in
CSF and blood is required.

• Normal CSF glucose concentration is 50–60% of serum values. A CSF/serum glucose

ratio less than 0.4–0.5 is considered to be pathological. A CSF:plasma glucose ratio cut
off of 0.36 for diagnosing bacterial meningitis has a high sensitivity and specificity
(93%) [Tamune et al.: Cerebrospinal fluid/blood glucose ratio as an indicator for bacterial meningitis. Am J Emerg Med
2014;32:263e6.]

• CSF glucose takes several hours to equilibrate with plasma glucose; therefore, in unusual
circumstances levels of CSF glucose can actually be higher than plasma levels for several
hours.

• During CSF storage glucose is degraded. Therefore, glucose determination must be

performed immediately after CSF collection.
What specific CSF diagnostic tests should be used
to determine the etiology of CNS infection?

Blood cultures (prior antibiotic administration)

±
Other sample cultures
±
Serologic assays
What specific CSF diagnostic tests should be used
to determine the etiology of CNS infection?

CSF Gram

CSF culture

Antigen test (sens 99%, spec

99%) and/or PCR (multiplex
including difficult to culture
microorganisms)
Meningiti
Accuracy of real-time PCR, Gram stain and culture for Streptococcus pneumoniae,
Neisseria meningitidis and Haemophilus influenzae meningitis diagnosis

Henry M Wu et al. BMC Infect Dis 2013; 13:26

Sens Spec
All pts n=451
CSF culture 81% 100%
CSF Gram stain 98% 99%
RT-PCR 95% 94%
No prior antibiotics n=341
CSF culture 86% 100%
CSF Gram stain 99% 99%
RT-PCR 96% 98%
Prior antibiotics n=98
CSF culture 85% 100%
CSF Gram stain 96% 99%
RT-PCR 96% 99%
 PAZIENTE con SOSPETTA/ ACCERTATA SINDROME
MENINGEA

Algoritmo gestionale

Alcune domande ricorrenti:

1. Quanto precoce deve essere la terapia antibiotica ?
2. CT scan encefalo pre- puntura lombare ?
3. Quali farmaci di prima linea ?
4. C’è indicazione all’uso di steroide in acuto ?
5. Quanto deve durare la terapia ?
6. C’è indicazione a PL di controllo a fine terapia ?
How Quickly Should Antimicrobial Therapy Be
Administered to Patients with Suspected
Bacterial Meningitis?
PRESENTATION, TIME to ANTIBIOTICS, and MORTALITY of PATIENTS
with BACTERIAL MENINGITIS at an URBAN COUNTY MEDICAL
CENTER
Miner JR et al, J Emerg Med, 2001

171 cases - 76% received antibiotics in the ED

mortality rate 14%

ED Medical Ward
mean time to mean time to p
Timing ATB antibiotics antibiotics
1: 08 h + 13’ 6+9h
.03
(8 min to 6) (1 -48 h)

Therapy in ED Therapy in MW
Mortality
7.9% 29% .003
 Delays in the administration of antibiotics are associated with
mortality from adult acute bacterial meningitis. Proulx N et al QJM 2005

123 cases of adult acute bacterial meningitis admitted from 1990 to

2002
VARIABLES RELATED TO MORTALITY case fatality rate 13%

afebrility at presentation 39,4(95%CI 4.3-358.1)

severely impaired mental status

12,6 (95%CI 2.2-72.0)

door-to-antibiotic time >6 h 8,4 (95%CI 1.7-40.9)

Community-Acquired Bacterial Meningitis in Adults: Antibiotic
Timing in Disease Course and Outcome
Lepur D, Barsic´ B Infection 2007; 35: 225–231

286 patients with community-acquired bacterial meningitis

aged 14 years and more were included in a retrospective
cohort study.

Observational period was between 1 January 1990 and 31

December 2004.

Unfavorable outcome was found in 125 (43,7%) patients.

Community-Acquired Bacterial Meningitis in Adults: Antibiotic
Timing in Disease Course and Outcome Lepur D, Barsic´ B
Infection 2007; 35: 225–231
Epidemiology of Meningitis and Encephalitis in the
United States, 2011–2014
Hasbun R et al. Clin Infect Dis 2017;65(3):359–63

Variables No. (%)

Number of unique patients 26429 (100)
Female sex 14076 (53.3)
Median age, y 43 18−101 (range)
Comorbidities
Diabetes mellitus 4061 (15.4)
Chronic pulmonary disease 3285 (12.8)
Renal disease 1580 (6.0)
Cerebrovascular disease 1531 (5.8)
Malignancy 1169 (4.4)
HIV/AIDS 1120 (4.2)
Type of inpatient admission
Through ED 21013 (87.2)
Through clinics 2210 (9.2)
Outside facility transfer 868 (3.6)
Epidemiology of Meningitis and Encephalitis in the
United States, 2011–2014
Hasbun R et al. Clin Infect Dis 2017;65(3):359–63

Antibiotic Therapy Antiviral Therapy

Etiology (No.) Median Days Median Days
No. (%) No. (%)
(IQR) (IQR)
Overall sample (22684) 22684 (89.7) 4 (5) 13791(57.2) 3 (3)
Enterovirus (13463) 51.6% 10490 (89.0) 3 (2) 6673 (56.6) 3 (2)
Unknown etiology
3838 (86.9) 5 (6) 2510 (56.8) 4 (4)
(4944) 21.4%
Bacterial meningitis
3611 (99.1) 8 (7) 1529 (41.9) 2 (3)
(3692) 14.1%
Herpes viruses (2184) 8,3% 1827 (84.7) 3 (3) 2042 (94.6) 5 (5)
Fungal meningitis
631 (89.0) 6 (10) 233 (32.9) 3 (5)
(720) 2.7%
Arboviruses (291) 1.1% 269 (92.4) 7 (8) 216 (74.2) 4 (3)
Other viruses (214) 0.8% 185 (87.3) 5 (7) 192 (90.6) 6 (7)
Non-ME diagnosis (921)
761 (86.8) 3 (2) 396 (45.1) 2 (2)
3.5%
Epidemiology of Meningitis and Encephalitis in the
United States, 2011–2014
Hasbun R et al. Clin Infect Dis 2017;65(3):359–63

Inpatient
Median Length Readmission
Etiology (No.) No. (%) Mortality, No.
of Stay (d) (IQR) Rate, No. (%)
(%)
Overall sample 26429 (100) 4 (5) 776 (2.9) 845 (3.2)
Enterovirus 13463 (51.6) 3 (2) 65 (0.5) 164 (1.2)
Unknown etiology 4944 (21.4) 5 (7) 247 (5.1) 253 (5.1)
Bacterial
3692 (14.1) 7 (8) 302 (8.2) 245 (6.7)
meningitis
Herpes viruses 2184 (8.3) 5 (5) 45 (2.1) 79 (3.6)

Fungal meningitis 720 (2.7) 13 (12) 59 (8.2) 39 (5.4)

Arbovirus 291 (1.1) 10 (11) 26 (8.9) 37 (12.7)
Other viruses 214 (0.8) 8 (9) 25 (11.7) 13 (6.1)
Noninfectious 921 (3.5) 3 (3) 7 (0.8) 15 (1.6)
CT of the head before LP in adults with suspected
meningitis Hasbun R et al, N Engl J Med 2001

301 pts with suspected meningitis

CT performed before LP: 235 pts
Abnormalities identified in 52 pts (24%)
5%
Lesions causing brain shift
1. New-onset seizures
2. Immunocompromised state
3. History of CNS disease
4. Signs that suggest space occupying
lesions (papilledema, focal deficits)
Normal 5. Moderate to severe impairment of
consciousness
 Patients with suspected meningitis should
undergo CT scan prior to lumbar puncture?

LP and brain hernaiation in ABM: a review

Joffe AR J Intensive Care Med 2007; 22:194-207
Brain herniation occurs in 5% of pts with ABM
11% before LP
38% within 3 h of LP
51% later during disease
 ESCMID guideline: diagnosis and
treatment of acute bacterial meningitis
Van de Beek et al. 2016

The UK joint specialist societies guideline on the

diagnosis and management of acute meningitis and
meningococcal sepsis in immunocompetent adults

McGill et al. J.Infect 2016

Potential risks if LP is delayed
Glimaker at al. Scand J Infect Dis 2013: 45: 657-663

The risk of death due to delayed AB treatment would

be up to 20 times the risk of fatality due to LP-induced
cerebral hernation
How Quickly Should Antimicrobial Therapy Be
Administered to Patients with Suspected
Bacterial Meningitis?
GRADE A
It is strongly recommended to start antibiotic therapy
as soon as possible in acute bacterial meningitis
patients. The time period until antibiotics are
administered should not exceed 1 hour.

Whenever lumbar puncture is delayed, e.g. due to

cranial CT, empiric treatment must be started
immediately on clinical suspicion, even if the
diagnosis has not been established.
Clin Microbiol Infect. 2016 May;22 Suppl 3:S37-62
 Therapeutic challenges

1. Early administration of empirical adequate (active)

antibiotics according to local epidemiology, patient age
and underlying conditions

2. Optimization of the delivery and effectiveness of

antibiotics
 3. Quali farmaci di prima linea ?

Sarebbero da preferirsi farmaci dotati di :

– Concentrazioni liquorali >> MIC dei microrganismi
– Basso PM
– Basso legame proteico
– Moderatamente lipofili
- Alte dosi per via sistemica
- Multirefracted regimen o infusione continua
ESCMID guideline: diagnosis and treatment of
acute bacterial meningitis
Clin Microbiol Infect. 2016 May;22 Suppl 3:S37-62
Global rates of pneumococcal penicillin resistance
van de Beek D et al. Lancet 2012: 380: 1693-702
Optimization of the delivery and effectiveness of
antibiotics → penetration across the blood-brain
barrier

AUCCSF/AUCS ratio
Barrier integrity

Antibiotic size, charge, lipophilicity, protein

binding ability and interaction with efflux
pumps
Nau R et al. Clin Microbiol Rev 2010; 23: 858
van de Beek D et al. Lancet 2012: 380: 1693-702
AUCCSF/AUCs RATIOS IN HUMANS
Nau R et al. Antimicrob Agents Chemother 1996; 42: 2012-6
Lutsar I & Friedland IR, Clin Pharmacokinet 2000; 39: 335-43
Pea F. et al. Antimicrob Agents Chemother 2003;47:3104-8
Nau R. et al. Clin Microbiol Rev 2010; 23:858-877
CEFOTAXIME ACTS SINERGISTICALLY WITH LEVOFLOXACIN IN EXPERIMENTAL
MENINGITIS DUE TO PENICILLIN RESISTANT PNEUMOCOCCI AND PREVENTS
SELECTION OF LEVOFLOXACIN-RESISTANT MUTANTS IN VITRO
Kuhn F et al. Antimicrob Agents Chemother 2003: 2487-91

7,00
6,00
5,00 Control
4,00 LFX
3,00 CTX
2,00 CTX+LFX

1,00
0,00
Initial titer log Killing rate over 8
CFU/mL) h (logCFU/mL)
AUCCSF/AUCs RATIOS IN HUMANS
Nau R et al. Antimicrob Agents Chemother 1996; 42: 2012-6
Lutsar I & Friedland IR, Clin Pharmacokinet 2000; 39: 335-43
Pea F. et al. Antimicrob Agents Chemother 2003;47:3104-8
Nau R. et al. Clin Microbiol Rev 2010; 23:858-877
4. C’è indicazione all’uso di steroide in acuto ?

NEONATES 1 study, size unpowered

Insufficient data
CHILDREN 15 studies, 13 prospective randomized, 12 placebo
controlled.
The available evidence supports the use of DXMH,
10-20 minutes prior to antimicrobials at 0.15
mg/kg/6 h for 2-4 days
ADULTS 5 studies, 3 randomized placebo controlled, 4
were inconclusive, 1 shown significant benefit.
2 large meta-analysis of 623 and 1800 pts showed
substantial reduction in fatality, hearing loss and
neurological sequelae
4. C’è indicazione all’uso di steroide in acuto ?

DEXAMETHASONE IN ADULTS WITH BACTERIAL MENINGITIS

De Gans J et al , N Engl J Med 2002

301 pts enrolled

% P = .03
25 10 mg/6h for 4 days

P = .04
Follow 15 15
up
at 8 w 7

patients with unfavourable death

outcome

placebo DXMT
4. C’è indicazione all’uso di steroide in acuto ?
Dexamethasone for the Treatment of Tuberculous
Meningitis in Adolescents and Adults Thwaites GE et
al, N Engl J Med 2004
545 patients randomly assigned to either dexamethasone (274) or placebo
(271)
P =
41,3 .001 HIV
%
31,8

placebo

DXMT

DEATHS at 9 m follow up
Our approach to the management of CNS
infection
Implementation of a meningitis care bundle in the
emergency room reduces mortality associated with acute
bacterial meningitis Viale P et al. Ann of Pharmacother 2015
Implementation of a meningitis care bundle in the
emergency room reduces mortality associated with acute
bacterial meningitis Viale P et al. Ann of Pharmacother 2015

Historical group Bundle group p

N=92 (%) N=85 (%)
Cephalosporin high dose prior LP 10 (10.9) 43 (50.6) <0.001
Any antibiotic before LP 26 (28.2) 53 (62.4) <.001
Lumbar puncture
Performed 89 (96.7) 85 (100) .89
CSF culture positive 45 (48.9) 54 (63.5) .05
Antigen test positive 13 (14.1) 9 (28) .50
Blood culture
Performed 34 (37) 49 (57.6) .007
Positive 14 (15.2) 25 (29.4) .03
Etiological diagnosis
Yes 67 (72.8) 65 (76.5) .61
Implementation of a meningitis care bundle in the
emergency room reduces mortality associated with acute
bacterial meningitis Viale P et al. Ann of Pharmacother 2015

Historical group Bundle group p

N=92 (%) N=85 (%)
Therapeutic management
Timing to first antibiotic dose <0.001
≤1 h 23 (25) 85 (100)
>1-3 h 27 (29.3) 0
>3 h 42 (45.7) 0
Dexamethasone 31 (33.7) 85 (100) <.001
Days of combination ther 12 (7-15) 8 (6-12) .002
Days of antibiotic ther 14 (10-18) 14 (10-17) .51
Outcome
In-hospital mortality 13 (14.1) 4 (4.7) .04
Neurological sequelae 15/79 (18.9) 11/81 (13.5) .40
A meningitis bundle to abate mortality

ALGORITMO per il MANAGEMENT delle INFEZIONI ACUTE

del SNC alla PRIMA OSSERVAZIONE in PRONTO
SOCCORSO
 SOSPETTA INFEZIONE ACUTA SNC

Esami ematochimici urgenti (emocromo, glicemia, creatininemia, Na, K, Cl, FBG, D-dimero, PCR)
Valutazione parametri vitali Valutazione status neurologico

desametasone 10 mg
 SOSPETTA INFEZIONE ACUTA SNC

Esami ematochimici urgenti (emocromo, glicemia, creatininemia, Na, K, Cl, FBG, D-dimero, PCR)
Valutazione parametri vitali Valutazione status neurologico

desametasone 10 mg
 SOSPETTA INFEZIONE ACUTA SNC

Esami ematochimici urgenti (emocromo, glicemia, creatininemia, Na, K, Cl, FBG, D-dimero, PCR)
Valutazione parametri vitali Valutazione status neurologico

desametasone 10 mg

VALUTAZIONE
INTENSIVISTICA
Emocolture (2 set)
TER. ANTIBIOTICA EMPIRICA
cefotaxime 4 g
CONS. INFETTIVOLOGICA
CONS. NEUROLOGICA
TC ENCEFALO urgente
SI NO
Paziente critico
Complicanze sistemiche
Complicanze neurologiche
Emocolture (2 set)
TER. ANTIBIOTICA EMPIRICA
cefotaxime 4 g
CONS. INFETTIVOLOGICA
CONS. NEUROLOGICA
TC ENCEFALO urgente
Ipertensione endocranica

Ipertensione endocranica CONSULENZA SI NO

NEUROCHIRURGICA
NO SI

rachicentesi immediata rachicentesi differita rachicentesi immediata

 ASPETTO LIQUOR

TORBIDO LIMPIDO

Prosegue terapia empirica LCR : 6-7 cc

Dose die: Se Glicorrachia ridotta: 1 cc x Esame chimico-fisico
Cefotaxime 3 g / 6h Ricerca colturale e PCR per BK 0,5 cc x Esame colturale
+ (da 1 aliquota di storaggio) 2 cc x PCR HSV, Enterovirus, WNV
Levofloxacina 500 BD Switch a Ampicillina 4 g 1 cc x sierologia WNV, Toscana
Dose die: 4 g / 6 h 1-2 cc x storaggio

LCR: 4-5 cc Un segno/sintomo maggiore

1 cc x Esame chimico-fisico acyclovir 10 mg/Kg EV
DOSE DIE : 10 g/kg/8 h di encefalite:
0,5 cc x Esame colturale - Alterazioni del sensorio
1 cc x Gram o Ag precoci EEG/RMN entro 48 h - Turbe del comportamento
1-2 cc x storaggio - Deficit neurologici focali
- Convulsioni
nella norma patologico
Gram/Ag neg Esito gram STOP PROSEGUE
Ter. Atb Ter. Atb acyclovir acyclovir
empirica mirata
Esame colturale negativo
STOP Terapia antibiotica
Esame colturale positivo
Terapia antibiotica mirata
 PAZIENTE con SOSPETTA/ ACCERTATA SINDROME
MENINGEA

Algoritmo gestionale
Alcune domande ricorrenti:
1. Quanto precoce deve essere la terapia antibiotica ? IL PIU’
POSSIBILE
2. CT scan encefalo pre- puntura lombare ? SI
3. Quali farmaci di prima linea ? CEF 3^gen ANTI-PNEUMO +
CHINO
4. C’è indicazione all’uso di steroide in acuto ? SI
5. Quanto deve durare la terapia ? Fino a remissione clinica
completa
6. C’è indicazione a PL di controllo a fine terapia ? NO
ESCMID guideline: diagnosis and treatment of
acute bacterial meningitis Clin Microbiol Infect. 2016 May;22 Suppl 3:S37-62
Case definitions, diagnostic algorithms, and priorities
in encephalitis: consensus statement of the
international encephalitis consortium
Venkatesan A et al. Clin Infect Dis 2013 Oct;57(8):1114-28
Diagnostic Criteria for Encephalitis and Encephalopathy of Presumed Infectious or
Autoimmune Etiology
Major Criterion (required)
Patients presenting to medical attention with altered mental status (defined as decreased or
altered level of consciousness, lethargy or personality change) lasting ≥24 h with no
alternative cause identified
Minor Criteria (2 required for possible encephalitis; ≥3 required for probable or
confirmed encephalitis)
Documented fever ≥38° C within the 72 h before or after presentation
Generalized or partial seizures not fully attributable to a preexisting seizure disorder
New onset of focal neurologic findings
CSF WBC count ≥5/cubic mm
Abnormality of brain parenchyma on neuroimaging suggestive of encephalitis
Abnormality on EEG that is consistent with encephalitis and not attributable to another
cause
 Case Definitions, Diagnostic Algorithms, and Priorities in Encephalitis:
Consensus Statement of the International Encephalitis Consortium
Venkatesan et al, CID 2013;57:1114-28

Confirmed encephalitis requires one of the following:

1.Pathologic confirmation of brain inflammation consistent with encephalitis.

2.Defined pathologic, microbiologic, or serologic evidence of acute infection with a microorganism

strongly associated with encephalitis from an appropriate clinical specimen.

3.Laboratory evidence of an autoimmune condition strongly associated with encephalitis.

Does this patient have an acute CNS infection?
Granerod J et al. Lancet 2010; 10: 835-44

Population-based prospective study in UK, 2005-2006

203 pts with encephalitis, median age 30 years (0-87), 54% were male
 15% immunocompromised pts

24% of patients with

HSV encephalitis were
afebrile, and 11% had
not CSF pleocytosis
Fever is a common finding in patients with acute encephalitis but is nonspecific.

The requirement for objective documentation of fever within a restricted time frame of ≤72
h after hospitalization was chosen to exclude secondary health-care associated infections. It is
recognized that fevers can occur as a result of a number of infections outside of the central
nervous system that can cause encephalopathy, as well as with noninfectious entities that mimic
encephalitis.

It is also recognized that fever may fluctuate and, as such, objective fever may be lacking in
patients with infectious encephalitis at the time of clinical assessment.

Immunosuppressed patients with encephalitis may not mount a fever.

Seizures associated with encephalitis may be generalized, suggestive of global CNS dysfunction,
or focal, indicating a localized process.

 Subclinical seizures may also occur and can be a cause of altered sensorium.

 Seizures associated with high temperatures are relatively common in young children and, if
occurring in isolation, do not mandate evaluation for encephalitis.

 The major requirement for at least 24 h of altered mentation was selected to exclude the
postictal state seen in patients with febrile seizures.
CSF pleocytosis is suggestive of an inflammatory process of the brain parenchyma, meninges,
or both (meningoencephalitis).

 The absence of CSF pleocytosis, however, does not exclude encephalitis. In particular, it is
recognized that the CSF may be devoid of cells in immunocompromised patients

 The CSF profile with inflammation limited to the meninges may be indistinguishable from that
in patients with encephalitis. In the majority of cases of encephalitis, however, the absolute
number of leukocytes is <1000/mm3 and lymphocytes typically predominate.

Granerod et al, Lancet Infect Dis 2010; 10: 835–44

Neuroimaging plays a crucial role in the evaluation of patients with suspected encephalitis, as
it may support the diagnosis of a specific etiology or identify alternate conditions that mimic
encephalitis.

 Magnetic resonance imaging (MRI) is the radiologic modality of choice for evaluation of
patients with suspected encephalitis.

 MRI may aid in defining an etiology, as localization of inflammation may be suggestive of

particular pathogens (eg, temporal lobe involvement in patients with herpes simplex virus
encephalitis) or of an autoimmune phenomenon (eg, demyelination in patients with acute
disseminated encephalomyelitis).

 A noncontrast CT scan is most useful in evaluating safety in the performance of a lumbar

puncture and in excluding alternative diagnoses such as subarachnoid hemorrhage.

 MRI or CT may not be available in resource-limited settings, in which case the diagnosis of
encephalitis will need to rely on clinical and laboratory criteria.
EEG abnormalities reported in cases of encephalitis range from nonspecific generalized
slowing to distinctive patterns suggestive of specific entities:

Repetitive sharp wave complexes over the temporal lobes or periodic lateralizing epileptiform
discharges in HSV-1. [Lai and Gragasin J Clin Neurophysiol 1988 5:87– 103]

Bilateral synchronous periodic sharp and slow waves associated with subacute sclerosing
panencephalitis. [Gutierrez et al. Dev Med Child Neurol 2010 52:901–7]

EEG abnormalities are frequently nonspecific and may be attributable to medications or

metabolic abnormalities. The EEG may identify epileptiform discharges in the absence of clinical
evidence of seizure activity (subclinical or nonconvulsive status epilepticus) as a cause of
obtundation.
Granerod J et al. Lancet 2010; 10: 835-44

 Cause was found for 128 out of

203 (63%) cases of encephalitis
Encephalitis in UK, 2005-2006
Granerod J et al. Lancet 2010; 10: 835-44
Worldwide distribution of major arboviral
encephalitides
(Malattie Infettive, Università di Bologna)
 Patogenesi
Trasmissione mediante puntura della zanzara
Replicazione virale nelle cellule di Langerhans della cute
Successiva migrazione e replicazione nei linfonodi loco-regionali
Viremia dopo circa 7 giorni
Clearance virale o invasione del SNC attraverso l’endotelio
vascolare con superamento BEE (trasporto passivo o replicazione
nelle cellule endoteliali)
Diffusione alle cellule nervose
Degenerazione e apoptosi dei neuroni con formazione di noduli
microgliali; formazione di infiltrato mononucleato
Sedi più colpite: gangli della base, talamo, ippocampo, corteccia
temporale, cervelletto, corni anteriori midollo spinale
Deficit genetico CCR5 e OAS1 associato ad aumentata replicazione
virale e maggiore letalità
 West Nile Infection

Mostly asymptomatic

About one in
five infected
develop fever

About one in
150 infected
develop SNC
disease
In New York, Romania, and Israel, the risk for neurologic disease increased
with age, which may explain, in part, the different epidemiologic patterns
seen in parts of Africa.
In Egypt and South Africa neurologic disease is rare.
Although immunosenescence affecting innate and/or adaptive immune
responses is a likely scenario, other observations indicate roles for functional
or structural CNS changes that facilitate neuroinvasion.
 WNV- Clinical manifestation

Neurologic disease occurs < 1% of infected individuals.

Patients typically have a febrile prodrome of 1-7 days,

which may be biphasic, before developing neurologic
symptoms.
In recent outbreaks, approximately two thirds of
hospitalized patients had encephalitis and one third had
meningitis.
Acute flaccid paralysis caused by virus infection of the
anterior horn of the spinal cord (myelitis) has been
recognized in recent outbreaks.
The clinical picture suggests poliomyelitis; paralysis is
frequently asymmetrical and may or may not be associated
with meningoencephalitis.
 WNV- Clinical manifestation
Other neurologic features include:
Cranial neuropathies,
Optic neuritis,
Ataxia.
Stiffness, rigidity, spasms, bradykinesia, and tremors,
associated with basal ganglia damage, have also recently
been recognized in WNE
 WNV- Clinical manifestation
In recent outbreaks, overall case-fatality rates for hospitalized
patients ranged from 4% to 14% but were higher in older patients.
Other risk factors for death include
 the presence of profound weakness,
 deep coma,
 failure to produce IgM antibody,
 impaired immunity,
 coexisting illness such as hypertension or diabetes mellitus.

Neurologic sequelae are common among survivors.

In one study, half of hospitalized patients still had a functional
deficit at discharge and only one third had recovered fully by 1
year.
IgG is the predominant antibody most likely confering long-term
immunity against WNV re-infection. Although not enough data
exists, immunity against WNV in convalescent patients is presumed
to be life-long.
 Malattia di West-Nile Neuroinvasiva (WNND)
Manifestazioni cliniche

(Sejvar JJ, Clin Infect Dis 2007)

 WNV- Diagnosis
PCR in serum, CSF, urine
Serology in serum and CSF
(Serum IgM in some WNV patients persist for longer than
16 months, potentially limiting the specificity of tests,
CROSS REACTIVITY among flaviviruses and recent
vaccination against Yellow Fever and Japanese
Encephalitis virus ).
Culture
 577 CASI
68 casi in donazioni di sangue

230 forme neuroinvasive, 100 in E-R

42 decessi
Verosimili cause:
-Primavera calda e piovosa
-Maggiore quantità di zanzara Culex
-Proporzione maggiore di zanzare infette per WNV
-Proporzione maggiore di uccelli morti positivi per
WNV
 Toscana Virus
Famiglia: Bunyavirus > 350 specie
virali

Genere: Plhebovirus > 50 specie

virali

Genoma: RNA (-)segmentato

85-120 nm
 Toscana Virus in Europa
Arthropode- borne virus

Isolato per la prima volta da

Pl. perniciosus nel 1971
nel Centro Italia

Trasmesso da pappataci
Meningite

Tropismo: SNC
Encefalite
 Disribuzione geografica
E’ collegata alla circolazione del vettore

BOLOGNA

Mediterraneo 
ITALIA: casi di
encefalite
rilevati nel periodo
tra maggio-ottobre
Con un picco elevato
in agosto
 TOSV: aspetti clinici
TOSV nell’uomo:

Meningite: febbre( 76-97%), mal di testa (100%), nausea e vomito (67-

88%), mialgia (18%), rigidità nucale (53-95%), perdita di coscienza
(12%), tremore (2,6%), paresi (1,7%).

Durata: 7gg, outcame favorevole

SIEROPREVALENZA: casi asintomatici ( no manifestazioni a carico del

SNC) o con sintomatologia blanda; in genere non occorre
ospedalizzazione

TOSCANA VIRUS PUO’ ESSERE CONSIDERATO UN PATOGENO EMERGENTE

Vector borne and zoonotic disease 2012; 12: 526
Iter diagnostico per la diagnosi di infezioni da
WNV, TOSV, USUV dal 2012
 ASCESSO CEREBRALE -
Processo infiammatotorio suppurativo encefalo
PATOGENESI

I microrganismi possono raggiungere l’encefalo tramite diversi meccanismi …

- per CONTIGUITA’ da un focus infettivo viciniore (40%) OTITE MEDIA

SINUSITE
MASTOIDITE
INFEZIONE DENTARIA
MENINGITE BATTERICA
TROMBOSI DEI SENI
- per DISSEMINAZIONE EMATOGENA da un focus infettivo distale (25%)
ENDOCARDITI
INF. POLMONARI CRONICHE
INF. INTRA-ADDOMINALI
INF. VIE URINARIE
OSTEOMIELITI
- per PENETRAZIONE DIRETTA (15%) TRAUMA PENETRANTE
FRATTURE TECA CRANICA
NEUROCHIRURGIA
- CRITPOGENESI (15-20%)
Brouwer et al. NEJM 2014
Introduction

 The incidence of brain abscesses has been estimated at 0.3 to 1.3 per
100,000 people per year but can be considerably higher in certain risk groups,
for example, patients with HIV/AIDS.

 Over the last 30 years, new diagnostic procedures, such as brain imaging
techniques (MRI and CT) and stereotactic biopsy, and the introduction of new
antibiotics have considerably changed the management of patients with brain
abscess, at least in high-income countries
 PATOGENESI

Fattori correlati al Fattori correlati al

MICRORGANISMO MACRORGANISMO

VIRULENZA (CAPSULA) RIDOTTA RISPOSTA

INFIAMMATORIA
SINERGISMO
deficit opsonizzazione
d’INFETTIVITA’
deficit risposta monocito-magrofagica
VASCULITE
EMBOLIZZAZIONE necrosi emorragica

ASCESSO per CONTIGUITA’ OSTEITE

TROMBOFLEBITE RETROGRADA VENE EMISSARIE
CARICA INFETTANTE / VIRULENZA

ASCESSO EMATOGENO NECROSI EMORRAGICA/ ISCHEMICA

ASCESSO per INOCULAZIONE CARICA INFETTANTE / VIRULENZA

EMORRAGIA / NECROSI POST-TRAUMATICA
Stages of brain abscess
 CEREBRITE PRECOCE PATOGENESI - STADI EVOLUTIVI
1-3 gg
soggetto normoergico / patogeno a virulenza contenuta
edema

CEREBRITE TARDIVA
4-9 gg

CAPSULA PRECOCE
10-13 gg

PMN
infiltrato infiamm. acuto
CAPSULA TARDIVA
14 gg
necrosi parte centrale della lesione

invasione periferica di macrofagi, plasmacellule, fibroblasti

inizio regressione dell’edema

sviluppo di capsula di collagene

aumento di densità e spessore della

capsula
 PATOGENESI - STADI EVOLUTIVI
soggetto ipoergico / patogeno a virulenza elevata / condizioni predisponenti
edema

PMN
infiltrato infiamm. acuto

necrosi parte centrale della lesione Lesione satellite

ridotta invasione periferica di macrofagi, fibroblasti

mancata regressione dell’edema

Ridotto sviluppo di capsula di collagene

>> dimensione ascesso

PRESENTAZIONE CLINICA

ESTREMAMENTE VARIABILE, da INDOLENTE ad IPERACUTA

PREVALGONO I SEGNI CORRELATI AL DANNO LOCALE SU QUELLI SISTEMICI

CEFALEA 70%
ALTERAZIONI FUNZIONI SUPERIORI 70%
SEGNI NEUROLOGICI FOCALI 60%
FEBBRE 40-50%
FEBBRE + CEFALEA + SEGNI FOCALI < 50%
CONVULSIONI 25-45%
VOMITO 25-50%
RIGIDITA’ NUCALE 25%
EDEMA della PAPILLA 25%

LA SEDE DELL’ASCESSO DEFINISCE LA PRESENTAZIONE CLINICA

PRESENTAZIONE CLINICA

Sede Sintomi correlati

------------------------------------------------------------------------------------------------
Frontale Cefalea / Apatia / Sonnolenza / Eloquio rallentato /
turbe della concentrazione / Emisindrome motoria

Cerebellare Atassia / Nistagmo / Dismetria / Vomito / sindrome cinetosica

Temporale Afasia se lesione nell’emisfero dominante / deficit del visus

Tronco Paralisi centrale del VII / disfagia / emisindrome motoria /

ipertermia
BoBrouwer et al. Neurology 2014
DIAGNOSI

ATTENZIONE DIAGNOSITCA di FRONTE a PAZIENTE con…

1. MANIFESTAZIONI NEUROLOGICHE AD ANDAMENTO SUB-ACUTO ma
INGRAVESCENTE
2. ANAMNESI POSITIVA per FATTORI PREDISPONENTI LOCALI o SISTEMICI

Indagini per
DIAGNOSI di MALATTIA

Indagini per
RICERCA FATTORI PREDISPONENTI

Indagini per
DIAGNOSI ETIOLOGICA
 DIAGNOSI
Indagini per
DIAGNOSI di MALATTIA

• TAC
• RMN
Indagini per
RICERCA FATTORI PREDISPONENTI

• Anamnesi
• TC rocche e seni paranasali,
• Rx ortopantomografia Indagini per
• Rx torace, DIAGNOSI ETIOLOGICA
• ecocardiogramma,
• sierologia x HIV • esame colturale
• sierologia x Toxoplasma gondii del materiale drenato (se disponibile)
• sierologia x Toxocara canis • esame colturale
• Mantoux del materiale da biopsia
• Ag Aspergillus (in pz. con condizioni • emocolture
predisponenti)
• criteri “ex juvantibus”
 TERAPIA

Prevede la collaborazione di tra professionalità: NEURORADIOLOGO

INFETTIVOLOGO
NEUROCHIRURGO

Indicazioni al drenaggio chirurgico “APERTO” :

- per gli ascessi con diametro > 2,5-3 cm,
- nei casi in cui non si evidenzia riduzione in corso di terapia
antibiotica
- in caso di deterioramento neurologico.

Controindicazioni al drenaggio chirurgico “APERTO” : BIOPSIA

- presenza di ascessi multipli STEREOTASSICA
- localizzazioni nelle strutture cerebrali profonde

Controindicazioni a qualsiasi manovra invasiva

- concomitanza di meningite ed ependimite,
- diatesi emorragica.
TERAPIA - Algoritmo gestionale alla diagnosi (1)

LESIONE SINGOLA Ø > 3 cm

DRENAGGIO CHIRURGICO

ESAME DIRETTO + GRAM

ATB TERAPIA RAGIONATA

ANAMNESI / OBIETTIVITA’ per F.R.

COLTURA MATERIALE DRENATO ATB TERAPIA

MIRATA/RAGIONATA