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ACUTE MENINGITIS: Diagnose en behandeling

08-11-2017

Wesley Appermans - Béatrice Santens

Onder supervisie van Prof. W. Meersseman

TABLE OF CONTENTS

1. Definition

2. Incidence

3. Signs and symptoms

4. Meningococcal vs pneumococcal meningitis

5. Interpretation cerebrospinal fluid

6. CT prior to LP

7. Use of corticosteroids

8. Antibiotic therapy

9. Profylaxis

10. Reporting Health Care

11. Cases

12. Take home messages

1. DEFINITION

� Acute < 5 days� Viral

� bacterial

� Subacute > 5 days / chronic� Tbc

� Mycose

� Pathogens

� Community acquired

� Healthcare associated

Organism Site of entry Age range Predisposing conditions

Neisseria meningitidis Nasopharynx All agesUsually none, rarely complement

deficiency

Streptococcus pneumoniae

Nasopharynx, direct extension

across skull fracture, or from contiguous or distant foci of

infection

All ages

All conditions that predispose to

pneumococcal bacteremia, fracture of cribriform plate,

cochlear implants, cerebrospinal

fluid otorrhea from basilar skull

fracture, defects of the ear ossicle

(Mondini defect)

Listeria monocytogenes Gastrointestinal tract, placenta Older adults and neonates

Defects in cell-mediated immunity

(eg, glucocorticoids, transplantation [especially renal

transplantation]), pregnancy, liver

disease, alcoholism, malignancy

Coagulase-negative staphylococci Foreign body All agesSurgery and foreign body,

especially ventricular drains

Staphylococcus aureus Bacteremia, foreign body, skin All ages

Endocarditis, surgery and foreign

body, especially ventricular drains; cellulitis, decubitus ulcer

Gram-negative bacilli Various Older adults and neonates

Advanced medical illness,

neurosurgery, ventricular drains, disseminated strongyloidiasis

Haemophilus influenzaeNasopharynx, contiguous spread

from local infection

Adults; infants and children if not

vaccinatedDiminished humoral immunity

2. INCIDENCE

� 1,2 million cases worldwide (1)

� USA (2)� 1998-99: 2.00 cases per 100,000 population (95% CI, 1.85 to 2.15)

� Case fatality rate 15,7%

� 2006-07: 1.38 cases per 100,000 population (95% CI 1.27 to 1.50)

� Case fatality rate 14.3% (P=0.50).

� 18 to 34 years – 0.66 cases per 100,000 population

� 35 to 49 years – 0.95 cases per 100,000 population

� 50 to 64 years – 1.73 cases per 100,000 population

� ≥65 years – 1.92 cases per 100,000 population

� Reduction of incidence of 31%

� Case fatality

� 17,8% Pneumococcal

� 10,1% meningococcal

� 7% H influenza

� 18,1% L monocytogenes

� Netherlands (3)� 2007-08: 1,72 cases per 100,000 population

� 2013-14: 0,94 cases per 100,000 population

� Case fatality 17%

� 18% pnemococcal

� 3% meningococcal

� 35% in L monocytogenes

USA 2003-2007 (2)

� S pneumoniae 71%

� N meningitidis 12%

� Group B strep 7%

� H influenzae 6%

� L monocytogenes 4%

Evolution to meningitis in (4)

� 4% of invasive pneuumococcal infections

� 48% of invasive ? Meningitidis infections

� 30% of invasive listeriosis

� 10% of invasive H influenzae infections

� 4% of invasive group B streptococcal infections

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Netherlands (3)

� S pneumoniae 72%

� N meningitidis 11%� Serogroup B 82%

� L monocytogenes 5%

� H influenzae 3%

� Other strepococcal sp 5%

� S aureus 1%

‘aseptic’ meningitis

� Absence of gram-staining� Viral (Enterovirus)

� Other (mycobacteria, funghi, spirochetes)

� Medication

� (Malignancy)

Symptomatology comparable, however self-limiting

Viralmeningitis

� Enteroviruses, HSV(-2), HIV, WNV, VZV, mumps

� LP: wbc <250/µL, protein <150mg/dL, normal glucose, PCR

‘other’

� Treponema pallidum

� Borrelia burgdorferi

� Cryptococcus neoformans

� Coccidioides immitis

� Tuberculosis

� Drug-induced

3. SIGNS AND SYMPTOMS

� = emergency

� Mortality

� TRIADE (3) (41%)� Fever (74%)

� Alterated mental state (71%)

� Nuchal rigidity / neck stifness (74%)

� Headache (83%)

� Nausea (62%)

� Photofobia

� Rash (8%)

� Classic triad (fever, neck stiffness, altered mental state or headache)� 50-95% present (partially or fully)

�40-45% sensitivity in bacterialmeningitis diangnosis (4)

� Intracranial hypertension, skin rash, neurologic deficit

� less common (less usefull) (4)

� In eldery: confusion

4. PNEUMOCOCCAL

VERSUS

MENINGOCOCCALMENINGITIS

� Pneumococcal meningitis� Triade in 58% of patients (5)

� Mortality 17% (2)

� Meningococcal meningitis: meningitis and/or sepsis� Triade in 27% + rash , myalgia (6)

� leg pain, cold hands and feet, and abnormal skin color

� Absence of focality

� Rash, shock (+- Waterhouse Friedrichson), DIC, Purpura fulminans

� Mortality 10 to 15 percent despite antibiotic treatment (2) (7)

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5. CEREBROSPINALFLUID (CSF)

�CSF should be sent for:� Cell count and differential� Glucose concentration� Protein concentration� Gram stain and bacterial culture

�depending upon the level of concern for other etiologies of meningitis or meningoencephalitis

�Traumatic lumbar puncture / intracerebral or subarachnoidhemorrhage

� WBC / RBC into subarachnoid space� Adjusted WBC count : to subtract one WBC for every 500 to 1500 red

blood cells (RBCs) measured in the CSF.

� Xanthogromia : dd traumatic LP dd SAB

�CSF abnormalities : CAVE� early presentation� recent prior antimicrobial therapy� neutropenia.

WBC counts

(/mm3)

Formula Glucose

(mg/dL)

(glc CSF/serum)

Protein

(mg/L)

Lactate

CSF

Normal clear acellular

< 5 (0-4)(< 5 RBC)

Normal 60-100 (>0.6) < 500 < 4

Bacterial cloudy > 200 –

20.000

> 75-80% PMN <40 (<0.4) > 2.000 > 4

TBC Cloudy 50-300 lymfo 5-45 750-3.000

Fungal blurred 20-300 Neutro 5-45 400-3.000

Viral clear < 500 lymfo 50-80 500

Aseptic clear 10 - 200 Normal 50-100 250-1.000

Listeria

monocytesis

pleiocytosis 100 % PMN to

100%

mononucl

> 25% lymfo

<40 (<0.4) elevated

Gramstaining

� suspicion of bacterial meningitis : bacterial etiology one day or more before culture results are known

� Gram-positive diplococci : pneumococcal infection

� Gram-negative diplococci : meningococcal infection

� Small pleomorphic gram-negative coccobacilli : Haemophilusinfluenzae infection

� Gram-positive rods and coccobacilli : Listerial infection

� Sensitivity: 60-90%

� Specificity: 100%

Lumbar puncture� Normal CSF pressure : 60 –

200 mmH2O

� Obese patients : up tot 250 mmH20

� Infection, bleeding or tumor : balance between CSF secretion and reabsorption

� � intracranial hypertension

Complications:

• Brain herniation <5%

Other tests

� Rapid tests (9) � Latex agglutination tests : AG of common meningeal pathogens in

the CSF

� do not appear to modify the decision to administer antimicrobial therapy

� NB false-positive results have been reported

� sensitivity is 95 to 100 percent

� Multiplex PCR

� <2 h

� Sensitivity and specificity in 90-100%

� Contribution in emergency diagnosis should be clarified

6. CT PRIOR TO LP

� Every patient with suspected meningitis should have CSF obtained unless lumbar puncture (LP) is contraindicated.

� head CT should be performed before LP - one or more of the following risk factors (10)

1. Immunocompromised state (eg, HIV infection, immunosuppressive therapy, solid organ or hematopoietic cell transplantation)

2. History of central nervous system (CNS) disease (mass lesion, stroke, or focal infection)

3. New-onset seizure (within one week of presentation)

4. Papilledema

5. Abnormal level of consciousness

6. Focal neurologic deficit

7. GCS <11 (11)

� CT : LP is contraindicated� � therapy for bacterial meningitis should be continued (if indicated) or evaluation

and treatment for an alternative diagnosis should be undertaken.

� Imaging should not delay antibiotic therapy� Mortality increases by 13% for every hour without antibiotics (11)

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7.COMPLICATIONSOF BACTERIALMENINGITIS (12)

� SYSTEMIC� DIC

� MOF

� ARDS

� Septic or reactive artritis

� NEUROLOGICAL� Impaired mental status

� Increased intracranial pressure and cerebral edema

� Seizures

� Focal neurologic deficits (eg, cranial nerve palsy, hemiparesis)

� Cerebrovascular abnormalities

� Sensorineural hearing loss

� Intellectual impairment

8. USE OF CORTICO-STEROIDS

� Neurological sequelae occur in 5-40% of patients (13) � to diminish rate of complications

� Unfavourable outcome (3)

� 10mg dexamethasone 4x/d, 4 days34% vs 41% (p<0,0001)

� Unfavourable outcome OR 0,54

� Death OR 0,46

� Hearing loss OR 1,32, (p 0,3)

� Cochrane review (13)� non-significant reduction in mortality (17.8% versus 19.9%; risk ratio (RR) 0.90,

95% confidence interval (CI) 0.80 to 1.01, P value = 0.07

� reduced mortality in Streptococcus pneumoniae (S. pneumoniae) meningitis (RR 0.84, 95% CI 0.72 to 0.98

� lower rates of severe hearing loss (RR 0.67, 95% CI 0.51 to 0.88), any hearing loss (RR 0.74, 95% CI 0.63 to 0.87) and neurological sequelae (RR 0.83, 95% CI 0.69 to 1.00).

� severe hearing loss in children with H. influenzae meningitis (RR 0.34, 95% CI 0.20 to 0.59)

9. ANTIBIOTIC TREATMENT

� Treatment should be initiated as soon as possible

� Prognostic markers: hypotension, altered mental status andseizures (14)

� Prediction of risk:� Low (0): 9% adverse outcome (death or neurologic deficit )

� Intermediate (1): 33% adverse outcome

� High (2-3): 56% adverse outcome

� Additional risk factor: advancement

Adolescents and adults N meningitidis, S

pneumoniae (H. influenzae

and group B Streptococcus )

ceftriaxone 2x2g IV or

cefotaxime 6x2g IV

Adults >50y,

immunocompromised

patients

S pneumoniae, N

meningitidis, L

monocytogenes

ceftriaxone 2x2g IV or

cefotaxime 6x2g IV PLUS

Amoxicilline 6x2g IV or co-

trimoxazole 4x160/800mg IV

Beta-lacta allergy:

vancomycin + moxifloxacin

1x400mg IV

After head trauma S aureus, G-bacillae, H

influenzae, S pneumoniae

ceftriaxone 2x2gIV or

cefotaxime 6x2g IV

After neurosurgery/CSF-

drainage

S Aureus, coagulase-

negative Staf, G- bacillae, P

aeruginosa

ceftazidime 3x2gIV PLUS

vancomycin 2x1g IV

Empiric therapy according to Antibioticagids.be

Fig. I. Making decisions on clinical

parameters and CSF

TREATMENT OF ACUTEMENINGITIS

1. Antibiotic therapy

2. Encefalitis � Iv aciclovir 10 mg/kg / 8u (3x/d)

� HSV PCR

3. Use of corticosteroids� Dexamethasone IV 10 mg/ 6u – 4 days (4x/d)

� In association with antibiotics

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Health care associated (16)

After 48 hours of hospitalisation until 7 days after release

Different spectrum of microorganisms

Craniotomy 0,8-1,5%,

Ventricular or lumbar catheters 8 / 5%

head trauma 1,4%

LP 1/50 000

Health care associated

PROFYLAXIS

1. What ?

� index case

� Invasive infection

� use of droplet precautions� be continued for 24 hours after institution of effective antibiotics in

patients with suspected or confirmed N. meningitidis infection [2

2. Whom to treat ?

� Close contacts

� as early as possible

� (>8 hours) contact

� directly exposed to the patient's oral secretions� 7days before the onset

� until 24 hours after initiation of appropriate antibiotic therapy [2].

� Prophylaxis is not indicated if exposure to the index case is brief. ex. healthcare workers <-> direct exposure to respiratory secretions

PROFYLAXIS

3. Timing of prophylaxis

� secondary disease : highest immediately after the onset of disease in the index patient.

� within 10 days of the primary case

� � as early as possible ( <24 )

4. Anitmicrobial profylaxis� Rifampicin : 2d 2x600 mg PO

� Ciprofloxacine : 1x 500 mg PO

� Ceftriaxone : 1x 250 mg I.M.

� Azithromycin is not recommended as a first-line agent for chemoprophylaxis.

Prevention -Vaccination

� Act-Hib

� Meningitec (2002)

� Prevenar 13, Pneumovax 23� PCV7 2006, PCV10 2011

� No serotype replacement of non vaccine serotypes (Netherlands (4))

� Incidence non PVC7-serotypes increased by 61% 95% CI 54-69)

Prevention –Vaccination(17)

� Introduction of PCV7 in 2000 in USA� Decreased incidence PM 64% in children <2y, 54% >65y

� Introduction of PCV13 in 2010 in USA� Decreased incidence PM 39% from 2008 to 2014

� Fatality rate was not affected

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10. REPORTING HEALTH CARE

REPORTING HEALTH CARE

11. CASUSSEN En dan nu, Praktische voorbeelden

CASUS 1v, 17 Jaar

Me

dis

che

vo

org

esc

hie

de

nis • blanco

Pre

sen

tati

e • 15-03

• 1e maal braken

• 16-03

• Deze nacht ziek geweest, overdag niet naar school geweest.

• gebraakt

• hevige hoofdpijn

• in ambulance

• ingedaald bewustzijn

• slecht reagerend op prikkels

• Bij aankomst op spoed

• niet meer responsief

• indalend bewustzijn.

• Ontstaan van rash op onderbenen.

• Geen reizen

• Voordien niet ziek geweest

Th

era

pie

bij

op

na

me • nihil

� Klinisch onderzoek� Ligt met de ogen open, kijkt niet aan.

� Spreekt niet, voert geen opdrachten uit.

� 3 vingers nekstijf.

� Pupillen eerder mydriatisch, slechts discreet lichtreactief.

� Geen terugtrekreactie op pijn in de 4 LM. Bij testing nekstijf grijpt pte naar nek/hoofd.

� VZR bilateraal in flexie.

� Petechiën thv OL > BL.

� Eerste labo én hemoculturen

� � onmiddellijk gestart met triple therapie na afname van hemoculturen

� Rocephine 2x2gIV

� Zovirax 3x10mg/kg/d

� Dexamethasone 4x10mg/d

� Na toediening van medicatie: � CT

� Intubatie

� Oplijnen

� LP

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� Lumbaal punctie:

�

� CT hersenen: 16/03� Normaal hersenparenchym.

� Geen verschuiving van de middellijn.

� Beperkte vernauwing van de voorhoornen van beide laterale ventrikels en de temporale hoornen.

� Bewaarde witgrijze stof differentiatie.

� Geen intra-craniële bloeding.

� Geen evidentie voor cerebrale massa.

� CT hersenen herevaluatie: 17/03 9u� Verdere verstrijking vd sulci en iets nauwer kaliber vd laterale

ventrikels ikv lichte toename vh hersenoedeem.

� Geen obliteratie vd basale cisternen.

� Geen tonsillaire inklemming

� Bewaarde witgrijze stof differentiatie.

� Geen intracraniële bloeding / abces / verweking.

Zeer snelle evolutie

� bilateraal mydriatische pupillen

� afwezigheid van hersenstamreflexen � controle CT schedel : lichte toename van het cerebrale oedeem

toonde.

� NCH : infauste prognose

� Geen ventriculo-externe drainage

� Hersendood

� Na overleg met ouders, screening voor orgaandonor

� Prelevatie van de organen werd uitgevoerd na 48 uur antibiotische behandeling.

CASUS 2, M 67 j

Me

dis

che

voo

rge

sch

ied

en

is •Operatie meniscus rechts

•Genitale HSV 2

Pre

sen

tati

e o

p s

pe

od

ge

valle

n •16/04:

•continue, drukkende pijn in de bovenbuik gekregen

• Bandvormige pijn

• Bij stappen superponerende pijn.

•Geen vomitus of nausea. Geen diarree.

•Heeft sinds deze middag ook last van hoofdpijn, nu nog aanwezig.

•parietaal

•continue zeurende pijn.

•Geen fotofobie of sonofobie.

•Deze middag 2x400mg brufen genomen zonder effect

• Geen koorts gemaakt.

•Geen spierpijn. Geen rillingen.

•Geen zieken in de omgeving.

•Verdere systeemanamnese negatief

Th

uis

the

rap

ie b

ij o

pn

am

e •geen

� Klinisch onderzoek : � Parameters:

� Bloeddruk (mmHg): 161/81

� Pols (/min): 87

� T 37.2°C

� AHfreq 16/min

� O2sat 97%

� Alg: helder en adequaat

� Hartauscultatie: RR, S1S2, geen souffle

� Longauscultatie: Zuiver VAG, geen bijgeluiden

� Abdomen: normoperistalsis, wisselend tympaan, soepel, geen drukpijn, geen hepatosplenomegalie, Murphy -

� Drukpijn basale ribben, erger bij rechtkomen

� Geen malleolaire oedemen, licht gestuwde CVD, HJR -

� Geen NSP, geen WSP

� Neuro: craniale zenuwen ok, bewaarde kracht en sensibiliteit in BL, Barre -, Mingazinni –

� Echo abdomen: � Gevorderde leversteatose.

� Geen argumenten voor pancreatitis met enige reserve gezien zeer beperkte sensitiviteit van echografie in de detectie van pancreatitis.

� Geen intra-abdominale infectiefocus aantoonbaar. 1/ Gevorderde leversteatose.

� BESLUIT: wandpijn en forse leversteatose, op basis van anamnese vermoedelijk alcoholisch

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� Op 17/04: opnieuw presentatie op spoedgevallen � toegenomen hoofdpijnklachten : 8x ibuprofen hebben ingenomen,

zonder enige beterschap.

� vertraagde respons volgens echtgenote

� Holocranieel

� niet bandvormig, niet kloppend, eerder zeuren

� Er is mogelijks lichte fotofobie maar geen sonofobie

� Geen koorts

� Geen misselijkheid, geen braken.

� Klinisch onderzoek: idem� Neuro: geen uitvalverschijnselen, geen lateralisatie, terminaal

nekstijf

� Behandeling? � Geen beeld van encefalitis noch myelitis

� immuuncompetent

� antivirale therapie ter behandeling van een postprimaire HSV 2 meningitis ?

� Hier vrij uitgesproken beeld: start anti-virale therapie (IV Zovirax10mg/kg, 3 keer per dag)

� 7-10 dagen.

� Cave weinig literatuur over, evidence based?

NB : Circa 20-30% van patiënten met genitale herpes zullen één of meerdere episoden van (een subklinische tot licht symptomatische) virale meningitis doormaken.

1. Community-acquired – healthcare associated

2. Pneumococcal – meningococcal

3. Triade not always present

4. Empiric antibiotics asap AFTER CSF analysis

5. Corticosteroids reduce neurologic sequelae

12.TAKE HOME MESSAGES

REFERENCES

(1) Pathophysiology of bacterial meningitis: mechanism(s) of neuronal injury. Scheld WM, Koedel U, Nathan B,

Pfister HW J Infect Dis. 2002;186 Suppl 2:S225.

(2) Bacterial meningitis in the United States, 1998-2007.Thigpen MC, Whitney CG, Messonnier NE, Zell ER,

Lynfield R, Hadler JL, Harrison LH, Farley MM, Reingold A, Bennett NM, Craig AS, Schaffner W, Thomas A,

Lewis MM, Scallan E, Schuchat A, Emerging Infections Programs Network N Engl J Med. 2011;364(21):2016.

(3) Community-acquired bacterial meningitis in adults in the Netherlands, 2006-14: a prospective cohort

study.AUBijlsma MW, Brouwer MC, Kasanmoentalib ES, Kloek AT, Lucas MJ, Tanck MW, van der Ende A,

van de Beek D SOLancet Infect Dis. 2016 Mar;16(3):339-47. Epub 2015 Dec 1.

(4) Clinical decision rules for acute bacterial menigitis : current insights

Clinical presentation varies according to several factors: age, duration, evolution of symptoms at time of

clinical examination

(5) Clinical features and prognostic factors in adults with bacterial meningitis. van de Beek D, de Gans J,

Spanjaard L, Weisfelt M, Reitsma JB, Vermeulen M N Engl J Med. 2004;351(18):1849.

(6) Clinical features, outcome, and meningococcal genotype in 258 adults with meningococcal meningitis: a

prospective cohort study. Heckenberg SG, de Gans J, Brouwer MC, Weisfelt M, Piet JR, Spanjaard L, van der

Ende A, van de Beek D Medicine (Baltimore). 2008;87(4):185.

(7) Population-based analysis of meningococcal disease mortality in the United States: 1990-2002. Sharip A,

Sorvillo F, Redelings MD, Mascola L, Wise M, Nguyen DM Pediatr Infect Dis J. 2006;25(3):191.

(8) Medical microbiology: laboratory diagnosis of invasive pneumococcal disease.AUWerno AM, Murdoch

DR SOClin Infect Dis. 2008;46(6):926.

(9) Computed tomography of the head before lumbar puncture in adults with suspected meningitis.AUHasbun

R, Abrahams J, Jekel J, Quagliarello VJ SON Engl J Med. 2001;345(24):1727.,

(10) clinical decision rules for acute bacterial meningitis: current insights

(11) Spectrum of complications during bacterial meningitis in adults. Results of a prospective clinical

study.AUPfister HW, Feiden W, Einhäupl KM SOArch Neurol. 1993;50(6):575.

(14) Ann Intern Med. 1998 Dec 1;129(11):862-9.

Community-acquired bacterial meningitis: risk stratification for adverse clinical outcome and effect of

antibiotic timing.Aronin Sl, peduzzi o, quagliarello VG

(16) Nosocomial Bacterial Meningitis Diederik van de Beek, M.D., Ph.D., James M. Drake, M.B., B.Ch., and Allan

R. Tunkel, M.D., Ph.D. N Engl J Med 2010; 362:146-154January 14, 2010DOI: 10.1056/NEJMra0804573

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