community acuired bactarial meningitis

8/2/2019 Community Acuired Bactarial Meningitis

1/16

REVIEWPract Neurol 2008; 8: 823

Community-acquiredbacterial meningitis in adultsEwout S Schut, Jan de Gans, Diederik van de Beek

E S SchutNeurology Resident

J de GansNeurologist

D van de BeekNeurologist

Department of Neurology, Centre

of Infection and Immunity

Amsterdam (CINIMA), Academic

Medical Centre, Amsterdam,

The Netherlands

Correspondence to:

Dr D van de Beek

Department of Neurology,

Academic Medical Centre,

University of Amsterdam,

PO Box 22660, 1100 DD

Amsterdam, The Netherlands;[email protected]

Practical Neurology

10.1136/jnnp.2007.139725


2/16

Despite the availability of effective antibiotics, vaccination programmes andskilled acute-care facilities, there is still a significant mortality and morbidityfrom bacterial meningitis. Neurologists are often called on to rule outbacterial meningitis, which can be difficult with the history and physicalexamination alone. In this review the authors will discuss the epidemiology,diagnosis and treatment of acute community-acquired bacterial meningitis inadults, focussing particularly on the management of patients withneurological complications, and stressing the importance of adjunctivedexamethasone.

Until the early 20th century the

prognosis for patients with acute

bacterial meningitis was dismal.1

Since then, improvements in public

health, the discovery of effective antimicro-

bial agents, the implementation of childhood

vaccination programmes and the develop-

ment of highly specialised acute-care facil-

ities have had a dramatic impact on the

mortality and morbidity associated with this

disease. However, despite these advances,

community-acquired bacterial meningitis

continues to exact a heavy toll, even in

developed countries. It is still therefore a

neurological emergency and the patients

require immediate evaluation and treatment.

EPIDEMIOLOGYThe incidence of bacterial meningitis is about5 cases per 100,000 adults per year in

developed countries24 and may be 10 times

higher in less developed countries. The

predominant causative pathogens in adults

are Streptococcus pneumoniae (pneumococ-

cus) and Neisseria meningitidis (meningococ-

cus) which are responsible for about 80% of

all cases:

N Pneumococcal meningitis most com-monly occurs in patients with an ante-

cedent illness such as pneumonia, acuteotitis media, and acute sinusitis. Groupsat increased risk include the elderly, theimmunocompromised, smokers, diabetics,alcoholics and those who develop cere-brospinal fluid (CSF) rhinorrhoea after abasal skull fracture.

N The meningococcus most commonlycauses meningitis and septicaemia inchildren and young adults, and is a majorcause of epidemic bacterial meningitisworldwide.

N Listeria monocytogenes is the third mostcommon cause of bacterial meningitis

and commonly occurs in patients withdefective cell-mediated immunity.

Since the early antibiotic era, the emer-

gence of antimicrobial resistance has been a

continuing problem.4, 5 Pneumococcal resis-

tance to penicillin, due to changes in its

penicillin binding proteins, started to appearin the 1960s and has since developed world-

wide, often necessitating initial therapy with

a combination of a third-generation cepha-

losporin with vancomycin, instead of mono-

therapy with penicillin.

Another important change in epidemiology

has been caused by the routine vaccination of

children against Haemophilus influenzaetype

b and seven serotypes ofS pneumoniae.6 As a

result, bacterial meningitis now occurs more

often in adults than in infants and young

children. Also, in the UK, a campaign waslaunched seven years ago7 to immunise

children with the serogroup C meningococcal

polysaccharide-protein conjugate vaccines

which resulted in a dramatic reduction in

serogroup C invasive meningococcal disease,

and this prompted other countries to intro-

duce similar programmes. In the USA, the

Advisory Committee on Immunization

Practices has recently recommended quad-

rivalent conjugate vaccine, which offers

protection against serogroups A, C, Y andW-135 for immunoprophylaxis of adolescents

before high school entry. Although not all

serotypes of meningococci are covered by this

vaccine, this measure should further reduce

the incidence of bacterial meningitis.

CLINICAL PRESENTATIONNeurologists are often called on to rule out

bacterial meningitis. In most cases the

patient is febrile, confused and complaining

of headache, and the question revolvesaround the need for a lumbar puncture.

9Schut, de Gans, van de Beek

www.practical-neurology.com


3/16


4/16

Figure 1

Algorithm for the management of

patients with suspected community-

acquired bacterial meningitis. (This

material was previously published as

part of an online supplementary

appendix to reference 4. Copyright

2006 Massachusetts Medical Society.

All rights reserved.)




5/16

Treponema pallidum. Focal brain lesions with

mass effect and oedema are most commonly

caused by Toxoplasma gondii and

Mycobacterium tuberculosis. Patients with

tuberculous meningitis tend to have a longer

duration of illness (>6 days), frequently have

an abnormal chest x ray, and often have a

lymphocytic CSF with a low glucose. Thesearch for acid-alcohol fast bacilli in the CSF

remains the cornerstone of diagnosis, but

requires diligence and time. In developed

countries, when HIV-infected patients present

with symptoms and signs of a mass lesion,

Toxoplasma encephalitis is the most common

aetiology, followed by primary central ner-

vous system lymphoma.

MAKING THE DIAGNOSIS AND

STARTING TREATMENTGiven the high mortality of acute bacterialmeningitis, starting treatment and completing

the diagnostic process should be carried out

simultaneously in most cases (fig 1). The first

step is to evaluate vital functions, obtain two

sets of blood cultures, and blood tests which

typically should not take more than one or

two minutes. At the same time, the severity of

the patients condition and the level of

suspicion for the presence of bacterialmeningitis should be determined. If the

patient is in shock low doses of hydrocorti-

sone (50 mg every six hours iv) and fludro-

cortisone (50 mg once daily through a

nasogastric tube) should be administered.9 If

the patient is not critically ill and there is no

coagulopathy (due to anticoagulants or

disseminated intravascular coagulation) a

lumbar puncture should be carried out

provided there are no contraindications (see

below). Examination of the cerebrospinal fluid

(CSF) is critically important in the diagnosis of

bacterial meningitis because it:

N is required to confirm the diagnosis,

N identifies the causative organism,

N allows the testing of antibiotic sensitiv-ities,

N and so helps to rationalise treatment.

INDICATION FOR COMPUTED

TOMOGRAPHY BEFORE LUMBARPUNCTUREThe advent of computed tomography (CT) in the

1970s has of course transformed neurological

TABLE 1 Indications for CT brain scanning before lumbar puncture

l Focal neurological deficit, not including cranial nerve palsiesl New-onset seizuresl Papilloedemal Abnormal level of consciousness, interfering with proper neurological

examination (Glasgow Coma Scale ,10)l Severe immunocompromised state

TABLE 2 Recommendations for empirical antimicrobial therapy in suspectedcommunity-acquired bacterial meningitis (adapted from van de Beek et al4)

Predisposingfactor

Common bacterialpathogens

Initial intravenousantibiotic therapy

Age

250 years N meningitidis,S pneumoniae

Vancomycin plus ceftriaxone orcefotaxime*

.50 years N meningitidis,S pneumoniae,

L monocytogenes, aerobic gram-negative bacilli

{Vancomycin plus ceftriaxone orcefotaxime plus ampicillin

With risk factorpresent{

S pneumoniae,L monocytogenes,H influenzae

{Vancomycin plus ceftriaxone orcefotaxime plus ampicillin

*In areas with very low penicillin-resistance rates monotherapy penicillin may be considered.{In areas with very low penicillin-resistance and cephalosporin-resistance rates combinationtherapy of amoxicillin and a third-generation cephalosporin may be considered.

{Alcoholism, altered immune status.

Practical Neurology

10.1136/jnnp.2007.139725


6/16

practice, in this context allowing the differ-

entiation of other types of pyogenic intracranial

infections and the detection of brain swelling

and mass lesions. The downside of its avail-

ability has been the concern among physicians

about the possibility of an occult mass lesion

leading to brain shift and herniation afterlumbar puncture, started to routinely perform

CT scans before lumbar punctureintroducing

inevitable delay in antimicrobial therapy, some-

times for many hours, with catastrophic results.

Numerous papers have tried to establish a clear

link between lumbar puncture and subsequent

herniation, but a causal relation has been

difficult to prove. Many patients known to have

raised intracranial pressure and papilloedema

have in the past undergone lumbar puncture

without adverse effects, and other patients have

herniated even without a lumbar puncture.

Clinicians must not use CT to rule out increased

intracranial pressure (as intracranial pressure is

almost always raised in acute bacterial menin-

gitis) but instead, in selected patients, to detect

brain shift either due to a focal space-occupying

lesion or severe diffuse brain swelling.

Consequently, a CT scan is not required before

lumbar puncture in every patient and clinical

features can be used10, 11 to select patients

where an abnormal CT scan is likely (table 1). In

patients with suspected bacterial meningitiswho are CT scanned before lumbar puncture,

initial therapy consisting of adjunctive dexa-

methasone (10 mg iv) and empirical antimicro-

bial therapy (table 2) should always be started

without delay, even before sending the patient

to the CT scanner. The yield of CSF Gram stain

and culture may be diminished by antimicrobial

therapy given for several hours prior to lumbar

puncture, but antimicrobial therapy will not

affect the CSF white blood cell count and

glucose concentration so much that bacterialmeningitis is not suspected.

INTERPRETING THE LUMBARPUNCTURE RESULTSFrank turbidity of CSF instantly suggests

bacterial meningitis. Microscopic examination

of CSF for white cells, red cells and organisms;

the measurement of glucose and protein; and

culture, are important investigations in any

case of possible meningitis. The CSF abnorm-

alities of bacterial meningitis include raisedopening pressure in almost all patients (40%

more than 40 cm water),2, 12 polymorpho-

nuclear leukocytosis, decreased glucose con-

centration, and an increased proteinconcentration.2, 1215

N In immunocompetent patients with bac-terial meningitis, the white blood cellcount is typically greater than 1000 cells/ml, while in viral meningitis it is less than300 cells/ml, although there is consider-able overlap (rarely, the count may benormal with ,6 cells/ml, all lymphocytes,but the CSF may still appear turbidbecause of the vast numbers of bacteria).The neutrophil count is typically raised in

bacterial compared with viral meningitis.More than 90% of cases present with aCSF white cell count of more than 100/ml.In immunocompromised patients, CSFwhite blood cell counts tend to be lower,although an acellular CSF is probably rare,except in patients with tuberculousmeningitis.

N The normal CSF glucose concentration isbetween 2.5 and 4.4 mmol/l with serumglucose of 3.96.7 mmol/l, or approxi-mately 65% of the serum glucose. In

bacterial meningitis the glucose concen-tration is usually less than 2.5 mmol/l, orless than 40% of a simultaneouslymeasured serum glucose.2, 1215

N The CSF protein in bacterial meningitis isusually raised (.50 mg/dl).

N Gram stain is positive in identifying theorganism in 5090% of cases2, 15 and CSFculture is positive in 80% of untreatedpatients.

N Latex particle agglutination tests thatdetect antigens of N meningitidis, S

p n e u m o n i a e , H i n f lu e n za e a n dStreptococcus agalactiae can providediagnostic confirmation, but they arenot routinely available.

N Increasingly, laboratories are offering abroad range PCR that can detect smallnumbersof viable andnon-viable organismsin CSF. When the broad-range PCR ispositive, a PCR that uses specific bacterialprimers to detect the nucleic acid ofS pneumoniae, N meningitidis, E coli,L monocytogenes, H influenzae and

S agalactiae should be done. However,although these tools are promising, further

A CT scan is not required before lumbar puncture inevery patient and clinical features can be used




7/16

refinements are needed before PCR can beroutinely recommended.16, 17

BLOOD TESTSWhen bacterial meningitis is suspected, blood

cultures should be drawn first, followed byleukocyte count with differential cell count,

C-reactive protein (CRP), erythrocyte sedi-

mentation rate (ESR), sodium, potassium,

urea, creatinine, glucose, haemoglobin, hae-

matocrit, platelets, activated partial thrombo-

plastin time (APTT), prothrombin time (PT) and

serum lactate. In most cases, and especially

when pneumonia or an impaired level of

consciousness are present, arterial blood

gases are also required.

N Measurement of CRP may be helpful indistinguishing viral from bacterial menin-gitis, with sensitivities from 6999% ands p e c i fi c i t i e s f r o m 2 8 9 9 %. 1 8 2 0

Procalcitonin might also be helpful; itincreases during severe infection, andhigh levels have been reported in childrenand adults with severe bacterial infection.More readily available, a leukocytosis withleft shift in the differential cell count isalso a marker for bacterial infection andhelps distinguish bacterial from viralmeningitis. Several prediction rules com-bining serum and CSF markers to excludebacterial meningitis have been published,especially for children, but their use forclinical decisions in individual patients isdiscouraged by the bacterial meningitisguideline of the Infectious DiseaseSociety of America.18

N Disorders of sodium homeostasis fre-quently accompany bacterial meningitisand will be discussed later.

N Monitoring kidney function is important,

especially in patients who develop septicshock, and those with pre-existing renaldisease.

N Hyperglycaemia and insulin resistanceoccur frequently in patients with sepsis.21

High serum glucose concentrations areassociated with lower scores on theGlasgow Coma Scale on admission andwith unfavourable outcome (van de BeekD, unpublished data).2 Although rando-mised trials should be carried out todemonstrate a beneficial effect of inten-

sive insulin therapy in patients withbacterial meningitis and hyperglycaemia,

TABLE 3 Specific antimicrobial therapy in community-acquiredbacterial meningitis based on cerebrospinal fluid culture results and invitro susceptibility testing

Microorganism,

susceptibility Standard therapy Alternative therapies

Streptococcus pneumoniae

Penicillin minimal inhibitory concentration (MIC)

,0.1 mg/l Penicillin G or ampicillin Cefotaxime or ceftriaxone,chloramphenicol

0.11.0 mg/l Cefotaxime orceftriaxone

Cefepime, meropenem

>2.0 mg/l Vancomycin pluscefotaxime orceftriaxone*

Fluoroquinolone{

Cefotaxime or ceftriaxone MIC

>1.0 mg/l Vancomycin pluscefotaxime or

ceftriaxone{

Fluoroquinolone{

Neisseria meningitidis

Penicillin MIC

,0.1 mg/l Penicillin G or ampicillin Cefotaxime or ceftriaxone,chloramphenicol

0.11.0 mg/l Cefotaxime orceftriaxone

Chloramphenicol, fluoroquinolone,meropenem

Listeria

monocytogenes

Penicillin G or ampicillin"Trimethoprim-sulfamethoxazole,meropenem,

Group B streptococcusPenicillin G or ampicillin"Cefotaxime or ceftriaxone

Escherichia coli and

otherenterobacteriaceae

Cefotaxime orceftriaxone"

Aztreonam," fluoroquinolone,meropenem," trimethoprim-sulfamethoxazole, ampicillin"

Pseudomonasaeruginosa Ceftazidime

" orcefepime" Aztreonam," ciprofloxacin,"meropenem"

Haemophilus

influenzae

b-Lactamasenegative

Ampicillin Cefotaxime or ceftriaxone,cefepime, chloramphenicol,fluoroquinolone

b-Lactamase

positive

Cefotaxime orceftriaxone

Cefepime, chloramphenicol,fluoroquinolone

Chemoprophylaxis1

Neisseria meningitidis Rifampicin (rifampin),ceftriaxone,ciprofloxacin,azithromycin

This material was previously published as part of an online supplementary appendix to

van de Beek et al.4 Copyright 2006 Massachusetts Medical Society. All rights reserved.*Consider addition of rifampicin (rifampin) if dexamethasone is given.

{Gatifloxacin or moxifloxacin; no clinical data in patients with bacterial meningitis.

{Consider addition of rifampicin (rifampin) if the MIC of ceftriaxone is >2 mg/l."Consider addition of an aminoglycoside.1Prophylaxis is indicated for close contacts, defined as those with intimate contact,which covers those eating and sleeping in the same dwelling as well as those having

close social and kissing contacts; or healthcare workers who perform mouth-to-mouthresuscitation, endotracheal intubation or endotracheal tube management. Patients withmeningococcal meningitis who are treated with monotherapy of penicillin or amoxicillin(ampicillin) should also receive chemoprophylaxis, because carriage is not reliablyeradicated by these drugs.1 4

Practical Neurology

10.1136/jnnp.2007.139725


8/16

maintaining normoglycaemia seems pru-dent for now.

N Coagulation tests and platelet count areimportant, especially in patients withknown coagulation disorders, before alumbar puncture is carried out, and inpatients suspected of developing disse-minated intravascular coagulation as asystemic complication of bacterial menin-gitis; however, these laboratory investi-gations should not delay a lumbarpuncture if there are no clinical signs ofcoagulopathy. In patients receiving anti-coagulants who are suspected of havingbacterial meningitis, empirical treatmentshould be started and anticoagulationshould temporarily be reversed in order tosafely perform a lumbar puncture.

ANTIMICROBIAL TREATMENTThe choice of antibiotic for empirical therapy

(that is, before the organism is known) is based

on the possibility that a penicillin- and

cephalosporin-resistant strain ofS pneumoniae

is the causative organism, and on the patients

age and any associated conditions that may

have predisposed to meningitis (table 2).

For adults up to 50 years old from

countries with high rates of pneumococcalpenicillin- or cephalosporin-resistance, this

should be a combination of either a third- or

fourth-generation cephalosporin plus vanco-

mycin.4, 18 In countries with very low rates of

pneumococcal penicillin-resistance (such as

The Netherlands), penicillin can still be used

safely as a first-line agent.22 In the UK, the

addition of vancomycin is also not considered

necessary and is not recommended unless the

patient presents from one of the geographic

regions associated with high-level ceftriaxone

resistance, such as Spain, Southern Africa,and certain parts of the USA.

In adults older than 50 years, and in the

immunocompromised patient, ampicillin

should be added to this combination because

of possible Listeriameningitis.

Once the bacterial pathogen is isolated and

the sensitivity of the organism to the antibiotic

is confirmed by in vitro testing, antimicrobial

therapy should be modified accordingly.

Recommendations for antibiotic therapy in

bacterial meningitis are summarised intables 35 and some important tips are:

N Bacterial meningitis due to S pneumo-niae, H influenzae and group B strepto-cocci is usually treated with intravenousantibiotics for 1014 days.

N Meningitis due to N meningitidis istreated for 57 days.

N Patients with clinically suspected menin-gococcal meningitis who are treated withpenicillin must be isolated for the first24 h after initiation of antibiotic therapyand also treated with rifampin 600 mgorally every 12 h for 2 days to eradicatenasopharyngeal colonisation (penicillindoes not eradicate the organisms in thenasopharynx).

N Meningitis due to L monocytogenes and

Enterobacteriaceae is treated for 34 weeks.

TABLE 4 General recommendations for intravenous empirical antibiotictreatment

Treatment Dose

Penicillin 2 million units every 4 h

Amoxicillin or ampicillin 2 g every 4 hVancomycin 15 mg/kg every 8 hThird generation cephalosporins

ceftriaxone 2 g every 12 hcefotaxime 2 g every 46 hcefepime 2 g every 8 hceftazidime 2 g every 8 h

Meropenem 2 g every 8 hChloramphenicol 11.5 g every 6 hFluoroquinolones

gatifloxacin 400 mg every 24 hmoxifloxacin 400 mg every 24 h

Trimethoprim-sulfamethoxazole 5 mg/kg every 612 hAztreonam 2 g every 68 hCiprofloxacin 400 mg every 812 hRifampicin (rifampin) 600 mg every 1224 hAminoglycoside

gentamicin 1.7 mg/kg every 8 h

TABLE 5 General recommendations for chemoprophylaxis

Treatment DoseRifampicin (rifampin) 600 mg oral twice daily for two daysCeftriaxone One dose 250 mg intramuscularlyCiprofloxacin One dose, 500 mg orallyAzithromycin One dose, 500 mg orally




9/16

N Gentamicin is added to ampicillin in

critically ill patients with L monocyto-genes meningitis.

ADJUNCTIVE DEXAMETHASONEAfter being argued about for decades it is now

clear from the results of a large randomised

trial that dexamethasone (10 mg iv 1520 min

before or with the first dose of antibiotic and

given every 6 h for 4 days) is beneficial in

adults with acute bacterial meningitis;23 unfa-

vourable outcome was reduced from 25% to

15%, and mortality from 15% to 7%. Thebenefits were most striking in patients with

pneumococcal meningitis. Furthermore,

patients on dexamethasone were less likely tohave impaired consciousness, seizures and

cardiorespiratory failure.

At present, the benefits of adjunctive

dexamethasone treatment are unclear when

dexamethasone is started several hours or days

after initiation of antibiotics, highlighting the

importance of prompt treatment.

Dexamethasone should preferably be given

with the first dose of parenteral antibiotics,

but we would use dexamethasone within a

timeframe of a few hours after the initiation ofparenteral antibioticsalthough this is not

Figure 2

Neurological complications of bacterial

meningitis. (A) T2-weighted MR brain

scan showing hyperintense signal in the

cerebral hemispheres (arrows)

indicating cerebral oedema. (B)

Unenhanced brain CT showing

complete effacement of the basal

cisterns (arrow) indicating impending

herniation. (C) Unenhanced brain CT

showing communicating hydrocephalus

with dilatation of the lateral and third

ventricles. (D) Contrast-enhanced brain

CT showing a hypodense subdural

collection (arrow) over the anterior

convexity of the left cerebral

hemisphere, with an enhancing rim,

indicating a subdural empyema.

Practical Neurology

10.1136/jnnp.2007.139725


10/16

supported by systematic evidence. For some

adults with suspected meningitis, the beneficial

effect of adjunctive dexamethasone is less

certain, or may even be harmful. We do not

recommend steroids in patients with post-

neurosurgical meningitis or those with a severe

immunocompromised state (HIV infection), nor

in those who are hypersensitive to steroids.

MONITORING OF THE PATIENTAFTER ADMISSION ANDCOMPLICATIONSPatients who are diagnosed with acute bacter-

ial meningitis are at risk of various neurological

and systemic complications, and to detect them

patients should be admitted to a high-

dependency unit where the following should

be monitored: vital signs (blood pressure, heart

rate, respiratory rate, temperature), oxygen

saturation, level of consciousness (using the

Glasgow Coma Scale), presence or absence of

focal neurological signs or symptoms, pupillary

diameter, and certain laboratory parameters,

like CRP, leukocyte count, electrolytes, urea and

creatinine. Analysis of arterial blood gases andmeasurement of serum lactate are important in

patients in whom septic shock is suspected and

the platelet count and coagulation tests are

important in those in whom disseminated

intravascular coagulation is suspected. Core

body temperatures exceeding 40 C should be

treated with antipyretic agents and cooling

blankets if necessary to avoid excessive fluid

loss.

SYSTEMIC COMPLICATIONSHypotension, septic shock andadult respiratory distresssyndromeSeptic shock is an important predictor of poor

outcome2, 24 and may manifest in several

ways: hypotension (systolic BP (90 mm Hg

or a reduction of>40 mm Hg from baseline)

despite adequate fluid resuscitation, tachy-

cardia (.100/min), tachypnoea (.20/min),

core body temperature .38 C or ,36 C,

drowsiness and oliguria. Dyspnoea, laboured

breathing, agitation, followed by progressive

drowsiness, tachycardia, scattered crackles on

pulmonary auscultation and hypoxaemia (as

documented by arterial blood gas analysis)point to the diagnosis of adult respiratory

Figure 3

Arterial cerebral infarction complicating

acute bacterial meningitis. (A) Axial T2-

weighted MR brain scan showing a

hyperintense signal in the cerebellar

vermis (arrow). (B) Axial diffusion-

weighted imaging (DWI) shows

increased signal in the same area. (C)

This bright DWI signal was confirmed to

represent an area of restricted diffusion

on the apparent diffusion coefficient

map. (D) Macroscopic postmortem

sagittal view of the cerebellum of the

same patient showing necrosis of part

of the vermis (arrow). (E) Areas of

confluent necrosis with loss of staining

for haematoxylin and eosin. (F)

Microscopic view of the affected part of

the vermis shows vacuolisation of

white matter (arrow) and loss of

Purkinje cells.




11/16

distress syndrome (ARDS). The chest x ray

usually reveals characteristic diffuse alveolar-

interstitial infiltrates in all lung fields. Both

septic shock and ARDS require management

in an intensive care unit, and specific

recommendations can be found else-

where.25, 26

HyponatraemiaHyponatraemia (serum sodium ,135 mmol/l)

on admission to hospital is found in 30% of

patients with culture-proven acute bacterial

meningitis.27 Most episodes of hyponatraemia

resolve within a few days without specific

treatment, and hyponatraemia does not

influence outcome. Severe hyponatraemia

(,130 mmol/l) is present in 6% of patients.

An exceptionally high frequency of hypona-traemia is seen in meningitis due to

L monocytogenes (73%) and S pyogenes.

(58%).28 The cause of hyponatraemia is

unclear29 but may be from cerebral salt

wasting, the syndrome of inappropriate

antidiuretic hormone secretion (SIADH), or

from too aggressive fluid resuscitation.

Differentiation between cerebral salt wasting

and SIADH requires measurement of extra-

cellular fluid volume.30 Unfortunately, the

clinical assessment of extracellular fluid

volume has a notoriously low sensitivity and

specificity, 31 and invasive measurement is

cumbersome. Patients with bacterial menin-

gitis who develop hyponatraemia should not

automatically be assumed to have SIADH and

be fluid restricted. Instead, the goal of fluid

management should be to maintain a

normovolaemic state and in patients with

severe hyponatraemia we would rather use

fluid maintenance therapy then fluid restric-

tion, although there is no clear evidence

supporting this approach.

HypernatraemiaWhile hyponatraemia is relatively frequent

and usually benign, the same cannot be said

of hypernatraemia (serum sodium

.143 mmol/l) which is found on admission

in 7% of patients with culture-proven

bacterial meningitis.32 Patients with sodium

levels >146 mmol/l (2% of patients) are more

likely to have seizures before admission

compared to those with lower levels.Sodium levels of>143 mmol/l are associated

with a higher heart rate, lower CSF protein

and lower CSF glucose levels. Overall, patients

with hypernatraemia are admitted with more

severe disease, reflected by lower levels of

consciousness, and hypernatraemia is inde-

pendently predictive of unfavourable out-

come and mortality; however, it is unclearwhether this is because it reflects severe

disease or directly contributes to the poor

outcome. Severe brain injury can lead to

reductions in antidiuretic hormone secretion

resulting in diabetes insipidus, but diabetes

insipidus has been described only sporadically

in bacterial meningitis. Physicians should be

aware of the potential importance of hyper-

natraemia in patients presenting with bacter-

ial meningitis and care should be taken in

their fluid management. Whether this

improves prognosis is still uncertain.

ArthritisThe coexistence of bacterial meningitis and

arthritis has been described in several

studies;24, 3335 it occurs in 7% of patients

overall,36 more in meningococcal meningitis

(12%). It is caused either by haematogenous

bacterial seeding of joints (septic arthritis) or

by immune-complex deposition in joints

(immunomediated arthritis). Non-gonococcalbacterial arthritis often presents with the

abrupt onset of a single hot, swollen and very

painful jointthe knee being the site of

infection in half the cases, but any joint

may be involved. Culture of synovial fluid

yields bacteria in only 26% of patients. A

patient with immunomediated arthritis during

meningococcal infection typically develops

symptoms from day 5 of the illness or during

recovery from the infection, generally invol-

ving the large joints.

Although history and physical examinationmay provide important clues, it is often difficult

to discriminate between infectious and non-

infectious causes. The differential diagnosis in

patients further includes gout and pseudogout,

which commonly flare up during stress and

acute medical illness. A definitive diagnosis of

septic arthritis requires identification of bac-

teria in the synovial fluid by Gram stain or

culture. The treatment of acute bacterial

arthritis requires antibiotics and joint drainage.

Although some limitation in the range ofmovement was found in 23% of our patients

Practical Neurology

10.1136/jnnp.2007.139725


12/16

with meningitis and arthritis, functional out-

come was good in most of them.

APPROACH TO THE PATIENTWITH A FALLINGCONSCIOUSNESS LEVELPatients with bacterial meningitis often

present with impairment of consciousness,

the cause of which is not completely under-

stood.15, 37 The release of proinflammatory

cytokines in the subarachnoid space leads to

an inflammatory response in the CNS that

contributes to increased permeability of the

blood-brain barrier, resulting in vasogenic

oedema and the formation of proteinaceous

exudates in the subarachnoid space. These

proteinaceous exudates cause obstruction to

outflow and resorption of CSF, leading tointerstitial oedema. The migration of poly-

morphonuclear cells into the CSF leads to

their degranulation and release of toxic

metabolites, resulting in cortical inflammation

and cytotoxic oedema. The net result is

cerebral oedema and an increase in intracra-

nial pressure. Loss of cerebral autoregulation,

thought to be caused by inflammation and

thrombosis of small cerebral arteries, results

in impairment of cerebral blood flow, further

compromising normal cortical function.

The development of coma in bacterial

meningitis portends a poor prognosis2, 24 and

the patients should be rapidly evaluated for

the most common causes: cerebral oedema,

hydrocephalus, seizure activity or infarction

of brain tissue due to inflammatory occlusion

of basal vessels or septic intracranial venous

thrombosis (figs 2 and 3). Some of these

complicationsfor example, cerebral oedema

and cerebral infarctionare difficult to treat,

others howeverfor example, hydrocephalus

or seizurescan often be treated effectively.To distinguish between these possibilities,

brain CT or MRI is critical.

Cerebral oedemaA CT scan is necessary to make the diagnosis of

cerebral oedema; early signs are effacement of

the perisylvian fissures, narrowing of ventri-

cular size, effacement of cerebral sulci, and

obliteration of the basal cisterns (fig 2B).

Although mannitol and hyperventilation are

often tried,38

there are no randomised trials tosupport their use. Given the invariably poor

outcome in patients with advanced stages of

cerebral oedema, we only recommend an

intracranial pressure monitoring device in

young (,50 years) patients without comorbid-

ity, and as a last resort.

HydrocephalusCerebrospinal fluid is formed by the choroid

plexus in the lateral ventricles, from where it

flows via the third and fourth ventricles

through the foramina of Luschka and

Magendie to the subarachnoid space. It is

absorbed through the arachnoid villi in the

intracranial venous sinuses. In bacterial menin-

gitis a purulent exudate forms over the cerebral

hemispheres where it interferes with CSF

absorption by the arachnoid villi, resulting in

communicating hydrocephalus (fig 2C). Whenthe inflammatory exudate involves the basal

cisterns and surrounds the cranial nerves at the

base of the brain (basilar meningitis), it may

block CSF flow at the foramina of Luschka and

Magendie, resulting in obstructive hydrocepha-

lus. Obstructive hydrocephalus may also com-

plicate infratentorial subdural empyema.

In patients with communicating hydroce-

phalus, we recommend repeated lumbar

punctures (with measurement of CSF pres-

sure) or the temporary insertion of a lumbardrain. In patients with mild enlargement of

the ventricular system without clinical dete-

rioration, spontaneous resolution may occur

and watchful waiting may be justified.

Acute obstructive hydrocephalus requires

ventricular drainage.39

Cerebral infarctionCerebral infarction (fig 3) due to arterial

occlusion complicates bacterial meningitis in

1015% of patients,2, 4 venous infarction dueto septic venous thrombosis occurs in 35%.

Infarction of paramedian thalamic or brain

stem nuclei due to septic arteriitis of basal

vessels or septic venous thrombosis may

rarely cause coma and we have seen patients

who developed this devastating complication

late (approximately 10 days) in the course of

their treatment. Arteritis of small and med-

ium-sized arteries and inflammatory involve-

ment of veins is probably caused by tissue-

destructive agents, such as oxidants andproteolytic enzymes, released by activated




13/16

leukocytes. Treatment is mainly supportive

and these patients have a poor outcome.

SeizuresSeizures occur in about 20% of patients with

bacterial meningitis.2, 4 These patients tend to

be older, are more likely to have focal

abnormalities on brain CT and to have

S pneumoniae as the causative micro-organ-

ism, and they have a higher mortality.40 If a

patient with a falling conscious level has a

normal brain CT and normal serum electro-

lytes, then an EEG should be performed to

look for seizure activity. The high mortality

warrants a low threshold for starting anti-

epileptic therapy in those with clinical suspi-

cion of seizures. A rare cause of seizures,

asterixis and encephalopathy is the neuro-

toxic effect of certain antimicrobial agents

(cefuroxime, penicillin, imipenem)41, 42 which

should be suspected in a patient with prior

stroke or Parkinsons disease and in those

with renal insufficiency, and when there are

no other obvious causes of seizures.

APPROACH TO THE PATIENTWHO DEVELOPS FOCALNEUROLOGICAL SIGNSIn patients who develop focal neurological

signs (hemiparesis, monoparesis, aphasia) the

following should be sought: cerebral infarction

(due to inflammatory occlusion of cerebral

arteries, septic venous thrombosis), seizures,

subdural empyema or a combination of these

causes.2, 4, 24, 43, 44 Again, an unenhanced brain

CT scan is needed to rule out many of these

causes.N The possibility of septic intracranial

venous thrombosis should be consideredin patients with an impaired level ofconsciousness, seizures, fluctuating focalsigns and stroke in non-arterial distribu-tions when MR venography can helpconfirm the diagnosis.44

N Subdural empyema should be suspected inpatients who have concomitant sinusitis ormastoiditis, or who have recently under-gone surgery for either of these disorders.45

In most cases contrast-enhanced brainCT will reveal the hypodense subdural

Figure 4

Prediction rule for risk of unfavourable

outcome in adults with bacterial

meningitis. Tachycardia is defined as a

heart rate greater than 120 beats/min,

low cerebrospinal fluid (CSF) leukocyte

count as ,1000 cells/mm3. Result of

CSF Gram stain: G2, gram-negative

cocci; No, no bacteria; Other, other

bacterial species; G+, gram-positive

cocci. Locate the age of the patient on

the top axis and determine how many

points the patient receives. Repeat this

for the remaining five axes. Sum the

points for all six predictors and locate

the total sum on the total point axis.

Draw a line straight down to the axis

labeled % unfavourable outcome to

find the estimated probability of an

unfavorable outcome for this patient.

(This material was previously published

as part of reference 57. Copyright 2007

John Wiley & Sons, Inc. All rightsreserved.)

The high mortality warrants a low threshold forstarting antiepileptic therapy in those with clinical

suspicion of seizures

Practical Neurology

10.1136/jnnp.2007.139725


14/16

collections (fig 2D). Brain MRI is moresensitive than CT in detecting subduralempyema along the convexity, and espe-cially for infratentorial subdural empyemabecause CT is bedevilled by scanningartefacts in the posterior fossa .46

Currently, MRI with diffusion-weighted

images (DWI) and apparent diffusioncoefficient mapping (ADC) remains thepreferred imaging modality for detectingsubdural empyema, especially infratentor-ial subdural empyema, because of itsmultiplanar capabilities, improved softtissue imaging, and the lack of scanningartefacts at the skull base. Subduralempyema should be surgically drained bycraniotomy but the outcome is poor if thepatient is unconscious.

WHEN TO REPEAT THE LUMBARPUNCTUREA repeat analysis of the cerebrospinal fluid

should only be carried out in patients whose

condition has not responded clinically after

48 hours of appropriate antimicrobial and

adjunctive dexamethasone treatment. It is

essential when pneumococcal meningitis

caused by penicillin-resistant or cephalos-

porin-resistant strains is suspected. Gram

staining and culture of the cerebrospinal fluid

should be negative after 24 hours of appro-

priate antimicrobial therapy.

RECURRENT BACTERIALMENINGITISRecurrent bacterial meningitis occurs in 5%

of community-acquired bacterial meningitis

cases, and most patients have a predisposing

condition, particularly head injury and CSF

leak, only occasionally impairment of humoral

immunity.47 In patients with no apparent

cause of recurrent meningitis or known

history of head trauma, the high prevalence

of remote head injury and CSF leakage

justifies an active search for anatomical

defects and CSF leakage. Detection of b-2

transferrine in nasal discharge is a sensitive

and specific method to confirm a CSF leak,48

and thin-slice CT of the skull base is best to

detect small bone defects. It should be borne

in mind however that the detection of a small

bone defect does not prove CSF leakage.

Surgical repair has a high chance of successwith low mortality and morbidity.49

OUTCOMEAcute bacterial meningitis caused by

S pneumoniae has a high mortality, from

1937%.2, 4, 24, 50 The mortality of meningococ-

cal meningitis is lower, from 313%. In up to a

third of survivors, long-term neurological

sequelae develop, including hearing loss

(14%) and focal neurological deficits (hemi-

paresis, monoparesis, aphasia). Cognitive

impairment occurs in up to one third of

patients,51 more so in those who have had

pneumococcal rather than meningococcal

meningitis. Over the years, patients tend to

report fewer complaints, but the cognitive

impairment does not seem to improve. The

strongest risk factors for poor outcome are

systemic compromise (shock, adult respiratory

distress syndrome, pneumonia), impairment of

consciousness, low white cell count (less than100/ml) in the CSF, and infection with

S pneumoniae.2 Recently, we have constructed

and validated a simple model for predicting

outcome, using six variables that are routinely

available within one hour of admission (age,

heart rate, score on the Glasgow Coma Scale,

presence or absence of cranial nerve palsies, a

CSF leukocyte count ,1000/ml, and the

presence of Gram positive cocci on CSF Gram

stain). This helps to identify high-risk indivi-

duals and provides important information forpatients and their relatives (fig 4).52

PRACTICE POINTS

l The most common causes of community-acquired bacterial meningitis inadults are Streptococcus pneumoniaeand Neisseria meningitidis.

l The absence of neck rigidity, Kernigs sign and Brudzinskis sign does notrule out acute bacterial meningitis.

l The first step in the management of acute bacterial meningitis is to obtainblood cultures and start adjunctive dexamethasone and antimicrobialtherapy; timing is critical, dexamethasone should be administered eitherbefore or with the first dose of antibiotic.

l Empirical antimicrobial therapy is based on the possibility that a penicillin-and cephalosporin-resistant strain of S pneumoniae is the causativeorganism, geography, patient age and any associated conditions.

l It is reasonably safe to do a lumbar puncture without a brain CT scan ifthere are no signs of a space-occupying lesion (papilloedema or focalneurological signs, not including cranial nerve palsy), new-onset seizure,moderate-to-severe impairment of consciousness, or animmunocompromised state.

l Patients with clinically suspected meningococcal meningitis must beisolated for the first 24 hours after initiation of antibiotic therapy.




15/16

ACKNOWLEDGEMENTThis article was reviewed by Guy Thwaites,

London, UK.

REFERENCES1. Swartz MN. Bacterial meningitis: a view of the past

90 years. N Engl J Med 2004;351:18268.2. van de Beek D, de Gans J, Spanjaard L, et al. Clinical

features and prognostic factors in adults with

bacterial meningitis. N Engl J Med

2004;351:184959 [Erratum, N Engl J Med

2005;352:950].

3. Schuchat A, Robinson K, Wenger JD, et al. Bacterial

meningitis in theUnited Statesin 1995. NEnglJMed

1997;337:9706.

4. van de Beek D, de Gans J, Tunkel AR, et al.

Community-acquired bacterial meningitis in adults.

N Engl J Med 2006;354:4453.

5. Whitney CG, Farley MM, Hadler J, et al. Increasing

prevanlence of multidrug-resistant Streptococcus

pneumoniae in the United States. N Engl J Med

2000;343:191724.6. Whitney CG, Farley MM, Hadler J, et al. Decline in

invasive pneumococcal disease after introduction

of protein-polysaccharde conjugate vaccine.

N Engl J Med 2003;348:173746.

7. Snape MD, Pollard AJ. Meningococcal

polysaccharide-protein conjugate vaccines. Lancet

Infect Dis 2005;5:2130.

8. Thomas KE, Hasbun R, Jekel J, et al. The diagnostic

accuracy of Kernigs sign, Brudzinskis sign, and

nuchal rigidity in adults with suspected meningitis.

Clin Infect Dis 2002;35:4652.

9. Annane D, Sebille V, Charpentier C, et al. Effect of

treatment with low doses of hydrocortisone and

fludrocortisine on mortality in patients with septic

shock. JAMA 2002;288:86271.

10. van Crevel H, Hijdra A, de Gans J. Lumbar puncture

and the risk of herniation: when should we first

perform CT? J Neurol 2002;249:12937.

11. Hasbun R, Abrahams J, Jekel J, et al. Computed

tomography of the head before lumbar puncture in

adults with suspected meningitis. N Engl J Med

2001;345:172733.

12. Durand ML, Calderwood SB, Weber DJ, et al. Acute

bacterial meningitis in adults: a review of 493

episodes. N Engl J Med 1993;328:218.

13. Sigurdardottir B, Bjornsson OM, Jonsdottir KE, et al.

Acute bacterial meningitis in adults: a 20-year

overview. Arch Int Med 1997;157:42530.

14. Hussein AS, Shafran SD. Acute bacterial meningitisin adults: a 12-year review. Medicine (Baltimore)

2000;79:3608.

15. Tunkel AR. Bacterial meningitis. Philadelphia:

Lippincott Williams & Wilkins, 2001.

16. Radstrom P, Backman A, Qian N, et al. Detection of

bacterial DNA in cerebrospinal fluid by an assay for

simultaneous detection of Neisseria meningitidis,

Haemophilus influenzae, and streptococci using a

seminested PCR strategy. J Clin Microbiol

1994;32:273844.

17. Schuurman T, de Boer RF, Kooistra-Smid AM, et al.

Prospective study of use of PCR amplification and

sequencing of 16S ribosomal DNA from

cerebrospinal fluid for diagnosis of bacterial

meningitis in a clinical setting. J Clin Microbiol2004;42:73440.

18. Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice

guidelines for the management of bacterial

meningitis. Clin Infect Dis 2004;39:126784.

19. Gerdes LU, Jorgensen PE, Nexo E, et al. C-reactive

protein and bacterial meningitis: a meta-analysis.

Scand J Clin Lab Invest 1998;58:38393.

20. Sormunen P, Kallio MJT, Kilpi T, et al. C-reactive

protein is useful in distinguishing Gram stain-

negative bacterial meningitis from viral meningitisin children. J Pediatr 1999;134:7259.

21. Marik PE, Raghavan M. Stress-hyperglycemia,

insulin and immunomodulation in sepsis. Intensive

Care Med 2004;30:74856.

22. van de Beek D, de Gans J, Spanjaard L, et al.

Antibiotic guidelines and antbiotic use in adult

bacterial meningitis in The Netherlands.

J Antimicrob Chemother 2002;49:6616.

23. de Gans J, van de Beek D. Dexamethasone in adults

with bactrial meningitis. N Engl J Med

2002;347:154956.

24. Pfister HW, Feiden W, Einhaupl KM. Spectrum of

complications during bacterial meningitis in adults:

results of a prospective clinical study. Arch Neurol

1993;50:57581.25. Raghavan M, Marik PE. Management of sepsis

during the early golden hours. J Emerg Med

2006;31:18599.

26. Wheeler AP, Bernard GR. Acute lung injury and the

acute respiratory distress syndrome: a clinical

review. Lancet 2007;369:155365.

27. Brouwer MC, van de Beek D, Heckenberg SGB, et al.

Hyponatremia in adults with community-acquired

bacterial meningitis. Q J Med2007;100:3740.

28. van de Beek D, de Gans J, Spanjaard L, et al. Group

A Streptococcal meningitis in adults: report of 41

cases and a review of the literature. Clin Infect Dis

2002;34:e326.

29. Moller K, Larsen FS, Bie P, et al. The syndrome of

inappropriate secretion of antidiuretic hormone

and fluid restriction in meningitis: how strong is

the evidence? Scand J Infect Dis 2001;33:1326.

30. Harrigan MR. Cerebral salt wasting syndrome: a

review. Neurosurgery 1996;38:15260.

31. Chung HM, Kluge R, Schrier RW, et al. Clinical

assessment of extracellular fluid volume in

hyponatremia. Am J Med 1987;83:9058.

32. van de Beek D, Brouwer MC, de Gans J.

Hypernatremia in bacterial meningitis. J Infect

2007;55:3812.

33. Ross JJ, Saltzman CL, Carling P, et al. Pneumococcal

septic arthritis: review of 190 cases. Clin Infect Dis

2003;36:31927.

34. Dillon M, Nourse C, Dowling F, et al. Primarymeningococcal arthritis. Pediatr Infect Dis J

1997;16:3312.

35. Likitnukul S, McCracken GH Jr, Nelson JD. Arthritis

in children with bacterial meningitis. Am J Dis Child

1986;140:4247.

36. Weisfelt M, van de Beek D, Spanjaard L, et al.

Arthritis in adults with community-acquired

bacterial meningitis: a prospective cohort study.

BMC Infectious Diseases 2006;6:64.

37. Koedel U, Scheld WM, Pfister HW. Pathogenesis and

pathophysiology of pneumococcal meningitis.

Lancet Infect Dis 2002;2:72136.

38. Lindvall P, Ahlm C, Ericsson M, et al. Reducing

intracranial pressure may increase survival among

patients with bacterial meningitis. Clin Infect Dis2004;38:38490.

Practical Neurology

10.1136/jnnp.2007.139725


16/16

39. Wijdicks EFM. The clinical practice of critical care

neurology. Second edition. New York: Oxford

University Press, 2003.

40. Zoons E,Weisfelt M,de GansJ, et al. Seizures in adults

with bacterial meningitis. Neurology 2008 (in press).

41. Herishanu YO, Zlotnik M, Mostoslavsky M, et al.

Cefuroxime-induced encephalopathy. Neurology

1998;50:18735.

42. Snavely SR, Hodges GR. The neurotoxicity ofantibacterial agents. Ann Intern Med

1984;101:92104.

43. Weststrate W, Hijdra A, de Gans J. Brain infarcts in

adults with bacterial meningitis. Lancet

1996;347:399.

44. Stam J. Thrombosis of the cerebral veins and

sinuses. N Engl J Med 2005;352:17918.

45. Dill SR, Cobbs CG, McDonald CK. Subdural

empyema: analysis of 32 cases and review. Clin

Infect Dis 1995;20:37286.

46. van de Beek D, Campeau NG, Wijdicks EFM. The

clinical challenge of recognizing infratentorial

empyema. Neurology 2007;69:47781.

47. Adriani KS, van de Beek D, Brouwer MC, et al.

Community-acquired recurrent bacterial

meningitis in adults. Clin Infect Dis2007;45:e4651.

48. Ryall RG, Peacock MK, Simpson DA. Usefulness of

beta-2-transferrin assay in the detection of

cerebrospinal fluid leaks following head injury.

J Neurosurg 1992;77:7379.

49. Lund VJ, Lloid S, Lloyd G, et al. Optimum imaging

and diagnosis of cerebrospinal fluid rhinorrhoea.J Laryngol Otol 2000;114:98892.


Clinical features, complications, and outcome in

adults with pneumococcal meningitis: a

prospective case series. Lancet Neurology

2006;5:1239.

51. Hoogman M, van de Beek D, Weisfelt M, et al.

Cognitive outcome in adults after bacterial

meningitis. J Neurol Neurosurg Psychiatry

2007;78:10926.


A risk score for unfavorable outcome in adults with

bacterial meningitis. Ann Neurol2007;Epub Sept 7.


community acuired bactarial meningitis

Documents