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Acute bacterial meningitis in adults a review

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573 Khartoum Medical Journal (2011) Vol. 04, No. 02, pp. 573 - 583

Review
Acute bacterial meningitis in adults
Osheik Abu’Asha Seidi
Faculty of Medicine and Soba University Hospital, University of Khartoum

Abstract
Meningitis is an ancient disease(1). During the historical Andalusian period (711 - 1492), Avenzoar, a Muslim
scholar, described meningitis(2). Acute bacterial meningitis is a serious disease, prevalent worldwide and is
a major health problem in Sub Saharan Africa in the heart of which is the Sudan(3). It kills thousands in
epidemics and leaves many with disabling sequalae(4-9). Its early recognition and prompt therapy greatly
improves the prognosis. The main causative agents are Neisseria meningitides, Haemophilus influenza type b
and Streptococcus pneumoniae. Another important causative bacteria, though rare, is Listeria moncytogenes.
The use of antibiotic and the recent introduction of steroids coupled with improvements and expansion of
vaccination are expected to make major improvement in the future. This review will highlight the major
features of acute bacterial meningitis in adults and its current treatment and future developments.

Introduction
Bacterial meningitis accounts for approximately 1.2
million cases and is responsible for approximately
135,000 deaths throughout the world each year.
Meningitis is among the ten most common infectious
causes of death. Neurological sequalae are serious
and rather common among survivors(3).
Thomas Willis (1621-1675) described patients with,
“inflammation of the meninges with a continual
fever” during the early phase of the (1661) epidemic
of meningitis(3).
The dawn of the last century witnessed major
epidemics of meningitis in the old world (Europe, Asia
and Africa) which killed millions and left many with
serious disabilities. Although it receded markedly in
the developed countries, meningitis remains a major
killer in tropical countries particularly in Sub Saharan
Africa where a belt extending from Senegal in the
West, through Nigeria, Niger, Mali, and Chad reaches
the eastern parts of the continent into Somalia and
Ethiopia(10,11) (Figure1).
From its original well-documented recognition in
1805 until the early 1900s, bacterial meningitis was
virtually uniformly fatal. The clinical outcome did
not dramatically improve until the advent of systemic
antimicrobial therapy in the 1930s. However, despite
the effectiveness of current antibiotics in clearing
bacteria from the cerebrospinal fluid (CSF), bacterial
meningitis continues to cause significant morbidity
and mortality worldwide(12-14). Sudan witnessed
some of the worst epidemics of bacterial meningitis
particularly among children and young adults(15).
Epidemiology
A number of studies have evaluated the prevalence
of different organisms that cause bacterial meningitis.
The results vary based primarily upon age group
and the type of infection: community-acquired,
nosocomial, or recurrent (8,16,17).
The main causative organisms of acute bacterial
meningitis are Neisseria meningitides. Bacterial
meningitis has an incidence of 0.6 -4 / 100,000
/ year worldwide. It is ten times higher in sub-
Saharan Africa(Figure1). Globally the incidence
has been remarkably reduced by the introduction of
the Meningococcal Group C polysaccharide-protein
vaccine. The vaccine against type C was introduced
in 1999. Unfortunately, there is no vaccine against
group A to date. Attempts to develop a vaccine
against serogroup A took place in Sudan in the
1970’s but did not materialize(18,19). Vaccines against
Haemophilus influanzae type b and the conjugate
vaccine 7 serotypes of Streptococcus pneumonia are
contributing to further reductions in the global burden
Osheik Abu’Asha Seidi
of bacterial meningitis. The incidence is influenced by
many factors including the virulence of the circulating
meningococci, host susceptibility and environmental
factors.
Vladimir Kernig and Josef Brudzinski described their
eponymous signs in 1882 and 1909 respectively(20).
Successful treatment of meningitis began with the
introduction of serum therapy for meningococcal
meningitis by Georg Joachmann in Germany and
Simon Flexner in America(21). Chemotherapeutic and
antibiotic treatment began in the 20th century with the
use of sulfonamides by Francois Schwentker (1904-
1954) and penicillin by Chester Keefer (1897-1972)22).
MacChiavello and his colleagues reported in 1954 a
famous human experiment of mass chemoprophylaxis
in Sudan to control epidemics of cerebrospinal
meningitis with sulfadimidine and penicillin(23).
Causative Organisms
Meningitis in the neonate, not covered in this
review, most commonly results from infection
that is acquired from the mother in utero or during
vaginal delivery. Streptococcus agalactiae and
Escherichia coli are the organisms most often
recovered; Listeria monocytogenes, various members
of the Enterobacteriaceae, Pseudomonas spp.,
Flavobacterium meningosepticum, Staphylococcus
aureus, and miscellaneous anaerobic bacteria are
recovered less frequently. For reasons that are
unknown, Citrobacter koseri (diversus) can cause a
devastating meningoencephalitis in the neonate (24-31).
In adults Neisseria meningitides (N meningitides),
Haemophilus influenza type B (H influenza B. Hib),
and Streptococcus pneumoniae (S pneumoniae)
are the major causative agents, identified in the
late 19th century. Other bacteria are rare causes and
usually cause limited epidemics or more commonly
sporadic cases; these include Listeria moncytogenes,
Staphyllococcus aureus and Kingella kingae(3,32-37).
Neisseria meningitides is a common commensal in
the human nasopharynx found in 8-20 % of healthy
individuals particularly adolescents. The carriage rate
varies seasonally, usually peaks in the dry season, and
drops with the start of the rainfall. This shadows the
pattern of epidemics in Sub Saharan Africa(38,39)
574
Based on the different capsular polysaccharide
components, 13 serotypes are identified, but only six
serogroups are associated with pathogenic potential
(A, B, C, W-135, Y and recently X). Sergroup A is
responsible for the major epidemics in the African
meningitis belt. Serogroup B causes sporadic and
endemic disease as well as prolonged epidemics in
Europe, Cuba, Chile, US Pacific islands and New
Zealand with significant morbidity and mortality.
Serogroup C caused major epidemics in in Sub Saharan
Africa and Brazil specially the serogroup expressing
the ET-37/ST-11 complex. Serogroup W-135 caused
major outbreaks in the 2000- 2002 Haj seasons(40-43).
Rates are higher among young children, possibly
reflecting waning maternal antibodies, and also in
young adult (14-24years) probably caused by higher
acquisition and transmission among this age group(38).
Pathogenesis of Acute Meningitis
Haematological spread
The organisms spread from the nasopharynx to the
blood stream and get seeded in the meninges. The
meningococci evade the host’s defences and first
anchor themselves to the nasopharyngeal mucosa
using tiny pilli. Soon after they are engulfed in
the cells, they multiply rapidly with the release of
outer membrane vesicles containing an endotoxin
(lipo-oligosaccharide), phospholipids and capsular
polysaccharides. These are the major factors in this
organism’s virulence. The meningococci burst by
autolysis releasing cell contents including DNA and
cell wall components which include the inflammatory
cascade(44). The organisms reach the blood stream
and patients can present with septicaemia and/or
meningitis. The capsular polysaccharide is a powerful
inflammatory signalling factor as well as playing
roles in adhesion and colonization of the susceptible
tissues, principally the meninges(44-47). The degree of
meningeal infection is usually high with bacterial loads
exceeding 100 million organism/ml. Most bacteria
die by autolysis releasing blebs of outer membrane
leading to a very intense inflammatory response in the
enclosed CSF space. This causes major morbidity and
mortality. Dexamethasone is now used routinely to
modulate this response(48-52).
The CSF becomes sterile within hours after starting
575
antibiotic therapy hence the paramount importance
of starting empiric antibiotic therapy immediately on
making the diagnosis.
Direct Spread
Rarely bacteria may spread directly to the meninges
from the middle ear, paranasal sinuses(53) or
complicated skull fractures(54) or neurosurgical
procedures(55-57). The organisms are various but mostly
Staphyllococci, Pseudomonus and streptococci.
Clinical Presentation
Fever, headache, vomiting, photophobia, nuchal
rigidity, alteration of the level of consciousness
and skin rashes are the main symptoms of acute
meningitis. Patients with severe bacteraemia may
present in haemodynamic shock.
The classic triad in meningitis of Kernig’s sign,
Brudziniski sign and neck rigidity are the main clinical
diagnostic features(58,59). Headache, fever, nausea,
vomiting and photophobia carry a high probability
of meningitis in the majority of cases (81%) when
present in a group of two or more in a patient (range
0.42 – 0.57). Neck rigidity may be absent in very sick
patients, elderly and immune-compromised patients
but it carries the highest value in detection of acute
bacterial meningitis. The Jolt accentuation test greatly
improves the sensitivity of the clinical examination(60).
This manoeuvre is underutilized and is barely known
among young doctors. It involves shaking the patients
head gently horizontally for 2-3 seconds, which
results in immediate increase in the headache. In a
prospective study involving 54 patients presenting
with headache and fever, neck stiffness was noted in
15% and Kernig’s sign in only 9%. The sensitivity of
the Jolt accentuation test was 97% and specificity was
60%. The study recommended that CSF should be
examined in patients with a positive Jolt accentuation
in the absence of neck rigidity and Kernig’s sign(60).
Differential Diagnosis
Acute meningitis can be of infectious or non-infectious
aetiologies. The first include viral and bacterial causes
while the latter encompass chemical, autoimmune and
drug induced meningitis. Rare causes such as neuro-
Behcet’s disease are not included in this review, which
is focusing on bacterial meningitis in adults.
Acute bacterial meningitis in adults
Acute meningitis is sometime very difficult to
differentiate from cerebral malaria particularly when
the level of consciousness is low. The task is even more
challenging where no suitable investigative facilitates
are accessible in remote areas in sub Saharan African
countries. It is a sound clinical approach to empirically
prescribe treatment want for both cerebral malaria
and bacterial meningitis as the risks of missing any of
them carries serious consequences while the empirical
treatment entails far less risks from the potential side
effects of the medications. The presence of neck
stiffness, seizures, focal neurological signs and/or
rashes favours meningitis, but there are no clinical
signs that can confidently differentiate the two. Where
affordability becomes an obstacle the clinician should
practice judgement(61).
When consciousness is impaired or seizures are
the predominant feature, the differential diagnosis
includes encephalitis and dural sinus thrombosis.
As for cerebral malaria, if encephalitis is a high
possibility on clinical grounds, aciclovir should be
added without any delay with all the appropriate
monitoring measures particularly of the renal function.
Electroencephalography (EEG) has characteristic
features for encephalitis, and imaging preferably with
an MRI of the brain will be a useful addition in larger
hospitals.
Investigations
Physical examination alone is not accurate enough
to confidently exclude meningitis. CSF examination
is necessary unless a lumbar puncture is clearly
contra-indicated. The CSF result must be interpreted
accurately to differentiate between acute viral and
bacterial meningitis, as treatment is different (Table
1).
Osheik Abu’Asha Seidi
Table1: Common CSF findings in acute meningitis: differential diagnosis
Index Normal Bacterial
WBC/micro L <5 >1,000
Differential <15% neutrophils >80% neutrophils <15% neutrophils <15% neutrophils
Glucose (mg/dL) 45-65 reduced
CSF: blood glucose 0.6 reduced
Protein (mg/dL) 20-45 >250
Opening pressure <20 Normal to high
(cm/H20)
A CSF total WBC count above 1000/µL, usually with
a neutrophilic predominance is seen from the early
stages of bacterial meningitis and a normal count
makes it unlikely in an immune competent patient. In
acute bacterial meningitis, there is a CSF concentration
of protein above 250 mg/dL and CSF concentration of
glucose below 45 mg/dL (2.5 mmol/L). However, the
spectrum of CSF values in bacterial meningitis is so
wide that there is substantial overlap with the findings
in viral infection.
Basic blood tests can point towards one diagnosis
but these are not enough without CSF examination to
confirm the diagnosis of meningitis. If the differential
includes acute encephalitis with clinical uncertainty,
estimation of CSF lactate may help as it is raised in
bacterial meningitis.
Recently CSF viscosity was tested as an adjunctive
tool to exclude meningitis in patients with a suggestive
clinical presentation.(62)
Examination of the CSF may provide critically
important diagnostic information in a number of
infectious and non-infectious medical conditions. It is
a corner stone test in the diagnosis of acute bacterial
meningitis(63).
In normal adults, approximately 20 mL of CSF is
produced each hour, and the CSF volume is 125 to
150 mL, 50% of this is intracranial while the rest is
intraspinal. The normal CSF opening pressure is 6 to
20 cmH2O; obese patients may have CSF pressures up
to 25 cmH20. Pressures >25 cmH20 are considered
576
Viral Fungal (tuberculosis)
<1,000 <1,000
normal reduced
normal Markedly reduced
50-250 >250
Normal to high Normal to high
to be elevated. Acute infections, such as meningitis,
can lead to rapid increases in CSF pressure. This is
measured using a manometer connected to the spinal
needle in a strictly sterile environment and is expressed
as centimetres of CSF (Normal 10 – 20).
An elevated CSF WBC concentration does not
diagnose an infection, since increases in the CSF
WBC concentration can occur in a variety of both
infectious and noninfectious inflammatory states such
as in the NSAIDS (non-steroidal anti-inflammatory
agents) induced meningitis (64). The CSF cell count
must always be correlated with clinical findings.
The normal CSF protein concentration in adults
ranges from 23 to 38 mg/dL (0.23 to 0.38 g/L). The
CSF protein concentration may be mildly elevated in
patients with diabetes mellitus and hypothyroidism.
The CSF-to-serum glucose ratio is approximately 0.6
in normal individuals. The CSF-to-serum glucose
ratio has limited utility in patients with severe
hyperglycemia. CSF glucose levels rarely exceed 300
mg/dL (16.7 mmol/L) even in patients with severe
hyperglycemia.
The CSF lactate concentration has been observed to
rise in experimental and clinical cases of bacterial
meningitis. In one study of infection following
neurosurgical procedures, lactate levels had a higher
sensitivity and specificity than determinations of the
ratio of CSF-to-blood glucose.
A head CT scan is not required in every patient prior to
577
lumber puncture and a normal CT scan cannot reliably
exclude the risk of tentorial herniation. It is required
when there is focal neurological deficit, new onset
seizures, altered level of consciousness, papilloedema
and in immune compromised patients.
A highly raised peripheral blood WBC’s count and ESR
are seen more in bacterial rather than viral meningitis.
Investigations to address other possibilities and be
base line for monitoring very sick patients include a
blood film for malaria, liver function tests and renal
profile.
Complications
Complications can arise during the early part of the
illness or become apparent years afterwards. Some of
these and the prognostic factors are shown in table 2.
Table 2: Prognostic Factors in Bacterial Meningitis
Risk Factor Mortality With Risk Factor
Altered mental status 49%
Age >60 years 37%
Seizures within 24 hours 72%
CSF protein >250 mg/dL 32%
Leukopenia 63%
Hemoglobin <11 mg/dL 16%
Platelets <100k 25%
not vary from usual strokes (65-72). More studies are
needed to explore these issues. Sensorineural hearing
loss is common in all ages particularly children. It
can recover after prompt antibiotic therapy coupled
with dexamethasone. Intellectual impairment is a
complication in neonates and younger children (71-72).
It is worth mentioning that ischemia of the genu of
the internal capsule is seen as a peculiar complication
of bacterial meningitis. It causes dementia that
is characterized by Abulia, lethargy and memory
loss without obvious motor palsy (capsular genu
syndrome). Decreased cerebral blood flow was found
in the genu of the internal capsule in six of 13 patients
with severe bacterial meningitis. It is characterized by
abulia, lethargy, and memory loss(73).
Acute bacterial meningitis in adults
Impaired mental status is a serious complication
usually seen during the acute phase. Increased
intracranial pressure and cerebral oedema that may
end up with transtentorial herniation and lead to death
are seen during the early phase of the illness and
should be actively monitored for by repeated fundal
examinations. Seizures can occur both acutely or
appear years later, hence it is important to ask patients
presenting with seizures in all ages about a history of
meningitis. Septic dural sinus thrombosis or subdural
empyema can occur in the first or second weeks
of the illness and adversely affect the prognosis.
Focal neurological deficits (e.g. cranial nerve palsy,
hemiparesis) are commoner with pneumococcal
meningitis but do occur with other bacterial pathogens.
Cerebrovascular accidents carry serious prognosis
in the acute phase, but in the longer terms these do
Mortality Without Risk Factor
16%
17%
18%
4%
11%
5%
6%
Osheik Abu’Asha Seidi 578

Current Management

Table 3: Empiric Antibiotic Therapy for Suspected Bacterial Meningitis in Adults+

Age Suspected Pathogens Empiric Antibiotics Penicillin Alternative

=or < 50 years Meningococcus, 3rd generation cephalosporin Meropenem,
pneumococcus, (ceftriaxone) + vancomycin chloramphenicol,
Haemophilus influenzae fluoroquinolones

> 50 years Pneumococcus, listeria, 3rd generation cephalosporin* Trimethoprim/sulfa

gram-negative bacilli (ceftriaxone) + vancomycin + fluoroquinolone
+ ampicillin

Hospital- Staphylococci, Ceftazidime or cefepime Meropenem

Acquired gram-negative bacilli, + vancomycin
pneumococcus

+ Dexamethasone should be give just before or with the first dose and continued as explained in the text
*Third generation cephalosporin alone don’t cover Listeria

Note: Antibiotic should be modified according to the sensitivity profile if an organism is isolated from
the CSF or blood cultures

Figure 1: The African Sub Saharan meningitis belt

Initial therapy in adults under 50 years includes
Ceftriaxone 2 gm IV or Cefotaxime 2 gm IV
plus Vancomycin 1 gm IV. With both regimens
Dexamethasone is proven to be of significant benefit(74).
10 mg Dexamethasone are to be administered with the
first antibiotic dose; ideally as soon as the diagnosis is
considered as with any delays the complications rate
increases(19). In older patients and pregnant women
ampicillin 2 gm IV is added to cover for Listeria
monocytogenes. In patients allergic to penicillin an
amionoglycoside, a fluroquinolone or cotrimoxazole
are recommended instead of ampicillin. It is worth
mentioning that third generation cephalosporins are
not active against Listeria. The antibiotics should be
readjusted later according to the sensitivity of the
isolated organism(s), if any. The treatment is ideally
579
administered for at least ten days but there are no
randomised controlled trials of adequate power to
give definitive duration for therapy for the various
organisms and in the different age group. Clinicians
should consider judgments for longer durations for
individual patients particularly for nosocomial and in
immunocompromised patients.
Chemoprophylaxis to eliminate the meningococci
from the carrier is recommended for close contacts as
the risk for them developing the disease is 400 -800
folds higher than the general population. It is also used
to control limited outbreaks as in barracks, camps
and residential schools. Rifampicin, ceftriaxone,
azithromycin and the quinolones all showed activity
against the meningococci in the human nasopharynx.
Future Perspectives
Developing an effective and safe polyvalent vaccine
to cover all the virulent serotypes of Nisseria
meningitides(75,76), particularly type A which is
causing the devastating epidemics in Africa has
taken pace recently and a few months ago (December
2010), the first meningococcal A conjugate vaccine
was introduced in Burkina Faso. It is hoped that all
25 countries in the African meningitis belt will have
introduced this vaccine by 2015. High coverage of the
target age group of 1-29 years is expected to eliminate
meningococcal A from the region of Africa.
National programs including regular campaigns
in the affected counties for awareness about the
disease, early diagnosis and therapy by medical and
paramedical staff who act as first contact points for
patients are encouraged. Integrated surveillance and
response units are proposed as one the future plans to
contain this devastating disease (77).
The development of therapeutic modalities to down
regulate host inflammatory responses, such as those
of monoclonal antibodies to cytokines, is of utmost
importance and promise.
Recent experimental data suggest that lipid
peroxidation and PARP activation play a role in the
development of meningitis-associated intracranial
complications and brain injury(78). Agents that
interfere with the production of reactive oxygen
species (ROS)(79) and peroxynitrite, or interfere with
lipid peroxidation and poly ADP ribose polymerase
Acute bacterial meningitis in adults
(PARP) activation, may represent novel, therapeutic
strategies by which meningitis-associated brain
damage can be limited(80-82).
Rapid, accurate and simple tests to determine the
aetiological agents are being developed and refined
for clinical use. These are mostly based on polymerase
chain reaction (PCR) and microarray techniques and
are expected to generate commercially available kits
at reasonable costs in the near future(83-86).
Conclusion and Recommendations
Bacterial meningitis is an old disease which is still
devastating humanity. Major progress followed the
introduction of antibiotic therapy and vaccination.
The recent evident beneficial effect of concomitant
use of steroids is expected to show impact on mortality
and morbidity in a short time. Early recognition and
prompt antibiotic therapy is the corner stone in the
fight against this deadly disease. In epidemics, mass
vaccination and eradication of the meningococci
from the nasopharynx of carriers as well as early
case detection and prompt therapy should reduce
the mortality and morbidity of this serious disease.
More studies are needed to address the epidemiology
and outcomes of bacterial meningitis in the Sudan,
as no such information is available to the best of
my knowledge now. This is important for national
planning to contain the disease. Highly specific and
sensitive rapid tests and broader polyvalent vaccines
are being developed whilst deeper understanding of
the pathogenesis at the cellular and molecular levels
is hoped to result in new and adjuvant therapies to
cure the disease and prevent its serious complications.
Dedication
This brief review on acute bacterial meningitis in
adults is dedicated to the memory of the great father of
medicine and neurology in Sudan, the late Professor
Dawoud Mustafa Khalid who gave neurology its
place and glory in Sudan over the years that passed
and many that will come.
Acknowledgements
Thanks to Dr Raad Shakir, consultant neurologist at
Charing Cross Hospital. London, for his help.
Osheik Abu’Asha Seidi
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