Infectious Diseases of the Brain and Meninges
Table 2.22 Meningitic syndromes
Syndrome Cell count
Acute bacterial 100 1000,
meningitis mainly polynuclear
Acute viral 100, more mono-
meningitis than polynuclear
Chronic meningitis 100, mainly
mononuclear
stricted to the diagnostic evaluation
of radiologically identified abnormal-
ities in the brain. Thus, a biopsy can
provide histologic differentiation of
tumors and inflammatory changes,
which is important for the planning
of further treatment. When a biopsy
is performed, tissue specimens
should be taken not only for histolog-
ical examination, but also for culture,
whenever a bacterial, mycotic, or my-
cobacterial infection is a diagnostic
possibility.
| Neuroimaging Studies
CT and MRI often provide critical di-
agnostic information about infections
of the central nervous system. MRI, in
particular, is indispensable for the di-
agnosis of abscess and encephalitis
(p. 93). Inflammatory changes are of-
ten visible only after the administra-
tion of contrast. Contrast-enhanced
scans are therefore recommended
whenever a CNS infection is sus-
pected.
Angiography may be of assistance in
the diagnosis of vasculitis. Mycotic
aneurysms are sometimes visible
only on an angiogram.
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83
Protein Glucose
Elevated Low or very low
Normal or mildly Normal or mildly
elevated low
Elevated or mark- Low or very low
edly elevated
Bacterial Infections
| Acute Bacterial Meningitis
(795)
Most cases of bacterial meningitis
arise by hematogenous spread of a
bacterial infection affecting the upper
respiratory tract. Less commonly,
they are caused by direct extension of
pathogenic bacteria from purulent
collections in the head, or else patho-
gens are directly inoculated into the
intracranial cavity by traumatic brain
injury, or iatrogenically by punctures
and shunt operations.
The most common pathogens are:
> in the newborn: Escherichia coli,
Group B streptococci;
> in children: Haemophilus influen-
zae, pneumococci, and meningo-
cocci;
> in adults: pneumococci and menin-
gococci.
The risk of meningococcal infection
increases in complement disorders or
properdin deficiency, while that of
pneumococcal meningitis increases
after splenectomy. Klebsiella, E. coli,
and Pseudomonas aeruginosa are the
most common pathogens affecting
aged persons, alcoholics, and persons
who have suffered traumatic brain in-
juries or undergone neurosurgical
procedures; Listeria monocytogenes
84 2 Diseases Mainly Affecting the Brain and its Coverings
may also cause meningitis at any age.
Fewer than 1 % of cases of meningitis
involve multiple pathogens. Endemic
and epidemic meningitis are a major
public health problem in underdevel-
oped countries and are usually
caused by H. influenzae, meningo-
cocci, and pneumococci.
Pathological Anatomy
A granulocytic infiltration of the me-
ninges and subarachnoid space is ob-
served. This may lead to disturbances
of cerebrospinal fluid flow (hydro-
cephalus), vasospasm, arterial and
venous thrombosis with consequent
infarction, infection of the brain tis-
sue (encephalitis, cerebritis, brain ab-
scess), cerebral edema, and intracra-
nial hypertension.
Clinical Features
The classic clinical triad of meningitis
consists of:
> headache,
> fever, and
> meningism (nuchal rigidity).
Headache may be extremely intense
and diffuse, commonly bioccipital.
Back pain, myalgia, photophobia,
nausea, and vomiting are further
symptoms. As many as 40 % of pa-
tients have epileptic seizures, and
1020 % have cranial nerve deficits.
Such patients are usually somnolent
or comatose and manifest a charac-
teristic combination of hypertension
and bradycardia. Papilledema may be
present. Fever and meningism may
be only mild in children, the elderly,
and immune-suppressed patients, in
whom headache and vomiting are the
major manifestations of disease.
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Diagnosis
Examination of the cerebrospinal
fluid is critical for diagnosis (Ta-
ble 2.22). If clinical signs of intracra-
nial hypertension are present (brady-
cardia, hypertension, papilledema),
an intracranial mass lesion should be
ruled out by CT or MRI prior to lum-
bar puncture. The cerebrospinal fluid
is turbid and contains 1,00010,000
cells per microliter, and occasionally
more. There is a predominantly gran-
ulocytic pleocytosis. The cerebrospi-
nal fluid pressure and protein con-
centration are practically always ele-
vated, and the glucose concentration
low. Gram staining reveals the bacte-
rial pathogen in 6090 % of cases. Ce-
rebrospinal fluid cultures are positive
in ca. 75 % of cases, and blood cultures
in 5075 %. Blood culture should be
performed in all cases, as it may be
positive even if the cerebrospinal
fluid culture is negative. Partially
treated bacterial meningitis and liste-
rial meningitis may be associated
with fewer than 1000 cells per micro-
liter in the cerebrospinal fluid and
should not be confused with viral
meningitis.
Neuroimaging studies such as CT and
MRI are generally not required for di-
agnosis, but they are helpful should
complications arise. They are normal
in the early stage of bacterial menin-
gitis, but later show compression of
the sulci and cisterns. Meningeal en-
hancement may be seen on MRI, and
more rarely on CT (Fig. 2.15). (760).
Bony defects of the base of the skull
that may be of pathogenetic signifi-
cance are usually seen in the bone
window of a fine-section CT scan.
 Infectious Diseases of the Brain and Meninges 85

Fig. 2.15a, b Chronic meningitis.

The patient is a 49-year-old woman. The pathogenic organism could not be identified. a
Coronal T1-weighted MRI with contrast. b Axial T1-weighted MRI with contrast. Note the
abnormal contrast enhancement in the meninges.

Fig. 2.16a, b Acute bacterial meningitis.

The patient is a 10-year-old boy. a Coronal T1-weighted MRI with contrast demonstrates
sphenoid sinusitis (arrows) spreading in the epidural space under the left temporal lobe
and causing meningitis by direct extension with involvement of the temporal lobe (arrow-
heads). b T1-weighted MRI with contrast in a coronal section posterior to a shows a prob-
able epidural empyema over the left temporal lobe (arrowheads). There is also extensive
signal change in the left thalamus, probably due to an arterial infarction as a complication
of meningitis.

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86 2 Diseases Mainly Affecting the Brain and its Coverings
Prognosis
The prognosis of acute bacterial men-
ingitis depends on:
> the pathogenic organism,
> the severity of the infection,
> concomitant illnesses,
> the state of the immune system,
and
> the type of treatment and time at
which it is instituted.
Mortality is highest in the newborn
(over 50 %). Meningitis accompanied
by meningococcal sepsis also confers
a high mortality, because it is fre-
quently complicated by bilateral ad-
renal hemorrhage and subsequent
circulatory collapse (Waterhouse-
Friderichsen syndrome). The mortal-
ity of other forms of meningitis is ap-
proximately 20 % (1014). Surviving
patients often suffer from permanent
sequelae including deafness, malre-
sorptive hydrocephalus, epilepsy, and
intellectual deficits, particularly in
children.
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Treatment
(Fig. 2.17) (777a)
If a lumbar puncture cannot be per-
formed immediately because of
clinical signs of intracranial hyper-
tension, blind parenteral antimi-
crobial treatment should be initi-
ated at once, as a few minutes may
make the difference between life and
death. If the pathogenic organism is
unknown, the antimicrobial treat-
ment is chosen empirically (Ta-
ble 2.23). It can then be modified in
accordance with the findings of the
cerebrospinal fluid and blood cul-
tures, including sensitivity and re-
sistance testing.
The duration of treatment is based
on the findings of serial clinical ex-
amination and cerebrospinal fluid
analysis. Some general recommen-
dations are:
> for meningococci and H. influen-
zae, 710 days;
> for pneumococci, 1014 days;
> for Listeria and Gram-negative
aerobes, 3 weeks.
Steroids (dexamethasone 0.4 mg/kg
every 12 hours in the first 2 days of
treatment) favorably affect the
course of the inflammatory process
in children and probably also in
adults, and should be given in addi-
tion to antimicrobial agents (560,
831).
 Infectious Diseases of the Brain and Meninges 87

Suspicion of meningitis

Papilledema or focal
Yes neurologic deficits No

Blood cultures Positive Positive Blood cultures

Immediate empirical Specific Lumbar puncture

antibiotic treatment antibiotic treatment

CT or MRI Positive Immediate empirical

antibiotic treatment

Diagnosis confirmed

Gram stain,
antigen tests, cultures

Meningitis confirmed, or
normal; no evidence of Lumbar puncture
intracranial hypertension

Other diagnosis found

Diagnosis
Other specific therapy Other diagnosis not confirmed

Fig. 2.17 Management flowchart for meningitis.

The essential element of treatment is immediate institution of antimicrobial therapy, at
first empirical and then tailored to the specific pathogen identified by culture.

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Table 2.23 Antimicrobial therapy of bacterial meningitis (824, 831, 836)

88
Patient group Most likely organism Agent(s) of first choice1 Alternatives
2
Newborn Group B streptococci, E. coli, Ampicillin and cefotaxime Ampicillin and aminoglycoside

2
Listeria monocytogenes

Diseases Mainly Affecting the Brain and its Coverings

Infants 13 months Same and H. influenzae, menin- Ampicillin and ceftriaxone or Chloramphenicol and aminogly-
gococci, pneumococci cefotaxime coside
Infants G 3 months, toddlers H. influenzae, meningococci, Ceftriaxone or cefotaxime Chloramphenicol and ampicillin
pneumococci
Children and adults Pneumococci, meningococci, Ceftriaxone or cefotaxime and Chloramphenicol and ampicillin,
Listeria monocytogenes ampicillin or penicillin G vancomycin if penicillin-
resistant
Adults G 60 years, alcoholics, Pneumococci, E. coli, Haemophi- Vancomycin and ceftriaxone2 Chloramphenicol and
patients with systemic lus influenzae, Listeria monocyto- and rifampicin trimethoprim-sulfamethoxazole
disease genes, Pseudomonas aeruginosa,
anaerobes3
Traumatic brain injury, Staphylococcus aureus, E. coli, Vancomycin and ceftriaxone
neurosurgical procedures Pseudomonas aeruginosa,4
pneumococci
Cerebrospinal fluid leak Pneumococci Cefotaxime or ceftriaxone
1 Unless otherwise specified, these recommendations are applicable to the most likely pathogens affecting the group of patients in ques-
tion. If the responsible pathogen is known, the treatment should be correspondingly tailored. Dosages may be found in drug compendia.
2 Or other (third-generation) cephalosporin.
3 Chloramphenicol or metronidazole.
4 Add gentamicin.
 Infectious Diseases of the Brain and Meninges 89

Prevention ache, meningism, asymmetrical cra-

The administration of Haemophilus
vaccine to infants confers 90 % protec-
tion against this type of meningitis.
Inoculation against the meningococ-
cus is recommended for travelers to
endemic areas. After exposure to
Haemophilus or meningococcus, anti-
microbial prophylaxis is recom-
mended (10 mg/kg in children or
600 mg in adults, b.i.d. for 2 days).
| Tuberculous Meningitis (1051)
Mycobacterium tuberculosis causes a
chronic bacterial infection character-
ized by granuloma formation. The
lung is usually affected. The menin-
ges may become involved during the
primary infection in children, or years
afterward in adults. Meningitis comes
about by reactivation of clinically si-
lent granulomas and secondary de-
posits in the subarachnoid space,
even in the absence of simultaneous
pulmonary tuberculosis. HIV-positive
persons are at particularly high risk of
infection both by M. tuberculosis and
by atypical mycobacteria.
nial nerve deficits, and ischemic
stroke. Coma is a bad prognostic sign.
For miliary tuberculosis, see p. 91.
Diagnosis
Cerebrospinal fluid examination re-
veals a picture of chronic meningeal
inflammation with at first granulo-
cytic and then monocytic pleocytosis
of 100500 cells, elevated protein
concentration, and low glucose con-
centration. The diagnosis is con-
firmed by the demonstration of acid-
fast bacilli by the Ziehl-Neelsen
method or with auramine
rhodamine staining, either in the
fresh cerebrospinal fluid sample or
after 46 weeks of culture.

Pathological Anatomy
An exudative basilar meningitis and
vasculitis is found, particularly in the
vicinity of the anterior and middle ce-
rebral arteries. Meningeal involve-
ment and vasculitis may lead to cra-
nial nerve deficits and to cerebral in-
farction. Hydrocephalus is commonly
seen.

Clinical Features
Over the course of several days or,
more rarely, weeks, these patients ex-
hibit progressive symptoms and signs
including subfebrile temperature,
fatigue, depression, personality
changes, and (sometimes) confusion.
One-third of patients develop head-
Fig. 2.18 Tuberculous meningitis.
This contrast-enhanced T1-weighted MR
image reveals enhancement of the in-
flamed meninges at the basal cisterns and
anterior to the brainstem. The asymmetri-
cal extension of inflammation along the
course of the middle cerebral artery is also
typical.

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90 2 Diseases Mainly Affecting the Brain and its Coverings
In addition to the cerebrospinal fluid,
the sputum, gastric juice, and urine
should be examined and cultured for
acid-fast bacilli. Contrast-enhanced
CT and MRI reveal meningeal involve-
ment at the skull base and along the
course of the middle cerebral artery
(151) (Fig. 2.18).
Differential Diagnosis
The differential diagnosis includes all
types of chronic lymphocytic menin-
goencephalitis (see below).
Treatment
The treatment consists of a combi-
nation of four tuberculostatic medi-
cations: rifampicin, isoniazid, pyra-
zinamide, and ethambutol. At the
same time, steroids and vitamin B6
should be given. The latter pre-
vents the pyridoxine deficiency
that may otherwise result from
long-term use of isoniazid.
This therapy should be continued
until the results of culture are
available. If culture is positive for
tubercle bacilli, a combination of
three medications is given for a fur-
ther 2 months, and then two medi-
cations for 810 months more.
Once the culture results are nega-
tive and the cerebrospinal fluid pic-
ture has renormalized, treatment
may be discontinued.
If the patient fails to improve on
this regimen, other etiologies of
chronic meningitis should be
sought, and, even if cultures for M.
tuberculosis are negative, it is pru-
dent to continue the tuberculo-
static therapy. The currently used
tuberculostatic agents have only
minor side effects even in long-
term use.
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Prognosis
Tuberculous meningitis is fatal if un-
treated, curable without sequelae if
treated in time. The diagnosis should
be made, and treatment initiated,
before the onset of cranial nerve defi-
cits or of impaired consciousness.
Thus: when tuberculous meningitis is
strongly suspected, obtain fluid sam-
ples for culture and then begin antitu-
bercular therapy immediately.
| Meningoencephalitis
| Listeriosis (957, 959, 695b)
Listeria are aerobic or facultatively
anaerobic bacilli that are usually in-
gested orally in food. They preferen-
tially infect the newborn, diabetics,
alcoholics, and aged or immune-
suppressed persons. The clinical pic-
ture is generally that of a typical bac-
terial meningitis, but the cerebrospi-
nal fluid cell count may be so low as
to arouse suspicion of viral meningi-
tis. Listeria also causes encephalitis,
often with brainstem manifestations,
as well as meningoencephalitis
and cerebral or spinal abscesses
(Fig. 2.19).
Treatment
The antimicrobial agents of first
choice are ampicillin and penicillin
G. An alternative is trimethoprim/
sulfamethoxazole. Cephalosporins
do not eliminate Listeria.
| Brucella Meningitis (127)
Brucellosis is transmitted in milk or
other animal products and usually
presents nonspecifically with fever,
arthralgias and myalgias, though it
causes localized disease in some
cases, and its manifestations are
sometimes restricted to the central
 Infectious Diseases of the Brain and Meninges 91

Fig. 2.19 Listeria meningoencephalitis.

A 45-year-old woman with multiple cranial nerve deficits and left ataxia.
a The FLAIR sequence reveals a plate-like signal abnormality in the brainstem and left cer-
ebellar hemisphere.
b The T1-weighted image shows several foci of contrast enhancement.

nervous system. These usually consist

of subacute or chronic meningitis,
more rarely meningoencephalitis,
myeloradiculitis or neuritis.
Twenty to 500 cells are found in the
cerebrospinal fluid. The diagnosis is
confirmed by the demonstration of
specific antibodies in the CSF.

Treatment
The treatment consists of doxycy-
cline and rifampicin for 4 months,
with surveillance of the cerebrospi-
nal fluid.

Fig. 2.20 Miliary tuberculosis.

| Meningoencephalitis in Miliary
Tuberculosis
In miliary tuberculosis, hematoge-
nous spread of tubercle bacilli leads
to the formation of millet-seed-sized
granulomas throughout the body. The
clinical manifestations are not spe-
cific to this disease but rather reflect
A 28-year-old woman with miliary tubercu-
losis. Cerebrospinal fluid examination re-
vealed a mild monocytic pleocytosis, a
markedly elevated protein concentration,
and a low glucose concentration. The MRI
reveals multiple pinhead-sized foci of con-
trast enhancement in the brain paren-
chyma and mild contrast enhancement of
the meninges as well.

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92 2 Diseases Mainly Affecting the Brain and its Coverings

the predominantly involved organ(s). rysms, or any combination of these

Symptoms and signs may include fe- entities.
ver, night sweats, anorexia, general-
ized weakness and fatigue, hepato- Clinical Features
splenomegaly, lymphadenopathy,
The symptoms and signs depend on
and (if the brain is affected) headache
the pathological processes occurring
and progressive impairment of con-
in each individual case. Embolic
sciousness. Miliary tuberculosis
events are prominent in 20 % of cases,
usually affects the brain parenchyma
encephalitis due to multiple micro-
more than the meninges. The cere-
emboli and microabscesses in 10 %,
brospinal fluid findings are the same
hemorrhage due to mycotic aneu-
as for tuberculous meningitis, except
rysms in 5 %, and meningitis in 5 %.
that pleocytosis is usually only
Emboli produce focal manifestations,
mild. MRI reveals multiple pinhead-
while the other types of lesion cause
sized, contrast-enhancing nodules
a diffuse encephalopathy with behav-
(Fig. 2.20).
ioral and cognitive disturbances, im-
For diagnosis and treatment, see Tu-
pairment of consciousness, focal or
berculous meningitis, above (p. 90).
generalized seizures, and sometimes
headache and meningism. Important
| Focal Embolic Encephalitis diagnostic clues include subfebrile or
(148, 315, 819) (in acute endocarditis) septic temper-
Neurological symptoms and signs de- ature, a feeling of severe illness and
velop in at least one-third of patients prostration, anemia, splenomegaly,
with infectious endocarditis and may subungual, palmar and retinal pete-
be the presenting manifestations of chiae, and heart murmur.
the disease.
Streptococcus is the most common Diagnosis
pathogen, followed by staphylococ-
The complete blood count reveals
cus and Gram-negative bacilli. Cen-
acute inflammation, and the erythro-
tral nervous manifestations arise by
cyte sedimentation rate and C-
several different pathogenetic mecha-
reactive protein are elevated. The re-
nisms:
sponsible organism can usually be
> occlusion of cerebral arteries by
demonstrated by blood culture, and
septic and thrombotic emboli aris-
endocarditis by transesophageal echo-
ing from heart valve vegetations;
cardiography (212). The cerebrospinal
> infection of the meninges, brain
fluid may be sterile, purulent or hem-
parenchyma, or vascular walls by
orrhagic, depending on the nature of
septic emboli or by bacteremia;
CNS involvement (772).
> toxic and probably also immune-
MRI is particularly useful for the
mediated injury.
demonstration of embolic and infec-
tious processes affecting the central
Pathological Anatomy nervous system. Angiography is the
There may be bland or hemorrhagic most reliable way to demonstrate
cerebral infarcts, intracerebral, sub- mycotic aneurysms, but need not be
arachnoid or subdural hemorrhage, performed routinely in every patient
meningitis, abscesses, mycotic aneu- (819).

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