Scand J Infect Dis 34: 811 – 814, 2002

Tuberculous Meningitis in a Country with a Low

Incidence of Tuberculosis: Still a Serious Disease
and a Diagnostic Challenge
Ê SE
CHRISTINE BIDSTRUP1 , PETER HENRIK ANDERSEN2 , PETER SKINHØJ1 and A
Ê
BENGARD ANDERSEN 1

From the 1 Department of Infectious Diseases, Rigshospitale t and 2 Department of Epidemiology, Statens Serum Institut,
Copenhagen, Denmark

In order to assess the present epidemiology, clinical presentation and outcome of patients with tuberculous meningitis (Tm),
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a retrospective study was conducted including 20 Tm patients admitted to a referral department in Denmark between January
1988 and July 2000. The Ž ndings were compared to those of a similar survey conducted 12 y earlier. A total of 65% of the
patients came from countries with a high endemicity of tuberculosis, compared to only 26% in the previous survey. The overall
mortality rate was 20%, with elderly patients with various pre-existing diseases being particularly affected. Neurological
sequelae were seen in 50% of patients and seemed to be related to the duration of symptoms and treatment delay. The
neurological state on admission and a rapid progression of symptoms seemed to be related to mortality. In 85% of the patients
treatment was initiated without a deŽ nitive bacteriological diagnosis having been reached. The Ž ndings indicate that Tm is a
rare but still serious disease, and one that is associated with high mortality and morbidity.
A. B. Andersen, MD, DSc, Department of Infectious Diseases, M5132, Rigshospitalet, Blegdamsvej 9, DK 2100 Copenhagen
Ø, Denmark. Tel.: »45 35 45 77 42; Fax: »45 35 45 66 48; E-mail: bengaard@dadlnet.dk

INTRODUCTION The outcome was graded as follows: 1, no sequelae; 2, mild

sequelae (e.g. chorioretinitis, reduced vision); 3, moderate sequelae
Tuberculous meningitis (Tm) is the most serious manifesta-
For personal use only.

(reduced memory, mild functional disability, e.g. reduced ability to

tion of tuberculosis, being associated with high mortality
and morbidity. Although Denmark has a low incidence of
tuberculosis, it has risen steadily since 1986, mainly due to
an increasing number of cases among immigrants (1). In
this study we report the results of a retrospective study
describing the clinical picture and outcome of 20 Tm cases
admitted to a major referral centre in Copenhagen during
the last decade and compare the Ž ndings to those in 23
cases described in a similar survey 12 y earlier (2).
MATERIAL AND METHODS
This study is based on a retrospective review of 20 patients with
Tm admitted to the Department of Infectious Diseases, Rigshospi-
talet, Copenhagen, between January 1988 and July 2000. During
that period 23 patients were registered with Tm but only 20 of the
case records could be obtained. Three patients with central nervous
system (CNS) tuberculomas without meningitis were included, in
analogy with the previous study (2). A total of 17 patients were
referred from other hospitals, while 3 patients were admitted
directly. Attention was paid to epidemiological parameters (gender,
age, ethnic origin), duration of symptoms, clinical condition at the
time of admission, microbiological and paraclinical observations,
treatment and the course of disease.
The severity of symptoms at the time of admission was classiŽ ed
by staging the patients according to the 1948 guidelines of the
British Medical Research Council (MRC) (3) as follows: stage I
(early), undisturbed consciousness and no focal neurological signs,
i.e. non-speciŽ c febrile illness; stage II (intermediate), disturbed
consciousness (excluding comatose or delirious status) or the pres-
ence of focal neurological signs or cranial nerve palsies; and stage
III (severe), comatose or delirious status regardless of any associ-
ated neurological signs.
walk); 4, severe sequelae (hemi- or paraparesis, cerebral palsy); and
5, death.
The microbiological procedures were performed on request at
the Department of Mycobacteriology, Statens Serum Institut,
Copenhagen. The liquid culture system BACTEC (Becton Dickin-
son) was used throughout the study. PCR was performed using the
Cobas Amplicor system (Roche), available from 1995. Univariate
analysis of prognosis was based on the x2 test.
RESULTS
Epidemiological data
Basic demographic data for the Tm patients are outlined in
Table I. The median age of the 20 patients was 29 y (range
2– 83 y). There was an equal sex distribution. Thirteen
patients were from countries with a high endemicity of
tuberculosis. Only 3 patients had a history of previous
tuberculosis (affecting the lungs, columnae or lymph
nodes). In 6 patients a potential source of infection was
identiŽ ed. The puriŽ ed protein derivative (PPD) test was
carried out in 16 patients, 11 of whom had a positive
reaction of ] 12 mm.
Underlying diseases
It was found that 5 patients had pre-existing diseases
believed to suppress the immune system: 1 patient was
HIV-positive; 1 was diagnosed with sarcoidosis; 1 had
insulin-dependent diabetes mellitus; 1 had an ill-deŽ ned
liver abnormality; and 1 suffered from myositis, for which
he was receiving low-dose prednisone.

© 2002 Taylor & Francis. ISSN 0036-554 8 DOI: 10.1080:0036554021000026938

 812 C. Bidstrup et al.
Presenting symptoms and clinical state on arrival
Typical symptoms were fever and neurological symptoms,
especially headache, dizziness, confusion and changes in
personality. The majority of the patients had symptoms
which would classiŽ ed them as stage II of the MRC classiŽ -
cation (3), with ] 1 of the following symptoms: febrile
illness with neck stiffness; and central nervous symptoms,
either cranial nerve palsies or disturbed consciousness. Only
3 patients were classiŽ ed as stage I and 1 was classiŽ ed as
stage III. It was noted that only half of the patients had the
classical symptoms of meningitis, i.e. neck stiffness and
fever.
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Cerebrospinal  uid Ž ndings
All the meningitis patients had spinal  uid leucocytosis
and 13 patients had leucocyte counts \100½106:l but
B1000 ½ 106:l, with primarily mononuclear leucocytes. All
but 1 patient had an elevated protein content of the cere-
brospinal  uid (CSF). The CSF:blood glucose ratio was
B 0.3 in 7:13 patients. No relation to outcome could be
demonstrated for any of the values observed.
CT results
A total of 11:19 patients exhibited changes on a CT scan of
the cerebrum. Anti-tuberculous treatment was initiated on
For personal use only.
the basis of the CT result in combination with the clinical
picture in 5 of the patients. Eight patients presented a
normal CT scan.
Microbiology data
In 14 of the patients the presence of Mycobacterium tuber-
culosis was veriŽ ed by either culture (n ¾ 11), direct mi-
croscopy (n¾ 1) or PCR (n ¾ 2). Four patients had M.
tuberculosis cultured from sites other than the CSF (2 from
sputum, 2 from gastric aspirate). Two of the patients only
had Mycobacteria recovered from extracerebral foci. All
isolates were fully sensitive to conventional anti-tubercu-
lous drugs.
The clinical decision
In 17 cases therapy was initiated based on clinical suspi-
cion, i.e. without a positive microbiological diagnosis hav-
ing been reached. This suspicion was based on the
symptoms and clinical state of the patient together with (i)
mononuclear leucocytosis, elevated protein and low glucose
content in the CSF; (ii) the patient coming from an area
with a high endemicity of tuberculosis; (iii) the patient
having been in contact with a tuberculous person; and (iv)
CT of the cerebrum exhibiting signs compatible with CNS
tuberculosis and a positive PPD response.
Delay in treatment
The delay in treatment (from the day of hospital admission)
ranged from 0 to 123 d (median 5 d). The delay in
treatment was not related to mortality but neurological
Scand J Infect Dis 34
sequelae occurred in 6:6 patients with a delay in treatment
of \ 5 d.
Prednisolone was used as adjuvant therapy in all but 2
patients: 1 died before treatment was initiated and in the
other case (an HIV-positive patient) the reason was not
stated. In 4 patients the prednisolone supplementation was
delayed by 4–25 d.
Supportive treatment and complications of therapy
Three patients were given artiŽ cial ventilation. Four pa-
tients developed hydrocephalus (20%), 3 of whom had
neurosurgery because of increased intracerebral pressure.
Three patients developed toxic hepatitis. One patient had
steroid-induced hallucinations.
Outcome
Six patients recovered without any sequelae. Four fatali-
ties were observed and neurological sequelae of varying
degrees occurred in 10 patients, 5 of whom suffered severe
sequelae. Three of the 4 fatalities involved elderly patients
aged \ 70 y who suffered from pre-existing diseases.
None of the 12 patients aged B 40 y died (pB 0.05). The
relationship between the duration of symptoms before
hospitalization and neurological sequelae and mortality is
outlined in Table I. The median duration of symptoms
was 14 d. A rapid progression of symptoms seemed to be
related to mortality while a long duration of symptoms
seemed to be related to neurological sequelae. For exam-
ple, 4:12 patients died and 2:8 of the surviving patients
had neurological sequelae when the duration of symptoms
was 5 14 d. Eight patients had symptoms for \ 14 d.
None of these patients died but all had neurological se-
quelae (pB 0.05).
DISCUSSION
Although the number of notiŽ ed cases of tuberculosis has
been steadily increasing in Denmark since 1986, Tm re-
mains a rare disease. Only 22 cases were reported to the
National Surveillance Register at the Statens Serum Insti-
tut during the period 1992–2000 (no data available from
1988 to 1992). In this study 23 patients were registered
with Tm between January 1988 and May 2000, apparently
comprising two-thirds of the total number of Tm cases in
Denmark during that time period. Of our patient popula-
tion, 65% were from countries with a high endemicity of
tuberculosis, compared to only 26% in a similar study
covering the period 1976–87; this re ects the increase in
the number of immigrants and asylum seekers arriving in
Denmark that has occurred in the past decade (1, 2, 4).
The observed mortality in this study was 20%, which is
a slight decrease compared to the Ž gure of 30% reported
in the period 1976– 87 (2). Other studies, which also fo-
cused mainly on adult Tm patients, have reported mortal-
ity rates ranging from 23% in a community-based study in
 Scand J Infect Dis 34 Tuberculous meningitis 813

Table I. Demographic data, duration of symptoms, major neurological sequelae and mortality

Duration of symptoms Delay in treatment Neurological

Patient no. Age (y) Sex Origin before hospitalization (d) after admission (d) sequelae Death

1 33 F D 4 0 – –
2 46 F D 90 8 » –
3 5 M D 14 5 – –
4 14 F I 19 3 » –
5 2 M I 14 5 – –
6 83 F D 2 3 n.a. »
7 2 F I 60 6 » –
8 74 M D 7 No treatment n.a. »
9 49 M I 28 0 » –
10 49 F I 7 12 n.a. »
11 22 M I 14 12 » –
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12 23 M I 60 1 » –
13 64 M D 45 11 » –
14 73 F D 14 5 n.a. »
15 37 M I 13 1.5 – –
16 23 F I 180 123 » –
17 a 21 M I ‘‘Several months’’ 13 » –
18 a 16 F I 6 3 – –
19 a 63 F I 3 5 – –
20 24 M I 14 0 » –

a
Patients with tuberculoma.
D ¾Danish; I¾ immigrant; n.a.¾ not applicable.
For personal use only.

the USA (5) to 69% in a South African study (6). How-
ever, the differences in settings, numbers of patients, age
groups of the patients and health facilities available make
comparisons difŽ cult.
The MRC staging of Tm (3) at the time of admission
did not predict the outcome. However, age may be an
important risk factor as the 4 cases with a fatal outcome
were all aged \ 40 y. Three out of 4 patients who died
were elderly patients of Danish origin who all had various
pre-existing diseases. The number of patients with neuro-
logical sequelae in this study (50%) was higher compared
to that (30%) found in the earlier study (2). The duration
of symptoms before hospitalization appeared to be related
to neurological sequelae. Early diagnosis and prompt ini-
tiation of therapy are considered crucial to prevent an
adverse outcome. In half of the patients the presenting
symptoms were comparable to those of purulent meningi-
tis caused by other bacteria, e.g. neck stiffness, headache,
confusion and fever. However, the duration of symptoms
was generally longer than is usually the case for purulent
meningitis. A variety of less speciŽ c symptoms, such as
dizziness, changes in personality and even gastrointestinal
symptoms, were also common. None of the symptoms
were deŽ nitively predictive of outcome although rapid
progression of symptoms and the neurological status on
admission (coma and stupor) seemed to be related to
mortality. The median delay in treatment was 5 d, which
is 5 d less than in the earlier study from this department
(2). Delay in treatment seemed to be related to neurologi-
cal sequelae but not to mortality.
The diagnosis of Tm is difŽ cult because the available
methods for detection of M. tuberculosis in CSF are of
low sensitivity. In 85% of patients the anti-tuberculous
treatment was initiated without a deŽ nitive bacteriological
diagnosis having been reached. In 70% of cases the micro-
biological diagnosis was conŽ rmed by culture or PCR, in
comparison to only 56% in the previous study. During the
later time period the liquid culture system BACTEC was
used routinely, which may explain the apparent increase in
sensitivity. However, in the initial phase of Tm the micro-
biology laboratory has little to offer the clinician. Most
important diagnostically were the clinical symptoms and
the biochemical CSF Ž ndings. Information about the eth-
nic origin of the patient and exposure to tuberculosis was
essential for making a clinical diagnosis. Surprisingly, 8:19
patients (42%) presented a normal CT scan.
In conclusion, Tm is a rare but still serious infectious
disease. The 20 cases analysed retrospectively exhibited a
mortality of 20% and 50% of patients had permanent
sequelae; these values are essentially unchanged compared
to the results from a study conducted 12 y previously in
the same department. In the initial phase of Tm the diag-
nosis is still mainly a clinical one and should be consid-
ered in patients originating from countries with a high
endemicity of tuberculosis and in elderly patients with
neurological symptoms and spinal pleocytosis.
 814 C. Bidstrup et al.
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Scand J Infect Dis 34
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Submitted January 7, 2002; accepted July 23, 2002