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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 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 de nitive bacteriological diagnosis having been reached. The 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
Presenting symptoms and clinical state on arrival sequelae occurred in 6:6 patients with a delay in treatment
Typical symptoms were fever and neurological symptoms, of \ 5 d.
especially headache, dizziness, confusion and changes in Prednisolone was used as adjuvant therapy in all but 2
personality. The majority of the patients had symptoms patients: 1 died before treatment was initiated and in the
which would classi ed them as stage II of the MRC classi - other case (an HIV-positive patient) the reason was not
cation (3), with ] 1 of the following symptoms: febrile stated. In 4 patients the prednisolone supplementation was
illness with neck stiffness; and central nervous symptoms, delayed by 4–25 d.
either cranial nerve palsies or disturbed consciousness. Only
3 patients were classi ed as stage I and 1 was classi ed as Supportive treatment and complications of therapy
stage III. It was noted that only half of the patients had the Three patients were given arti cial ventilation. Four pa-
classical symptoms of meningitis, i.e. neck stiffness and tients developed hydrocephalus (20%), 3 of whom had
fever. neurosurgery because of increased intracerebral pressure.
Three patients developed toxic hepatitis. One patient had
Scand J Infect Dis Downloaded from informahealthcare.com by University of California Irvine on 10/27/14
the basis of the CT result in combination with the clinical was 14 d. A rapid progression of symptoms seemed to be
picture in 5 of the patients. Eight patients presented a related to mortality while a long duration of symptoms
normal CT scan. seemed to be related to neurological sequelae. For exam-
ple, 4:12 patients died and 2:8 of the surviving patients
Microbiology data had neurological sequelae when the duration of symptoms
In 14 of the patients the presence of Mycobacterium tuber- was 5 14 d. Eight patients had symptoms for \ 14 d.
culosis was veri ed by either culture (n ¾ 11), direct mi- None of these patients died but all had neurological se-
croscopy (n¾ 1) or PCR (n ¾ 2). Four patients had M. quelae (pB 0.05).
tuberculosis cultured from sites other than the CSF (2 from
sputum, 2 from gastric aspirate). Two of the patients only DISCUSSION
had Mycobacteria recovered from extracerebral foci. All
Although the number of noti ed cases of tuberculosis has
isolates were fully sensitive to conventional anti-tubercu-
been steadily increasing in Denmark since 1986, Tm re-
lous drugs.
mains a rare disease. Only 22 cases were reported to the
The clinical decision National Surveillance Register at the Statens Serum Insti-
In 17 cases therapy was initiated based on clinical suspi- tut during the period 1992–2000 (no data available from
cion, i.e. without a positive microbiological diagnosis hav- 1988 to 1992). In this study 23 patients were registered
ing been reached. This suspicion was based on the with Tm between January 1988 and May 2000, apparently
symptoms and clinical state of the patient together with (i) comprising two-thirds of the total number of Tm cases in
mononuclear leucocytosis, elevated protein and low glucose Denmark during that time period. Of our patient popula-
content in the CSF; (ii) the patient coming from an area tion, 65% were from countries with a high endemicity of
with a high endemicity of tuberculosis; (iii) the patient tuberculosis, compared to only 26% in a similar study
having been in contact with a tuberculous person; and (iv) covering the period 1976–87; this re ects the increase in
CT of the cerebrum exhibiting signs compatible with CNS the number of immigrants and asylum seekers arriving in
tuberculosis and a positive PPD response. Denmark that has occurred in the past decade (1, 2, 4).
The observed mortality in this study was 20%, which is
Delay in treatment a slight decrease compared to the gure of 30% reported
The delay in treatment (from the day of hospital admission) in the period 1976– 87 (2). Other studies, which also fo-
ranged from 0 to 123 d (median 5 d). The delay in cused mainly on adult Tm patients, have reported mortal-
treatment was not related to mortality but neurological 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
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- (2). Delay in treatment seemed to be related to neurologi-
ever, the differences in settings, numbers of patients, age cal sequelae but not to mortality.
groups of the patients and health facilities available make The diagnosis of Tm is dif cult because the available
comparisons dif cult. methods for detection of M. tuberculosis in CSF are of
The MRC staging of Tm (3) at the time of admission low sensitivity. In 85% of patients the anti-tuberculous
did not predict the outcome. However, age may be an treatment was initiated without a de nitive bacteriological
important risk factor as the 4 cases with a fatal outcome diagnosis having been reached. In 70% of cases the micro-
were all aged \ 40 y. Three out of 4 patients who died biological diagnosis was con rmed by culture or PCR, in
were elderly patients of Danish origin who all had various comparison to only 56% in the previous study. During the
pre-existing diseases. The number of patients with neuro- later time period the liquid culture system BACTEC was
logical sequelae in this study (50%) was higher compared used routinely, which may explain the apparent increase in
to that (30%) found in the earlier study (2). The duration sensitivity. However, in the initial phase of Tm the micro-
of symptoms before hospitalization appeared to be related biology laboratory has little to offer the clinician. Most
to neurological sequelae. Early diagnosis and prompt ini- important diagnostically were the clinical symptoms and
tiation of therapy are considered crucial to prevent an the biochemical CSF ndings. Information about the eth-
adverse outcome. In half of the patients the presenting nic origin of the patient and exposure to tuberculosis was
symptoms were comparable to those of purulent meningi- essential for making a clinical diagnosis. Surprisingly, 8:19
tis caused by other bacteria, e.g. neck stiffness, headache, patients (42%) presented a normal CT scan.
confusion and fever. However, the duration of symptoms In conclusion, Tm is a rare but still serious infectious
was generally longer than is usually the case for purulent disease. The 20 cases analysed retrospectively exhibited a
meningitis. A variety of less speci c symptoms, such as mortality of 20% and 50% of patients had permanent
dizziness, changes in personality and even gastrointestinal sequelae; these values are essentially unchanged compared
symptoms, were also common. None of the symptoms to the results from a study conducted 12 y previously in
were de nitively predictive of outcome although rapid the same department. In the initial phase of Tm the diag-
progression of symptoms and the neurological status on nosis is still mainly a clinical one and should be consid-
admission (coma and stupor) seemed to be related to ered in patients originating from countries with a high
mortality. The median delay in treatment was 5 d, which endemicity of tuberculosis and in elderly patients with
is 5 d less than in the earlier study from this department neurological symptoms and spinal pleocytosis.
814 C. Bidstrup et al. Scand J Infect Dis 34