revue neurologique 170 (2014) 512–519
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General review
Risk assessment of the outcome for cerebral infarction in tuberculous meningitis L’e´valuation des risques a` l’issue de l’infarctus ce´re´bral dans la me´ningite tuberculeuse C.-H. Chen a,*,f, Y.-J. Chang b, H.-N. Sy c, W.L. Chen d, H.-C. Yen e a
Division of infectious disease, department of internal medicine, Changhua-Christian hospital, 135, Nanhsiau street, Changhua, Taiwan, Republic of China b Laboratory of epidemiology and biostatistics, Changhua-Christian hospital, 135, Nanhsiau street, Changhua, Taiwan, Republic of China c Department of neurology, Changhua-Christian hospital, 135, Nanhsiau street, Changhua, Taiwan, Republic of China d Department of medical imaging, Changhua-Christian hospital, 135, Nanhsiau street, Changhua, Taiwan, Republic of China e Department of neurosurgery, Changhua-Christian hospital, 135, Nanhsiau street, Changhua, Taiwan, Republic of China f Department of Nursing, College of Medicine & Nursing, Hung Kuang University, Taichung, Republic of China
info article
abstract
Article history:
Introduction. – Cerebral infarction in tuberculous meningitis is a major risk factor for per-
Received 17 February 2014
manent disability. This study assessed the clinical presentation of tuberculous meningitis
Received in revised form
and risks factors for cerebral infarction.
10 May 2014
Observation. – Thirty-eight adult patients with tuberculous meningitis were studied be-
Accepted 18 June 2014
tween 2002 and 2006. Clinical, radiological, and laboratory data of patients with cerebral
Available online 5 September 2014
infarction were compared with those of patients without cerebral infarction. Patients with
Keywords:
scores (3.7 vs 2.2), and more often had basal meningeal enhancement on imaging (92.3% vs
cerebral infarction were significantly older (65.1 vs 52.1 years), had higher risk assessment Tuberculosis
60.0%), mild to moderate sequelae (69.2% vs 4%), an overall poor brain outcome (69.2% vs 8%),
Meningitis
aspirin prescription (84% vs 8%), and neurosurgical intervention for hydrocephalus (54.0% vs
Cerebral infarction
16.0%). Cerebral infarction patients were also more likely to have experienced doctor-related
Outcome
delays in antituberculosis (61.5% vs 36%) and corticosteroid (61.5% vs 32%) therapy.
Risk assessment
Discussion and conclusion. – The Framingham risk score would be an option for tuberculous
Mots cle´s :
helpful for exploring basal meningeal enhancement, in order to obtain an early diagnosis.
meningitis patients to access cerebral infarction risk. Contrast-enhanced brain imaging is Tuberculose
Antituberculosis, corticosteroid, and aspirin therapies should be started immediately when
Me´ningite
tuberculous meningitis is suspected.
Infarctus ce´re´bral Re´sultats E´valuation des risques
* Corresponding author. E-mail address: [email protected] (C.-H. Chen). http://dx.doi.org/10.1016/j.neurol.2014.06.004 0035-3787/# 2014 Elsevier Masson SAS. All rights reserved.
# 2014 Elsevier Masson SAS. All rights reserved.
revue neurologique 170 (2014) 512–519
513
r e´ s u m e´ Introduction. – L’infarctus ce´re´bral dans la me´ningite tuberculeuse est un facteur de risque majeur d’incapacite´ permanente. Cette e´tude a e´value´ la pre´sentation clinique de la me´ningite tuberculeuse et les facteurs de risque d’infarctus ce´re´bral. Observations. – Les cas de trente-huit patients adultes atteints de me´ningite tuberculeuse ont e´te´ e´tudie´s entre 2002 et 2006. Les donne´es de laboratoire et celles cliniques et radiologiques des patients avec un infarctus ce´re´bral ont e´te´ compare´es a` celles des patients sans infarctus ce´re´bral. Les patients avec un infarctus ce´re´bral e´taient significativement plus aˆge´s (65,1 contre 52,1 anne´es), avaient des scores plus e´leve´s dans l’e´valuation des risques (3,7 vs 2,2), avaient le plus souvent vu une ame´lioration me´ninge´e fondamentale sur l’imagerie (92,3 % vs 60,0 %), des se´quelles de le´ge`res a` mode´re´es (69,2 % contre 4 %), un re´sultat global me´diocre du cerveau (69,2 % contre 8 %), une prescription d’aspirine (84 % contre 8 %) et une intervention neurochirurgicale pour hydroce´phalie (54,0 % contre 16,0 %). Les patients ayant subi un infarctus ce´re´bral e´taient e´galement plus susceptibles de profiter en retard d’une the´rapie antituberculeuse (61,5 % contre 36 %) et corticoste´roı¨de (61,5 % contre 32 %) de´cide´e par des me´decins expe´rimente´s. Discussion et conclusion. – Le score de risque de Framingham serait une option pour les patients atteints de me´ningite tuberculeuse pour acce´der au risque d’infarctus ce´re´bral. Le renforcement du contraste en imagerie ce´re´brale est utile pour explorer l’ame´lioration me´ninge´e fondamentale et ce, afin d’obtenir un diagnostic pre´coce. Des the´rapies antituberculeuses, a` base de corticoı¨des ou d’aspirine, doivent eˆtre lance´es de`s qu’une me´ningite tuberculeuse est suspecte´e. # 2014 Elsevier Masson SAS. Tous droits re´serve´s.
1.
Introduction
Tuberculous meningitis (TBM) is the most frequent cause of subacute or chronic meningitis [1,2] and is estimated to constitute 1.5–5% of cases of tuberculosis (TB) in Taiwan [3]. TBM remains a catastrophic illness with significant neurological sequelae. The neurological complications of TBM are diverse, and include hydrocephalus, vasculitis, cranial neuropathies, epilepsy, dementia, and cerebral infarction (CI) [4–7]. Computed tomography (CT) scanning studies show infarctions in 17% to 63% of patients with TBM [8,9]. CI is also a major risk factor for permanent disability [10–12], and the prevention of this complication is an important issue in TBM patients. Infarct is a poor prognostic predictor in children with TBM [13]. Although many studies have evaluated CI in TBM [10,12,14–17], most have been radiological studies, and only a few have focused on the correlations between CI and clinical factors in TBM patients [6,11,17]. No comprehensive study has conducted a risk assessment for CI in patients with TBM [10,12,17]. Furthermore, the underlying mechanisms of CI in TBM are not yet fully understood, and the most effective means of prevention remains unknown. Therefore, we compared the clinical characteristics of TBM patients with and without CI, and determined the risk factors for CI in TBM patients.
2.
Patients and methods
2.1.
Inclusion criteria
Changhua Christian Hospital (CCH). CCH, an 1800-bed medical centre situated in central Taiwan, provides both primary care and referred care in Taiwan. From January 2002 through to December 2009, hospitalized patients aged over 18 years and diagnosed with TBM were recruited. Inclusion criteria were based on clinical, radiological, and mycobacterial data [17]. The diagnosis of TBM was established on the basis of the presence of symptoms and/or signs suggestive of meningitis and, for a definitive diagnosis, a positive culture for Mycobacterium tuberculosis, and a positive smear for acid-fast bacilli (AFB) from cerebrospinal fluid (CSF). The criteria for presumptive diagnosis were: positive M. tuberculosis culture, positive smear for AFB, or positive polymerase chain reaction from another body fluid; tissue-proven TB involvement of other organs; negative CSF culture for virus, bacteria, and fungi, plus clinical response to empirical antituberculosis therapy. Brain CT and/or magnetic resonance imaging (MRI) studies were performed on admission, according to the discretion of the physician, and follow-up brain images were obtained within 3 months of admission for all patients. Patients also underwent repeated brain imaging when neurological deterioration occurred during hospitalization. Exclusion criteria included concomitant positive findings for other CNS infections or malignancy, previous receipt of antituberculosis therapy, and failure to undergo brain imaging studies.
2.2.
The study was approved by the institutional review board of Changhua Christian Hospital. This study was carried out at the
Evaluation and investigation
The diagnosis of symptomatic CI secondary to TBM was based on new-onset acute neurological deficits demonstrated to be due to new infarction by brain imaging analysis. The
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definitions of silent CI, lacunar infarction (LI), and large artery infarction (LAI) were those used in previous studies [17–19]. Severity of stroke was defined according to the Canadian Neurological Scale [20]. The severity of meningitis was graded as stage I (meningitis only), stage II (meningitis with focal signs without alteration in sensorium), and stage III (meningitis with altered sensorium) [21]. Concomitant diseases included hypertension, chronic kidney disease, diabetes, hyperlipidemia, pre-existing cardiovascular disease, and previous stroke. Hypertension, chronic kidney disease, diabetes, and hyperlipidemia were defined according to previous recommendations [22–25]. Stroke, heart failure, atrial fibrillation, and congestive heart failure were identified by history taking and medical chart review. We calculated the Framingham risk scores [26]. Neurological status on admission was classified according to the staging system established by the Medical Research Council [21]. In stage I, patients were fully conscious and had no focal neurological signs. In stage II, patients were confused or had focal neurological signs, such as cranial nerve palsies or hemiparesis. In stage III, patients were comatose or had dense hemiplegia or paraplegia. We used the definition of delay previously reported in Sheu’s study [17]. Patient delay was defined as the interval between the onset of symptoms and initial presentation to the hospital. Doctor delay of antituberculosis therapy was defined as the interval between the initial presentation to the hospital and the start of antituberculosis therapy. Doctor delay of steroid therapy was defined as the interval between the initial presentation to the hospital and the start of steroid therapy. Prolonged delay was defined as a delay greater than the median.
2.3.
Treatment and follow-up
Patients were treated with a 4-drug antitubercular daily regimen according to the recommendations of the World Health Organization [27]. All 4 drugs were continued for 2 months, and were followed by a combination of 3 drugs (isoniazid, rifampicin, and ethambutol) for 10–16 months. A course of systemic corticosteroids (dexamethasone 12–16 mg/ day or prednisolone 60–80 mg/day initially with gradual tapering) for 6 weeks to 2 months was provided for patients with stage II or III neurological status on presentation, those exhibiting clinical deterioration during hospitalization, and those with conspicuous basal meningeal enhancement on brain images. Aspirin was prescribed only to patients with suspected CI (if not contraindicated). The outcomes at discharge were classified into 4 categories: complete recovery; mild to moderate sequelae (unaided or aided gait, mild mental impairment, independent or partially independent for activities of daily living); severe sequelae (wheelchair-bound, bedridden, severe mental impairment, totally dependent for activities of daily living); death. For the statistical analysis, we regarded mild to moderate sequelae and severe sequelae as poor brain outcomes.
2.4.
Statistical analysis
We compared clinical, neuroradiological, and CSF data between patients with and without CI. The x2 or Fisher’s exact test was used for binary variables, and Student’s t test was employed for age comparisons between the 2 groups. As patient delay, doctor delay of antituberculosis therapy, doctor delay of corticosteroid therapy, and total delay were not normally distributed, the non-parametric Mann–Whitney test was used to compare differences in the delays between the 2 groups. Odds ratios (ORs) and their corresponding 95% confidence intervals were also estimated using ordinary logistic regression. After univariate estimates were calculated, ORs were obtained in multivariate models including all independent variables. A P value of < 0.05 was considered to be statistically significant. All data were analyzed using SPSS software (version 17).
3.
Results
Thirty-eight TBM patients were enrolled. Of these, 13 (34.2%) had diabetes mellitus, 2 (5.2%) were human immunodeficiency virus-positive, and 2 (5.2%) had non-CNS malignancies. Of the 38 TBM patients, CI was noted in 13 (34.2%) patients (eleven with definite TBM and 2 with presumptive TBM). Of the 13 patients with CI, 8 exhibited symptomatic CI that had occurred before admission, and 5 had silent CI. Five (38.5%) of the 13 CI patients had single CI and the other 8 (61.5%) had multiple CI. The locations of single infarctions were basal ganglia (2), cortical area (1), internal capsule (1), and subcortical area (1). Nine (69.2%) of the 13 CI patients had LI, and the other 4 (30.8%) had LAI.
3.1.
Description of symptomatic CI
In the 8 TBM patients who had symptomatic CI occurring before admission, the interval between the onset of symptoms and initial presentation was 1–124 (median 10) days. Of these 8 patients, 7 had LI, and the other had LAI. All 8 patients had headache, fever, and alteration in consciousness, and 7 had meningeal signs. However, only 5 of these 8 patients were diagnosed with CNS infection, while the other 3 were diagnosed with stroke on admission. Five patients were examined using non-contrast brain CT or MRI studies on admission, and 4 of these 5 patients showed meningeal enhancement on follow-up contrast-enhanced brain images during hospitalization. The other 3 patients were examined using contrast-enhanced brain CT or MRI studies on admission, and all showed meningeal enhancement. Five patients had hydrocephalus that was detected by brain CT or MRI studies on admission, while the other 3 had no hydrocephalus. These 5 patients developed hydrocephalus during hospitalization, which was identified using the follow-up brain images.
3.2.
Risk assessment
Table 1 summarizes the important clinical, neuroradiological, and CSF findings in the CI and non-CI groups. When compared
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Table 1 – Comparison of clinical, neuroradiological, and laboratory findings between the cerebral infarction (CI) and nonCI groups.
Male sex Mean age (years) ( SD) Age > 60 years Underlying diseases and risk assessment Hypertension Diabetes mellitus Previous cardiovascular diseases Smoking Atrial fibrillation by history BMI 24 kg/m 2 24 BMI 35 kg/m 2 BMI 35 kg/m 2 Alcohol intake Framingham risk score (mean, SD) Clinical presentation Stage I on admission Fever on admission Headache on admission Altered consciousness on admission Focal weakness on admission Neuroradiological findings Basal meningeal enhancement Hydrocephalus Tuberculoma Spinal involvement Laboratory data CSF white cell count (cell/mm3) (mean, SD) CSF% lymphocytes (mean, SD) CSF protein (mg/dL) (mean, SD) CSF/blood glucose (mean, SD) CSF response (day 14 vs day 1) (mean, SD)
CI group
Non-CI group
Total
n = 13 (%)
n = 25 (%)
n = 38
8 (61.5) 65.1 9.9 9 (69.2)
17 (68.0) 52.1 19.8 8 (32.0)
25
10 (76.9) 5 (38.5) 3 (23.1) 4/8 (50) 3/8 (37.5) 2/8 (25) 4/8 (50) 2/8 (25) 6/10 (60) 3.7 0.5
12 (48.0) 8 (32.0) 3 (12.0) 5/16 (31.3) 2/16 (12.5) 4/16 (36.4) 5/16 (45.5) 2/16 (18.2) 12/23 (52.2) 2.2 0.5
22 13 6 9/24 5/24 6 9 4 18/33
5 (38.5) 11 (84.6) 9 (69.2) 9 (69.2) 8 (61.5)
8 (32.0) 22 (88.0) 15 (60.0) 16 (64.0) 4 (16.0)
12/13 (92.3) 10 (76.9) 1 (7.7) 0
15/25 (60.0) 11 (44.0) 3 (12.0) 1 (4.0)
175.3 204.0
187 165.0
0.849
83.4 32.6 207.4 109.8 0.25 0.22 94 175.1
80.4 30.6 177.4 82.8 0.22 0.20 90 155.2
0.781 0.350 0.674 0.943
P value
Univariate logistic regression analysis
95% confidence interval
P value
0.900
0.246–3.297
0.874
0.722 60 years Clinical status Patient delay (days), mean (range) Doctor delay of antituberculosis therapy (days), mean (range) Prolonged doctor delay of antituberculosis therapy (> 6 days) Total delay (days), mean (range) Corticosteroid therapy Doctor delay of corticosteroid therapy (days), mean (range) Prolonged doctor delay of corticosteroid therapy (> 8 days) Aspirin prescription Hydrocephalus Neurosurgical intervention Outcome at discharge Recovery of neurological symptoms (discharge day) Mild to moderate sequelae Severe sequelae Overall poor brain sequelae Overall death Death (30 days), due to TBM Death, due to underlying cardiovascular disease Death, uncertain relationship Laboratory data CSF response (day 14 vs day 1) (mean, SD) Neuroimaging findings Basal meningeal enhancement Tuberculoma
CI group
Non-CI group
Total
n = 13 (%)
n = 25 (%)
n = 38
8 (61.5) 65.1 9.9 9 (68.2)
17 (68.0) 52.1 19.8 8 (32.0)
25
10 (1–124) 8 (0–33)
9 (1–91) 4 (0–37)
8 (61.5)
9 (36.0)
17
0.009
19 (1–124) 8 (61.5) 9 (0–33)
17 (1–91) 16 (64.0) 7 (0–27)
24 16
0.459 1.000 0.589
8 (61.5)
8 (32.0)
16
11 (84.0) 10 (76.9) 7 (54.0)
2 (8.0) 11 (44.0) 4 (16.0)
4 (30.7) 9 3 9 4 2 1
(69.2) (23.0) (69.2) (30.8) (15.0) (8.0)
1 (8.0) 94 175.1 12 (92.3) 1 (7.7)
P value
Univariate logistic regression analysis
95% confidence interval
P value
0.900
0.246–3.297
0.874
1.667
0.164–14.210
0.650
0.048
1.879
0.274–11.230
0.750
13 21 11
< 0.001 0.086 0.024
3.067
0.184–15.150
0.005
1.056
0.234–9.181
0.025
3 (12.0)
7
0.052
1 2 2 4 3 0
10 5 11 8 5 1
0.002 0.538 0.011 0.407 1.000 0.342
2.067
0.174–13.130
0.045
0.879
0.284–11.130
0.650
2
1.000
1.167
0.384–13.130
0.065
(4.0) (8.0) (8.0) (16.0) (12.0)
1 (4.0)
20
0.389 0.478
90 155.2 15 (60.0) 3 (12.0)
Odds ratio 0.730 0.049 0.032
0.943 27 4
0.060 1.000
TBM: tuberculous meningitis; CSF: cerebrospinal fluid; SD: standard deviation.
for hydrocephalus (OR = 1.056, 95% confidence interval = 0.234– 9.181, P = 0.025), and mild to moderate sequelae (OR = 2.067, 95% confidence interval = 0.174–13.130, P = 0.045) were significantly higher in the CI group.
4.
Discussion
This the first study to evaluate the risk factors and clinical outcomes of CI in TBM patients in central Taiwan. In this study, 34.2% of patients with TBM experienced stroke, and stroke was associated with poor outcome at 3 months. The frequency of stroke in TBM patients has been reported to be between 28% and 50% [28–32]. This wide variation in the frequency of infarction in TBM patients may be due to differences in patient populations and methodologies. In our study, transient ischemic attack, reversible ischemic neurologic deficit, or stuttering progression of cerebrovascular accident were present in 30% of patients, based on clinical presentation and radiological findings; this rate is similar to that of a previous report [33].
In our study, however, 8 patients had acute hemiplegia or hemiparesis on admission, whereas 5 had hospital-onset focal weakness or no focal weakness. It is possible that in the presence of the more striking features of altered sensorium, headache, and vomiting, a mild or even significant weakness may escape the attention of patients or their families. CI secondary to TBM can be silent or symptomatic; in cases of the latter, it occurs as a presenting feature on admission or during hospitalization. In addition, 9 of these 13 CI patients had LI, and 6 of the 9 patients with LI showed altered consciousness; this is not the usual presentation of LI. These unusual characteristics of CI should remind clinicians of the possibility of other etiologies of stroke, such as CNS infection. Similar to the results of Chan et al., 10 of 19 (63.3%) patients had multiple CIs in our study. However, only 4 of these 19 patients were symptomatic. We recommend routine follow-up brain images for the detection of sub-clinical CI in TBM patients with cognitive impairment. Patients with CI were, on average, older than patients without CI in this study. This finding is consistent with the results of the CHADS2 index [34]. However, Srikanth et al.
revue neurologique 170 (2014) 512–519
found strong inflammatory responses to M. tuberculosis in the CSF space resulting from an inflammatory exudate produced within the subarachnoid cisterns in younger patients; in their study, patients with CI were younger than those without CI [35]. Inflammatory exudate in the basal cisterns of young patients is presumed to cause strangulation, spasm, constriction, arteritis, and eventual thrombosis of the vessels of the circle of Willis, which may lead to CI [14,36]. We agree that age is a risk factor for CI [34], as supported by our findings. As compared with patients with atherothrombotic CI [37], TBM patients with CI were older (mean age, 65.1 years) and had longer duration of symptoms (median, 10 days). Our study showed that the triad of neuroradiological findings (basal meningeal enhancement, hydrocephalus, and CI) of TBM are highly correlated; this is similar to the findings of previous studies [15,16,38]. Thus, the poor outcomes of patients with CI may be related to CI itself, associated hydrocephalus, or combination of both [15]. Hydrocephalus on presentation was found to indicate a higher risk of CI on follow-up brain images [12], and dilated ventricles were thought to stretch the compromised vessel and aggravate cerebral ischemia. However, our study showed that 10 of 13 patients with CI had hydrocephalus at presentation, while 12 of these 13 patients showed meningeal enhancement on brain images. There is no evidence to suggest that neurosurgical intervention for hydrocephalus can prevent CI in TBM [39]. The role of hydrocephalus in the pathogenesis of CI in TBM needs further study. Our study showed an association between doctor delay of antituberculosis therapy and the risk of CI, and this result is compatible with those of Sheu at al. [17]. Although there was wide range of intervals between presentation and the initiation of antituberculosis therapy in our study due to the non-specific and highly variable presentations of TBM, we strongly recommend that early empirical antituberculosis therapy should be considered when persistent fever or deteriorated consciousness occurs during the initial stages of empirical antibacterial therapy. The frequency of stroke and hydrocephalous has been shown to reduce after corticosteroid therapy [40], although inflammatory markers were found to be unaffected by corticosteroid treatment in experimental studies [41]. Although there was no significant difference in the use of corticosteroid therapy between the CI and non-CI patients in our study, the rationale for the use of adjuvant corticosteroids lies in reducing the harmful effects of inflammation in the subarachnoid space [42]. Although adjuvant corticosteroid therapy can improve survival in TBM patients regardless of disease severity, its effect in preventing CI or alleviating infarct-causing periarteritis remains controversial [41,43,44]. It is mandatory to start 3 combined regimens, consisting of a standard antituberculosis regimen plus adjuvant corticosteroid plus aspirin, when TBM is suspected [45]. Our study has several strengths. Most importantly, the strengths of this study lie in the quality and near complete variables of risk assessment for CI in patients with TBM using the dataset of CCH. The geographic data and demographic information of TBM had been previously reported, and the results varied. Our validated data showed the risk assessment for CI in patients with TBM. Second, as shown in Table 1, 38.5% of patients with CI presented with stage I disease, and 32.0% of
517
patients without CI presented with stage I disease. Thus, our study included patients with a diversity of disease severity. In addition, CCH provides both primary care and referred care in central Taiwan, and hence, our study may be representative of TBM patients in other Taiwanese locations. Third, we found an association between doctor delay of corticosteroid therapy and risk of CI among corticosteroid-treated patients, although a causal relationship could not be established in this retrospective study. The role of corticosteroids in the prevention of CI secondary to TBM deserves investigation in further prospective studies. There are some important limitations to this study. First, there may have been selection bias present because of the retrospective nature of the study. Additionally, the causal relationship between corticosteroid treatment and CI in TBM could not be precisely established in this retrospective study. TBM patients with CI were found to be older than those without CI, and CI was associated with:
higher Framingham risk score; focal weakness on presentation; aspirin therapy; neurosurgical intervention; mild to moderate sequelae.
We strongly recommend using the Framingham risk score for each patient with TBM to determine their risk of CI attack. Contrast-enhanced brain imaging is helpful for exploring basal meningeal enhancement in CI patients, and can help to expedite diagnosis and treatment of TBM. Furthermore, antituberculosis drugs, corticosteroids, and aspirin should be started immediately when TBM is suspected.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Acknowledgements All authors thank the assistant of Department of Information Systems of Changhua-Christian Hospital. This research project would not have been possible without the support of many people. All authors wish to express their gratitude to staffs of Division of Infectious Diseases and Department of Neurology of Changhua Christian Hospital who were abundantly helpful and offered patient care, invaluable assistance, and support.
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General review
Risk assessment of the outcome for cerebral infarction in tuberculous meningitis L’e´valuation des risques a` l’issue de l’infarctus ce´re´bral dans la me´ningite tuberculeuse C.-H. Chen a,*,f, Y.-J. Chang b, H.-N. Sy c, W.L. Chen d, H.-C. Yen e a
Division of infectious disease, department of internal medicine, Changhua-Christian hospital, 135, Nanhsiau street, Changhua, Taiwan, Republic of China b Laboratory of epidemiology and biostatistics, Changhua-Christian hospital, 135, Nanhsiau street, Changhua, Taiwan, Republic of China c Department of neurology, Changhua-Christian hospital, 135, Nanhsiau street, Changhua, Taiwan, Republic of China d Department of medical imaging, Changhua-Christian hospital, 135, Nanhsiau street, Changhua, Taiwan, Republic of China e Department of neurosurgery, Changhua-Christian hospital, 135, Nanhsiau street, Changhua, Taiwan, Republic of China f Department of Nursing, College of Medicine & Nursing, Hung Kuang University, Taichung, Republic of China
info article
abstract
Article history:
Introduction. – Cerebral infarction in tuberculous meningitis is a major risk factor for per-
Received 17 February 2014
manent disability. This study assessed the clinical presentation of tuberculous meningitis
Received in revised form
and risks factors for cerebral infarction.
10 May 2014
Observation. – Thirty-eight adult patients with tuberculous meningitis were studied be-
Accepted 18 June 2014
tween 2002 and 2006. Clinical, radiological, and laboratory data of patients with cerebral
Available online 5 September 2014
infarction were compared with those of patients without cerebral infarction. Patients with
Keywords:
scores (3.7 vs 2.2), and more often had basal meningeal enhancement on imaging (92.3% vs
cerebral infarction were significantly older (65.1 vs 52.1 years), had higher risk assessment Tuberculosis
60.0%), mild to moderate sequelae (69.2% vs 4%), an overall poor brain outcome (69.2% vs 8%),
Meningitis
aspirin prescription (84% vs 8%), and neurosurgical intervention for hydrocephalus (54.0% vs
Cerebral infarction
16.0%). Cerebral infarction patients were also more likely to have experienced doctor-related
Outcome
delays in antituberculosis (61.5% vs 36%) and corticosteroid (61.5% vs 32%) therapy.
Risk assessment
Discussion and conclusion. – The Framingham risk score would be an option for tuberculous
Mots cle´s :
helpful for exploring basal meningeal enhancement, in order to obtain an early diagnosis.
meningitis patients to access cerebral infarction risk. Contrast-enhanced brain imaging is Tuberculose
Antituberculosis, corticosteroid, and aspirin therapies should be started immediately when
Me´ningite
tuberculous meningitis is suspected.
Infarctus ce´re´bral Re´sultats E´valuation des risques
* Corresponding author. E-mail address: [email protected] (C.-H. Chen). http://dx.doi.org/10.1016/j.neurol.2014.06.004 0035-3787/# 2014 Elsevier Masson SAS. All rights reserved.
# 2014 Elsevier Masson SAS. All rights reserved.
revue neurologique 170 (2014) 512–519
513
r e´ s u m e´ Introduction. – L’infarctus ce´re´bral dans la me´ningite tuberculeuse est un facteur de risque majeur d’incapacite´ permanente. Cette e´tude a e´value´ la pre´sentation clinique de la me´ningite tuberculeuse et les facteurs de risque d’infarctus ce´re´bral. Observations. – Les cas de trente-huit patients adultes atteints de me´ningite tuberculeuse ont e´te´ e´tudie´s entre 2002 et 2006. Les donne´es de laboratoire et celles cliniques et radiologiques des patients avec un infarctus ce´re´bral ont e´te´ compare´es a` celles des patients sans infarctus ce´re´bral. Les patients avec un infarctus ce´re´bral e´taient significativement plus aˆge´s (65,1 contre 52,1 anne´es), avaient des scores plus e´leve´s dans l’e´valuation des risques (3,7 vs 2,2), avaient le plus souvent vu une ame´lioration me´ninge´e fondamentale sur l’imagerie (92,3 % vs 60,0 %), des se´quelles de le´ge`res a` mode´re´es (69,2 % contre 4 %), un re´sultat global me´diocre du cerveau (69,2 % contre 8 %), une prescription d’aspirine (84 % contre 8 %) et une intervention neurochirurgicale pour hydroce´phalie (54,0 % contre 16,0 %). Les patients ayant subi un infarctus ce´re´bral e´taient e´galement plus susceptibles de profiter en retard d’une the´rapie antituberculeuse (61,5 % contre 36 %) et corticoste´roı¨de (61,5 % contre 32 %) de´cide´e par des me´decins expe´rimente´s. Discussion et conclusion. – Le score de risque de Framingham serait une option pour les patients atteints de me´ningite tuberculeuse pour acce´der au risque d’infarctus ce´re´bral. Le renforcement du contraste en imagerie ce´re´brale est utile pour explorer l’ame´lioration me´ninge´e fondamentale et ce, afin d’obtenir un diagnostic pre´coce. Des the´rapies antituberculeuses, a` base de corticoı¨des ou d’aspirine, doivent eˆtre lance´es de`s qu’une me´ningite tuberculeuse est suspecte´e. # 2014 Elsevier Masson SAS. Tous droits re´serve´s.
1.
Introduction
Tuberculous meningitis (TBM) is the most frequent cause of subacute or chronic meningitis [1,2] and is estimated to constitute 1.5–5% of cases of tuberculosis (TB) in Taiwan [3]. TBM remains a catastrophic illness with significant neurological sequelae. The neurological complications of TBM are diverse, and include hydrocephalus, vasculitis, cranial neuropathies, epilepsy, dementia, and cerebral infarction (CI) [4–7]. Computed tomography (CT) scanning studies show infarctions in 17% to 63% of patients with TBM [8,9]. CI is also a major risk factor for permanent disability [10–12], and the prevention of this complication is an important issue in TBM patients. Infarct is a poor prognostic predictor in children with TBM [13]. Although many studies have evaluated CI in TBM [10,12,14–17], most have been radiological studies, and only a few have focused on the correlations between CI and clinical factors in TBM patients [6,11,17]. No comprehensive study has conducted a risk assessment for CI in patients with TBM [10,12,17]. Furthermore, the underlying mechanisms of CI in TBM are not yet fully understood, and the most effective means of prevention remains unknown. Therefore, we compared the clinical characteristics of TBM patients with and without CI, and determined the risk factors for CI in TBM patients.
2.
Patients and methods
2.1.
Inclusion criteria
Changhua Christian Hospital (CCH). CCH, an 1800-bed medical centre situated in central Taiwan, provides both primary care and referred care in Taiwan. From January 2002 through to December 2009, hospitalized patients aged over 18 years and diagnosed with TBM were recruited. Inclusion criteria were based on clinical, radiological, and mycobacterial data [17]. The diagnosis of TBM was established on the basis of the presence of symptoms and/or signs suggestive of meningitis and, for a definitive diagnosis, a positive culture for Mycobacterium tuberculosis, and a positive smear for acid-fast bacilli (AFB) from cerebrospinal fluid (CSF). The criteria for presumptive diagnosis were: positive M. tuberculosis culture, positive smear for AFB, or positive polymerase chain reaction from another body fluid; tissue-proven TB involvement of other organs; negative CSF culture for virus, bacteria, and fungi, plus clinical response to empirical antituberculosis therapy. Brain CT and/or magnetic resonance imaging (MRI) studies were performed on admission, according to the discretion of the physician, and follow-up brain images were obtained within 3 months of admission for all patients. Patients also underwent repeated brain imaging when neurological deterioration occurred during hospitalization. Exclusion criteria included concomitant positive findings for other CNS infections or malignancy, previous receipt of antituberculosis therapy, and failure to undergo brain imaging studies.
2.2.
The study was approved by the institutional review board of Changhua Christian Hospital. This study was carried out at the
Evaluation and investigation
The diagnosis of symptomatic CI secondary to TBM was based on new-onset acute neurological deficits demonstrated to be due to new infarction by brain imaging analysis. The
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definitions of silent CI, lacunar infarction (LI), and large artery infarction (LAI) were those used in previous studies [17–19]. Severity of stroke was defined according to the Canadian Neurological Scale [20]. The severity of meningitis was graded as stage I (meningitis only), stage II (meningitis with focal signs without alteration in sensorium), and stage III (meningitis with altered sensorium) [21]. Concomitant diseases included hypertension, chronic kidney disease, diabetes, hyperlipidemia, pre-existing cardiovascular disease, and previous stroke. Hypertension, chronic kidney disease, diabetes, and hyperlipidemia were defined according to previous recommendations [22–25]. Stroke, heart failure, atrial fibrillation, and congestive heart failure were identified by history taking and medical chart review. We calculated the Framingham risk scores [26]. Neurological status on admission was classified according to the staging system established by the Medical Research Council [21]. In stage I, patients were fully conscious and had no focal neurological signs. In stage II, patients were confused or had focal neurological signs, such as cranial nerve palsies or hemiparesis. In stage III, patients were comatose or had dense hemiplegia or paraplegia. We used the definition of delay previously reported in Sheu’s study [17]. Patient delay was defined as the interval between the onset of symptoms and initial presentation to the hospital. Doctor delay of antituberculosis therapy was defined as the interval between the initial presentation to the hospital and the start of antituberculosis therapy. Doctor delay of steroid therapy was defined as the interval between the initial presentation to the hospital and the start of steroid therapy. Prolonged delay was defined as a delay greater than the median.
2.3.
Treatment and follow-up
Patients were treated with a 4-drug antitubercular daily regimen according to the recommendations of the World Health Organization [27]. All 4 drugs were continued for 2 months, and were followed by a combination of 3 drugs (isoniazid, rifampicin, and ethambutol) for 10–16 months. A course of systemic corticosteroids (dexamethasone 12–16 mg/ day or prednisolone 60–80 mg/day initially with gradual tapering) for 6 weeks to 2 months was provided for patients with stage II or III neurological status on presentation, those exhibiting clinical deterioration during hospitalization, and those with conspicuous basal meningeal enhancement on brain images. Aspirin was prescribed only to patients with suspected CI (if not contraindicated). The outcomes at discharge were classified into 4 categories: complete recovery; mild to moderate sequelae (unaided or aided gait, mild mental impairment, independent or partially independent for activities of daily living); severe sequelae (wheelchair-bound, bedridden, severe mental impairment, totally dependent for activities of daily living); death. For the statistical analysis, we regarded mild to moderate sequelae and severe sequelae as poor brain outcomes.
2.4.
Statistical analysis
We compared clinical, neuroradiological, and CSF data between patients with and without CI. The x2 or Fisher’s exact test was used for binary variables, and Student’s t test was employed for age comparisons between the 2 groups. As patient delay, doctor delay of antituberculosis therapy, doctor delay of corticosteroid therapy, and total delay were not normally distributed, the non-parametric Mann–Whitney test was used to compare differences in the delays between the 2 groups. Odds ratios (ORs) and their corresponding 95% confidence intervals were also estimated using ordinary logistic regression. After univariate estimates were calculated, ORs were obtained in multivariate models including all independent variables. A P value of < 0.05 was considered to be statistically significant. All data were analyzed using SPSS software (version 17).
3.
Results
Thirty-eight TBM patients were enrolled. Of these, 13 (34.2%) had diabetes mellitus, 2 (5.2%) were human immunodeficiency virus-positive, and 2 (5.2%) had non-CNS malignancies. Of the 38 TBM patients, CI was noted in 13 (34.2%) patients (eleven with definite TBM and 2 with presumptive TBM). Of the 13 patients with CI, 8 exhibited symptomatic CI that had occurred before admission, and 5 had silent CI. Five (38.5%) of the 13 CI patients had single CI and the other 8 (61.5%) had multiple CI. The locations of single infarctions were basal ganglia (2), cortical area (1), internal capsule (1), and subcortical area (1). Nine (69.2%) of the 13 CI patients had LI, and the other 4 (30.8%) had LAI.
3.1.
Description of symptomatic CI
In the 8 TBM patients who had symptomatic CI occurring before admission, the interval between the onset of symptoms and initial presentation was 1–124 (median 10) days. Of these 8 patients, 7 had LI, and the other had LAI. All 8 patients had headache, fever, and alteration in consciousness, and 7 had meningeal signs. However, only 5 of these 8 patients were diagnosed with CNS infection, while the other 3 were diagnosed with stroke on admission. Five patients were examined using non-contrast brain CT or MRI studies on admission, and 4 of these 5 patients showed meningeal enhancement on follow-up contrast-enhanced brain images during hospitalization. The other 3 patients were examined using contrast-enhanced brain CT or MRI studies on admission, and all showed meningeal enhancement. Five patients had hydrocephalus that was detected by brain CT or MRI studies on admission, while the other 3 had no hydrocephalus. These 5 patients developed hydrocephalus during hospitalization, which was identified using the follow-up brain images.
3.2.
Risk assessment
Table 1 summarizes the important clinical, neuroradiological, and CSF findings in the CI and non-CI groups. When compared
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Table 1 – Comparison of clinical, neuroradiological, and laboratory findings between the cerebral infarction (CI) and nonCI groups.
Male sex Mean age (years) ( SD) Age > 60 years Underlying diseases and risk assessment Hypertension Diabetes mellitus Previous cardiovascular diseases Smoking Atrial fibrillation by history BMI 24 kg/m 2 24 BMI 35 kg/m 2 BMI 35 kg/m 2 Alcohol intake Framingham risk score (mean, SD) Clinical presentation Stage I on admission Fever on admission Headache on admission Altered consciousness on admission Focal weakness on admission Neuroradiological findings Basal meningeal enhancement Hydrocephalus Tuberculoma Spinal involvement Laboratory data CSF white cell count (cell/mm3) (mean, SD) CSF% lymphocytes (mean, SD) CSF protein (mg/dL) (mean, SD) CSF/blood glucose (mean, SD) CSF response (day 14 vs day 1) (mean, SD)
CI group
Non-CI group
Total
n = 13 (%)
n = 25 (%)
n = 38
8 (61.5) 65.1 9.9 9 (69.2)
17 (68.0) 52.1 19.8 8 (32.0)
25
10 (76.9) 5 (38.5) 3 (23.1) 4/8 (50) 3/8 (37.5) 2/8 (25) 4/8 (50) 2/8 (25) 6/10 (60) 3.7 0.5
12 (48.0) 8 (32.0) 3 (12.0) 5/16 (31.3) 2/16 (12.5) 4/16 (36.4) 5/16 (45.5) 2/16 (18.2) 12/23 (52.2) 2.2 0.5
22 13 6 9/24 5/24 6 9 4 18/33
5 (38.5) 11 (84.6) 9 (69.2) 9 (69.2) 8 (61.5)
8 (32.0) 22 (88.0) 15 (60.0) 16 (64.0) 4 (16.0)
12/13 (92.3) 10 (76.9) 1 (7.7) 0
15/25 (60.0) 11 (44.0) 3 (12.0) 1 (4.0)
175.3 204.0
187 165.0
0.849
83.4 32.6 207.4 109.8 0.25 0.22 94 175.1
80.4 30.6 177.4 82.8 0.22 0.20 90 155.2
0.781 0.350 0.674 0.943
P value
Univariate logistic regression analysis
95% confidence interval
P value
0.900
0.246–3.297
0.874
0.722 60 years Clinical status Patient delay (days), mean (range) Doctor delay of antituberculosis therapy (days), mean (range) Prolonged doctor delay of antituberculosis therapy (> 6 days) Total delay (days), mean (range) Corticosteroid therapy Doctor delay of corticosteroid therapy (days), mean (range) Prolonged doctor delay of corticosteroid therapy (> 8 days) Aspirin prescription Hydrocephalus Neurosurgical intervention Outcome at discharge Recovery of neurological symptoms (discharge day) Mild to moderate sequelae Severe sequelae Overall poor brain sequelae Overall death Death (30 days), due to TBM Death, due to underlying cardiovascular disease Death, uncertain relationship Laboratory data CSF response (day 14 vs day 1) (mean, SD) Neuroimaging findings Basal meningeal enhancement Tuberculoma
CI group
Non-CI group
Total
n = 13 (%)
n = 25 (%)
n = 38
8 (61.5) 65.1 9.9 9 (68.2)
17 (68.0) 52.1 19.8 8 (32.0)
25
10 (1–124) 8 (0–33)
9 (1–91) 4 (0–37)
8 (61.5)
9 (36.0)
17
0.009
19 (1–124) 8 (61.5) 9 (0–33)
17 (1–91) 16 (64.0) 7 (0–27)
24 16
0.459 1.000 0.589
8 (61.5)
8 (32.0)
16
11 (84.0) 10 (76.9) 7 (54.0)
2 (8.0) 11 (44.0) 4 (16.0)
4 (30.7) 9 3 9 4 2 1
(69.2) (23.0) (69.2) (30.8) (15.0) (8.0)
1 (8.0) 94 175.1 12 (92.3) 1 (7.7)
P value
Univariate logistic regression analysis
95% confidence interval
P value
0.900
0.246–3.297
0.874
1.667
0.164–14.210
0.650
0.048
1.879
0.274–11.230
0.750
13 21 11
< 0.001 0.086 0.024
3.067
0.184–15.150
0.005
1.056
0.234–9.181
0.025
3 (12.0)
7
0.052
1 2 2 4 3 0
10 5 11 8 5 1
0.002 0.538 0.011 0.407 1.000 0.342
2.067
0.174–13.130
0.045
0.879
0.284–11.130
0.650
2
1.000
1.167
0.384–13.130
0.065
(4.0) (8.0) (8.0) (16.0) (12.0)
1 (4.0)
20
0.389 0.478
90 155.2 15 (60.0) 3 (12.0)
Odds ratio 0.730 0.049 0.032
0.943 27 4
0.060 1.000
TBM: tuberculous meningitis; CSF: cerebrospinal fluid; SD: standard deviation.
for hydrocephalus (OR = 1.056, 95% confidence interval = 0.234– 9.181, P = 0.025), and mild to moderate sequelae (OR = 2.067, 95% confidence interval = 0.174–13.130, P = 0.045) were significantly higher in the CI group.
4.
Discussion
This the first study to evaluate the risk factors and clinical outcomes of CI in TBM patients in central Taiwan. In this study, 34.2% of patients with TBM experienced stroke, and stroke was associated with poor outcome at 3 months. The frequency of stroke in TBM patients has been reported to be between 28% and 50% [28–32]. This wide variation in the frequency of infarction in TBM patients may be due to differences in patient populations and methodologies. In our study, transient ischemic attack, reversible ischemic neurologic deficit, or stuttering progression of cerebrovascular accident were present in 30% of patients, based on clinical presentation and radiological findings; this rate is similar to that of a previous report [33].
In our study, however, 8 patients had acute hemiplegia or hemiparesis on admission, whereas 5 had hospital-onset focal weakness or no focal weakness. It is possible that in the presence of the more striking features of altered sensorium, headache, and vomiting, a mild or even significant weakness may escape the attention of patients or their families. CI secondary to TBM can be silent or symptomatic; in cases of the latter, it occurs as a presenting feature on admission or during hospitalization. In addition, 9 of these 13 CI patients had LI, and 6 of the 9 patients with LI showed altered consciousness; this is not the usual presentation of LI. These unusual characteristics of CI should remind clinicians of the possibility of other etiologies of stroke, such as CNS infection. Similar to the results of Chan et al., 10 of 19 (63.3%) patients had multiple CIs in our study. However, only 4 of these 19 patients were symptomatic. We recommend routine follow-up brain images for the detection of sub-clinical CI in TBM patients with cognitive impairment. Patients with CI were, on average, older than patients without CI in this study. This finding is consistent with the results of the CHADS2 index [34]. However, Srikanth et al.
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found strong inflammatory responses to M. tuberculosis in the CSF space resulting from an inflammatory exudate produced within the subarachnoid cisterns in younger patients; in their study, patients with CI were younger than those without CI [35]. Inflammatory exudate in the basal cisterns of young patients is presumed to cause strangulation, spasm, constriction, arteritis, and eventual thrombosis of the vessels of the circle of Willis, which may lead to CI [14,36]. We agree that age is a risk factor for CI [34], as supported by our findings. As compared with patients with atherothrombotic CI [37], TBM patients with CI were older (mean age, 65.1 years) and had longer duration of symptoms (median, 10 days). Our study showed that the triad of neuroradiological findings (basal meningeal enhancement, hydrocephalus, and CI) of TBM are highly correlated; this is similar to the findings of previous studies [15,16,38]. Thus, the poor outcomes of patients with CI may be related to CI itself, associated hydrocephalus, or combination of both [15]. Hydrocephalus on presentation was found to indicate a higher risk of CI on follow-up brain images [12], and dilated ventricles were thought to stretch the compromised vessel and aggravate cerebral ischemia. However, our study showed that 10 of 13 patients with CI had hydrocephalus at presentation, while 12 of these 13 patients showed meningeal enhancement on brain images. There is no evidence to suggest that neurosurgical intervention for hydrocephalus can prevent CI in TBM [39]. The role of hydrocephalus in the pathogenesis of CI in TBM needs further study. Our study showed an association between doctor delay of antituberculosis therapy and the risk of CI, and this result is compatible with those of Sheu at al. [17]. Although there was wide range of intervals between presentation and the initiation of antituberculosis therapy in our study due to the non-specific and highly variable presentations of TBM, we strongly recommend that early empirical antituberculosis therapy should be considered when persistent fever or deteriorated consciousness occurs during the initial stages of empirical antibacterial therapy. The frequency of stroke and hydrocephalous has been shown to reduce after corticosteroid therapy [40], although inflammatory markers were found to be unaffected by corticosteroid treatment in experimental studies [41]. Although there was no significant difference in the use of corticosteroid therapy between the CI and non-CI patients in our study, the rationale for the use of adjuvant corticosteroids lies in reducing the harmful effects of inflammation in the subarachnoid space [42]. Although adjuvant corticosteroid therapy can improve survival in TBM patients regardless of disease severity, its effect in preventing CI or alleviating infarct-causing periarteritis remains controversial [41,43,44]. It is mandatory to start 3 combined regimens, consisting of a standard antituberculosis regimen plus adjuvant corticosteroid plus aspirin, when TBM is suspected [45]. Our study has several strengths. Most importantly, the strengths of this study lie in the quality and near complete variables of risk assessment for CI in patients with TBM using the dataset of CCH. The geographic data and demographic information of TBM had been previously reported, and the results varied. Our validated data showed the risk assessment for CI in patients with TBM. Second, as shown in Table 1, 38.5% of patients with CI presented with stage I disease, and 32.0% of
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patients without CI presented with stage I disease. Thus, our study included patients with a diversity of disease severity. In addition, CCH provides both primary care and referred care in central Taiwan, and hence, our study may be representative of TBM patients in other Taiwanese locations. Third, we found an association between doctor delay of corticosteroid therapy and risk of CI among corticosteroid-treated patients, although a causal relationship could not be established in this retrospective study. The role of corticosteroids in the prevention of CI secondary to TBM deserves investigation in further prospective studies. There are some important limitations to this study. First, there may have been selection bias present because of the retrospective nature of the study. Additionally, the causal relationship between corticosteroid treatment and CI in TBM could not be precisely established in this retrospective study. TBM patients with CI were found to be older than those without CI, and CI was associated with:
higher Framingham risk score; focal weakness on presentation; aspirin therapy; neurosurgical intervention; mild to moderate sequelae.
We strongly recommend using the Framingham risk score for each patient with TBM to determine their risk of CI attack. Contrast-enhanced brain imaging is helpful for exploring basal meningeal enhancement in CI patients, and can help to expedite diagnosis and treatment of TBM. Furthermore, antituberculosis drugs, corticosteroids, and aspirin should be started immediately when TBM is suspected.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Acknowledgements All authors thank the assistant of Department of Information Systems of Changhua-Christian Hospital. This research project would not have been possible without the support of many people. All authors wish to express their gratitude to staffs of Division of Infectious Diseases and Department of Neurology of Changhua Christian Hospital who were abundantly helpful and offered patient care, invaluable assistance, and support.
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