Original Contribution

Frequency and Impact of Cerebral Infarctions in

Patients With Tuberculous Meningitis
Mohammad Wasay, MD, FRCP; Maria Khan, FCPS, MSc; Salman Farooq, MBBS;
Zubair Ali Khowaja, MBBS; Zeeshan Ali Bawa, MBBS; Shehzad Mansoor Ali, MBBS, MPH;
Safia Awan, MSc; M. Asim Beg, MBBS, PhD, FRCP (Edin)

Background and Purpose—Cerebral infarctions complicate a variable proportion of tuberculous meningitis (TBM) cases
and adversely affect outcomes. The objective of this study was to evaluate the predictors of cerebral infarcts in patients
with TBM and to assess their impact on mortality.
Methods—The study was based on a retrospective chart review of all patients with TBM admitted to a tertiary care hospital
between 2002 and 2013. Data were collected on basic demographics, conventional vascular risk factors, radiological
findings, severity of TBM, and neurological outcomes. Data were analyzed using SPSS version 19.0. Binary logistic
regression was done to determine the factors predictive of cerebral infarcts and of mortality in patients with TBM.
Results—A total of 559 patients were admitted with TBM during the study period. Mean age was 41.9 years (SD,
17.7 years), and 47% were women. A quarter of the patients had stage III disease. One hundred forty-four (25.8%)
patients had cerebral infarcts on brain imaging of which 3 quarters were acute or subacute. Those with cerebral
infarcts were more likely to be >40 years of age (adjusted odds ratio [AOR], 1.7; 95% CI, 1.1–2.7) and to have
hypertension (AOR, 1.8; 95% CI, 1.1–2.8), dyslipidemia (AOR, 9.7; 95% CI, 3.8–24.8), and diabetes mellitus
(AOR, 2.2; 95% CI, 1.3–3.6). Presence of cerebral infarction was an independent predictor of mortality among
patients with TBM (AOR, 2.1; 95% CI, 1.22–3.5).
Conclusions—Cerebral infarcts complicate a substantial proportion of TBM cases. Conventional vascular risk factors are
the most important predictors of infarction, and future efforts need to focus on these high-risk patients with TBM to
reduce morbidity and mortality.   (Stroke. 2018;49:00-00. DOI: 10.1161/STROKEAHA.118.021301.)
Key Words: cerebral infarction ◼ diabetes mellitus ◼ risk factors ◼ stroke ◼ tuberculosis, meningeal

T uberculosis is a major contributor to global morbidity

and mortality and now ranks above HIV in this respect.1
There were ≈10.4 million incident cases of tuberculosis
worldwide in 2016 and ≈1.7 million tuberculosis deaths.2
Although there has been a decline in the burden related over
the years, South East Asia continues to harbor almost half of
all tuberculosis cases even today. Pakistan ranks fifth highest
in its tuberculosis burden and accounts for 5% of all global
tuberculosis cases.
Tuberculous meningitis (TBM) is one of the most severe
forms of extrapulmonary tuberculosis. Because of the diffi-
culty in diagnosis and under-reporting, the true burden of
TBM is not known; however, it is estimated to correlate with
the prevalence of tuberculosis overall.3 Cerebral infarctions
are a common complication observed in these patients, with
estimates ranging between 6% and 47%4 of all TBM cases.
Occurrence of infarction is one of the main predictors for per-
manent disability in these patients.5 In our recent review of
404 TBM cases, we reported a poor outcome associated with
presence of cerebral infarction on imaging.6
The mechanisms of infarction in patients with TBM, how-
ever, are not well understood. Several varying pathogeneses
are suggested for them including but not limited to vasculitis,
arterial thrombosis, and vascular proliferation.7 As a result,
despite infarctions being an important predictor of outcome in
TBM, no effective therapeutic strategy is agreed on for their
prevention. Both corticosteroids and acetyl salicylic acid have
been evaluated, and to date neither has been shown to be an
effective preventive therapy8,9 against infarctions.
The objective of our study was to evaluate the predic-
tors of cerebral infarction in patients with TBM to better un-
derstand potential mechanism of stroke in these patients. A
second objective was to evaluate the impact of these infarcts
on the morbidity and mortality of patients with TBM in this
larger sample. Identification of potential mechanisms may be
helpful to determination of potential treatment options.

Received February 23, 2018; final revision received July 10, 2018; accepted August 8, 2018.
From the Departments of Neurology (M.W., S.F.), Medicine (S.A.), Pathology and Microbiology (M.A.B.), Aga Khan University, Karachi, Pakistan;
Department of Neurology, Rashid Hospital, Dubai, United Arab Emirates (M.K.); Department of Physical Medicine and Rehabilitation, Institute of
Physical Medicine and Rehabilitation, Dow University of Health Sciences, Karachi, Pakistan (Z.A.K.); Department of Medicine, Ankleseria Hospital,
Karachi, Pakistan (Z.A.B.); and Department of Public Health, University of Texas Health Science, Houston (S.M.A.).
Correspondence to Mohammad Wasay, MD, Department of Neurology, Aga Khan University, Stadium Rd, Karachi-74800, Pakistan. Email mohammad.
wasay@aku.edu or mohammadwasay@hotmail.com
© 2018 American Heart Association, Inc.
Stroke is available at https://www.ahajournals.org/journal/str DOI: 10.1161/STROKEAHA.118.021301

1
2  Stroke  October 2018
Methods
All data can be made available from the corresponding author on
request.
Study Design and Subjects
The study was an analytic cross-sectional study, based on retrospec-
tive chart review. All subjects admitted to the Aga Khan University
hospital, Karachi, Pakistan, during a period of 12 years (2002–2013)
with a diagnosis of TBM were included. The following search terms
and International Classification of Diseases codes were used to iden-
tify cases from the medical records: (tuberculosis meningitis), 01320
to 01326 (tuberculosis brain), 01330 to 01336 (tuberculous abscess
of brain), 01380 to 01386 (other specified tuberculosis of central
nervous system), and 01390 to 01396 (unspecified tuberculosis of
central nervous system). Once these cases were identified, detailed
chart review was performed to collect information. The diagnostic
criteria for central nervous system tuberculosis that was used has al-
ready been highlighted in an earlier publication.6 Briefly, we included
patients if they had cerebrospinal fluid stain or culture positive for tu-
berculosis, or biopsy of the lesion showed the organism or caseation
and granuloma, or if they had biopsy or culture proven extracranial
tuberculosis with abnormal cerebrospinal fluid and enhancing brain
lesions on imaging, or if they had abnormal cerebrospinal fluid or
brain lesions that responded to antituberculosis treatment (ATT).
Study Variables and Definitions
Data were collected on the following variables:
• Basic demographics-age, sex
• Vascular risk factors:
◦◦ Hypertension: defined as blood pressure >140 systolic and
90 diastolic on repeated measurements during hospitaliza-
tion or if the patient was receiving antihypertensive medica-
tion at the time of hospital admission.
◦◦ Diabetes mellitus: self-reported history, or fasting glucose
level of ≥120 mg/dL, or if the patient was receiving oral hy-
poglycemic agents or insulin on admission.
◦◦ Dyslipidemia: fasting serum total cholesterol of ≥200 mg/
dL, and a serum low-density lipoproteins of ≥100 mg/dL,
and a serum high-density lipoproteins of ≤40 mg/dL, or if
the patient was receiving lipid-lowering drugs at admission.
◦◦ Smoking: smoking was considered a risk factor if the patient
had smoked ≥10 cigarettes daily for >10 years.
• HIV status of the patient
• Infarction was defined as an area of hypodensity in ≥1 arte-
rial territory on a noncontrast head computerized tomography
(CT). On magnetic resonance imaging (MRI), infarctions were
defined as abnormal signal intensity areas in ≥1 vascular ter-
ritories, without mass effect. They had to be hypointense on
T1-weighted images and hyperintense on T2-weighted as well
as fluid attenuated inversion recovery (FLAIR) sequences.10
All scans were read by a radiologist with expertise in neuroradiology.
• Severity of TBM at presentation was measured according to the
Modified British Research Council clinical criteria for TBM
severity.11
• Neurological disability was measured using modified Rankin
Scale12 at admission and at discharge.
Data Analysis
Data were analyzed using SPSS version 19. Descriptive statistics are
reported as medians with interquartile ranges for quantitative vari-
ables and as frequencies for categorical variables. Univariate logistic
regression was used to assess the association between presence of in-
farction and various risk factors, including severity of TBM. Variables
with a P<0.2 in univariate analysis were included for multivariate lo-
gistic regression. Stepwise logistic regression was then performed to
determine variables that were independently related to presence of
infarction in patients with TBM. Similar analysis was done to deter-
mine the predictors of mortality in patients with infarcts. In addition,
survival analysis was performed using log-rank test. P<0.05 was con-
sidered significant.
All patients admitted at Aga Khan University sign a consent that
their data could be used for research. This study was approved by eth-
ical review committee of Aga Khan University.
Results
A total of 559 patients were admitted to our hospital with
the diagnosis of TBM between January 2002 and December
2013. The mean age of these patients was 41.9 years (SD, 17.7
years), and 47% were women. Only 49 patients underwent
testing for HIV, and only 1 came back positive.
Distribution according to TBM grading was almost
equal for grades I and II (212, 37.9% and 211, 37.7%) re-
spectively. There were 136 (24.3%) participants in grade III.
Tuberculomas were present in 206 (36.9%) patients. Two
hundred fourteen patients (38.3%) had motor deficits at pre-
sentation (Table 1).
All patients received 4 drug regimen (ATT) including
rifampicin, isoniazid, ethambutol, and pyrazinamide in
standard doses for 3 to 4 months and then received 3 drug ATT
(excluding ethambutol or pyrizinamide) for 9 to 12 months.
ATT was partially or fully discontinued in 34 patients, largely
because of hepatotoxicity. More than 90% patients received
ATT for 1 year. Streptomycin was used in 44 patients in com-
bination with other ATT.
Radiological Features
All 559 patients underwent neuroimaging. Trained neurora-
diologists reviewed 661 first scans (CT=209; MRI=452), 105
second scans (CT=52; MRI=53), and 21 third scans (CT=14;
MRI=7). Magnetic resonance angiogram and magnetic reso-
nance venogram were done in only 67 patients. None of the
patients had CT angiogram or cerebral angiogram.
One hundred forty-four patients (25.8%) had cerebral
infarctions on brain imaging. One hundred five patients had
acute or subacute infarctions, meaning that they had devel-
oped while their TBM was active. The rest had chronic infarc-
tions. Twenty-five of the 105 patients did not have infarcts on
initial CT or MRI but developed them on follow-up scans.
Table 1.  Characteristics of TBM Patients With Cerebral Infarctions (n=144)
Age, y, mean (SD) 47.8 (17.5)
Male, n (%) 86 (59.7)
TBM grade, n (%)
 I 35 (24.3)
 II 60 (41.7)
 III 49 (34.0)
Active pulmonary tuberculosis, n (%) 84 (58.3)
Fever, n (%) 81 (56.3)
Seizures, n (%) 17 (11.8)
Positive previous chest x-ray for tuberculosis, n (%) 44 (30.6)
Lymph node tuberculosis, n (%) 2 (1.4)
Miliary tuberculosis, n (%) 5 (3.5)
TBM indicates tuberculous meningitis.
 Wasay et al   Cerebral Infarction in Tuberculous Meningitis   3

Of the 144 patients with infarctions, more than half had Table 3.  Factors Associated With Infarcts on Neuroimaging Among TBM Patients
multiple infarcts on imaging. Eighty percent of the lesions Univariate Multivariate
were located in supratentorial region. A majority of the infarcts
Unadjusted Adjusted
were located in subcortical white matter, with around one-fifth
Variable OR 95% CI OR 95% CI
of them located in basal ganglia/thalamus and brain stem/cer-
ebellum, respectively. Only 12.9% of the infarcts were located Hypertension 3.4 2.3–5.1 1.8 1.1–2.8
in lobar region. Tuberculomas, hydrocephalus, and basal en- Hyperlipidemia 11.7 4.9–27.7 8.4 3.4–20.8
hancement were other common findings in patients with in- Diabetes mellitus 3.3 2.2–5.0 2.0 1.2–3.3
farction (Table 2).
Age (41+ y) 2.7 1.8–4.0 1.7 1.1–2.7

Predictors of Cerebral Infarction Sex (female) 0.7 0.5–1.0 0.7 0.5–1.1

We compared the characteristics of the 144 patients with Active tuberculosis 1.7 1.1–2.5 1.5 1.0–2.3
infarcts on neuroimaging with those of 415 without infarcts. TBM indicates tuberculous meningitis.
Those with infarcts were significantly older (50 versus 35
years) and were significantly more likely to have conventional independent predictor of mortality among patients with TBM
risk factors like diabetes mellitus, hypertension, and dyslipid- (AOR, 2.1; 95% CI, 1.22–3.5).
emia. Five hundred twelve patients (91% of total TBM cases) Diabetes mellitus and presence of tuberculoma were inde-
received steroids for a period of 4 to 6 weeks. pendent predictors of mortality among patients with cerebral
Multivariable logistic regression showed age >40 years, infarcts. None of the radiological characteristics, including in-
hypertension (adjusted odds ratio [AOR]=1.7; 95% CI, farct location, basilar enhancement, and hydrocephalus, were
1.1–2.8), dyslipidemia (AOR=9.7; 95% CI, 3.8–24.8), and associated with mortality among patients with infarcts (Table 4).
diabetes mellitus (AOR=2.2; 95% CI, 1.3–3.6), to be inde- We also performed survival analysis using log-rank test
pendent predictors of infarcts when controlling for other but found no significant difference between the survival times
variables (Table 3). A large proportion of patients (58%) with of patients with and without infarction (Figure).
cerebral infarcts had active pulmonary tuberculosis; however,
this did not come out significant when adjusting for all other
factors. In addition, the use of steroids had no effect on the
Discussion
In our study of 559 TBM cases, we have demonstrated that ce-
development of cerebral infarctions.
rebral infarcts were present in 26% of these patients. The com-
monest sites affected are subcortical white matter followed
Predictors of Mortality by basal ganglia and thalamus. Major predictors for infarcts
Of 559 patients, seventy-seven (13.8%) died during hospital in our patients were the classical risk factors of age, hyper-
stay. Of these, 35 patients (45% of all who died) had stroke tension, diabetes mellitus, and dyslipidemia. Controlling for
on neuroimaging. Presence of cerebral infarction was an other predictors, infarcts were independently related with
poor outcomes in terms of functional disability and death.
Table 2.  Radiological Findings in TBM Patients With Cerebral Infarcts (n=144) Tuberculoma and diabetes mellitus were also major predictors
Total infarcts in 144 scans 263 for mortality in patients with infarcts.
Several mechanisms for development of infarction have
 Single infarcts 68 (47.2)
been proposed in patients experiencing TBM. Basal exudates
 Multiple infarcts 76 (52.8) are considered to be the main culprits for ischemia.13 These in-
Supratentorial location 211 (80.2) flammatory exudates lead to vasculitis, thrombosis, as well as
Acute or subacute infarcts 105 (72.9)
vasospasm and strangulation of blood vessels that are passing
through the base of skull.14 There is some evidence to support
Location of infarct (total 263) the view that stroke that occur early on in the course of the di-
 Lobar 34 (12.9) sease is secondary to vasospasm and vasculitis, whereas those
 Subcortical white matter 122 (46.4) seen later tend to be a result of intimal proliferation.15 Yet
another suggested mechanism is a prothrombotic state seen
 Basal ganglia and thalamus 55 (20.9)
more with stage III meningitis16 and for which acetyl salicylic
 Brain stem and cerebellum 52 (19.8) acid has been evaluated as a potential preventive therapy.9
Other imaging findings Certain areas of the brain also have a predilection for de-
 Tuberculomas 83 (57.6)
velopment of infarctions. These areas referred to as tuber-
culosis zones include basal ganglia, internal capsule, and
 Hydrocephalus 70 (48.6) thalamus.17 The exudates of TBM are usually most severe in
 Basal enhancement 61 (42.4) this area of circle of Willis, and hence this pattern of involve-
 Cerebral edema 33 (22.9) ment is seen. However, our findings are different from these
previous reports. We found the greatest number of infarctions
 Ventriculitis 7 (4.9)
in the subcortical white matter and only a fifth in the basal gan-
 Spinal tuberculosis 3 (2.1) glia and thalamus. This may be suggestive of another possibly
TBM indicates tuberculous meningitis. noninflammatory mechanism of ischemia in these cases.15 One
4  Stroke  October 2018

Table 4.  Factors Associated With Mortality Among Patients With Cerebral for this finding may be the small sample size compared with
Infarcts (n=144)
our study. One study used data from 507 cases of TBM to de-
Univariate Multivariate velop a prediction model for unfavorable outcome and found
Unadjusted Adjusted
altered consciousness, diabetes mellitus, immunosuppression,
Variable OR 95% CI OR 95% CI neurological deficits, hydrocephalus, and vasculitis as signif-
icant predictors.19 This study did not look at radiologically
Diabetes mellitus 3.4 1.6–7.6 2.9 1.2–7.1
proven infarction as was the case with our study. In our search,
Hypertension 2.6 1.2–6.0 2.4 0.9–6.2 we failed to find other larger studies evaluating predictors of
Active tuberculosis 0.7 0.3–1.5 0.4 0.2–1.0 infarcts in TBM cases.
Our study also found that cerebral infarcts in TBM are in-
Tuberculoma 2.5 1.2–5.4 2.6 1.1–6.4
dependent predictors of poor functional outcome and of mor-
tality in these patients, a finding supported by several previous
probable hypothesis is that the initial inflammatory vasculitis is studies.13,20,21
followed by a proliferative process in the intima, which leads HIV was tested in <10% of the patients, and only one tested
to stenosis and ischemia.18 Also less than a fifth of our patients positive. This frequency is low but not surprising. Prevalence
had involvement of brain stem and cerebellum, which is con- of HIV is extremely low among patients with tuberculosis in
sistent with findings from some other studies.10 Pakistan. A large population-based study on 12 000 confirmed
We also looked at the predictors of infarctions in this pa- patients with tuberculosis found only 42 (0.34%) patients who
tient population and found that the classical risk factors, like were HIV positive.22 This may be the reason why HIV status
age, diabetes mellitus, hypertension, and dyslipidemia, were was not evaluated in a large majority of our patients with tu-
the most important determinants. We failed to find presence berculosis meningitis.
of other TBM-related factors, such as presence of basal exu- Therapeutic interventions to reduce complications of
dates, hydrocephalus, and presence of tuberculomas, to be ac- TBM including infarctions have included steroids and anti-
countable for these strokes. This finding is consistent with a platelets. The fact that corticosteroids reduce mortality in
study from India where even though univariate analysis sug- patients with TBM is now well established.23 However,
gested other tuberculosis-related factors but in multivariate whether they reduce the incidence of stroke in these cases
analysis only age came out significant.10 Age was found to be has not yet been fully evaluated. Two recent studies, 1 in the
the only predictor of stroke in patients with TBM in another pediatric population24 and 1 in adults, explored adjunctive use
study from India.9 of acetyl salicylic acid in patients with TBM.9 The results of
Yet another study that evaluated the predictors of stroke these 2 studies are not conclusive enough to influence current
in patients with TBM13 found significant association between guidelines; however, there was a trend toward fewer strokes
stroke and hypertension, stage of meningitis, presence of hy- with aspirin in the adult population.
drocephalus, and exudates. However, in multiple regression The above data on predictors and therapeutics lead us to
analysis, none of these factor came out significant. One reason suggest a more complex mechanism for development of stroke

Figure. Survival analysis-tuberculous menin-

gitis (TBM) data: (cerebral infarct=144); log-rank
P=0.62. Survival time for TBM patients with/
without cerebral infarction.
 Wasay et al   Cerebral Infarction in Tuberculous Meningitis   5
in TBM, of which an important final pathway may be acceler-
ated atherosclerosis. This may follow the initial vasculitis seen
with TBM, but later atherosclerotic process, however, may be
dependent more on the conventional cardiovascular risk fac-
tors. This is supported by findings from our study, where the
major predictors both for occurrence of infarcts as well as
mortality were cardiovascular risk factors, like diabetes mel-
litus and hypertension. This would also explain these infarcts
being in the subcortical white matter which is a common site
for atherosclerotic lacunes.
A recent review of stroke in South Asian population25 re-
ported the conventional vascular risk factors to be highly prev-
alent but also commented on infectious causes as an important
contributor in the region. Our study suggests a unique overlap
between infectious and noninfectious risk factors contributing
toward development of infarcts in an individual patient.
Moreover, patients who had infarcts had worse outcomes
compared with those without, independent of the grade of tu-
berculosis. The conventional cardiovascular risk factors were
again the more important predictors of mortality in TBM
patients with infarcts. This poor outcome has been suggested
by other studies as well.10,13,20,21
Our study carries several limitations. This was a retro-
spective study, based on chart review, and therefore carries
all the limitations of such observational studies. A prospec-
tive study would have enabled us to identify the incidence
of strokes in TBM and also the stage of the disease in which
they are likely to occur. This might have shed more light
on the differing mechanisms for stroke proposed at different
stages of TBM. Another major limitation is that MRI was
not done for all the patients. Different modalities of imaging
can affect the sensitivity of diagnosing infarcts, particularly
in the brain stem region.26 Furthermore, CT scans are not
reliable in determination of the age of infarction. Also CT
angiography was performed in only a few cases, and there-
fore, we cannot conclusively comment on presence of ather-
osclerotic narrowing at least in the major vessels. Majority
of patients with infarctions did not undergo a basic stroke
work up, including carotid ultrasound, echocardiogram, and
sometimes even ECG. A workup for hypercoagulable states
was not done in any patient.
Although cerebral infarction was reported as an inde-
pendent predictor of mortality among patients with TBM,
it did not seem to affect the survival time in patients with
cerebral infarcts compared with those without cerebral
infarcts according to Kaplan-Meier analysis. The results
of the 2 techniques differ because the technique used in
Table 3 (binary logistic regression) used a binary out-
come only while Kaplan-Meier technique also used sur-
vival time. It is possible that frequency of mortality may
be statistically different in the 2 groups (binary logistic
regression) while survival time may be nonsignificant
(log-rank test).
Despite these limitations, to the best of our knowledge, our
study represents the largest data set, to date, of patients with
TBM and of stroke in the presence of TBM. Although efforts
have been made previously to identify predictors of infarction
in patients with TBM, the number of patients was small and
that of strokes was even smaller. As a result, none of the risk
factors evaluated in those studies reached statistical signifi-
cance. Our study is also unique because for the first time such
extensive data on other risk factors for cerebral infarction have
been collected on patients with TBM and shown to have a sig-
nificant impact not just on the occurrence of infarct but also on
the mortality following it. Our study shows that patients with
conventional cardiovascular risk factors should be managed
aggressively with respect to these risk factors to avoid devel-
opment of strokes.
Conclusions and Future Directions
Our study shows that cerebral infarctions complicate a quarter
of the cases of TBM and lead to poor outcomes. They are more
likely to occur in patients with vascular risk factors; however,
there is a need to evaluate further the role of TBM itself in
causation of these infarcts through age- and sex-matched con-
trolled studies. For now, we recommend aggressive identifi-
cation and treatment of these risk factors in all patients with
TBM. In addition, there is a need to conduct better designed
trials where this high-risk population is randomized to eval-
uate the role of antiplatelets in stroke prevention in patients
with TBM. Aspirin has already shown to have some beneficial
effects, and other antiplatelets like cilostazol with fewer hem-
orrhagic complications may show more promise.
Disclosures
None.
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