Original Investigation | Global Health

Global Frequency and Clinical Features of Stroke in Patients

With Tuberculous Meningitis
A Systematic Review
Marie Charmaine C. Sy, MD, MBA; Adrian I. Espiritu, MD; Jose Leonard R. Pascual V, MD

Abstract Key Points

Question What is the global frequency
IMPORTANCE Stroke in tuberculous meningitis (TBM) is associated with significant morbidity and
of stroke in patients with tuberculous
mortality.
meningitis (TBM)?

OBJECTIVE To determine the country-specific, regional, and overall prevalence of stroke among Findings In this systematic review
patients with TBM, including their clinical manifestations, stroke locations, and outcomes. including 852 articles involving 2194
patients with stroke in TBM, the
EVIDENCE REVIEW This systematic review searched records in MEDLINE by PubMed, Scopus, and estimated frequency of stroke in TBM
EMBASE until July 2020 for relevant articles on the occurrence and characteristics of stroke in TBM. was 0.30 (95% CI, 0.26-0.33), and
Randomized clinical trials and cohort studies that included a population of patients with TBM were ranged from 0.08 in Saudi Arabia to
analyzed for clinical manifestations, type of stroke, area of stroke, vascular territory, and outcomes. 0.56 in France.
Studies that did not report the occurrence of stroke, reported as abstract only with no full-texts
Meaning These results suggest that
available, and articles not in English were excluded. The country-specific, regional, and overall
global trends of stroke occurrence in
frequencies of stroke among patients with TBM were determined; secondary analysis enumerated
TBM may have regional or country-
the summary estimates of the clinical presentations, common locations of stroke, and outcomes. The
specific characteristics that may be
Murad tool was used to assess methodological quality.
associated with disability and mortality
in these patients.
FINDINGS From 852 articles identified, 71 studies involving 2194 patients with stroke in TBM were
included. The sample size for each study ranged from 17 to 806 patients. The frequency of stroke in
TBM showed an estimate of 0.30 (95% CI, 0.26-0.33). The most common clinical manifestations + Supplemental content
were fever and headache. The lateral striate, middle cerebral, and medial striate arteries were Author affiliations and article information are
typically affected. The basal ganglia, cortex and lobar, and internal capsule were the frequently listed at the end of this article.

involved areas of the brain. The pooled proportions of mortality and poor outcomes were 0.22 (95%
CI, 0.16-0.29) and 0.51 (95% CI, 0.37-0.66), respectively.

CONCLUSIONS AND RELEVANCE The results of this systematic review suggest that stroke is
considerably frequent among patients with TBM. The reported frequencies of stroke in TBM and its
clinical features vary across the studies and populations.

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Introduction
Tuberculosis (TB) is a serious infectious disease that causes high morbidity and mortality especially
in developing countries.1 TB typically affects the lungs, but the pathogen can travel through the
bloodstream and damage any organ in the body. Mycobacterium tuberculosis is the most common
organism causing tuberculous infection in the central nervous system reaching 10% to 15%
prevalence among all extrapulmonary manifestations.2,3
Tuberculous meningitis (TBM) accounts for 1% to 2% of cases of active TB and may lead to
severe neurologic disability.4 The spectrum of complications of TBM include hydrocephalus,

Open Access. This is an open access article distributed under the terms of the CC-BY License.

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 JAMA Network Open | Global Health Global Frequency and Features of Stroke in Tuberculous Meningitis

tuberculoma formation, and stroke.3,4 Stroke among patients with TBM can cause irreversible brain
damage and lead to poor clinical outcomes.5 The pathophysiologic mechanism responsible for
cerebral infarction include obliterative vasculitis, intimal proliferation, and hypercoagulable state.3,6
Currently, the reported frequencies of stroke in TBM and its clinical features seem to vary across
studies conducted in different countries. Thus, the purpose of this study was to determine the
country-specific, regional, and overall frequencies of stroke among patients with TBM. We also aimed
to determine the summary estimates of the clinical presentations, common locations of stroke, and
outcomes of these patients.

Methods
This review complied with the Preferred Reporting Items for Systematic reviews and Meta-analyses
(PRISMA) reporting guideline for systematic reviews.7 The protocol was registered in PROSPERO
(CRD42020209704).

Criteria for Selection of Studies

We considered randomized controlled trials and cohort studies that included a population of patients
diagnosed with TBM and reported frequencies of stroke. We included studies that reported
information on clinical manifestations, type of stroke, area of stroke, vascular territory, and
outcomes. We considered the following outcomes for this review: mortality, recovered, and poor
outcome. In this review, mortality was defined as patients with TBM who have died from the
complications of TBM; recovery was implied in the studies by discharge from the hospital; and poor
outcome was defined as having a modified Rankin scale score of 3 to 6. There were no restrictions
implemented in terms of age, sex, and ethnicity of the population. We excluded studies that did not
report the occurrence of stroke in TBM, reported as abstract only with no full-texts available and
articles not in English. The Murad tool was used to evaluate the risk of bias in noncomparative
cohorts.8 We considered poor, moderate, or good quality when 3 or fewer, 4, or 5 of the 5 criteria
were fulfilled, respectively. The investigators evaluated the methodological quality and resolved the
discrepancies of the included studies.

Search Methods for the Identification of Studies and Study Selection

We conducted a comprehensive systematic search of records in MEDLINE by PubMed, Scopus, and
EMBASE. We used the following general and Medical Subject Headings terms: “tuberculosis,
meningeal,” tubercular meningitides, TB meningitis, meningeal tuberculosis, or meningeal
tuberculoses occurring with stroke, cerebrovascular disease, cerebral infarction, brain infarction,
cerebral hemorrhage, brain hemorrhage, or vasculitis. The literature search was limited to studies
published from the inception of records in these major databases until July 2020.

Data Collection
Two investigators (M.C.S. and A.I.E.) independently extracted data from the eligible studies and any
discrepancies were resolved by both investigators. The following data were extracted from the
relevant studies: author and year, publication date, study design, setting or geographic region, the
number of included patients, age, sex, clinical manifestations, imaging findings, type of stroke, area
of stroke, vascular territory affected, and outcomes. We also obtained information on the TBM stroke
zones as defined by Hsieh et al,9 namely the TB zones and the ischemic zones. The TB zone is the
area supplied by the medial lenticulostriate, thalamotuberal, and thalamoperforating arteries
affecting the head of the caudate nucleus, genu, and anterior limb of internal capsule and
anteromedial thalamus regions, while the ischemic zone is supplied by the lateral lenticulostriate,
anterior choroidal, and thalamogeniculate artery affecting the lentiform nucleus, posterolateral
thalamus, and posterior limb of internal capsule areas.9

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 JAMA Network Open | Global Health Global Frequency and Features of Stroke in Tuberculous Meningitis

Statistical Analysis
We used frequencies and proportions for categorical variables and means (SD) or median (range) for
continuous variables to summarize the data. Moreover, the 95% CIs for the population mean were
computed when more than 1 study was available. Statistical analysis was performed using SPSS
Statistics software for Macintosh, Version 24 (IBM Corporation). A value of P < .05 was considered
statistically significant.

Results
Study and Population Characteristics
All included studies involved patients diagnosed with TBM who developed stroke in the course of
their illness. The included articles consisted of 42 retrospective studies,9-50 25 prospective
studies5,51-74 and 4 randomized controlled trials75-78 with a total of 2194 patients with stroke among
8460 patients with TBM. For the demographics, the age of the patients ranged from 2 months to
85 years, with an overall women-to-men ratio of 0.6:1.

Included Studies
A total of 852 journal articles (MEDLINE by PubMed, 343; Scopus, 471; Embase, 38) were identified
using the search strategy. After duplicates were removed, 617 titles and abstracts were screened.
After exclusion of 498 articles that did not fulfill the screening criteria, 119 full-text reports were
assessed for eligibility. Forty-eight articles were subsequently excluded (ie, articles not in English,
case reports or series, literature reviews, and articles with no report of stroke). We included a total of
71 studies in the final analysis (eFigure in the Supplement). Nearly all included patients who reported
a stroke had cerebral infarction (2192 patients [99.9%]). Only 2 patients had intracerebral
hemorrhage among patients with stroke (2 [0.1%]). The sample size for each study ranged from 17 to
806 patients (Table 1).

Global Estimate of Proportions of Stroke in TBM

Across all 71 studies including 2194 patients with stroke and 8460 total patients with TBM, the
frequency of stroke in TBM showed an overall point estimate of 0.26 (95% CI, 0.26-0.33) (Table 2).
The pooled regional proportions of stroke among total patients with TBM ranged from a point
estimate of 0.08 to 0.40 (Figure 1). In the East Asia and Pacific region, the point estimate was 0.31
(95% CI, 0.27-0.36) across 21 studies, with 455 patients with stroke and 1489 total patients with
TBM (Figure 1). For Europe and Central Asia, the point estimate was 0.17 (95% CI, 0.10-0.27) in 12
studies, including 338 patients with stroke and 1843 total patients. The Latin America and the
Caribbean region had a pooled point estimate of 0.34 (95% CI, 0.20-0.48) in 3 studies with 108
patients with stroke and 399 total patients. The sub-Saharan Africa region had an estimate of 0.40
(95% CI, 0.25-0.55) across 10 studies, with 274 patients with stroke and 711 total patients. The point
estimate for the South Asia region was 0.31 (95% CI, 0.26-0.36) across 23 studies with 918 patients
with stroke and 3132 total patients. In a single study (including 6 patients with stroke and 80 total
patients), the Middle East and North Africa region had a point estimate of 0.12. There was also a single
study of the North America region, with a point estimate of 0.08 across 95 patients with stroke and
806 total patients. The country-specific proportions of stroke in patients with TBM varied across the
countries included (Table 2).

Overall Clinical Manifestations of Stroke in TBM

The frequency for each clinical manifestation reported in patients with stroke in TBM ranged from
0.26 to 0.86 (eTable 1 in the Supplement). The point estimate was 0.69 (95% CI, 0.58-0.81) for
altered sensorium in 8 studies with 126 cases among 189 total patients with TBM experiencing
stroke; 0.42 (95% CI, 0.12-0.73) for cranial nerve palsy in 5 studies including 43 cases among 107 total
patients; 0.86 (95% CI, 0.68-0.94) for fever across 7 studies including 226 cases among 302 total

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Table 1. Features of the Included Studies and Population

Study Duration, y Setting Study design Sample, No. Median (range) Women:men ratio
Al-edrus et al,10 2007 NNR Malaysia Retrospective cohort 42 34.4 (18-62) 0.35:1
Alarcon et al,21 2011 15 Ecuador Retrospective cohort 310 34.5a 0.57:1
Anderson et al,32 2010 18 New Zealand Retrospective cohort 104 26.8 (1-81) 0.41:1
Andronikou et al,43 2006 4 South Africa Retrospective cohort 130 3 (2 mo-13) 0.47:1
Anuradha et al,51 2010 1 India Prospective cohort 100 30 (14-84) 0.49:1
Azeemuddin et al,46 2019 10 Pakistan Retrospective cohort 559 42 (17-97) 0.47:1
Bandyopadhyay et al,62 2009 3 India Prospective cohort 82 36.1 (8.3)a NR
Bhargava et al,47 1982 NR India Retrospective cohort 60 NR NR
Bullock et al,48 1982 1 South Africa Retrospective cohort 52 NR NR
Cagatay et al,49 2004 11 Turkey Retrospective cohort 42 33.9 (13.2)a 0.5:1
Cantier et al,50 2018 12 France Retrospective cohort 90 43 (29-58) 0.6:1
Chan et al,68 2005 6 Hong Kong Prospective cohort 40 53 (18-85) 0.4:1
Chen et al,69 2014 4 Taiwan Prospective cohort 38 52.1 (19.8)a 0.52:1
11
Chou et al, 2009 10 Taiwan Retrospective cohort 43 53.3 (20-88) 0.48:1
Ersöz et al,12 2012 11 Turkey Retrospective cohort 60 27.5 (14-62) 0.82:1
George et al,13 2012 2 India Retrospective cohort 98 43.6 (14.4)a 0.60:1
14
Gu et al, 2015 4 China Retrospective cohort 156 32.9 (18.6)a 0.59:1
Haji et al,70 2019 3 Pakistan Prospective cohort 110 NR NR
Helbok et al,15 2006 6 Thailand Retrospective cohort 43 29.7 (16)a 0.72:1
Hosoglu et al,16 2002 12 Turkey Retrospective cohort 434 33 (13-83) 0.76:1
Hsieh et al,9 1992 5 Taiwan Retrospective cohort 40 57.9 (38-74) NR
Hsu et al,17 2010 6 Taiwan Retrospective cohort 108 54.9 (18.6)a 0.52:1
18
Jinkins et al, 1991 NR Saudi Arabia Retrospective cohort 80 (2-76) 0.86:1
Kalita et al,71 2017 1 India Prospective cohort 122 32 (4-82) 0.90:1
Kalita et al,72 2009 NR India Prospective cohort 26 23 (11-75) 1.17:1
Karande et al,72 2005 3 India Prospective cohort 123 72 (58.5)a 0.89:1
Karstaedt et al,19 1998 3 South Africa Retrospective cohort 56 33.9 (18-59) 0.66:1
Kingsley et al,74 1987 1 United Kingdom Prospective cohort 25 (1-70) Not reported
Koh et al,52 2006 5 Korea Prospective cohort 38 34 (16-77) 1.24:1
Lan et al,20 2001 5 Taiwan Retrospective cohort 36 55 (16-83) 1.6:1
Leiguarda et al,53 1988 NR Argentina Prospective cohort 65 NR NR
Li et al,22 2017 3 China Retrospective cohort 154 41 (24-59) 0.77:1
Lu et al,54 2015 7 China Prospective cohort 36 47 (16-83) 0.56:1
Lu et al,23 2001 5 Taiwan Retrospective cohort 101 36.7 (14-81) 0.71:1
Mai et al,75 2017 2 Vietnam Randomized controlled trial 120 40 (31-53) 0.52:1
Merkler et al,24 2017 8 US Retrospective cohort 806 50 (17.1)a 0.59:1
Misra et al,25 2000 3 India Randomized controlled trial 17 18.8 (5-62) 0.31:1
Misra et al,76 2010 NR India Retrospective cohort 118 30 (6-82) 1.03:1
Modi et al,55 2017 5 India Prospective cohort 209 30.4 (13.8)a 1:1
More et al,56 2017 2 India Prospective cohort 115 34.86 (16.57)a 0.89:1
Morgado et al,26 2013 6 South Africa Retrospective cohort 22 31 (19-57) 0.83:1
Napoli et al,27 2019 7 Italy Retrospective cohort 69 51.6 (16.9)a 0.35:1
Omar et al,28 2011 2 South Africa Retrospective cohort 34 3.5 (3 mo-15) 1.62:1
Ozates et al,29 2000 8 Turkey Retrospective cohort 289 29.9 (12.7)a 0.84:1
Pasticci et al,30 2013 39 Italy Retrospective cohort 30 NR NR
Pienaar et al,31 2009 NR South Africa Retrospective cohort 30 4.7 (1-13) 1.14:1
Qu et al,33 2016 7 China Retrospective cohort 105 NR 0.84:1
Raut et al,57 2013 2 India Prospective cohort 80 30.1 (14-68) 0.86:1
Roca et al,34 2008 15 Spain Retrospective cohort 29 34 (17-78) 0.41:1
Rohlwink et al,58 2016 3 South Africa Prospective cohort 44 3.3 (3 mo-13) 0.57:1
Rojas-Echeverri et al,59 1996 3 Mexico Prospective cohort 24 37 (18-65) 0.5:1

(continued)

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Table 1. Features of the Included Studies and Population (continued)

Study Duration, y Setting Study design Sample, No. Median (range) Women:men ratio
Samuel et al,60 1987 2 India Prospective cohort 127 (7 mo-5) NR
Shah et al,77 2014 NR India Prospective cohort 63 NR 1.25:1
Sharma et al,35 2011 10 India Prospective cohort 158 31.95 (13.96)a 0.74:1
Sharma et al,61 2017 2 India Prospective cohort 146 31.8 (15.01)a 0.46:1
36
Sheu et al, 2010 4 Taiwan Prospective cohort 91 53.2 (19.8)a 0.64:1
Shoeman et al,64 1988 2 South Africa Retrospective cohort 198 NR 0.96:1
Shoeman et al,63 1995 8 South Africa Retrospective cohort 27 3.5 (1-7) NR
Shukla et al,65 2008 2 India Prospective cohort 30 28.7 (14-56) NR
Singh et al,66 2012 2 India Prospective cohort 47 28 (12-65) 0.96:1
Soni et al,37 2019 4 India Retrospective cohort 90 32 (10-82) 1.14:1
Springer et al,38 2009 5 South Africa Retrospective cohort 118 31.8 (18.3)a NR
Sutlas et al,39 2003 12 Turkey Retrospective cohort 61 34.5 (16-74) 0.56:1
Synmon et al,67 2016 2 India Prospective cohort 93 32.3 (17.05)a 0.62:1
Tai et al,40 2016 5 Malaysia Retrospective cohort 51 35.1 (12.9)a 0.7:1
41
Teoh et al, 1989 NR Hong Kong Retrospective cohort 64 27.4 (21.7)a 0.68:1
Thwaites et al,78 2015 2 Vietnam Randomized controlled trial 27 31 (15-66) NR
van Well et al,42 2009 20 Netherlands Retrospective cohort 554 2 (2-18) 0.91:1
Wasay et al,44 2019 11 Pakistan Retrospective cohort 559 NR NR
Yasar et al,45 2010 11 Turkey Retrospective cohort 160 32.18 (13.62)a 1:1
5
Zhang et al, 2019 3 China Prospective cohort 52 30.3 (9.9)a 0.36:1

Abbreviation: NR, not reported.

a
Mean value with SD (if available).

patients; 0.62 (95% CI, 0.41-0.84) for focal weakness or hemiplegia in 10 studies including 167 cases
among 288 total patients; 0.76 (95% CI, 0.62-0.90) for headache across 6 studies including 119
cases among 158 total patients; 0.74 (95% CI, 0.61-0.87) for neck stiffness across 3 studies including
52 cases among 71 total patients; and 0.26 (95% CI, 0.13-0.45) for seizure across 7 studies including
62 cases among 290 total patients.

Vascular Territories and Affected Areas of Stroke in TBM

The frequency of vascular territories involved were the following: 0.04 (95% CI, 0.02-0.10) anterior
cerebral artery across 5 studies including 5 cases among 151 total patients with TBM experiencing
stroke; 0.11 (95% CI, 0.03-0.35) for internal carotid artery across 2 studies including 10 cases among
77 total patients; 0.37 (95% CI, 0.21-0.53) for middle cerebral artery across 10 studies including 82
cases among 229 patients; 0.13 (95% CI, 0.06-0.28) for posterior cerebral artery across 8 studies
including 31 cases among 226 total patients; 0.55 (95% CI, 0.35-0.76) for lateral striate artery across
3 studies including 55 cases among 97 total patients; 0.31 (95% CI, 0.19-0.44) for medial striate
artery across 3 studies including 30 cases among 97 total patients; 0.04 (95% CI, 0.02-0.10) for
superior cerebellar artery across 4 studies including 4 cases among 116 total patients; 0.11 (95% CI,
0.05-0.22) for vertebrobasilar artery across 3 studies including 7 cases among 62 total patients; 0.53
(95% CI, 0.34-0.71) for anterior circulation across 11 studies including 145 cases among 304 total
patients; and 0.17 (95% CI, 0.09-0.31) for posterior circulation across 10 studies including 57 cases
among 287 total patients (Figure 2A). The summary estimates for areas affected by the stroke were
as follows: 0.60 (95% CI, 0.44-0.75) in the basal ganglia across 27 studies including 551 cases among
1060 total patients; 0.23 (95% CI, 0.12-0.38) in the internal capsule across 13 studies including 134
cases among 524 total patients; 0.18 (95% CI, 0.12-0.28) in the thalamus across 14 studies including
120 cases among 651 total patients; 0.26 (95% CI, 0.19-0.24) in the cortex and lobar across 22
studies including 324 cases among 963 total patients; 0.16 (95% CI, 0.10-0.24) in the brainstem
across 15 studies including 137 cases among 763 total patients; 0.10 (95% CI, 0.07-0.13) in the

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 JAMA Network Open | Global Health Global Frequency and Features of Stroke in Tuberculous Meningitis

cerebellum across 10 studies including 39 cases among 435 total patients; and 0.49 (95% CI, 0.41-
0.57) in multifocal areas across 17 studies including 373 cases among 707 total patients (Figure 2B).

Outcomes of Patients With Stroke in TBM

The overall estimated proportions of mortality from patients with stroke in TBM were 0.22 (95% CI,
0.16-0.29) across 15 studies including 114 cases among 473 total patients (eTable 2 in the
Supplement). The proportion of poor outcomes was 0.51 (95% CI, 0.37-0.66) across 10 studies
including 141 cases among 284 total patients.

Discussion
To the best of our knowledge, our review presents the most comprehensive evaluation of stroke in
TBM with relevant information from 71 studies involving 2194 patients. This review provides
extensive analyses of proportions of stroke across all regions as well as the clinical manifestations,
type of stroke, area of stroke, vascular territory affected, and outcomes associated with this
condition.
The consolidated evidence showed that the global frequency of stroke in TBM is approximately
30%, ie, 3 out of 10 patients with TBM may eventually develop a stroke. It is one of the most common

Table 2. Summary Estimates of Stroke in Tuberculous Meningitis per Country

Patients with Total patients, Point estimate
Region/country No. of studies stroke, No. No. (95% CI)
Middle East and North Africa
Saudi Arabia 1 6 80 0.08
North America
US 1 95 806 0.12
Latin America and the
Caribbean
Argentina 1 25 65 0.38
Ecuador 1 72 310 0.23
Mexico 1 11 24 0.46
East Asia and Pacific
China 5 154 568 0.27 (0.22-0.31)
Hong Kong 2 29 104 0.28 (0.19-0.36)
Korea 1 8 38 0.21
Malaysia 2 46 93 0.46 (0.10-0.85)
New Zealand 1 34 104 0.33
Vietnam 2 51 147 0.35 (0.27-0.42)
Europe and Central Asia
France 1 50 90 0.56
Italy 2 17 99 0.17 (0.10-0.24)
Netherlands 1 164 554 0.30
Spain 1 4 29 0.14
Turkey 6 91 1046 0.09 (0.05-0.15)
United Kingdom 1 12 25 0.48
South Asia
India 20 567 1904 0.32 (0.25-0.38)
Pakistan 3 351 1228 0.29 (0.25-0.33)
Taiwan 7 117 392 0.31 (0.21-0.42)
Thailand 1 16 43 0.37
Sub-Saharan Africa
South Africa 10 274 711 0.40 (0.25-0.55)
Total 71 2194 8460 0.30 (0.26-0.33)

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complications of TBM patients across all age groups. Other complications of TBM include
hydrocephalus (60%) followed by tuberculoma (10%), myelitis (10%), and seizure (10%).70 The
previous reports by Misra et al6 described that approximately 13% to 57% of TBM patients had
cerebral ischemia.25 Of note, nearly all patients who had stroke in the included studies developed
cerebral infarction and only 2 patients had intracerebral hemorrhage. Several pathomechanisms
were suggested in the development of this complication, including arteritis, vasospasm, arterial
thrombosis, and compression of arteries by basal inflammatory exudate.24
Interestingly, TB was found to be widespread in resource-constrained areas. The global burden
is estimated at 8.8 million incident cases, higher in Africa followed by Asia and Latin America.79 In
our study, the top regions with the highest estimate of proportions of stroke in TBM were in
sub-Saharan Africa (40%), Latin America and the Caribbean (34%), South Asia (31%), and East Asia
and Pacific (31%). A review of stroke specifically in the South Asian population reported the
conventional vascular risk factors to be highly prevalent, but infectious cause was also a significant
contributor.80 Only 1 study was found in North America and the Middle East and North Africa. These
are also regions which had a low incidence of TB according to the global tuberculosis report of
2019.79 The variation in numbers can be explained by regional differences in treatment practices,
income, government policies, and the local effect of large countries like South Africa, where poor
quality treatment extends the duration of the disease.30,45 On the other hand, we surmise that
increased access to effective treatment leads to relatively lower frequency of stroke in TBM for the
North American region. The top countries with the highest frequencies of stroke in TBM were
Malaysia, South Africa, Vietnam, and India. These were considered middle-to-low–income countries
that have a high burden of TB and limited access to health care.42
Stroke in TBM patients may be asymptomatic or present as silent stroke.5 Fever and headache
are known to be the most common symptoms in TBM.5 Altered consciousness has been reported
about 17% to 69% in patients with TBM, which was 69% in our pooled estimate.5,30 Moreover,
patients with TBM experiencing stroke were more likely to present with focal weakness, which was
found in 62% of patients in our analysis.20,26,40 Cranial nerve palsy is also an important symptom in

Figure 1. Regional Proportions of Stroke in Tuberculous Meningitis

n = 71
Overall proportion
0.30 (95% CI, 0.26-0.33)

Middle East and East Asia and Pacific

North Africa n = 21
n=1 SPE = 0.31 (95% CI, 0.27-0.36)
SPE = 0.08

North America Latin America and Sub-Saharan Africa South Asia Europe and Central Asia
n=1 the Caribbean n = 10 n = 23 n = 12
SPE = 0.12 n=3 SPE = 0.40 (95% CI, 0.25-0.55) SPE = 0.31 (95% CI, 0.26-0.36) SPE = 0.17 (95% CI, 0.10-0.27)
SPE = 0.34 (95% CI, 0.20-0.48)

The map shows the number of included studies and proportions of stroke in each region and overall. SPE indicates stroke point estimate.

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 JAMA Network Open | Global Health Global Frequency and Features of Stroke in Tuberculous Meningitis

patients with TBM, which may be due to increased intracranial pressure or exudates in the basilar
region of the brain.24 Some studies have reported that these basilar exudates may be the culprit for
stroke in the vulnerable areas of the brain, specifically the anteromedial thalamus, caudate nucleus,
and anterior horn of the internal capsule.5,9 These structures make up the tubercular zone as
described by Hsieh et al,9 which are supplied by the medial lenticulostriate, thalamotuberal, and
thalamoperforating arteries. Cerebral ischemia have a predilection to develop in these areas and may
subsequently aid clinicians in identifying the cause of stroke. Among the involved vascular territories,
the most commonly affected by TB are those from the anterior circulation specifically the lateral
striate artery, medial striate artery and middle cerebral artery. This corresponds to the brain region
usually affected by stroke, specifically the basal ganglia, and internal capsule, which is consistent with
our analysis.
In our analysis, we found pooled mortality and poor outcomes of 22% and 51% among patients
with TBM experiencing stroke, respectively. In order to achieve better outcomes, early initiation of
appropriate therapy is crucial. The current treatment guidelines recommend a first-line regimen for 2
months of isoniazid, rifampicin, pyrazinamide, and ethambutol followed by 10 months of isoniazid
and rifampicin.75 Therapeutic interventions to reduce the frequency of stroke in patients with TBM
have included steroids and antithrombotic therapy.77 It has been concluded in studies that the safety
and efficacy of aspirin use needs further investigation by including a larger sample size and evaluating

Figure 2. Studies and Summary Estimates of Vascular Territories and Areas of Stroke in Tuberculous Meningitis

A Vascular territories
Internal carotid artery
(n = 2)
SPE = 0.11 (95% CI, 0.03-0.35)
Tuberculous zone
Ischemic zone
Anterior cerebral artery
(n = 5)
SPE = 0.04 (95% CI, 0.02-0.10)
Medial striate artery
(n = 3)
SPE = 0.31 (95% CI, 0.19-0.44)
Lateral striate artery
(n = 3)
SPE = 0.55 (95% CI, 0.35-0.76)
Middle cerebral artery
(n = 10)
SPE = 0.37 (95% CI, 0.21-0.53)
Posterior cerebral artery
(n = 8)
SPE = 0.13 (95% CI, 0.06-0.28)
Superior cerebellar artery
(n = 4)
SPE = 0.04 (95% CI, 0.02-0.10)
Vertebrobasilar artery
(n = 3)
SPE = 0.11 (95% CI, 0.05-0.22) Posterior circulation
(n = 10)
Anterior circulation SPE = 0.17 (95% CI, 0.09-0.31)
(n = 11)
SPE = 0.53 (95% CI, 0.34-0.71)

B Areas of stroke
Cortex or lobar
(n = 22)
SPE = 0.26 (95% CI, 0.19-0.34)
Basal ganglia
(n = 27)
SPE = 0.60 (95% CI, 0.44-0.75)
Internal capsule
(n = 13)
SPE = 0.23 (95% CI, 0.12-0.38)
Thalamus
(n = 14)
SPE = 0.18 (95% CI, 0.12-0.28)
Cerebellum
(n = 10)
SPE = 0.10 (95% CI, 0.07-0.13)
Brain stem
(n = 15) The figure shows the number of studies included in the
SPE = 0.16 (95% CI, 0.10-0.24)
analysis and frequency of stroke for various vascular
Multifocal territories and areas. SPE indicates stroke point
(n = 17)
SPE = 0.49 (95% CI, 0.41-0.57) estimate.

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 JAMA Network Open | Global Health Global Frequency and Features of Stroke in Tuberculous Meningitis

the long term survival and disability.75,76 Therefore, more research should be conducted to prevent
stroke in this set of population to improve their clinical outcomes.
Our study provides a large data set of patients with TBM and stroke. We have reported
extensive data that describes the overall, regional, and country-specific differences in the
proportions of stroke in TBM. Due to the considerable number of stroke cases in the setting of TBM,
further research on the interventions that aim to reduce the frequency of stroke are needed. We also
recommend the evaluation of possible demographic and clinical factors associated with stroke in the
TBM population, such as age, sex, duration and severity of disease, and the role of other
comorbidities known to be associated with stroke such as hypertension, diabetes, dyslipidemia, and
HIV. Finally, robust prognostic studies that evaluate the factors of outcomes in this population are
warranted to guide clinical interventions.

Limitations
This study had several limitations. The first was the heterogeneity of several pooled estimates.
Another limitation was the exclusion of unpublished studies and non-English publications. In terms
of clinical parameters, the population included were from varying age groups, including both adult
and pediatric population, sex, and ethnicity. These parameters were difficult to assess because most
studies reported pooled data. Consequently, different imaging modalities were used to diagnose
stroke such as cranial CT scan, MRI, and angiography. The timing of stroke in TBM and the reported
outcomes varied across the studies. Retrospective studies are known to have an inherent recording
bias that can obscure the validity of the estimates.

Conclusions
In this systematic review, stroke was considerably prevalent among patients with TBM, ie, 3 out of 10
patients with TBM would be estimated to develop stroke in the course of their illness based on these
data. The common clinical presentations of TBM with stroke were fever, headache, neck stiffness, al-
tered sensorium, focal weakness or hemiplegia, cranial nerve palsy, and seizure. Nearly all reported
cases were cerebral infarctions; lateral striate, middle cerebral and medial striate arteries were com-
monly affected while basal ganglia, cortex or lobar, and internal capsule were the frequently injured
areas. Based on these results, approximately 5 out of 10 patients would be estimated to have poor out-
comes while 2 out of 10 may expire. Global trends of stroke occurrence in TBM may have regional or
country-specific characteristics that may influence disability and mortality in these patients.

ARTICLE INFORMATION
Accepted for Publication: July 6, 2022.
Published: September 1, 2022. doi:10.1001/jamanetworkopen.2022.29282
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Sy MCC
et al. JAMA Network Open.
Corresponding Author: Marie Charmaine C. Sy, MD, MBA, Philippine General Hospital, Taft Avenue, Ermita, Manila
1000, Philippines (mcsy2@up.edu.ph).
Author Affiliations: Division of Adult Neurology, Department of Neurosciences, College of Medicine and
Philippine General Hospital, University of the Philippines Manila, Manila, Philippines (Sy, Espiritu, Pascual);
Department of Clinical Epidemiology, College of Medicine, University of the Philippines Manila, Manila, Philippines
(Espiritu).
Author Contributions: Drs Sy and Espiritu had full access to all of the data in the study and take responsibility for
the integrity of the data and the accuracy of the data analysis. Drs Sy and Espiritu were co–first authors of
this article.
Concept and design: All authors.
Acquisition, analysis, or interpretation of data: Sy, Espiritu.

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 JAMA Network Open | Global Health Global Frequency and Features of Stroke in Tuberculous Meningitis

Drafting of the manuscript: Sy, Espiritu.

Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Espiritu.
Administrative, technical, or material support: Sy, Espiritu.
Supervision: All authors.
Conflict of Interest Disclosures: None reported.
Additional Contributions: We would like to acknowledge Drs Claudine Lukban and Leland Lukban of the College
of Medicine and Philippine General Hospital for assisting the authors with the creation of Figures 2 and 3. These
contributors received no compensation.

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SUPPLEMENT.
eTable 1. Summary Estimates of Clinical Manifestations of Stroke in Tuberculous Meningitis
eTable 2. Pooled Estimates of Outcomes of Stroke in Tuberculous Meningitis
eFigure. PRISMA Information Diagram for the Inclusion of Relevant Articles
eAppendix. Search Strategy

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