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indian journal of tuberculosis xxx (xxxx) xxx

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Review article

Hyponatremia in tuberculous meningitis: A

systematic review and meta-analysis

Truong Hong Hieu a,b,1,2, Mohammad Rashidul Hashan b,c,1,2,

Sara Morsy b,d,1,2, Gehad Mohamed Tawfik b,e,1,2, Federica Cuce b,f,2,
Akash Sharma b,g,2, Tran Thuy Huong Quynh b,h,2,
Hazem Abdelkarem Faraj b,i,2, Ahmad Taysir Atieh Qarawi b,j,2,
Nguyen Tien Huy k,*
a
Faculty of Medicine, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Viet Nam
b
Online Research Club, Nagasaki, Japan
c
Ministry of Health and Family Welfare, Government of Bangladesh, Dhaka, Bangladesh
d
Faculty of Medicine, Tanta University, Egypt
e
Faculty of Medicine, Ain Shams University, Cairo, Egypt
f
Department of Medicine, University of Padova, Padova, Italy
g
University College of Medical Sciences and Guru Teg Bahadur Hospital, Dilshad Garden, Delhi, India
h
School of Medicine, Viet Nam National University, Viet Nam
i
Faculty of Medicine, University of Tripoli PO Box 13275 Tripoli, Libya
j
Lower Westchester Medical Associates, P.C., Mount Vernon, NY, 10550, USA
k
School of Tropical Medicine and Global Health, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan

article info abstract

Article history: Background: Tuberculous meningitis (TBM), manifests as the most severe involvement of
Received 22 February 2021 the nervous system by Mycobacterium tuberculosis, it has a high mortality rate and a spec-
Accepted 8 June 2021 trum of systemic and neurological complications that can lead to debilitating or fatal
Available online xxx sequelae, whereas hyponatremia is the commonly encountered life-threatening electrolyte
disturbance. Thus, our study aimed to determine the prevalence, risk factors and differ-
Keywords: ences in outcomes of hyponatremia in TBM.
Hyponatremia Methods: This systematic review was registered in PROSPERO (CRD42018088089). A
Tuberculous meningitis comprehensive electronic search was conducted through ten databases to find relevant
Prevalence articles.
Mortality Results: A total of 42 studies were included, 24 case reports and 18 retrospective studies.
The prevalence rate of hyponatremia among TBM patients was 52% and the rate of death
among those patients was 29%. The meta-regression analysis revealed that there was no
significant effect of sodium level on the death rate in TBM patients (P-value ¼ 0.9). Addi-
tionally, there was no significant difference in sodium level based on sex, and etiologies of
hyponatremia.

* Corresponding author. School of Tropical Medicine and Global Health, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523,
Japan.
E-mail address: tienhuy@nagasaki-u.ac.jp (N.T. Huy).
1
These authors contributed equally to this study.
2
http://www.onlineresearchclub.org.
https://doi.org/10.1016/j.ijtb.2021.06.004
0019-5707/© 2021 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.

© 2021 published by Elsevier. This manuscript is made available under the Elsevier user license
https://www.elsevier.com/open-access/userlicense/1.0/
2 indian journal of tuberculosis xxx (xxxx) xxx

Conclusions: Hyponatremia is commonly present in patient with TBM, but it is not signifi-
cantly correlated to the rate of death. However, it is necessary to treat this potentially life-
threatening condition appropriately according to its etiology, further research is needed on
its pathophysiology in TBM, its risk factors, and the most appropriate treatment.
© 2021 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.

cerebral salt waste syndrome (CSW), or adrenal insufficiency.

1. Introduction
Tuberculosis (TB) still prevails as a major public health issue
and is regarded as one of the main causes of mortality from
any single infectious agent globally. An estimated 10 million
new cases of tuberculosis were reported worldwide in 2017,
encompassing around two-thirds of the African and Asian
populations.1 Tuberculous meningitis (TBM) disrupts the
nervous system causing in some cases systemic and neuro-
logical complications that can progress to long term compli-
cations, chronic debilitation and/or death of the patient.2e5
People co-infected with HIV carry 20 times higher risk of
developing TB compared to non-HIV people, because of an
increased possibility of activation of latent infection or of
rapid deterioration of primary infection.6 TBM can have a high
impact on severely immune-deficient patients and those with
inadequate access to anti-retroviral therapy.7e9
Despite the availability of multi-drug chemotherapy, prog-
nosis of TBM still remains poor,4 a multitude of fatal complica-
tions ranging from hyponatremia, hydrocephalus, stroke,
cranial nerve palsies, epileptic seizures, diabetes insipidus,
tuberculoma, myelo-radiculopathy and hypothalamic syn-
dromes are frequently related with TBM.10 Expected outcomes of
TBM cases depend on a multidimensional approach involving
early diagnosis and subsequent rapid initiation of multidrug
chemotherapy with simultaneous appropriate management of
co-morbid clinical conditions and associated complications.11
Hyponatremia is a life-threatening electrolyte disturbance, it
has been reported as the most common condition involving
electrolytes in the emergency department and among hospital-
ized patients.12 It has been independently associated with dele-
terious changes among hospitalized patients,13 and enhanced
risk for neurological patients. Significant adverse association of
hyponatremia with poor prognosis and mortality was observed
in patients with different conditions such as heart failure, liver
cirrhosis, hepatorenal syndrome, hepatic encephalopathy, liver
transplantation, patients undergoing surgery, critically ill pa-
tients, geriatric patients.14e20 Hyponatremia is frequently re-
ported also in nervous system disorders, such as encephalitis,
meningitis, subarachnoid hemorrhage and head injury.21,22
Several authors found occurrence of hyponatremia among
TBM patients in a frequency ranging from 35% to 71%.13,23e25
Leptomeningeal inflammation, hydrocephalus, high
intracranial pressure and ventriculitis may be responsible for
a higher frequency of hyponatremia in TBM cases and can be
attributed to fatal outcome.11 Usually, hyponatremia in
neurological patients, with normal renal function, is due to
syndrome of inappropriate antidiuretic hormone (SIADH),
These clinical conditions differ in clinical features, risk factors
and, most importantly the management, hence their charac-
teristics have to be carefully evaluated in formulating a diag-
nosis. In addition, other clinical etiologies like poor oral
intake, extrarenal losses (vomiting, diarrhea), heart failure,
endocrine disturbances need to be considered before diag-
nosing SIADH or CSW.26
There are few prospective studies investigating occurrence
of hyponatremia in TBM cases, but many case reports and
case series can be found describing such clinical scenario.
There is paucity of comprehensive evidence reporting hypo-
natremia among TBM patients ranging from its current
epidemiology, associated risk factors, case fatality, predictive
value for the patients’ prognosis.
2. Methods
2.1. Search strategy
This systematic review rigorously followed the recommenda-
tions of the preferred reporting items for systematic reviews
and meta-analyses (PRISMA) checklist27 and other reported
article.28 The protocol was registered in PROSPERO, University
of York (CRD42018088089). A comprehensive electronic search
was developed in February 2018, conducted through ten data-
bases, including PubMed, Science Direct, Scopus, Google
Scholar, Cochrane Library, SIGLE, WHO Global Health Library
(GHL), ISI Web of Science, Virtual Health Library (VHL), and
EMBASE, to systematically find relevant articles. All databases
were explored using this search strategy (hyponatremia OR
(Low sodium) OR (cerebral salt) OR (cerebral salting) OR (salt
wasting) OR SIADH) AND (tuberculous OR tubercular OR
tuberculosis OR tuberculoma) AND (meningitis OR meningo-
encephalitis OR meningocerebritis). Different syntax and
search terms were modified for Google Scholar with the aim to
retrieve potentially relevant articles. Furthermore, we also
conducted a manual search in June 2018 through the bibliog-
raphies of our eligible articles, previous reviews, cited articles
in PubMed and Google Scholar to collect relevant articles.
2.2. Eligibility criteria
The results from the electronic search were imported to
EndNote X8 to delete duplicated articles. We included original
articles that reported the condition of hyponatremia in
tuberculous meningitis patients regardless of the classifica-
tion of diagnosis either definite or probable. We excluded
 indian journal of tuberculosis xxx (xxxx) xxx
studies with unreliable data, abstract only articles, and re-
views. In addition, no restriction was applied to language,
publication date, patient's age or location during the screening
process. Three researchers independently screened the titles
and abstracts of the retrieved articles to select the eligible
ones. In case any disagreement arose among reviewers, the
method chosen to reach an agreement was to discuss it and to
consult senior researchers if needed. After this stage, a further
full-text screening was carried out by three reviewers to
extract data from the text.
2.3. Data extraction
Three senior reviewers developed a standardized extraction
sheet, analysing the five most relevant studies, then three
independent researchers embarked in a detailed extraction
through the sheet to record relevant data. Throughout this
stage, if any novel variables were determined, the extraction
sheet would be modified to include the relevant data. The
following information were recorded: study characteristics
(authors, year of publication, year of research, country of the
first author, country of the patients, inclusion and exclusion
criteria, and sample size), basic and demographic data (age,
ethnicity, co-morbidities, previous drug usage, family medical
history), methods of diagnosis, radiological findings, types of
diagnosis, length of hospital stay, duration of treatment,
natremia values (mEq/L), clinical signs and symptoms, the
severity of TBM, the outcome of patients, the treatments
(Antitubercular therapy, corticosteroids, fluid replacement)
employed against TBM and hyponatremia. Authors were
contacted if there were any missing data.
2.4. Statistical analysis
We performed a statistical analysis from the data obtained from
case reports. We used the ShapiroeWilk test for continuous
variables to check the normality distribution.29 The results were
presented as mean ± standard deviation (SD) for normally
distributed continuous variables or as median and inter-quartile
range (IQR) for non-normally distributed continuous variables.
Categorical variables were presented as frequencies and per-
centages. The Wilcoxon rank test was used to detect the differ-
ence in non-parametric groups.30 The KruskaleWallis test was
used when there were more than two groups.31 We performed
analysis of the data before and after imputing missing values.
Imputation was performed using K-nearest neighbors with K ¼ 5.
To assess factors affecting blood sodium level in these
cases, we correlated both baseline sodium level and after
follow-up with age, cerebrospinal fluid (CSF) tests and blood
tests. We used Kendall's tau correlation to determine the
relationship between two non-normally distributed variables,
otherwise, the Pearson's correlation (r) was used.32 A signifi-
cant correlation was considered when P-value is less than 0.05.
When a significant correlation was found, a regression model
was applied to detect relationships between each two corre-
lated variables. Analyses were conducted in R (3.4.4), using the
caret package.33,34 A random effects model meta-analysis was
conducted to pool the mean sodium level in TBM patients.
Meta-regression was conducted to understand the effect of
confounders on the mean sodium level in TBM. We pooled the
3
deaths rate in TBM and regressed the mean sodium level to
understand the relationship between level of natremia and
rate of death. First, heterogeneity was assessed with Q sta-
tistics and I2-test considering it significant with I2 value > 50%
or P value < 0.10. A fixed-effect model was used when there
was a lack of significant heterogeneity while a random-effects
model was used when it was present. Publication bias was
assessed with the Egger's linear regression test, being signifi-
cant if p-value < 0.10 and represented graphically by Begg's
funnel plot when there were ten or more studies.35
3. Results
3.1. Literature search
The electronic search retrieved 989 titles and abstracts, 391 of
the articles were then removed due to duplication by using
EndNote software (Fig. 1). After screening title and abstract,
only 169 articles were considered relevant to our objective and
were screened in full text. 40 relevant reports were found. By
manually searching the bibliography of included articles and
past reviews, we retrieved only 2 articles. At the end of the
process there were 42 papers consisting of: 24 case reports,
eight studies used for qualitative analysis and other 10 studies
reported in quantitative analysis.
3.2. Patients’ characteristics and TBM diagnosis
The included case reports described a total of 48 cases with
median age of 16 years (range 4e32) which included 15 fe-
males (32.6%) and 31 males (67.4%). The median duration of
hospitalization was 24 days (range 11e49) (Table 1).
The analysis of cerebrospinal fluid (CSF) demonstrated a
median glucose concentration around 1.39 mg/dl (range
0.68e2.35) mg/dl, a median protein level of 1.60 (range 1e2.64)
mg/dl, and a white cell count of 175 cells/mm3 with a
lymphocyte dominance of 90%. These CSF biochemical test
results were compatible with a tuberculous meningitis diag-
nosis and other methods were used to confirm the presence of
Mycobacterium tuberculosis.
Acid-Fast Bacilli (AFB) test staining was carried out in
almost all cases; at admission it was positive in ten patients
(38.5%), only four patients were tested at follow up of which
only one was still positive. Cell cultures were used in only 15
cases, but a small number were positive (4 cases, 26.7%) at the
time of admission and two cases were tested at follow-up
resulting negative. Nine patients were tested through poly-
merase chain reaction (PCR), the most sensitive tool among
those used and this was confirmed by the high percentage of
positive cases, 54.5%.
Among those 48 included cases precision for diagnosis
confirmation was variable with definite cases (n ¼ 24) and
probable cases (n ¼ 14). Half of cases recovered completely
(56.1%), more than one third died (34.9%), and the remaining
cases underwent sequelae e.g. disability and neurological
impairment (n ¼ 3), marked neurologic sequelae (n ¼ 1),
minimal neurological sequelae (n ¼ 1).
The Characteristics of the included case reports and the
main manifestations, treatments used for hyponatremia and
4 indian journal of tuberculosis xxx (xxxx) xxx
Fig. 1 e The PRISMA flow diagram of the search process in our study.
outcomes of the included case reports was reported in details
in Supplementary Tables 1 and 2.
In the 25 reported cases with biochemically hyponatremia,
CSW was the main cause (20 cases), only four cases were due
to SIADH and in the last patient differentiation between
SIADH and CSW could not be done (Table 2). Other conditions
that have been reported as possible causes of hyponatremia
such as adrenal insufficiency, poor oral intake, extra-renal
losses (vomiting, diarrhea), heart failure or endocrine distur-
bances, were not described.
3.3. Factors determining sodium level and hyponatremia
We performed correlation analysis using individual levels of
different laboratory parameters reported in the case reports.
There was no significant Spearman correlation between blood
sodium level in TBM patients and their age (p-value ¼ 0.39),
various CSF parameters e.g. glucose level (r ¼ 0.001, p ¼ 0.63),
lymphocyte count (r ¼ 0.06, p ¼ 0.42), total WBCs count
(r ¼ 0.12, p ¼ 0.58), neutrophil count (r ¼ 0.08, p ¼ 0.10) and
protein levels (r ¼ 0.02, p ¼ 0.96) (Fig. 2). In addition, there was
no significant difference in sodium level between male and
female (p ¼ 0.87), different causes of hyponatraemia (p ¼ 0.27)
or patients’ outcome (p ¼ 0.41) (Fig. 3).
The mortality rate among cases of TBM was 29% [95% CI
(18%; 42%)] (Fig. 4). Because the number of deaths in cases of
hyponatremic patients versus the cases with normal sodium
level was not available in the included papers, we used meta-
regression to illustrate the effect of sodium level on the mor-
tality rate of TBM.
We found that there was no significant effect of sodium
levels on the mortality rate in TBM cases [b ¼ 0.01, standard
error (SE) ¼ 0.09, p ¼ 0.9] (Supplementary Fig. 1).
Furthermore, we observed that the pooled mean sodium
level in all TBM patients was 131.08 [95%CI (125.14e137.02)];
with a prediction interval of (108.79e153.37) (Fig. 5).
There was no publication bias (p ¼ 0.7), however, there was
significant heterogeneity (I2 ¼ 99%, p ¼ 0.001). The Baujat plot
revealed that Ambekar et al had the highest influence on
heterogeneity (Supplementary Fig. 2).
A random effects model meta-analysis of 9 studies
revealed that the overall rate of hyponatraemia in TBM was
52% [95%CI (35.8%e61.1%)] (Fig. 6). There was significant het-
erogeneity (p < 0.1).
Regarding the difference of natremia levels between TBM and
other bacterial meningitis, there was only one study conducted
by Sengupta P. et al.36 Patients with meningitis in this study were
divided depending on the causative agent, eight patients
 indian journal of tuberculosis xxx (xxxx) xxx 5

Table 1 e The characteristics of included cases of TBM.

Overall
N 48
Age (median [IQR]) 16.00 [4.00, 32.00]
Sex (%) Female 15 (31.2)
Male 31 (64.6)
Duration of hospital stay (median [IQR]) 24.00 [11.00, 49.00]
Glucose (median [IQR]) 1.39 [0.68, 2.35]
Protein (median [IQR]) 1.60 [1.00, 2.64]
WBCs counts (median [IQR]) 175.00 [51.50, 374.50]
Lymphocytes (median [IQR]) 0.90 [0.45, 0.95]
Neutrophils (median [IQR]) 0.10 [0.05, 10.00]
AFB stain (%) Negative 16 (61.5)
Positive 10 (38.5)
AFB stain after follow-up (%) Negative 3 (75.0)
Positive 1 (25.0)
Culture initial (%) Negative 11 (73.3)
Positive 4 (26.7)
Culture after follow-up (%) Negative 2 (100.0)
PCR for tubercular antigen (%) Negative 5 (45.5)
Positive 6 (54.5)
Precision of tuberculosis diagnosis (%) Definite 24 (61.6)
Probable 14 (35.9)
Outcome (%) Recovery 24 (56.1)
Death 15 (34.9)
Developed disability and neurological impairment 3 (7.0)
Marked neurologic sequelae 1 (2.3)
Minimal neurological sequelae 1 (2.3)
Reported cause of hyponatremia (%) (n ¼ 25) CSW 20 (80.0)
SIADH 4 (16.0)
SIADH or CSW 1 (4.0)
Initial sodium level (median [IQR]) (mmol/dl) 127.00 [124.50, 130.00]

presented a tubercular meningitis for whom sodium level was
128.63 ± 7.44 and 22 patients with bacterial meningitis with a
natremia of 128.55 ± 4.93.36
4. Discussion
In this review, we analysed how low blood sodium influences
outcomes of individuals infected with M. tuberculosis that
manifested as tuberculous meningitis (TBM). Hyponatremia
has been reported as a common complication in TBM patients
but a specific analysis in this category of patients has not been
reported so far. Exploring such relationships is clinically rele-
vant given the important physiologically effects caused by
electrolyte imbalances.
According to the current meta-analysis, the prevalence of
hyponatremia in TBM patients, is estimated to be 52%. The
pooled mean sodium level in all TBM patients was 131.08 mEq/
L. We found no significant correlation between blood sodium
level in TBM patients and their age, various CSF parameters
i.e. glucose level, lymphocyte, total WBCs, neutrophil count,
and protein levels. In addition, there was no significant dif-
ference in sodium level based on sex of patients, or outcome.
Tuberculous meningitis (TBM) is associated with high mor-
tality and morbidity despite administering anti-tuberculous
chemotherapy to the patients.37 The number of deaths in cases
of hyponatremic patients versus the cases with normal sodium
level was not available in the included papers; we therefore used
meta-regression analysis to illustrate the effect of sodium level
on the mortality rate of patients with TBM that did not reveal a
significant (b-coefficient ¼ 0.18, standard error ¼ 0.08, p-value ¼
0.03). The rate of death among TBM patients was 21.9%, a figure
lower than the most current mortality rates reported from 23% to
around 50%, this probably depends on the demographics of our
sample, different from the wider population.2,38e40
Differential diagnosis between the different types of
meningitis like TBM, other bacterial meningitis or viral men-
ingitis (VM) is difficult in some clinical situations, however
there was only one study conducted in Dhaka Medical College
and Hospital (DMCH) where patients with meningitis were
divided depending on the causative agent, eight patients
presented a tubercular meningitis for whom sodium level was
128.63 and 22 patients with bacterial meningitis with a
natremia of 128.55.36 In the sample of this study, CSW was the
most common (80%) cause of hyponatremia, SIADH was pre-
sent in 16% of patients only and the etiology of the electrolyte
imbalance in one patient was undetermined.
In the current study no significant difference in measur-
able patient parameters was found when comparing the two
etiologies of hyponatremia. We compared demographic in-
formation, serum sodium level before and after treatment,
and CSF parameters (CSF glucose level, lymphocyte, total
WBCs, neutrophil count, and protein levels) without finding
statistically significant differences.
 6
Table 2 e Comparison between different causes of the hyponatremia in TBM patients.
Level CSW SIADH SIADH or CSW P-value
N 20 4 1
Age (median (year) [IQR]) 12.50 [5.00, 39.00] 22.00 [17.50, 24.75] 11.00 [11.00, 11.00] 0.834
Sex (%) Female 6 (31.6) 0 (0.0) 0 (0.0) 0.426
Male 13 (68.4) 3 (100.0) 1 (100.0)

indian journal of tuberculosis xxx (xxxx) xxx

Duration of hospital stay (day) (median [IQR]) 21.00 [12.50, 54.25] 21.00 [14.00, 31.50] 8.00 [8.00, 8.00] 0.534
CSF glucose (mg/dl) (median [IQR]) 1.14 [0.17, 2.11] 0.33 [0.16, 1.00] NA 0.532
CSF protein (mg/dl) (median [IQR]) 1.51 [1.12, 1.82] 2.00 [0.75, 3.91] NA 0.764
CSF WBCs (cell/mm3) (median [IQR]) 200.00 [55.00, 357.50] 105.00 [76.25, 243.00] NA 0.915
Lymphocytes (cell/mm3) 0.92 [0.70, 1.00] 0.72 [0.52, 0.85] NA 0.068
(median [IQR])
Neutrophils (cell/mm3) (median [IQR]) 0.06 [0.00, 0.10] 0.14 [0.14, 0.14] NA 0.235
AFB Stain (%) Negative 9 (64.3) 2 (66.7) 0 (NA) NA
Positive 5 (35.7) 1 (33.3) 0 (NA)
AFB stain after follow up (%) Negative 2 (100.0) 0 (Na) 0 (NA) NA
Positive 0 (0.0) 0 (Na) 0 (NA)
Culture initial (%) Negative 2 (66.7) 1 (50.0) 0 (NA) NA
Positive 1 (33.3) 1 (50.0) 0 (NA)
Culture after follow up (%) Negative 1 (100.0) 0 (Na) 0 (NA) NA
PCR for tubercular antigen (%) Negative 3 (60.0) 1 (50.0) 0 (NA) NA
Positive 2 (40.0) 1 (50.0) 0 (NA)
Initial sodium level (mmol/dl) (median [IQR]) 126.50 [123.50, 130.00] 131.00 [128.50, 131.50] 118.00 [118.00, 118.00] 0.137
Final sodium level after treatment (mmol/dl) (median [IQR]) 131.00 [121.75, 140.00] 118.00 [115.50, 124.25] 116.00 [116.00, 116.00] 0.159
Type for diagnosis of TBM (%) Brain CT, chest CT scan, CSF 0 (0.0) 0 (0.0) 0 (0.0) NA
Precision of diagnosis of TBM n (%) Definite 10 (52.6) 2 (50.0) 1 (100.0)
Probable 8 (42.1) 2 (50.0) 0 (0.0)
Outcome (%) Death 3 (17.6) 1 (33.3) 1 (100.0) NA
Developed disability and neurological impairment 0 (0.0) 0 (0.0) 0 (0.0)
Discharged 12 (70.6) 2 (66.7) 0 (0.0)
Marked neurologic sequela 1 (5.9) 0 (0.0) 0 (0.0)
Minimal neurological sequelae 1 (5.9) 0 (0.0) 0 (0.0)
 indian journal of tuberculosis xxx (xxxx) xxx
Fig. 2 e The Spearman correlation matrix between sodium
level and different possible. CSF characteristics that could
be risk factors. The correlation co-efficient is reported in
each square.
It is interesting to notice that even sodium levels and pa-
tient outcomes were similar in patients with confirmed CSW
and SIADH.
Hyponatremia is relatively common in hospitalized pa-
tients, especially if they are in the older population or chil-
dren, affecting annually between 3.2 million to 6.1 million
persons in the U.S.41 Among the causes of this electrolyte
imbalance there are commonly infections, including those
Fig. 3 e Comparison of the median sodium level between A) gender of patients, B) causes of hyponatremia, C) outcome of
patients.
7
from M. tuberculosis. In adult hospitalized patients in South
Africa, pulmonary TB was reported as the most common
cause of severe hyponatremia (blood Na < 120 mEq/L),
affecting 24% of patients in the study.38
Hyponatremia among TB patients with meningitis (TBM) is
figured out as affecting from 52% of patients. A prospective
study conducted in India in 2017 had a prevalence of hypo-
natremia of 44.7% among TBM patients, but more than 40%
were caused by non-neurological causes such as vomiting,
drugs, nutritional or endocrine distress, unlike our sample in
which only neurological etiologies were reported.39,40 In other
prospective studies, the prevalence has been described to be
much higher, in a pediatric sample, Maesaka et al reported
that, on admission, 65% of patients had hyponatremia,42 one
explanation could be the higher vulnerability of pediatric pa-
tients. While in another prospective cohort 57% of the patients
had low sodium blood levels, and this condition put them at
higher risk of stroke.43
Similar figures were found when analyzing all TB cases. A
prevalence of 51% of low blood sodium concentration, has
been reported in pulmonary TB cases in Iran,44 and a rate of
62% in a study in adult patients in India.45
The prevalence found in our study seems lower but
compatible with the prevalence of this condition previously
reported in TB patients, with and without CNS involve-
ment42,43. The reported rates vary broadly across different
studies, probably because the development of this condition is
highly dependent on the demographics of the population
studied and can be affected by a low numerosity of partici-
pants. Because of these reasons it is also difficult to assess if
8 indian journal of tuberculosis xxx (xxxx) xxx
Fig. 4 e Random effect model meta-analysis showing the prevalence rate of death among TBM patients.
hyponatremia is more common between patients with TBM or
in all TB patients.
Hyponatremia has been reported as predictor of poor
prognosis in various diseases, such as: malignancies, acute
heart failure, cirrhosis, and kidney disease. When analyzing
patients undergoing treatment in intensive care unit, sodium
blood level on admission correlated with mortality and this
electrolyte imbalance was were associated with significantly
prolonged hospital stays.46e48
Although in pulmonary tuberculosis patients, no signifi-
cant correlation was found between hyponatremia and mor-
tality,44 but low blood sodium in TBM has been linked to a
typically neurological etiology, therefore this insignificance
can be related to the lack of a neurological affection in other
patients with pulmonary TB.
Hyponatremia with neurological manifestations has been
reported where some neurosurgical patients with low sodium
levels were subject of worse sequelae and in some cases
death.49 Similarly, presenting this electrolyte imbalance at
admission, even in a mild form, was reported as an indepen-
dent predictor of 3-year mortality and poorer discharge dis-
positions in acute stroke patients.50
For other neurological conditions the opposite has been re-
ported, with no significant association between a decrease in
sodium-levels and cognitive status in traumatic brain injuries.51
Conflicting evidence exists for aneurysmal Subarachnoid
Hemorrhage patients, that have been reported by Vrsajkov et al
Fig. 5 e Random effect model meta-analysis illustrating the overall mean sodium level (in mg/dl) in TBM patients.
as more likely to develop deficits and to stay longer in intensive
Care when hyponatremic; while in another study no difference
was found with patients with normal sodium levels in 3 month
outcomes.52,53 Hyponatremia has been found to be a frequent
complication in patients with tuberculous meningitis (TBM)54
and is associated with mortality, especially when there is a co-
infection with HIV. Although there were three cases infected
with HIV 52,55,56, it was not reported as a risk factor for hypo-
natremia. On the other hand, hydrocephalus was considered a
risk factor in paediatric patients developed hyponatremia
where all of them had intracranial tumor.57
It is worth noting that hyponatremia did not cause a
worsening of symptoms, complications or unfavourable out-
comes, similarly to the TBM patients studied in our current
meta-analysis. Our findings also conform with a prospective
study by Misra et al, in which no significant difference in
mortality was recorded between TBM patients with or without
hyponatremia.40
However, the severity of hyponatremia was linked to worse
outcomes in pediatric patients diagnosed with bacterial
meningitis.58 Likewise in a pediatric sample with TBM it was
observed a 1.5- fold higher in-hospital mortality rate
compared to patients without hyponatremia, even though in
this study TBM could not be officially confirmed because of the
lack of available nucleic acid amplification tests.25,53
An influence of patient's age on the impact of hypona-
tremia on patient outcomes could be possible, but further
 indian journal of tuberculosis xxx (xxxx) xxx
Fig. 6 e Random Effect model meta-analysis showing the prevalence rate of hyponatremia among TBM patients.
studies are needed, since such analysis could not be carried
out in our study and existing literature does not report data on
the topic.
The hemodynamic changes in the human body behind the
increased prevalence of hyponatremia in all TB patients can
be difficult to assess. There are multiple factors that can pre-
sent concurrently, examples are: adrenal insufficiency, renal
diseases, poor oral intake, extra renal losses (vomiting, diar-
rhea). In TBM, neurological causes can contribute heavily to
the electrolyte disorder, but they are not always the primary
cause of hyponatremia. Misra et al reported that an extra-CNS
condition was to blame in 41.2% of TBM patients presenting
with hyponatremia.40 It is important to evaluate and exclude
these and other common causes before a neurological
involvement can be ascertained.
Neurological causes of hyponatremia have two main eti-
ologies, SIADH and/or CSW. The pathogenesis of these syn-
dromes is not fully understood but leptomeningeal
inflammation, hydrocephalus, raised intracranial pressure
and ventriculitis may play an important role.59 CSW and
SIADH share similar symptoms. Hence, it is important to
differentiate between the diagnosis of CSW and SIADH, as the
treatment for cerebral salt wasting, fluid replenishing, can be
detrimental for patients with the other condition.
Even if less common among the population in our study,
TBM is an established cause of SIADH, a condition that involves
production of excess anti-diuretic hormone that stops kidneys
from excreting water and causes hyponatremia with a normal
or increased plasma volume.53,60,61 It is probably due to
inflammation or increased intracranial pressure but one case of
possible ectopic antidiuretic hormone production as a possible
mechanism causing hyponatremia has been reported.62
Nakashita et al also reported a case of SIADH caused by
ethionamide (an antitubercular agent) in a patient with pul-
monary TB, the exact mechanism is not yet established but
the dose of this drug does not seem to affect the incidence of
the disease.63,64
Many intracranial conditions can cause CSW, a renal loss of
sodium due to traumatic events or infectious diseases that
affect the CNS. The main cause seems to be a neurological
dysfunction that decreases firing of the sympathetic nervous
system diminishing sodium reabsorption in the proximal
9
tubules. Inhibition of the renineangiotensin system, the release
of brain natriuretic factor (BNP), atrial natriuretic peptide (ANP)
and other natriuretic proteins also play a role in the pathogen-
esis. This leads to the typical hypovolemia present in this con-
dition that can increase the secretion of ADH and confound
clinicians trying to differentiate it from SIADH.42,59,65,66
4.1. Limitations
There are some potential limitations to our findings, given the
nature of the study. In a meta-analysis data collection cannot
be controlled directly, so different reporting systems may
have been used to record confirmed cases and deaths. This
could have led to differential reporting of these outcomes and
thereby an inaccurate estimate of the condition and its out-
comes in either direction. Neither of the analyzed clinical
parameters nor patient outcome in this study was statistically
different depending on the etiology, so none of these could be
an advisable clinical tool for an accurate diagnosis and thus
correct management of hyponatremia. The lack of relevant
results could be influenced by the low numerosity of reported
cases of hyponatremia in TBM cases in general. Furthermore,
our sample contains patients from very different age ranges,
this surely influences prevalence and etiology of hypona-
tremia and can impact overall mortality, further studies
comparing different age ranges could help discern possible
influence of this confounding factor.
Due to current limited knowledge of this condition, we
should consider hyponatremia a complication of tuberculous
meningitis that cannot help clinicians predict an increased
risk of mortality. It should be, instead treated as an indepen-
dent factor when evaluating the severity of the condition.
Further prospective studies are needed to confirm or disprove
these data and to understand better the mechanism behind
hyponatremia in TBM with the ultimate goal of establishing
effective treatment strategies.
5. Conclusions
Hyponatremia cannot be considered a poor prognostic factor
for mortality in tuberculous meningitis patients. Patients with
10 indian journal of tuberculosis xxx (xxxx) xxx
TBM should be closely observed for electrolyte imbalances as
it represents a common complication. Further studies could
focus on the predisposing factors of electrolyte imbalance in
patients suffering from Tuberculous meningitis and the in-
fluence of patient's age and of hyponatremia etiology.
Author's contribution
Conception or design of the work: Truong Hong Hieu.
Data collection: all authors.
Data analysis and interpretation: Sara Morsy, Gehad
Mohamed Tawfik.
Drafting the article: Truong Hong Hieu, Mohammad Rashidul
Hashan, Sara Morsy, Federia Cuce .
Critical revision and supervision of the study: Nguyen Tien
Huy.
Final approval of the version to be published: All authors.
Conflicts of interest
The authors have none to declare.
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