Central Nervous System Tuberculosis Following Delayed and Initially Missed Lung Miliary Tuberculosis: a Case Report.

Abstract

Central nervous system (CNS) tuberculosis includes three clinical entities: tuberculous meningitis, intracranial tuberculoma, and spinal tuberculous arachnoiditis. All three categories are encountered frequently in regions of the world where the incidence of TB is high. Meningeal tuberculosis is a medical emergency: it is the most severe, lethal and disabling form of tuberculosis. Early diagnosis and treatment can be lifesaving. Even, in developed countries the diagnosis of tuberculous meningitis is difficult, frequently delayed or missed, and is often not microbiologically confirmed. Here I report a case of miliary tuberculosis, in a patient with diabetes mellitus and chronic kidney disease, but
without HIV infection. Although the patient had regular contact with healthcare staff (hemodialysis), miliary tuberculosis diagnosis was considerably delayed. This patient, subsequently evolved into tuberculous meningitis. In spite of quadruple anti-tuberculosis treatment, corticosteroids, and general supportive care, this case resulted in death.

Full text

CASE REPORTS
270
Corresponding author
Meregildo Rodriguez, Edinson Dante
E-mail: dante_meregildo@hotmail.com
Central nervous system tuberculosis
following delayed and initially
missed lung miliary tuberculosis:
a case report
Edinson Dante Meregildo Rodriguez
Internal Medicine Master of Medicine, Chiclayo, Lambayeque, Peru;
Emergency Department of Regional Hospital of Lambayeque, Chiclayo, Lambayeque, Peru
Central nervous system (CNS) tuberculosis includes
three clinical entities: tuberculous meningitis, intracra-
nial tuberculoma, and spinal tuberculous arachnoidi-
tis. All three categories are encountered frequently in
regions of the world where the incidence of TB is high.
Meningeal tuberculosis is a medical emergency: it is
the most severe, lethal and disabling form of tubercu-
losis. Early diagnosis and treatment can be lifesaving.
Even, in developed countries the diagnosis of tuber-
culous meningitis is difcult, frequently delayed or
missed, and is often not microbiologically conrmed.
Here I report a case of miliary tuberculosis, in a patient
SUMMARY
with diabetes mellitus and chronic kidney disease, but
without HIV infection. Although the patient had regu-
lar contact with healthcare staff (hemodialysis), miliary
tuberculosis diagnosis was considerably delayed. This
patient, subsequently evolved into tuberculous menin-
gitis. In spite of quadruple anti-tuberculosis treatment,
corticosteroids, and general supportive care, this case
resulted in death.
Keywords: tuberculosis, central nervous system tuber-
culosis, miliary tuberculosis, diagnosis, delayed diag-
nosis.
n INTRODUCTION
Tuberculosis (TB) is a global public health
problem [1, 2]. According to the World Health
Organization, Peru is a country of high endemici-
ty and belongs to the top 30 high burden countries
for resistant TB. About 20% of all TB cases are ex-
trapulmonary [1]. Central Nervous System (CNS)
tuberculosis (TB) accounts for 1% of all TB cases
and 5% of extrapulmonary TB cases. In resource
limited countries, though is highly endemic, TB
diagnosis remains very difcult. So, a high index
of suspicious is required [2-5]. Here, I present a
case of miliary TB that subsequently evolved into
CNS tuberculosis (tuberculous meningitis and in-
tracranial tuberculomas).
n CASE PRESENTATION
A 63-year-old woman was admitted to Emergency
Department on February 09th 2018 with a 3-week
history of headache, drowsiness, hypoactivity, an-
orexia, and asthenia. She had previous history of
diabetes mellitus (DM), hypertension (HTN), and
Chronic Renal Disease (CRD) on regular hemodi-
alysis (HD). Physical examination: blood pressure
160/90 mmHg, respiratory rate 20 bpm, heart rate
84 bpm, T 37.8 °C, Sat. O2 95% (FiO2 0.21). Body
weight 50 kg, height 1.65 m, BMI 18.3 kg/m2; res-
piratory, cardiovascular, and gastrointestinal sys-
tem were unremarkable. Neurologic examination
showed stupor (Glasgow Coma Scale 13), unre-
Le Infezioni in Medicina, n. 3, 270-275, 2018

271Central Nervous System tuberculosis
sponsive to calling, no focal decit, isochoric pu-
pils with normal reaction to light, no meningeal
signs, the Babinski’s sign was positive bilaterally.
Basic analysis, Chest X-ray (CXR) (Figure 1), and
non-contrast head computed tomography (CT)
were performed (Figure 2 and Figure 3). Evolu-
tion: on February 10th, 2018, the patient remained
with stupor and low-grade fever. Based on head
CT a provisional diagnosis of neurocysticercosis
was entertained, and Western Blot serology and
contrast-enhanced brain magnetic resonance im-
aging (MRI) were ordered. On February 15th 2018,
the patient became comatose. She was intubated
and connected to mechanical ventilation (MV).
On February 18th 2018, a diagnosis of miliary TB
was made based upon an “unexpected nding”
of a CXR taken three months before (Figure 4).
There was no evidence in the patient’s medical re-
cord of the reason why this CXR was taken. But is
probable that it was indicated by nephrologist for
checking proper position of central venous cathe-
ter for hemodialysis after it was inserted, because
this is a routine practice.
Because, no cause of coma could be determined at
this point, negative serology for cysticercosis, and
an established diagnosis of miliary TB, a diagno-
sis of CNS tuberculosis was entertained and spi-
nal tap was performed. Based on clinical grounds
and preliminary cerebrospinal uid (CSF) labo-
ratory results, anti-TB therapy was initiated. CSF
adenosine deaminase (ADA) result was obtained
2 days after spinal tap. During the following days,
Figure 1 - CXR (February 9th, 2018) showing enlarged
heart shadow and miliary pattern of pulmonary opac-
ities suggestive of interstitial lung disease, including
fibrosis.
Figure 2 and Figure 3 - Non-contrast head CT (February 09th, 2018), coronal (left) and sagittal (right) views showing
multiples hyperdense lesions (calcifications) compatible with tuberculomas and prominent perilesional edema.

272 E.D. Meregildo Rodriguez
this patient continued with MV and general sup-
portive care, including broad spectrum antibiotics
and vasopressors. She died 20 days after initiation
of anti-TB treatment.
Lab Tests: remarkable basic hematology and bio-
chemistry were hypoproteinemia (6.1 g/dL), hy-
poalbuminemia (2.79 g/dL), moderate anemia
(9 g/dL), and severe lymphopenia (252 lympho-
cytes/μL or 4% out of 6 300 white blood cells).
Serologies for cysticercosis (Western Blot), human
immunodeciency virus (HIV), hepatitis B and C,
and VDRL were also negative. CSF: turbid, 310
leucocytes/uL, polymorphonuclear 85%; Gram
smear, china ink smear, Ziehl-Neelsen (ZN) smear
were negative; glucose 18 mg/dL, proteins 272.3
mg/dL, ADA 38.2 U/L. Non-contrast head CT:
Normal. ZN smear and culture for M. tuberculo-
sis in urine (two samples), gastric aspirate (two
samples), bronchial secretion (two samples), feces
(one sample), all were negative. Cultures for com-
mon pathogens: bronchial secretion, urine, and CSF
were also negative. Electrocardiogram was com-
patible with left ventricular (LV) hypertrophy;
echocardiography showed LV hypertrophy, LV
ejection fraction (by modied Simpson’s rule) of
52%, grade II diastolic dysfunction, no valvular
abnormalities, no pericardial effusion, and bor-
derline pulmonary artery pressure. Polymerase
chain reaction (PCR) was not available in our in-
stitution at the time of the case presentation; and
because of the denial of patient’s family autopsy
was not performed.
Final diagnosis: tuberculosis miliary and CNS tu-
berculosis (tuberculous meningitis and intracra-
nial tuberculomas).
Standard quadruple anti-TB therapy included
isoniazid 5 mg/kg, rifampicin 15 mg/kg, etham-
butol 20 mg/kg, pyrazinamide 25 mg/kg adjust-
ment for CRD in HD. Dexamethasone 0.4 mg/
kg/d was administered concomitantly. CSF cul-
ture in solid media yielded Mycobacterium tuber-
culosis (MTB) susceptible to all rst line anti-TB
drugs, which was obtained 6 weeks after death.
n DISCUSSION
Tuberculosis remains one of the leading causes of
adult deaths from infectious diseases worldwide.
During last years, a constant proportional in-
crease of extrapulmonary disease has been report-
ed [1, 2]. This case emphasizes the importance of
clinicians’ awareness on life-threatening forms of
extrapulmonary TB, especially CNS disease, be-
cause it is hard to diagnose without having it con-
stantly in mind. Delayed diagnosis and treatment
is associated with a poor prognosis such as in the
presented case [2-5].
CNS tuberculosis (TB) includes three clinical cate-
gories: tuberculous meningitis (TBM), intracranial
tuberculoma, and spinal tuberculous arachnoidi-
tis. All three categories are encountered frequent-
ly in endemic regions such as Peru [6]. During the
bacillaemia that follows primary infection or late
reactivation tuberculosis (TB), scattered tubercu-
lous foci (tubercles) are established in the brain,
meninges, or adjacent bone. The chance occur-
rence of a subependymal tubercle, with progres-
sion and rupture into the subarachnoid space, is
the critical event in the development of tubercu-
lous meningitis. The widespread and dense dis-
tribution of infectious foci seen in association with
progressive miliary tuberculosis greatly increases
the chance that juxta-ependymal tubercles will be
established. Consequently, meningitis develops
most commonly as a complication of progressive
primary infection in infants and young children
and from chronic reactivation bacillaemia in older
adults with immune deciency caused by aging,
alcoholism, malnutrition, malignancy, HIV infec-
tion, etc. [2-4]. The case presented here, had sever-
Figure 4 - Chest X-Ray (November 23th, 2017) showing
a typical miliary pattern of pulmonary opacities and
cardiomegaly.

273Central Nervous System tuberculosis
al risk factors (DM, CRD on HD, elderly), but no
HIV infection.
TBM evolves into three phases:
1) prodromal phase, presents insidiously (2-3
weeks) with malaise, asthenia, headache, fe-
ver, and personality changes;
2) meningitic phase follows with meningismus,
protracted headache, vomiting, lethargy, con-
fusion, and cranial nerve and long-tract signs;
3) paralytic phase supervenes with stupor, coma,
seizures, and hemiparesis.
Several TBM severity scales have been developed.
One of the most useful and extensively used is
the Modied Medical Research Council Scale
(mMRC). This system classies:
1) Grade I: GCS 15, no focal neurologic decit;
2) Grade II: GCS 11-14, or 15 with focal neurologic
decit;
3) Grade III: GCS ≤10 [2-4].
MTB is the most severe, lethal, and disabling form
of TB. Mortality ranges from 20 to 50% but can
be 100% in patients with resistant TB and HIV
coinfection. Clinical outcomes depend mainly
on stage when treatment is initiated. Therefore,
early TBM diagnosis has critical importance [2].
Death rate or severe neurologic disability in stage
mMRC I, II, y III is 15%, 30% and 50%, respective-
ly for non-HIV-infected patients [3]. Our patient
presented on paralytic phase and began treatment
in mMRC stage III. This explains, at least in part,
its adverse outcome. Other prognostic factors are
age, and duration of disease. Mortality is higher
in patients less than 5 years (20%) and more than
50 years (60%), and in those with symptoms last-
ing more than 2 months (80%) [2, 4]. It is evidence
based that BCG vaccination at birth protects new-
borns and infants from the most serious manifes-
tation of disseminated TB [2].
The cornerstone in TBM diagnosis is CFS analysis.
Protein concentration is elevated; glucose concen-
tration is low (CSF/serum plasma glucose ratio
<0.5 in 90% of cases); cell count ranges from 0 to 1
500 cells/mm3; pleocytosis lymphomononuclear
(LMN) is typical, but polymorphonuclear (PMN)
predominance may occur in up to 25-34% of TBM
patients, especially at the beginning of the dis-
ease, as occurred in our case [2-6]. This CSF pat-
tern, usually changes rapidly to LMN response in
subsequent CSF examinations. After initiation of
anti-TB therapy, CSF changes rapidly to a PMN
response in approximately 30% of TBM, which is
associated with transient clinical deterioration.
This phenomenon is known as “paradoxical reac-
tion”, and according to some experts, is pathog-
nomonic of TBM [2, 4, 7, 8].
It is required at least 104 microorganisms so that
ZN smear becomes positive. This fact explains
why microscopy sensitivity is poor in paucibac-
illary forms of TB, such as TBM [5]. In order to
increase sensitivity, it is necessary to examine a
large volume of CSF in repeated lumbar punc-
tures. CSF analysis showed acid fast bacilli in 10-
37% of an initial exam; but, increases up to 87%
when large volume (~10 mL) of four lumbar taps
are examined [4]. Another way, is to obtain a large
volume of CSF and centrifuge it at 3 000g, which
can improve sensitivity to more than 80%. This
technique can also increase culture yield for M.
tuberculosis [2-5]. Nonetheless, these methods are
not practical for use in resource-limited settings,
because ideally, they should be performed in bi-
osecurity tertiary-level facilities [5, 9]. Cultures
are more sensible and specic than ZNS, but they
take at least 10 days on liquid media and up to
8-12 weeks on solid media [2-5]. Both, ZN smear
and culture can be positive even after treatment
has begun [2].
The sensitivity of PCR for TB is low in the CSF:
only 60-90% [2-5]. The adenosine deaminase
(ADA) test is useful to support a TBM diagnosis
and to start treatment, but its diagnostic yield de-
pends on the cut-off value used. Using a cut-off
value ≥10U/L, is 92.5% and specicity 97% [2, 3,
5, 10].
In about 75% of TBM cases, there are extra-me-
ningeal TB concomitantly; miliary lung TB is the
most common nding, as presented in our Case
[2, 4, 11, 12]. In fact, miliary TB could be an indi-
cator for TBM in countries with high prevalence
of TB [13]. So, as meningitis reactivation may be
presented in miliary TB, TBM should be kept in
mind in differential diagnosis of miliary TB.
In order to improve diagnostic accuracy of TBM,
several clinical prediction rules have been de-
scribed. One of the main pitfalls of Twaites’ scor-
ing system is that it has been developed and vali-
dated manly in populations with low prevalence
of HIV infection [3-5, 14-16]. In Latin America and
Peru, validation studies have shown inconsistent
results. So, in general, this tool has a limited utili-
ty for diagnosis of TBM and differential diagnosis
with other etiologies of meningitis [17-21].

274 E.D. Meregildo Rodriguez
In a similar way to TBM, for patients with lung
miliary TB, predictors of adverse outcomes have
been described [22-24]. According to Kim et al.,
a high nutritional risk score (NRS ≥3) is an inde-
pendent predictor of acute respiratory failure and
mortality. NRS was dened by the total number
of the following risk factors (one point assigned
for each factor present): 1) BMI <18.5 kg/m2, 2)
serum albumin <3.0 mg/dL, 3) serum cholester-
ol <90 mg/dL, 4) total lymphocyte count <7×105
cells/L [24]. Our patient has at least three of these
adverse risk factors.
TBM is a medical emergency, therapy should be
initiated immediately in every patient with me-
ningeal syndrome and a typical CSF pattern, es-
pecially if there is evidence (past or current) of TB
in another organ; or if there is no convincing alter-
native diagnosis [2-6, 11, 12]. In our case, anti-TB
treatment was initiated based on clinical suspi-
cion without waiting for conrmation for TBM
nor even CFS ADA result. Finally, this case exem-
plies the difculty in diagnosing TB. In spite of
having regular health care contact (hemodialysis),
TB diagnosis was delayed three months.
Conict of interest
None to declare
External grants and funding
None to declare
n REFERENCES
[1] World Health Organization. Global Tuberculosis Re-
port 2017. License: CCBY-NCSA 3.0IGO. Retrieved from
http://www.who.int/tb/publications/global_report/
MainText_13Nov2017.pdf Last accessed Jun 16, 2018.
[2] Fitzgerald D.W., Sterling T.R., Haas D.W. Mycobac-
terium tuberculosis, In Mandell, Douglas, and Bennett’s
Principles and Practice of Infectious Diseases (Bennett J.E.,
Blaser M.J., and Dolin R., Eds), 2015, pp 2787-2818. El-
sevier Saunders, Philadelphia.
[3] Wilkinson R.J., Rohlwink U., Kant M.U., et al. Tuber-
culous meningitis. Nat. Rev. Neurol. 13, 10, 581-598, 2017.
[4] Leonard J.M., von Rey C.F., Edwards M.S. Central
nervous system tuberculosis. Baron L, ed. UpToDate.
Waltham, MA: UpToDate Inc. Retrieved from http://
www.uptodate.com Last accessed Jun 10, 2018.
[5] Török M.E. Tuberculous meningitis: advances in di-
agnosis and treatment. Br. Med. Bull. 113, 1, 117-131, 2015.
[6] Espinoza C. Características de la Meningitis Tuber-
culosa en un hospital Regional Huancayo 2014-2016
[Undergraduate Thesis]. [Huancayo, Peru]: Univer-
sidad Peruana los Andes; 2017. 54 p. Retrieved from
http://repositorio.upla.edu.pe/handle/UPLA/164
Last accessed 23 april 2018
[7] Kim S.H., Kim Y.S. Immunologic paradox in the di-
agnosis of tuberculous meningitis. Clin. Vaccine Immu-
nol. 16, 12, 1847-1849, 2009.
[8] Singh A.K., Malhotra H.S., Garg R.K., et al. Paradox-
ical reaction in tuberculous meningitis: presentation,
predictors and impact on prognosis. BMC Infect. Dis.
16, 306-312, 2016.
[9] Krishnan V., Mittal M.K., Sinha M., Kumar M.,
Thukral B.B. Central nervous system tuberculosis: Rare
presentations of a common disease. Astrocyte 4, 3, 174-
185, 2017.
[10] Chacko F., Modi M., Lal V., Prabhakar S., Rana S.V.,
Arora S.K. Diagnostic efcacy of adenosine deaminase
levels in cerebrospinal uid in patients of tubercular
meningitis: A comparison with PCR for Mycobacteri-
um tuberculosis. Ann. Neurosci. 17, 3, 126-130, 2010. [11]
Romero W., Pamo O., Cordero L. Morbimortalidad en
meningoencefalitis tuberculosa [Undergraduate The-
sis]. [Lima, Peru]: Universidad Peruana Cayetano He-
redia; 2013. 14 p.
[12] Guillen D., Campos P., Hernández H., Chaparro E.
Meningoencefalitis tuberculosa en niños: Diez años de
experiencia en el Hospital Nacional Cayetano Heredia.
Rev. Med. Hered. 4, 4, 1-9, 1993.
[13] Gursoy S., Kehribar H.A., Yasar K.K, et al. Can mil-
iary tuberculosis be an indicator for tuberculous men-
ingitis? Evaluation of the twenty-ve adult cases with
meningitis accompanied by miliary tuberculosis. J. Mi-
crobiol. Infect. Dis. 6, 2, 74-79. 2016.
[14] Thwaites G.E. The diagnosis and management
of tuberculous meningitis. Pract. Neurol. 2, 250-261,
2002.
[15] Thwaites G.E., Tran T.H.Tuberculous meningitis:
many questions, too few answers.Lancet Neurol. 4, 3,
160-170, 2005.
[16] Thwaites G.E., Duc Bang N., Huy Dung N., et al.
The inuence of HIV infection on clinical presentation,
response to treatment, and outcome in adults with tu-
berculous meningitis. J. Infect. Dis. 192, 12, 2134-2141,
2005.
[17] Saavedra J.A., Urrego S., Perez A., Toro M.E. Di-
agnosis of tuberculous meningitis. Acta Neurol. Colomb.
31, 2, 223-230, 2015.
[18] Lasso M. Meningitis tuberculosa: claves para su di-
agnóstico y propuestas terapéuticas. Rev. Chil. Infect. 28,
3, 238-247, 2011.
[19] Llanos A. Evaluación del Árbol de Clasicación
y Regresión de Thwaites para el Diagnóstico de Men-
ingitis Tuberculosa en Pacientes Hospitalizados en el
Servicio de Medicina Interna del Hospital Nacional
Hipólito Unánue 2003-2012 [Undergraduate Thesis].
[Lima, Perú]: Universidad Ricardo Palma; 2014. 48 p.

275Central Nervous System tuberculosis
Retrieved from http://repositorio.urp.edu.pe/han-
dle/urp/292 Last accessed 20 may 2018
[20] Cruzate H. Valoración del Score de Thwaites para
el Diagnóstico de Meningitis Tuberculosa en Pacientes
Hospitalizados en el Servicio de Medicina Interna con
el Diagnóstico de Meningitis en los años 2003-2012 del
Hospital Nacional Hipólito Unanue [Thesis of Grad-
uation as a Specialist in Internal Medicine]. [Lima,
Perú]: Universidad Nacional Mayor de San Marcos;
2014. 58 p.
[21] Chávez L., Pérez J. Utilidad diagnóstica de la regla
de predicción clínica de Thwaite en la Meningoencefal-
itis Tuberculosa en Pacientes atendidos en el Hospital
María Auxiliadora desde el 2005 al 2015 [Undergrad-
uate Thesis]. [Huancayo, Perú]: Universidad Nacional
del Centro del Perú; 2016. 188 p. Retrieved from http://
repositorio.uncp.edu.pe/handle/UNCP/510 Last ac-
cessed 13 may 2018
[22] Cegielski J.P., McMurray D.N. The relationship
between malnutrition and tuberculosis: evidence from
studies in humans and experimental animals. Int. J. Tu-
berc. Lung Dis. 8, 3, 286-298, 2004.
[23] Aggarwal D., Mohapatra P.R. Nutritional decit in
miliary tuberculosis: prognostic value. Eur Respir J. 32,
6, 1663-1675, 2008.
[24] Kim D.K., Kim H.J., Kwon S.Y., et al. Nutritional
decit as a negative prognostic factor in patients with
miliary tuberculosis. Eur. Respir. J. 32, 4, 1031-1036, 2008.