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Review article

Neurotuberculosis: A mystery seeking it's answers

in pulmonary tuberculosis

Masaraf Hussain a,*, Bhupen Barman b, Md Jamil b, Yasmeen Hynniewta c

a
Department of Neurology, AIIMS, Guwahati, India
b
Department of Medicine, AIIMS, Guwahati, India
c
Department of Medicine, NEIGRIHMS, Shillong, India

article info abstract

Article history: Neurotuberculosis remains a mystery and presents a formidable challenge in diagnosis
Received 29 September 2022 and management. While pulmonary tuberculosis has a well understood pathophysiology
Received in revised form and well researched management strategies, CNS tuberculosis still has plenty of unan-
23 April 2023 swered questions. The purpose of this review is to highlight the debatable issues in the
Accepted 28 April 2023 current understanding of the clinical, diagnostic, and therapeutic aspects of
Available online 3 May 2023 Neurotuberculosis.
© 2023 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.
Keywords:
Neurotuberculosis
Tuberculous meningitis (TBM)
CNS tuberculosis
Pulmonary tuberculosis

While pulmonary tuberculosis has a well understood

1. Introduction pathophysiology and well researched management strategies,
CNS tuberculosis still has plenty of unanswered questions.
Tuberculosis (TB) remains a major health problem in the What are the pathognomic clinical features of CNS tuber-
world, especially in developing and underdeveloped culosis? What is the best way to diagnose CNS tuberculosis?
countries. What is the optimal treatment of this disease?
Neurotuberculosis accounts for approximately 1% of all What can be done to reduce the neurological sequelae and
cases of tuberculosis.1 Neurotuberculosis caused by Mycobac- morbidity among the survivors ? How can CNS tuberculosis be
terium tuberculosis is relatively uncommon but highly devas- rapidly diagnosed?
tating, with a high mortality (approximately 25% of the The pathogenesis of CNS tuberculosis remains poorly un-
patients) and neurological morbidity.2 This condition was derstood. These questions remain open.
universally fatal in the era before anti-tuberculosis therapy. The purpose of this review is to highlight the debatable
Neurotuberculosis remains a mystery and presents a issues in the current understanding of the clinical, diagnostic,
formidable challenge in diagnosis and management. and therapeutic aspects of Neurotuberculosis.

* Corresponding author.
E-mail address: masarafhussain@[Link] (M. Hussain).
[Link]
0019-5707/© 2023 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.

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74 i n d i a n j o u r n a l o f t u b e r c u l o s i s 7 1 ( 2 0 2 4 ) 7 3 e7 8

1.1. Epidemiology however the model was incomplete as it did not include cells
from the brain side of BBB.17
Reliable estimates of the global incidence of neuro- As M. tuberculosis primarily affects humans, developing
tuberculosis are lacking. Under-reporting, over-diagnosis, and an animal model that truly mimics human infection remains
under-diagnosis, make unadjusted incidence rates obtained unsettled.
from national statutory reporting registries and vital regis- Further research has revealed that the disease phenotype
tration records inadequate to estimate the incidence of may not be explained by a single pathogenic mechanism but
neurotuberculosis.3 by Host and Pathogen genotype interaction mechanism. A
Examination of multiple overlapping causes of national number of studies have been done to investigate the potential
registries, vital registration records, hospital records, and role of host genetic factors in the immunopathogenesis of
microbiology laboratory reports is necessary to provide pop- Neurotuberculosis. Two host receptors have been studied.
ulation based estimates of neurotuberculosis incidence.
Though challenging, large scale epidemiological studies 1. TIRAP (toll-interleukin 1 receptor domain containing
has shown CNS involvement in 5%e10% of extrapulmonary adaptor protein): TIRAP influences disease susceptibility by
tuberculosis cases.4 CDC data has shown that 6.5% of modulating the inflammatory response.18
extrapulmonary cases (1.3% of total tuberculosis cases) 2. TLR2 (toll-like receptor 2): this was associated with
involve the CNS.5 The risk of developing CNS tuberculosis was increased susceptibility to tuberculosis, more strongly with
1.0% as seen in a Canadian cohort.6 TBM than pulmonary. It has been shown to be more
Risk factors for CNS tuberculosis include: children, HIV co- associated with increased disease severity, indicated by
infected individuals, malnutrition, alcoholism, malignancies, TBM disease grade.19
use of immunosuppressive agents. Recent measles in children
is also identified as a risk factor.7 Neurotuberculosis patients Studies of Host and Pathogen genotype interaction have
are over-represented in individuals born outside of developed shown that individuals with TLR2 were more likely to have
countries, in studies conducted in developed countries.8 tuberculosis caused by East-Asian/Beijing genotype.20 These
evidence of Host and Pathogen interaction is important from
1.2. Pathogenesis the pathogenesis and therapeutic aspects of
Neurotuberculosis.
M. tuberculosis is an aerobic, non-motile, non-spore forming,
Acid Fast Bacilli (AFB) that infects primarily humans.9 The 1.3. Clinical features
acquisition of M. tuberculosis infection occur through the
inhalation of droplet nuclei containing the bacilli and subse- The presentation of Neurotuberculosis is non-specific. TBM
quent deposition in the lung alveoli. may mimic other causes of chronic meningoencephalitis.21
The bacilli primarily disseminate to distant sites in the Moreover rapid diagnosis of Neurotuberculosis is crucial s
body by hematogenous seeding, most frequently in regions of delay in initiating treatment is universally fatal.
the body which are highly oxygenated, including the brain.10
However this mode of transmission does not explain the 1.4. Classification of neurotuberculosis
pathogenesis of CNS tuberculosis as demons trated from the
meticulous studies carried out by Rich and McCordock at John 1.4.1. Intracranial
Hopkins hospital and reported in 1933.11 Using guinea pigs Tuberculous meningitis Tuberculous encephalopathy Tuber-
and rabbits they demonstrated that the meninges were not culous vascultopathy CNS tuberculoma Tuberculous brain
infected by the hematogenous seeding of the bacilli, but ac- abscess Spinal:
quired through direct inoculation of the bacilli into the CNS.12 Pott's spine.
Based on these observations it has been accepted that the Non-osseous spinal tuberculosis Spinal meningitis.
presence of a caseating vascular focus in the brain cortex or Although the classic presentation of TBM is with a sub-
the meninges is required for the tubercle bacilli to enter the acute meningitis illness, similar to other causes of meningo-
sub arachnoid space. This caseating focus is called the “Rich encephalitis, unusual presentation may present diagnostic
focus”.13 However the controversy does not end there, as this difficulty.
mode of entry does not explain the frequent association of Unusual manifestations of tuberculous meningitis include.
Neurotuberculosis and miliary tuberculosis.14 Subsequent
studies concluded that hematogenous dissemination plays an 1. Movement disorders: due to infarction of basal ganglia, can
important role in the development of tuberculous meningitis present with tremor, chorea, ballismus or myoclonus.22
in children and increases the probability that a Rich focus will 2. Tuberculous encephalopathy: especially in children,
develop.15 Though the mode of entry has been ultimately without clinical or CSF evidence of any meningitis.23
postulated but the mechanism by which the bacilli crosses the 3. Metabolic presentation: hyponatremia can be detected in
bloodebrain-barrier (BBB) into the CNS is not well understood. more than 50% of patients with the disease.24 This may be
It is yet not well characterized whether the free bacilli traverse due to a “cerebral salt wasting syndrome” attributed to
across the endothelial layer of the BBB, or whether the bacilli renal tubular defect; or SIADH. However many patients
enter via the passage of infected macrophages.16 Studies with have hyponatremia with normal concentration of ADH.
in-vitro model of BBB has supported that M. tuberculosis Therefore “hyponatremic natriuretric syndrome” is a bet-
H37Rv and CDC1551 can traverse the endothelial monolayer, ter term for this condition.24

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 i n d i a n j o u r n a l o f t u b e r c u l o s i s 7 1 ( 2 0 2 4 ) 7 3 e7 8 75

4. Children with TBM often present with fever, seizure, and The staining methods have low sensitivity (up to 20%).36
abdominal symptoms such as nausea and vomiting.25 They The reason are that the acid-fast dye cannot stain M. tuber-
may also present with irritability. The presence of bulged culosis once it enters into the cell and that high volumes of
fontanelle may help in the diagnosis in infants with TBM. CSF are needed since approximately 10^4 organisms are
5. TBM can present with Sub Arachnoid Hemorrhage due to needed for their reliable detection. However even with a high
ruptured aneurysm. They can also present as Cerebral volume of CSF the sensitivity rarely exceeds 60%. With the
venous thrombosis.26 recent development of a highly efficient Ziehl-Neelsen stain
6. Patients with co-infected with HIV do not have an altered 93.8% intracellular detection rate and 100% extracellular
clinical presentation of TBM, although parenchymal dis- detection rate was managed, however the results need to be
ease is reported to be more common in HIV patients (15%e replicated.37
44% of patients with CNS tuberculosis).27 For the HIV CSF culture takes 4e8 weeks for the identification. Their
infected patient, it is important to differentiate between sensitivity ranges from 25 to 85%.38 Newer culture media can
TBM and cryptococcal meningitis (CCM). Both share similar give the results in 7e10 days.
and overlapping clinical presentation. TBM is associated
with higher temperature, neck stiffness and lower Glasgow 2.1. Diagnostic features of tuberculous meningitis
Coma Scale score as compared with CCM.28 Cases of con-
current TBM and CCM have been reported.29

Clinical
2. Diagnosis Fever and headache (>14 days)
Vomiting25
The CSF analysis is the most important investigation in the Altered sensorium and Focal neurological deficit
diagnostic workup of CNS tuberculosis. The CSF profile of CSF
Neurotuberculosis mimics the profile of a large list of both Pleocytosis (>20 cells, >60% lymphocytes)
infectious and non-infectious diseases.30 The typical CSF Increased protein (>100mg/dl)
Low sugar (<60% of corresponding blood sugar)
findings in CNS tuberculosis include a moderate lymphocytic
pleocytosis. Moderately elevated protein level, and low Imaging
glucose (hypoglycorhacia). Basal exudates
Basal ganglia infarcts
From a clinical standpoint, the best predictors of TBM are
Gyral enhancement
as follows31.
Tuberculoma

1. Duration of symptoms more than 6 days.

2. CSF total cell count <1000/microl with lymphocytic Newer more rapid and accurate diagnostic methods have
predominance been developed which include nucleic acid amplification
3. Peripheral blood white cell count <15,000 x 10^3/ml methods, PCR based methods, antibody detection, antigen
detection, and chemical assays like adenosine deaminase and
The Atypical CSF findings include: tuberculostearic acid measurements. However these tech-
1. Normal CSF32 niques have been successfully used in the diagnosis of pul-
2. Neutrophilic predominance during the first 24e48 hours in monary tuberculosis using respiratory specimens, and have
20%e25% non-HIV infected patients.33 been evaluated for their applicability in Neurotuberculosis.
3. Persistent neutrophilic meningitis34: neutrophils persists However the utility of these methods in the diagnosis of
in CSF in this syndrome of varied etiology, including Neurotuberculosis is difficult to evaluate as the inclusion
tuberculosis. This is more frequently seen in TBM in HIV criteria of patients of neurotuberculosis, techniques, collec-
infected people especially meningeal infection by multi- tion and purification modifications, of these tests are not
drug resistant mycobacteria. uniform and highly heterogenous.39
4. Therapeutic paradox35: here an initial mononuclear pleo- Antibody detection: Though the results are rapid, these
cytosis may briefly change in the direction of polynuclear tests are limited by their inability to differentiate acute
predominance a few days after anti-tuberculous therapy is infection from chronic infection, and cross reactivity.40 They
initiated. This may be associated with clinical deteriora- also have a variable and poor sensitivity and specificity.
tion. This “therapeutic paradox” has been reported by Antigen detection: this method was found to be more
some authors as virtually pathognomic of tuberculous sensitive than PCR method.
meningitis. Molecular methods: Nucleic Acid Amplification tests are an
important diagnostic tool for testing respiratory specimens in
In case of normal CSF in suspected patients of Neuro- tuberculosis. However no NAA method have been approved
tuberculosis, a repeat spinal tap is suggested after 24e48 for testing of CSF, although a number of studies have evalu-
hours. ated their performance in Neurotuberculosis.41 A recent meta-
Classical microbiological techniques of identification of analysis has shown NAA having a specificity of 98%, and
AFB in CSF through both smear and culture methods remains therefore has a role in confirming TBM, but because of it’s low
the most important and widely available means to diagnose sensitivity of 56% it is not ideal for ruling out TBM.42 Moreover,
CNS tuberculosis. performance of PCR assays is heterogenous, which make it

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76 i n d i a n j o u r n a l o f t u b e r c u l o s i s 7 1 ( 2 0 2 4 ) 7 3 e7 8

difficult to compare between studies. PCR is helpful in 4. Host directed therapies: These therapies are used to either
assisting in the diagnosis of TBM after anti-tuberculous ther- enhance host protective immunity or regulate tissue
apy has been started as PCR studies remain positive up to 1 damaging immunity by pathogens.
month after anti-tuberculous therapy.43
ADA: CSF ADA values have been found to be useful in the The most widely used and researched host directed ther-
prediction of poor prognosis in pediatric TBM cases. Studies apy is Corticosteroids.48 Dexamethasone as an adjunctive
have shown heterogenous results in the diagnosis of Neuro- treatment in TBM has been shown to demonstrate a survival
tuberculosis. Moreover standardized cut off values have not benefit, but failed to demonstrate an effect on long term
been established for the diagnosis of Neurotuberculosis. In morbidity.49 There is lack of data to show that dexamethasone
this situation practical application of this assay is difficult.44 as adjunctive treatment demonstrate a survival benefit in
No single test can provide the diagnosis of Neuro- TBM associated with HIV1. It is yet unclear regarding the
tuberculosis. Diagnostic tests cannot rule out Neuro- mechanism of survival benefit of dexamethasone.
tuberculosis by a negative test, and clinical judgement A focus of recent research is the role of genetic poly-
remains paramount. morphism in immune response gene for the response to
corticosteroids.
2.1.1. Treatment
The optimal therapy for Neurotuberculosis is not the result of 5. The duration of therapy for Neurotuberculosis is extrapo-
controlled studies and therefore not well established.45 The lated from the experience of treatment of pulmonary
difficulty to conduct randomized trials in Neurotuberculosis is tuberculosis. However unlike pulmonary tuberculosis
due to the relative rarity of cases, the difficulty of early and where decades of clinical trials have refined the treatment
definitive diagnosis, and the high mortality in advanced cases. regimen duration, little evidence exists for the treatment of
Therefore the therapy for Neurotuberculosis is extrapolated Neurotuberculosis. Different professional bodies recom-
from it's pulmonary counterpart. mend different duration for the anti-tuberculous regimen.
As the clinical inclusion criteria of TBM had no similar
1. Many patients will be empirically treated due to diagnostic definition, the treatment endpoints had unclear definition,
difficulties in Neurotuberculosis. Not infrequently the comparison has not been possible between the various
response to therapy constitutes a key to the diagnosis. studies and recommendations.
However the duration and protocol of this is not well
established. Paradoxical reaction in tunerculous meningitis is charac-
2. The treatment regimen does not take into account the terized by either the worsening of the lesions, or the appear-
differential ability of the drugs to penetrate the blood brain ance of new lesions after initial improvement with anti-
barrier.46 INH penetrates the BBB freely, but Rifampicin tuberculous treatment. Corticosteroids have shown to have
does not cross the BBB as well and CSF concentration is a beneficial effect.
only 10%e20% of that in plasma. However this 10%e20% Two manifestations of intracranial tuberculosis that
may be comparable to levels of active drug in plasma, as require surgery are hydrocephalus and brain tuberculomas.
very little of this drug is protein bound in CSF unlike in Hydrocephalus can be managed by ventriculoperitoneal (VP)
plasma where majority of Rifampicin is protein bound. shunt, and endoscopic third ventriculostomy (ETV). The
There has been some research on the role of high dose of treatment of tuberculomas is mainly medical. Surgery is
Rifampicin in Neurotuberculosis.47 required when the diagnosis is in doubt, to reduce focal mass
3. In the present regimen, Ethambutol has the poorest CSF effect, and to obtain tissue for culture and sensitivity. Ste-
penetration, even when BBB is inflamed, raising questions reotactic biopsy, and stereotactic craniotomy, are used in the
of it's value in Neurotuberculosis.47 In view of this a debate surgical management.50
has been initiated regarding the choice of a fourth drug in Sequelae of tuberculosis include cognitive impairment,
drug sensitive Neurotuberculosis. motor deficits, optic atrophy, other cranial nerve palsies. TCV
(tuberculous cerebral vasculitis), is a devastating sequelae
Recommended treatment regimen for CNS tuberculosis occurring between 6 and 41% patients with tuberculous
caused by fully susceptible. meningitis.51 The etiopathogenesis of TCV is pan-arteritis of
M. tuberculosis. the basal arteries of the circle of Willis and also lenticulos-
triate arteries. Neuroimaging modalities are helpful in the
diagnosis.
Spinal tuberculosis: popularly known as Pott's spine is
Drug Daily dose (adults) Duration
caused by the hematogenous spread of.
Isoniazid 300Mg 10e12 months M. tubeculosis from the primary site of a pulmonary lesion
Rifampicin 450mg (<50kg) 10e12 months
or genitourinary lesion to the dense vasculature of cancellous
600mg (>50kg)
bone of the vertebral body. There is destruction of the inter-
Pyrazinamide 1.5gm (<50kg) 2months
vertebral disk space and adjacent vertebral bodies leading to
2.0gm (>50kg)
spinal deformities. Paraplegia is the most devastating
Ethambutol 15Mg/kg 2months
outcome of spinal tuberculosis.

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