Tuberculous meningitis (TBM) is caused by Mycobacterium tuberculosis seeding the meninges. It presents with symptoms like fever, headache, and altered sensorium. Diagnosis is difficult as CSF analysis resembles viral meningitis and culture has low yield. Treatment involves antibiotics for at least 2 months, with corticosteroids improving outcomes. TBM prognosis depends on early treatment but complications like hydrocephalus and stroke remain risks. An interprofessional team approach including infectious disease specialists is important for managing this serious condition.

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Tuberculous Meningitis
Authors
Valori H. Slane ; Chandrashekhar G. Unakal .
Affiliations
Kendall Regional Medical Center
The University of the West Indies
Last Update: November 18, 2022.
Continuing Education Activity
Tuberculous meningitis (TBM) manifests extrapulmonary tuberculosis caused by the seeding of the meninges with the bacilli of
Mycobacterium tuberculosis (MTB). MTB is first introduced into the host by droplet inhalation infecting the alveolar macrophage. The
primary infection localizes in the lung with dissemination to the lymph nodes. At this point in the infectious process, a high degree of
bacteremia can seed the entire body. In tuberculous meningitis, the meninges are seeded by MTB and form sub-ependymal collections
called Rich foci. These foci can rupture into the subarachnoid space and cause an intense inflammatory response that causes meningitis
symptoms. The exudates caused by this response can encase cranial nerves and cause nerve palsies. They can entrap blood vessels
causing vasculitis, and block cerebral spinal fluid (CSF) flow leading to hydrocephalus. These immune responses can lead to
complications associated with tuberculous meningitis and chronic sequela in patients who recover from TBM. This activity reviews
evaluation, management, and current public health preventative measures to prevent tuberculous meningitis. This activity highlights
the interprofessional teams involved in preventing and managing this global health threat.
Objectives:
Describe the etiology of tuberculous meningitis.
Review the risk factors for developing tuberculous meningitis.
Outline the typical presentation of tuberculous meningitis.
Summarize the importance of improving care coordination among the interprofessional team to enhance care delivery for
patients with tuberculous meningitis.
Access free multiple choice questions on this topic.
Introduction
Mycobacterium tuberculosis infection in the central nervous system (CNS) may manifest as meningitis, tuberculoma, and spinal
arachnoiditis. Tuberculous meningitis (TBM) is caused by the seeding of the meninges with the bacilli of Mycobacterium tuberculosis
(MTB) and is characterized by inflammation of the membranes (meninges) around the brain or spinal cord. Approximately one-third of
the world’s population is presumed to be infected with MTB. The number of persons infected with tuberculosis continues to increase
despite advances in treatment and worldwide efforts to provide accessibility to medications and universal standard protocoled
treatment programs.
Etiology
Predicting which patients with TB infection will develop tuberculous meningitis is difficult. Children with MTB, especially that aged 0 to
4, have a higher incidence of TBM. This infection is more prevalent in the developing world, with a higher incidence of MTB in
children. By contrast, in the developed world, TBM is more often seen in adults who experience the reactivation of TB. Other
immunocompromised states like chronic steroid use, diabetes mellitus, and chronic alcoholism carry the same risk of developing TBM.
[1] The highest correlation remains with HIV co-infection, with reports that these patients are five to ten times more likely to develop
CNS disease.[2]
Epidemiology
Despite being a preventable and curable disease, tuberculosis is the leading worldwide cause of death due to infectious etiology.
Approximately one-third of the world’s population is presumed to be infected with MTB. Tuberculous meningitis carried a fatal
prognosis before the development of anti-tuberculous medications, and it remains the number one cause of death and disability in
children infected with MTB. TBM may also occur during immune reconstitution syndrome that can occur shortly after treatment
initiation for HIV with antiretrovirals when undiagnosed MTB infection is present.
Tuberculous meningitis presents in 1% of all cases of extra-pulmonary TB. In the developed world, where there is a lower prevalence of
TB in the population, estimates are that TBM accounts for 6% of all causes of meningitis. In locations with a higher prevalence of MTB
in the population, estimates are that TBM accounts for up to one-third to one-half of all bacterial meningitis.[3] Those with a concurrent
HIV infection have a five-fold increased risk of having CNS involvement and disseminated TB, and the risk increases among patients
with CD4 count <100 cells/microL.[4]
Pathophysiology
MTB is first introduced into the host by droplet inhalation infecting the alveolar macrophage. The primary infection localizes in the
lung with dissemination to the lymph nodes. At this point in the infectious process, a high degree of bacteremia can seed the entire
body. In tuberculous meningitis, the meninges are seeded by MTB and form sub-ependymal collections called Rich foci. These foci can
rupture into the subarachnoid space and cause an intense inflammatory response that causes meningitis symptoms. The exudates
1 2
1
2

2. caused by this response can encase cranial nerves and cause nerve palsies. They can entrap blood vessels causing vasculitis, and block
cerebral spinal fluid (CSF) flow leading to hydrocephalus, which may be communicating or non-communicating. These immune
responses can lead to complications associated with tuberculous meningitis and chronic sequela in patients who recover from TBM.[5]
Tuberculous vasculitis leads to constriction, spasm, thrombosis, and occlusion of intracerebral vessels. This ultimately causes multiple,
small, bilateral infarcts, frequently located in the periventricular regions. The basal ganglia, thalamus, and internal capsule are most
frequently involved. These infarcts can cause stroke syndromes of the cerebral cortex, basal ganglia, pons, and/or cerebellum.[6]
History and Physical
The clinical presentation of tuberculous meningitis is similar to other forms of chronic meningitis, making the diagnosis difficult and
the differential broad. The clinical presentation is associated with fever, headache, altered sensorium, and focal neurologic deficits.
Typical neurologic deficits include facial palsy.[2] The additional diagnostic difficulty is that the symptoms can be present anywhere
from a few days to six months. The clinical presentation of TBM is similar regardless of HIV status.[1]
Three distinct phases of clinical presentation are usually found:[7]
1. The early prodromal phase is characterized by the insidious onset of low-grade fever, malaise, headache, and personality change.
It usually lasts for one to three weeks.
2. It is followed by the meningitic phase, characterized by prominent neurologic features, such as protracted headache, vomiting,
meningismus, lethargy, confusion, and varying presentation of cranial nerve and long-tract signs.
3. Confusion gives way to stupor, seizures, coma, and often hemiparesis in the paralytic phase. Death frequently ensues within five
to eight weeks of the onset of untreated illness.
Atypical manifestations include rapidly progressive meningitic syndrome suggesting pyogenic meningitis, slowly progressive dementia
over months, personality change, social withdrawal, memory deficits, and loss of libido. Patients may sometimes also present with an
encephalitic course characterized by convulsions, stupor, and coma without overt signs of meningitis.[8]
Evaluation
Tuberculous meningitis assessment is done by obtaining cerebrospinal fluid (CSF) for analysis. Typically, the CSF reveals low glucose,
elevated protein, and modestly elevated WBC count with a lymphocytic predominance. The CSF analysis most closely resembles the CSF
analysis of viral meningitis.[3]
Confirming the diagnosis of TB is a difficult diagnostic dilemma; this is especially true in resource-poor areas. Definitive diagnosis
results from the identification of MTB in the CSF. Standard Ziehl-Neelsen acid-fast bacilli (AFB) identification smears from CSF are
highly unreliable. The positive yield of the AFB smear is broad, with results ranging from 0% to 87%.[2] CSF mycobacterium cultures
vary in their yield and are only positive 40 to 83% of the time and can take from 6 to 8 weeks to grow.[3] Over several days, daily large-
volume spinal taps sent for microbiological analysis can improve the culture sensitivity by greater than 85%.[9]
Various new sophisticated modalities for testing for antigens and antibodies specific for TB exist using PCR, but they have not won wide
acceptance or utilization; this is due to a lack of access to the testing and high variability in the specificity of the results of the tests. The
choice of diagnosis in most cases is going to depend on the resources available. Despite advances in developing improved and accurate
diagnostic modalities MTB, confirmation by culture in the CSF remains the gold standard globally.[2][3][9] Culture allows for the
assessment of drug sensitivity results. Drug-resistant MTB carries up to twice the mortality.[9]
Other tests that can be utilized are antigen testing in the urine and adenosine deaminase.[10]
These diagnostic difficulties lead to decreased recognition of tuberculous meningitis. They have led to the development of clinical
algorithms to help diagnose TBM and differentiate it from other forms of meningitis. The diagnostic algorithm bases its results on CSF
values and patient clinical presentation. The criteria consist of the duration of symptoms greater than or equal to 5 days, neurologic
impairment, CSF to serum blood glucose level ratio less than 0.5, and CSF protein level greater than 100 mg/dl. These algorithms have
been tested in several trials; however, these have been retrospective trials and have not received validation through prospective trials.
Therefore, high clinical suspicion must remain based on patient risk factors to diagnose TBM.[11][12]
Neuroimaging can further aid in the diagnosis of TBM. Magnetic resonance imaging (MRI) has demonstrated superiority to computed
tomography (CT), as it is of higher quality for assessing the brainstem and spine in detecting TBM. Imaging can assess cerebral infarcts,
cerebral edema, and meningeal enhancement. CT imaging is best used to rule out the emergent complication of TBM-related
hydrocephalus that could result in the need for immediate neurosurgical intervention. T imaging can also show basal exudates.[9]
Treatment / Management
Anti-tuberculous treatment must start promptly to reduce morbidity and mortality in tuberculous meningitis. First-line anti-
tuberculous treatments have excellent CSF penetration. Treatment for TBM consists of two months of an intensive phase of daily
isoniazid (INH), rifampin (RIF), pyrazinamide (PZD), and either streptomycin (SM) or ethambutol (EMB). This regimen is followed by
the continuation phase of 7 to 10 months of INH and RIF. This treatment plan is based on the assumption that the MTB is not a resistant
strain. However, drug sensitivity results can take months to receive, and treatment can be tailored to identify the drug sensitivities.
[9] In children, ethambutol (EMB) Is replaced by either an aminoglycoside or ethionamide because of difficulty monitoring for
ethambutol-associated optic neuritis.
Treatment with daily rifampin, ethambutol, pyrazinamide, and fluoroquinolone is advised with isoniazid-resistant CNS TB. Moreover,
the duration of therapy should be extended to 18 to 24 months, depending on the clinical response to treatment, the severity of the
illness, and the patient's immune status.
Adjunctive therapy with corticosteroids has been used in the treatment of TBM. The goal of steroid treatment is to dampen the immune
system's exaggerated response, which causes most of the neurologic complications seen with TBM, including tissue damage and brain
edema. There has been concern that steroids would reduce the penetration in the CSF of the anti-tuberculous medication, but to date,

3. studies have not shown this to occur. Studies have demonstrated improved clinical outcomes and reduced mortality with the
administration of steroids. While there are no trials comparing which steroid is superior, the mainstay treatment has been daily
intravenous dexamethasone for up to four weeks, followed by a four-week oral taper.[9]
Differential Diagnosis
Bacterial meningitis
Viral meningitis
Encephalitis of all causes
Intracranial space-occupying lesions of various etiologies, including infectious and non-infectious
Non-specific viral syndromes
Sepsis
Acute cerebral vascular accident
A sympathomimetic syndrome due to drug abuse
Delirium associated with urinary tract infection
Treatment Planning
Table 1. First-line drugs for the treatment of CNS tuberculosis [13]
Table 2. Second-line antituberculosis drugs in adults [14] [15]
Prognosis
Tuberculous meningitis is considered the deadliest form of MTB infection.[16] TBM carries a mortality rate between 20 and 67% with
anti-tuberculous treatment and is fatal without treatment.[3] Patients at both ends of extremes of age and patients with HIV co-
infection carry the highest mortality.[16][17] The prognosis of TBM depends on the patient's neurologic status at the time of initial
presentation and the timeliness of the initiation of anti-tuberculous agents.[2] Patients who develop hydrocephalus secondary to MTB
also have a poor prognosis, even with neurosurgical intervention.[9][17]
Complications
Tuberculous meningitis can cause a myriad of neurologic sequela that can be present at initial presentation and can produce residual
effects even after successful treatment.[18]
Some significant complications to remember include the following:
Hydrocephalus due to obstruction of CSF outflow causing raised intracranial pressure
Hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion is seen in 40 to 50% of patients with TBM.[19]
Tuberculomas can occur independently of TBM and have not been shown to be affected by adjunctive steroid treatment.
Vasculitis and stroke occur in 15 to 57% of patients with TBM depending on which diagnostic modalities are used in diagnosis,
with MRI being diagnostically superior in diagnosis to CT.
Seizures, generally focal, result from hyponatremia, infarction, and meningeal irritation[20]
Loss of vision that could be permanent due to compression of the optic chiasma by the dilated third ventricle as the optic chiasma
and optic nerve are encased by thick tuberculous exudates[21]
Transverse myelitis manifests as paraparesis or quadriparesis, sensory symptoms, and urinary retention in the lower limbs.[22]
Consultations
Patients with TBM usually present in the emergency, where the first medical contact is emergency or medicine practitioners.
Consultation with neurologists and infectious disease specialists is almost always needed.
Deterrence and Patient Education
The primary goal in TB treatment of all forms involves medication regimen adherence. The treatment of all varieties of TB is lengthy,
and without strict adherence, resistance develops, which creates a considerable public health risk.
Enhancing Healthcare Team Outcomes
MTB eradication is a top priority in global health. Healthcare professionals across all disciplines are vital to the continued progress of
this global effort. Globally, eradication efforts have involved every aspect of society. Collaboration between frontline clinicians,
infectious disease nurses, pharmacists, and all government health entities will significantly improve the outcomes of these efforts.
Public and private sector contributions are imperative to the advancements in diagnostic modalities and treatments in MTB.[23]
Tuberculous meningitis is a serious condition that requires an interprofessional team that includes clinicians, emphasizing an
infectious disease specialist, specialty infection control nurses, and infectious disease specialized pharmacists. When these
interprofessional team members work together and maintain open communication, the patient can receive prompt, appropriate care.
[Level 5]
Review Questions

4. 1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
Access free multiple choice questions on this topic.
Comment on this article.
References
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RJ, Pai M, Richeldi L, Salfinger M, Shinnick TM, Sterling TR, Warshauer DM, Woods GL. Official American Thoracic
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Disclosure: Valori Slane declares no relevant financial relationships with ineligible companies.
Disclosure: Chandrashekhar Unakal declares no relevant financial relationships with ineligible companies.

5. Tables
Drug Preparations Daily dose (adults) Notes
Isoniazid
Tablets (50 mg, 100 mg, 300 mg)
Elixir (50 mg/5 mL)
Aqueous solution (100 mg/mL) for
intravenous or intramuscular
injection
5 mg/kg (maximum dose 300
mg)
Pyridoxine (vitamin B6; 25 t
mg daily) is given to prevent
neuropathy. 100 mg/day is
recommended for patients w
peripheral neuropathy.
Ethambutol
Tablets (100 mg, 400 mg) Based on estimated lean body
weight
Patient weight 40 to 55 kg: 800
mg (14.5 to 20 mg/kg)
Patient weight 56 to 75
kg: 1200 mg (16 to 21.4 mg/kg)
Patient weight 76 to 90
kg: 1600 mg (17.8 to 21.1
mg/kg)
Renal dysfunction with
creatinine clearance <30
mL/min (by Cockroft-Gault
equation) or requiring
intermittent hemodialysis,
dosing consists of 20 to 25 m
(ideal body weight) per dose
orally 3 times a week.
1600 mg is the maximum do
regardless of weight.
Rifampin (rifampicin)
Capsules (150 mg, 300 mg)
Aqueous solution for intravenous
injection
10 mg/kg (maximum dose 600
mg)
Reduce plasma estrogen
concentrations and efficacy
oral contraceptives.
Rifabutin
Capsule (150 mg) 5 mg/kg (maximum dose 300
mg)
The dose may need adjustme
with the concomitant use of
nonnucleoside reverse
transcriptase inhibitors or
protease inhibitors.
Pyrazinamide
Tablet (500 mg) Based on estimated lean body
weight
Patient weight 40 to 55 kg:
1000 mg (18.2 to 25 mg/kg)
Patient weight 56 to 75 kg:
1500 mg (20 to 26.8 mg/kg)
Patient weight 76 to 90 kg:
2000 mg (22.2 to 26.3 mg/kg)
Renal dysfunction with
creatinine clearance <30
mL/min (by Cockroft-Gault
equation) or requiring
intermittent hemodialysis,
dosing consists of 25 to 35 m
(ideal body weight) per dose
orally 3 times a week.
Patients weighing more than
kg should have serum
concentration monitoring.
Weight-based dosing is likely
best based on measurement
ideal (versus total) body wei
in obese patients.

6. Drug Adult dose with
normal renal
function
Main adverse effects CSF penetration Pregnancy Notes
Imipenem-cilastatin 1000 mg IV every 6 to 8
hours; each dose must
be given with
clavulanate 125 mg
orally
GI toxicity, seizures. Poor-Low Can be used when
there are no suitable
alternatives
Meropenem 1000 mg IV every 8
hours; each dose must
be given with
clavulanate 125 mg
orally
GI toxicity, seizures. Moderate Can be used when
there are no suitable
alternatives
Amoxicillin-
clavulanate
2000 mg
amoxicillin/125 mg
clavulanate orally
every 8 to 12 hours
GI toxicity. Poor May be used Coadministered w
imipenem-cilastat
meropenem
Ethambutol 15 mg/kg once a day
(when used as a
companion drug), or
25 mg/kg (for use as a
bacteriostatic agent to
complete a fully active
regimen)
Visual disturbance (optic
neuropathy, decreased
visual acuity, or red-
green colorblindness)
observed at higher
doses.
Poor-Low May be used
Amikacin
15 mg/kg IM or IV once
daily (maximum dose
1 g) adjusted according
to serum
concentrations.
Alternative: 25 mg/kg
IM or IV three times
per week.
Ototoxicity, vestibular
toxicity, nephrotoxicity,
electrolyte disturbances,
and local pain with IM
injection.
Low-Moderate Avoid
Target trough <1
mcg/mL and targe
peak of 56 to 64
mcg/mL for once-a
administration.
5 to 7 days a week
depending on dise
severity
The initial duratio
therapy is at least
3 months. After
documentation of
culture conversion
days-per-week do
can be used for th
remaining duratio
injectable use
(normally through
least six months
beyond culture
conversion).
Bedaquiline 400 mg orally once a
day for 2 weeks,
followed by 200 mg 3
times weekly for 24
weeks (total duration
26 weeks)
QT prolongation, GI
toxicity, and hepatitis
High May be used
Capreomycin 15 mg/kg IM or IV once
a day (maximum 1 g)
adjusted according to
serum concentrations
Electrolyte disturbances,
ototoxicity, vestibular
toxicity, nephrotoxicity,
and local pain with IM
injections.
Insufficient data Avoid
Levofloxacin 750 to 1000 mg orally
or IV once a day
CNS effects, QT
prolongation, GI toxicity,
dysglycemia, rash,
tendonitis, tendon
rupture
Good Can be used when
there are no suitable
alternatives
Moxifloxacin 400 mg orally or IV
once a day (doses up to
800 mg once daily
CNS effects, QT
prolongation, GI toxicity,
dysglycemia, rash,
Moderate Can be used when
there are no suitable
alternatives

7. have been used, but
need more safety data)
tendonitis, tendon
rupture, hepatotoxicity.
Linezolid 600 mg orally or IV
once a day
Myelosuppression, GI
toxicity, neuropathy
(optic and peripheral)
Good and fast,
following IV
administration
Avoid Pyridoxine (100 m
orally once daily)
be used to preven
reduce peripheral
neuropathy.
Cycloserine 10 to 15 mg/kg (250 to
750 mg/day) orally in 2
divided doses
(maximum dose 500
mg twice a day)
adjusted according to
serum concentrations
CNS toxicity (psychiatric
symptoms, seizures
usually occur at peak
concentrations >35
mcg/mL but may occur
in the normal
therapeutic range),
peripheral neuropathy,
and dermatologic effects
include serious
cutaneous
hypersensitivity
reactions.
Good Can be used when
there are no suitable
alternatives
Pyridoxine (100 m
orally once daily)
be used to preven
reduce peripheral
neuropathy.
Ethionamide 15 to 20 mg/kg orally
(usually 500 mg per
day) as a single daily
dose or 2 divided doses
(maximum dose 1 g
per day)
GI toxicity (may need
antiemetic
premedication), hepatic
toxicity, metallic taste,
neurotoxicity including
optic neuritis, endocrine
effects including
hypothyroidism (treat
with thyroid
replacement therapy).
Excellent Can be used when
there are no suitable
alternatives
Pyridoxine (100 m
orally once daily)
be used to preven
reduce peripheral
neuropathy.
Start with 250 mg
daily and increase
gradually as tolera
is recommended.
Delamanid 100 mg orally twice
daily with food
(maximum duration
studied 26 weeks)
GI toxicity, QT
prolongation.
No data Avoid
Ethambutol 15 mg/kg once daily
(used as a companion
drug) or 25 mg/kg (for
use as a bacteriostatic
agent to complete a
fully active drug
regimen)
Visual disturbance (optic
neuropathy, manifested
as decreased visual
acuity or red-green
colorblindness) at
higher doses.
Poor-Low May be used
Para-aminosalicylic
acid
4 g orally twice or
thrice daily
Hepatotoxicity, GI
toxicity, hypothyroidism
(treat with thyroid
replacement therapy).
More data is needed,
poor
Can be used when
there are no suitable
alternatives
Isoniazid, high dose 15 mg/kg orally, IM, or
IV once a day
Hypersensitivity,
hepatitis, peripheral
neuropathy
Excellent May be used Pyridoxine (100 m
orally once daily)
be used to preven
reduce peripheral
neuropathy.
Kanamycin 15 mg/kg IM or IV once
a day (maximum dose
1 g) adjusted according
to serum
concentrations
Ototoxicity, electrolyte
disturbances, vestibular
toxicity, nephrotoxicity.
Low Avoid
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