Tuberculous meningitis (TBM) is a serious form of tuberculosis infection that affects the membranes (meninges) surrounding the brain and spinal cord. It is difficult to diagnose due to nonspecific symptoms in early stages. The diagnosis requires a high index of suspicion and is confirmed through cerebrospinal fluid analysis, imaging, and culture. Prompt treatment with a combination of antituberculosis drugs for 6-9 months as well as corticosteroids is needed but prognosis depends on the stage at presentation, with advanced stages having worse outcomes. BCG vaccination provides some protection against TBM.

1. Tuberculous Meningitis
Dr. Neelu Chugh
PGY2
Department of Pulmonary medicine,
GGS Medical College Hospital
Faridkot.

2. INTRODUCTION
1. Currently, more than 2 billion people (ie, one third
of the world’s population) are infected with
tuberculosis. The incidence of central nervous system
(CNS) TB is related to the prevalence of TB in the
community ---1% of all TB cases, 5% of all EPTB, 5th
EPTB. More common in children, PLHIV(2 per 100), in
miliary disease. it is still the most common type of
chronic CNS infection in developing countries.

3. 2. TBM is a very critical disease in terms of fatal
outcome and permanent sequelae, requiring rapid
diagnosis and treatment.
3. TBM may have an acute presentation. Sometimes it
may present with cranial nerve deficits, or it may have
a more indolent course involving headache,
meningismus and altered mental status. The
prodrome is usually nonspecific including headache,
vomiting, photophobia and fever. The duration of
presenting symptoms may vary from 1 day to 9
months.

4. 4. Prediction of prognosis of TBM is difficult because
of the protracted course, diversity of underlying
pathological mechanisms, variation of host immunity,
and virulence of M tuberculosis. Prognosis is related
directly to the clinical stage at diagnosis.
5. Prompt treatment is essential; death may occur as
a result of missed diagnoses and delayed treatment

5. Pathophysiology
• TBM develops in 2 steps:
a) Mycobacterium tuberculosis bacilli enter the host
by droplet inhalation, the initial point of infection
being the alveolar macrophages. Localized infection
escalates within the lungs, with dissemination to
the regional lymph nodes to produce the primary
complex. During this stage, a short but significant
bacteremia is present that can seed tubercle bacilli
to other organs.

6. Bacilli seed to the meninges or brain parenchyma,
resulting in the formation of small subpial or
subependymal foci of metastatic caseous lesions.
These are termed Rich foci.
b) second step in the development of TBM is an
increase in size of a Rich focus until it ruptures into
the subarachnoid space. The location of the
expanding tubercle (ie, Rich focus) determines the
type of CNS involvement. Tubercles rupturing into the
subarachnoid space cause meningitis.

9. c) Those deeper in the brain or spinal cord
parenchyma cause tuberculomas or abscesses.
While an abscess or hematoma can rupture into the
ventricle, a Rich focus does not.
A thick gelatinous exudate infiltrates the cortical or
meningeal blood vessels, producing inflammation,
obstruction, or infarction. Basal meningitis accounts
for the frequent dysfunction of cranial nerves (CNs)
III, VI, and VII, eventually leading to obstructive
hydrocephalus from obstruction of basilar cisterns.

10. An early neutrophilic reaction is followed by
infiltration of lymphocytes, plasma cells, and
macrophages, leading to progressive destruction of
the adventitia, disruption of elastic fibers, and, finally,
intimal destruction. Eventually, fibrinoid degeneration
within small arteries and veins produces aneurysms,
multiple thrombi, and focal hemorrhages, alone or in
combination.

11. Etiology
• The causative organism is Mycobacterium
tuberculosis.
• The mechanisms by which neurovirulence
may occur are unknown.
• Various risk factors have been identified like
HIV, DM, Steroids etc.

12. Clinical Presentation
• HISTORY:
TBM is difficult to diagnose, and a high index of
suspicion is needed to make an early diagnosis.
In an immunocompetent individual, central
nervous system (CNS) TB usually takes the form
of meningitis that causes an acute to sub-acute
illness characterized by fever, headache,
drowsiness, meningism, and confusion over a
period of approximately 2-3 weeks.

13. Usually, during the prodromal period, nonspecific
symptoms are present, including fatigue, malaise,
myalgia, and fever.
The duration of presenting symptoms may vary from
1 day to 9 months, although 55% presented with
symptoms of less than 2 weeks' duration.
Headache and mental status changes are much more
common in elderly persons.

14. In one study, only 2% of patients reported meningitic
symptoms.
Fever and headache can be absent in 25% of patients,
and malaise can be absent in as many as 60% of
patients.
Visual symptoms, Sudden onset of focal neurologic
deficits, SIADH, spinal meningitis, Potts disease or
spinal caries, psoas abscess, encephalopathy,
radiculomyelitis (TBRM).

15. Physical Examination
• Perform careful general, systemic, chest and
neurologic examinations, looking especially for
lymphadenopathy, papilledema, and
tuberculomas during fundus exam., and
meningismus.
• Look also for a BCG vaccination scar.
• Most often involving CN VI, may be noted. CNs III,
IV, VII, and, less commonly, CNs II, VIII, X, XI, and
XII, also may be affected. Focal neurological
deficits may include monoplegia, hemiplegia,
aphasia, and tetraparesis.

16. STAGING (BMRC)
• In 1948, the British Medical Research Council
developed a method for staging the severity
of the disease.
• Prognosis is related directly to the clinical
stage at diagnosis.

17. Stage I describes the early nonspecific symptoms and
signs including apathy, irritability, headache, malaise,
fever, anorexia, nausea, and vomiting, without any
alteration in the level of consciousness.
Stage II describes altered consciousness without
coma or delirium but with minor focal neurological
signs; symptoms and signs of meningism and
meningitis are present, in addition to focal
neurological deficits, isolated CN palsies, and
abnormal involuntary movements.
Stage III describes an advanced state with stupor or
coma, dense neurological deficits, seizures, posturing,
and/or abnormal movements.

18. Differential diagnosis
TBM should be considered in the differential diagnosis in any
patient presenting with fever and a change in sensorium.
Other problems to be considered include the following:
1. Infectious Meningitis (bacterial,fungal,parasitic,viral)
2. Encephalitis
3. Subdural empyema
4. Subdural Hematoma
5. Status epilepticus
6. Intracranial epidural abscess
7. Neoplastic
8. Vascular/ Vasculitis

19. 9. Aseptic meningitis
10. Chemical meningitis
11. Acute hemorrhagic leukoencephalopathy
12. Chronic benign lymphocytic meningitis
13. Acute disseminated encephalomyelitis

20. Work up/ Investigations
• The diagnosis of tuberculous meningitis (TBM) cannot
be made or excluded on the basis of clinical findings.
• Variable natural history and accompanying clinical
features of TBM hinder the diagnosis.
1. CBC, ESR
2. RBS to compare with CSF
3. S.electrolytes ( SIADH)
4. B. urea, S. creatinine
5. Urinalysis

21. 6. Tuberculin Skin Testing---Negative results from the purified
protein derivative test do not rule out tuberculosis (TB); if the
5-tuberculin test skin test result is negative, repeat the test
with 250-tuberculin test. Note that this test is often
nonreactive in persons with TBM.
7. Ziehl-Neelsen staining lacks sensitivity, and culture----A
positive smear is present in 25% adults and only 3% of
children.
8. Lumbar Puncture: It typically is clear or slightly turbid. If
the CSF is left to stand, a fine clot resembling a pellicle or
cobweb may form. This faintly visible "spider's web clot" is
due to the very high level of protein in the CSF (ie, 1-8 g/L, or
1000-8000 mg/dL) typical of this condition. Hemorrhagic CSF
also has been recorded in proven cases of TBM;

22. CSF analysis
a. Cell counts (223 cells/µL ), 100-500 (rarely >1000), DLC –
Lymphocytic (60%) Pleocytosis; in HIV- may be acellular.
b. Glucose – Decreased <45mg/dl or 2/3rd of blood, Protein–
Increased 100-200(224 mg/dl), may be >500.
c. Acid-fast stain/Fluorochrome, Gram stain, appropriate
bacteriologic culture and sensitivity, India ink stain.
d. CBNAAT
e. Cryptococcal antigen and herpes antigen testing
f. Culture for MTB- Positive CSF culture 61% of adults and
58% of children.
g.ELISA & PCR: Results imply that PCR can provide a rapid and
reliable diagnosis of TBM, although false-negative results
potentially occur in samples containing very few organisms (<
2 colony-forming units per mL).
h. Syphilis serology

23. i. ADA – not much helpful;1 to 4 helps to exclude TBM, >8
helps to make Dx and b/w 4-8 inconclusive.
j. Dot-immunobinding assay: A dot-immunobinding assay
(Dot-Iba) has been standardized to measure circulating
antimycobacterial antibodies in CSF specimens for the rapid
laboratory diagnosis of TBM.
9. Chest Radiography : PA and lateral views may reveal hilar
lymphadenopathy, pneumonia, infiltrate, fibro nodular,
cavitation, pleural effusion, pleural thickening.
10. Brain and Spinal Imaging: Reveal hydrocephalus, basilar
meningeal thickening, infarcts, edema, and tuberculomas .
# The characteristic CT finding is a nodular, enhancing lesion
with a central hypo dense lesion. [30] Contrast enhancement is
essential.

24. Early stages are characterized by low-density or isodense
lesions, often with edema out of proportion to the mass
effect and little encapsulation. At a later stage, well-
encapsulated tuberculomas appear as isodense or hyper
dense lesions with peripheral ring enhancement.
## Calcification occurs commonly in the basal meninges.
These calcifications sometimes harbor tubercle bacilli, which
may be responsible for a relapse of the disease.
11. Angiography: Shows narrowing of the arteries at the base
of the brain, and narrowed or occluded small and medium-
sized arteries.

25. 13. Electroencephalography: EEG findings correlated with
severity of meningitis and degree of coma.
14. Brainstem Auditory Evoked Response Testing
15. Use of Neurochemical Markers: CSF levels of amino acids,
nitrite (a metabolite of nitric oxide), vitamin B-12 and
homocysteine . Levels of taurine were decreased and levels of
phenylalanine increased only in patients with TBM. Levels of
nitrite, homocysteine increased and levels of vitamin B-12
decreased in patients with TBM.

27. Treatment & Management
• The duration of antimicrobial therapy for
tuberculous meningitis (TBM) is unclear, and the
benefits of adjuvant corticosteroids remain in
doubt. Death may occur as a result of missed
diagnoses and delayed treatment.
• In the US legal system, the model indicates that if
persons with potentially transmissible tuberculosis
(TB) refuse to take treatment, they can and should
be quarantined to protect the public.

28. ???? WHICH DRUGS
The best antimicrobial agents in the treatment of TBM
include isoniazid (INH), rifampin (RIF), pyrazinamide (PZA),
and streptomycin (SM), all of which enter cerebrospinal fluid
(CSF) readily in the presence of meningeal inflammation.
Ethambutol is less effective in meningeal disease unless used
in high doses. The second-line drugs include ethionamide,
cycloserine, ofloxacin, and para -aminosalicylic acid (PAS).
INH, RIF, and PZA are bactericidal. RIF and SM achieve optimal
CSF levels only when the meninges are inflamed. Usually,
intrathecal drugs are not necessary. Treatment is best started
with INH, RIF, and PZA. The addition of a fourth drug is left to
the choice of the local physicians and their experience, with
little evidence to support the use of one over the other.

29. ???? Duration of treatment
The duration of conventional therapy is 6-9 months, although
some investigators still recommend as many as 24 months of
therapy. No guidelines exist as to the components and
duration of treatment in the case of multidrug-resistant TBM
???? Corticosteroids
The use of corticosteroids in adults is controversial; decrease
penetration of ATT. They may be indicated in the presence of
increased intracranial pressure (ICP), altered consciousness,
focal neurological findings, spinal block, and tuberculous
encephalopathy. Treatment of tuberculoma consists of high-
dose steroids and continuation of antituberculous therapy,
often for a prolonged course.
Pred 1mg/kg or Dexa 0.4mg/kg/day or 8-16mg/day x3-6
wks taper over 2-4 weeks.

30. ???? Broad spectrum antibiotics
Mannitol, Glycerol, Acetazolamide – to decrease
cerebral edema..
IFN-gamma, G-CSF: in immunocompromised pt. with
refractory MDR TBM

31. Paradoxical Reaction:
It usually develops after approximately 2 weeks of treatment.
It is characterized by the clinical or radiological worsening of
preexisting tuberculous lesions or the development of new
lesions not attributable to the normal course of disease in a
patient who initially improved with antituberculosis therapy.
This syndrome is probably the result of an uncommon
hypersensitivity reaction to the massive release of tubercular
proteins into the subarachnoid space. An increase in the
incidence and severity of the paradoxical response is noted in
HIV-infected patients on highly active antiretroviral
therapy. Patients demonstrating a paradoxical response are
more likely to have lower baseline lymphocyte counts,
followed by a surge.

32. SURGICAL MANAGEMENT: Drain or Shunt Placement
In patients with evidence of obstructive hydrocephalus and
neurological deterioration who are undergoing treatment for
TBM, placement of a ventricular drain or ventriculoperitoneal
or ventriculoatrial shunt should not be delayed. Studies
suggest that prompt ventriculoatrial or ventriculoperitoneal
shunting improves outcome, particularly in patients
presenting with minimal neurological deficit.

33. Prevention of Tuberculous Meningitis
• BCG vaccination offers a protective effect
(approximately 64%) against TBM. Improvement in
weight for age was associated with a decreased risk
of the disease.
• Monitoring : Cure rate and Drug
resistance/compliance/home visits.