1) CNS tuberculosis is typically treated with a two-phase regimen consisting of 4 drugs for 2 months followed by 2 drugs for 7-10 months totaling 9-12 months. Glucocorticoids are also administered. 2) For drug-susceptible cases, the intensive phase includes isoniazid, rifampin, pyrazinamide, and a fourth drug like ethambutol or streptomycin. The continuation phase includes isoniazid and rifampin. 3) For drug-resistant cases, treatment involves first-line drugs if susceptible and a fluoroquinolone plus additional second-line drugs to make a 5-drug regimen, lasting 18-24 months

1. CNS –TB TREATMENT
DR MOHAMMED SHANIL P
JUNIOR RESIDENT
GENERAL MEDICINE

3. DIAGNOSIS

7. MRC staging The British Medical Research Council (MRC)
staging is a widely recognized system for classifying disease
severity in TBM (MRC, 1948)

8. COMPLICATION

10. CNS TUBERCULOMA

15. TREATMENT
• Traditional regimen — In general, treatment of CNS TB consists of an
initial intensive phase (4 drugs administered for 2 months) followed
by a prolonged continuation phase (usually 2 drugs administered for
an additional 7 to 10 months), for a total treatment duration of 9 to
12 months. All patients with TB should be treated with clinical case
management and DOT.

16. ● Intensive phase − Empiric intensive phase drug regimens consist of
the following:
• Adults − In adults, for empiric treatment of CNS TB (not known or
suspected to be drug resistant), the intensive-phase four-drug
regimen consists of isoniazid, rifampin, pyrazinamide, and a fourth
agent administered daily for two months [2,3]. • In children, the
intensive phase four-drug regimen consists of isoniazid, rifampin,
pyrazinamide, and either ethionamide or streptomycin (in place of
ethambutol, given difficulty associated with monitoring for
ethambutol-associated optic neuritis) administered daily for two
months

17. • Isoniazid, rifampin, and pyrazinamide are bactericidal, penetrate
inflamed meninges, and achieve CSF levels that exceed the minimum
inhibitory concentration for sensitive strains. Isoniazid has excellent
CNS penetration and is more active against rapidly dividing than
against semi-dormant organisms. Rifampin is active against both
rapidly dividing organisms and semi-dormant organisms, despite its
relatively poor CNS penetration. Pyrazinamide readily penetrates the
CNS and is highly active against intracellular mycobacteria

18. • For selection of the fourth drug, there is a lack of consensus among
authorities, and there are no data from controlled trials. Options
include ethambutol, streptomycin, levofloxacin, or ethionamide. The
WHO guidelines favor streptomycin over ethambutol

19. • Use of higher-dose rifampin and levofloxacin during the intensive
phase has not been associated with improved survival. In a
randomized trial including 817 patients with tuberculous meningitis
(of whom 349 were had HIV infection), patients were randomly
assigned to treatment with a standard regimen or an intensified
regimen that included higher-dose rifampin (15 mg/kg per day) and
levofloxacin (20 mg/kg per day) during the intensive phase; during 9
months of follow-up, no survival benefit was observed between the
groups (survival probability approximately 75 percent) . Use of even
higher rifampin dosing (>30 mg/kg) warrants further study; this may
improve CSF penetration and may overcome the issue of isoniazid
monoresistance

20. • Children − In children, monitoring for ethambutol-associated optic
neuritis can be difficult; therefore, we are in agreement with the
American Academy of Pediatrics which recommends the substitution
of either ethionamide or an aminoglycoside (such as streptomycin) in
place of ethambutol in the initial empiric treatment regimen, given
difficulty associated with monitoring for ethambutol-associated optic
neuritis. Pediatric dosing of antituberculous agents is summarized
separately.

21. • Continuation phase − In the setting of infection known or presumed
to be caused by susceptible strains, the continuation phase consists
of isoniazid and rifampin (given daily), continued for 7 to 10 months.
The optimal duration of treatment is uncertain; in general, an
extended period of treatment is administered because tuberculous
meningitis is associated with high rates of disability and deaths. In
one review and meta-analysis comparing 6 months versus longer
treatment duration for tuberculous meningitis with at least isoniazid,
rifampin, and pyrazinamide, there was no difference in 2-year relapse
rate between groups (1.5 versus 0 percent), suggesting 6 months
might be sufficient.

22. • Shortened regimen — Data on a shortened regimen for treatment of
tuberculous meningitis are promising. While the WHO stated in 2021
that use of a shortened regimen may be used as a possible alternative
treatment approach for children and adolescents, we continue to
favor use of the traditional regimen pending further data.
• A six-month regimen of daily isoniazid, rifampin, pyrazinamide, and
ethionamide has been evaluated as an alternative option for the
treatment of children and adolescents with tuberculous meningitis .
In a systematic review and meta-analysis including three studies and
more than 1000 participants, lower mortality (8 versus 24 percent)
and higher treatment success rate (83 versus 75 percent) were
observed with the shortened regimen compared with the traditional
regimen

23. • Drug resistant infection — The prevalence of M. tuberculosis strains
resistant to one or more first-line drugs is increasing. The presence of
risk factors should prompt susceptibility testing (by molecular and
conventional methods) on diagnostic specimens.
• The optimal approach to treatment of drug-resistant tuberculous
meningitis is uncertain:

24. • For treatment of isoniazid-resistant tuberculous meningitis, we favor
intensive phase treatment with daily rifampin, ethambutol,
pyrazinamide, and a fluoroquinolone for 2 months, followed by a
continuation phase of rifampin, pyrazinamide, and a fluoroquinolone
for at least 10 months. This approach is derived from management of
drug-resistant pulmonary TB, the evidence for which is discussed
separately.

25. For treatment of multidrug-resistant tuberculous meningitis, regimen
selection should be guided by the approach to treatment of
pulmonary disease; the regimen should include any first-line drugs to
which the isolate is susceptible, with addition of a fluoroquinolone
and additional second-line drugs with good CSF penetration (such as
ethionamide and cycloserine) to make a regimen including at least
five effective drugs . A combination of levofloxacin, kanamycin,
ethionamide, linezolid, and pyrazinamide is a favorable regimen for
multidrug-resistant tuberculous meningitis; kanamycin penetration is
adequate if meninges are inflamed .

26. • Data on CSF penetration of bedaquiline, clofazimine, and delamanid
are extremely limited. In one case report, therapeutic drug
monitoring performed over 24 hours in a patient with multidrug-
resistant tuberculous meningitis later in his treatment course
(approximately 11 weeks after starting antituberculosis treatment
and 6 weeks after starting bedaquiline) demonstrated undetectable
drug levels in CSF . Additional data are needed, especially early in the
course of the disease when inflammation may affect CNS penetration.

27. • The optimal duration of therapy for treatment of drug-resistant CNS
disease is uncertain. It may be advisable to extend the duration of
therapy to 18 to 24 months, taking into account the severity of illness,
the clinical response, and the patient's immune status.

28. • Glucocorticoids — Adjunctive glucocorticoid therapy should be
administered to all patients with tuberculous meningitis (suspected or
confirmed). We administer glucocorticoids to patients with and
without HIV infection. The optimal approach is uncertain; we favor
the following approach

29. • For patients >14 years of age − Dexamethasone 0.3 to 0.4 mg/kg/day
intravenously (IV) for 2 weeks, then 0.2 mg/kg/day IV week 3, then
0.1 mg/kg/day IV week 4, then 4 mg per day orally and taper 1 mg off
the daily dose each week; total duration approximately 8 weeks. In
conscious patients, oral prednisolone 0.5 mg/kg (up to 40 mg/day)
may be given for 4 weeks and then tapered over the following 4
weeks .
● For patients ≤14 years of age − Dexamethasone 0.6 mg/kg/day IV for
4 weeks, followed by a reducing course over 4 weeks. An alternative
(oral) regimen consists of prednisone 2 mg/kg daily (maximum 60
mg/day), or its equivalent for 4 to 6 weeks, followed by tapering

30. MANAGEMENT OF COMPLICATIONS
• Hydrocephalus — In some circumstances, during initiation of
antituberculous therapy and glucocorticoids, hydrocephalus may be
managed with serial lumbar punctures in conjunction with clinical
monitoring. However, for patients with stupor, coma, or progressive
neurologic impairment, surgical decompression of the ventricular
system should be pursued promptly. In addition, early surgical
consultation is indicated for patients with noncommunicating
hydrocephalus.

31. • Optochiasmatic arachnoiditis — Optochiasmatic arachnoiditis,
encasement of optic nerves and optic chiasma by thick tuberculous
exudates, is an important cause of vision loss in tuberculous
meningitis. This condition may develop paradoxically, despite
administration of appropriate antituberculous therapy. The optimal to
management of this complication is uncertain. Some patients regain
vision with antituberculous therapy and corticosteroids. Neurosurgery
may be considered in patients who do not respond to these
interventions. Thalidomide, an inhibitor of tumor necrosis factor-
alpha, has been associated with clinical improvement in case reports