Edward De Leon 2Y2-5 219-518B

What is tuberculosis Meningitis?

Tuberculous meningitis is the most severe form of tuberculosis. It causes severe neurologic deficits or
death in more than half of cases.The pattern of tuberculous meningitis in the population is different in
different areas of the world. In areas with much tuberculosis, tuberculous meningitis usually affects
young children. It develops typically 3 to 6 months after the primary tuberculosis infection. By contrast,
in areas with less tuberculosis, tuberculous meningitis tends to strike adults. It may follow a primary
infection but, more frequently, is due to reactivation of an old focus of tuberculosis that had been
dormant, sometimes for many years.

Pathophysiology of the disease

Signs and Symptoms
The symptoms often start slowly, and may include:

 Fever and chills

 Mental status changes
 Nausea and vomiting
 Sensitivity to light (photophobia)
 Severe headache
 Stiff neck (meningismus)

Other symptoms that can occur with this disease may include:

 Agitation
 Bulging fontanelles (soft spots) in babies
 Decreased consciousness
 Poor feeding or irritability in children
 Unusual posture, with the head and neck arched backward (opisthotonos). This is usually found
in infants.

Diagnostic/Laboratory examinations
A complete medical evaluation for TB includes the following:

1. Medical History
Clinicians should ask about the patient’s history of TB exposure, infection, or disease. It is also important
to consider demographic factors (e.g., country of origin, age, ethnic or racial group, occupation) that
may increase the patient’s risk for exposure to TB or to drug-resistant TB. Also, clinicians should
determine whether the patient has medical conditions, especially HIV infection, that increase the risk of
latent TB infection progressing to TB disease.

2. Physical Examination
A physical exam can provide valuable information about the patient’s overall condition and other factors
that may affect how TB is treated, such as HIV infection or other illnesses.

3. Test for TB Infection

The Mantoux tuberculin skin test (TST) or the TB blood test can be used to test for M. tuberculosis
infection. Additional tests are required to confirm TB disease. The Mantoux tuberculin skin test is
performed by injecting a small amount of fluid called tuberculin into the skin in the lower part of the
arm. The test is read within 48 to 72 hours by a trained health care worker, who looks for a reaction
(induration) on the arm.

The TB blood test measures the patient’s immune system reaction to M. tuberculosis.

4. Chest Radiograph
A posterior-anterior chest radiograph is used to detect chest abnormalities. Lesions may appear
anywhere in the lungs and may differ in size, shape, density, and cavitation. These abnormalities may
suggest TB, but cannot be used to definitively diagnose TB. However, a chest radiograph may be used to
rule out the possibility of pulmonary TB in a person who has had a positive reaction to a TST or TB blood
test and no symptoms of disease.

5. Diagnostic Microbiology
The presence of acid-fast-bacilli (AFB) on a sputum smear or other specimen often indicates TB disease.
Acid-fast microscopy is easy and quick, but it does not confirm a diagnosis of TB because some acid-fast-
bacilli are not M. tuberculosis. Therefore, a culture is done on all initial samples to confirm the diagnosis.
(However, a positive culture is not always necessary to begin or continue treatment for TB.) A positive
culture for M. tuberculosis confirms the diagnosis of TB disease. Culture examinations should be
completed on all specimens, regardless of AFB smear results. Laboratories should report positive results
on smears and cultures within 24 hours by telephone or fax to the primary health care provider and to
the state or local TB control program, as required by law.

6. Drug Resistance
For all patients, the initial M. tuberculosis isolate should be tested for drug resistance. It is crucial to
identify drug resistance as early as possible to ensure effective treatment. Drug susceptibility patterns
should be repeated for patients who do not respond adequately to treatment or who have positive
culture results despite 3 months of therapy. Susceptibility results from laboratories should be promptly
reported to the primary health care provider and the state or local TB control program.

Medication/ Treatment
 Antibiotic Therapy and Adjunctive Corticosteroid Therapy
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.
Evidence concerning the duration of treatment is conflicting. 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.
 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.
Unless a mass effect is compromising vital structures, surgical intervention is rarely required in
the treatment of tuberculomas.
 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; however, further studies are
needed to evaluate the association, if any, between nutritional status and vaccine efficacy.
  Long-Term Monitoring
The effectiveness of the treatment guidelines is determined by 2 major factors: (1) the cure rate
and (2) the level of acquired drug resistance.
The cure rate is defined, for all registered patients whose sputum smear or culture result is
positive, as the proportion of patients who completed treatment and had negative sputum
cultures at 4 months and at the end of the treatment period. It is evaluated from the result of
the cohort analysis performed yearly by the National Tuberculosis Control Program. The cure
rate is the most important factor in determining final outcomes and is related inversely to the
rate of acquired drug resistance and directly to the rate of noncompliance with treatment.
As drug resistance becomes more prevalent, the requirement of rapid sensitivity testing
becomes more urgent. This is particularly so in TBM because inappropriate treatment can be
fatal.

First-line therapy includes isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), streptomycin (SM),
and ethambutol. Second-line therapy includes ethionamide, cycloserine, para-aminosalicylic
acid (PAS), aminoglycosides, capreomycin, and thiacetazone.
Potential new agents include oxazolidinone and isepamicin. Fluoroquinolones useful in the
treatment of TBM include ciprofloxacin, ofloxacin, and levofloxacin. A new rifamycin called
rifapentine has been developed.
 Antitubercular Agents
Any regimen must contain multiple drugs to which the mycoplasma is susceptible. In addition,
the therapy must be taken regularly and continued for a sufficient period. First-line therapy
includes isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), streptomycin (SM), and ethambutol.
Second-line therapy includes ethionamide, cycloserine, para-aminosalicylic acid (PAS),
aminoglycosides, and capreomycin.
 Capreomycin (Capastat)
Capreomycin is a second-line drug for concomitant use with other appropriate anti-TB drugs
when first-line drugs are ineffective or cannot be used because of toxicity.
 Cycloserine
Cycloserine is a second-line anti-TB drug effective against Mycobacterium tuberculosis. It is a
competitive antagonist of the racemase enzyme involved in bacterial cell wall synthesis. It is also
active against other mycobacteria such as Mycobacterium fortuitum, Mycobacterium kansasii,
and Mycobacterium malmoense. It is indicated in TB resistant to first-line drugs, in combination
with other drugs.
 Ethambutol (Myambutol)
Ethambutol is bactericidal at 25 mg/kg at pH between neutral and alkaline. It is bacteriostatic at
15 mg/kg. Its site of action is extracellular. It acts on rapidly growing pathogens in cavity walls. It
is also effective in slow-growing pathogens. Ethambutol is indicated as a first-line anti-TB drug.
 Ethionamide (Trecator)
Ethionamide is bacteriostatic against M tuberculosis. It is also active against atypical
mycobacteria such as Mycobacterium kansasii, some strains of Mycobacterium avium complex,
and Mycobacterium leprae. It is indicated as a second-line anti-TB agent.
 Isoniazid
INH is bactericidal against actively dividing pathogens but bacteriostatic against nondividing
organisms. It is highly effective against M tuberculosis. It is indicated for treatment of all forms
of TB. Usually, preventive therapy with INH is delayed in pregnant women until delivery unless
the patient is likely to have been infected recently. There have been reports of severe and
potentially fatal hepatitis related to isoniazid therapy. Hepatic enzymes, including aspartate
aminotransferase (AST) and alanine aminotransferase (ALT), should be measured prior to the
initiation of therapy and monitored at monthly intervals during treatment.
The Centers for Disease Control (CDC) reported in November 2010 the results of a national
project on monitoring severe adverse events associated with the treatment of latent
tuberculosis infection (LTBI). This report was published in the Morbidity and Mortality Weekly
Report. The report includes 17 cases of severe INH-associated liver injury identified from 2004-
2008. INH-induced liver injury may occur in persons of any age and at any time during
treatment. It is important to discontinue isoniazid treatment immediately if patients develop
symptoms of nausea, vomiting, abdominal discomfort, or fatigue. [44]
 Pyrazinamide
PZA has bactericidal action against M tuberculosis in the acidic environment present in
macrophages and inflamed tissue; it works both intracellularly and extracellularly. Together with
RIF, it provides the greatest sterilizing action, with a reduction in the replace rate. It reduces
tubular secretion of uric acid. PZA is indicated as part of multidrug regimens during the first 2
months; it may be continued if necessary.
 Rifampin (Rifadin)
RIF has bactericidal action against a wide range of organisms, including intracellular organisms
and semidormant or persistent ones. Generally, it is reserved for the treatment of TB and
leprosy and opportunistic atypical mycobacterial infections such as those in patients with AIDS
or HIV infection. RIF inhibits DNA-dependent RNA polymerase enzyme, resulting in suppression
of nucleic acid synthesis. It is indicated as part of multidrug anti-TB regimens.
 Streptomycin
SM sulfate has bactericidal action and inhibits bacterial protein synthesis. Susceptible organisms
include M tuberculosis, Pasteurella pestis, Pasteurella tularensis, Haemophilus influenzae,
Haemophilus ducreyi, donovanosis (granuloma inguinale), Brucella species, Klebsiella
pneumonia, Escherichia coli, Proteus species, Aerobacter species, Enterococcus faecalis, and
Streptococcus viridans (in endocarditis, with penicillin). SM sulfate is always given as part of a
total anti-TB regimen.
 Para-aminosalicylic acid (Paser)
Para-aminosalicylic acid is a weak bacteriostatic agent that is available as an enteric-coated
granule designed for gradual drug release. It is believed to competitively inhibit conversion of
aminobenzoic acid to dihydrofolic acid and/or to inhibit iron uptake. In treatment of clinical TB,
PAS should not be given alone.
 Rifapentine (Priftin)
Rifapentine possesses in vitro activity superior to that of RIF against isolates of M tuberculosis
and M avium complex. Both rifapentine and its metabolite are protein bound. Rifapentine is FDA
approved for the treatment of pulmonary tuberculosis.
 Aminoglycosides
The aminoglycosides bind reversibly to 1 of 2 aminoglycoside binding sites on the 30S ribosomal
subunit, causing an inhibition of bacterial protein synthesis. Examples of aminoglycosides used
in the treatment of tuberculosis include amikacin and kanamycin.
 Kanamycin
Kanamycin is an aminoglycoside containing 1 or 2 amino sugars linked to an aminocyclitol
nucleus. The nucleus is 2-deoxystreptamine. Kanamycin is bactericidal and is believed to inhibit
protein synthesis by binding to the 30S ribosomal subunit. It is effective against extracellular
mycobacteria.
  Amikacin
Amikacin is an aminoglycoside containing 1 or 2 amino sugars linked to an aminocyclitol nucleus.
The nucleus is 2-deoxystreptamine. Amikacin is highly bactericidal against M tuberculosis in
vitro.
 Fluoroquinolones
Several fluoroquinolones have shown in vitro activity against M tuberculosis. The target of the
quinolones is the enzyme DNA gyrase. Ofloxacin and ciprofloxacin are compounds of this family
that are licensed for use in the United States. However, neither of these drugs are FDA approved
for the treatment of TB.
The minimal inhibitory concentration of floxacin and ciprofloxacin is approximately 1 mcg/mL
for a wide range of strains of M tuberculosis, compared with a peak serum concentration of 4.3
mcg/mL 1-2 h after a 750-mg dose of ciprofloxacin, and a 4.6 mcg/mL peak serum concentration
after multiple 400-mg doses of ofloxacin. One study showed a similar minimal inhibitory
concentration for ofloxacin in the macrophage model, and minimal bactericidal concentration
was found to be 2 mcg/mL; however, the bactericidal activity of ofloxacin was less than that of
RIF. Another study found identical minimal bactericidal concentration levels of 2 mcg/mL for
both ciprofloxacin and ofloxacin in 7H12 broth medium. In general, quinolones are well
tolerated.
 Ciprofloxacin (Cipro, Cipro XR)
Ciprofloxacin has been shown to have in vitro activity in M tuberculosis, but data on clinical use
of these agents in TB are limited. Ciprofloxacin is not approved in United States for treatment of
TB. It probably has greater efficacy at higher doses. The target is the enzyme DNA gyrase.
Ciprofloxacin is generally well tolerated. Toxicity is related more to duration of therapy than to
dose. The agent is cleared primarily by renal excretion; adjust dosage for creatinine clearance of
less than 50 mL/min.
 Ofloxacin
Ofloxacin is a broad-spectrum fluoroquinolone that inhibits DNA gyrase. It has good gram-
positive coverage and excellent gram-negative coverage but poor anaerobic coverage.
 Levofloxacin (Levaquin)
Levofloxacin is a fluoroquinolone antibiotic that is used in the treatment of tuberculosis in
combination with rifampin and other antituberculosis agents.
Corticosteroids
Class Summary
The use of corticosteroids in adults is controversial; 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. In
tuberculous radiculomyelitis (TBRM), as in other forms of paradoxical reactions to anti-TB
treatment, evidence shows that steroid treatment might have a beneficial effect.
Studies have shown that young children with TBM can be treated safely for 6 months with high
doses of anti-TB agents without overt hepatotoxicity and with a low risk of relapse. Children
must be treated for 12 months with combination antibiotic therapy and adjunctive
corticosteroids. The rationale behind the use of adjuvant corticosteroids lies in reducing the
harmful effects of inflammation as the antibiotics kill the organisms.
 Prednisone (Rayos)
Prednisone may decrease inflammation by reversing increased capillary permeability and
suppressing PMN activity.
  Dexamethasone (Baycadron)
Dexamethasone has many pharmacologic benefits but significant adverse effects. It stabilizes
cell and lysosomal membranes, increases surfactant synthesis, increases serum vitamin A
concentration, and inhibits prostaglandin and proinflammatory cytokines (eg, TNF-alpha, IL-6, IL-
2, and IFN-gamma). The inhibition of chemotactic factors and factors that increase capillary
permeability inhibits recruitment of inflammatory cells into affected areas.