Tuberculous Meningitis Treatment & Management

Updated: Nov 10, 2021
  • Author: Gaurav Gupta, MD, FAANS, FACS; Chief Editor: Niranjan N Singh, MBBS, MD, DM, FAHS, FAANEM  more...
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Treatment

Approach Considerations

Multidrug antitubercular antibiotic therapy is considered the mainstay of treatment in tuberculous meningitis (TBM), however the optimal duration is unclear, and the efficacy of drugs may be limited due to variable CSF penetration. In addition, data on dosage and specific combinations of medications are limited. [55]  Complications of TBM, such as hydrocephalus, vasculopathy, ischemia or hemorrhage, seizures, and metabolic derangements (eg, hyponatremia) should also be considered. [55]  Death or significant disability may occur as a result of missed diagnosis and delayed treatment.

There are also public health concerns regarding transmission of tuberculosis (TB) (and other associated diseases, such as HIV), which may have legal implications, such as quarantine, variably obligatory vaccinations and treatment, and exclusion from immigration. In the United States, all TBM cases should be reported to the Centers for Disease Control and Prevention (CDC). If persons with potentially transmissible TB refuse treatment, they may be subject to mandatory quarantine. Directly observed therapy is gaining popularity. 

In TBM, despite adequate treatment of hydrocephalus and various other complications, patients commonly fail to improve. This poor outcome is often associated with the extensive tuberculous exudate in the subarachnoid cisterns of the brain, which affects cerebral vessels and induces ischemia. Hence, treatment modalities should include optimizing physiologic variables to preserve cerebral perfusion. [35]

The hypercoagulable state in childhood TBM is comparable to that described in adults with pulmonary tuberculosis and may further increase the risk for infarction. Therapeutic measures that reduce the risk for thrombosis could therefore be potentially beneficial in childhood TBM. [36]

Hyaluronidase has been used in spinal arachnoiditis with good results. Gourie-Devi and Satish Chandra recommend the use of hyaluronidase administered intrathecally in cases of arachnoiditis complicating TBM. [37]

Go to Meningitis, Meningococcal Meningitis, Staphylococcal Meningitis, Haemophilus Meningitis, Viral Meningitis, and Aseptic Meningitis for more complete information on these topics.

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Antibiotic Therapy and Adjunctive Corticosteroid Therapy

The best antimicrobial agents in the treatment of tuberculous meningitis (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 (EMB) may be less effective in meningeal disease unless used in high doses. The second-line drugs include ethionamide, cycloserine, ofloxacin, and para -aminosalicylic acid (PAS).

Antitubercular treatment for TBM should generally be initiated with INH, RIF, PZA, and EMB for the first two months. After that time period, if the TBM is known or most likely due to susceptible TB strains, the clinical may consider discontinuing EMB and PZA. RIF and INH should generally be continued for an additional 7–10 months, although it is not uncommon to continue treatment for up to 24 months. The optimal duration of treatment, particularly for multidrug-resistent TB strains, has not been well defined. [63]  Poor compliance to therapy may lead to relapse of the disease.

Adjunctive corticosteroids should be given in patients with TBM, as evidence suggests a mortality benefit. [63]  Dexamethasone or prednisolone should be given in a taper during the first 6–8 weeks of treatment. [57, 63]

In pediatric patients, the clinician should start an initial four-drug regimen of INH, RIF, PZA, and ethionamide, if possible, or an aminoglycoside, followed by 7–10 months of INH and RIF as the preferred regimen. [63]

Ethambutol and ethionamide have poor penetration into the CSF once inflammation has resolved. Fluoroquinolones, which have very good CSF penetration, may be effective fourth drugs, particularly for multidrug-resistant cases. [57]

Adverse effects of medications should also be monitored during the course of therapy. Rifampin may result in gastrointestinal symptoms, hepatotoxicity, orange dicoloration of bodily fluids, headaches, and drowsiness. Isoniazid is associated with gastrointestinal symptoms, peripheral and optic neuropathy in higher doses, and hepatotoxicity. PCA is also associated with hepatotoxicity. Ethambutol is associated with optic neuritis,  red-green color blindness, and peripheral neuritis. [59]

Generally, intrathecal antituberculous medications are not necessary.

Serial lumbar punctures should be performed to monitor response to therapy, particularly changes in CSF cell count, protein, and glucose. Serial neuroimaging should also be performed, particularly in cases of tuberculomas (which generally respond to medical treatment).

Since uveitis is often treated with immunosuppressive and corticosteroid therapy, such treatment may have catastrophic consequences if patients with tuberculous granulomatous uveitis were not properly diagnosed and managed.

Unlike patients with TB who do not have TBM, newly diagnosed HIV-positive patients should not be started on anti-retroviral therapy (ART) until approximately 8 weeks after initiation of anti-TBM therapy, due to the high risk of immune reconsitutional inflammatory syndrome (IRIS). [63]  In HIV patients at risk for opportunistic infections, antibiotic prophylaxis should also be considered.

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Neurosurgical Management

Neurosurgical consultation should be obtained in tuberculous meningitis (TBM) patients who have tuberculomas and in those with hydrocephalus, as these may require surgical intervention.

Hydrocephalus (most commonly communicating hydrocephalus) occurs in two-thirds of TBM patients, particularly in children and those with a prolonged disease course. The Vellore grading may be used to grade hydrocephalus in TBM patients. [64]  Patients with hydrocephalus and a poor neurological exam should emergently undergo placement of an external ventricular drain (EVD), as hydrocephalus may be a reversible cause of poor neurological status. The EVD also provides easy access for CSF testing. The EVD, which generally should not be kept in for longer than 10–14 days due to the risk of bacterial infection, may then be weaned by the neurosurgeon. Intracranial pressure, daily CSF output, neurological exam, and CT scans monitor the patient during the weaning process. If the patient fails a weaning trial, generally a shunt (eg, ventriculoperitoneal shunt) is required for permanent CSF diversion. Due to the prolonged course of disease, shunt complications (eg, shunt infection, malfunction, abdominal pseudocysts) may occur in 20%–40% of cases. [64]  Depending on ventricular anatomy, an endoscopic third ventriculostomy (ETV) may be considered instead of a shunt, as it obviates the need to implant permanent hardware.

Although most tuberculomas respond to medical treatment, surgery may be required for larger lesions (particularly those causing significant mass effect), lesions that result in obstructive hydrocephalus, those compressing vital structure (eg, in the posterior fossa compressing the brainstem), those with poor response to medical treatment on serial neuroimaging, or in patients who require biopsy/excision of the lesion due to uncertain diagnosis. To remove the tuberculoma, a craniotomy is performed in the operating room and the lesion is removed. In cases where only a biopsy is needed (eg, to differentiate a tuberculoma from another lesion, such as a brain tumor), minimally invasive stereotaxy may be performed. [64]  A similar approach to surgical treatment may be considered in the setting of a tuberculous abscess. 

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Prevention of Tuberculous Meningitis

Bacille Calmette-Guerin (BCG) vaccination offers a protective effect (approximately 64%) against tuberculous meningitis (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.

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Long-Term Monitoring

The effectiveness of the treatment guidelines for tuberculous meningitis (TBM) 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.

Treatment and review defaulters must be identified, and every effort must be made to locate them and promptly reinstitute therapy or observation.

Treatment defaulters are those who fail to attend supervised daily or biweekly chemotherapy or fail to collect their supply of drugs for self-administered oral chemotherapy. Review defaulters are those who fail to attend a follow-up appointment for review of sputum or other examinations, for progress review, and for further management after the examinations have been completed. Patients also tend to default review while undergoing investigations to rule out active TB.

Defaulter contacts could be made by phone, mail, and, if the yield is negative, a home visit. Home visits are made for defaulter retrieval, health education of newly diagnosed patients and their families, and contact investigation. The nurse, physician assistant, nurse practitioner, medical social worker, or public health inspector of the health facility generally makes home visits. When facilities are not available for home visiting, the treating physician has the responsibility to notify the health department.

Patients should be asked for information about their contacts so that these individuals may be traced and investigated. All family contacts must be investigated. Household contacts who admit to having cough lasting for more than 2 weeks and children without a noticeable bacillus Calmette-Guérin (BCG) scar during home visits should be advised to attend the nearest health facility for further investigations.

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