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, there is a high degree of bacteremia that 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 seen 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 the prevention and management of this global health threat.
- 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.
Tuberculous meningitis (TBM) is a manifestation of 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, there is a high degree of bacteremia that 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 the development of complications associated with tuberculous meningitis and chronic sequela seen in patients who recover from TBM.
Predicting which patients with TB infection will develop TBM 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, where there is an overall higher incidence of MTB in children. By contrast, in the developed world, TBM is more often seen in adults who experience reactivation TB. Other immunocompromised states like chronic steroid use, diabetes mellitus, and chronic alcoholism carry the same risk of developing TBM. The highest correlation remains with HIV co-infection, with reports that these patients being five to ten times more likely to develop CNS disease.
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. The number of persons infected with tuberculosis continues to increase despite advances in treatment and worldwide efforts to provide accessibility to the medications and universal standard protocoled treatment programs. Tuberculous meningitis carried a fatal prognosis before the development of anti-tuberculous medications. Despite the treatment available, 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 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.
History and Physical
The clinical presentation of tuberculous meningitis is similar to other forms of chronic meningitis, making the diagnosis difficult to make and the differential broad. The clinical presentation is associated with fever, headache, altered sensorium, and focal neurologic deficits. Typical neurologic deficits include facial palsy. 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.
Tuberculous meningitis assessment is 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.
Confirming the diagnosis of TB is a difficult diagnostic dilemma; this is especially true in resource-poor areas. Definitive diagnosis results from positive 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%. 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. Over a series of several days, daily large volume spinal taps sent for microbiological analysis can improve the culture sensitivity greater than 85%.
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 diagnostic 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. Culture allows for the assessment of drug sensitivity results. Drug-resistant MTB carries up to twice the mortality.
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.
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 the detection of 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. CT imaging can also show basal exudates.
Treatment / Management
Anti-tuberculous treatment must start in a timely fashion 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 daily isoniazid (INH), rifampin (RIF), pyrazinamide (PZD), and either streptomycin (SM) or ethambutol (EMB). This regimen is then followed by 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, at which time, treatment can be tailored to the identification of the drug sensitivities.
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, 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, mainstay treatment has been daily intravenous dexamethasone for up to four weeks followed by a four-week oral taper.
Encephalitis of all causes
Intracranial space-occupying lesions of various etiologies, including infectious and non-infectious
Non-specific viral syndromes
Acute cerebral vascular accident (CVA)
A sympathomimetic syndrome due to drug abuse
Delirium associated with urinary tract infection
Tuberculous meningitis is considered the deadliest form of MTB infection. TBM carries a mortality rate between 20 and 67% with anti-tuberculous treatment and is fatal without treatment. Patients at both ends of extremes of age and patients with HIV co-infection carry the highest mortality. The prognosis of TBM depends on the patients’ neurologic status at the time of initial presentation and timeliness of the initiation of anti-tuberculous agents. Patients who develop hydrocephalus secondary to MTB also have a poor prognosis even with neurosurgical intervention.
Tuberculous meningitis can cause a myriad of neurologic sequela that can be present at the time from the initial presentation and can produce residual effects even after successful treatment.
Some significant complications to remember include:
- 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.
- 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 patient with TBM depending on which diagnostic modalities is used in diagnosis with MRI being superior in diagnosis than CT.
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. Health care 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 greatly improve the outcomes in these efforts. Public and private sector contributions are imperative to the advancements in diagnostic modalities and treatments in MTB.
Tuberculous meningitis is a serious condition that requires an interprofessional team that includes physicians, emphasizing an infectious disease specialist, specialty infection control nurses, and pharmacy. By working together and maintaining open communication, the patient can receive appropriate care in a timely fashion. [Level 5]