Tuberculous Meningitis

Etiology

Predicting which patients with MTB infection will progress to TBM is challenging. Children, particularly those aged 4 and younger, are at higher risk of developing TBM. This condition is more common in the developing world, where MTB infection rates are significantly higher among children. By contrast, in the developed world, TBM is more often seen in adults who experience the reactivation of tuberculosis. Other immunocompromised states like chronic steroid use, diabetes mellitus, and chronic alcoholism carry a risk of developing TBM.[1] The highest correlation remains with human immunodeficiency virus (HIV) co-infection, with reports that these patients are 5 to 10 times more likely to develop CNS disease.[2]

Epidemiology

Despite being a preventable and curable disease, tuberculosis is the leading cause of death worldwide due to an infectious etiology; approximately one-third of the world’s population is presumed to be infected with MTB. TBM carried a fatal prognosis before the development of antituberculosis medications, and it remains the number 1 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.

TBM presents in 1% of all cases of extrapulmonary tuberculosis. In the developed world, where there is a lower prevalence of tuberculosis 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.[3] Those with a concurrent HIV infection have a 5-fold increased risk of having CNS involvement and disseminated tuberculosis, and the risk increases among patients with a CD4 count of less than 100 cells/µL.[4]

Pathophysiology

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, a high degree of bacteremia can seed the entire body. In TBM, the meninges are seeded by MTB and form subependymal 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, which may be communicating or non-communicating. These immune responses can lead to complications associated with TBM and chronic sequela in patients who recover from TBM.[5]

Tuberculous vasculitis leads to constriction, spasm, thrombosis, and occlusion of intracerebral vessels. This ultimately causes multiple, small, bilateral infarcts, frequently located in the periventricular regions; the basal ganglia, thalamus, and internal capsule are most frequently involved. These infarcts can cause stroke syndromes of the cerebral cortex, basal ganglia, pons, and/or cerebellum.[6]

History and Physical

The clinical presentation of TBM is similar to other forms of chronic meningitis, making the diagnosis difficult and the differential broad. The clinical presentation is associated with fever, headache, altered sensorium, and focal neurologic deficits. Typical neurologic deficits include facial palsy.[2] The additional diagnostic difficulty is that the symptoms can be present anywhere from a few days to 6 months. The clinical presentation of TBM is similar regardless of HIV status.[1]

Three distinct phases of clinical presentation are usually found as follows: 

1. The early prodromal phase is characterized by the insidious onset of low-grade fever, malaise, headache, and personality change—usually lasting for 1 to 3 weeks.                                                                            
2. The meningitic phase then follows, which is characterized by prominent neurologic features, such as protracted headache, vomiting, meningismus, lethargy, confusion, and varying presentation of cranial nerve and long-tract signs.                                                                                                               
3. Confusion gives way to stupor, seizures, coma, and often hemiparesis in the paralytic phase. Death frequently ensues within 5 to 8 weeks of the onset of untreated illness.[7]

Atypical manifestations include rapidly progressive meningitic syndrome suggesting pyogenic meningitis, slowly progressive dementia over months, personality change, social withdrawal, memory deficits, and loss of libido. Patients may sometimes also present with an encephalitic course characterized by convulsions, stupor, and coma without overt signs of meningitis.[8]

Evaluation

TBM assessment is performed by obtaining CSF for analysis, which typically reveals low glucose, elevated protein, and modestly elevated white blood cell count with a lymphocytic predominance. The CSF analysis most closely resembles the CSF analysis of viral meningitis.[3] Confirming the diagnosis of TBM is a difficult diagnostic dilemma; this is especially true in resource-poor areas. Definitive diagnosis results from the 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%.[2] CSF mycobacterium cultures vary in yield and are only positive 40% to 83% of the time and can take 6 to 8 weeks to grow.[3] Over several days, daily large-volume spinal taps sent for microbiological analysis can improve the culture sensitivity by more than 85%.[9] 

Various new modalities for testing for antigens and antibodies specific to TBM exist using polymerase chain reaction, but they have not won wide acceptance or utilization due to a lack of access to the testing and high variability in the specificity of the test results. The choice of diagnosis in most cases will 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.[2][3][9] Culture allows for the assessment of drug sensitivity results. Drug-resistant MTB carries up to twice the mortality.[9] Other tests that can be utilized are antigen testing in the urine and adenosine deaminase.[10] Recent study results have estimated the sensitivity of several diagnostic tests as follows:

• Ziehl-Neelsen smear (large volume CSF that is centrifuged to concentrate MTB): 34%
• GeneXpert: 25%
• MTB culture: 32% [11]
• CSF lipoarabinomannan: 22% [12]
• GeneXpert Ultra: 44% [12]

These diagnostic difficulties can lead to delayed recognition of TBM. 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 5 or more days, neurologic impairment, CSF to serum blood glucose ratio less than 0.5, and CSF protein level greater than 100 mg/dL. These algorithms have been tested in several retrospective trials and have not received prospective trial validation. Therefore, to diagnose TBM, a high clinical suspicion must remain based on patient risk factors.[13][14]

Neuroimaging can further aid in the diagnosis of TBM. Magnetic resonance imaging (MRI) has demonstrated superiority to computed tomography (CT) scans, as it is of higher quality for assessing the brainstem and spine in detecting TBM.[15] 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 can result in the need for immediate neurosurgical intervention. 

Treatment / Management

Anti-tuberculosis treatment must start promptly to reduce morbidity and mortality in patients with TBM. First-line anti-tuberculosis treatments have excellent CSF penetration (see Table 1. First-Line Drugs for the Treatment of CNS Tuberculosis). Treatment for TBM consists of 2 months of an intensive phase of daily isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and either streptomycin or ethambutol (EMB).

This regimen is followed by the continuation phase of 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 using standard methods can take months to receive.[9] The advent of nucleic acid amplification tests has dramatically reduced the time for drug sensitivity testing. In children, EMB is replaced by either an aminoglycoside or ethionamide because of difficulty monitoring for ethambutol-associated optic neuritis (see Table 2. Second-Line Anti-Tuberculosis Drugs in Adults). Treatment with daily RIF, EMB, PZA, and fluoroquinolone is advised with INH-resistant CNS tuberculosis. Moreover, the duration of therapy should be extended to 18 to 24 months, depending on the clinical response to treatment, the severity of the illness, and the patient's immune status. (B3)

Adjunctive therapy with corticosteroids has been used to treat TBM. There is a limited number of published trials that have assessed the value of adjunctive corticosteroid therapy to treat TBM. A Cochrane Database review concludes that adjunctive corticosteroids provide a mortality benefit but do not reduce rates of neurologic disability.[16] 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 can reduce the penetration in the CSF of the anti-tuberculosis medication, but to date, study results have not shown this to occur. While no trials are comparing which steroid is superior, the mainstay treatment has been daily intravenous dexamethasone for up to 4 weeks, followed by a 4-week oral taper.[9](A1)

Differential Diagnosis

When evaluating a patient with suspected TBM, it is crucial to consider a broad range of differential diagnoses, as TBM shares symptoms with several other central nervous system conditions. Accurate differentiation between TBM and other forms of meningitis or neurological disorders is essential for timely and appropriate treatment. Conditions that should be considered in the differential diagnosis to ensure a comprehensive evaluation include the following:

• Bacterial meningitis
• Viral meningitis
• Encephalitis of all causes
• Intracranial space-occupying lesions of various etiologies, including infectious and noninfectious
• Nonspecific viral syndromes
• Sepsis
• Acute cerebral vascular accident
• A sympathomimetic syndrome due to drug abuse

Prognosis

TBM is considered the deadliest form of MTB infection.[17] TBM carries a mortality rate between 20% and 67% with anti-tuberculosis treatment and is fatal without treatment.[3] Patients at the extremes of age and patients with HIV co-infection carry the highest mortality.[17][18] The prognosis of TBM depends on the patient's neurologic status at the time of initial presentation and the timeliness of the initiation of anti-tuberculous agents.[2] Patients who develop hydrocephalus secondary to MTB also have a poor prognosis, even with neurosurgical intervention.[9][18]

Complications

TBM can cause a myriad of neurologic sequela that can be present at initial presentation and can produce residual effects even after successful treatment.[19] Complications include the following:

• Hydrocephalus due to obstruction of CSF outflow causes raised intracranial pressure.                                           
• Hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion is seen in 40% to 50% of patients with TBM.[20]                                                                                                                                 
• Tuberculomas can occur independently of TBM.                                                                                                   
• Vasculitis and stroke occur in 15% to 57% of patients with TBM, depending on which diagnostic modalities are used in diagnosis, with MRI being diagnostically superior in diagnosis to CT.                                                       
• Seizures, generally focal, result from hyponatremia, infarction, and meningeal irritation.[21]                                        
• Loss of vision that could be permanent due to compression of the optic chiasma by a dilated third ventricle or as a result of optic nerve compression due to thick tuberculous exudates.[22]                                         
• Transverse myelitis manifests as paraparesis or quadriparesis, sensory symptoms, and urinary retention in the lower limbs.[23]