Tuberculous Meningitis

Etiology

Predicting which patients with TB infection will develop tuberculous meningitis 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, with a higher incidence of MTB in children. By contrast, in the developed world, TBM is more often seen in adults who experience the reactivation of TB. Other immunocompromised states like chronic steroid use, diabetes mellitus, and chronic alcoholism carry the same risk of developing TBM.[1] The highest correlation remains with HIV co-infection, with reports that these patients are five to ten times more likely to develop CNS disease.[2]

Epidemiology

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. Tuberculous meningitis carried a fatal prognosis before the development of anti-tuberculous medications, and 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 in 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.[3] Those with a concurrent HIV infection have a five-fold increased risk of having CNS involvement and disseminated TB, and the risk increases among patients with CD4 count <100 cells/microL.[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 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, which may be communicating or non-communicating. These immune responses can lead to complications associated with tuberculous meningitis 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 tuberculous meningitis 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 six months. The clinical presentation of TBM is similar regardless of HIV status.[1]

Three distinct phases of clinical presentation are usually found:[7]

1. The early prodromal phase is characterized by the insidious onset of low-grade fever, malaise, headache, and personality change. It usually lasts for one to three weeks.
2. It is followed by the meningitic phase, 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 five to eight weeks of the onset of untreated illness.

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

Tuberculous meningitis assessment is done 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.[3]

Confirming the diagnosis of TB 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 their yield and are only positive 40 to 83% of the time and can take from 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 greater than 85%.[9] 

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 diagnosis 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.[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]

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.[11][12]

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 detecting 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. T imaging can also show basal exudates.[9]

Treatment / Management

Anti-tuberculous treatment must start promptly 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 an intensive phase of daily isoniazid (INH), rifampin (RIF), pyrazinamide (PZD), and either streptomycin (SM) 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 can take months to receive, and treatment can be tailored to identify the drug sensitivities.[9] In children, ethambutol (EMB) Is replaced by either an aminoglycoside or ethionamide because of difficulty monitoring for ethambutol-associated optic neuritis.(B3)

Treatment with daily rifampin, ethambutol, pyrazinamide, and fluoroquinolone is advised with isoniazid-resistant CNS TB. 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.

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, the mainstay treatment has been daily intravenous dexamethasone for up to four weeks, followed by a four-week oral taper.[9](B3)

Differential Diagnosis

• Bacterial meningitis

• Viral meningitis

• Encephalitis of all causes

• Intracranial space-occupying lesions of various etiologies, including infectious and non-infectious

• Non-specific viral syndromes

• Sepsis

• Acute cerebral vascular accident

• A sympathomimetic syndrome due to drug abuse

• Delirium associated with urinary tract infection

Treatment Planning

Table 1. First-line drugs for the treatment of CNS tuberculosis[13]

 Table 2. Second-line antituberculosis drugs in adults[14][15]

Prognosis

Tuberculous meningitis is considered the deadliest form of MTB infection.[16] TBM carries a mortality rate between 20 and 67% with anti-tuberculous treatment and is fatal without treatment.[3] Patients at both ends of extremes of age and patients with HIV co-infection carry the highest mortality.[16][17] 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][17]

Complications

Tuberculous meningitis can cause a myriad of neurologic sequela that can be present at initial presentation and can produce residual effects even after successful treatment.[18]

Some significant complications to remember include the following:

• 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.[19]
• 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 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[20]
• Loss of vision that could be permanent due to compression of the optic chiasma by the dilated third ventricle as the optic chiasma and optic nerve are encased by thick tuberculous exudates[21]
• Transverse myelitis manifests as paraparesis or quadriparesis, sensory symptoms, and urinary retention in the lower limbs.[22]