Tuberculous Meningitis 

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

Overview

Background

Currently, more than 2 billion people (ie, one third of the world’s population) are infected with tuberculosis (TB), 10% of whom develop clinical disease, and 1.4 million of whom die of the disease annually.[50]  Tuberculous meningitis (TBM) is a manifestation of extrapulmonary TB, develping in 1%–5% of the approximately 10 million cases of TB worldwide.[47, 48, 50]  Although rare in the United States and Europe, TB is a common cause of meningitis (and the most common cause of chronic meningitis) in endemic areas worldwide, particularly among patients co-infected with HIV.[48, 49, 50]

Mycobacterium tuberculosis bacilli enter the host by droplet inhalation, after which the localized infection escalates within the lungs and then disseminates to the regional lymph nodes. The bacilli may then seed to the central nervous system (CNS) and result in three forms of CNS TB: tuberculous meningitis, intracranial tuberculoma, and spinal tuberculous arachnoiditis.[49] In the brain, the bacilli may form small subpial or subependymal foci of metastatic caseous lesions, termed Rich foci. As the disease progresses, the Rich foci enlarge and may eventually rupture into the subarachnoid space, resulting in meningitis (See Pathophysiology).

Despite great advances in immunology, microbiology, and drug development, TB remains a significant public health challenge. Although progress has been made, issues such as poverty, lack of functioning public health infrastructure, lack of funding to support basic research aimed at developing new drugs, diagnostics, and vaccines, and the co-epidemic of HIV contribute to the ongoing epidemic of TB (See Epidemiology).

If untreated, TBM may have a poor outcome and permanent neurological sequelae, thus requiring rapid diagnosis and treatment. Prognosis is related directly to the clinical stage at diagnosis (See Prognosis).

Unlike many forms of bacterial meningitis, TBM is often difficult to diagnose, as initial symptoms are generally subacute and often nonspecific (although occasionally may present more acutely), and neck stiffness is typically not present in the early course of the illness.[51, 57]  The duration of presenting symptoms may vary from 1 day to 9 months (generally, a week to a month), and the prodrome is usually nonspecific, including headache, vomiting, photophobia, and fever. Meningismus may also occur. Unlike most forms of bacterial meningitis, TBM is more likely to cause neurological deficits, including altered mental status, personality changes, and, as the lesions may result in neurovascular compression, cranial nerve deficits and infarcts.[51] (See Clinical Presentation).

The clinician should have a high index of clinical suspicion if a patient presents with a clinical picture of meningoencephalitides, especially in high-risk groups or in endemic areas. There is frequently diagnostic uncertainty when differentiating TBM from other meningoencephalitides, in particular partially treated meningitis. TBM must be differentiated not only from other forms of acute and subacute meningitis, but also from conditions such as viral infections and cerebral abscesses (See Diagnosis).

The diagnosis of TBM cannot be made or excluded solely on the basis of clinical findings. Tuberculin testing is of limited value. Variable natural history and accompanying clinical features of TBM may confuse the clinician. A lumbar puncture is necessary if meningitis is suspected, with the caveat that there is some risk of herniation of the medulla if intracranial hypertension is suspected. A small-volume lumbar puncture may be considered in such cases. CNS imaging modalities lack specificity but may aid in suggesting the diagnosis and monitoring for complications that require neurosurgical intervention (See Workup).

Prompt treatment is essential, as death or signfiicant neurological disability may occur as a result of missed diagnoses and delayed treatment. Antimicrobial therapy is best started with isoniazid, rifampin, and pyrazinamide; addition of a fourth drug is left to local choice. Although unclear, the optimal duration of antimicrobial therapy should generally be for approximately 9–12 months (longer than for isolated pulmonary TB). The benefits of adjuvant corticosteroids remain in doubt; their use in adults is controversial, though they may be indicated in the presence of increased ICP, altered consciousness, focal neurological findings, spinal block, and tuberculous encephalopathy.

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. Prompt CSF diversion improves outcomes, particularly in patients presenting with minimal neurological deficit (See Treatment and Management).

New research avenues include research into vaccine design, mechanisms of drug resistance, and virulence determinants. Rapid sensitivity testing using bacteriophages considers the problem of drug resistance.

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

Pathophysiology

Many of the signs, symptoms, and sequelae of tuberculous meningitis (TBM) are the result of an immunologically directed inflammatory reaction to the infection. Mycobacterium tuberculosis bacilli enter the host by droplet inhalation, and initially infect alveolar macrophages. Localized infection worsens in the lungs, and then disseminates to the regional lymph nodes occurs, resulting in the primary complex. During this stage, a short but significant bacteremia is present that can seed bacilli to other organs. 

The bacilli may then seed to the central nervous system (CNS) and result in any of three forms of CNS TB: tuberculous meningitis, intracranial tuberculoma, and spinal tuberculous arachnoiditis.[49]  Tuberculous pneumonia may result in heavier and more prolonged tuberculous bacteremia, which renders CNS dissemination more likely, particularly if miliary TB develops. In the brain, the bacilli may form small subpial or subependymal foci of metastatic caseous lesions, known as Rich foci, after the original pathologic studies of Rich and McCordick.[1]  As the disease progresses, the Rich foci enlarge and may eventually rupture into the subarachnoid space, resulting in meningitis.

The location of the expanding tubercle (ie, Rich focus) determines the type of CNS involvement. Tubercles rupturing into the subarachnoid space cause meningitis, whereas those deeper in the brain parenchyma or in the spinal cord cause tuberculomas or abscesses. While an abscess or tuberculoma may rupture into the ventricle, a Rich focus does not.

A thick gelatinous exudate may infiltrate the cortical or meningeal blood vessels, producing inflammation, obstruction, or infarction. Unlike most forms of bacterial meningitis, TBM tends to occur at the skull base (basal meningitis), which accounts for the frequent dysfunction of cranial nerves (including III, VI, and VII), and obstructive hydrocephalus from obstruction of basilar cisterns. Subsequent neurological pathology is produced by three general processes: adhesion formation, obliterative vasculitis, and encephalitis or myelitis.

Formation of tuberculomas

Tuberculomas are conglomerate caseous foci that form within the parenchyma of the brain, as shown in the image below. They may occur anywhere in the brain, but have a predilection for subcortical structures.[52]  Centrally located, active lesions may reach considerable size without producing meningitis.[1] Under conditions of poor host resistance, this process may result in focal areas of cerebritis or frank abscess formation, but the usual course is coalescence of caseous foci and fibrous encapsulation (ie, tuberculoma).

Tuberculoma is the round gray mass in the left cor Tuberculoma is the round gray mass in the left corpus callosum. The red meninges on the right are consistent with irritation and probable meningeal reaction to tuberculosis. Courtesy of Robert Schelper, MD, Associate Professor of Pathology, State University of New York Upstate Medical University.

Tuberculomas may coalesce together or grow in size, even during ongoing antitubercular therapy[2] ; this process may have an immunological basis.[3] Tuberculomas can also involve adjacent intracranial arteries, often causing vasculitis and resulting strokes.[4] Probable embolic spread of tuberculomas in the brain in multi-drug resistant TBM has been reported.[5]

Spinal Involvement

The spinal meninges may become involved secondarily due to extension of intracranial meningitis, or may develop primarily from a tuberculous focus on the surface of the cord (which then ruptures into the subarachnoid space), or via transdural extension of an infection from caries in the spine (e.g. Pott's disease).

Pathologically, a gross granulomatous exudate fills the subarachnoid space and extends over several segments. Vasculitis involving spinal arteries and veins may occur, sometimes resulting in ischemic spinal cord infarction.

A lesion in the vertebra is almost invariably due to hematogenous spread from a pulmonary source, often involving the body of the vertebra near an intervertebral disk. Unlike bacterial osteomyelitis and discitis, in TB, involvement of the posterior elements is more common, and the disc space is more commonly spares. Associated abscesses (which may include retropharyngeal abscesses in cervical cases) also tend to be larger relative to the bony involvement. Generally, the infection begins anteriorly (inferior or superior endplate), extends under the anterior longitudinal ligament, and spreads via the venous plexus of Bateson.  

As the disease progresses, increasing decalcification and erosion result in progressive collapse of the bone and destruction of intervertebral disks, involving as many as 3-10 vertebrae in one lesion, resulting in kyphosis. The abscess may rupture intraspinally, resulting in primary spinal meningitis, hyperplastic peripachymeningitis, intraspinal abscess, or tuberculoma.

Pathological effects and sequale on vision and cerebrovascular phenomena

Papilledema is the most common sequela of TBM on the optic apparatus In children, papilledema may progress to primary optic atrophy and blindness resulting from direct involvement of the optic nerves and chiasm by basal exudates (ie, opticochiasmatic arachnoiditis). In adults, papilledema may progress more commonly to secondary optic atrophy, provided the patient survives long enough. Other causes of visual impairment include chorioretinitis, optic neuritis, internuclear ophthalmoplegia, and, occasionally, an abrupt onset of painful ophthalmoplegia.

Ocular involvement is rare in TB. When it occurs, the typical lesion is often a choroidal granuloma. Baha Ali and coworkers describe 3 cases of choroidal TB associated with 3 different clinical situations, including tuberculous meningitis, multifocal TB, and military TB with HIV.[6]

As TBM has a predilection for the skull base (unlike bacterial meningitis), cranial nerve palsies are more common. CN VI is affected most frequently by TBM, followed by CNs III, IV, VII, and, less commonly, CNs II, VIII, X, XI, and XII.[7]

Sudden onset of focal neurological deficits, including monoplegia, hemiplegia, aphasia, and tetraparesis, may occur. Most commonly, these acute deficits are due to TBM-associated vasculitis which results in ischemia (with possible hemorrhagic conversion); less commonly the etiology may be postictal, proliferative arachnoiditis, or hydrocephalus.

Vasculitis with resultant thrombosis and hemorrhagic infarction may develop in vessels that traverse the basilar exudate, spinal exudate, or lie within the brain substance. Mycobacterium also may invade the adventitia directly and initiate the process of vasculitis.

An early neutrophilic reaction is followed by infiltration of lymphocytes, plasma cells, and macrophages, leading to progressive destruction of the adventitia, disruption of elastic fibers, and, finally, intimal destruction. Eventually, fibrinoid degeneration within small arteries and veins produces aneurysms, thrombi, and focal hemorrhages, alone or in combination.[8]

Tremor is the most common movement disorder seen in the course of TBM. In a smaller percentage of patients, abnormal movements, including choreoathetosis and hemiballismus, have been observed, more so in children than in adults. In addition, myoclonus and cerebellar dysfunction have been observed. Deep vascular lesions are more common among patients with movement disorders.

Etiology

Causative organism

The causative organism of tuberculous meningitis (TBM) is Mycobacterium tuberculosis. The first description of TBM is credited to Robert Whytt, in his 1768 monograph, Observations of Dropsy in the Brain. TBM first was described as a distinct pathological entity in 1836, and Robert Koch demonstrated that TB was caused by M. tuberculosis in 1882.

M. tuberculosis is an aerobic gram-positive rod that stains poorly with hematoxylin and eosin (H&E) because of its thick cell wall that contains lipids, peptidoglycans, and arabinomannans. The high lipid content in its wall makes the cells impervious to Gram staining. However, Ziehl-Neelsen stain forms a complex in the cell wall that prevents decolorization by acid or alcohol, and the bacilli are stained a bright red, which stands out clearly against a blue background.

Mycobacteria vary in appearance from spherical to short filaments, which may be branched. Although they appear as short to moderately long rods, they can be curved and frequently are seen in clumps. Individual bacilli generally are 0.5–1 µm in diameter and 1.5–10 µm long. They are nonmotile and do not form spores.

One of the distinct characteristics of mycobacteria is their ability to retain dyes within the bacilli that usually are removed from other microorganisms by alcohols and dilute solutions of strong mineral acids such as hydrochloric acid. This ability is attributed to a waxlike layer composed of long-chain fatty acids, the mycolic acids, in their cell wall. As a result, mycobacteria are termed acid-fast bacilli.

The mechanisms by which neurovirulence may occur are unknown.

Risk factors

Human migration plays a large role in the epidemiology of TB. Massive human displacement during wars and famines has resulted in increased case rates of TB and an altered geographic distribution. With the advent of air travel, TB has a global presence. In the United States, the prevalence of TB, mostly in foreign-born persons, has steadily increased.

Once infected with M. tuberculosis, HIV co-infection is the strongest risk factor for progression to active TB; the risk has been estimated to be as great as 10% per year, compared with 5-10% lifetime risk among persons with TB but not HIV infection. Although patients who have HIV infection and TB are at increased risk for TBM, the clinical features and outcomes of TB do not seem to be altered by HIV. Go to HIV-1 Associated CNS Conditions - Meningitis for more complete information on this topic.

Patients infected with HIV, especially those with AIDS, are at very high risk of developing active TB when exposed to a person with infectious drug-susceptible or drug-resistant TB. They have a higher incidence of drug-resistant TB, in part due to Mycobacterium avium-intracellulare, and have worse outcomes.

Other predisposing factors for the development of active TB include malnutrition, alcoholism, substance abuse, diabetes mellitus, corticosteroid use, malignancy, and head trauma. Homeless persons, people in correctional facilities, and residents of long-term care facilities also have a higher risk of developing active TB compared with the general population.

Epidemiology

More than 2 billion people (ie, one third of the world’s population) are infected with tuberculosis (TB), 10% of whom  develop clinical disease, and 1.1–1.3 million of whom die of the disease annually.[50]  Tuberculous meningitis (TBM) is a manifestation of extrapulmonary tuberculosis, develping in 1%–5% of the approximately 10 million cases of TB worldwide.[47, 48, 50]  Although rare in the United States and Europe, TB is a common cause of meningitis (and most common cause of chronic meningitis) in endemic areas worldwide, particularly among patients co-infected with HIV.[48, 49, 50]  TB is the seventh leading cause of death and disability worldwide. 

United States statistics

TB in the United States is uncommon; in 2019 there were 8,916 confirmed cases of TB (2.7 cases per 100,000 persons), downtrending from 11,077 approximately a decade earlier.[53]  The majority of cases are among foreign-born individuals. Of confirmed TB cases in 2019, there were 1,833 reported cases of extrapulmonary TB, 85 of whom had TBM.[53]  These figures have also been downtrending over the past decade from 2,411 and 138 cases in 2010, respectively. In 2018, of the 9,024 patients diagnosed with TB in the United States, 542 died of the disease (6.0%).

Between 1969 and 1973, TBM accounted for approximately 4.5% of the total extrapulmonary TB morbidity in the United States. Between 1975 and 1990, 3,083 cases of TBM were reported by the US Centers for Disease Control and Prevention (CDC), an average of 193 cases per year, accounting for 4.7% of total extrapulmonary TB cases during that 16-year period. In 1990, however, 284 cases of TBM were reported, constituting 6.2% of the morbidity attributed to extrapulmonary TB. This increase in TBM was most likely due to increasing CNS TB among patients with HIV/AIDS and to the increasing incidence of TB among infants, children, and young adults of minority populations. Data suggest that TBM accounts for 2.1% of pediatric cases and 9.1% of extrapulmonary TB cases.[9] TB accounts for approximately 0.04% of all cases of chronic suppurative otitis media.[10] The Tuberculosis: Advocacy Report released by the World Health organization (WHO) in 2003 suggests the persistence of TB otitis, as well as possibly an increase in the incidence of TB otitis.[11] Tuberculomas account for 10%–30% of intracranial masses in TB-endemic areas.

International statistics

The WHO estimates that the incidence of new TB infections has been increasing over the past decade, from 5.7 million diagnosed in 2009 to 7.1 million in 2019.[50]  More than a quarter of total new cases annually (estimated to be approximately 10 million) may be missed. From 2013 to 2019, the countries with the greatest contributions to new diagnoses were India and Indonesia. In 2019, there were approximately 1.2 million TB deaths among HIV-negative inidividuals (a reduction from 1.7 million in 2000), and an additional 208,000 among HIV-positive patients. TBM develops in 1%–5% of the approximately 10 million cases of TB worldwide.[47, 48, 50]

In 2005, the TB incidence rate was stable or in decline in all six WHO regions. However, the total number of new TB cases was still rising slowly; the case-load continues to grow in the African, eastern Mediterranean, and Southeast Asia regions.[13] In many areas of Africa and Asia, the annual incidence of TB infection for all ages is approximately 2%, which would yield an estimated 200 cases of TB per 10,000 population per year. Approximately 15%–20% of these cases occur in children younger than 15 years.

The worldwide prevalence of TB in children is difficult to assess because data are scarce and poorly organized, although the WHO estimates that approximately 10% of cases occur in children, primarily among those ages 2–4 years.[47] The available reports likely underestimate the true incidence, however, as lack of surveillance testing in most areas of the world limits the ability to assess the true prevalence of the disease. The developing world has 1.3 million cases of TB and 40,000 TB-related deaths annually among children younger than 15 years. In the developing world, 10%–20% of persons who die of TB are children. TBM complicates approximately 1 of every 300 untreated primary TB infections.

Age distribution for TBM

In the United States in 2019, 4.1% of cases of TB were diagnosed in children aged 14 years and younger, 9.5% of cases were amont those 15–24 years of age, 29.3% in those 25–44 years of age, 29.9% in those 45–64 years of age, and 27.2% in those >/= 65 years of age.[53]  Among TB patients, the highest rates of TBM proportionally per TB infection are found in children aged 2–4 years.[47] . A study of TBM in Texas during the period 2010–2017 found that although children 4 years of age and younger accounted for 4.0% of TB cases, they accounted for 14.6% of cases of TBM.[54]  TBM is uncommon, however, in children younger than 6 months and extremely rare in infants younger than 3 months, as the causative pathological sequelae generally take at least 3 months to develop.

Children aged 5–14 years often have been referred to as the favored age because they have lower rates of TB than any other age group. Younger children are more likely to develop meningeal, disseminated, or lymphatic TB, whereas adolescents more frequently present with pleural, genitourinary, or peritoneal disease. Childhood TB has a limited influence on the immediate epidemiology of the disease because children rarely are a source of infection to others.

Sex distribution for TBM

Among persons younger than 20 years, TB infection rates are similar for both sexes; the lowest rates are observed in children aged 5–14 years. During adulthood, TB infection rates are consistently higher for men than for women; the male-to-female ratio is approximately 2:1.[53]

Prevalence of TBM by race

In the United States, 88% of TB cases occur among racial and ethnic minorities.[53] Case rates are lowest among Caucasians, and highest among Asians and Pacific Islanders. Rates among African Americans and Hispanics are intermediate. 

Several important factors likely contribute to the disproportionate burden of TB in minorities. In foreign-born persons from countries where TB is common, active TB disease may result from infection acquired in the country of origin. Approximately 95% of cases in the Asian/Pacific Islander group occurred in foreign-born persons, compared with 70% of cases in Hispanics and 20% of cases in non-Hispanic blacks.

In racial and ethnic minorities, unequal distribution of TB risk factors, such as HIV infection, also may contribute to an increased exposure to TB or to the risk of developing active TB once infected with M. tuberculosis. However, much of the increased risk of TB in minorities has been linked to lower socioeconomic status and the effects of crowding, particularly among US-born persons.

Prognosis

Mortality

Overall, tuberculosis meningitis (TBM) results in death or significant disability in approximately half of cases, and mortality rates among patients co-infected with HIV is apprixiamtely 50%.[55, 57] In a long-term longitudinal cohort study of patients with TBM in New York City from 1992 to 2001,[56]  376 patients had TBM, the majority of whom (63%) were co-infected with HIV. Ten percent of patients died prior to initiating antituberculosis therapy (median 7 days from diagnosis), and 57% died prior to completing the treatment. Overall, long-term survival was approximately 40%; however, among HIV-negative patients with TBM, this figure was approximately 65%. Antibiotic-resistance correlated with reduced survival, and multi-drug resistant (MDR) TBM was nearly universally fatal (95% case fatality rate). 

Prediction of outcome

Prediction of prognosis of TBM is difficult because of the protracted course, diversity of underlying pathological mechanisms, variation of host immunity, and virulence of M. tuberculosis. Initially, only clinical indices were used for predicting the outcome, such as level of consciousness, stage of meningitis, bacillus Calmette-Guérin (BCG) vaccination status, cerebrospinal fluid (CSF) findings, and evidence of raised intracranial pressure (ICP). After MRI and CT scanning became available, radiological findings such as hydrocephalus, infarction, severity of exudate, and tuberculoma also were considered for predicting the prognosis of TBM.

Prognosis is in part related to the clinical stage of TBM and neurological status at diagnosis, as early diagnosis and treatment is the strongest determinant of favorable outcome.[57]  A widely accepted grade of the disease, which factors in the patient's neurological status via the modified Glasgow Coma Scale, is the British Medical Research Council TBM grade, a strong predictor of outcome: Grade 1 GCS = 15, no focal deficits; Grade 2 GCS = 15 with focal deficits or GCS = 11–14, or Grade 3 GCS of < /= 10.[58]  In general, patients with poorer neurological exam on presentation have poorer outcomes. 

Co-infection with HIV, particularly ineffectively treated HIV, is also a strong predictor of poor outcome.[56, 58]  

Resistance to antitubercular therapy (particularly rifampin and isoniazid) is a strong predictor of poor outcome, as was shown in the New York study.[56]

In a study that looked at clinical parameters, laboratory studies, and CT scan features in 49 adults and children with TBM used a multivariate logistic regression model to show that the most significant variables for predicting outcome in TBM were age, stage of disease, focal weakness, cranial nerve palsy, and hydrocephalus.[15] Children with advanced disease with neurological complications have poor outcomes.

The occurrence of syndrome of inappropriate diuretic hormone secretion (SIADH) as well as Cerebral Salt Wasting occurs in > 50% of TBM patients, and may suggest a poorer prognosis.[59]

Visual disturbances may suggest a poorer outcome, as they are often the result of associated optochiasmatic arachnoiditis or optochiasmal tuberculoma.[16]  

Seizures affect 16.3%–31.5% of TBM patients, with higher rates in children and in those with HIV, and worsen mortality and disability.[60]  Surviving patients who had TBM-associated seizures may develop chronic epilepsy. Unlike many other forms of meningitis, there are more EEG abnormalities in TBM.[60]  Motor-evoked potentials and somatosensory evoked potentials also have been reported to predict a 3-month outcome of TBM. Misra et al found that focal weakness, Glasgow Coma Scale score, and somatosensory evoked potential findings were the best predictors of 6-month outcome in patients with TBM.[17]

Kumar et al reported that children with TBM who have been vaccinated with BCG appear to maintain better mentation and have superior outcomes. They believe this may be explained, in part, by the better immune response to infection, as is reflected in the higher CSF cell counts in their patient group.[18]

Patient Education

Health education efforts must be directed at the patients to make them more informed and aware of all aspects of the disease and its treatment. Patients must be informed of the basic rules to prevent spreading the infection to others in the family or the community.

Whereas one end of the spectrum of educational efforts is directed toward the health-related behavior of the general public, the other end should be directed toward gaining the support of those who influence health policies and funding of governments and institutions. Information, education, and communication (IEC) campaigns should be designed to act as an intermediary between the 2 groups. This strategy includes social marketing, health promotion, social mobilization, and advocacy programs.

For patient education resources, see the Bacterial and Viral Infections Center, Brain and Nervous System Center, and Procedures Center, as well as Tuberculosis, Meningitis in Adults, Meningitis in Children, and Spinal Tap.

 

Presentation

History

Tuberculous meningitis (TBM) is often difficult to diagnose, as it presents subacutely and often without classic signs of meningitis.

Inquire about the patient’s medical and social history, including recent contact with patients with tuberculosis (TB). Elicit any known history of a positive result on the purified protein derivative (PPD) test, especially a recent conversion.

Determine if the patient has a history of immunosuppression from a known disease (especially HIV) or from drug therapy.

Check if the patient has a negative history for bacillus Calmette-Guérin (BCG) vaccination. BCG vaccination is known to be effective at preventing TB and TBM in children in particular.[61] Walker et al reported that BCG vaccination is partially protective against TB meningitis; therefore, a history of BCG vaccination or the presence of a BCG vaccination scar affords some degree of reassurance when considering a diagnosis of TBM (grade C).[19] In patients in whom TBM is suspected clinically, the diagnosis must be rigorously investigated, and a history of BCG vaccination does not rule out the diagnosis (grade C).

In an immunocompetent individual, TBM typically presents as an acute-to-subacute illness characterized by a prodrome of fever, headache, malaise, weight loss, drowsiness, and confusion over a period of approximately 2–3 weeks (although the duration of presenting symptoms may vary from 1 day to 9 months, with 55% presenting by 2 weeks). Only some patients have classic meningitis signs and symptoms initially, such as nuchal rigidity. The headache tends to progress over 1–2 weeks, after which vomiting and altered mental status occur, and finally obtundation, coma, and death if untreated.[57]  

During the prodrome, patients often have a concurrent infection of the upper respiratory tract. As a result, TBM should be suspected in at-risk patients with respiratory tract signs and symptoms if fever and irritability or lethargy seem out of proportion to the respiratory pathology itself, or if they persist after the respiratory symptoms have improved. Fever and headache can be absent in 25% of patients, and malaise can be absent in as many as 60% of patients. Headache and mental status changes are much more common in elderly persons.

As TBM may result in strokes and seizures, a sudden onset of focal neurologic deficits, including monoplegia, hemiplegia, aphasia, and cranial nerve deficits may occur, particularly if the disease is more advanced at presentation. Tremor and, less commonly, abnormal movements, including choreoathetosis and hemiballismus, have been observed, more so in children than in adults. Myoclonus and cerebellar dysfunction have also occurred.

Visual symptoms include visual impairment or blindness and, occasionally, abrupt onset of painful ophthalmoplegia. Ocular tuberculosis presents as a form of granulomatous uveitis. Delayed or wrong diagnosis may result in blindness.[20]

The occurrence of syndrome of inappropriate diuretic hormone secretion (SIADH) as well as Cerebral Salt Wasting occurs in > 50% of TBM patients.[59]

Children may present with cough, fever, vomiting (with or without diarrhea), poor feeding, weight loss, and irritability.[57]  

Tuberculous spinal meningitis

Tuberculous spinal meningitis may manifest as an acute, subacute, or chronic form. The clinical picture in primary spinal meningitis is often characterized by myelopathy, with progressive ascending paralysis, eventually resulting in basilar (cranial) meningitis and associated sequelae. In some cases with acute onset, in addition to variable constitutional symptoms, patients develop acute paraplegia with sensory deficits and urinary retention. The clinical picture often mimics transverse myelitis or Guillain-Barré syndrome. The subacute form generally presents as myeloradiculopathy, with radicular pain and progressive paraplegia or tetraplegia. A less virulent chronic form may mimic slowly progressive spinal cord compression or nonspecific arachnoiditis.

Tuberculous spondylitis

Tuberculous spondylitis is also known as Pott's disease or spinal caries. In endemic areas (eg, Asia and Africa), this condition still accounts for 30%–50% of all cases of compressive myelopathy resulting in paraplegia. Spinal TB also accounts for approximately 50% of all bone and joint TB cases. It usually presentes subacutely or chronically, with symptoms such as back pain, fever, radicular pain, and variable neurological deficits (eg, motor and sensory disturbances, changes in bowel and bladder function). In the lumbar region, tuberculous spondylitis may result in a psoas abscess that often calcifies. Eventually, complete spinal cord compression with paraplegia, the most dreaded complication, may occur if untreated.

Serous tuberculous meningitis and tuberculous encephalopathy

Two rare forms of TBM are serous: TB meningitis and TB encephalopathy. Serous TB meningitis is characterized by signs and symptoms of a mild meningitis with spontaneous recovery. TB encephalopathy usually occurs in young children with progressive primary TB; the presentation is that of reduced levels of consciousness with few focal signs and minimal meningism. Diffuse edema and white matter pallor with demyelination are found upon pathologic examination. The pathogenesis is uncertain but is presumed to be immune mediated. Diagnosis is important because anecdotal reports suggest a good response to corticosteroids.

Tuberculous radiculomyelitis

Tuberculous radiculomyelitis (TBRM) is a rare complication of TBM.

Physical Examination

Perform careful general, systemic, and neurologic examinations, looking especially for lymphadenopathy, papilledema, and tuberculomas during funduscopy, and meningismus. Look also for a bacille Calmette-Guerin (BCG) vaccination scar, as it is partially protective against tuberculous meningitis (TBM) (but does not necessarily rule out the diagnosis).[19]

Visual findings

Fundus examination may reveal papilledema, often related to increased intracranial pressure, and occasionally a retinal tuberculoma or a small grayish-white choroidal nodule, highly suggestive of TB. These lesions are believed to be more common in miliary TB than in other forms of TB. In children, fundus examination may reveal pallor of the disc. Examination may elicit visual impairment and/or cranial nerve palsies (III, IV, VI). 

Neurological exam

Nuchal rigidity is variable, and often absent. 

Depending on the stage of TBM on presentation, patients may have altered mental status, ranging from confusion to coma. 

Cranial neuropathies are more common than in bacterial meningits, as TBM has a predilection for the skull base. The most common cranial nerves affect, in order of decreasing frequency, are, VI>III>IV>VII.[57] Less commonly, CNs II, VIII, X, XI, and XII are affected.

Focal neurological deficits may include monoplegia, hemiplegia, aphasia, and tetraparesis.

Movement disorders, most commonly tremor, may be seen.

In children, where hydrocephalus is more common, signs of increased intracranial pressure may predominate, such as decreased level of consciousness, abducens nerve palsies, and bulging anterior fontanelle.[57]

Complications

Complications of tuberculous meningitis (TBM) include:

  • Hydrocephalus

  • Cranial nerve palsies

  • Visual impairment and blindness

  • Stroke (ischemic or hemorrhagic)

  • Seizures and epilepsy

  • Spinal TB

  • Tuberculous radiculomyelitis (TBRM)

  • Hyponatremia (eg, SIADH, CSWS)

  • Arachnoiditis

  • Tuberculoma formation

  • Permanent neurological disability

  • Death

Staging

The British Medical Research Council TBM grade has been in wide use since the 1940s, and since then was updated to include the GCS score.[58]  

  • Stage I describes the early nonspecific symptoms and signs including apathy, irritability, headache, malaise, fever, anorexia, nausea, and vomiting, without any alteration in the level of consciousness (GCS 15).

  • Stage II describes altered consciousness without coma or delirium but with minor focal neurological signs; symptoms and signs of meningism and meningitis are present, in addition to focal neurological deficits, isolated CN palsies, and abnormal involuntary movements (GCS 15 with focal deficits, or GCS 11–14 without focal deficits).

  • Stage III describes an advanced state with stupor or coma, dense neurological deficits, seizures, posturing, and/or abnormal movements (GCS < /= 10).

Prognosis is strongly associated with the clinical stage at diagnosis.

Uniform Tuberculous Meningitis Research Case Definition Criteria

The Uniform Tuberculous Meningitis Research Case Definition Criteria, described in an article by Marais et al in Lancet,[62] provides thorough, diagnostic criteria for TBM.

Table of TBM Criteria. (Open Table in a new window)

Clinical criteria (maximum category score = 6)
 Symptom duration of > 5 d 4
 Systemic symptoms suggestive of TB (≥ 1): weight loss/(poor weight gain in children), night sweats, or persistent cough > 2 wk 2
 History of recent close contact with an individual with pulmonary TB or a positive TST/IGRA in a child aged < 10 y 2
 Focal neurological deficit (excluding cranial nerve palsies) 1
 Cranial nerve palsy 1
 Altered consciousness 1
CSF criteria (maximum category score = 4)
 Clear appearance 1
 Cells: 10–500/µL 1
 Lymphocytic predominance (> 50%) 1
 Protein concentration > 1 g/L 1
 CSF to plasma glucose ratio of < 50% or an absolute CSF glucose concentration < 2.2 mmol/L 1
Cerebral imaging criteria (maximum category score = 6)
 Hydrocephalus (CT and/or MRI) 1
 Basal meningeal enhancement (CT and/or MRI) 2
 Tuberculoma (CT and/or MRI) 2
 Infarct (CT and/or MRI) 1
 Precontrast basal hyperdensity (CT) 2
Evidence of tuberculosis elsewhere (maximum category score = 4)
 Chest radiograph suggestive of active TB (excludes miliary TB) 2
 Chest radiograph suggestive of miliary TB 4
 CT/MRI/US evidence for TB outside the CNS 2
 AFB identified or Mycobacterium tuberculosis cultured from another source (ie, sputum, lymph node, gastric washing, urine, blood culture) 4
 Positive commercial M. tuberculosis NAAT from extraneural specimen 4
Exclusion of alternative diagnoses: An alternative diagnosis must be confirmed microbiologically, serologically, or histopathologically.
Definite TBM: AFB seen on CSF microscopy, positive CSF M. tuberculosis culture, or positive CSF M. tuberculosis commercial NAAT in the setting of symptoms/signs suggestive of meningitis; or AFB seen in the context of histological changes consistent with TB brain or spinal cord together with suggestive symptoms/signs and CSF changes, or visible meningitis (on autopsy).
Probable TBM: total score of ≥ 12 when neuroimaging available or total score of ≥10 when neuroimaging unavailable. At least 2 points should either come from CSF or cerebral imaging criteria.
Possible TBM: total score of 6–11 when neuroimaging available, or total score of 6–9 when neuroimaging unavailable.

Abbreviations: AFB, acid-fast bacilli; CNS, central nervous system; CSF, cerebrospinal fluid; CT, computed tomography; IGRA, interferon-γ release assay; MRI, magnetic resonance imaging; NAAT, nucleic acid amplification test; TB, tuberculosis; TBM, tuberculous meningitis; TST, tuberculin skin test; US, ultrasound.

 

DDx

Diagnostic Considerations

Unlike many forms of bacterial meningitis, tuberculous meningitis (TBM) is often difficult to diagnose, as initial symptoms are generally subacute and often nonspecific (although occasionally may present more acutely), and neck stiffness is typically not present in the early course of the illness.[51, 57]  The duration of presenting symptoms may vary from 1 day to 9 months (on average, 2 weeks), and the prodrome is usually nonspecific, including headache, vomiting, photophobia, and fever. Meningismus may also occur. Unlike most of forms of bacterial meningitis, TBM is more likely to cause neurological deficits, including altered mental status, personality changes, and, as the lesions may result in neurovascular compression, cranial nerve deficits and infarcts.[51]  

The clinician should have a high index of clinical suspicion if a patient presents with a clinical picture of subacute meningitis or encephalitis (particularly if > 5 days) in high-risk groups or in endemic areas. There is frequently diagnostic uncertainty when differentiating TBM from other meningoencephalitides, such as partially treated meningitis. TBM must be differentiated not only from other forms of acute and subacute meningitis but also from conditions such as viral infections and cerebral abscesses. High-risk groups include patients from endemic areas (eg, from Africa or Asia), those with HIV infection or alcohol or drug abuse, homeless persons, people in correctional facilities, residents of long-term care facilities, and malnourished patients.

Diagnostic confusion often exists between TBM and other meningoencephalitides, in particular partially treated meningitis. Acid-fast bacilli are seen in only approximately 25% of cerebrospinal fluid (CSF) smears. CSF culture is time-consuming and may not yield positive results. Recent advances have sought to improve smear sensitivity, such as by nucleic acid amplification tests.[59]

In one study, 5 features independently predicted the diagnosis of TBM:

  • Prodromal stage lasting 7 days or longer

  • Optic atrophy on fundal examination

  • Focal deficit

  • Abnormal movements

  • CSF leukocytes comprising < 50% polymorphonuclear leukocytes

Validation of these criteria on another set of 128 patients revealed a sensitivity of 98.4% if at least one feature was present and a specificity of 98.3% if 3 or more were present. This simple rule is useful for physicians working in regions where TB is prevalent.

TBM must be differentiated not only from other forms of acute and subacute meningitis but also from conditions such as viral infections and cerebral abscess. The radiological differential diagnosis, which should take into account HIV status, includes cryptococcal meningitis, cytomegalovirus encephalitis, sarcoidosis, meningeal metastases, and lymphoma.

TB of any form is a notifiable disease in the United States. Mandatory notification of the appropriate health department is the responsibility of the physician who makes the diagnosis.

TBM should be considered in the differential diagnosis in any high-risk patient presenting with fever and a change in sensorium. Other problems to be considered include:

  • Infections: Fungal (cryptococcal, histoplasmosis, actinomycetic, nocardiasis, Arachnia infection, candidiasis, coccidiosis); spirochetal (Lyme disease, syphilis, leptospirosis); bacterial (partially treated bacterial meningitis, brain abscess, listeriosis, Neisseria species infection, tularemia); brucellosis; parasitic (cysticercosis, acanthamebiasis, angiostrongylosis, toxoplasmosis, trypanosomiasis); and viral (herpes, mumps, retrovirus, enterovirus [in hypogammaglobulinemics])

  • Acute hemorrhagic leukoencephalopathy

  • Behçet disease

  • Chemical meningitis

  • Chronic benign lymphocytic meningitis

  • Neoplastic: metastatic, lymphoma

  • Systemic lupus erythematosus

  • Vascular: Multiple emboli, subacute bacterial endocarditis, sinus thrombosis

  • Vasculitis: Isolated central nervous system (CNS) angiitis, systemic giant cell arteritis, Wegener granulomatosis, polyarteritis nodosa, noninfectious granulomatosis, lymphomatoid granulomatosis

  • Vogt-Koyanagi-Harada syndrome

Differential Diagnoses

 

Workup

Approach Considerations

The diagnosis of tuberculous meningitis (TBM) cannot be made or excluded on the basis of clinical findings. Tuberculin testing is of limited value. Variable natural history and nonspecific clinical features make the diagnosis of TBM difficult.[21, 22, 23, 24, 25]

Spinal tap carries some risk of brain herniation in any instance when intracranial pressure (ICP) is increased (which may occur in TBM), but if meningitis is suspected, the procedure should generally be performed, using suitable precautions and obtaining informed consent before the procedure. A low-volume tap may be performed to rule out other more common types of meningitis (eg, bacterial), although this may limit diagnostic sensitivity of TBM.

Computed tomography (CT) scanning and magnetic resonance imaging (MRI) lack specificity but may aid in identifying complications, such as hydrocephalus, ischemic or hemorrhagic strokes, and tuberculomas, some of which may require neurosurgical evalauation. (See Imaging in Bacterial Meningitis).

Ziehl-Neelsen staining lacks sensitivity, and culture results are often too late to aid clinical judgment. Semiautomated radiometric culture systems, such as the Bactec 460, and automated continuously monitored systems have reduced culture times. Newer methods involving amplification of bacterial DNA by polymerase chain reaction (PCR) and comparable systems have not been assessed completely and may not be suitable for laboratories in developing countries with limited resources. Interferon-gamma assays may have promising sensitivity and specificity for extra-pulmonary TB (including TBM).[24, 57]

A complete blood count should be performed, and the erythrocyte sedimentation rate should be determined.

A hepatic function panel should be obtained before starting antituberculous medications, many of which are hepatotoxic.

The serum glucose level should be measured; this value is a useful comparison with the glucose level measured in the cerebrospinal fluid (CSF).

HIV testing should be performed, and include CD4 count and viral load if positive. 

Serologic testing for syphilis should be performed. Complementation testing or its equivalent for fungal infections should also be performed.

Serum and Urine Chemistry Studies

Electrolyte concentrations should be assessed. Mild-to-moderate hyponatremia is present in roughly 45% of patients, which may be due to SIADH or CSWS. Blood urea nitrogen (BUN) and creatinine levels should be measured as well. Urinalysis should be performed.

Tuberculin Skin Testing

Despite its many limitations, tuberculin skin testing, by necessity, remains in widespread use. The Centers for Disease Control and Prevention (CDC), the American Thoracic Society, and the Infectious Disease Society of America have updated the guidelines, and they are quite useful in practice.[26]

These guidelines stress that in general, one should not obtain a tuberculin skin test unless treatment would be offered in the event of a positive test result. Cutoff points for induration (5, 10, or 15 mm) for determining a positive test result vary based on the pretest category into which the patient falls. While this approach might decrease the specificity of the test, it increases the sensitivity for capturing those at highest risk for developing the disease in the short term.

Negative results from the purified protein derivative (PPD) test do not rule out tuberculosis (TB); if the 5-tuberculin test skin test result is negative, repeat the test with 250-tuberculin test. Note that this test is often nonreactive in persons with TBM.

Lumbar Puncture

A lumbar puncture should be performed in most cases of suspected tuberculous meningitis (TBM), unless there is significant concern for precipitating herniation (eg, in the case of hydrocephalus, in which case a ventriculostomy may be performed to divert CSF, from which CSF could be obtained). A high-volume LP should be performed (if there is no concern for herniation), as it improves the sensitivity of detecting TB. 

As with any standard lumbar puncture, manometry should be performed to check CSF pressure. The patient may have a normal opening pressure (OP), but in 50% of patients, the opening pressure is > 25cm H2O.[57]

Inspect the CSF visually and note its gross appearance. It typically is clear or slightly turbid. If the CSF is left to stand, a fine clot resembling a pellicle or cobweb may form. This faintly visible "spider's web clot" is due to the very high level of protein in the CSF (1–8 g/L, or 1000–8000 mg/dL) typical of this condition. Hemorrhagic CSF also has been recorded in proven cases of TBM; this is attributed to fibrinoid degeneration of vessels resulting in hemorrhage (Smith, 1947).

CSF analysis

Tests that may be performed on CSF specimens obtained by lumbar puncture include:

  • Cell counts, differential count, cytology

  • Glucose level, with a simultaneous blood glucose level

  • Protein level

  • Acid-fast stain, Gram stain, appropriate bacteriologic culture and sensitivity, India ink stain

  • Cryptococcal antigen and herpes antigen testing

  • Culture for Mycobacterium tuberculosis (50-80% of known cases of TBM yield positive results)

  • PCR: Results imply that PCR can provide a rapid and reliable diagnosis of TBM, although false-negative results potentially occur in samples containing very few organisms (< 2 colony-forming units per mL).

  • Syphilis serology

CSF typically has a pleocytosis, an elevated protein level, and marked hypoglycorrhachia.

In adults, the mean white blood cell (WBC) count averages around 223 cells/µL (range, 0–4000 cells/µL), while the proportion with neutrophilic pleocytosis (> 50% neutrophils) averages 27% (range, 15%–55%) and the proportion with normal cell count averages 6% (range, 5%–15%). In children, these numbers are 200 cells/µL (range, 5–950 cells/µL), 21% (range, 15%–30%), and 3% (range, 1%–5%), respectively.

The mean protein level in adults averages 224 mg/dL (range, 20–1000 mg/dL), and in children it is 219 mg/dL (range, 50–1300 mg/dL). The proportion with a normal protein content averages 6% (range, 0%–15%) for adults and 16% (range, 10%–30%) for children.

The proportion with depressed glucose levels (< 45 mg/dL or 40% of serum glucose) averages 72% (range, 50%–85%) for adults and 77% (range, 65%–85%) for children.

A positive smear result is present in an average of 25% (range, 5%–85%) of adults and only 3% (range, 0%–6%) of children, whereas the numbers with a positive CSF culture average 61% (range, 40%–85%) and 58% (range, 35%–85%) for adults and children, respectively. Failure to respond to treatment should prompt a search for fungal infections or malignancy.

For patients with HIV and/or immunosuppression, while the mean WBC count in the CSF is 230 cells/µL, as many as 16% of HIV-infected patients may have acellular CSF, compared with 3%–6% of HIV-negative patients. Patients whose CSF samples are acellular may show pleocytosis if a spinal tap is repeated 24–48 hours later. The proportion who have neutrophilic pleocytosis of the CSF (>50% neutrophils) is 42% (range, 30%–55%).

While HIV-infected patients generally have a mean protein level of 125 mg/dL (range, 50–200 mg/dL), as many as 43% of these patients may have a normal CSF protein content. The proportion who have depressed CSF glucose levels (< 45 mg/dL or 40% of serum glucose) averages around 69% (range, 50%–85%). The number who have a positive CSF culture results averages 23%.

Within a few days after commencement of anti-TB therapy, the initial mononuclear pleocytosis may change briefly in some patients to one of polymorphonuclear predominance, which may be associated with clinical deterioration, coma, or even death. This therapeutic paradox has been regarded by some authors as virtually pathognomonic of TBM. This syndrome is probably the result of an uncommon hypersensitivity reaction to the massive release of tuberculoproteins into the subarachnoid space.

In patients with tuberculous radiculomyelitis (TBRM), CSF evaluation usually demonstrates an active inflammatory response with a very high protein level.

When CSF analysis offers no clues and the diagnosis remains elusive, a brain biopsy may be warranted under appropriate circumstances. Depending on the location of the brain to be biopsied, there may be significant risks, including hemorrhage, surgical site infection, stroke, and seizure. 

Dot-Immunobinding Assay

A dot-immunobinding assay (Dot-Iba) has been standardized to measure circulating antimycobacterial antibodies in CSF specimens for the rapid laboratory diagnosis of tuberculous meningitis (TBM).[27]  Specific CSF immunoglobulin G antibody to M. tuberculosis from a patient with culture-proven TBM was isolated and coupled with activated cyanogen bromide-Sepharose 4B. A 14-kd antigen present in the culture filtrates of M. tuberculosis was isolated by immunosorbent affinity chromatography and used in the Dot-Iba to quantitate specific antimycobacterial antibodies. The Dot-Iba gave positive results in all 5 patients with culture-proven TBM; no false-positive results were obtained from CSF specimens from patients with partially treated pyogenic meningitis. In the opinion of Sumi et al, the Dot-Iba developed in their laboratory is a simple, rapid, and specific method and, more importantly, is suited for routine application in laboratories with limited resources.[27] This is not yet available for routine use, and proof of its utility requires further studies.

Researchers evaluated previous multicenter/multinational studies to determine the frequency of the absence of CSF pleocytosis in patients with central nervous system infections, as well as the clinical impact of this condition. It was found that 3% of TBM cases did not display CSF pleocytosis. Most patients were not immunosuppressed, and patients without pleocytosis had a high rate of unfavorable outcomes.[28]

Sun et al describe a novel, highly sensitive molecular diagnostic method, one-tube nested PCR-lateral flow strip test (OTNPCR-LFST), for detecting M. tuberculosis. This one-tube nested PCR offers improved sensitivity compared with traditional PCR; the limit of detection was up to 1 fg DNA isolated from M. tuberculosis. Since this assay is specific for M. tuberculosis, it reduces both the chance of cross-contamination and the time required for analysis. The PCR product was detected by a lateral flow strip assay, which provided a basis for migration of the test to a point-of-care (POC) microfluidic format. It has shown 89% overall sensitivity and 100% specificity for TBM patients. In TBM, where rapid and sensitive detection of M. tuberculosis in CSF is crucial in diagnosis and treatment, this one-tube nested PCR-lateral flow strip assay offers hope due to its rapidity, high sensitivity, and simple manipulation.[29]

Chest Radiography

Chest radiography posteroanterior and lateral views may reveal hilar lymphadenopathy, simple pneumonia, infiltrate, fibronodular infiltrate/cavitation, and/or pleural effusion/pleural scar.

Go to Imaging in Bacterial Meningitis for more complete information on this topic.

Brain and Spinal Imaging

Neuroimaging should be obtained in all patients with suspected tuberculous meningitis (TBM). This includes a CT head with and without contrast, and MRI brain with and without gadolinium contrast (remember to check renal function). CT scanning and MRI of the brain reveal hydrocephalus, basilar meningeal thickening, infarcts, edema, and tuberculomas (see the image below). Although they lack specificity, they may suggest the diagnosis, and help in monitoring complications that require neurosurgical intervention.

MRI of the brain in a patient with TBM and concurr MRI of the brain in a patient with TBM and concurrent AIDS (with 8 CD4 cells/mL). The patient's history includes previous interstitial pneumonia, pericarditis, adnexitis, and a positive result on the Mantoux test. His recent history includes fever, headache, strabismus, diplopia, and cough. Laboratory studies revealed hyponatremia. CSF findings strongly suggested a diagnosis of tuberculous meningitis, and culture results were positive for Mycobacterium tuberculosis. The MRI shows the presence of exudates, in and over the sellar seat, with parasellar extension to the left, with irregular margins, marked heterogenous enhancement, and compression of the optic chiasm and third ventricle. Presence of nodular areas with marked enhancement of basal cisterns is an expression of basilar leptomeningeal involvement. This patient died after 2 months of inadequate antituberculosis therapy (due to poor compliance). Courtesy of Salvatore Marra, AIDS Imaging (http://members.xoom.it/Aidsimaging).

Hydrocephalus may be present (on non-contrast and contrasted studies). 

Unlike bacterial meningitis, which tends to occur at the convexities, TBM tends to affect the skull base. As a result, in TBM, the basal cisterns often enhance strikingly, corresponding to the thick tubercular exudate that is observed on pathological examination. In particular, the quadrigeminal cistern, interpeduncular fossa, ambient cistern, and chiasmatic region are frequently involved, with associated arachnoiditis. Meningeal enhancement may occur, although it is more common among HIV-infected patients.

Contrast administration may show focal enhancement of parenchymal and space-occupying lesions.

Intracranial tuberculomas may also be viasualized. The characteristic CT finding is a nodular, enhancing lesion with a central hypodense lesion.[30]  Early stages are characterized by low-density or isodense lesions, often with edema out of proportion to the mass effect, and with little encapsulation. At a later stage, well-encapsulated tuberculomas appear as isodense or hyperdense lesions with peripheral ring enhancement. On MRI, characteristics depend on the maturity of the tuberculoma. In general, non-caseating tuberculomas as T1 hypointense and T2 hyperintense, and homogenously enhance. Caseating tuberculomas are generally hypo- to isointense on T1 and T2, and have rim enhancement. Tuberculous abscesses, which are larger than tuberculomas, may also be seen. On MR spectroscopy, tuberculous lesions generally have raised lipid peaks, which helps distinguish them from non-tuberculous lesions.[57]

As TBM may result in vasculitis, vascular imaging (eg, CT angiogram, formal angiogram), may be considered to assess patency of intracranial large vessels, particularly if a TBM-related stroke is suspected. MRI would show diffusion restriction on DWI sequence in the setting of acute stroke. 

Srikanth et al concluded that CT features of TBM in elderly patients were few, atypical, and noncontributory for diagnosis, probably because of age-related immune senescence.[31] Hence, strong clinical suspicion and correlation with laboratory findings is necessary for early diagnosis.

Skull radiography may reveal evidence of increased intracranial pressure in children, in the form of sutural diastasis. During follow-up of patients with TBM, intracranial calcifications may be evident.

Calcifications may occur in two main sites, (1) more commonly in the basal meninges and, (2) to a lesser extent, within brain parenchyma. Calcifications are generally in the sellar region, either as a single lesion or as a cluster of small calcifications. These calcifications sometimes harbor tubercle bacilli, which may be responsible for a relapse of the disease.

For tuberculous spinal meningitis, MRI shows that the subarachnoid space is obliterated, with focal or diffusely increased intramedullary signal on T2-weighted images and variable degrees of edema and mass effect. Most spinal cord lesions appear hyperintense on T2-weighted images and isointense or hypointense on T1-weighted images. MRI findings in patients with spinal cord TB have both diagnostic and prognostic significance. Cord atrophy or cavitation and the presence of syrinx on MRIs may be associated with a poor outcome.[1]  With gadolinium administration, contrast enhancement is often seen surrounding the spinal cord and the nerve roots. The nerve roots may appear clumped and show contrast enhancement, secondary to inflammation and edema, depending on the degree of involvement.

Rarely, tuberculomas occur in the spinal cord, and they may occur on the surface of the cord, as dural lesions, or deep inside in an intramedullary location. Less frequently, intramedullary tuberculous abscesses have been reported.

On neuroimaging, tuberculous spondylitis (Pott's disease) generally reveals bony destruction with relative sparing of the disc space, unlike pyogenic infections. In addition, the involvement of the posterior elements is more common, and the paraspinal abscess, if present, tends to be much larger relative to bony involvement. An associated psoas abscess may be present. The infection tends to begin anteriorly, extend under the anterior longitudinal ligament, and spread hematogenously via the venous plexus of Bateson. MRI has a sensitivity of 94% in vertebral osteomyelitis. It reveals hypointense T1-weighted areas in the vertebral bodies, alternating with areas of hyperintense T2-weighted signal in the disk spaces and the paravertebral soft tissue. Infected bone and disk often reveal contrast enhancement. A psoas abscess with calcifications, which is better detected on CT rather than MRI, strongly raises suspicion for a tuberculous etiology. Epidural deposits are best shown by MRI, which reveals a soft-tissue mass that is isointense to hypointense compared with the spinal cord on T1-weighted images and hyperintense on proton-density and T2-weighted images and has variable degrees of contrast enhancement.

Tuberculous myelitis and tuberculous radiculomyelitis (TBRM) are predominantly diseases of the thoracic spinal cord. MRI and CT scanning are critical for the diagnosis of TBRM, revealing loculation and obliteration of the subarachnoid space along with linear intradural enhancement.

Diffusion tensor imaging (DTI)-derived anisotropy has been shown to demonstrate meningeal inflammation and this could be a valuable tool to assess the response to antituberculous therapy, in addition to the standard neuroimaging techniques.[32]

Go to Imaging in Bacterial Meningitis for more complete information on this topic.

Additional imaging may be seen at https://radiopaedia.org/articles/tuberculous-meningitis?lang=us. 

Angiography

As tuberculous meningitis (TBM) may result in vasculopathy, vascular imaging (eg, CT angiogram, MR angiogram, formal catheter angiogram) may be considered to assess patency of large vessels, particularly if a TBM-related stroke is suspected. TBM vasculitis affects up to one third of cases, and is more common in pediatric cases. Vascular imaging may reveal arterial narrowing or occlusion. 

Electroencephalography

Seizures affect 16.3% to 31.5% of tuberculous meningitis (TBM) patients, may be focal or generalized, and occur more frequently in children and in those with HIV, and worsen mortality and disability.[60]  Surviving patients who had TBM-associated seizures may develop chronic epilepsy. Unlike many other forms of meningitis, there are more electroencephalography (EEG) abnormalities in TBM.[60]  EEG changes vary depending on the site of the ongoing inflammatory process. There may be diffuse slowing with or without focal changes and epileptiform discharged.[60]  In one study, findings from EEG were abnormal in 24 patients. EEG abnormalities included diffuse theta-to-delta slowing in 22 patients, intermittent rhythmic delta activity in the frontal region in 15 patients, right-to-left asymmetry in 5 patients, and epileptiform discharges in 4 patients. At the end of 3 months, 5 patients had died, while recovery was poor in 13 patients, partial in 3, and complete in 11. EEG findings correlated with severity of meningitis and degree of coma; outcome at 3 months was assessed using the Barthel index score.

Brainstem Auditory Evoked Response Testing

Brainstem auditory evoked responses (BAERs) have been observed in more than 50% of patients with tuberculous meningitis (TBM). Motor and somatosensory evoked potentials may be helpful in objective documentation of respective motor and sensory functions in patients with TBM and altered sensorium.

Use of Neurochemical Markers

Use of neurochemical markers has been investigated in patients with aseptic meningitis or tuberculous meningitis (TBM). CSF levels of amino acids, nitrite (a metabolite of nitric oxide), vitamin B-12, and homocysteine were quantitated in both groups of patients. Levels of excitatory amino acids aspartic acid and glutamic acid, gamma-aminobutyric acid (GABA), glycine, and tryptophan all were increased significantly in both groups, whereas levels of taurine were decreased and levels of phenylalanine were increased only in patients with TBM. Levels of nitrite and its precursor arginine were significantly higher in patients with TBM, whereas they were unchanged in patients with aseptic meningitis. Levels of homocysteine were increased significantly, and levels of vitamin B-12 decreased only in patients with TBM, whereas these levels were unchanged in patients with aseptic meningitis. This indicates that patients with TBM are particularly prone to vitamin B-12 deficiency, resulting in increased levels of homocysteine and free radicals, showing the potential importance of these biological markers in the development and design of therapeutic approaches.

Janvier et al report that once purulent bacterial meningitis and cryptococcosis have been ruled out, adenosine deaminase activity measurement could be an inexpensive, valuable tool in the diagnosis of early tuberculous meningitis.[33]

Histologic Findings

The Ziehl-Neelsen stain uses the properties of the cell wall to form a complex that prevents decolorization by acid or alcohol. Fluorochrome tissue stains also can be helpful in the diagnosis of TBM (see the image below).

Fluorochrome for tuberculosis. Fluorescent stainin Fluorochrome for tuberculosis. Fluorescent staining procedures are used with auramine O or auramine-rhodamine as the primary fluorochrome dye. After decolorization with an acid-alcohol preparation, the smear is counterstained with acridine orange or thiazine red and scanned at a lower magnification with a 25X dry objective fluorescent microscope. Acid-fast bacilli appear as yellow-green fluorescent thin rods against a dark background. Courtesy of Robert Schelper, MD, Associate Professor of Pathology, State University of New York Upstate Medical University.
Hematoxylin and eosin stain showing caseation in t Hematoxylin and eosin stain showing caseation in tuberculosis. Courtesy of Robert Schelper, MD, Associate Professor of Pathology, State University of New York Upstate Medical University.

Clinically silent single or multiple enhancing granulomata are observed in a significant minority of cases of TBM and in some cases of miliary TB without meningitis.[34]

 

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.

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.

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. 

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.

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.

 

Medication

Medication Summary

First-line therapy for tuberculous meningitis (TBM) 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. Trials for novel agents for the treatment of tuberculosis (TB) are under way. Long-acting rifamycin derivatives and potent fluoroquinolone antibiotics have been studied, and they lead the way for improved regimens against active and latent TB. The recent rapid increase in knowledge of mycobacterial pathogenesis is likely to lead to the advent of potent new drugs in latent disease and against the phenomenon of persistence. Without a doubt, sustained and increased funding for basic research plays a key role in eradicating this global epidemic altogether.

Finally, because of the intensity of the inflammatory and fibrotic reactions at the meningeal site, adjunctive corticosteroid therapy, in addition to standard antituberculous therapy, is recommended in TBM. Studies have confirmed the benefit of adjunctive corticosteroid therapy on survival and intellectual outcome in children with TBM, with enhanced resolution of basal exudates but no effect on intracranial pressure (ICP) or the incidence of basal ganglia infarction.[39]  (See Antibiotic Therapyand Adjunctive Corticosteroid Therapy.)

The paradoxical response to antituberculous therapy is well known; it usually develops after approximately 2 weeks of treatment. It is characterized by the clinical or radiological worsening of preexisting tuberculous lesions or the development of new lesions not attributable to the normal course of disease in a patient who initially improved with antituberculous therapy. Up to 10% of patients with CNS TB report the paradoxical response, and this number may be as high as 30% in HIV-infected patients.[40, 41, 42] The paradoxical response has been attributed to a component of immune reconstitution inflammatory syndrome or immune restoration syndrome, which results from an exuberant inflammatory response toward incubating opportunistic pathogens.[43] An increase in the incidence and severity of the paradoxical response is noted in HIV-infected patients on highly-active antiretroviral therapy.[44] Patients demonstrating a paradoxical response are more likely to have lower baseline lymphocyte counts, followed by a surge.[45]

Antitubercular Agents

Class Summary

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 that is obtained from Streptomyces capreolus for coadministration with other antituberculous agents in pulmonary infections caused by capreomycin-susceptible strains of M tuberculosis. Capreomycin is used only when first-line agents (eg, isoniazid, rifampin) have been ineffective or cannot be used because of toxicity or the presence of resistant tubercle bacilli

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 diffuses into actively growing mycobacterial cells (eg, tubercle bacilli). It impairs cell metabolism by inhibiting the synthesis of 1 or more metabolites, which in turn, causes cell death. No cross-resistance has been demonstrated.

Mycobacterial resistance is frequent with previous therapy. In such cases, use ethambutol in combination with second-line drugs that have not been previously administered. Administer q24h until permanent bacteriologic conversion and maximal clinical improvement are observed. Absorption is not significantly altered by food.

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

Class Summary

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.

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

Class Summary

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 ofloxacin 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.

The quinolones are cleared primarily by renal excretion; adjust dosage for those with CrCl less than 50 mL/min. Few long-term studies have been preformed on the use of quinolones, but one review found that toxicity is dependent more on dose than on duration of therapy.

Data on the use of these agents for the treatment of TB are limited. A study from Japan reported patients who had chronic cavitary lung TB were excreting bacilli resistant to various anti-TB agents. Of 17 patients who received ofloxacin in combination with other anti-TB agents as single doses of 300 mg/d for 6-8 months, 14 patients showed a decrease in culture positivity and 5 had a negative conversion. No adverse effects were observed.

Another study of ofloxacin reported 22 patients receiving 300 or 800 mg of ofloxacin in a single daily dose for 9 mo to 1 y. All patients tolerated the drug well, and indications were noted of higher efficacy at higher doses.

Prudent use of antituberculous drugs is a must to decrease drug resistance. Infection with Mycobacterium tuberculosis resistant to the standard drugs causes grave concerns, threatening a return to the prechemotherapeutic days. In addition to isoniazid resistance, multidrug-resistant tuberculosis has emerged, accounting for almost half a million cases of tuberculosis. Extensively drug-resistant tuberculosis (resistant to several additional second-line drugs) has emerged, which makes the treatment difficult and costly, in addition to having a poor prognosis.

Ciprofloxacin (Cipro)

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 was controversial, although most clinicians agree the evidence suggests a benefit, particularly in mortality. They should be given as a taper during the first 6–8 weeks of treatment. They should be considered in all cases, and particularly in patients with 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. 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 (Decadron, Dexabliss)

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.