Tuberculous Meningitis

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Background

Tuberculous meningitis (TBM) develops in 2 steps. Mycobacterium tuberculosis bacilli enter the host by droplet inhalation. Localized infection escalates within the lungs, with dissemination to the regional lymph nodes. In persons who develop TBM, bacilli seed to the meninges or brain parenchyma, resulting in the formation of small subpial or subependymal foci of metastatic caseous lesions, termed Rich foci.

The second step in the development of TBM is an increase in size of a Rich focus until it ruptures into the subarachnoid space. The location of the expanding tubercle (ie, Rich focus) determines the type of CNS involvement. Tubercles rupturing into the subarachnoid space cause meningitis. (See Pathophysiology.)

Currently, more than 2 billion people (ie, one third of the world’s population) are infected with tuberculosis (TB), of which approximately 10% will develop clinical disease. The incidence of central nervous system (CNS) TB is related to the prevalence of TB in the community, and it is still the most common type of chronic CNS infection in developing countries.

Despite great advances in immunology, microbiology, and drug development, TB remains among the great public health challenges. 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 continue to fuel the ongoing epidemic of TB. (See Epidemiology.)

TBM is a very critical disease in terms of fatal outcome and permanent sequelae, requiring rapid diagnosis and treatment. 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. Prognosis is related directly to the clinical stage at diagnosis. (See Prognosis.)

TBM may have an acute presentation. Sometimes it may present with cranial nerve deficits, or it may have a more indolent course involving headache, meningismus, and altered mental status. The prodrome is usually nonspecific, including headache, vomiting, photophobia, and fever. The duration of presenting symptoms may vary from 1 day to 9 months. (See Clinical Presentation.)

TBM continues to pose a diagnostic problem. A high index of clinical suspicion is absolutely essential. TBM should be a strong consideration when a patient presents with a clinical picture of meningoencephalitides, especially in high-risk groups. Diagnostic confusion often exists between TBM and 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 abscess. (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 hinder the diagnosis. Spinal tap carries some risk of herniation of the medulla in any instance when intracranial pressure (ICP) is increased (eg, TBM), but if meningitis is suspected, the procedure must be performed regardless of the risk. CNS imaging modalities lack specificity but help in monitoring complications that require neurosurgery. (See Workup.)

Prompt treatment is essential; death may occur as a result of missed diagnoses and delayed treatment. Antimicrobial therapy is best started with isoniazid, rifampin, pyrazinamide; addition of a fourth drug is left to local choice. The optimal duration of antimicrobial therapy is unclear. 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 shunting improves outcome, 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.

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

Pathophysiology

Many of the symptoms, signs, and sequelae of tuberculous meningitis (TBM) are the result of an immunologically directed inflammatory reaction to the infection. TBM develops in 2 steps. Mycobacterium tuberculosis bacilli enter the host by droplet inhalation, the initial point of infection being the alveolar macrophages. Localized infection escalates within the lungs, with dissemination to the regional lymph nodes to produce the primary complex. During this stage, a short but significant bacteremia is present that can seed tubercle bacilli to other organs.

In persons who develop TBM, bacilli seed to the meninges or brain parenchyma, resulting in the formation of small subpial or subependymal foci of metastatic caseous lesions. These are termed Rich foci, after the original pathologic studies of Rich and McCordick.[1] Tuberculous pneumonia develops with heavier and more prolonged tuberculous bacteremia. Dissemination to the central nervous system (CNS) is more likely, particularly if miliary tuberculosis (TB) develops.

The second step in the development of TBM is an increase in size of a Rich focus until it ruptures into the subarachnoid space. The location of the expanding tubercle (ie, Rich focus) determines the type of CNS involvement. Tubercles rupturing into the subarachnoid space cause meningitis. Those deeper in the brain or spinal cord parenchyma cause tuberculomas or abscesses. While an abscess or hematoma can rupture into the ventricle, a Rich focus does not.

A thick gelatinous exudate infiltrates the cortical or meningeal blood vessels, producing inflammation, obstruction, or infarction. Basal meningitis accounts for the frequent dysfunction of cranial nerves (CNs) III, VI, and VII, eventually leading to obstructive hydrocephalus from obstruction of basilar cisterns. Subsequent neurological pathology is produced by 3 general processes: adhesion formation, obliterative vasculitis, and encephalitis or myelitis.

Formation of tuberculomas

Tuberculomas are conglomerate caseous foci within the substance of the brain, as shown in the image below. 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).


View Image

Tuberculoma is the round gray mass in the left corpus callosum. The red meninges on the right are consistent with irritation and probable meningeal re....

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 the adjacent intracranial trunk artery, largely causing vasculitis.[4] Probable embolic spread of tuberculomas in the brain in multidrug resistant TBM has been reported.[5]

Spinal involvement

In the tuberculous process, the spinal meninges may be involved, owing to the spread of infection from intracranial meningitis, primary spinal meningitis in isolation as a result of a tuberculous focus on the surface of the cord rupturing into the subarachnoid space, or transdural extension of infection from caries of the spine.

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

The earliest lesion in the vertebra is invariably due to hematogenous spread, often involving the body of the vertebra near an intervertebral disk. The intervertebral disk is almost always involved with the spread of the disease to the adjacent vertebra and eventually along the anterior or posterior longitudinal ligaments or through the end plate. Soon, a cold abscess develops, either as a paraspinal abscess in the dorsal and lumbar regions or as a retropharyngeal abscess in the cervical region.

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 on other organs

Papilledema is the most common visual effect of TBM. In children, papilledema may progress to primary optic atrophy and blindness resulting from direct involvement of the optic nerves and chiasma 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]

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, has been reported. Although these could be postictal phenomena, they mostly are due to vasculitic changes resulting in ischemia. While some of these could be the result of proliferative arachnoiditis or hydrocephalus, vasculitis still appears to be the leading cause.

Vasculitis with resultant thrombosis and hemorrhagic infarction may develop in vessels that traverse the basilar or 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, multiple 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

The causative organism is Mycobacterium tuberculosis. Various risk factors have been identified.

The first description of TBM is credited to Robert Whytt, on the basis of 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

TB is the seventh leading cause of death and disability worldwide. In 1997, TBM was the fifth most common form of extrapulmonary TB. TBM accounted for 5.2% (186) of all cases of exclusively extrapulmonary disease and 0.7% of all reported cases of TB.

United States statistics

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 one third of the world’s population is infected by M tuberculosis. The WHO’s 2003 publication Tuberculosis: Advocacy Report stated that 8 million new cases of TB are reported annually and 2 million deaths occur each year.[11] An estimated 8.8 million new TB cases were recorded in 2005 worldwide, 7.4 million in Asia and sub-Saharan Africa. A total of 1.6 million people died from TB, including 195,000 patients infected with HIV.[12]

In 2005, the TB incidence rate was stable or in decline in all 6 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. The available reports grossly underestimate the true incidence. Lack of surveillance testing in most areas of the world restricts the ability to assess the 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

Prior to the appearance of HIV, the most important determinant for the development of TBM was age. Data published in 2000 revealed that the risk increased with age across racial and ethnic groups.

In populations with a low prevalence of TB, most cases of TBM occur in adults. In the United States in 1996, case rates were low in infancy and decreased somewhat during early childhood. After the age of puberty, they showed a steady increase with age.

In general, however, TBM is more common in children than in adults, especially in the first 5 years of life. In fact, children aged 0-5 years are affected more commonly with TBM than any other age group. TBM is uncommon, however, in children younger than 6 months and almost unheard of in infants younger than 3 months because the causative pathological sequence takes 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.

Prevalence of TBM by race

Case rates in whites are lowest at all age groups, and rates in Asians and Pacific Islanders are the highest, particularly among adults. Rates among Blacks, Hispanics, and Native Americans/Alaskan Natives are intermediate. Black men have appreciably higher rates than Hispanic and Native American/Alaskan Native men, except in the oldest age group.

In 2000, approximately 75% of all reported TB cases occurred in racial and ethnic minorities, including 32% in non-Hispanic blacks, 23% in Hispanics, 21% in Asians and Pacific Islanders, and 1% in Native Americans and Alaskan Natives. Approximately 22% of all reported cases occurred in non-Hispanic whites.

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

TBM is a very critical disease in terms of fatal outcome and permanent sequelae, requiring rapid diagnosis and treatment. The number of deaths due to TB has decreased dramatically since 1953. In 1953, 19,707 deaths from TB were reported in the United States, for a rate of 12.4 deaths per 100,000 population. In 1997, 1,166 deaths were reported, for a rate of 0.4 deaths per 100,000 population.

The number of TB deaths and the TB death rate increased slightly during a recent TB resurgence, reaching a high in 1989 of 1,970 deaths and a rate of 0.8 deaths per 100,000 population before decreasing again.

Patients with TBM continue to do poorly in the long term, in spite of optimal anti-tuberculous therapy. While increasing age and co-infection with HIV might offer some explanation, they do not explain the whole picture.[14]

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. Prognosis is related directly to the clinical stage at diagnosis.

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 computed tomography (CT) scanning became available, radiological findings, such as hydrocephalus, infarction, severity of exudate, and tuberculoma, also were considered for predicting the prognosis of TBM.

A recent 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, CN palsy, and hydrocephalus.[15] Children with advanced disease with neurological complications have poor outcomes.

The occurrence of syndrome of inappropriate diuretic hormone secretion (SIADH) is common and is also linked to a poor prognosis.

Sinha et al report that they found visual impediment a predictable prelude to severe disability or death.[16] It was often the result of optochiasmatic arachnoiditis or optochiasmal tuberculoma.

Few studies on neurophysiological changes are reported in TBM. EEG has been reported to be useful in assessing the gravity of lesions and was reported recently to help in prediction of outcome. Motor evoked potentials and somatosensory evoked potentials also have been reported recently 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]

Hydrocephalus was the only factor shown to be significant in predisposing patients with TBM who had positive culture results to a poorer outcome. A trend toward a poorer prognosis was also seen in those with advanced stages of the disease.

While clinical features in children with TBM who were also infected with HIV and those who were not co-infected with HIV were not markedly different, abnormal radiological findings were more common in the HIV-infected group and outcomes were considerably worse. Coexisting HIV encephalopathy and diminished immune competence undoubtedly contributed to the more severe clinical and neuroradiological features.

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. To achieve this, 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.

We do have a successful model of smallpox eradication; if all interested and influential partners come together in a concerted effort, we could and would eliminate TB.

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.

History

Tuberculous meningitis (TBM) is difficult to diagnose, and a high index of suspicion is needed to make an early diagnosis.

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 test, especially a recent conversion. Determine if the patient has a history of immunosuppression from a known disease or from drug therapy.

Check if the patient has a negative history for bacillus Calmette-Guérin (BCG) vaccination. 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; a history of BCG vaccination does not rule out the diagnosis (grade C).

In an immunocompetent individual, central nervous system (CNS) TB usually takes the form of meningitis that causes an acute-to-subacute illness characterized by fever, headache, drowsiness, meningism, and confusion over a period of approximately 2-3 weeks.

Usually, during the prodromal period, nonspecific symptoms are present, including fatigue, malaise, myalgia, and fever. In one study, only 2% of patients reported meningitic symptoms. The duration of presenting symptoms may vary from 1 day to 9 months, although 55% presented with symptoms of less than 2 weeks' duration.

Often, in the first stage of meningitis, patients have infection of the upper respiratory tract, a fact that should be remembered when the concurrent fever and irritability or lethargy seem out of proportion to the obvious infection or when general symptoms persist after improvement in the local manifestations. 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.

Visual symptoms include visual impairment or blindness and, occasionally, abrupt onset of painful ophthalmoplegia. Ocular tuberculosis presents a form of granulomatous uveitis. Delayed or wrong diagnosis may be detrimental to the ocular structures and the health of the individual.[20]

Sudden onset of focal neurologic deficits, including monoplegia, hemiplegia, aphasia, and tetraparesis, has been reported. 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.

The syndrome of inappropriate antidiuretic hormone (SIADH) secretion is a common complication and is linked to a poor prognosis.

Less frequent presentations include atypical febrile seizures in children, isolated cranial nerve (CN) palsies, bilateral papilledema, and acute confusional state.

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 basal 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 is often dominated by myeloradiculopathy, with radicular pain and progressive paraplegia or tetraplegia. A less virulent chronic form might mimic a very slowly progressive spinal cord compression or a nonspecific arachnoiditis.

The dorsal cord seems to be affected most commonly, followed by the lumbar and the cervical regions.

Tuberculous spondylitis

Tuberculous spondylitis is also known as Pott disease or spinal caries. In regions where the disease is endemic, such as 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.

In the lumbar region, tuberculous spondylitis may result in a psoas abscess that often calcifies. It usually runs a subacute or a chronic course, with back pain and fever and variable neurological deficits. Spondylitis can also result in various symptoms, including local and radicular pain, limb motor and sensory loss, and sphincter disturbances.

Eventually, complete spinal cord compression with paraplegia, the most dreaded complication, may supervene.

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 a young child 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 BCG vaccination scar. Because BCG vaccination is partially protective against TB meningitis, the presence of a BCG vaccination scar affords some degree of reassurance when considering a diagnosis of TBM.[19] Nevertheless, prior BCG vaccination does not rule out the diagnosis.

Visual findings

Apart from papilledema, fundus examination occasionally reveals 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.

Neurologic findings

Cranial neuropathies, most often involving CN VI, may be noted. CNs III, IV, VII, and, less commonly, CNs II, VIII, X, XI, and XII, also may be affected. Focal neurological deficits may include monoplegia, hemiplegia, aphasia, and tetraparesis.

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.

Complications

TBRM is a complication of TBM that has been reported only rarely in the modern medical literature. It develops at various intervals after TBM, even in adequately treated patients after sterilization of the CSF. The most common symptoms are subacute paraparesis, radicular pain, bladder disturbance, and subsequent paralysis.

Staging

In 1948, the British Medical Research Council developed a method for staging the severity of the disease, as follows:

Prognosis is related directly to the clinical stage at diagnosis.

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 accompanying clinical features of TBM hinder the diagnosis.[21, 22, 23, 24, 25]

Spinal tap carries some risk of herniation of the medulla in any instance when intracranial pressure (ICP) is increased (eg, TBM), but if meningitis is suspected, the procedure must be performed regardless of the risk, using suitable precautions and obtaining informed consent before the procedure.

Computed tomography (CT) scanning and magnetic resonance imaging (MRI) lack specificity but help in monitoring complications that require neurosurgery. Go to Imaging in Bacterial Meningitis for more complete information on this topic.

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.

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

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

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, in some cases constituting a true syndrome of inappropriate diuretic hormone secretion (SIADH). 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 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

Use manometrics to check CSF pressure. Typically, the pressure is higher than normal.

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 (ie, 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 the following:

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. This carries significant risks, however, including epidural hematoma and hydrocephalus.

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 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 the routine application in laboratories with limited resources.[27] This is not yet available for routine use, and proof of its utility requires further studies.

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

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 help in monitoring complications that require neurosurgery.


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MRI of the brain in a patient with 8 CD4 cells/mL. The patient's history includes previous interstitial pneumonia, pericarditis, adnexitis, and a posi....

Imaging studies, both CT scanning and MRI, are performed with and without enhancement, as long as the renal function of the patient is not compromised.

Basal cisterns often enhance strikingly, corresponding to the thick exudate that is observed pathologically. The quadrigeminal cistern, interpeduncular fossa, ambient cistern, and chiasmatic region are particularly involved, owing to associated arachnoiditis. Meningeal enhancement is more common in HIV-infected patients.

Contrast enhancement further delineates focal parenchymal and space-occupying lesions, with or without associated hydrocephalus.

The characteristic CT finding is a nodular, enhancing lesion with a central hypodense lesion.[28] Contrast enhancement is essential. Early stages are characterized by low-density or isodense lesions, often with edema out of proportion to the mass effect and little encapsulation. At a later stage, well-encapsulated tuberculomas appear as isodense or hyperdense lesions with peripheral ring enhancement.

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.[29] Hence, strong clinical suspicion and correlation with laboratory findings is necessary for early diagnosis.

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

Calcification occurs in 2 main sites, (1) more commonly in the basal meninges and, (2) to a lesser extent, within brain substance. Calcification is 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, contrast enhancement is often seen surrounding the spinal cord and the 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.

Tuberculous spondylitis neuroimaging invariably reveals bone destruction and fragmentation with involvement of the disk space and calcified paravertebral mass.

MRI has an accuracy 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.

CT scanning is superior to MRI in detecting psoas abscess calcification that, when present, strongly raises the suspicion of 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.[30]

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

Angiography

Perform magnetic resonance angiography (MRA) and venography if indicated. Findings on conventional 4-vessel angiography and MRA most typically have included evidence of hydrocephalus, narrowing of the arteries at the base of the brain, and narrowed or occluded small and medium-sized arteries.

Electroencephalography

In one study, findings from electroencephalography (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

In the same study described above, brainstem auditory evoked potential abnormalities were observed in more than 50% of patients with 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 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 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.[31]

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).


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Fluorochrome for tuberculosis. Fluorescent staining procedures are used with auramine O or auramine-rhodamine as the primary fluorochrome dye. After d....


View Image

Hematoxylin and eosin stain showing caseation in tuberculosis.

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.[32]

Approach Considerations

The duration of antimicrobial therapy for tuberculous meningitis (TBM) is unclear, and the benefits of adjuvant corticosteroids remain in doubt. Death may occur as a result of missed diagnoses and delayed treatment.

Obviously, concerns regarding transmission of other infectious diseases have led to legal constraints including quarantine, variably obligatory vaccinations, and exclusion from immigration. In the US legal system, the model indicates that if persons with potentially transmissible tuberculosis (TB) refuse to take treatment, they can and should be quarantined to protect the public. Directly observed therapy is gaining popularity, with the broadening perception that directly observed therapy should be the standard of practice.

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.[33]

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.[34]

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.[35]

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 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 is less effective in meningeal disease unless used in high doses. The second-line drugs include ethionamide, cycloserine, ofloxacin, and para -aminosalicylic acid (PAS).

INH, RIF, and PZA are bactericidal. RIF and SM achieve optimal CSF levels only when the meninges are inflamed. Usually, intrathecal drugs are not necessary. Treatment is best started with INH, RIF, and PZA. The addition of a fourth drug is left to the choice of the local physicians and their experience, with little evidence to support the use of one over the other.

Evidence concerning the duration of treatment is conflicting. The duration of conventional therapy is 6-9 months, although some investigators still recommend as many as 24 months of therapy. No guidelines exist as to the components and duration of treatment in the case of multidrug-resistant TBM.

Studies have shown that young children with TBM can be treated safely for 6 months with high doses of anti-TB agents without overt hepatotoxicity and with a low risk of relapse. Children must be treated for 12 months with combination antibiotic therapy and adjunctive corticosteroids. Twelve months is probably a conservative estimate of the time required for bacterial cure. The rationale behind the use of adjuvant corticosteroids lies in reducing the harmful effects of inflammation as the antibiotics kill the organisms.

The use of corticosteroids in adults is controversial; they may be indicated in the presence of 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.

To ascertain the immediate and underlying causes of death in adults who died in hospital with an antemortem diagnosis of tuberculosis, Martinson et al, in their autopsy studies, demonstrated disseminated, extensive tuberculosis associated with advanced HIV disease.[36] Severe bacterial infections, including salmonellosis, were the leading comorbidity, suggesting that hospitalized HIV-infected adults in whom tuberculosis is suspected may benefit from broad-spectrum antibiotic therapy.

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.

Drain or Shunt Placement

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. Studies suggest that prompt ventriculoatrial or ventriculoperitoneal shunting improves outcome, particularly in patients presenting with minimal neurological deficit.

Unless a mass effect is compromising vital structures, surgical intervention is rarely required in the treatment of tuberculomas.

Prevention of Tuberculous Meningitis

BCG vaccination offers a protective effect (approximately 64%) against 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 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 Summary

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, 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 tuberculous meningitis (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.[37]

Wasay, in his 2006 editorial, discusses at length central nervous system (CNS) TB and the paradoxical response.[38] 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.[39, 40]

The paradoxical response has been attributed as a component of immune reconstitution inflammatory syndrome or immune restoration syndrome, which results from an exuberant inflammatory response toward incubating opportunistic pathogens.[41] An increase in the incidence and severity of the paradoxical response is noted in HIV-infected patients on highly active antiretroviral therapy.[42] Patients demonstrating a paradoxical response are more likely to have lower baseline lymphocyte counts, followed by a surge.[43]

Capreomycin (Capastat)

Clinical Context:  Capreomycin is a second-line drug for concomitant use with other appropriate anti-TB drugs when first-line drugs are ineffective or cannot be used because of toxicity.

Cycloserine (Seromycin)

Clinical Context:  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)

Clinical Context:  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)

Clinical Context:  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 (Laniazid, Nydrazid)

Clinical Context:  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]

Prothionamide

Clinical Context:  Prothionamide is a thionamide derivative, active against M tuberculosis. Its action is similar to that of ethionamide, with which it is considered interchangeable. Resistance develops quickly if it used alone. It is better tolerated than ethionamide. Prothionamide is indicated as a second-line anti-TB drug. It is not available in the United States.

Pyrazinamide (Tebrazid)

Clinical Context:  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, Rimactane)

Clinical Context:  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

Clinical Context:  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 (Sodium PAS)

Clinical Context:  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.

Thiacetazone

Clinical Context:  Although not available in the United States, thiacetazone is used in many developing countries because it is inexpensive. Although it is related to INH biochemically, it is bacteriostatic and more toxic than INH. It is commonly combined in a single tab containing 300-400 mg of INH and 150 mg of thiacetazone.

Rifapentine (Priftin)

Clinical Context:  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.

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, capreomycin, and thiacetazone.

Kanamycin (Kantrex)

Clinical Context:  Kanamycin is an aminoglycoside containing 1 or 2 amino sugars linked to an aminocyclitol nucleus. The nucleus is 2-deoxystreptamine. Kanamycin is bactericidal and is believed to inhibit protein synthesis by binding to the 30S ribosomal subunit. It is effective against extracellular mycobacteria.

Amikacin (Amikin)

Clinical Context:  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.

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 and kanamycin.

Ciprofloxacin (Cipro, Cipro XR)

Clinical Context:  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 (Floxin)

Clinical Context:  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)

Clinical Context:  Levofloxacin is a fluoroquinolone antibiotic that is used in the treatment of tuberculosis in combination with rifampin and other antituberculosis agents.

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.

Prednisone

Clinical Context:  Prednisone may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Dexamethasone (Baycadron, DexPak 10-Day TaperPak)

Clinical Context:  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.

Class Summary

The use of corticosteroids in adults is controversial; they may be indicated in the presence of 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.

Studies have shown that young children with TBM can be treated safely for 6 months with high doses of anti-TB agents without overt hepatotoxicity and with a low risk of relapse. Children must be treated for 12 months with combination antibiotic therapy and adjunctive corticosteroids. The rationale behind the use of adjuvant corticosteroids lies in reducing the harmful effects of inflammation as the antibiotics kill the organisms.

Author

Tarakad S Ramachandran, MBBS, FRCP(C), FACP, FRCP, Professor Emeritus of Neurology and Psychiatry, Clinical Professor of Medicine, Clinical Professor of Family Medicine, Clinical Professor of Neurosurgery, State University of New York Upstate Medical University; Neuroscience Director, Department of Neurology, Crouse Irving Memorial Hospital

Disclosure: Boeringer-Ingelheim Honoraria Speaking and teaching

Chief Editor

Karen L Roos, MD, John and Nancy Nelson Professor of Neurology, Professor of Neurological Surgery, Department of Neurology, Indiana University School of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Pieter R Kark, MD, MA, FAAN, FACP Instructor in Palliative Care, The Lifetime Healthcare Companies

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Florian P Thomas, MD, MA, PhD, Drmed Director, Spinal Cord Injury Unit, St Louis Veterans Affairs Medical Center; Director, National MS Society Multiple Sclerosis Center; Director, Neuropathy Association Center of Excellence, Professor, Department of Neurology and Psychiatry, Associate Professor, Institute for Molecular Virology, and Department of Molecular Microbiology and Immunology, St Louis University School of Medicine

Florian P Thomas, MD, MA, PhD, Drmed is a member of the following medical societies: American Academy of Neurology, American Neurological Association, American Paraplegia Society, Consortium of Multiple Sclerosis Centers, and National Multiple Sclerosis Society

Disclosure: Nothing to disclose.

Frederick M Vincent Sr, MD Clinical Professor, Department of Neurology and Ophthalmology, Michigan State University Colleges of Human and Osteopathic Medicine

Frederick M Vincent Sr, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American College of Forensic Examiners, American College of Legal Medicine, American College of Physicians, and Michigan State Medical Society

Disclosure: Nothing to disclose.

References

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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.

MRI of the brain in a patient 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. Liquoral findings strongly suggested a diagnosis of tuberculous meningitis, and culture results were positive for Mycobacterium tuberculosis. The MRI shows the presence, in and over the sellar seat, with parasellar left extension, of tissue with irregular margins, marked inhomogeneous enhancement, and compression of optic chiasm and of the third ventricle. Presence of nodular areas with marked enhancement of basal cisterns is an expression of leptomeningeal involvement. This patient died after 2 months of inadequate antituberculosis therapy (ie, poor compliance). Courtesy of Salvatore Marra, AIDS Imaging (http://members.xoom.it/Aidsimaging).

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.

Hematoxylin and eosin stain showing caseation in tuberculosis.

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.

MRI of the brain in a patient 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. Liquoral findings strongly suggested a diagnosis of tuberculous meningitis, and culture results were positive for Mycobacterium tuberculosis. The MRI shows the presence, in and over the sellar seat, with parasellar left extension, of tissue with irregular margins, marked inhomogeneous enhancement, and compression of optic chiasm and of the third ventricle. Presence of nodular areas with marked enhancement of basal cisterns is an expression of leptomeningeal involvement. This patient died after 2 months of inadequate antituberculosis therapy (ie, poor compliance). Courtesy of Salvatore Marra, AIDS Imaging (http://members.xoom.it/Aidsimaging).

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.

Hematoxylin and eosin stain showing caseation in tuberculosis.