Tuberculous Meningitis

Updated: Dec 07, 2017

Author: Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP,
FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS; Chief Editor: Niranjan N
Singh, MBBS, MD, DM, FAHS, FAANEM

Overview

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).
 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 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.

Presentation

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:

 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
 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
  Stage III describes an advanced state with stupor or coma,
dense neurological deficits, seizures, posturing, and/or abnormal
movements

Prognosis is related directly to the clinical stage at diagnosis.

DDx

Diagnostic Considerations

Tuberculous meningitis (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,
including persons with malnutrition, those who abuse alcohol or drugs,
homeless persons, people in correctional facilities, residents of long-
term care facilities, and patients with known HIV infection.

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 seldom yields
positive results. The sensitivities of many of the new tests are still
under study, and these tests may not become generally available for
some time; when they do, they are likely to prove costly.

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 less than 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 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.

Other problems to be considered

TBM should be considered in the differential diagnosis in any patient

presenting with fever and a change in sensorium. Other problems to be
considered include the following:

 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

 Acute Disseminated Encephalomyelitis

 Acute Subdural Hematoma in the ED
 Aseptic Meningitis
 Haemophilus Meningitis
 Intracranial Epidural Abscess
 Meningococcal Meningitis
 Pediatric Status Epilepticus
 Subdural Empyema
 Viral Encephalitis
 Viral Meningitis

Workup

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 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:
  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.
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.

Researchers evaluated previous multicenter/multinational studies to

determine the frequency of the absence of cerebrospinal fluid
pleocytosis in patients with central nervous system infections, as well
as the clinical impact of this condition. It was found that 3%
of tuberculous meningitis cases did not display cerebrospinal fluid
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 cerebrospinal fluid 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

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.

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).

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.[30] 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.[31] 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.[32]

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.[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 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 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

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.[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 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.[38]
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

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.[39]

Wasay, in his 2006 editorial, discusses at length central nervous

system (CNS) TB and the paradoxical response.[40] 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.[41,
42]

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.[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 for concomitant use with other

appropriate anti-TB drugs when first-line drugs are ineffective or
cannot be used because of toxicity.

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 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 and kanamycin.

Kanamycin

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

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, Cipro XR)

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 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.

Prednisone (Rayos)

Prednisone may decrease inflammation by reversing increased

capillary permeability and suppressing PMN activity.

Dexamethasone (Baycadron)

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.