REVIEW

Tuberculous meningitis in patients infected with humanimmunodeficiency virus

Ravindra Kumar Garg • Manish Kumar Sinha

Received: 21 June 2010 / Accepted: 1 September 2010 / Published online: 17 September 2010

� Springer-Verlag 2010

Abstract Tuberculosis is the most common opportunistic

infection in human immunodeficiency virus (HIV) infected

persons. HIV-infected patients have a high incidence of

tuberculous meningitis as well. The exact incidence and

prevalence of tuberculous meningitis in HIV-infected

patients are not known. HIV infection does not signifi-

cantly alter the clinical manifestations, laboratory, radio-

graphic findings, or the response to therapy. Still, some

differences have been noted. For example, the histopa-

thological examination of exudates in HIV-infected

patients shows fewer lymphocytes, epithelioid cells, and

Langhan’s type of giant cells. Larger numbers of acid-fast

bacilli may be seen in the cerebral parenchyma and

meninges. The chest radiograph is abnormal in up to 46%

of patients with tuberculous meningitis. Tuberculous

meningitis is likely to present with cerebral infarcts and

mass lesions. Cryptococcal meningitis is important in dif-

ferential diagnosis. The recommended duration of treat-

ment in HIV-infected patients is 9–12 months. The benefit

of adjunctive corticosteroids is uncertain. Antiretroviral

therapy and antituberculosis treatment should be initiated

at the same time, regardless of CD4 cell counts. Tubercu-

lous meningitis may be a manifestation of paradoxical

tuberculosis-associated immune reconstitution inflamma-

tory syndrome. Some studies have demonstrated a signifi-

cant impact of HIV co-infection on mortality from

tuberculous meningitis. HIV-infected patients with multi-

drug-resistant tuberculous meningitis have significantly

higher mortality. The best way to prevent HIV-associated

tuberculous meningitis is to diagnose and isolate infectious

cases of tuberculosis promptly and administer appropriate

treatment.

Keywords BCG vaccination � Extrapulmonary

tuberculosis � Human immunodeficiency virus �Dexamethasone � Mycobacterium tuberculosis

Introduction

In endemic regions of tuberculosis, tuberculous meningitis

is a frequently encountered neurological disorder. Despite

adequate chemotherapy, tuberculous meningitis is fatal in

up to 50% of the cases. A high frequency of disabling

morbidity is observed among survivors [1]. Even in

advanced countries, such as the United States, tuberculous

meningitis is associated with a high mortality. It was

observed that even after a long follow-up of several years,

only 40% (total 135 patients) of confirmed cases of

tuberculous meningitis were still alive as compared to 85%

(total 75 patients) of patients with unconfirmed tuberculous

meningitis [2].

Human immunodeficiency virus (HIV)-infected patients

have a high incidence of all forms of tuberculosis,

including tuberculous meningitis. HIV infection influences

the pathological, clinical, and laboratory findings in

patients with tuberculous meningitis in various ways and

may be associated with poorer outcome. HIV tuberculosis

co-infection contributes to HIV-related pathogenesis and

often increases the viral load in HIV-infected people. In

this review, we will be discussing the impact of HIV

infection on epidemiology, pathogenesis, clinical features,

neuroimaging, and management of tuberculous meningitis.

An extensive review of the literature was performed using

the PubMed and Google Scholar databases. The search

R. K. Garg (&) � M. K. Sinha

Department of Neurology, Chhatrapati Shahuji Maharaj Medical

University, Lucknow 226003, Uttar Pradesh, India

e-mail: garg50@yahoo.com

123

J Neurol (2011) 258:3–13

DOI 10.1007/s00415-010-5744-8

terms used included HIV and tuberculosis; HIV and

tuberculous meningitis; AIDS and tuberculosis; AIDS and

tuberculous meningitis; tuberculous meningitis; meningeal

tuberculosis; and central nervous system tuberculosis.

Epidemiology

Tuberculosis is a leading cause of death among people

infected with HIV. According to the latest World Health

Organization estimate, in 2008 there were 33.4 million

HIV-infected cases [3]. In the same year, there were

approximately 1.4 million new cases of tuberculosis among

persons with HIV infection, and tuberculosis accounted for

23% of AIDS-related deaths. Worldwide, 14 million people

are currently co-infected with tuberculosis and HIV. In

some countries with high HIV prevalence, up to 80% of the

people with tuberculosis test positive for HIV [4, 5]. In

advanced stages of HIV infection, tuberculosis may have

atypical presentations, including extrapulmonary tubercu-

losis. Up to 25% of tuberculosis cases in HIV-infected

persons may present with extrapulmonary tuberculosis.

Extrapulmonary tuberculosis is more common with lower

CD4 cell counts [6].

Data from developed countries indicate an increasing

trend for extrapulmonary tuberculosis (including tubercu-

lous meningitis) in the population because of prevalent

HIV infection [7, 8]. According to the latest tuberculosis

report from the United States of America, among 253,299

cases (from 1993 to 2006) 73.6% had pulmonary tuber-

culosis and 18.7% had extrapulmonary tuberculosis.

Approximately 5% of the cases had tuberculous meningitis.

The risk factors for extrapulmonary tuberculosis were

female sex and foreign birth of the patient, positive HIV

status, homelessness and excessive consumption of alcohol

[7]. The national tuberculosis surveillance data from 1999

to 2006 for England and Wales (a total of 55,607 cases)

also suggested an increasing trend in the proportion of

extrapulmonary tuberculosis. Among all the cases of

tuberculosis, the proportion with extrapulmonary disease

increased from 48% in 1999 to 53% in 2006. The largest

increase was seen in miliary tuberculosis, where the pro-

portion rose threefold. The proportion of tuberculous

meningitis cases also significantly increased from 1.5%

(86) to 2% (165). Miliary tuberculosis and tuberculous

meningitis were associated with age over 60 years, foreign

birth of Indian, Pakistani, or Bangladeshi ethnic origin and

co-infection with HIV [8].

The epidemiological data of tuberculous meningitis

from resource poor countries with a very high incidence of

pulmonary tuberculosis are not readily available. In one of

the studies from a large teaching hospital in India, 375

patients (all patients admitted between 2001 and 2003)

with HIV infection were evaluated for opportunistic dis-

ease. Tuberculosis was the most common opportunistic

disease, seen in 163 patients, and 25 (7%) patients had

tuberculous meningitis [9]. In Thailand, among 114 con-

secutive patients with chronic meningitis, the most com-

mon causative agents were Cryptococcus neoformans

(54%) and Mycobacterium tuberculosis (37%). Out of the

43 patients with tuberculous meningitis, 3 patients were

HIV-positive [10].

Microbiology

Tuberculous meningitis is caused by Mycobacterium

tuberculosis, which is an acid-fast bacterium. An extensive

heterogeneity in the genetic composition of M. tuberculosis

has been demonstrated.

There are several strains of M. tuberculosis, which have

a distinct geographical distribution, interactions with the

host, and may even differ in their transmission potential.

The Beijing genotype of M. tuberculosis is considered a

more virulent strain which frequently affects HIV-infected

patients [11]. The Beijing M. tuberculosis genotype is

globally present with the highest prevalence found in Asia

and the territory of the former Soviet Union. In Thailand

58% of patients with tuberculous meningitis were found to

be infected with this genotype. The proportion of tuber-

culous meningitis caused by the Beijing strain was found

significantly higher than previously reported figure for

pulmonary tuberculosis caused by the Beijing strain [12].

In a large cohort of Vietnamese adults with tuberculous

meningitis, authors have recently demonstrated a strong

association between the Beijing genotype, drug resistance,

and HIV infection [13].

Tuberculosis and HIV infection pathogenesis

HIV co-infection results in an increased risk of all forms of

tuberculosis. In patients harboring M. tuberculosis who do

not have HIV infection, the lifetime risk of developing

tuberculosis is between 10 and 20%. However, in persons

co-infected with M. tuberculosis and HIV, the annual risk

of developing active tuberculosis may exceed 10% [14].

The pathogenesis of tuberculosis in HIV-1 infected persons

includes both reactivation of prior infection and aggrava-

tion of existing primary infection. In advanced stages of

HIV infection, a disseminated, miliary, or extrapulmonary

form of tuberculosis is much more frequent [15].

Active tuberculosis has a major impact on the course of

HIV infection. Tuberculosis can accelerate the course of

HIV disease by enhancing viral replication. Increased HIV

replication, in turn, leads to enhanced CD4 T cell

4 J Neurol (2011) 258:3–13

123

destruction and higher mortality in co-infected patients.

The levels of plasma viremia are reduced after successful

treatment of the active tuberculosis [16].

Several mechanisms have been proposed to explain the

tuberculosis-HIV association. For example, HIV has been

shown to impair tumor necrosis factor-alpha (TNF-a)

mediated macrophage apoptosis. Apoptosis of macro-

phages, in response to M. tuberculosis infection, is a crit-

ical host defense response, and decreased apoptosis may be

responsible for increased susceptibility to M. tuberculosis

in HIV-infected persons [17, 18]. In an in vitro study, in

response to HIV and tuberculosis co-infection, a variety of

genes of human macrophages were found to be up-regu-

lated. However, genetic changes in response to HIV

infection alone were fewer in number and significantly

lower in magnitude. Normally, these genes encode for pro-

inflammatory chemokines and cytokines, their receptors,

signaling associated genes, type-I interferon signaling

genes and genes of the tryptophan degradation pathway

[19]. According to another proposed mechanism, the HIV

infection may produce a rapid loss of M. tuberculosis-

specific T helper-1 cells in the peripheral blood [20].

Pathogenesis of tuberculous meningitis

Mycobacterium tuberculosis infection is acquired by the

inhalation of bacilli as aerosols, which reach and multiply

in alveolar macrophages. Through the hematogenous

route, the bacilli reach into the central nervous system.

M. tuberculosis breaches the blood–brain barrier (com-

posed of tightly apposed brain microvascular endothelial

cells). The mechanisms involved in the process of breach

of the blood–brain barrier are poorly understood. Inside the

central nervous system the bacilli produce small granulo-

mas in the meninges and adjacent brain parenchyma. These

tuberculomas may remain dormant for several months or

years. Tuberculous meningitis develops when a caseating

Rich focus ruptures and discharges its contents into the

subarachnoid space [21]. What triggers the rupture of Rich

foci is not exactly known. Decreased immunity of the host

may be a factor. Following rupture of a Rich focus into the

cerebrospinal spaces, the content containing mycobacteria

induces an intense immune response and, subsequently,

exudate formation.

Mycobacterium tuberculosis is capable of entering and

replicating within macrophages. The microglial cells (the

resident macrophages of the brain) are the principal targets

of M. tuberculosis. Tumor necrosis factor-alpha released

from microglial cells has been shown to play a critical role

in the containment of infection, granuloma formation,

alteration of blood–brain barrier permeability, and cere-

brospinal fluid leukocytosis [1]. Several other cytokines

present in the microglia, such as b2-integrin (CD-18),

interleukin-6, interleukin-1b, chemokine (C–C motif)

ligand 2 and chemokine (C–C motif) ligand-5, and che-

mokine (C–X–C motif) ligand-10, are also involved in

the host’s defense mechanisms [22]. However, in patients

with tuberculous meningitis, variable cerebrospinal fluid

inflammatory responses were observed. For example, a

South African study could not demonstrate any significant

difference in the cerebrospinal fluid cytokine concentra-

tions and CD4 counts between HIV seropositive and HIV

seronegative patients of tuberculous meningitis [23]. HIV-

infected patients of tuberculous meningitis had lower

cerebrospinal fluid interleukin-10 and interferon-gamma

concentrations [24].

Pathology

The hallmark pathological feature of tuberculous menin-

gitis is the presence of thick gelatinous exudates which are

prominent in the basilar regions of the brain. The exudates

may block the cerebrospinal fluid pathways resulting in the

development of hydrocephalus. The entrapment of intra-

cranial vessels within exudates manifests as cerebral

infarcts. The entrapment of cranial nerves manifests as

cranial nerve palsies. The basal inflammatory process may

also affect the brain parenchyma, resulting in encepha-

lopathy. Frequently, there is formation of cerebral

tuberculoma.

HIV infection may influence the pathological features of

tuberculous meningitis in several ways. Tuberculous exu-

dates in the HIV-infected patients are minimal, thinner, and

of a serous type. The exudates in the HIV-positive patients

contain fewer lymphocytes, epithelioid cells, and Lan-

ghan’s type of giant cells as compared to HIV-negative

patients. Larger numbers of acid-fast bacilli may be seen in

the cerebral parenchyma and meninges of HIV-infected

patients. Hydrocephalus is not common. Mild ventricular

dilatation may be observed secondary to cerebral atrophy

[25]. Patients with HIV-associated tuberculous meningitis

may present with lower leukocyte counts in peripheral

blood and cerebrospinal fluid and may be more likely than

HIV-uninfected patients to have concomitant active

extrapulmonary extrameningeal tuberculosis [26].

Clinical features—impact of HIV infection

In immunocompetent patients, headache, vomiting, men-

ingeal signs, focal deficits, vision loss, cranial nerve pal-

sies, and raised intracranial pressure are the characteristic

clinical features of tuberculous meningitis. The sixth cra-

nial nerve is the most frequently affected cranial nerve.

J Neurol (2011) 258:3–13 5

123

Vision loss, secondary to optic nerve involvement, is a

disabling complication. The possible reasons for optic

nerve involvement include optochiasmatic arachnoiditis, a

large hydrocephalus, optic nerve granulomas, or etham-

butol toxicity. Changes in cerebral vessels are character-

ized by inflammation, spasms, constriction, and eventually

thrombosis of cerebral vessels. Infarcts are located at

internal capsule, basal ganglion, and thalamic regions and

frequently manifest as focal neurological deficits. Tuber-

culous radiculomyelopathy is characterized by the subacute

paraparesis [1].

Usually, human immunodeficiency virus infection does

not significantly alter the clinical manifestations, labora-

tory, or neuroimaging findings in patients with tuberculous

meningitis. However, some authors have suggested that

some clinical differences exist between immunodeficiency

virus-infected and immunodeficiency virus-negative

patients [27]. Overall, HIV-positive patients with tubercu-

lous meningitis with higher CD4 cell counts often present

in the ‘classic’ form, whereas patients with low CD4 cell

counts are more likely to present atypically [28]. Mani-

festations of tuberculous meningitis are subtle and less

specific in patients with low CD4 cell counts. These

patients present late in the course of the disease with a

prolonged duration of illness and a severe grade of tuber-

culous meningitis [28].

The most common clinical manifestations observed in

HIV-infected patients with tuberculous meningitis were

fever and an abnormal mental status [29]. The classical

clinical manifestations of tuberculous meningitis such as

fever, headache, vomiting, and weight loss occurred in

equal frequency in patients with and without HIV infection

[30]. Even in a pediatric study, both HIV-infected patients

and HIV-uninfected patients with tuberculous meningitis

had almost similar clinical manifestations [31]. A Viet-

namese study observed, in a comparison to patients with

HIV-negative tuberculous meningitis, that HIV-infected

patients with tuberculous meningitis were younger in age

and were more commonly male. HIV-infected patients with

tuberculous meningitis weighed less but had a higher

incidence of other types of extrapulmonary tuberculosis

[26].

Differences in several hematological and blood bio-

chemical parameters have also been noted. Concentrations

of aspartate transaminase and alanine aminotransferase

were significantly higher in HIV-infected patients. A

greater proportion of HIV-infected patients with tubercu-

lous meningitis had hepatitis B surface antigenemia. The

authors suggested that these differences relate partly to the

epidemiological pattern of HIV infection (young male drug

users with a high prevalence of viral hepatitis) and partly to

the effects of systemic immunodeficiency (low weight, low

hematocrit level, and high prevalence of extrapulmonary/

meningeal tuberculosis) [26]. Other studies have also

reported frequent liver function abnormalities in these

patients [2]. HIV-infected children with tuberculous men-

ingitis may have a lower hemoglobin level (\8 gm/dL)

[32]. These patients have more frequent concurrent pul-

monary infection, even in the absence of respiratory

symptoms. Lymphadenopathy and hepatosplenomegaly

were also frequent findings in HIV-infected patients with

tuberculous meningitis [33].

Diagnosis

Cerebrospinal fluid findings

Cerebrospinal fluid examination is the cornerstone of the

diagnosis of tuberculous meningitis. The ‘gold standard’

for the diagnosis is the demonstration of M. tuberculosis

bacilli in the cerebrospinal fluid. In human immunodefi-

ciency virus-associated tuberculous meningitis, a relatively

higher 69% positivity for smear and 87.9% positivity for

bacterial culture have been demonstrated [34].

The values of routinely measured cerebrospinal fluid

parameters are almost similar in HIV-positive and negative

patients with tuberculous meningitis [26, 31, 35]. Some

studies, however, noted a lower cerebrospinal fluid leuko-

cyte count and a lower protein level in HIV-positive

patients [25, 33]. Patients with advanced HIV disease

usually have low numbers of lymphocytes in the peripheral

blood, which may reflect in a low lymphocyte count in the

cerebrospinal fluid. Moreover, tuberculous meningitis may

stimulate increased HIV replication in the central nervous

system, resulting in the destruction of cerebrospinal fluid

lymphocytes [34]. M. tuberculosis may be isolated from

the cerebrospinal fluid in a higher proportion of HIV-

infected patients than in HIV-uninfected patients, perhaps

due to greater mycobacterial dissemination within the

central nervous system [30]. In a Vietnamese study,

microbiological confirmation of tuberculous meningitis

was obtained in 45% of HIV-positive patients, in contrast

to 33% of HIV-negative patients [26]. The quantity of acid-

fast bacilli seen in the cerebrospinal fluid smear appeared

to be higher, with a shorter time for detection of acid fast

bacilli in HIV-associated tuberculous meningitis than in

HIV-negative tuberculous meningitis [34]. M. tuberculosis

can be isolated from significantly smaller cerebrospinal

fluid volumes from HIV-infected individuals compared to

uninfected ones [36]. Cerebrospinal fluid examination

findings may be normal in 5% of HIV-positive patients

with tuberculous meningitis. The percentages of HIV-

positive tuberculous meningitis patients with normal cere-

brospinal fluid parameters are as follows: glucose 15%,

protein 40% and leukocyte count 10% [37].

6 J Neurol (2011) 258:3–13

123

Immunological tests such as tuberculin skin testing and

interferon gamma release assays should not be relied upon,

as HIV-related immunosuppression might be associated

with false-negative results. The frequency of false-negative

and indeterminate interferon gamma release assay results

increases with advancing immunodeficiency [38]. How-

ever, recently the quantitative region of difference (RD)-1

interferon-gamma-T-cell ELISPOT assay (an immunolog-

ical test), using CSF mononuclear cells, has demonstrated

an accurate rapid test in HIV-infected patients with tuber-

culous meningitis [39]. Lipoarabinomannan is a glycolipid

forming part of the M. tuberculosis cell wall. The lipo-

arabinomannan antigen-detection test in serum or cere-

brospinal fluid is a rapid and relatively simple assay.

A recent South African study evaluating the cerebrospinal

fluid lipoarabinomannan antigen has reported sensitivity

and specificity of 64 and 69%, respectively, for serum and

cerebrospinal fluid [40].

The microscopic observation drug susceptibility

(MODS) assay is a low-cost liquid mycobacterial culture

technique. In HIV-infected patients, the MODS assay

detected M. tuberculosis with greater sensitivity and speed

and ruled out tuberculosis more quickly and with fewer

indeterminate culture results in comparison to that of the

Lowenstein–Jensen culture [41].

Chest radiography

The presence of pulmonary tuberculosis in a chest radio-

graph often helps in diagnosing tuberculous meningitis.

The chest radiograph is abnormal in up to 46% of HIV-

positive patients with tuberculous meningitis [26]. Patients

with HIV infection and pulmonary tuberculosis may pres-

ent with an atypical chest radiograph. In patients with low

CD4 cell counts, a primary tuberculosis-like pattern, with

diffuse interstitial or miliary infiltrates, little or no cavita-

tion, and intrathoracic lymphadenopathy, is more common.

Lobar infiltrates with or without hilar adenopathy or diffuse

infiltrates resembling the interstitial pattern of Pneumo-

cystis jirovecii pneumonia may also be seen.

Neuroimaging

The dominant neuroradiologic findings in tuberculous

meningitis include basal meningeal enhancement, hydro-

cephalus, tuberculoma, and infarctions in the brain paren-

chyma. The influence of HIV infection on intracranial

imaging of tuberculous meningitis has been extensively

investigated, and the findings suggested that basal menin-

geal enhancement and hydrocephalus on computed

tomography of the brain were less common in HIV-infec-

ted patients [25, 31]. HIV-infected individuals were also

more likely to present with cerebral infarcts and mass

lesions [35]. Infarcts were more commonly located in the

cortex in HIV-infected patients and basal ganglia in HIV-

uninfected patients [25]. (Figs. 1, 2, and 3).

Differential diagnosis

In HIV-infected patients, a variety of central nervous sys-

tem opportunistic infections and malignancies need to be

considered as a differential diagnosis of tuberculous men-

ingitis. Six features (duration of illness more than 5 days,

presence of headache, cerebrospinal fluid white blood cell

count of \1,000/mm [3], clear appearance, lymphocyte

count[30% and protein content of[100 mg/dL) favor the

diagnosis of tuberculous meningitis [1].

Cryptococcal meningitis is the most important differ-

ential diagnosis. It generally occurs in patients with very

low CD4 T cell counts (\100/lL). In cryptococcal men-

ingitis, headache is often the most dominant and sometimes

may be the sole manifestation. In cryptococcal meningitis,

meningeal signs may not be demonstrable. Neuroimaging

evaluation is often normal. The cerebrospinal fluid exam-

ination may be normal in 16% of patients [37]. The diag-

nosis of cryptococcal meningitis is made by identification

of fungus in cerebrospinal fluid by India ink preparation.

Other fungi that may rarely cause meningitis in patients

with HIV infection are Coccidiodes immitis and Histo-

plasma capsulatum. Acute aseptic meningitis may develop

Fig. 1 Contrast enhanced computed tomography showing basal

exudates, meningeal enhancement and ventricular dilatation in a

HIV-infected patient with tuberculous meningitis

J Neurol (2011) 258:3–13 7

123

at the time of seroconversion. The clinical manifestations

are similar to other viral meningitis, with fever, headache,

stiff neck, photophobia, and cranial nerve palsies.

Patients with toxoplasmosis can also present with dif-

fuse meningoencephalitis. Toxoplasmosis is a common late

complication of HIV infection, usually occuring in patients

with CD4 T cell counts \200/lL. Progressive multifocal

leukoencephalopathy and primary central nervous system

lymphoma are other conditions which may present with

headache, confusion, and focal deficits mimicking chronic

meningitis. All these conditions produce focal lesions of

the brain and can be diagnosed on the basis of character-

istic neuroimaging findings.

Treatment

In patients with tuberculous meningitis, antituberculosis

treatment should be started as quickly as possible. The

basic principles, which are applicable for the treatment of

pulmonary tuberculosis, remain the same for the treatment

of tuberculous meningitis [42].

The standard antituberculosis treatment regimens are

equally efficacious in HIV-negative and HIV-positive

patients with tuberculous meningitis. Hence, in HIV-infec-

ted patients there is no need to alter the choice or duration of

anti-tuberculosis treatment [42]. The recommended duration

of treatment for tuberculous meningitis is at least

9–12 months. The usual treatment consists of an initial

phase of isoniazid, a rifamycin, pyrazinamide, and etham-

butol for the first 2 months. This is followed by a continu-

ation phase of isoniazid and a rifamycin for 7–9 months.

World Health Organization guidelines suggest that in

patients with tuberculous meningitis, ethambutol should

preferably be replaced by streptomycin [42], as ethambutol

has the potential to cause vision impairment. Tuberculosis

patients with positive HIV status and all tuberculosis

patients living in HIV-prevalent settings should receive

daily antituberculosis treatment [43]. The incidence of

relapse and failure among HIV-positive pulmonary tuber-

culosis patients who are treated with intermittent antitu-

berculosis treatment may be 2–3 times higher than that in

patients who received a daily intensive phase [42].

Fig. 2 Gadolinium enhanced cranial magnetic resonance imaging

showing a tuberculoma in the pontine region of the brain

Fig. 3 Cranial magnetic resonance imaging (T2-weighted, FLAIR, and diffusion weighted images) shows an infarct in the left perisylvian region

8 J Neurol (2011) 258:3–13

123

Role of corticosteroids

The exact benefit of corticosteroids in HIV-infected

patients with tuberculous meningitis is uncertain. A study

conducted on 545 Vietnamese adults (which also included

98 HIV-infected patients) found a non-significant reduction

in death and severe disability in dexamethasone-treated

HIV-infected patients with tuberculous meningitis [44].

Still, the British Infectious Diseases Society guidelines

suggest that concomitant corticosteroids should be given

[45]. Corticosteroids may also be of possible value in the

management of tuberculous meningitis secondary to

tuberculosis associated immune reconstitution inflamma-

tory syndrome [46].

Co-administration of antituberculosis

and antiretroviral therapy

The World Health Organization treatment guidelines rec-

ommend early antiretroviral treatment for all HIV-infected

individuals with active tuberculosis irrespective of CD4

cell count [41]. The first-line anti-retroviral therapy regi-

men should contain two nucleoside reverse transcriptase

inhibitors plus one non-nucleoside reverse transcriptase

inhibitor [42]. Efavirenz is a preferred non-nucleoside

reverse transcriptase inhibitor for tuberculosis HIV co-

infected patients [47].

Antiretroviral therapy has been reported to reduce

tuberculosis rates by up to 90% at an individual level, by

60% at a population level, and to reduce tuberculosis

recurrence rates by 50% [42, 48]. Initiation of antiretroviral

treatment in patients with HIV/tuberculosis co-infection, if

accompanied by high levels of coverage and drug com-

pliance, reduces the number of tuberculosis cases, mortal-

ity rates, and tuberculosis transmission [49].

Four important considerations are relevant for antitu-

berculosis treatment in HIV-infected patients: timing of

antiretroviral therapy initiation, drug interactions between

antiretroviral therapy and rifamycins, an increased fre-

quency of paradoxical reactions, and development of drug-

resistant tuberculosis.

Timing of anti-retroviral therapy initiation

It is uncertain whether antiretroviral therapy should be

started with antituberculosis therapy or after a delay.

Simultaneous initiation of antituberculosis therapy and

anti-retroviral therapy may lead to unwanted drug inter-

actions and toxicities. Some authors suggest that anti-ret-

roviral treatment may be delayed for those with higher

CD4 counts, but should not be delayed in those with severe

immune suppression (CD4 count\100 cells/lL) [50]. The

Center for Disease Control and Prevention recommends

that for patients with a CD4 count \100 cells/lL, antiret-

roviral therapy should be started after more than 2 weeks

of antituberculosis treatment [51]. Delay in initiating

antiretroviral therapy is associated with serious risk of

other opportunistic infections. The recent SAPiT trial

(starting antiretroviral therapy in tuberculosis) from South

Africa found that mortality among people co-infected with

HIV and tuberculosis could be halved if antiretroviral

therapy was initiated either within 4 weeks of starting

antituberculosis treatment or within 4 weeks of completing

the intensive phase of antituberculosis therapy [52].

According to the World Health Organization recom-

mendations, antituberculosis treatment should be started

first, followed by antiretroviral therapy as soon as possible

after starting antituberculosis treatment, preferably within

the first 8 weeks of starting tuberculosis treatment [42].

Co-trimoxazole preventive therapy

In all HIV-positive tuberculosis patients, co-trimoxazole

preventive therapy should be initiated as soon as possible

and given throughout the course of antituberculosis treat-

ment. Co-trimoxazole therapy substantially reduces mor-

tality in HIV-positive tuberculosis patients. The exact

mode of activity is not clear but co-trimoxazole is known to

have preventive impact on Pneumocystis jirovecii, malaria,

toxoplasmosis, and on several other bacterial infections

[42].

Drug interactions between antiretroviral therapy

and rifamycins

Concomitant use of rifampicin and antiretroviral drugs is

likely to be complicated by drug-to-drug interactions.

These drug interactions can result in subtherapeutic anti-

retroviral drug concentrations, loss of antiviral efficacy,

and the development of viral resistance [43].

Rifampicin, a potent enzyme inducer of the cytochrome

P450 system, may lower serum levels of many HIV pro-

tease inhibitors and some nonnucleoside reverse trans-

criptase inhibitors. The World Health Organization

recommends that first-line antiretroviral therapy regimens

for tuberculosis patients are those that contain efavirenz,

since interactions of efavirenz with antituberculosis drugs

are minimal [42].

Rifabutin is a rifamycin with significantly less induction

of P450 enzymes. Therefore, rifabutin has less effect on the

serum concentrations of antiretroviral agents. In individu-

als who need antituberculosis treatment and who require an

J Neurol (2011) 258:3–13 9

123

antiretroviral therapy containing a boosted protease inhib-

itor, a rifabutin-based antituberculosis treatment is recom-

mended [42].

Immune reconstitution inflammatory syndrome

and tuberculous meningitis

The immune reconstitution inflammatory syndrome is an

important complication of antiretroviral therapy, espe-

cially in patients with tuberculosis. There are two forms

(paradoxical and unmasking) of tuberculous immune

reconstitution inflammatory syndrome. The ‘paradoxical’

type is characterized by clinical worsening of a patient on

tuberculosis treatment, and the ‘unmasking’ type is

characterized by undiagnosed tuberculosis becoming

apparent after starting antiretroviral therapy [53]. Immune

reconstitution inflammatory syndrome associated with M.

tuberculosis is common in high tuberculosis-prevalent

areas, occurring in approximately 11–36% cases. Risk

factors for immune reconstitution inflammatory syndrome

include a high pathogen load and very low CD4 T-cell

count (\50 cells/lL) when anti-retroviral therapy is ini-

tiated [54].

Paradoxical neurologic tuberculosis-associated immune

reconstitution inflammatory syndrome accounts for

approximately 12% of all paradoxical tuberculosis-associ-

ated immune reconstitution inflammatory syndrome cases

[45]. Dominant manifestations, in addition to tuberculous

meningitis, were intracranial tuberculoma and tuberculous

radiculo-myelopathy [45, 55]. Neuroimaging revealed that

in patients with meningitis, meningeal enhancement and

hydrocephalus were infrequent [55].

Paradoxical tuberculous reactions should not be labeled

as a new or resistant infection. Differential diagnoses

include failure of antituberculosis treatment because of

drug resistance or suboptimal antituberculosis drug con-

centrations, drug reactions, and alternative opportunistic

conditions such as toxoplasma and cryptococcal

meningitis.

Drug-resistant tuberculous meningitis in HIV-positive

patients

Multidrug-resistant tuberculosis is caused by bacteria that

are resistant to at least isoniazid and rifampicin. It has been

estimated that 440,000 people had multidrug-resistant

tuberculosis worldwide in 2008 and that one-third of them

died [56]. Drug-resistant tuberculosis is a major public

health concern in European countries as well. The esti-

mated number of multidrug-resistant tuberculosis cases in

Europe in 2008 is approximately 81,000. Eastern European

countries have the highest rates of multidrug-resistant

tuberculosis in the world. HIV-positive tuberculosis

patients are at higher risk of harboring multidrug-resistant

tuberculosis strains. Tuberculosis patients living with HIV

in Eastern European countries are at a high risk of har-

boring multidrug-resistant tuberculosis strains [57].

Drug-resistant tuberculous meningitis has frequently

been reported in patients with HIV infection. For example,

out of 90 HIV-infected Brazilian patients with tuberculous

meningitis, 7% had primary resistance to isoniazid and 9%

to multidrug-resistant strains [27]. Authors from South

Africa reported drug resistance to at least isoniazid and

rifampicin in 8.6% of their patients with tuberculous

meningitis. Sixty percent of them were HIV-positive. In

this study, during the period of 1999–2002, 350 patients

with tuberculous meningitis were identified by cerebro-

spinal fluid culture for M. tuberculosis [58]. In the Viet-

namese study, drug resistance to one or more first-line

drugs was found in 54.3% and multi-drug resistance in

8.7% of HIV-positive tuberculous meningitis patients. All

patients with multidrug-resistant tuberculous meningitis

died, but streptomycin and/or isoniazid resistance were not

associated with mortality [34]. In Argentina, multidrug-

resistance was observed in 41.6% isolates from HIV-

infected patients with tuberculous meningitis. In this

investigation, 42 out of 101 isolates were multidrug-resis-

tant strains. Ten isolates had isolated resistance to single

antituberculosis drugs. Because of multidrug-resistant

strains, tuberculous meningitis was more frequent in

patients who received irregular antituberculosis treatment

[59, 60]. Patients with multidrug-resistant tuberculous

meningitis and HIV-infection have lower cure rates and

higher mortality rates than patients with drug-susceptible

tuberculous meningitis, and most patients die within

3 months [26, 61].

In addition to drug resistance, several other mecha-

nisms may also be responsible for treatment failure in

HIV-infected patients with tuberculosis. It has been

observed that HIV-infected individuals had significantly

low peak serum rifampicin and isoniazid concentration

compared to HIV-uninfected individuals [62]. The per-

cent of rifampicin dose excreted in the urine positively

correlated with CD4 count, indicating greater malab-

sorption in patients with more advanced HIV disease

[63]. The patients with advanced HIV disease (CD4 T

cell counts \100/lL) are more prone to treatment failure

and relapse with rifampicin-resistant organisms when

treated with ‘‘highly intermittent’’ (for example, once- or

twice-weekly) rifampin or rifabutin-containing regimens

[64].

Current treatment guidelines recommend that an anti-

tuberculosis treatment regimen for multidrug-resistant

tuberculosis should include at least five drugs during the

10 J Neurol (2011) 258:3–13

123

intensive phase. Treatment regimen should include drugs

that a patient has not received before and to which the

bacilli are susceptible. The regimen should also include an

injectable medication. Appropriate second-line drugs, those

that produce significant concentrations in the cerebrospinal

fluid (ethionamide, cycloserine, and fluoroquinolones),

should be included. In five drug regimens, one of the

antituberculosis drugs should be fluoroquinolones. The

initial phase of 6 months should be followed by a contin-

uation phase of 12–18 months [58].

Adverse drug reactions

Adverse drug reactions are more common among HIV-

infected patients than among HIV-uninfected patients

being treated for tuberculosis. Risk of drug reaction

increases with declining CD4 cell counts. The antituber-

culosis drugs and first-line antiretroviral drugs have many

common side effects, such as skin rashes, gastrointestinal

intolerance, hepatoxicity, central nervous system symp-

toms, peripheral neuropathy, and blood dyscrasias [65].

Most reactions occur in the first two months of treatment.

Skin rash is the most common reaction, and fever often

precedes and accompanies a rash. Mucous membrane

involvement is common. Severe skin reactions, which may

be fatal, include exfoliative dermatitis, Stevens–Johnson

syndrome, and toxic epidermal necrolysis. Rifampicin-

associated anaphylactic shock and thrombocytopenia have

also been reported [46].

Prognosis

There are conflicting reports available about the effect of

HIV infection on the outcome of tuberculous meningitis.

Some authors observed no significant impact of HIV

infection on the mortality due to tuberculous meningitis

[35, 66], whereas others have reported higher mortality

rates in HIV-infected tuberculous meningitis patients [25,

26]. Two Vietnamese studies reported mortality rates of 65

and 67% in HIV-infected patients with tuberculous men-

ingitis, in contrast to approximately 28% deaths in HIV-

uninfected patients [26, 34]. Advanced stage of tuberculous

meningitis, low serum sodium, and decreased cerebrospinal

fluid lymphocyte percentage were associated with

increased risk of death [34]. A CD4 T-cell count less than

50 cells/lL, infection caused by multidrug-resistant strains,

altered sensorium and hemiplegia were also found to be

associated with poor prognosis [25, 61]. Asignificantly

higher number of treatment failures in the HIV-infected

group suggests that HIV infection may influence the

response to treatment [67].

Prevention

Bacillus Calmette-Guerin (BCG) vaccination is effective in

preventing childhood tuberculous meningitis and miliary

tuberculosis. Unfortunately, BCG vaccination in HIV-

uninfected children is associated with disseminated BCG

infection and deaths. The risk of disseminated BCG disease

increased several hundred times in HIV-infected infants

compared to HIV-uninfected infants. The World Health

Organization does not recommend BCG vaccination for

children with symptomatic HIV infection [68].

According to a recent systematic review, treatment of

latent tuberculosis infection reduces the risk of active

tuberculosis in HIV-positive individuals [69]. HIV-infected

patients who have been exposed to an infectious tubercu-

losis patient should also receive isoniazid preventive ther-

apy regardless of the Mantoux test result. A 9-month

course of isoniazid at a daily dose of 5 mg/kg (up to

300 mg/day) reduces the risk of active tuberculosis in

infected people by up to 90%. The protective effect is

believed to be life-long in the absence of re-infection. The

World Health Organization recommends a 3Is policy

(intensified tuberculosis case finding, infection control, and

isoniazid preventive therapy) for prevention of HIV-asso-

ciated tuberculosis [5]. Several tuberculosis vaccines are

entering into field trials and have shown promise for the

future [70].

Conclusion

Tuberculous meningitis is a serious life-threatening dis-

ease, especially in HIV-infected persons. Infection by

multidrug-resistant strains poses a major challenge for the

clinician, as it is an important predictor of mortality. To

fight this deadly combination, clinicians should be aware of

the pathogenesis of infection and disease, rapid diagnosis

and identification of resistant strains, optimal regimens of

antituberculosis treatment and adjunctive corticosteroids,

and the optimal time to initiate antiretroviral therapy.

Currently, the 3Is policy remains the best way to fight this

menace.

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