11

EXTRAPULMONARY TUBERCULOSIS: MANAGEMENT AND CONTROL

11

CHAPTER

Extrapulmonary Tuberculosis:
Management and Control
I

Fraser Wares, R. Balasubramanian, A. Mohan, S.K.Sharma

Introduction
The goal of the RNTCP is to decrease mortality and morbidity due to TB, and to interrupt
the chain of transmission so that TB is no longer a major public health problem in India1.
To achieve this goal, the RNTCP has two objectives: to cure at least 85 percent of the new
smear-positive pulmonary TB (PTB) cases registered for treatment; and to detect at least
70 percent of the estimated new smear-positive pulmonary TB cases existing in the
community once the first objective has been reached2,3. Although the highest priority under
the RNTCP is thus given to the new sputum smear-positive PTB cases, all types of TB are
treated under the programme.
The clinical manifestations of TB are of two types: Pulmonary and Extrapulmonary
forms of TB (EPTB), the former being the commonest. In EPTB highly vascular areas such
as lymph nodes, meninges, kidney, spine and growing ends of the bones are commonly
affected. The other sites are pleura, pericardium, peritoneum, liver, gastro-intestinal tract,
genito-urinary tract and skin.
The definition of EPTB disease under the RNTCP follows the international classification4.
EPTB is defined as TB of organs other than the lungs, such as pleura, lymph nodes, abdomen,
genito-urinary tract, skin, joints, bones, tubercular meningitis, tuberculoma of the brain,
etc2,3. Diagnosis is based on one culture-positive specimen from the extrapulmonary site;
or histological evidence; or strong clinical evidence consistent with active EPTB disease
followed by a medical officers decision to treat with a full course of anti-TB therapy.
Patients suspected of having EPTB should also have their sputum examined for AFB if
they have chest symptoms, irrespective of the duration of these symptoms. A patient
diagnosed with both pulmonary and EPTB is classified as a case of pulmonary TB.
The problem of EPTB is still high, both in developing and developed countries. In
India, EPTB forms 10 to 15 percent of all types of TB, in comparison to 25 percent in
France and 50 percent in Canada, partly due to the dual infection of TB with human
immunodeficiency virus (HIV)5,6. Since 1987, EPTB has been accepted as an AIDS defining
disease7. Lymph node TB (LNTB) is the commonest form of EPTB. Most studies in
peripheral LNTB have described a female preponderance, while pulmonary TB is more
common in adult males8. In the era before the HIV pandemic, and in studies involving
immunocompetent adults, it was observed that EPTB constituted about 15 to 20 percent of
95

TUBERCULOSIS CONTROL IN INDIA I

all cases of TB in general practice. HIV infected persons are at markedly increased risk for
primary or reactivation TB and for second episodes of TB from exogenous re-infection. In
some settings, EPTB can account for up to 53 to 62 percent of cases of TB in HIV-positive
individuals9-12.

Diagnosis and Treatment of EPTB under the RNTCP

EPTB cases are diagnosed by attending physicians, and if required, referred to the District
TB Centre, Chest Clinic or the Medical Officer-TB Control for investigations.All
investigative procedures undertaken to arrive at the diagnosis of EPTB should be entered
in the patients RNTCP Treatment Card.
The treatment of extrapulmonary TB follows standard RNTCP treatment guidelines
depending on categorisation, and is consistent with international recommendations by WHO
and the International Union Against Tuberculosis and Lung Disease (IUATLD) 4,13.
Categorisation is done according to history, and clinical and diagnostic criteria. All RNTCP
regimens are given thrice weekly, and Rifampicin-containing regimens given for six to
eight months. If patients are seriously ill with extrapulmonary TB, they are treated with the
RNTCP Category I regimen consisting of, initially, two months Isoniazid (H), Rifampicin
(R), Pyrazinamide (Z) and Ethambutol (E) given thrice a week, with each dose given under
the direct observation of a DOT Provider (Table 1). This two-month intensive phase is
Category of Treatment

Type of Patient

Regimen*

Category I

New sputum smear-positive pulmonary TB (PTB)

Seriously ill** new sputum smear-negative PTB
Seriously ill** new EPTB

2H3R3Z3E3 + 4H3R3

Category II

Sputum smear-positive relapse

Sputum smear-positive failure
Sputum smear-positive treatment after default
Others***

2S3H3R3Z3E3+1H3R3Z3E3+
5H3R3E3

Category III

New sputum smear-negative PTB

New EPTB, not seriously ill

2H3R3Z3+4H3R3

*The number before the letters refers to the number of months of treatment. The subscript after the letters refers to
the number of doses per week. The dosage strengths are as follows: H: Isoniazid (600 mg), R: Rifampicin (450
mg), Z: Pyrazinamide (1500 mg), E: Ethambutol (1200 mg), S: Streptomycin (750 mg). Patients who weigh 60 kg
or more receive additional Rifampicin 150 gm. Patients who are more than 50 years old recieve Streptomycin 500
mg. Patients who weigh less than 30 kg receive drugs per body weight. Patients in Categories I and II who have a
positive sputum smear at the end of the initial intensive phase receive an additional month of intensive phase
treatement.
**Seriously ill includes any patient, pulmonary or extra-pulmonary, who is HIV positive and declares his serostatus to the categorising/treating medical officer. For the purpose of categorisation, HIV testing should not be
done.
***In rare and exceptional cases, patients who are sputum smear-positive or who have extra-pulmonary disease
can have relapse or failure. The diagnosis in all such cases should be made by the MO and should be supported
by culture or histological evidence of current active TB. In these cases, the patient should be categorised as
Others and given Category II treatment.
Table 1

RNTCP treatment categories and regimens

96

11

EXTRAPULMONARY TUBERCULOSIS: MANAGEMENT AND CONTROL

followed by a four-month continuation phase of Isoniazid and Rifampicin, given thrice a

week, with at least the first of the thrice-weekly doses given under the direct observation of
the DOT Provider. In patients with TB meningitis (TBM), Streptomycin is given instead of
Ethambutol. In addition, the continuation phase of treatment in TBM should be given for
six to seven months, extending the total duration of treatment to eight-nine months.
Steroids should be used initially in hospitalised cases of TBM and TB pericarditis, and
reduced gradually over six to eight weeks. If patients are not seriously ill with
extrapulmonary TB, they are treated with the RNTCP Category III regimen consisting of,
initially, two months Isoniazid, Rifampicin and Pyrazinamide given thrice a week, with
each dose given under the direct observation of a DOT Provider. As in the Category I
regimen, the two-month Category III intensive phase is followed by a four-month
continuation phase of Isoniazid and Rifampicin, given thrice a week, with at least the first
of the thrice-weekly doses
given under the direct
Seriously ill
Not seriously ill
observation of the DOT
Provider.
G TB meningitis
G Lymph node TB
Whether the EPTB is
classified as seriously ill or
not seriously ill is dependent
on the site of the disease. For
example, TB meningitis is
classified as seriously ill and
would be treated with a
RNTCP Category I regimen.
Lymph node TB, however, is
classified as not seriously ill
and will be treated with a
Category III regimen (Table 2).

Disseminated TB

Pleural effusion (unilateral)

TB pericarditis

Bone (excluding spine)

TB peritonitis & intestinal TB

Peripheral joint(s)

Bilateral or extensive pleurisy

Spinal TB with neurological

complications

Genito-urinary tract

Table 2

RNTCP classification of extrapulmonary TB

Review of Case Finding, Diagnostic Practices and Treatment Outcomes

of EPTB Cases in the RNTCP
In 2002, the Central TB Division (CTD), Directorate General of Health Services, Ministry
of Health and Family Welfare, Government of India, undertook a review of case management
of EPTB patients under the RNTCP. The aims of the review were:
G

To provide an overview of case finding patterns for a one-year period of extrapulmonary

TB cases under RNTCP nationally and in 16 selected districts;

To provide an overview of diagnostic practices amongst extrapulmonary TB cases

registered under the RNTCP in 16 selected districts;

To provide an overview of treatment outcomes of extrapulmonary TB cases under the

RNTCP nationally and in 16 selected districts; and

To identify the challenges faced by the RNTCP with regard to extrapulmonary TB cases.

Data were collected from both national and district levels. The national data came from
the central level EpiCentre dataset of the RNTCP held by the CTD. This central-level
dataset contains the routine quarterly report data that is submitted from all districts that are
97

TUBERCULOSIS CONTROL IN INDIA I

implementing the RNTCP14. Data were collected and analysed for a period of one year
from July 1, 2000 to June 30, 2001 (i.e. from Quarter 3, 2000 to Quarter 2, 2001). Data
available from this routine dataset included a total of different TB types, the gender of the
patient, treatment category and treatment outcomes (Table 3).
District-level data came from 16 conveniently sampled districts with a combined
population of 32.6 million (Figure 1), out of the 124 districts implementing RNTCP on
July 1, 2000. Criteria for selection were that the: district had to be implementing RNTCP
on July 1, 2000 (i.e. at the start of Q3, 2000); the percentage of extrapulmonary TB cases
National

16 Districts

Total new cases

290,005

33,999

New smear positive PTB

140,279

17,017

New smear negative PTB

109,530

14,166

Extrapulmonary TB

40,196 (13.9 percent)

2,816 (8.3 percent)

Treatment Category III

33,563 (83.5 percent)

2,467 (88 percent)

Male : Female

46.8 percent : 53.2 percent

49 percent : 51 percent

Treatment complete

36,337 (91 percent)

2,553 (90.9 percent)

Died

814 (2 percent)

43 (1.5 percent)

Default

2,541 (6.4 percent)

206 (7.3 percent)

EPTB treatment outcome

Table 3

RNTCP case finding, Q3 2000 -Q2 2001. Source: RNTCP central dataset

State

Figure 1 Study districts (n=16)

98

Districts

Haryana

Sonipat

Gujarat

Dohad, Mahesana

Karnataka

Raichur

Rajasthan

Dausa, Sikar, Nagaur,

Alwar, Ajmer, Sawai
Madhepur

Orissa

Jharsuguda

West Bengal

Murshidabad, Malda

Madhya Pradesh

Rajgarh

Himachal
Pradesh

Solan

Maharashtra

Raigarh

11

EXTRAPULMONARY TUBERCULOSIS: MANAGEMENT AND CONTROL

amongst new cases was not outside a range of 5-20 percent; and the district had to be
electronically connected. Data were collected and analysed for a period of one year from
July 1, 2000 to June 30, 2001 (i.e. from Quarter 3, 2000 to Quarter 2, 2001). The analyses
included the data available from the central-level EpiCentre dataset and that collected via
a questionnaire sent by e-mail to the selected 16 districts. Information for the questionnaire
was gathered from the RNTCP Patient Treatment Cards of extrapulmonary TB cases
registered under the RNTCP during the study period and from the RNTCP TB Register.
Additional data available from the questionnaire included diagnostic and treatment outcome
details by site of extrapulmonary TB (Tables 4 to 8).
Results showed that EPTB cases comprised between 8.3 percent (16 districts) and 13.9
Site

Total

Percent

Lymph node

1630

57.3

Pleural effusion

624

21.9

Bone

253

8.9

Abdominal

202

7.1

Others

134

4.7

Skin, eyes etc

42

1.5

TB meningitis

39

1.4

Renal/GUT

33

1.2

Miliary

12

0.4

Pericarditis

0.2

Tuberculoma

<0.1

Table 4

Extrapulmonary TB case finding by disease site in the 16 districts,

Q3 2000-Q2 2001 (n=2843)

Diagnostic examination

Total

Facility where test performed

Clinical gro0unds alone

696

Government Health Facility (GHF)

Government Medical College (GMC)
Private Health Facility (PHF)

595
25
4

After antibiotic trial

GMC

341
2

GHF
Fine Needle Aspiration Cytology
and AFB smear
GHF
GMC
PHF

202

GHF
GMC
PHF

51
16
183

LN biopsy, AFB smear and histology

Table 5

252

418
59
119
218

Diagnostic practices in cases of lymph node TB (n=1630)*

* Not all patients had all the relevant information recorded in their RNTCP Treatment Cards. In addition, some patients had more than one of the above
diagnostic examinations performed. Hence the totals presented in the tables do not equal the total number of cases (n).

99

TUBERCULOSIS CONTROL IN INDIA I

Diagnostic examination

Total

Facility where test performed

Clinical grounds alone

10

GHF

Chest X-ray

610

GHF

272

GMC

78

PHF

249

Pleural aspirate, AFB smear,

total lymphocyte count and differential,
and biochemistry

153

GHF
GMC
PHF

55
7
65

Pleural biopsy and histology

PHF

Table 6

Diagnostic practices in cases of pleural effusion TB (n=624)*

Diagnostic examination

Total

Facility where test performed

Clinical grounds alone

19

GHF
PHF

16
1

X-ray

224

GHF
GMC
PHF

82
22
112

Tissue and / or synovial biopsy,

and histology

17

GHF
GMC
PHF

4
3
10

Table 7

Diagnostic practices in cases of bone/joint(s) TB (n=253)*

Site

Treatment
complete

Died

Treatment
failure

Default

Transfer Out

Total

Lymph node

1498 (93)

103 (6.4)

1611

Pleural effusion

549 (89.6)

19

45 (7.3)

61

Bone / joint(s)

220 (88)

29 (11.6)

250

Abdominal

174 (86.1)

12

15 (7.4)

202

Other

109 (82)

18 (13.5)

133

All sites

2550 (90.8)

44 (1.6)

1 (0)

210 (7.5)

4 (0.1)

2809

Table 8

Treatment outcomes of Category I and III EPTB cases by site (n=2809)

* Not all patients had all the relevant information recorded in their RNTCP Treatment Cards. In addition, some patients had more than one of the above
diagnostic examinations performed. Hence the totals presented in the tables do not equal the total number of cases (n).

percent (national) of new cases registered under the RNTCP during the study period (Table
3). Overall 83.5 to 88 percent were treated with the Category III regimen and male (M) to
female (F) ratio was roughly 1:1, compared with a 2.3 male to 1 female ratio for PTB cases.
Paediatric cases (0-14 years) comprised almost 15 percent (n=412) of the EPTB cases in
the 16 districts. In these districts, lymph node (LN) TB comprised 57 percent of all the
EPTB cases (1M : 1.4F), pleural effusion (PE) 22 percent (2M : 1F), and bone/joint(s) 9
100

11

EXTRAPULMONARY TUBERCULOSIS: MANAGEMENT AND CONTROL

percent (1M : 1F) (Table 4). Amongst the paediatric EPTB cases, LN TB made up almost
80 percent of the cases (324/412), with PE contributing about 8 percent (31/412) and bone/
joint(s) 7 percent (27/412).
Overall 28 percent of EPTB cases in the 16 districts were diagnosed on clinical grounds
alone, with no confirmatory laboratory or radiological examination being performed. In
lymph node TB cases, 43 percent were diagnosed on clinical grounds alone, with almost
identical figures seen for paediatric and adult cases separately (Table 5). Of those lymph
node cases that did have a confirmatory laboratory examination performed, including fine
needle aspirate (FNAC) and smear, and lymph node biopsy with smear and histology, 62
percent (401/646) had the test performed in a private health facility (Table 5). Twenty-one
percent (135) had the tests performed in a government medical college and 17 percent
(110) in a government health facility.
In contrast, over 97 percent of the pleural effusion patients had had at least one chest xray performed (Table 6). Similarly 88 percent of bone/joint(s) cases had had at least one xray performed (Table 7). However 16 percent of abdominal TB cases had had no confirmatory
laboratory or radiological examination being performed prior to diagnosis and treatment
(data not shown). As seen in the lymph node TB cases, a significant proportion of the
laboratory or radiological examinations that were performed in these patients, were done
in private health facilities.
Overall 91 percent of EPTB patients under the RNTCP completed their treatment both
at the national and the study districts levels (Tables 3 and 8), while 1.5-2 percent of patients
died and 6-8 percent defaulted from treatment. Treatment completion rates ranged from
82-93 percent amongst lymph node, pleural effusion, bone/joint(s) and other cases, with
no difference between the genders (Table 8). Default was the major problem, especially in
bone/joint(s) (11.6 percent) and other sites (13.5 percent).
It can thus be concluded that EPTB cases form a significant proportion (8-14 percent)
of the RNTCPs new case load. Amongst the EPTB cases, lymph node TB predominate
(>60 percent). Overall there were almost equal numbers of female and male cases, compared
with PTB where males outnumber females at least two-fold consistently. However, only
amongst lymph node cases did females actually outnumber male cases (1.4 to 1), whereas
in pleural effusion cases males outnumbered female cases 2 to 1.
Overall, 28 percent of cases were diagnosed on clinical grounds alone with no
confirmatory laboratory or radiological examination being performed. This rose to 43 percent
amongst the LNTB cases. The private sector performed a significant proportion of the
confirmatory laboratory or radiological examinations being done.
Treatment completion rates were high, with 91 percent of cases successfully completing
their treatment. The main problem was default (overall 6-7 percent), especially in bone/
joint(s) (11.6 percent) and other sites (13.5 percent).
The study recommended that despite the encouraging notification levels and high
treatment completion rates seen under the RNTCP for EPTB cases, there is need for a
review of the current diagnostic practices. The formation of an expert committee, to formulate
practical diagnostic algorithms for EPTB suspects under the RNTCP, should be considered.
Once the diagnostic algorithms have been laid out, they should be included in future revisions
of the RNTCP manuals and guidelines, and immediately disseminated to all staff involved
in RNTCP activities. There is an important role for medical colleges in the provision of
101

TUBERCULOSIS CONTROL IN INDIA I

diagnostic facilities for EPTB cases to offset the present reliance on the private sector for
diagnostic services in these cases. Research is needed to answer questions such as why
lymph node TB cases predominate amongst EPTB patients, and why female cases outnumber
male cases amongst lymph node TB cases in India.

Evidence-based Management of EPTB

The major pitfalls in the diagnosis of EPTB are atypical clinical presentations simulating
other inflammatory and neoplastic conditions, resulting in delay or deprivation of treatment.
Therefore a high index of suspicion is necessary to make an early diagnosis.
In developing countries, the lack of diagnostic resources adds to the problems.This
often leads to empirical treatment based on clinical grounds without pathological and/or
bacteriological confirmation, leading to over-diagnosis and unnecessary treatment. This
was shown in a study at TRC, Chennai, where only 34 percent of 373 biopsies done on
clinically diagnosed cases of LNTB, had histopathological confirmation15.
In clinical practice, the cutaneous reaction to PPD is used as an aid to the diagnosis. Its
value as a diagnostic tool is limited in adults in India, since about 40 percent of the adult
population is infected with TB2. However, it may be of use in children aged five years or
below.
The selection of the diagnostic procedures depends on the organ of involvement in
EPTB. Fine needle aspiration of lymph nodes and cytological examination plus AFB smear
and culture examination, appears to be the diagnostic procedure of choice in superficial TB
lymphadenitis16. However, if the FNAC examination results are inconclusive, excision
biopsy may need to be done. Laparoscopy with target peritoneal biopsy is the current
investigation of choice in the diagnosis of peritoneal TB. Direct inspection of yellowish
white miliary tubercles or erythematous patches plus peritoneal adhesions and the
demonstration of acid-fast bacilli or characteristic caseating granulomas in biopsy specimens,
may confirm diagnosis in 80 to 95 percent of patients17.
Quite often, more than one procedure is necessary for the confirmation of diagnosis. By
undertaking relevant diagnostic procedures in different types of abdominal TB patients,
such as laparoscopic biopsy, liver biopsy, barium meal series, bacteriological and
biochemical examination of ascitic fluid, it was possible to establish the diagnosis in 138
(72 percent) of 193 patients in a study conducted by TRC18.
Attempts should always be made to confirm the diagnosis by histopathological and/or
bacteriological examinations. In TRC studies, all biopsy specimens were cultured in multiple
solid and liquid media, namely Lowenstein-Jenson medium with or without pyruvate,
Middlebrook 7H11 medium and Kirschner medium, and the culture positivity rates varied
from 33 to 62 percent in different forms of EPTB19. Since EPTB is essentially a paucibacillary
condition, smear and culture examination of specimens, including biopsy, sputum, urine
and other body fluids like ascitic and pleural fluid, are recommended. It was also observed
that atypical Mycobacteria were not commonly the pathogens leading to EPTB disease.
Even though a number of reports on molecular biological tests such as SAFA, Elisa,
slide agglutination techniques and PCR are available in EPTB, the specificity and sensitivity
of these tests are variable20. The results need to be interpreted in the light of clinical findings.
Smith et al had advocated the use of PCR in clinical specimens as the results were comparable
102

11

EXTRAPULMONARY TUBERCULOSIS: MANAGEMENT AND CONTROL

to that of culture for M. tuberculosis21. It was also reported that the use of Adenosine De
Aminase (ADA) in ascitic fluid was a sensitive and specific marker approaching 100 percent
in the diagnosis of peritoneal TB22. It was recently reported that demonstration of
mycobacterial antigens in tissue specimens discriminate between an active and a resolving
granuloma. This may be more sensitive than finding the bacilli23.
For the purpose of treatment, EPTB can be classified into severe and non-severe forms.
There has been some uncertainty regarding the most appropriate combination of drugs,
duration of chemotherapy and the role of surgery in the treatment of EPTB24. The difficulty
in evolving a clear cut end point in assessing the efficacy of treatment of EPTB led to
varying durations of treatment (6 to 24 months). Several randomised control trials (RCTs)
over the last two decades have established Short-Course Chemotherapy (SCC) as the
standard treatment for sputum positive TB. This has stimulated the research into shorter
regimens for the treatment of EPTB25. EPTB is usually paucibacillary and any treatment
regimen effective in PTB is likely to be effective as well in the treatment of EPTB.
TRC, with its rich experience in the conduct of RCTs, has undertaken several
collaborative studies on EPTB such as spinal TB, Potts paraplegia, TB meningitis, brain
tuberculoma, LNTB and abdominal TB15,18,19,26-31 with the government teaching hospitals of
Chennai. The common objective of these studies was to assess the efficacy of SCC in
EPTB. The results, at the end of treatment and relapses over a varying period of three to 10
years, were assessed systematically. In studies on TB spine and abdominal TB, the role of
surgery was also addressed. Individual reports discuss the diagnostic criteria used, treatment
regimens tried and the outcomes in detail. For all patients, every dose of drugs was
administered under the direct supervision of a staff member at least for the intensive phase
of two months. Patients attended the clinic as out-patients and were hospitalised only if
they were sick.
Evidence of pulmonary TB on x-ray was variable, ranging from 9 to 55 percent. Onethird of abdominal TB patients had a disseminated form of TB. The mantoux induration
was 10 mm or more in 44 to 92 percent of the various forms of EPTB patients.
TRC studies have clearly established the efficacy of short-course treatment (six to nine
months) in both children and adults19. Intermittent regimens have been proven to be as
effective as daily regimens. Table 9 describes the efficacy of treatment regimens in different
forms of EPTB15, 18, 19, 26-30. The overall favourable response varied from 87 to 99 percent in
all forms of EPTB, except in TB meningitis where only one-third of patients responded to
treatment (Table 9).
Lymph nodes can enlarge, persist and become superinfected with bacteria in the course
of TB treatment, which are called paradoxical reactions. Generally, no modification or
prolongation in antituberculosis treatment regimen is indicated15.
Even though treatment gives good results in most forms of EPTB, there are a few
exceptions such as meningitis and spinal TB (Potts disease) in which the outcome greatly
depends on early diagnosis. In tuberculous meningitis, the outcome is related to the stage
of the disease at the time of the start of treatment; only a minority of patients with severe
disease recover completely. Predictors of poor outcome are younger age and advanced
stage, neurological sequelae are directly related to the stage of the disease and the duration
of symptoms prior to admission31,32. Donald et al had reported a mortality rate of 16 percent
and a relapse rate of 2 percent among 95 children diagnosed as tuberculous meningitis
103

TUBERCULOSIS CONTROL IN INDIA I

Studies

Rx. regimen

Duration Nos. of
in months patients

Follow-up
period
months

Overall favourable
response
percent

TB spine**

6HR7+ Modified
Hongkong Surgery

78

120

90

TB meningitis*

6HR7
9HR7

78

120

94

Potts paraplegia**

2HRS7/4HE7S2 /6HE7

79

120

99

2HRZS7/ 10HE7

12

69

24

33

2R2HZS7 /10HE7

12

24

24

29

Radical surgery+

12

70

24

36

2SHER7 / 7HR2

20

60

90

2SHER7 / 7HR2

11

60

73

2SHRZ3 / 4SH2

168

36

97

2HRZ7 / 4HR7

85

60

94

12

93

60

87

3HRZ7 /3HR2

47

24

89

3HRZ3 /6HR2

44

24

91

TB lymphadenitis*

Abdominal TB***

EHS/HE7
Brain Tuberculoma**

Table 9

Study population and the efficacy of treatment regimens

H - Isoniazid R - Rifampicin Z Pyrazinamide E - Ethambutol S Streptomycin

*Only paediatric patients **Both paediatric and adult patients ***Only adult patients

treated with a SCC regimen of Rifampicin, Isoniazid, Pyrazinamide and Ethambutol daily
for six months33. Similarly, in patients with spinal TB, the time taken for neurological
recovery was not related to the type of treatment regimen but appeared to be influenced by
factors such as initial motor power, presence or absence of bed sores and duration of
kyphosis29.
The long-term efficacy of short-course treatment regimens of six to 12 month duration
in various forms of EPTB has shown relapse rates of less than 4 percent2.9
The introduction of SCC for EPTB has made surgery less important. The relative role of
surgery and treatment of patients with spinal TB was investigated by the British Medical
Research Council trials34. Operative procedures were generally shown to be unnecessary
for spinal TB. Ambulatory short-course treatment regimens were highly effective, and
surgery was indicated only in patients aged less than 15 years and having an initial angle of
kyphosis more than 3035. The surgery recommended is anterior and posterior spinal fusion
to reduce kyphosis and improve function of the spine36.
Hepatitis is one of the major adverse reactions necessitating interruption or termination
of drugs. In TRC studies, 39 percent of TB meningitis patients developed jaundice when
Isoniazid 20 mg/kg was given and 16 percent developed it with Izoniazid 12 mg/kg. This
increased to 21 percent when Pyrazinamide was added. However, when Rifampicin was
given twice a week instead of daily, only 5 percent developed hepatitis. Thus hepatitis was
shown to be dose related. It was higher among patients subjected to surgery and anaesthetic
agents (operated spinal TB 18 percent, 12 percent operated Potts paraplegia). In abdominal
104

11

EXTRAPULMONARY TUBERCULOSIS: MANAGEMENT AND CONTROL

TB patients who might have overt involvement of liver, 17 percent developed hepatitis.
Hepatitis was more common with daily therapy with Rifampicin, Isoniazid and Pyrazinamide
and occurred within six weeks of treatment. However, hepatitis was not a problem when
the same drugs were given intermittently. During hepatitis, hepatotoxic drugs like
Rifampicin, Isoniazid and Pyrazinamide should be withheld and substituted with
Streptomycin and Ethambutol. However after recovery from jaundice these drugs can be
resumed, eventfully in the majority of patients.

Clinical Picture and Management of Different Forms of EPTB

Patients with EPTB often present with constitutional symptoms such as fever, loss of
appetite, weight loss, malaise and fatigue. In addition, these patients manifest symptoms
and signs related to the organ system involved.
Lymph Node TB
Lymph Node TB (LNTB) is the commonest form of EPTB. LNTB is considered to be
the local manifestation of a systemic disease. Patients usually present with slowly enlarging
lymph nodes and may otherwise be asymptomatic. In HIV-negative patients, isolated cervical
lymphadenopathy is most often seen in about two-thirds of the patients. In HIV-positive
patients, multifocal involvement, intra-thoracic and intra-abdominal lymphadenopathy and
associated pulmonary disease are more common. Physical examination may be unremarkable
but for palpable lymphadenopathy. Occasionally, a lymph node abscess may burst leading
to a chronic non-healing TB sinus and ulcer formation10.
Pleural Effusion and Empyema Thoracis
TB pleural effusion usually presents as an acute illness and the symptom duration ranges
from a few days to a few weeks. Patients complain of fever, pleuritic chest pain, nonproductive cough and dyspnoea. Patients with TB empyema present with chest pain,
breathlessness, cough with expectoration, fever, and toxaemia. TB empyema may present
as a chest wall mass or draining sinus tract (TB empyema necessitatis)37.
Bone and Joint TB
Skeletal TB is a haematogenous infection and affects almost all bones. TB commonly
affects the spine and hip joint38,39. Other sites include knee joint, foot bones, elbow joint
and hand bones. Rarely, it also affects the shoulder joint. Two basic types of disease patterns
have been observed: granular and exudative (caseous). Though both patterns have been
observed, one form may predominate.
Spinal TB is the most common form of skeletal TB. Constitutional symptoms generally
occur before the symptoms related to the spine manifest. Thoracic and lumbar vertebrae
are the most common sites of involvement followed by middle thoracic and cervical
vertebrae. Usually, two contiguous vertebrae are involved but several vertebrae may be
affected and skip lesions are also seen (Figures 2a and 2b). The infection begins in the
cancellous area of the vertebral body, commonly in the epiphyseal location and less
commonly in the central or anterior area of vertebral body. The infection spreads and
destroys the epiphyseal cortex, the intervertebral disc and the adjacent vertebrae. It may
spread beneath the anterior longitudinal ligament to reach the neighbouring vertebrae. The
vertebral body becomes soft and gets compressed to produce either wedging or total collapse.
105

TUBERCULOSIS CONTROL IN INDIA I

Anterior wedging is commonly seen in the thoracic spine where the normal kyphotic curve
accentuates the pressure on the anterior part of vertebrae.The exudate penetrates the
ligaments and follows the path of least resistance along fascial planes, blood vessels and
nerves, to distant sites from the original bony lesion as a cold abscess. In the cervical
region, the exudate collects behind the prevertebral fascia and may protrude forward as a
retropharyngeal abscess. The abscess may track down to the mediastinum to enter into the
trachea, oesophagus or the pleural cavity. It may spread laterally into the sternomastoid
muscle and form an abscess in the neck.
In the thoracic spine, the exudate may remain confined locally for a long time and may
appear in the radiographs as a fusiform or bulbous paravertebral abscess and may compress
the spinal cord. Rarely, a thoracic cold abscess may follow the intercostal nerve to appear

Figure 2a MRI scan of the dorsolumbar spine, (coronal view, T1 weighted image) showing central
hypointense lesion (arrow) with reduced vertical height of the vertebra and paraspinal cold
abscess
Figure 2b MRI dorsolumbar spine of another patient (sagittal view, T2 weighted image) showing destruction
of D10 and D11 vertebrae reduction in the intervening disc with anterior granulation tissue and
cord compression (arrow)

anywhere along the course of nerve. It can also penetrate the anterior longitudinal ligament
to form a mediastinal abscess or pass downwards through medial arcuate ligament to form
a lumbar abscess. The exudate formed at lumbar vertebrae most commonly enters the psoas
sheath to manifest radiologically as a psoas abscess or clinically as a palpable abscess in
the iliac fossa. The abscess can gravitate beneath the inguinal ligament to appear on the
medial aspect of thigh or spread laterally beneath the iliac fascia to emerge at the iliac crest
near anterior superior iliac spine. Sometimes an abscess forms above the iliac crest
posteriorly. The collection can follow the vessels to form an abscess in Scarpas triangle or
the gluteal region if it follows femoral or gluteal vessels respectively.
A retropharyngeal abscess can present with local pressure effects such as dysphagia,
dyspnoea, or hoarseness of the voice. Further dysphagia may also occur due to a mediastinal
abscess. Flexion deformity of hip can develop due to a psoas abscess. The abscesses may
be visible and palpable if they are superficially located. Therefore, neck, chest wall, groin,
106

11

EXTRAPULMONARY TUBERCULOSIS: MANAGEMENT AND CONTROL

inguinal areas and thighs where cold abscesses occur frequently, must be carefully examined
in addition to the location of a bony lesion.
Paraplegia (Potts paraplegia) is the most serious complication of spinal TB and its
occurrence is reported to be as high as 30 percent in patients with spinal TB. Early onset
paraplegia develops during the active phase of infection. Paraplegia of late onset can appear
many years after the disease has become quiescent even without any evidence of reactivation.
Most commonly, paraplegia develops due to mechanical pressure on the cord, but in a
small number of patients cord dysfunction may occur due to non-mechanical causes.
The clinical presentation of TB of the hip and knee joints depends on the
clinicopathological stage and each stage has a definite pattern of clinical deformity. Pain,
circumferential reduction of movements at the joint are evident. Night cries may develop
due to relaxation of muscle spasm and unguarded movements at the joint. TB osteomyelitis
may mimic chronic osteomyelitis of other causes. Poncets arthritis has been described in
patients with an active TB focus elsewhere40.
Neurological TB
TB Meningitis
TB meningitis (TBM) accounts for 70 to 80 percent of cases of neurological TB40-42. In
the bacteraemic phase of primary lung infection, metastatic foci can become established in
any organ, which can become active after a variable period of clinical latency. Rupture of
a subependymally located tubercle (Rich focus) results in the release of infectious material
into the subarachnoid space. Salient pathological features of TBM include: inflammatory
meningeal exudate; ependymitis; vasculitis; encephalitis; and disturbance of cerebrospinal
fluid (CSF) circulation and absorption.
In the developing world, TBM is still a disease of childhood with the highest incidence
in the first three years of life. The disease usually evolves gradually over two to six weeks.
The prodromal phase lasts for two to three weeks and is characterised by a history of vague
ill-health, apathy, irritability, anorexia and behavioural changes. With the onset of meningitis,
headache and vomiting become evident and fever develops. Focal neurological deficits
and features of raised intracranial tension may precede signs of meningeal irritation. Focal
or generalised seizures are encountered in 20 to 30 percent of patients. Cranial nerve palsies
can occur in 20 to 30 percent of patients, the sixth nerve involvement being the most
common. Complete or partial loss of vision is a major complication of TBM. In untreated
cases, progressive deterioration in the level of consciousness, pupillary abnormalities and
pyramidal signs may develop due to increasing hydrocephalus and tentorial herniation.
The terminal illness is characterised by deep coma and decerebrate or decorticate posturing.
Without treatment, death usually occurs in five to eight weeks.
Atypical presentations include acute meningitic syndrome simulating pyogenic
meningitis, progressive dementia, status epilepticus, psychosis, stroke syndrome, lockedin-state, trigeminal neuralgia, infantile spasm and movement disorders.
Tuberculomas
Intracranial tuberculomas in patients under the age of 20 are usually infratentorial, but
supratentorial lesions predominate in adults. Solitary tuberculomas are more frequent than
multiple lesions. Tuberculomas still constitute about 5 to 10 percent of intracranial space
occupying lesions in the developing world. Patients with epilepsy who showed ring
107

TUBERCULOSIS CONTROL IN INDIA I

enhancing single CT lesions have

been described from India (Figure
3). TB has been implicated as one
of the causes for this form of
presentation40-42.
Abdominal TB
Peritoneal TB
TB peritonitis may have an acute
onset and such patients may often
be subjected to emergency surgery.
Three varieties of chronic TB
peritonitis have been described.
Ascitic form often has an insidious
onset. Abdominal distension, dilated
veins and transverse solid mass in
Figure 3 Contrast enhanced MRI of the brain
the abdomen due to greater
(sagittal view, T1 weighted image)
omentum which is rolled up and may
showing solitary enhancing ring lesion
be infiltrated with tubercles, are
important clinical features. Patients
with encysted or loculated form present with localised abdominal swelling. In the fibrous
form, widespread adhesions may cause coils of intestine to be matted together and distended
which may act as blind-loop and result in steatorrhoea, malabsorption syndrome and
abdominal pain. The disease may present as acute or subacute intestinal obstruction. The
adherent loops of intestine and the thickened mesentery may be felt as lump(s) in the
abdomen. Purulent form of TB peritonitis rarely develops secondary to TB salpingitis.
Cold abscess, entero-cutaneous and entero-enteric fistulae can develop.
Gastrointestinal TB
Gastrointestinal TB is usually secondary to a TB focus elsewhere in the body. With
widespread pasteurisation of milk, abdominal TB caused by M. bovis is now seldom seen,
and M. tuberculosis is the most frequently isolated pathogen. Gastrointestinal TB can be
of ulcerative, hypertrophic, ulcerohypertrophic, diffuse colitis and sclerotic forms.
Gastrointestinal TB is a chronic illness with abdominal pain as the most common symptom.
Diarrhoea, anorexia, weight loss and fever are also common. Other symptoms include a
moving lump in the abdomen, nausea, vomiting, malaena, and constipation. A doughy feel
of the abdomen, mass in the right iliac fossa due to hyperplastic caecal TB, lymph node
enlargement and rolled up omentum, are often found. Abdominal distension with increased
peristaltic activity is generally associated with intestinal obstruction. When intestinal
perforation develops, signs of peritonitis may be apparent43,44 .
Other Gastrointestinal Sites
TB at other gastrointestinal sites such as hepatobiliary and pancreatic TB are rare, often
associated with disseminated/miliary TB (DTB/MTB) and occur more often in
immunocompromised patients. The clinical manifestations are non-specific and depend on
the site and extent of disease. Anorexia, malaise, low grade fever, weight loss, night sweats,

108

11

EXTRAPULMONARY TUBERCULOSIS: MANAGEMENT AND CONTROL

malaena, pancreatic mass or abscess and obstructive jaundice, have all been described.
Pancreatic TB may present as acute or chronic pancreatitis, or may mimic malignancy.
Splenic TB presents as hypersplenism or splenic abscess, or as a solitary splenic lesion.
Multiple TB abscesses have been described in patients with HIV infection. Pre-operative
diagnosis is difficult and the diagnosis is often confirmed on histopathological examination
of excised specimen10.
Pericardial TB
TB pericardial involvement may present as acute pericarditis, chronic pericardial effusion,
cardiac tamponade or pericardial constriction. Pericardial involvement most commonly
results from direct extension of infection from adjacent mediastinal lymph nodes, or through
lympho-haematogenous route from a focus elsewhere.
Genitourinary TB
Genitourinary TB (GUTB) may complicate up to 3 to 4 percent of patients with
pulmonary TB. Patients present with dysuria, haematuria which may be painless, flank
pain, renal mass, sterile pyuria, and recurrent urinary tract infection. Rarely acute
presentation mimicking pyelonephritis has also been described. Other uncommon
manifestations include non-healing wounds, sinuses or fistulae and haemospermia.
Female Genital TB
Primary female genital TB (FGTB) has rarely been described in female partners of
males affected by active GUTB. More often, FGTB is secondary to TB infection elsewhere
in the body. It is an important cause of infertility. Patients may also present with chronic
lower abdominal or pelvic pain, or alterations in the menstrual pattern. Symptoms of TB
toxaemia may not be evident and physical examination may be unremarkable.
Cutaenous TB
Cutaneous TB accounts for 0.1 to 2.5 percent of all patients with skin diseases. Several
clinical types of cutaneous TB have been described. In those not previously exposed to M.
tuberculosis, TB of the skin and TB chancre has been described. Previously sensitised
hosts develop lupus vulgaris, scrofuloderma and tuberculosis verrucosa cutis. Other lesions
seen are tuberculids which includes lichen scrofulosorum, papulonecrotic tuberculid,
erythema induratum and erythema nodosum. Lupus vulgaris is the most common variety
seen in India, followed by tuberculosis verrucosa cutis and scrofuloderma. The other types
are distinctly rare. Localised and generalised skin complications due to Bacille CalmetteGuerin (BCG) vaccination have also been described45.
TB in Otorhinolaryngology
Before the advent of antituberculosis treatment, patients with active pulmonary TB often
developed laryngeal, otological, nasal and paranasal sinus involvement and deteriorated
progressively. Focus has once again shifted on to otorhinolaryngological TB with the advent
of HIV infection and AIDS46.
Patients with laryngeal TB present with hoarseness of the voice. Pain is also an important
feature which may radiate to one or both ears and may lead to odynophagia. Occasionally,
presentation can be similar to that encountered in acute viral laryngitis. Laryngeal TB may
co-exist with carcinoma.

109

TUBERCULOSIS CONTROL IN INDIA I

Ocular TB
In ocular TB, the choroid is the most commonly affected structure. Primary ocular TB is
extremely rare and ocular TB is usually secondary to a TB focus elsewhere in the body.
Lupus vulgaris may spread to the face and involve the eyelid. Conjunctival TB and lupus
vulgaris are the common manifestations of primary TB while tuberculids and phlyctenulosis
occur in post-primary TB. Phlyctenulosis can involve conjunctiva, cornea or the lid margin.
TB has also been implicated in the causation of Parinauds oculoglandular syndrome and
Eales disease. TB uveitis can present as pan uveitis or as chronic granulomatous iridocyclitis.
Choroidal tubercles when present can provide valuable diagnostic clues to the diagnosis of
DTB/MTB.
Disseminated/Miliary TB
DTB refers to the involvement of two or more non-contiguous sites by TB disease.
Dissemination can occur during primary infection or after reactivation of a latent focus/reinfection. In the post-primary period, acute MTB can occur when these foci fail to heal and
progress. Later in life, re-activation of these latent foci, caseation and erosion into blood
vessels can result in haematogenous embolisation and the development of MTB47,48.
Clinical manifestations of DTB/MTB are protean. Though the association of MTB and
acute lung injury (ALI) and acute respiratory distress sydnrome (ARDS) is well known,
only a few cases of this association have been published48,49. Even in areas where TB is
highly endemic, the diagnosis of MTB can be difficult as the clinical symptoms are nonspecific.
Principles of Diagnosis of EPTB
When EPTB is suspected as a possible diagnosis, every attempt should be made to
obtain samples of tissue/relevant body fluid for diagnostic testing. The most easily accessible
tissue should be obtained for histopathological, cytopathological and microbiological
diagnosis. For example, when working up a patient with suspected LNTB, the most easily
accessible representative peripheral lymph node should be aspirated, biopsied or excised
and subjected to diagnostic testing. Similarly cerebrospinal fluid (CSF) and ascitic fluid
examination can provide valuable diagnostic clues in patients with neurological and
peritoneal TB respectively.
With the advent of ultrasound scanning, and subsequently CT scan and magnetic
resonance imaging (MRI), and widespread availability of thoracoscopy, upper
gastrointestinal endoscopy, colonoscopy, laparoscopy, cystoscopy and biopsy under visual
guidance and other invasive investigations such as hysterosalpingography and colposcopy,
tremendous progress has been achieved in precise anatomical localisation of the lesions in
EPTB antemortem43,50. If no accessible tissue/fluid is available for analysis, radiologically
guided fine needle aspiration and cytopathology (FNAC) or biopsy may be required to
secure tissue for diagnosis.
Treatment of EPTB
Antituberculosis treatment is the mainstay in the management of EPTB. However, the
issue of the ideal regimen and duration of treatment have not yet fully been resolved. The
RNTCP which follows the WHO-recommended DOTS strategy, advocates the use of shortcourse intermittent chemotherapy for patients with EPTB also1-4. According to the DOTS
110

11

EXTRAPULMONARY TUBERCULOSIS: MANAGEMENT AND CONTROL

guidelines, patients with less severe forms of EPTB are categorised under the treatment
Category III and those with severe form of EPTB under the treatment Category I (Tables 1
and 2). While the six-month treatment is sufficient for the vast majority of patients, each
patient should be individually assessed and, where appropriate, treatment duration may be
extended for a given patient51. The treatment outcome of patients with EPTB receiving
DOTS under the RNTCP has been good (Table 8). Patients receiving antituberculosis
treatment should be carefully monitored for adverse drug reactions, especially drug induced
hepatotoxicity52,53.
The usefulness of corticosteroids in the treatment of EPTB is controversial and not well
established54. When the diagnosis of TB is established with certainty, additional oral
corticosteroid treatment may be helpful in selected patients with life-threatening forms of
EPTB.
Published evidence suggests that a majority of the TB patients with HIV infection respond
well to DOTS55. In EPTB patients known to have co-existent HIV infection, Category I
regimen is to be used under the DOTS strategy. All HIV co-infected TB patients should
receive a Rifampicin-containing regimen. To address the problem of drug interaction between
Rifampicin and some of the anti-retroviral (ARV) drugs, such as Nevirapine, antiretroviral
treatment can be initiated after DOTS treatment is completed. In HIV co-infected TB patients
in the later stages of immunosuppression, concomitant anti-retroviral and antituberculosis
treatment may be required and in such cases the ARV regimen needs to be suitably modified,
e.g. Nevirapine replaced with Efavirenz56.
A high index of clinical suspicion, timely and judicious use of invasive diagnostic methods
and confirmation of the diagnosis, early institution of DOTS and close clinical monitoring
for adverse drug reactions, are the key to the successful management of EPTB.

111

TUBERCULOSIS CONTROL IN INDIA I

References
1.

Central TB Division (CTD), Directorate General of Health Services, Ministry of Health and Family
Welfare, Government of India. Revised National TB Control Programme. Operational guidelines for
TB Control. New Delhi: CTD, 1997.

2.

CTD. Revised National TB Control Programme. Technical guidelines for TB Control. New Delhi:
CTD, 1997.

3.

CTD. Managing the Revised National TB Control Programme in your area. A training course.
Modules 1-4. New Delhi: CTD, 1998.

4.

World Health Organization (WHO). Treatment of Tuberculosis. Guidelines for National

Programmes, 3rd ed. WHO/CDS/TB 2003.313. Geneva, Switzerland: WHO, 2003.

5.

Sudre, P., Hirschel, B.J,, Gatell, J.M., et al.: Tuberculosis among European patients with the
acquired immune deficiency syndrome. The AIDS in Europe Study Group. Tuber Lung Dis
1996;77:322-8.

6.

Stelianides, S., Belmatoug, N., Fantin, B.: Manifestations and diagnosis of extrapulmonary
tuberculosis. Rev Mal Respir. 1997;14 Suppl 5:S72-87.

7.

Pitchenik, A.E., Cole, C., Russell, B.W., et al.: Tuberculosis, atypical mycobacteriosis and acquired
immunodeficiency syndrome among Haitian and non-Haitian patients in south Florida. Ann Intern
Med 1984;101:641-5.

8.

Balasubramanian, R., Ramachandran, R.: Management of non-pulmonary forms of tuberculosis:

review of TRC studies over two decades. Indian Journal of Pediatrics 2000;67:S34-S40.

9.

Fanning, A.: Tuberculosis: 6. Extrapulmonary disease. CMAJ 1999;160:1597-603.

10. Sharma, S.K., Mohan, A.: Extrapulmonary tuberculosis. Indian J Med Res 2004;120:316-53.
11.

Mohan, A., Sharma, S.K.: Epidemiology. In: Sharma, S.K,, Mohan, A. (editors). Tuberculosis. New
Delhi: Jaypee Brothers Medical Publishers; 2001.p.14-29.

12. Corbett, E.L., Watt, C.J., Walker, N., et al.: The growing burden of tuberculosis: global trends and
interactions with the HIV epidemic. Arch Intern Med 2003;163:1009-21.
13. International Union Against Tuberculosis and Lung Disease (IUATLD). Management of
tuberculosis: a guide for low-income countries. 5th ed. Paris: IUATLD, 2000.
14. CTD. Managing the Revised National TB Control Programme in your area. A training course.
Modules 5-10. New Delhi: CTD, 1998.
15. Jawahar, M.S., Sivasubramanian, S., Vijayan, V.: Short-course chemotherapy for tuberculous
lymphadenitis in children. BMJ 1990;301:359-62.
16. Prasad, R.R., Narasimhan, Sankaran V., Neliath, A.J.: Fine needle aspiration cytology in the
diagnosis of superficial lymphadenopathy: an analysis of 108 cases. Diagnosis Cytopathol
1996;15:382-6.
17. Bhargava, B.K., Shriniwas, Chopra P., et al.: Peritoneal tuberculosis: laparoscopic patterns and its
diagnostic accuracy. Am J Gastroenterol 1992;87:109-12.
18. Balasubramanian, R., Nagarajan, M., Balambal, R., et al.: Randomised controlled clinical trial of
short course chemotherapy in abdominal tuberculosis: a five-year report. Int J Tuberc Lung Dis
1997;1:44-51.
19. Balasubramanian, R., Ramachandran, R.: Management of non-pulmonary forms of tuberculosis:
review of TRC studies over two decades. Indian Journal of Pediatrics 2000;67:S34-S40.
20. Barnes, P.F.: Rapid Diagnostic tests for tuberculosis: progress but no gold standard. Am J Respir
Crit Care Med 1997;165:1497-8.

112

11

EXTRAPULMONARY TUBERCULOSIS: MANAGEMENT AND CONTROL

21. Smith, K.C., Starke, J.R., Fishena, C.H., et al.: Detection of M. tuberculosis in clinical specimens
from children using PCR. Paediatrics 1996;97:155-60.
22. Martin, R.E., Bradsher, R.W.: Elusive diagnosis of tuberculosis peritonitis. South Med J
1986;79:1076-9.
23. Shakila, H., Jayasankar, K., Ramanathan, V.D.: The clearance of tubercle bacilli and mycobacterial
antigen vis--vis the granuloma in different organs of guinea pigs. Indian J Med Res 1999;110:4-10.
24. Dutt, A.K., Stead, W.W.: Short-course chemotherapy for extrapulmlonary tubrculosis. Annals Intern
Med 1986; 104: 7-12.
25. Girling, D.J., Derbyshire, J.H., Humphries, M.J., et al.: Extrapulmonary tuberculosis. Br Med Bull
1988;44:738-56.
26. Indian Council of Medical Research / British Medical Research Council. A controlled trial of short
course regimens of chemotherapy in patients receiving ambulatory treatment or undergoing radical
surgery for tuberculosis of the spine. Indian J Tuberc 1989;36 (suppl):1-21.
27. Tuberculosis Research Centre. Short course chemotherapy for tuberculosis of the spine. A
comparison between ambulatory treatment and radical surgery 10 year report. J Bone Joint Surg
(Br) 1998;81:464-71.
28. Ramachandran, P., Duraipandian, M., Nagarajan, M., et al.: Three chemotherapy studies of
tuberculous meningitis in children. Tubercle 1986;67:17-29.
29. Rajeswari, R., Balasubramanian, R., Venkatesan, P.: Short-course chemotherapy in the treatment of
Potts paraplegia: report on five year follow. Int J Tuberc Lung Dis 1997;1:152-8.
30. Rajeswari, R., Sivasubramanian, S., Balambal, R.: A controlled clinical trial of short-course
chemotherapy for tuberculoma of the brain. Tuber Lung Dis 1995;76:111-7.
31. Girgis, N.I., Sultan, Y., Farid, Z., et al.: Tuberculosis meningitis, Abbassia Fever Hospital-Naval
Medical Research Unit No. 3-Cairo, Egypt, from 1976 to 1996. Am J Trop Med Hyg 1998;58:28-34.
32. Humphries, M.J., Teoh, R., Lure, J., Gabriel, M.: Factors of prognostic significance in Chinese
children with tuberculous meningitis. Tubercle 1990;71:161-8.
33. Donald, P.R., Shoeman, J.F., Vanzyle, E.: Intensive short-course chemotherapy in the management
of tuberculous meningitis. Int J Tuberc Lung Dis 1998;2:704-11.
34. Thirteenth report of MRC working party on TB of spine. A 15-year assessment of controlled trials
of the management of tuberculosis of the spine in Korea and Hong Kong. J Bone Joint Surg Br
1998;80: 456-62.
35. Parthasarathy, R., Sriram, K., Santha, T., et al.: Short-course chemotherapy for tuberculosis of the
spine. A comparison between ambulant treatment and radical surgery-ten-year report. J Bone Joint
Surg Br 1999;81:464-71.
36. Upadhyay, S.S., Saji, M.S., Sell, P., et al.: The effect of age on the change in deformity after
anterior debridement surgery for tuberculosis of the spine. Spine 1996;21:2356-62.
37. Light, R.W.: Management of pleural effusions. J Formos Med Assoc 2000;99:523-31.
38. Bhan, S., Nag, V.: Skeletal tuberculosis. In: Sharma, S.K., Mohan, A., editors. Tuberculosis. New
Delhi: Jaypee Brothers Medical Publishers; 2001:237-60.
39. Malaviya, A.N., Kotwal, P.P.: Arthritis associated with tuberculosis. Best Pract Res Clin Rheumatol
2003;17:319-43.
40. Radhakrishnan, K., Kihore, A., Mathuranath, P.S.: Neurological tuberculosis. In: Sharma, S.K.,
Mohan, A., editors. Tuberculosis. New Delhi: Jaypee Brothers Medical Publishers; 2001:209- 28.

113

TUBERCULOSIS CONTROL IN INDIA I

41. Tandon, P.N., Bhatia, R., Bhargava, S.: Tuberculous meningitis. In: Harris, A.A., editor. Handbook of
clinical neurology (revised series). Amsterdam: Elsevier Science; 1988(8). p.195-226.
42. Prasad, K., Menon, G.R.: Tuberculous meningitis. J Assoc Physicians India 1997;45:722-9.
43. Ibrarullah, M., Mohan, A., Sarkari, A., et al.: Abdominal tuberculosis: diagnosis by laparoscopy and
colonoscopy. Trop Gastroenterol 2002;23:150-3.
44. Bhansali, S.K.: The challenge of abdominal tuberculosis in 310 cases. Indian J Surg 1978;40:65-77.
45. Kumar, B., Muralidhar, S.: Cutaneous tuberculosis: a twenty-year prospective study. Int J Tuberc Lung
Dis 1999;3:494-500.
46. Rupa, V., Bhanu, T.S.: Laryngeal tuberculosis in the eighties an Indian experience. J Laryngol Otol
1989;103:864-8.
47. Hill, A.R., Premkumar, S., Brustein, S., et al.: Disseminated tuberculosis in the acquired
immunodeficiency syndrome era. Am Rev Respir Dis 1991;144:1164-70.
48. Sharma, S.K., Mohan, A., Prasad, K.L., et al.: Clinical profile, laboratory characteristics and outcome
in miliary tuberculosis. QJM 1995;88:29-37.
49. Mohan, A., Sharma, S.K., Pande, J.N.: Acute respiratory distress syndrome in miliary tuberculosis: a
12-year experience. Indian J Chest Dis Allied Sci 1996; 38: 147-52.
50. Jain, R., Sawhney, S., Bhargava, D.K., Berry, M.: Diagnosis of abdominal tuberculosis: sonographic
findings in patients with early disease. Am J Roentgenol 1995;165:1391-5.
51. Blumberg, H.M., Burman, W.J., Chaisson, R.E., et al.: American Thoracic Society, Centers for Disease
Control and Prevention and the Infectious Diseases Society. Treatment of tuberculosis. Am J Respir Crit
Care Med 2003;167:603-62.
52. Sharma, S.K., Balamurugan, A., Saha, P.K., et al.: Evaluation of clinical and immunogenetic risk
factors for the development of hepatotoxicity during antituberculosis treatment. Am J Respir Crit Care
Med 2002;166:916-9.
53. Bothamley, G.H.: Treatment, tuberculosis, and human leukocyte antigen (editorial). Am J Respir Crit
Care Med 2002;166:907-8.
54. Dooley, D.P., Carpenter, J.L., Rademacher, S.: Adjunctive corticosteroid therapy for tuberculosis: a
critical reappraisal of the literature. Clin Infect Dis 1997;25:872-7.
55. Sharma, S.K., Mohan,A.: Co-infection with human immunodeficiency virus (HIV) and tuberculosis:
Indian perspective. Indian J Tuberc 2004;51:5-16.
56. World Health Organization. TB/HIV: A clinical manual. WHO/HTM/TB/2004.329. Geneva: World
Health Organization; 2004.

114