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Extrapulmonary Tuberculosis

November 26, 2004

Extrapulmonary involvement can occur in isolation or along with a pulmonary focus as in the case of patients with disseminated tuberculosis (TB). The recent human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) pandemic has resulted in changing epidemiology and has once again brought extrapulmonary tuberculosis (EPTB) into focus. EPTB constitutes about IS to 20 per cent of all cases of tuberculosis in immunocompctent patients and accounts for more than 50 per cent of the cases in HIV-positive individuals. Lymph node; are the most common site of involvement followed by pleural effusion and virtually every site of the body can be affected. Since the clinical presentation of EPTB is atypical, tissue samples for the confirmation of diagnostic can sometimes be difficult to procure, and the conventional diagnostic methods have a poor yield, the diagnosis is often delayed. Availabiity of computerised tomographic sean, magnetic resosnance imaging laparoscopy, endoscopy have tremendously helped in anatomical localisation of EPTB. The disease usually responds to standard antituberculosis drug treatment. Biopsy and/or surgery is required to procure tissue samples for diagnosis and for managing complications. Further research is required for evolving the most suitable treatment regimens, optimal duration of treatment and safety when used with highly active antiretroviral treatment (HAART).

Key words Abdominal tuberculosis * bone and joint tuberculosis * disseminated tuberculosis * extrapulmonary tuberculosis * genitourinary tuberculosis * laryngeal tuberculosis * lymph node tubcrculosis * miliary tuberculosis * neurological tuberculosis * pericardial tuberculosis * tuberculosis in otorhinolaryngology * tuberculosis meningitis * tuberculosis pleurul effusion

Tuberculosis can involve any organ system in the body. While pulmonary tuberculosis is the most common presentation, extrapulmonary tuberculosis (EPTB) is also an important clinical problem1-3. The term EPTB has been used to describe isolated occurrence of of tuberculosis at body sites other than the lung. However, when an extrapulmonary locus is evident in a patient with pulmonary tuberculosis, such patients have been categorized under pulmonary tuberculosis as per the guidelines of the World Health Organization (WHO)4. Since tuberculosis can virtually involve any organ system and a detailed description regarding EPTB at each of these sites is too exhaustive, an attempt is made to provide a critical overview of the more commonly encountered forms of EPTB in this review.

Epidemiology

In the era before the human immunodeficiency virus (HIV) pandemic, and in studies involving immunocompetent adults, it has been observed that EPTB constituted about 15 to 20 per cent of all cases of TB (Fig. 1a)1,5-13. In HIV-positivc patients. EPTB accounts for more than 50 per cent of all cases of TB (Fig. 1b)14-22. The diagnosis of EPTB, especially involving deeply located inaccessible areas is very difficult. Sparse literature is available regarding the relative contributions of pulmonary and extrapulmonary disease to the total number of tuberculosis cases from India as reliable epidemiological data are lacking13. Considering the stigma associated with and the reluctance to perform invasive procedures especially in HIV-positive patients in the Indian setting, even notified estimates of RPTB under the Revised National Tuberculosis Control Programme (RNTCP) are often based on presumptive diagnosis and are an overestimate of the problem23. Though it is estimated that EPTB constitutes 15 to 20 per cent of tuberculosis cases in general practice among HIV-negative adults in India13, a higher proportion of EPTB cases have been documented in tertiary care centres. For example, at the Tuberculosis Clinic at the All India Institute of Medical Sciences, (AIIMS), New Delhi (n=1137) and the Sri Venkateswara Institute of Medical Sciences (SVIMS), Tirupati (n=612), patients with EPTB constituted 53 and 30.4 per cent respectively during the period 1994-2002 (unpublished observations). Since several patients are referred to tertirary care centres for confirmation of diagnosis, these high figures could be a result of referral bias. Impact of human immunodeficiency virus infection: HIV infected persons are at increased risk for primary or reactivation tuberculosis24-27 and for second episodes of tuberculosis from exogenous reinfection28,29. CD4+ T-helper (Th) cells, upon antigenic challenge, are thought to differentiate along the separate pathways resulting in cell populations with different cytokine production profile termed Thl and Th230-32. In murine models, Thl cells that produce interferon-γ (IFN-γ) and interleukin-2 (IL-2) confer resistance to infection with mycobacteria32,33. Th2 cells that produce interleukin-3 (IL-3), interleukin-4 (IL-4), interleukin- 5 (IL-5), interleukin-6 (IL-6) and interleukin-10 (IL-10), do not contribute much to antimycohacterial immunity24,32. It has been observed that when peripheral blood lymphocytes from HIV-positive patients with tuberculosis are exposed in vitro to Mycobacterium tuberculosis, they produce less IFN-γ but similar amounts of IL- 4 and IL-10 as compared with lymphocytes from tuberculosis patients who are HIV-negative34. Thus, reduced Thl response observed in HIV- infected patients is thought to increase their susceptibility to tuberculosis24,34.

The risk of tuberculosis increases as immunosuppression progresses2,14,19,35. The most common extrapulmonary site in HIV- positive individuals is the lymph node. However, neurological, pleural, pericardial, abdominal involvement has been described and virtually every site in the body can be involved in HIV-positive patients1,2,14,19,35. In studies reported from India, EPTB constituted 45 to 56 per cent of all the cases of tuberculosis in persons with AIDS36,37.

Constitutional symptoms

Patients with EPTB may manifest constitutional symptoms such as fever, anorexia, weight loss, malaise and fatigue. In India patients with EPTB especially when the disease is located at an obscure site, may present with pyrexia of unknown origin (PUO) and this may be the only diagnostic clue in them. In addition, patients with EPTB manifest sympyoms and signs related to the organ system involved and these are discussed under the repective anatomic sites.

Lymph node tuberculosis

Historically, lymph node tuberculosis (LNTB) has been called the “King’s evil” referring to the divine benediction which was presumed to be the treatment for it. It was also referred to as “scrofula” meaning “glandular swelling” (Latin) and “full necked sow” (French)38. Peripheral lymph nodes are most often affected and cervical involvement is the most,38-40.

In India and other developing countries LNTB continues to be the most common form of EPTB and lymphadenitis due to non-tuberculous mycobacteria (NTM) is seldom seen41-43. On the other hand, NTM are the most common cause of lymphadenopathy in the developed world’1445. In patients with mycobacterial lymphadenitis in the USA, M. tuberculosis has been the most common pathogen among adults whereas NTM were the most common pathogens among children46. In England, there has been a decline in LNTB and a rise in NTM lymphadenitis47, and persons of Indian ethnic origin were more often affected than the local residents40,47. Similar results have been reported among native Americans and in persons originating from south cast Asia and Africa48,49. Asians and Hispanic patients and African American also seem to have a high predilection for developing mycobacterial lymphadenitis48,49.

Fig. 1a. Distribution of tuberculosis cases by anatomical site in HIV-negative patients. Data derived from references 3,5,6,10,11. PTB. pulmonary tuberculosis: EPTB. extrapulmonary tuberculosis: GUTB. genitourinary tuberculosis; MTB, miliary tuberculosis; TBM. tuberculosis meningitis; ABD, abdominal tuberculosis: LNTB, lymph node tuberculosis.

Fig. 1b. Distribution of tuberculosis cases by anatomical site in HIV-positive patients data derived from references 14-22. PTH. pulmonary tuberculosis; EPTB. extrapulmonary tuberculosis; LNTB. lymph node tuberculosis.

Pathogenesis: LNTB is considered to be the local manifestation of a systemic disease whereas NTM lymphadenitis is thought to be a truly localised disease. M. tuberculosis gains entry into the body via the respiratory tract and undergoes liaematogenous and lymphatic dissemination. Hilar and mediastinal lymph nodes are initially involved. This may occur at the time of primary infection or may occur later in life due to reinfection or reactivation of previous infection. Sometimes, tonsil is an important portal of entry. The infection then spreads via the lymphatics to the draining cervical lymph nodes. Initially, the nodes are discrete. Periadenitis results in matting and fixation of the lymph nodes. The lymph nodes coalesce and break down due to formation of caseous pus. This may perforate the deep fascia and present as a collar-stud abscess. Overlying skin becomes indurated and breaks down, resulting in sinus formation which may remain unhealed for years. Healing may occur from each of the stages with calcification and scarring. In contrast NTM, gain entry into the lymph nodes directly via oropharyngeal mucosa, salivary glands, tonsils, gingiva or conjunctiva46,50, and lymph node involvement represents a localised disease.

Clinical pres\entation: LNTB often affects children and young adults40-42. Female predilection has been reported in some stu0 dies40-42,51,52. 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 patients40-42,51,52. Bern et al53 observed that among HIV-negative as well as HIV-positive patients, cervical lymph nodes were most commonly affected followed by axillary and inguinal lymph nodes. Multifocal involvement was observed in 39 and 90 per cent among HIV-negative and HIV-positive patients respectively. In HIV-positive patients, multifocal involvement, intrathoracic and intraabdominal lymphadenopathy and associated pulmonary disease are more common40-42,53,54. Some patients with LNTB may manifest systemic symptoms and these include fever, weight loss, fatigue and occasionally night sweats. Patients with mediastinal lymphadenopathy (Fig.2a and 2b) may present with cough and dysphagia40-42,51-58. With wider availability of computerised tomographic (CT) scan, it is expected that more cases of intrathoracic and intraabdominal lymphadenopathy and other associated lesions (Fig.2c and 2d) may be reported.

Peripheral tuberculosis lymphadenopathy has been classified into five stages59. These include: (i) stage 1, enlarged, firm mobile discrete nodes showing non-specific reactive hyperplasia; (ii) stage 2, large rubbery nodes fixed to surrounding tissue owing to periadenitis; (iii) stage 3, central softening due to abscess formation; (iv) stage 4, collar-stud abscess formation; and (v) stage 5, sinus tract formation. Physical findings depend upon the stage of the disease. The enlarged lymph nodes may be of varying size, are usually firm and may be discrete or matted. If necrosis and abscess formation have taken place they may become cystic in consistency. The lymph nodes are usually not tender unless secondary bacterial infection has occurred. Physical examination may be unremarkable but for palpable lymphadenopathy. Occasionally, lymph node abscess may burst leading to a chronic non-healing sinus and ulcer formation. Classically, tuberculosis sinuses have thin, bluish, undermined edges with scanty watery discharge. Uncommon manifestations observed in patients with mediastinal lymph node involvement include dysphagia60,61, oesophagomediastinal fistula62- 64, and tracheo-oesophageal fistula65. Upper abdominal and mediastinal lymph nodes may cause thoracic duct obstruction and chylothorax, chylous ascites or chyluria66,67. Rarely, biliary obstruction due to enlarged lymph nodes can result in obstructive jaundice68. Cardiac tamponade has also been reported due to mediastinal lymph node tuberculosis69.

Fig.2. Contrast enhanced computerized lomographic (CECT) scan of the chest of a young woman who presented with low grade fever for 3 months, cough and dysphagia showing subcarinal (a) and riglil hilar (b) lymph nodes. Arrows points to hypodensity which indicates necrosis in the lymph node. CECT scan of the abdomen of the same patient showing bilateral psoas abscesses (c) (arrows). Coronal reconstruction of the CBCT scan of the abdomen of the same patient showing bilateral psoas abscesses (d) (arrows). CT guided line needle aspirate from the psoas abscess revealed numerous acid-last bacilli.

Nontuberculous mycobacterial lymphadenitis’. Very little is known regarding lymphadenitis due to NTM from India. In the western literature, NTM lymphadenitis has often been described in children. Both sexes are equally affected48,50,59,70. Constitutional symptoms seldom, develop and the disease generally remains localised to the upper cervical area. If untreated, the nodes often progress to softening, rupture, sinus formation, healing with fibrosis and calcification48,50,59,70.

Pleural effusion and empyema thoracis

Tuberculosis pleural effusion is categorised as extrapulmonary despite an intimate anatomic relationship between pleura and the lungs71,75.

Pathogenesis’. It is thought that a small subpleural focus ruptures into the pleural space, setting up an interaction between the tubercle bacilli or their specific components inducing a delayed hypersensitivity reaction. Recent evidence suggests that patients with TB pleural effusion have significantly higher levels of IFN- γ in the pleural fluid as compared to peripehral blood thus exhibiting localisation of predominantly Thl-type immunity in the pleural fluid75. Rupture of a cavity containing caseous material into the pleural space results in empyema thoracis. Less often, rupture of caseous paratracheal lymph nodes, paravertebral abscess or osteomyelitis of the ribs can result in empyema thoracis.

Clinical features: TB pleural effusion usually presents as an acute illness and the symptom duration ranges from a few days to few weeks. Most patients complain of pleuritic chest pain, non- productive cough and dyspnoea. Majority of the patients manifest fever, though a few may not have fever. Occasionally, the onset may be less acute, with only mild chest pain, low-grade pyrexia, cough, weight loss and loss of appetite.

Patients with tuberculosis empyema present with chest pain, breathlessness, cough with expectoration, fever, and toxaemia. Anaemia and hypoproteinaemia are often present. Physical examiantion may reveal digital clubbing, clinical findings suggestive of effusion and intercostal tenderness. Occasionally, tuberculosis empyema may present as a chest wall mass or draining sinus tract (tuberculosis empyema necessitatis).

Abdominal tuberculosis

Abdominal tuberculosis is the term used to encompass TB of the gastrointestinal tract, peritoneum, omentum, mesentery and its nodes and other solid intra-abdominal organs such as liver, spleen and pancreas76. Peritoneal and intestinal TB have been covered in another review article published in this issue of the journal77. Hence, TB at other abdominal sites such as hepatobiliary, pancreatic and splenic tuberculosis will be covered.

Hepatobiliary, pancreatic and splenic tuberculosis

Hepatobiliary and pancreatic TB are rare and are often associated with miliary tuberculosis, and occur more often in immunocompromised patients78. The clinical manifestations are non-specific and depend on the site and extent of disease. Anorexia, malaise, low grade fever, weight loss, night sweats, malaena, pancreatic mass or abscess or obstructive jaundice have all been described79,80. Pancreatic TB may present as acute or chronic pancreatitis or may mimic malignancy79,80. Isolated splenic tuberculosis is very rare in immunocompetent persons. Splenomegaly can occur in patients with disseminated/miliary tuberculosis. Splenic tuberculosis presents as hypersplenism or splenic abscess or as a solitary splenic lesion81. Multiple tuberculosis abscesses have been described in patients with HIV infection82,83. Preoperative diagnosis of tuberculosis at these obscure sites is difficult and the diagnosis is often confirmed on histopathological examination of excised specimen.

Neurological tuberculosis

Neurological tuberculosis may be classified into three clinico- pathological categories: tuberculosis meningitis (TBM), tuberculoma, and arachnoiditis84-86.

Tuberculosis meningitis

TBM accounts for 70 to 80 per cent of cases of neurological tuberculosis84-86. A majority of cases of TBM are caused by M. tuberculosis. Isolated cases of meningitis caused by NTM have also been documented86. Neurological tuberculosis is invariably secondary to tuberculosis elsewhere in the body. In the bacteraemic phase of primary lung infection, metastatic foci can get established in any organ, which can become active after a variable period of clinical latency. The critical event in the development of meningitis is the rupture of a subependymally located tubercle (Rich focus) resulting in the release of infectious material into the subarachnoid spaced Whether the critical subependymal tubercle develops during primary hacmatogenous dissemination or due to secondary haematogenous spread from an area of extracranial extrapulmonary tuberculosis is not clear. The following features comprise the salient pathological features of TBM: (i) inflammatory mcningeal cxudatc: (ii) epcndymitis; (iii) vasculitis; (iv) encephalitis; and (v) disturbance of cerebrospinal fluid (CST) circulation and absorption.

Clinical features: In the developing world, TBM is still a disease of childhood with the highest incidence in the first three years of life86. The disease usually evolves gradually over two to six weeks. However, acute onset has also been described. 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 per cent of patients. Cranial nerve palsies can occur in 20 to 30 per cent of patients, the sixth nerve involvement being the most common86,88. Complete or partial loss of vision is a major complication of TBM. Various mechanisms postulated for the loss of vision include presence of exudates around the optic chiasma, arteritis, compression of the anterior visual pathways due to hydrocephalus or tuberculoma, and ethambutol toxicity among others. 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.

According to the severity of the illness, patients with TBM can be categorised into three clinic\al stages. The clinical staging helps to optimise therapy and to predict the prognosis. The prognosis of TBM is determined by the clinical stage at the time of initiation of treatment. The Medical Research Council89 and Kennedy and Fallen systems90 stage the patients into three categories: stage 1, patients are conscious and oriented with or without signs of meningcal irritation, but no focal neurological deficit; stage 2, patients with altered sensorium or focal deficits: and stage 3, patients are comatose and have dense deficits. During the last two decades, the clinical presentation of TBM has changed91,92. Atypical presentations include acute meningitic syndrome simulating pyogenic meningitis, progressive dementia, status epilepticus, psychosis, stroke syndrome, locked-in-state, trigeminal neuralgia, infantile spasm and movement disorders86,88,93.

Intracranial tuberculomas and, small, enhancing brains lesions

Tuberculoma is a mass of granulation tissue made up of a conglomeration of microscopic small tubercles84. The size of cerebral tuberculomas is highly variable. In most cases their diameters range from a few millimetres (mm) to three to four centimeters (cm)94, lntracranial tuberculomas in patients under the age of 20 yr are usually infratentorial, butsupratentorial lesions predominate in adults. Solitary tuberculomas are more frequent than multiple lesions. Although their frequency has decreased in the last two to three decades, tuberculomas still constitute about 5 to 10 per cent of intracranial space occupying lesions in the developing world.86,95. Patients with epilepsy who showed ring enhancing single CT lesions have been described almost exclusively from India96-100. The enhancing lesion is

Fig.3a and 3b. Chest radiograph (postero-anterior view) of a patient with tuberculosis pericardial effusion showing a globular heart shadow (a) before treatment. Chest radiograph taken 9 months after antituberculosis treatment (b) reveals considerable resolution of the pericardial effusion.

Neurological involvement is five times more frequent in HIV- positive compared to HIV-negative patients101-102. HIV infected patients account for over 50 per cent of the cases of TBM seen in the industrialised nations101,102. Bishburg et al102 reported that intravenous drug abusers with AIDS exhibited increased risk of developing neurological tuberculosis and brain abscesses. Yechoor et al103 found that 20 of the 31 patients (65%) identified as definite or probable TBM over a 12 yr period were infected with HIV. In general, HIV status does not alter the clinical manifestations, CSF findings and response to therapy103. However, HIV-positive subjects with TBM can have normal CSF more frequently101,103.

Pericardial tuberculosis

Pericardial; involvement in tuberculosis may result in acute pericarditis, chronic pericardial effusion, cardiac tamponade or pericardial constriction104,107. In India, TB accounts for nearly two-thirds of the cases of constrictive pericarditis104,106. TB has been reported to be the cause of acute pericarditis in four per cent of patients in the developed world and 60 to 80 per cent of the patients in the developing world104-110. TB pericarditis has been estimated to occur in one to eight per cent patients with pulmonary tuberculosis”111,112. In industrialised countries TB pericarditis is not so common except in patients with HIV infection and AIDS104.

Pericardial involvement most commonly results from direct extension of infection from adjacent mediastinal lymph nodes, or through lymphohaematogenous route from a focus elsewhere. TB pericarditis has the following stages: (i) dry stage; (ii) effusive stage; (iii) absorptive stage; and (iv) constrictive stage”2. The disease may progress sequentially from first to fourth stage or may present as any of the stages. Sometimes, pericardial TB can persentas fever with no clinical localisation. Presence of cardiomegaly on the chest radiograph may be the only diagnostic clue and echocardiography may reveal pericardial effusion.

Clinical features: TB pericarditis occurs most commonly in the third to fifth decade of life. The disease has an insidious onset and presents with fever, malaise and weakness. The patients may manifest pericardial rub, vague chest pain or cardiomegaly on a chest radiograph (Figs.Sa and 3b). Acute onset has been reported in 20 per cent of patients and some patients can present with cardiac tamponade106,107. Dyspnoea, cough, and weight loss are common symptoms. Chest pain, orthopnoea and ankle oedema occur in nearly 40 to 70 per cent of patients113-116.

Pericardial effusion: Patients with TB pericarditis usually present with chronic pericardial effusion104,113,115,116. Patients may also present acutely with cardiac tamponade and may manifest severe distress, retrosternal compression, tachycardia and raised jugular venous pressure (JVP) with blunt γ descent113,115,116 distant heart sounds, pericardia! rub and pulsus paradoxus may be evident.

Fig.3c, 3d and 3e. Contrast enhanced CT scan of the chest of a patient with constructive pericarditis showing thickened pericardium (black arrow) and dilated right atrium (while arrow) (c). Right and left ventricular pressure tracings (paper speed 100 mm/sec and 100 mm Hg gain) of the same patient showing markedly elevated and equal diustolic pressures with mild elevation of right ventricular systolic pressure (45 mm Hg) (d). Operative photograph showing thickened pericardium (e).

Effusive constrictive pericarditis: In patients with effusive constrictive pericarditis, constriction can be due to thickening of either the visceral or the parietal pericardium. Cardiomegaly, pedal oedema and raised JVP with a blunt γ descent may be present. After removal of fluid, JVP is still raised with a prominent γ descent. This stage could occur within few weeks of TB pericarditis. With effective antituberculosis treatment, some cases may resolve. Commonly, chronic constriction ensues107,117,118.

Chronic constrictive pericarditis: In patients with chronic constrictive pericarditis, the inflow of blood is impeded due to thickened unyielding pericardium, especially in the late diastole (Figs 3c, 3d and 3e). Consequently, these patients have systemic as well as pulmonary venous congestion and manifest aexertional dyspnoea, orthopnoea, ankle oedema and ascites. Cardiac output is mildly reduced at rest. Tachycardia, raised JVP with a prominent y descent occur. The JVP may rise further on inspiration (Kussmaul’s sign). Pulsus paradoxus is seen in less than one-third of cases and signifies presence of some fluid or a relatively elastic pericardium. Cardiac size is normal. A systolic retraction of apex can be evident104. A pericardial knock may be present but murmurs are not common. The ascites is disproportionate to the oedema (ascites praecox)104. Severe elevation of venous pressure may result in congestive splenomegaly and protein losing enteropathy resulting in hypoalbuminaemia. After many years of hepatic venous congestion cardiac cirrhosis may develop in some patients. The disease worsens gradually and in chronic cases, significant myocardial atrophy occurs due to extension of inflammation and possibly disuse of the muscle. Such patients have suboptimal improvement and higher mortality with pericardiectomy104.

Fig.4. Magnetic resonance imaging (MRI) scan of the dorsolumbar spine, (sagittal view, T1 weighted image) showing central hypointensc lesion (arrow) with reduced vertical height of the vertebra (a). MRI scan of the dorsolumbar spine (sagittal view, T2 weighted image) showing destruction of D10 and D11 vertebrae (arrow), reduction in the intervening disc (inset, arrow) with anterior granulation tissue and cord compression (b).

Bone and joint tuberculosis

Skeletal tuberculosis is a haematogenous infection and affects almost all bones. Tuberculosis commonly affects the spine and hip joint119,120. Other sites of involvement include knee joint, foot bones, elbow joint and hand bones. Rarely, it also affects shoulder joint. Two basic types of disease patterns have been observed: granular and exudative (caseous). Though both the patterns have been observed in osseous and synovial tuberculosis infection, one form may predominate.

Spinal tuberculosis (TB spine) is the most common form of skeletal tuberculosis. Majority of patients are under thirty years of age at the time of diagnosis. Constitutional symptoms such as weakness, loss of appetite and weight, evening rise of temperature and night sweats generally occur before the symptoms related to the spine manifest. Lower thoracic and lumbar vertebrae are the most common sites of spinal tuberculosis followed by middle thoracic and cervical vertebrae. Usually, two contiguous vertebrae are involved but several verebrae may be affected and skip lesions are also seen. The infection begins in the cancellous area of vertebral body commonly in epiphyseal location and less commonly in the central or anterior area of vertebral body (Figs 4a and 4b). The infection spreads and destroys the epiphyseal cortex, the intervertebral disc and the adjacent vertebrae (Fig.4b). It may spread beneath the anterior longitudinal ligament to reach neighbouring vertebrae. The vertebral body becomes soft and gets easily compressed to produce either wedging or total collapse. 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 cold abscess. In the cervical region, the exudate collects behind prevertebral fascia and may protrude forward as a retrophar\yngeal 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 neck119,120.

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 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. Abscess can gravitate beneath the inguinal ligament to appear on the medial aspect of thigh. It can 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. Collection can follow the vessels to form an abscess in Scarpa’s triangle or gluteal region if it follows femoral or gluteal vessels respectively119,120.

Retropharyngeal abscess can present with local pressure effects such as dysphagia, dyspnoea, or hoarseness of voice. Further, dysphagia may also occur due to mediastinal abscess. Flexion deformity of hip develops due to psoas abscess. The abscesses may be visible and palpable if they are superficially located. Therefore, neck, chest wall, groin, inguinal areas and thighs where cold abscesses occur frequently must be carefully examined in addition to the location of a bony lesion119,120.

Paraplegia (Pott’s paraplegia) is the most serious complication of spinal tuberculosis and its occurrence is reported to be as high as 30 per cent in patients with spinal tuberculosis119,120. 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 nonmechanical causes119,120.

Clinical presentation of tuberculosis 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 joint121,122. Tuberculosis osteomyelitis may mimic chronic mosteomyclitis of other causes119,120.

Genitourinary tuberculosis

Genitourinary tuberculosis (GUTB) complicates three to four per cent of patients with pulmonary tuberculosis121,124. Hacmatogenous dissemination from an active site of infection results in GUTB. Initially metastatic lesions (tubercles) are formed in the kidneys. Macroscopic progression of the disease is often unilateral125. Usually, these lesions heal spontaneously or as a result of treatment. However, they may enlarge even after years of inactivity and rupture into the nephrons producing bacilluria. There is descending spread of infection, inflammation and scarring.

Active GUTB usually develops 5 to 25 yr after the primary pulmonary infection and is usually encountered between the second and fourth decades of life121. 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 presentations include: non healing wounds, sinuses or fistulae, hacmospermia among others121.

Female genital tuberculosis

Primary female genital tuberculosis has rarely been described in female partners of males affected by active GUTB125,128. More often, female genital tuberculosis is secondary to tuberculosis infection elsewhere in the body. Haematogenous or lymphatic spread is the most common method of spread. Infection may also spread from the contiguous intraabdominal sites through the fallopian tubes125-128.

Female genital tuberculosis is an important cause of infertility. Patients may also present with chronic lower abdominal or pelvic pain, or alterations in the menstrual pattern. Sympotms of tuberculosis toxaemia may not be evident and physical examination may be unremarkable126-128.

Cutaneous tuberculosis

Cutaneous tuberculosis accounts for 0.11 to 2.5 per cent of all patients with skin diseases129-133. Several clinical types of cutaneous tuberculosis have been described. In those not previously exposed to M. tuberculosis, miliary tuberculosis of the skin and tuberculosis chancre have been described. Previously sensitised hosts develop lupus vulgaris, scrofuloderma, tuberculosis verrucosa cutis129. Other lesions seen are tuberculids which include 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 scrofuloderma129133. The other types are distinctly rare. Localised and generalised skin complications due to Bacille Calmette-Guerin (BCG) vaccination have also been described134,135.

In patients with HIV infection and AIDS, the lesions may not fit into the above described categories and usually present as papules, nodules, vesicles or induration129. Ulceration and discharge from the surface of the lesions may occur. The diagnosis is usually not suspected clinically and it has been suggested that all atypical cutaneous lesions developing in immunosuppressed individuals should be biopsied and subjected to mycobacterial culture133,136,140.

Tuberculosis in otorhinolaryngology

Before the advent of antituberculosis treatment, patients with active pulmonary tuberculosis very often developed laryngeal, otological, nasal and paranasal sinus involvement and deteriorated progressively. Laryngeal involvement was a dreaded consequence and was considered to be a harbinger of death141. With the advent of effective treatment the incidence of otorhinolaryngological TB had come down significantly. Otorhinolaryngological TB constitutes less than five per cent of all cases of EPTB. Focus has shifted on to otorhinolaryngological TB with the advent of HIV infection and AIDS142.

Tuberculosis of larynx

In the present era, in countries where TB is highly endemic, almost all patients with laryngeal tuberculosis have been found to have radiological evidence of pulmonary TB and many of them may be sputum smear-positive142,143. On the contrary, in countries with a low prevalence of tuberculosis, associated pulmonary tuberculosis is rarely seen in patients with laryngeal TB144-145. In a study of 500 patients with pulmonary tuberculosis from India145, Iaryngeal involvement was observed in four percent of them.

Clinical features: Patients often present with hoarseness of voice. Pain is also an important feature which may radiate to one or both ears and may lead to odynophagia. Occasionally, patients may present with rapid onset of hoarseness of voice similar to that encountered in acute viral laryngitis. Laryngeal tuberculosis may co- exist with carcinoma. Clinical features of these conditions may overlap and the lesions may look similar143,144.

Tuberculosis of the pharynx oral cavity and salivary glands

Tuberculosis involvement of the tonsils and pharynx is uncommon. The presenting features include: (i) ulcer on the tonsil or oropharyngeal wall; (ii) granuloma of the nasopharynx; and (iii) neck abcess. The oral cavity is an uncommon site of involvement by tuberculosis. Infection in the oral cavity is usually acquired through infected sputum coughed out by a patient with open pulmonary tuberculosis or by haematogenous spread. Tongue is the most common site of involvement and accounts for nearly half the cases. The lesions are usually found over the tip, borders, dorsum and base of the tongue. They may be single or multiple, the lesions may or may not be painful. Other sites of involvement include floor of mouth, soft palate, anterior pillars and uvula146,147. Secondary involvement of the draining lymph nodes may occur. Majority of these patients also have pulmonary tuberculosis141,147-151

TB sialitis is usually secondary to tuberculosis infection of the oral cavity or primary pulmonary tuberculosis151. Primary infection of the salivary glands is also known, but, is rare. Parotid gland is most commonly involved. Clinical presentation can be acute or chronic. Acute presentation may resemble acute non-tuberculosis sialitis and clinical differentiation may be difficult. Occasionally, the diagnosis of tuberculosis may be a surprise following surgery performed for a suspected salivary gland tumour151. Unsuspected tuberculosis parotid abscess may be wrongly drained mistaking it to be a pyogcnic abscess. This may lead to the formation of a persistent sinus.

Tuberculosis of the ear

Tuberculosis of the external ear is uncommon. However, lupus vulgaris of the external ear has been reported152. Tuberculosis of the ear develops when the bacilli invade the eustachian tube while the infant is being fed, or, by haematogenous spread to the mastoid process. The focus in the middle ear cleft may present as painless otorrhoea. Pale granulation tissue may be present in the middle ear with dilatation of vessels in the anterior part of the tympanic membrane. Multiple perforations of tympanic membrane may occur as a result of caseation necrosis. Facial nerve palsy may sometimes develop.

Tuberculosis of paranasal sinuses and nasopharynx

Tuberculosis of nose, paranasal sinuses and nasopharynx is uncommon. However, occasionally maxillary sinus may be involved153,154. Other sites which can be involve\d include inferior turbinate, scptal mucosa and the vestibular skin. Nasal discharge, mild pain and partial nasal obstruction are important presenting features. Involvement of nasolacrimal duct can rarely occur. Tuberculosis of the nose can cause complications like septal perforation, atrophie rhinitis and scarring of nasal vestibule.

Ocular tuberculosis

Ocular involvement has described in 2 to 30 per cent of patients with tuberculosis1,7,12,155, and usually develops as a result of haematogenous dissemination. While tuberculosis can affect all the part ofthe eye, choroid is the most commonly affected structure. Primary ocular tuberculosis though has been described is extremely rate155. Tuberculosis affects the eyelids infrequently. Lupus vulgaris may spread to the face and involve the eyelid. Conjunctival tuberculosis and lupus vulgaris are the common manifestations of primary tuberculosis while tubcrculids and phlyctenulosis occur in postprimary tuberculosis. Phlyctenulosis can involve conjunctiva, cornea or lid margin. Tuberculosis has also been implicated in the causation of Prinaud’s oculoglandular syndrome and Bale’s disease155. Tuberculosis uveitis can present as panuveitis or as chronic granulomatous iridocyclitis. Choroidal tubercles, when present, can provide valuable diagnostic clues to life threatening forms of disseminated tuberculosis such as miliary tuberculosis. These may be single or multiple and vary in size from quarter of a disc diameter to several disc diameters and are most frequently situated at the posterior pole155.

Tuberculosis of the breast

Tuberculosis mastitis can occur as primary disease or can be secondary to tuberculosis elsewhere in the body. Primary tuberculosis mastitis is extremely rare and is thought to occur due to direct inoculation of the breast by M. tuberculosis through skin abrasions or duct openings in the nipple. Secondary involvement of breast is more common. The organisms may reach the breast through lymphatic route or haematogenous routes, or by contiguous spread from the ribs, pleural space. Lymphatic spread by retrograde extension from the axillary lymph nodes is considered to be the most common mode of spread though spread from cervical and mediastinal lymph nodes has been occasionally reported83. Clinical presentation is atypical and often, histopathological evidence suggests the diagnosis.

Disseminated/miliary tuberculosis

Disseminated tuberculosis (DTB) refers to involvement of two or more non-contiguous sites. Dissemination can occur during primary infection or after reactivation of a latent focus/re-infection. During primary infection, small numbers of tubercle bacilli gain access to the circulation through the lymphatics and disseminate to visceral sites which have rich vascular supply and good oxygenation such as the liver, spleen, bone marrow and the brain. These foci heal by calcification in a majority of the patients. In the post- primary period, acute miliary tuberculosis (MTB) can occur when these foci fail to heal and progress. Later in life, reactivation of these latent foci, caseation and erosion into blood vessels can result in haematogenous embolisation and the development of MTB. Rarely, MTB can also develop due to caseation of an extrapulmonary site into the portal circulation and initial hepatic involvement with the classical pulmonary involvement occurring late.

Clinical presentation: Clinical manifestations of DTB/MTB are protean36,156-171. Even in areas where TB is highly endemic, the diagnosis of MTB can be difficult as the clinical symptoms have been subacute and non specific and the chest symptoms can be obscure till late in the disease. Fever and inanition are relatively common. Cough and dyspnoea are often present. Chills and rigors, usually seen in patients with malaria, or, sepsis and bacteraemia have often been described in patients with MTB156-171. Organomegaly is also a frequent physical finding. Choroidal tubercles are bilateral pale greyish white oblong patches which occur less commonly in adult patients with MTB than children. When present, they can be a valuable diagnostic clue160,167. Skin involvement in the form of erythematous macules and papules and unusual manifestations such as ulcerative lesions have also been described156-171. Signs of hepatic involvement may be evident in the form of icterus and hepatomegaly. Neurological involvement in the form of meningitis ortuberculomas is common. Clinically significant cardiac or renal involvement are uncommon in patients with MTB160,172. Overt adrenal insufficiency at presentation, or during treatment has also been described173. In some studies, headache and abdominal pain when present are supposed to have specific implications in MTB, headache signifying the presence of meningitis and abdominal pain signifying abdominal involvement167,168.

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 published160,164,174,175. Severe pulmonary vascular damage has been implicated to be the pathophysiological basis for the development of ARDS in patients with MTB176. Immune reconstitution disease is a well known complication of highly active antiretroviral therapy (HAART). Recently, ARDS developing as a manifestation of severe immune reconstitution disease secondary to pulmonary tuberculosis has been reported177. Increases in CD4+ T- lymphocytes induced by HAART with subsequent inflammation in tissues affected by ongoing infection have been postulated to be the mechanism rsponsible for this. The mortality in ARDS of any cause is high, ranging from 40 to 60 per cent171,178,179. Therefore, identification of the primary cause is vital to initiate the appropriate therapy early. In patients with MTB complicated by ARDS, the classical miliary mottling occurs less commonly and bilateral diffuse interstitial or alveolar infiltrates similar to those described in ARDS of other causes occur nearly in all patients160,162,164 which make the diagnosis even more difficult.

Diagnosis

Methodological issues

Definitive diagnosis of tuberculosis involves demonstration of M. tuberculosis by microbiological, cytopathological or histopathological methods. Clinical presentation of EPTB is atypical. Especially when the disease involves obscure occult sites, EPTB may not even be considered in the initial list of differential diagnosis. Further, invasive methods may have to be employed to secure tissue/body fluids for analysis. Many times representative tissue/body fluid may not be accessible. Even when adequate tissue is procured, the pathological findings may be suggestive of “granulomatous infection” which encompasses a wide range of differential diagnoses rather than “definitive tuberculosis”. Therefore, the clinicians more often rely upon the clinical impression, radiological and endoscopie appearances and non- conventional diagnsotic methods as evidence to diagnose EPTB.

Principles of diagnosis

When EPTB is suspected as a possible diagnosis, every attempt should be made to procure tissue/relevant body fluid for diagnostic testing. Most accessible tissue should be procured Co r histopathological, cytopathological and micrbiological diagnosis. For example, when working up a patient with suspected lymph node tuberculosis, the most easily accessible representative peripheral lymph node should be excised and subjected to diagnostic testing. Similarly, cerebrospinal fluid (CSF) and ascitic fluid examination provide most valuable diagnostic clue in patients with neurological and peritoneal tuberculosis respectively.

With the advent of ultrasound scan and subsequently CT scan and the magnetic resonance imaging (MRI) and widespread availability of 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 of EPTB antemortem. 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.

Tuberculin skin test: In countries like India where tuberculosis is higly endemic, tuberculin skin test result alone is not sufficient evidence to diagnose RPTB in adult patients. Tuberculin positivity in patients with various forms of EPTB is shown in Table I.

Table I. Tuberculin posilivity in various forms of extrapulmonary tuberculosis

Histopathological, cytopathological and microbiologial examination of tissue specimens and body fluids

Fine needle aspiration cytopathology (FNAC), biopsy: In patients with lymph node tuberculosis, FNAC, excision biopsy of the most accessible peripheral lymph node confirms the diagnosis most of the times. CT scan is helpful in localising intrathoracic and intraabdominal lymphadenopathy and radiologically guided FNAC and biopsy192-200, When available, video-assisted thoracoscopic surgery (VATS) can be a valuable minimally invasive procedure to procure tissue for diagnostic testing in patients with intrathoracic lymphadenopathy and pleural disease201. Transporting the collected lymph node specimen in Kirschners transport medium is helpful in increasing the microbiological yield202. In patients with DTB/MTB, various invasive methods have been employed to ascertain the diagnosis their relative diagnostic yield is shown in Table II.

Laparoscopy will facilitate visual inspection of the lesions and faciliatatc procurement of tissue for histopathological confirmation of the diagnosis76. These details are discussed in elsewhere in this issue77.

Table II. Method of confirmation of diagnosis in patients with disseminated/miliary tuberculosis*

Table III. Characteristic body fluid findings in patients with various forms of extrapulmo\nary tuberculosis

Table IV. Yield of various tissues and body fluid specimens by the conventional smear and culture methods in palients with extrapulmonary tuberculosis

Fig.5. Chest radiograph (postero-amerior view) showing right sided pleural effusion.

Fig.6. Chest radiograph (postero-anterior view) showing left sided encysted pleural effusion (a) Contrast enhanced CT scan of the chest of the same patient (b) showing left sided loculated empyema surrounded by thick enhancing pleura (arrow).

Examination of body fluids and other biochemical tests

The characteristic features of various body fluids and their yield by the conventional microbological, histopathological, cytopathological, and nonconventional methods in patients with EPTR is shown in Tables IU-VI.

Pleural fluid: The pleural fluid is typically clear or straw coloured, but cloudy or serosanguinous fluid may also be obtained. The pleural fluid is exudative and lymphocyte rich. Early in the disease, the pleural fluid may reveal predominantly ncutrophils, but on serial thoracocenteses, lymphocytosis may become evident71-75. Presence of a large number of mesothelial cells (> 1 % of white blood cells) is a strong evidence against the diagnosis of tuberculosis, though, a few cases with numerous mesothelial cells in the fluid have been reported71-75.

Fig.7. Chest radiograph (postero-anterior view) showing classical miliary pattern (a). Contrast enhanced CT scan of the chest (b) showing classical miliary pattern. Branching nodular (2 to 3 mm) and linear opacities resulting in a tree-in-bud appearance can also be discerned. These nodules resemble millet seeds (c).

Fig.8. Intravenous pyelogram showing calyceal cut-off sign black arrow and ureteral narrowing (white arrow) (a) thimble bladder (black arrows) (b). Percutaenous nephrogram showing irregularity, narowing and stricture of ureter (white arrow) (c).

Fig.9. Contrast enhanced CT scan of the abdomen showing intraabdominal (a) and rclroperitoneal (b) lymphadenopathy (arrows). Both the white and black arrows point to hypodensity which indicates necrosis in the lymph node. This central attenuation with peripheral rim enhancement is considered classical (though not pathogenomic) for tuberculosis.

Fig. 10. Contrast enhanced CT scan of the abdomen showing multiple hypointense areas in the liver and spleen (arrows) (a), hypodense lesions in the right kidney (arrow) with extension into the poas and paraspinal muscles (arrow) (b) CT guided fine needle aspiration confirmed the diagnosis of tuberculosis

Details about ascitic fluid examination are described eleswhere77.

Cerebrospinal fluid: Clear CSF with moderately raised cells and protein and low glucose constitute the typical CSF picture of TBM. However, these characteristics are shared by other forms of chronic meningitis and partially treated pyogenic meningitis. In the presence of coexisting spinal meningitis and spinal block the CSF may he xanthochromic. If allowed to stand, a pellicle or cobweb may form, indicating the presence of fibrinogen. The pellicle is highly suggestive but not pathognomonic of TBM. CSF protein has been reported to be normal in some patients with AIDS and TBM84. CSF glucose levels are abnormal in the majority of cases, being less than 40 per cent of the corresponding blood sugar level. However, CSF glucose levels are never undetectable as in patients with pyogenic meningitis.

Pericardial fluid: Echocardiography, pericardiocentesis and examination of pericardial fluid can help in confirming the diagnosis of pericardial tuberculosis. The characteristic pericardial fluid findings in patients with tuberculosis pericarditis are shown in Table III.

Urine: The yield of urine examination by smear and culture for detecting the tubercle bacillus is low probably because of the intermittent shedding of the baclli. Nevertheless, in patients with suspected genitourinary tuberculosis, urine examination is mandatory.

Fig.11. Contrast enhanced (CE) CT head showing basal meningitis, ventricular dilatation.

Fig.12. Contrast enhanced (CE) CT head showing intracranial tuberculonia (black arrows) and perilesional oedema (white arrows).

Fig.13. Contrast enhanced MRI of the brain (sagittal view, T1 weighted image) showing solitary enhancing ring lesion (arrow).

Cold abscess pus: Smear and culture examination of the pus aspirated from cold abscesses either directly or under radiological guidance can be rewarding and must be attempted whenever feasible.

Imaging

Plain radiograph: The association of pulmonary tuberculosis assessed by the chest radiograph in patients with various forms of EPTB is depicted in Table VH. In patients with pleural tuberculosis, the chest radiograph usually reveals a unilateral pleural effusion (Fig.5). Sometimes the pleural effusion or empyema can be encysted or multiloculated (Fig. 6a and 6b). Encysted effusion may be confused with a mass lesion of the pleura, mediastinum, chest wall and lungs. Most often encystment occurs in the costoparietal regions, usually along the posterior parietal pleural surface on the right side. A lateral decubitus film may be useful in dstinguishing subpulmonic encystment from subpulmonic collection of free fluid as both these conditions present with a raised hemidiaphragm with convexity lateral than usual with or without a blunted costophrenic angle. Very rarely, encysted mediastinal pleural effusion can present as an unexplained bulge of the mediastinum.

Fig.14. Contrast enhanced MRI of the brain (sagittal view, T1 weighted image) showing intramedullary enhancing ring lesion (arrow) opposite C6 vertebral body (a) before treatment. The lesion resolved completely following nine months of antituberculosis treatment (b).

The hallmark of acute disseminated MTB is the miliary pattern on the chest radiograph (Figs. 7a, 7b and 7c). The term miliary refers to the “millet seed” size of the nodules (2-3 mm) seen on classical chest films158,160. Some patients with MTB, however, may have normal chest radiographs and some may have patterns that are indistinguishable from interstitial pneumonia160. Some of the patients may manifest coalescent opacities. When patients with MTB develop ARDS, the chest radiograph may be identical to that seen in ARDS due to other causes160. In a large study of HIV-negative MTB patients from New Delhi, majority of the patients (88%)160 had chest radiographs consistent with MTB, and in some these classical radiological changes evolved over the course of the disease. The diagnosis of MTB is easier when the patient presents with classical miliary shadowing on chest radiograph in an appropriate setting. However, the diagnosis may be difficult in those situations where chest radiograph does not show classical miliary shadows.

Intravenous pyelography (Figs.8a and 8b) and percutaneous nephrogram (Fig.8c) are useful in imaging GUTB.

Ultrasonography: Ultrasonography of the chest may be helpful in demonstrating winding structures of different lengths which may represent fibrin bands, mobile delicate septations, regular pleural thickening, and occasional nodularity amidst the effusion. Ultrasonography and CT scan (Fig.6b) are useful in the diagnosis of encysted and multiloculated pleural effusions.

Computerised tomography and magnetic resonance Imaging: In patients with pleural effusion and empyema, contrast enhanced (CE) CT scan of the thorax may be useful in identifying the underlying pulmonary lesion, mediastinal, hilar or paratracheal lymphadenopathy (Figs.2a and 2b) and assessing the pleural loculation and thickening (Fig.6b). Sometimes, CECT of the thorax has also been used to assess pericardial thickening in patient with pericardial effusion (Fig.3c).

Abdominal CT scan scores over ultrasonography for detecting high density ascites238-241. Retroperitpneal, peripancreatic, porta hepatis and mesenteric/omental lymph node enlargement may be evident (Figs9a and 9b). Abdominal CT scan also detects caseous necrosis of lymph node which appears as low attenuating, necrotic centres and thick, enhancing inflammatory rim238-241. Granulomas or abscesses in the liver, pancreas and spleen may be seen (Figs. 10a and 10b). In addition to ascites, mesenteric infiltration, omental masses, peritoneal enhancement/thickening and disorganised masses of soft tissue densities may be seen.

In patients with DTB/MTB, CT scan and MRI scan may reveal evidence of neurotuberculosis, intraabdominal lymphadenopathy, infiltrative lesions in liver, spleen and kidney (Fig. 10b).

CT scan or MRI of the brain may reveal thickening and enhancement of basal meninges, hydrocephalus, infarction, periventricular oedema, and mass lesions due to associated tuberculoma or tuberculosis abscess (Figs 11 and 12). Common sites of exudates are basal cisterna ambiens, suprasellar cistern and sylvian fissures. Serial CT scans are very helpful in assessing the course of tuberculomas and hydrocephalus. Gadolinium enhanced MRI is superior to the CT scan in detection of basal meningeal enhancement and small tuberculomas (Figs13,14a and 14b). Contrast enhanced MRI has been found to be superior to the contrast enhanced CT scan in detection of diffuse and focal meningeal granulomatous lesions, in delineating focal infarcts of the basal ganglia and diencephalon. Further, MRI is superior to CT in defining the presence, location and extent of associated brainstem lesions. MRI of the spine is also useful in the diagnosis of lesions of spinal tuberculosis (Figs 4a and 4b).

If there is a high index of suspicion of the diagnosis of MTB and the chest radiograph is atypical, it is suggested that high resolution computed tomographic scan (HRCT scan) (Fig.7b) be done to support the diagnosis. HRCT scan is superior to the conventional CT scan in defining the parenchymal detail. Further, HRCT of the chest with contrast can also be useful in detecting lymph nodal enlargement, calcification and pleural lesions.

Details regarding va\rious imaging modalities in the diagnosis of abdominal tuberculosis are described elsewhere77.

Echocardiography and cardiac catherisation

Echocardiography is useful for detecting the presence of pericardial fluid and features such as collapse of right atrial or right ventricular free wall in diastole which are diagnostic of cardiac tamponade. In fact, these features may sometimes precede the other clinical evidence of pericardial tuberculosis. Echocardiogram, however, is not an accurate test to detect pericardial thickening. Indirect echocardiographic signs such as flat posterior left ventricular wall motion in the diastole, premature opening of the pulmonary valve, may suggest chronic constrictive pericarditis104.

In cardiac tamponade, cardiac catherisation revelas a prominent γ descent in the right atrial tracing. In chronic constrictive pericarditis, a prominent γ descent in the atrial pressure tracing and a dip-plateau ventricular pressure tracing are characteristic of chronic constrictive pericarditis. Cardiac tamponade as well as chronic constrictive pericarditis produce a similar elevated right and left atrial, right and left ventricular end-diastolic pressures104 (Fig.3d).

Serologial, molecular and other non-conventional methods

A number of non-conventional diagnostic methods are often resorted to for diagnosing EPTB. These test results are relied upon as “concrete evidence” to initiate or withold antituberculosis treatment. When many of these non-conventional methods are validated at the time of initial introduction, the criteria employed to define the “gold standard” for diagnosis against which these methods are standardised would include “a clinical presentation compatible with tuberculosis” and “good response to antituberculosis treatment”. Subsequently, the same diagnostic tests are recommended for substantiating the clinical diagnosis. Further, the small sample size and the lack of reproducibility of the tests in most studies render the information generated by these tests inconclusive242. It should be remembered that a positive non-conventional test may perhaps “rule in” a diagnsosis, but certainly a negative test cannot “rule out” a diagnosis of tuberculosis Thus, it is not suprising that the diagnosis of EPTB is often delayed or missed.

Table V. Sensitivity and specificity of immunodiagnostic and molecular methods applied to the pleural fluid and cerebrospinal fluid

Table VI. Sensitivity and specificity of some commonly used non- conventional diagnostic tests in the diagnosis of extrapulmonary tuberculosis

Table VII. Associated pulmonary/pleural disease in patients with various froms of extrapulmonary tuberculosis

Immunodiagnoslic methods

Applied to body fluids: Most often, enzyme linked immunosorbent assay (ELISA) for detecting mycobacterial antigens, antibodies and immunecomplexes in the blood and body fluids have been used in the diagnosis of EPTB. Some workers have advocated testing for a panel of antigens rather than single antigens243. There are numerous publications regarding the application of immunodiagnositc methods for the diagnosis of every form of tuberculosis ranging from sputum positive pulmonary tuberculosis to smear and culture negative EPTB at inaccessible body sites. However, ELISA based methods for the detection of mycobacterial antigens in body fluids have been resorted to most often for the diagnosis of neurological (CSF) and pleural tuberculosis (pleural fluid). The diagnostic yield of ELISA methods in the CSF and pleural fluid EPTB is listed in Table V.

Applied to blood: The diagnostic utility of serodiagnostic methods applied to the blood samples in patients with EPTB is controversial. In a study from India244, the utility and efficacy of detection of antimycobacterial antibodies to A60 antigen in serum and/or CSF was analysed in 100 patients with various forms of EPTB such as neurotuberculosis, abdominal tuberculosis and others. The overall positivity rale for the test was 75 per cent . The positivity rate of the test in serum and/or CSF was 79.2 per cent in neurotuberculosis and 62.5 per cent for other forms of EPTB.

Table IX. Summary of recent randomised controlled trials of additional corticosteroid treatment in patients with extrapulmonary tuberculosis

Table X. Complications and sequelae of extrapulmonary tuberculosis

In another study245, the utility of detecting immunoglobulin G (IgG) and immunoglobulin A (IgA) against A60 antigen was studied in 42 patients with confirmed EPTB, none had clinical or radiological evidence of pulmonary involvement. In addition, 24 subjects with healed pulmonary or EPTB, 44 patients with a defined disease other than tuberculosis, and 88 healthy volunteers were studied. In patients with EPTB, the sensitivity and specificity of IgG and IgA tests were 0.738 and 0.961; and 0.69 and 0.936 respectively. When both the results were combined, the sensitivity was 0.809 and the specificity was 0.923245 . Detection of lipopolysaccharide antigen (LPS) has also been found to be useful in the diagnosis of EPTB207.

Adenosine deaminase: Adenosine deaminase (ADA) is




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