The silent pandemic in South Africa: Extra-pulmonary tuberculosis from head to heel

Extra-pulmonary tuberculosis (EPTB), caused by Mycobacterium tuberculosis, is the leading cause of communicable disease-related deaths in people with human immunodeficiency virus (HIV) worldwide and in South Africa. Mycobacterium tuberculosis disseminates haematogenously from an active primary lung focus and may affect extra-pulmonary sites in up to 15% of patients. Extra-pulmonary TB may present with a normal chest radiograph, which often causes a significant diagnostic dilemma. This review describes the main sites of involvement in EPTB, which is illustrated by local imaging examples.


Introduction
Worldwide and in South Africa, tuberculosis (TB), a communicable airborne disease caused by Mycobacterium tuberculosis, remains the leading cause of death, followed closely by circulatory system diseases. In addition, it is one of the main causes of mortality amongst patients with human immunodeficiency virus (HIV) infection worldwide. 1,2 Tuberculosis predominantly affects the lungs; however, in up to 15% of patients, extra-pulmonary sites may be involved. Extra-pulmonary tuberculosis (EPTB) may be the result of haematogenous dissemination from an active primary focus in the lung to other organ system(s) in the body, and this may present years after the initial pulmonary infection. 3 A normal chest radiograph or negative laboratory tests do not exclude EPTB, a diagnosis that necessitates a high index of suspicion, especially when the patient also tests HIV positive. 3,4 This review briefly outlines the main radiological findings of TB in extra-pulmonary sites, of which pleural and lymph node involvement was found to be the most prevalent in this research setting.

Central nervous system tuberculosis
Tuberculosis may involve the parenchyma, meninges or spine.
imaging and surrounded by marked oedema on all modalities. On MRI, a tuberculous abscess is hypointense on T1W, hyperintense with a hypointense rim on T2W and reveals rim enhancement on T1W post-gadolinium-contrasted imaging. 5,6,7 Infarcts typically involve the deep grey nuclei, that is, basal ganglia, thalamus and internal capsule. 5,6,7 Meninges Meningeal spread occurs because of either rupture of a subpial focus or haematogenous spread via the meningeal vessels, resulting in a thick basal leptomeningeal exudate that enhances avidly on post-contrast imaging ( Figure 2). Dural involvement with pachymeningitis is also possible.
The sequelae of meningeal involvement include hydrocephalus, infarcts, vasculitis and cranial nerve palsies. Hydrocephalus is caused by reduced CSF absorption at the level of the arachnoid villi. Cerebrospinal fluid analysis and typical imaging findings aid in distinguishing tuberculous meningitis from other infective aetiologies. 3,4,5

Spine
The bacilli spread haematogenously via Batson's venous plexus or as a result of reactivation of dormant foci. 5 In severe cases, multiple microabscesses may be scattered throughout the spine with involvement of the meninges ( Figure 3).
The vertebral spine is the most common site of musculoskeletal involvement, with the lower thoracic and upper lumbar spine being the most frequently affected sites. Classic findings of tuberculous spondylitis (Pott disease) are contiguous involvement of more than one vertebral level, with a predilection for the anterior vertebral body adjacent to the end plates. Involvement of the posterior elements is rare in comparison with the end plate changes. 6,8 Presentation with ivory vertebra or complete vertebral collapse (plana) is possible.
Subsequent spread of infection is beneath the anterior or posterior longitudinal ligament or through the vertebral end plates (Figure 4). 6,8 Paraspinal and extradural soft tissue and gibbus formation are the most common findings reported. On MRI, the paraspinal or subligamentous abscesses demonstrate T2-weighted (T2W) hyperintense and T1W hypointense signal. 6,8 Extradural abscess may cause cord compression with neurological fallout ( Figure 5). 6,8 Psoas abscess formation with possible associated calcifications is often a clue to the diagnosis. 6  Mycobacterium tuberculosis preferentially affects end plates, with relative sparing of the intervertebral disc, whilst pyogenic infection affects the intervertebral disc during the early stage of the disease. Metastases typically involve the posterior elements more commonly with expansion of the vertebral body.

Intra-medullary tuberculoma
Intra-medullary tuberculomas demonstrate signal intensities identical to intracranial tuberculomas ( Figure 6). 6,7,8 Arachnoiditis Arachnoiditis is characterised by clumped, thickened, and enhancing nerve roots adherent to the dura, with CSF loculation and attenuation of the CSF spaces as typical features on both CT and MRI. 6,7 Head and neck tuberculosis The lymphatic system is the second most common extrapulmonary site affected by TB in this study setting. The most common presentation is matted, painless lymphadenitis (scrofula), with only mild inflammatory superficial skin changes. Cervical lymph nodes are typically involved. 5,6,8 Central necrosis is a typical finding and may be seen as hypoechoic lymph node centres on ultrasound and low-density central attenuation on CT, depending on the degree of caseation, with possible rim enhancement on post-contrast imaging ( Figure 7). 6,8 Paradoxical transient nodal enlargement during treatment is usually observed in HIV patients. 9 Lymphoma and other infective causes of lymph node enlargement must be excluded, usually by fine needle aspiration or core biopsy of the involved lymph nodes. The sinonasal cavity, larynx and glottis may also be involved, with non-specific imaging findings. 10

Breast tuberculosis
Breast involvement occurs rarely, with the most frequent presentation being a hard painless mass or mastalgia in a young, multiparous woman. Sinus tracts and abscesses are the associated findings. 8 Three types of breast involvement are recognised: nodular, diffuse and sclerosing. The nodular form presents as a dense round area, which represents a caseating lesion, whilst the diffuse form leads to sinus tracts and ulceration. Fibrosis with nipple retraction is the dominant feature of the sclerosing form. 11

Cardiovascular tuberculosis Pericardium
Spread of infection to the pericardium may occur via haematogenous dissemination or direct thoracic lymph node extention. The typical findings include a globular cardiac configuration on chest radiography related to pericardial effusion, with late-stage pericardial calcifications ( Figure 8a).
Echocardiography may demonstrate a fibrinous effusion. Slow accumulation of pericardial effusion is typically seen without tamponade. Mild pericardial thickening and enhancement may be evident on CT (Figure 8b). 8 Constrictive pericarditis is a consequence of pericardial involvement, with typical pericardial calcifications seen at chest radiography.

Myocardium
Although very rare, three types of involvement are recognised, which include the miliary, infiltrating interstitial and caseating nodular types. 12

Abdominal tuberculosis
Spread of infection may occur via ingestion of mycobacteria, haematogenous dissemination, contiguous spread from adjacent organs or lymphatic involvement. 5,6

Peritoneal involvement
Three types of peritoneal involvement can occur, namely, the wet, fibrotic and dry. The wet type is the most common, presenting as free ascites or loculated pockets of high-protein content fluid. The dry type leads to fibrous adhesions with mesenteric thickening. The fibrous type may manifest as omental or mesenteric masses. 5,6 Omentum Omental involvement may result in a combination of omental caking or mass formation. 5 Differential diagnosis includes carcinomatosis in the case of a known primary neoplasm or mesothelioma, if possible asbestos exposure is present.

Lymph nodes, liver and spleen
Intra-abdominal lymph nodes demonstrate the typical lowdensity, central caseous necrosis and rim enhancement at CT, similar to lymph node involvement in the neck or chest.

Gastrointestinal tract
There is a predilection for the terminal ileum and caecum, with acute findings including mural thickening, narrowed terminal ileum and adjacent lymphadenopathy (often necrotic). 5,6,8 A widely gaping, iliocaecal valve (Fleischner sign, Figure 9b) and a shrunken conical caecum (Figure 9b) are seen in the chronic stages. Differential diagnoses include Crohn's disease and lymphoma.

Adrenal glands
The adrenal glands typically demonstrate bilateral involvement. There is gland enlargement and rim enhancement with central low-density necrosis in keeping with adrenalitis. 5 The acute gland enlargement may either resolve or lead to small, dystrophic calcified glands.
Tuberculosis is the most common cause of Addison's disease (Figure 10), and the patient may present with an acute Addisonian crisis. 5

Genito-urinary
Irregular renal cortical calcifications ( Figure 10) and focal caliectasis are the common findings. Other possible findings include renal papillary necrosis, ureteric stenosis (pipe stem), ureteric calcifications ( Figure 11a) and pelviureteric junction narrowing (Kerr's kink, Figure 11b). Renal atrophy with  ground glass calcifications (Putty kidney, Figure 10) are late sequelae. 5,6,8 Bladder wall irregularity, with peripheral calcifications and a small-volume ('thimble') bladder, may be found, which may result in vesico-ureteric reflux with hydronephrosis related to fibrosis at the ureteric orifice. 8 Epididymal and testicular involvement may cause epididymo-orchitis. Seminal vesicles and vas deferens may be affected with wall thickening or calcifications. Prostatic involvement may take the form of abscess or prostatitis. Diffuse dystrophic calcification is seen in the chronic form. 14 Salpingitis, with a fallopian stricture, typically occurs at the junction of the isthmus and ampulla. 6,7 Endometrial adhesions or synechiae formation may develop. 6,8 Musculoskeletal Monoarthritis of weight-bearing joints is common. 6,8 Patterns of involvement include spondylitis, tuberculous arthritis ( Figure 12 -knee), osteitis or osteomyelitis (Figure 13), soft tissue involvement, bursitis ( Figure 14), tenosynovitis ( Figure 15) and dactylitis. 5,6,8 Periarticular osteopenia, marginal erosions and subtle joint space loss are seen with articular involvement and are called the Phemister triad ( Figure 12). 5,6,8 A recent case series by Swarap et al., 15 demonstrates atypical sites of musculoskeletal involvement, and emphasises the need for maintaining a high index of suspicion in order to make the correct diagnosis.

Conclusion
Tuberculosis remains a common diagnosis made on a daily basis by radiologists in South Africa, and hence, is known to be a silent pandemic when misdiagnosed. Extra-pulmonary TB remains underdiagnosed, with patients often presenting

FIGURE 14:
A 20-year-old human immunodeficiency virus-negative female presented with chronic hip pain, which progressively worsened over 3 months. Coronal T1-weighted fat sat post-contrasted magnetic resonance imaging of the pelvis demonstrates rim-enhancing masses within the greater trochanter and intertrochanteric space (images not included), which communicates with the right trochanteric bursa. Rim-enhancing abscesses (solid white arrows) extend from the bursa, inferiorly underneath the ilio-tibial band. Tuberculous osteitis with overlying bursitis and cold abscess formation was confirmed on tissue Gene expert. at advanced stages of the disease with extensive destruction of the organ system(s) involved, which is mainly because of the stigma and its association with HIV infection.
Tuberculosis is known as the great mimicker and remains the leading cause of communicable-disease-related deaths in our country. It must be considered as a differential when evaluating patients with sequelae of chronic infection in all pandemic areas.