Scholarly article on topic 'Imaging in Extrapulmonary Tuberculosis'

Imaging in Extrapulmonary Tuberculosis Academic research paper on "Clinical medicine"

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Abstract of research paper on Clinical medicine, author of scientific article — Sanjay Gambhir, Mudalsha Ravina, Kasturi Rangan, Manish Dixit, Sukanta Barai, et al.

Summary Tuberculosis (TB) remains a major global public health problem, with 1.5 million deaths annually worldwide. One in five cases of TB present as extrapulmonary TB (EPTB), posing major diagnostic and management challenges. Mycobacterium tuberculosis adapts to a quiescent physiological state and is notable for its complex interaction with the host, producing poorly understood disease states ranging from latent infection to active clinical disease. New tools in the diagnostic armamentarium are urgently required for the rapid diagnosis of TB and monitoring of TB treatments, and to gain new insights into pathogenesis. The typical and atypical imaging features of EPTB are reviewed herein, and the roles of several imaging modalities for the diagnosis and management of EPTB are discussed.

Academic research paper on topic "Imaging in Extrapulmonary Tuberculosis"

Accepted Manuscript

Title: Imaging in Extrapulmonary Tuberculosis

Author: Sanjay Gambhir Mudalsha Ravina Kasturi Rangan Manish Dixit Sukanta Barai Jamshed

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S1201-9712(16)31220-6 IJID 2766

To appear in: International Journal of Infectious Diseases

Received date: 12-10-2016

Revised date: 31-10-2016

Accepted date: 1-11-2016

Please cite this article as: Gambhir S, Ravina M, Rangan K, Dixit M, Barai S, Bomanji J, the International Atomic Energy Agency extra-pulmonary TB Consortium1 Imaging in Extrapulmonary Tuberculosis, International Journal of Infectious Diseases (2016),

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• Diagnosis of Extra-pulmonary tuberculosis (EPTB) remains challenging due to protean clinical manifestations and difficulties in making accurate diagnosis.

• Advances in imaging technologies now allow for accurate localization of diseased sites and access to obtaining biological samples for microbiological, histo-pathological and molecular testing.

• Evidence is building towards use of newer imaging modalities for monitoring response to treatment and for relapse.

Review for IJID series for World TB Day 2017

20 21 22


Imaging in Extrapulmonary Tuberculosis Authors:

Sanjay GambhirA, Mudalsha RavinaA, Kasturi RanganA, Manish DixitA, Sukanta BaraiA, Jamshed Bomanji#, and *the International Atomic Energy Agency extra-pulmonary TB Consortium*

Institutional affiliations:

# Department of Nuclear Medicine, of Nuclear Medicine, UCLH NHS Foundation Trust London, UK

ASanjay Gandhi Post Graduate Institute of Nuclear Medicine, Lucknow India and Institute

*the International Atomic Energy Agency extra-pulmonary TB Consortium: Rajnish Sharma, Bhagwant Rai Mittal, Sanjay Gambhir, Ahmad Qureshy, Shamim Momtaz Ferdousi Begum, Mike Sathekge, Mariza Vorster, Dragana, Sobic Saranovic, Pawana Pusuwan, Vera Mann, Shobhan Vinjamuri, Allimudin Zumla, Thomas Pascual, Jamshed Bomanji -author affiliations below-next page) .

Keywords: Tuberculosis, Imaging, CT, PET-CT, MRI, extrapulmonary tuberculosis, diagnosis, biomarker, , 18F-fluorodeoxyglucose (FDG) PET-CT

Corresponding Authors:

Dr Jamshed Bomanji MBBS, PhD, FRCR, FRCP Institute of Nuclear Medicine, 5th Floor, UCLH NHS Foundation Trust, 235 Euston Road,London NW1 2BU

Prof. Sanjay Gambhir, MBBS, DNB Nuclear Medicine, SGPGIMS, Lucknow, India, Head, Nuclear Medicine Sanjay Gandhi Post Graduate Institute of Medical Science, Rae Bareli Road, Lucknow, India Tel:+91 522 2494623 Fax: +91 522 2668017

48 AUTHOR AFFILIATIONS: for the International Atomic Energy Agency extra-pulmonary TB

49 Consortium*

50 Rajnish Sharma, Director & Head , Division of Nuclear Medicine & PET Imaging, Specialist

51 in Nuclear Medicine &Thyroid diseases, Molecular Imaging & Research Center ( MIRC),

52 INMAS, Delhi. Email:

54 Bhagwant Rai Mittal, Director & Head, Dept. of Nuclear Medicine & PET, Post Graduate

55 Institute of Medical Education and Research, Sector 12, Chandigarh - 160012, India.

56 Email:

58 Sanjay Gambhir, Director and Head, Dept. of Nuclear Medicine, SGPGIMS, Rae Bareli Road,

59 Lucknow-226014 Email:

61 Ahmad Qureshy, INMOL Hospital, New Campus Road, Lahore 54600, Pakistan,

62 Email:

64 Shamim Momtaz Ferdousi Begum, National Institute of Nuclear Medicine & Allied Sciences

65 (NINMAS) 7th-10th Floor, Block-D, BSM Medical University Campus, Shahbag, Dhaka-1000.

66 Email:

68 Mike Sathekge, Department of Nuclear Medicine, Steve Biko Academic Hospital, University

69 of Pretoria, Pretoria, South Africa. Email:

71 Mariza Vorster, Department of Nuclear Medicine, Steve Biko Academic Hospital, University

72 of Pretoria, Pretoria, South Africa. Email:

74 Dragana Sobic Saranovic, Faculty of Medicine University of Belgrade and Center of Nuclear

75 Medicine Clinical Center of Serbia, Belgrade, Serbia.

76 Email:

78 Pawana Pusuwan, Division of Nuclear Medicine, Faculty of Medicine, Siriraj Hospital,

79 Mahidol University, Bangkok-noi, Bangkok 10700, Thailand

80 Email:

82 Vera Mann, Institute of Nuclear Medicine, UCLH NHS Foundation Trust, 235 Euston Road,

83 London NW1 2BU, UK

84 Email:

86 Shobhan Vinjamuri, Royal Liverpool University Hospital, Liverpool L7 8XP, UK

87 Email:

89 Alimuddin Zumla, Center for Clinical Microbiology, Division of Infection and Immunity,

90 University College London, and the National Institute of Health Research Biomedical

91 Research Centre at UCL Hospitals, , London, United Kingdom. Email:

93 Thomas NB Pascual, Section of Nuclear Medicine and Diagnostic Imaging, Division of

94 Human Health, Department of Nuclear Sciences and Applications, International Atomic

95 Energy Agency, Vienna International Centre, PO Box 100, 1400 Vienna,

96 Email:

98 Jamshed Bomanji, Institute of Nuclear Medicine, UCLH NHS Foundation Trust, 235 Euston

99 Road, London NW1 2BU, UK

100 Email:

122 123


125 Today TB remains a major global public health problem with 1.5 million deaths annually.

126 One in five cases of TB present as extrapulmonary TB (EPTB) posing major diagnostic and

127 management challenges. Mycobacterium tuberculosis adapts to a quiescent physiological

128 state and is notable for its complex interaction with the host, producing poorly understood

129 disease states ranging from latent infection to active clinical disease. New tools in the

130 diagnostic armamentarium are urgently required for the rapid diagnosis of TB, monitoring of

131 TB treatments, and acquisition of newer insights into pathogenesis. We review the typical

132 and atypical imaging features of extrapulmonary TB and discuss the roles of several imaging

133 modalities for the diagnosis and management of EPTB.


135 Tuberculosis today remains a major global public health problem with 1.5 million deaths

136 annually (WHO 2014). One in five cases of TB present as extrapulmonary TB (EPTB) posing

137 major diagnostic and management challenges. Accurate diagnosis of active pulmonary

138 tuberculosis may be challenging in patients without any microbiological evidence of the

139 presence of Mycobacterium tuberculosis from sputum samples. Tuberculin skin tests or

140 serum interferon-gamma release assays can determine TB exposure in such patients but

141 cannot differentiate between active and latent disease. Culture remains the gold standard

142 but it can take upto 8-10 weeks and variable sensitivities depending on the host and sites

143 are noted. Mainly blood cultures, urine cluture and culture of other body fluids aids in the

144 diagnosis.

145 The most frequent sites of extrapulmonary TB include lymph nodes, the peritoneum,

146 and the ileocecal, hepatosplenic, genitourinary, central nervous system (CNS), and

147 musculoskeletal regions; multisystem involvement is common.

148 Population groups with increased risk of TB are immunocompromised individuals

149 (AIDS, lymphoma, leukemia, post-organ transplant), diabetics, children, the elderly,

150 alcoholics, persons with a low socioeconomic status, persons with poor compliance,

151 immigrants from Third World countries, prisoners, nursing home residents, health care

152 workers, and the homeless1-3. The increase in TB has been witnessed not only in Africa and

153 Asia but also in European countries; hence TB remains an important cause of morbidity and

154 mortality worldwide4,5.

155 In this mix of risk factors multidrug-resistant (MDR) TB continues to flourish. MDR

156 TB requires prolonged administration of toxic second-line drugs, associated with higher

157 morbidity and mortality rates. Patients also remain infectious for a longer period once

158 treatment has been started. A new strain, of extensively drug-resistant (XDR) TB, is evolving;

159 this MDR strain is also resistant to second-line drugs including any fluoroquinolone and at

160 least one of three injectable drugs (capreomycin, kanamycin, and amikacin). Despite the

161 enormous burden of disease, current diagnostics are still woefully inadequate to meet

162 research and clinical needs.

163 Radiologic investigations play a crucial role in the early and correct identification of

164 extrapulmonary TB. Imaging modalities of choice are Computerised Tomography

165 (CT,lymphadenopathy and abdominal TB) and Magnetic Resonance imaging (MRI,CNS and

180 181 182

musculoskeletal TB). MRI is also indicated in pediatric or pregnant patients, in whom radiation is to be avoided. In addition, bone scanning is performed in skeletal TB and 18F-fluorodeoxyglucose (FDG) PET-CT in assessment of disease extent and response monitoring. Tuberculosis demonstrates a variety of clinical and radiologic features depending on the organ site involved and has a known propensity for dissemination from its primary site. Thus, TB can mimic a number of other disease entities, and it is important to be familiar with the various radiologic features of TB. Herein we illustrate the imaging findings of ETB and their relevance in the present scenario. Familiarity with the same helps in early diagnosis, initiation of therapy and monitoring patients on treatment.

Literature review

A pubmed search of the relevant articles discussing role of imaging in ETB was done. Tuberculous lymphadenopathy

Also known as scrofula, tuberculous lymphadenopathy is a common form of extrapulmonary TB seen in endemic populations as well as immunocompromised patients in developed nations. The most commonly affected lymph nodes, in decreasing order, are the cervical (63%), mediastinal (27%), and axillary (8%-10%). Most cases present as unilateral cervical lymphadenopathy. Imaging features

Imaging alone cannot distinguish between the causes of lymphadenopathy. Ultrasonography

Nodal matting with surrounding edema is seen. Doppler study may reveal increased vascularity, mostly at the hilum. This feature allows differentiation from malignant lymph nodes, which show peripheral vascularity6. CT and MRI

The lymph nodes are usually matted. However, density depends on the amount of

caseation, which increases with time7.


F-FDG PET-CT may show peripheral uptake and central hypometabolism, depending on the

amount of caseation . 18F FDG PET-CT has the advantage of identifying all affected lymph

196 node groups within a single setting and allows selection of lymph node group most suitable

197 for biopsy (Fig. 1).

199 Fig. 1A,B.

200 Abdominal tuberculosis

201 Abdominal TB may occur directly, as in the case of primary pulmonary TB, or indirectly, via

202 spread from the primary. It generally affects the following organs:

203 • Lymph nodes

204 • Peritoneum

205 • Ileocecal junction

206 • Colon

207 • Liver

208 • Spleen

209 • Adrenal glands

210 Solid viscera are affected to a greater extent than the gastrointestinal tract. CT is the

211 mainstay for investigation of possible abdominal TB; however, knowledge of other

212 imaging modalities, such as barium enema examination, is important to avoid

213 misdiagnosis in cases in which TB is not initially suspected.

215 Abdominal lymphadenopathy

216 Abdominal lymphadenopathy is the most common manifestation of abdominal TB,

217 seen in 55%-66% of patients8. On CT the nodes are usually matted, appearing in groups

218 with mild fat stranding, hypoattenuating center with or without ca lcification. 18F-FDG PET-CT

219 shows increased metabolic activity in the nodes and plays a role in the assessment of

220 treatment response.

222 Peritoneal tuberculosis

223 Peritoneal TB affects one-third of patients and is oneof the most common manifestations of

224 abdominal TB. Subdivision, into wet, fibrotic, and dry types has been proposed9. On imaging,

225 there may be significant overlap between the three.

226 • Wet type: manifests in more than 90% of patients, has high protein and cellular

227 content, leading to high-attenuating pockets of loculated fluid or free ascites. The

228 Hounsfield unit (HU) ranges from 20 to 45.

229 • Dry type: cake-like omentum with fibrous adhesions and mesenteric thickening.

230 • Fibrotic type: presents as omental or mesenteric masses.

231 The main imaging differential diagnoses are malignancy and peritoneal carcinomatosis10.

235 Gastrointestinal tract tuberculosis

236 Due to the abundance of lymphoid tissue, the ileocecal junction (90%) is one of the most

238 hypertrophic, or ulcerohypertrophic11,12.

239 Imaging features

240 Barium studies

241 In early stages, narrowing of the terminal ileum, thickening and gaping of the ileocecal

242 valve, and thickening and hypermotility of the cecum are noted. In chronic stages, the

243 ileocecal valve appears fixed, rigid, and incompetent, while the cecum appears shrunken in

244 size. In later stages a "pulled-up" cecum is usually noted.

246 On CT circumferential wall thickening of the terminal ileum and cecum is noted, usually in

247 association with mesenteric lymphadenopathy. The differential diagnosis includes Crohn's

248 disease, carcinoma, and lymphomatous involvement.

249 Involvement of the esophagus, stomach, duodenum, and small bowel is still rare.

250 Esophageal TB is mainly from the carinal lymph nodes. Small bowel TB may present as

251 mucosal thickening. The antrum and distal body are the most commonly affected sites in

252 the stomach. The presence of a fistula or a sinus confirms the diagnosis.

237 common sites of involvement in the bowel8,9. The presentation may be ulcerative,

245 CT

260 261 262

280 281 282

Hepatosplenic tuberculosis

Hepatosplenic TB may present as miliary or macronodular involvement. The lesions are hypoattenuating on CT and may show peripheral postcontrast enhancement. The most common route of involvement is hematogenous either through hepatic artery in military TB or through portal vein fromgastrointestinal lesions. Macronodular involvement is less frequent and is manifested by single or multiple focal density lesions with or without peripheral rim enhancement.

On MRI, macronodular lesions appear hypointense on T1-weighted images and hypoto hyperintense on T2-weighted images, with thin peripheral and/or internal septal enhancement.

Differential diagnosis includes fungal infections, sarcoidosis, lymphoma, and, rarely, metastasis.

Adrenal tuberculosis

The adrenal glands are the most common endocrine glands involved by TB. The spread is predominantly via the hematogenous route and may be unilateral or bilateral, with central areas of caseation. The involvement of adrenal cortex, may lead to primary adrenal insufficiency and where more than 90% of the cortex is involved, a life-threatening addisonian crisis may ensue13.

In early stages, smooth enlargement of the gland with low-density areas andrelative central hypoenhancement is noted on CT14. In later stages and/or in previously treated patients, gland atrophy with punctate, localized, or diffuse calcification is observed. The MRI features are analogous to the CT appearances except for limitations when calcification is present. 18F-FDG PET-CT shows increased metabolic activity in adrenals in TB or any infection. Often this may be an incidental finding on PET-CT done for another diagnosis. The gland may show diffuse or patchy uptake on 18F-FDG images. Genitourinary tuberculosis

Tuberculosis may involve the genitourinary tract as a secondary site following hematogenous dissemination from the lungs15.

Renal tuberculosis

283 Tuberculosis at these sites accounts for 15%-20% of cases of extrapulmonary TB16.

284 Routinely, two morphological appearances are seen: pyelonephritis or a pseudotumoral

285 type presenting as single or multiple nodules.

286 The collecting system is involved in isolation or due to contiguous spread from the

287 parenchyma. In early stages, papillary necrosis resulting in uneven caliectasis is noted.

288 Hydronephrosis and multifocal strictures with mural thickening and enhancement are

289 observed in progressive disease. Progressive hydronephrosis and parenchymal thinning with

290 dystrophic calcification are noted in end-stage disease.

291 Imaging features

292 Plain radiography

293 On plain radiographs, foci of calcification are noted in 25%-45% of patients17. Triangular

294 ring-like calcification in the collecting system is observed in cases of papillary necrosis.

295 Amorphous focal ground glass-like calcification (putty kidney) is seen in end-stage disease18.

296 Intravenous urography

297 Plain film intravenous urography is quite sensitive in detecting rena l TB19: Only 10%-15% of

298 those affected have normal imaging. A range of findings may be observed, including

299 parenchymal scars (50%), moth-eaten calyces due to necrotizingpapillitis, irregular

300 caliectasis, phantom calyx, and hydronephrosis. Lower urinary tract signs include the "Kerr

301 kink", which occurs due to abrupt narrowing at the pelviureteric junction20.

302 Ultrasonography

303 In early-stage disease, ultrasonography may show an irregular cortical outline with

304 calcification. As the disease progresses, papillary destruction with echogenic masses and

305 distorted renal parenchyma can be observed. In end-stage disease, heavy dystrophic

306 calcification with a small shrunken kidney is noted.

307 Ultrasonography is less sensitive in detecting isoechoic masses and small calcifications and

308 in identifying small cavities communicating with the collecting system.

309 CT and MRI

310 CT intravenous pyelography is most sensitive in identifying all manifestations of renal TB.

311 Depending on the site of the stricture, various patterns of hydronephrosis may be seen,

312 including focal caliectasis, caliectasis without pelvic dilatation, and generalized

313 hydronephrosis. Other common findings include parenchymal scarring and low-attenuation

parenchymal lesions. CT is also useful in depicting the extension of disease into the extrarenal space21,22.

The radiologic differential diagnosis of renal TB includes other causes of papillary necrosis, transitional cell carcinoma, and other infections. 18F-FDG PET-CT may be used to evaluate renal masses (Fig. 2), to identify latent or active TB in the lung, or to monitor therapy.

aim >■« *


Fig. 2A,B

Ureteric Tuberculosis Imaging features Intravenous Urography

In the chronic state, beaded areas due to alternate strictures and dilatation are noted. CT

Ureteral wall thickening is observed in the acute setting. In chronic disease, strictures and shortening of the ureter, leading to pipe stem ureter, are noted. Urinary bladder tuberculosis

Urinary bladder involvement is secondary to descending spread of infection along the urinary tract22.An irregular wall with a small capacity bladder is noted. Fibrotic changes at the ureteric orifices lead to vesicoureteric reflux and hydroureteronephrosis23.

Female genital organs

Involvement of the genital organs occur in 1.5% of females affected with TB. Spread may be via the hematogenous or the lymphatic route. On hysterosalpingography, obstruction is usually noted at the junction of the isthmus and the ampulla24,25. A beaded appearance is seen due to multiple constrictions. A normal uterine cavity may be observed in more than 50% of cases. A further possible presentation is as an irregular filling defect with uterine

340 synechiae and shrunken cavity (3%-18% of cases).Lesions may show uptake on 18F-FDG PET-

341 CT (Fig. 3).

Fig. 3.

Male genital organs

Involvement of the genital organs in males is generally confined to the seminal vesicles or prostate gland, with occasional calcification (10% of cases). The testes and epididymides are rarely involved. Hypoattenuating lesions are noted on contrast-enhanced CT, likely representing foci of caseous necrosis. Nontuberculous pyogenic prostatic abscesses have a similar CT appearance22. The spread is hematogenous and self-limiting. Ultrasonography

shows focal or diffuse areas of decreased echogenicity; however, these findings are very nonspecific23,26.

Musculoskeletal tuberculosis

Musculoskeletal TB accounts for about 3% of all TB infections. The main route of spread is hematogenous, from lungs, or via activation of dormant infection in bone or joint post trauma27. Cases of musculoskeletal TB are usually subclassified as tubercular spondylitis

(50%) (popularly called Potts' spine), peripheral tuberculous arthritis (60%), osteomyelitis (38%), and soft tissue TB, including tenosynovitis and bursitis28-30.

Tubercular spondylitis

The disease spread is via the venous plexus of Batson. The most commonly affected vertebrae are the lower thoracic and upper lumbar. The vertebral body is involved to a greater extent than the posterior elements, and the classical presentation is involvement of two or more contiguous vertebrae with or without paravertebral abscess. The presence of calcification, which may sometimes be absent, almost confirms the diagnosis. In cases of anterior subligamentous involvement, the infection spreads inferiorly or superiorly without vertebral disk involvement.

Imaging features

Plain radiography

Potential early changes include irregular end plates and a decrease in vertebral height. Sharp angulation or gibbus deformity is noted, with anterior wedging or collapse. Displacement of paraspinal lines suggestive of psoas involvement may be noted. The calcified psoas is suggestive of an abscess.

Spinal TB might lead to vertebra plana where there is a reduction in anterior and posterior height, preserved intervertebral disk andsome forms of vertebral end plate change.


Ultrasonography is usually helpful in identifying iliopsoas abscess and its percutaneous drainage.

Cross-sectional imaging is required to better establish the extent of vertebral involvement and the possible presence of a paravertebral abscess.

MRI is the gold standard investigation for tubercular spondylitis. MRI helps to identify the presence of an epidural component and cord compression. An early finding is focal T2 hyperintense and T1 hypointense bone marrow edema in the anterior part of vertebral body adjacent to endplates, with patchy postcontrast enhancement. An abnormal T2 hyperintense signal is noted in the involved disk space, with reduced height. Multifocal TB, compression of the spinal cord, abnormal T2 hyperintense signal in the spinal cord, and neural foraminal and neural compromise secondary to epidural collections are well demonstrated on MRI. MRI may also demonstrate the complete extent of an iliopsoas or paraspinal abscess. Small foci of involvement of posterior elements are better observed on

MRI than CT31-33. Bone scintigraphy

99mTc-Methylene diphosphonate bone scan may identify multifocal sites and can sometimes be used to rule out metastasis suggested by the involvement of multiple contiguous vertebrae (Fig. 4).

Fig. 4.

18f-fdg pet-ct

18F-FDG PET-CT may show increased uptake in tubercular spondylitis, with identification of multiple sites, and offer further help in response monitoring34,35 (Figs. 5, 6).

412 Fig. 5A-F.

• ' 1 E

Fig. 6A-F

Tubercular arthritis

Tubercular arthritis is the most common extra-axial form of musculoskeletal TB. In 90% of cases, it is monoarticular, commonly affecting large weight-bearing joints such as the hip and knee36,37. Less commonly it involves the shoulder, elbow, and sacroiliac joints. Periarticular osteoporosis, peripherally located osseous erosion, and progressive decrease in the joint space suggest the diagnosis of TB and are popularly referred to as the "Phemister triad". In later stages, fibrosingankylosis ensues37-39. Atrophic changes in bones may occur and lead to atrophic arthropathy, especially in the shoulder joint.

Imaging features

426 Ultrasonography

427 Ultrasonography mainly helps in identifying joint effusion, although the appearances are

428 nonspecific.

430 CT

431 CT helps to establish the degree of bone destruction. Sequestrum or sinus formation can be

432 demonstrated on postcontrast scan.

434 MRI

435 Lesions are usually T1 hyperintense and T2 hypointense and show brilliant post-gadolinium

436 enhancement which is a result of blood degradation products and inflammation. Sinus tracts

437 appear as linear T2 hyperintensity with marginal "tram track enhancement"28,37.

439 Tubercular osteomyelitis

440 Tubercular osteomyelitis is most commonly seen in bones of the extremities (femur, tibia),

441 including the small bones of the hands and feet (Figs. 7, 8), often involving the epiphyses. In

442 children, metaphyseal foci can involve the growth plate, a feature that differentiates TB

443 from pyogenic infection40. Radiologically, foci of osteolysis with varying degrees of

444 eburnation and periostitis are observed.

446 Tubercular dactylitis

447 Tuberculous dactylitis, in which there is painless involvement of the short tubular bones of

448 the hands and feet, is more common in children. At radiography, pronounced fusiform soft

449 tissue swelling with or without periostitis is the most common finding41,42.

451 Fig. 7.

i w ' :ét ; <* 4è » » > t, ,1 t 1 '1 С \ 'J 4< #1

: : • ß 1 r)l, ' 11 ■ ■ RA fc •

.В' ' ' . In'. Ж ' ill. 1 n RA i f

Fig. В.

Central nervous system tuberculosis (CNS TB)

457 The spread is either hematogenous, or by direct extension from local infection, such as

458 tuberculous otomastoiditis. CNS TB accounts for 1% of all TB and 10%-15% of

459 extrapulmonary TB. It is a leading cause of morbidity and mortality in endemic regions43,44.

461 Manifestations of cranial TB include:

462 • Extra-axial

463 - Tubercular leptomeningitis

464 - Tubercular pachymeningitis

465 • Intra-axial

466 - Tuberculoma

467 - Focal cerebritis

468 - Tubercular abscess

469 - Tubercular rhomboencephalitis

470 - Tubercular encephalopathy

472 Tubercular leptomeningitis

473 Tubercular leptomeningitis (TBM) is more common than pachymeningitis. It presents with

474 thick tuberculous exudate in the base of brain in the subarachnoid space, the most common

475 location being the interpeduncular fossa. Extension to the surface of the cerebral

476 hemispheres is rare.

477 Cerebrospinal fluid (CSF) flow may be disrupted, leading to obstructive hydrocephalus or

478 communicating hydrocephalus due to obstruction in the basal cisterns. Ischemic infarcts due

479 to arteritis are also noted. In addition, involvement of the cranial nerves may be observed,

480 with the second, third, fourth, and seventh most frequently affected45-47.

481 On MRI, abnormal meningeal enhancement is noted. The magnetization transfer (MT)

482 technique is reported to be superior in differentiating TBM from other causes of meningitis.

483 Meninges appear hyperintense on precontrast T1-weighted MT images and enhance further

484 on postcontrast T1-weighted MT images. The MT ratio in TBM is significantly higher than in

485 viral meningitis, while fungal and pyogenic meningitis show a higher MT ratio compared

486 with TBM48.

488 Tubercular pachymeningitis

489 Tubercular pachymeningitis is rare and is characterized by plaque-like regions of

490 pachymeningeal enhancement that appear hyperdense on plain CT scan, isointense to brain

491 on T1-weighted imaging, and isointense to hypointense on T2-weighted imaging.

492 Homogeneous post-contrast scan enhancement is noted.

494 Tuberculoma

495 Lesions may be solitary, multiple, or miliary. The most commonly affected areas are the

496 frontal and parietal lobes. Tuberculomas account for 15%-50% of space-occupying lesions in

497 endemic areas.

498 Imaging features

499 CT

500 The classical presentation is homogeneous ring-enhancing lesions with irregular walls of

501 varying thickness. One-third of patients demonstrate the "target sign" (i.e., central

502 calcification or punctate enhancement with surrounding hypoattenuation and ring

503 enhancement)45.

506 Appearances on MRI depend on whether the tuberculoma is caseating or noncaseating.

507 Noncaseating tuberculomas are hypointense on T1-weighted and hyperintense on T2-

508 weighted images, with homogeneous post-contrast enhancement. Caseating granulomas

509 are isointense to hypointense on both T1- and T2-weighted images, with peripheral

510 postcontrast enhancement. Caseating granuloma may show central T2 hyperintensity

511 owing to liquefaction. Associated TBM may be seen. In miliary TB, tiny 2- to 5-mm T2

512 hyperintense disk enhancing tuberculomas are seen with TBM. They are better visualized on

513 MT spin echo T1-weighted images49. MR spectroscopy is promising in the specific diagnosis

514 of tuberculomas. A large lipid lactate peak at 1.3 ppm is characteristic, with associated

515 reduced N-acetyl aspartate and/or slightly increased choline levels.

517 18F FDG PET-CT and MRI might be complementary to each other in identifying the lesions

518 (Fig 9).

505 MRI

Fig 9.

Tubercular abscess

Tubercular abscess accounts for 4%-7% of cases in the endemic region. Presentation is as a large solitary lesion, which may be multiloculated, with surrounding vasogenic edema and mass effect. Such abscesses have pus-filled centers, vascular granulation tissue, and absence of epithelioid granulomatous reaction. The causative organism may be isolated from the pus, in contrast to tuberculomas.

The lesion may show central low intensity on T1-weighted images and peripheral low intensity due to vasogenic edema. Diffusion-weighted imaging reveals restricted diffusion with low apparent diffusion coefficient values. On imaging, pyogenic and fungal abscesses may mimic tuberculous abscess. Tuberculous abscess shows a large lipid lactate peak at 1.3 ppm on MR spectroscopy owing to the presence of mycolic acid within the mycobacterial walls, which represents a distinguishing feature from pyogenic abscess50.


Rhomboencephalitis is a particular form of neurotuberculosis affecting the hind brain. The

most common manifestation is tuberculoma.


Encephalopathy in the context of TB is most commonly observed in children and infants with pulmonary TB. The postulated mechanism is a delayed type IV hypersensitivity reaction initiated by a tuberculous protein which leads to extensive damage of white matter with infrequent perivascular demyelination. Imaging shows extensive unilateral or bilateral brain edema51.

Spinal and meningeal involvement


Spinal TB (Fig. 10) commonly manifests as TBM and rarely as intramedullary tuberculoma. MRI is the modality of choice for spinal TB assessment. Spinal TBM manifests as linear enhancing exudates along the spinal cord in the subarachnoid spaces and clumping of cauda

equina nerve roots

Fig. 10.

Tubercular otomastoiditis

Tubercular otomastoiditis, which occurs acutely secondary to tuberculosis infection, is more frequently observed in immunocompromised patients. It may present with painless chronic otorrhea with an intact tympanic membrane or as pain, purulent discharge, and ossicular erosion. There may be associated cervical lymph nodal involvement in the interparotid, upper cervical, and preauricular regions. Pachymeningeal involvement with potential dural sinus thrombosis is also sometimes seen.

Tubercular mastitis

Tubercular mastitis is a rare occurrence, although the incidence has been rising (0.1%-3%) in endemic areas like Africa and India52. The first case was reported in 1829 by Sir Ashley Cooper, who referred to it as "scrofulous swelling of the bosom"53. The significance of breast TB lies in the fact that its masquerades the symptoms of breast cancer and inflammatory

disease of the breast. It may present in nodular form or as multifocal disease. 53Radiological imaging is not diagnostic as there is significant overlap with other pathologies. Breast ultrasonography may show a hypoechoic mass or focal or sectorial duct ectasia. Caseating granulomas in a tissue sample are diagnostic. Cardiac tuberculosis

Cardiac TB is a rare infection involving the cardiac muscles that is seen in 1%-2% of patients with pulmonary TB54,55. There is predominantly pericardial and myocardial involvement, and endocardial spread may occur from the myocardium.

Imaging features Plain radiography

The radiographic appearance may be normal in the early stages while pericardial calcification may be evident in later stages. CT and MRI

CT may reveal pericardial effusion, thickening, or calcification in the chronic stages. On cardiac MRI, Tl-weighted images may show a nodular lesion which appears isointense to slightly hyperintense. On T2-weighted images the lesion appears isointense, with mild enhancement post gadolinium.

Role of PET-CT: challenges and limitations

FDG is a non-physiological glucose analog that undergoes metabolism by the same physiological processes as glucose, including being taken up by cell surface transporters (mainly the glucose transporter-1, GLUT-1) and transformed by the rate-limiting glycolytic enzyme, hexokinase, into FDG-6-phosphate. An interesting early observation by Kubota and co-workers was that a substantial component of 18F-FDG uptake in tumor tissue is a result of

activity localizing to peritumoral inflammatory cells, such as macrophages, which

demonstrate greater F-FDG uptake than tumor cells. Multiple mechanistic similarities are now recognized between inflammatory and malignant cells in terms of the underlying metabolic pathways56. It is this differential increase in tissue glycolysis in inflamed tissue, as opposed to normal cells, that forms the pathophysiological basis for use of 18F-FDG PET-CT in TB.

600 601 602

610 611 612

620 621 622 623

F-FDG PET-CT is useful in identifying the extent of disease in patients with extrapulmonary TB. Tubercular lymphadenopathy shows high-grade metabolism, and 18F-FDG PET-CT may therefore help in selecting nodes suitable for biopsy based on metabolic uptake/SUVs. Moreover, PET-CT is more sensitive than structural imaging methods in detecting lesions. Apart from assisting in selection of the site for biopsy, PET-CT may play a significant role in monitoring response to treatment: its ability to detect changes in metabolic uptake means that it may be considered a specific complementary tool to structural imaging for this purpose57. Refining of imaging techniques like dual time point imaging may further improve the detection of disease60 (Fig 11).

Repeat biopsy in bone TB is not advised, and in this context metabolic uptake on 18F-FDG PET-CT may be taken into consideration. Indeed, 18F-FDG PET-CT represents an ideal noninvasive modality for assessment of treatment response and disease activity. In patients with increase metabolic uptake on treatment, most likely suggest disease progression/disease burden. In such cases patient might benefit from prolongation of treatment duration/changing

drug regime, thus individualising treatment protocol

I 1 ■ M t '■''fall t s Jam NJt

1 vpH ■ Illf -j^B H< ■'' .JA Jktid&J^H KIL ' _ . y^mmt^W^ jf^H

Fig. 11.

TB associated with HIV infection

The immunocompromised status associated with HIV infection reduces the threshold for reactivation of dormant diseases such as TB. In such patients treatment of TB goes hand in hand with HIV treatment, and can be similarly followed up with serial PET-CT scans.

624 However, frequent monitoring is mandatory in these cases as faster conversion of bacteria

625 into resistant forms is often seen.60

626 With the increase in XDR and MDR TB and HIV infection, an individualized therapeutic

627 approach is gaining greater importance in this chronic inflammatory disease, which requires

628 a sensitive diagnostic method for assessment of not only treatment efficacy but also initial

629 disease spread as well as for guidance of biopsy when equivocal findings are observed.

630 Patients with HIV and TB are prone to developing certain concomitant malignant lesions. As

631 mentioned previously, the major limitation of PET in this context is that it cannot adequately

632 differentiate etiology of various lesions/lymph nodes.

633 Table 1: Comparison of CT, MRI and 18F FDG PET-CT in diagnosing EPTB.

Computerised tomography Magnetic resonance imaging 18FF FDG PET/CT

Anatomy Yes Yes Yes

Functionality No No No

Radiation burden Yes No Yes

Treatment response Yes (Size based) Yes (Size based) Both anatomical and functional

Protocol Regional Regional Whole body image in single setting

CNSETB Inferior to MR Superior image quality Less lesions detected depending on resolution or If the patient is on steroids

Musculoskeletal TB Inferior to MR Modality of choice Assessing disease burden and response assessment

Abdominal TB and lymphadenopathy Modality of choice Response assessment and disease burden.

634 Conclusion

635 Radiological investigations continue to play an important role in the evaluation of various

636 manifestations, sites of infection and disease burden in patients with TB, especially

637 extrapulmonary TB keeping in mind that TB can mimic a number of other disease entities.

638 The authors understand that biopsy and culture studies stay as the Gold Standard for

639 diagnosing TB. FDG PET-CT provides a visual metabolic map, complementary to

640 conventional imaging techniques. Also, whole-body PET-CT imaging may shorten the time

641 period involved in the assessing of disease burden and may play an important role in decision

642 making regarding duration of therapy, especially in developing countries in cases with

643 extrapulmonary TB. More precise characterization of the role of PET-CT in clinical management

644 decision making awaits further studies of larger numbers of patients.

646 Acknowledgements:

647 All authors are grateful to the International Atomic Energy Agency for their support of the

648 Coordinated Research Project (CRP) E15021

650 Conflict of Interest: None

660 661 662

680 681


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794 Figure legends

795 Fig. 1A,B. Case of tubercular lymphadenopathy A Transaxial 18F-FDG PET-CT demonstrated a

796 right supraclavicular lymph node with a maximum standardized uptake value (SUVmax) of

797 5.7. B Coronal slices revealed multiple mediastinal lymph nodes with a SUVmax of 9.9 in the

798 right lower paratracheal region. Hypometabolic areas noted in the nodes are suggestive of

799 casseation/necrosis. The advised site for biopsy was the right supraclavicular lymph node,

800 and histopathology subsequently revealed TB.

801 Fig. 2A,B. Case of tubercular pyelonephritis. A Coronal fused 18F-FDG PET-CT images

802 showing two lesions in the middle and the lower pole of the left kidney. BMaximum

803 intensity projection images revealing two foci in the left kidney with no other lesion

804 detected elsewhere in the body.

805 Fig. 3.18F-FDG-avid lesion in the right adnexa (SUVmax 4.4).

807 Fig. 4A,B.99mTc-MDP bone scan (anterior and posterior views) revealing increased tracer

808 uptake in L3-4 vertebrae (A, B), with soft tissue component noted on SPECT-CT and CT

809 images (D, C).

811 Fig. 5A-F. Case of cervical spondylitis, pretreatment18F-FDG PET-CT (A sagittal view; C

812 coronal view; E MIP), showing contiguous involvement of the C3/C4 vertebrae with a

813 paravertebral component and a SUVmax of 4.4. The corresponding post-treatment PET-CT

814 after 6 months (B, D, F) shows a complete metabolic response.

816 Fig. 6A-F. Case of tubercular spondylitis, pretreatment scanning (A and C sagittal 18F-FDG

817 PET-CT and MIP respectively; B CT) that showed disco-vertebral changes with partialcollapse

818 in multiple dorsal lumbar vertebrae. Post-treatment scans (D-F) showed near-complete

819 resolution of all lesions except for mild tracer uptake in the L3 vertebra.

821 Fig. 7. An 18F-FDG-avid lesion is noted in the lateral aspect of the medial condyle of the left

822 femur, which is a rare involvement in TB osteomyelitis.

823 Fig. 8. Prior to treatment, 18F-FDG-avid lesions are noted in both lungs and the left iliac bone

824 adjoining the sacrum (top row). After appropriate treatment, complete metabolic

825 resolution of both the lesions. (bottom row).

828 anterior cerebellum (B) which was missed on MRI (A), demonstrating that these modalities

829 may be complementary in identifying brain lesions.

831 Fig. 10.18F-FDG-avid lesion noted along the entire spinal canal prior to treatment (bottom

832 row). The lesion has entirely disappeared following treatment (top row).

834 Fig. 11A-H. Dual point imaging of the patient at 1 h (A-D) and 3 h (E-H), showing a

835 substantial increase in lesion contrast.

827 Fig. 9. Case of tubercular meningitis. A solitary 18F-FDG avid lesion was seen in the right