Accepted Manuscript Title: Imaging in Extrapulmonary Tuberculosis Author: Sanjay Gambhir Mudalsha Ravina Kasturi Rangan Manish Dixit Sukanta Barai Jamshed Bomanji PII: DOI: Reference:
S1201-9712(16)31220-6 http://dx.doi.org/doi:10.1016/j.ijid.2016.11.003 IJID 2766
To appear in:
International Journal of Infectious Diseases
Received date: Revised date: Accepted date:
12-10-2016 31-10-2016 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 Consortium,1 Imaging in Extrapulmonary Tuberculosis, International Journal of Infectious Diseases (2016), http://dx.doi.org/10.1016/j.ijid.2016.11.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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HIGHLIGHTS Diagnosis of Extra-pulmonary tuberculosis (EPTB) remains challenging due to
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protean clinical manifestations and difficulties in making accurate diagnosis.
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Advances in imaging technologies now allow for accurate localization of diseased
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sites and access to obtaining biological samples for microbiological, histo-
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pathological and molecular testing.
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Evidence is building towards use of newer imaging modalities for monitoring response to treatment and for relapse.
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Review for IJID series for World TB Day 2017
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Title:
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Imaging in Extrapulmonary Tuberculosis
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Authors:
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Sanjay Gambhir^, Mudalsha Ravina^, Kasturi Rangan^, Manish Dixit^, Sukanta Barai^,
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Jamshed Bomanji#, and *the International Atomic Energy Agency extra-pulmonary TB
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Consortium*
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Institutional affiliations: # Department of Nuclear Medicine, of Nuclear Medicine, UCLH NHS Foundation Trust London, UK
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^Sanjay Gandhi Post Graduate Institute of Nuclear Medicine, Lucknow India and Institute
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*the International Atomic Energy Agency extra-pulmonary TB Consortium: Rajnish Sharma,
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Bhagwant Rai Mittal, Sanjay Gambhir, Ahmad Qureshy, Shamim Momtaz Ferdousi Begum,
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Mike Sathekge, Mariza Vorster, Dragana, Sobic Saranovic, Pawana Pusuwan, Vera Mann,
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Shobhan Vinjamuri, Allimudin Zumla, Thomas Pascual, Jamshed Bomanji -author affiliations
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below-next page) .
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Keywords: Tuberculosis, Imaging, CT, PET-CT, MRI, extrapulmonary tuberculosis, diagnosis, biomarker, , 18F-fluorodeoxyglucose (FDG) PET-CT
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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 Email:
[email protected] 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 Email:
[email protected]
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AUTHOR AFFILIATIONS: for the International Atomic Energy Agency extra-pulmonary TB
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Consortium*
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Rajnish Sharma, Director & Head , Division of Nuclear Medicine & PET Imaging, Specialist in Nuclear Medicine &Thyroid diseases, Molecular Imaging & Research Center ( MIRC), INMAS, Delhi. Email:
[email protected]
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Bhagwant Rai Mittal, Director & Head, Dept. of Nuclear Medicine & PET, Post Graduate Institute of Medical Education and Research, Sector 12, Chandigarh – 160012, India. Email:
[email protected]
Sanjay Gambhir, Director and Head, Dept. of Nuclear Medicine, SGPGIMS, Rae Bareli Road, Lucknow-226014 Email:
[email protected]
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Ahmad Qureshy, INMOL Hospital, New Campus Road, Lahore 54600, Pakistan,
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Email:
[email protected]
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Shamim Momtaz Ferdousi Begum, National Institute of Nuclear Medicine & Allied Sciences (NINMAS) 7th–10th Floor, Block-D, BSM Medical University Campus, Shahbag, Dhaka-1000. Email:
[email protected]
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Mike Sathekge, Department of Nuclear Medicine, Steve Biko Academic Hospital, University of Pretoria, Pretoria, South Africa. Email:
[email protected]
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Mariza Vorster, Department of Nuclear Medicine, Steve Biko Academic Hospital, University of Pretoria, Pretoria, South Africa. Email:
[email protected]
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Email:
[email protected]
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Dragana Sobic Saranovic, Faculty of Medicine University of Belgrade and Center of Nuclear Medicine Clinical Center of Serbia, Belgrade, Serbia.
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Pawana Pusuwan, Division of Nuclear Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok-noi, Bangkok 10700, Thailand
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Email:
[email protected]
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Vera Mann, Institute of Nuclear Medicine, UCLH NHS Foundation Trust, 235 Euston Road, London NW1 2BU, UK Email:
[email protected]
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Shobhan Vinjamuri, Royal Liverpool University Hospital, Liverpool L7 8XP, UK
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Email:
[email protected]
Alimuddin Zumla, Center for Clinical Microbiology, Division of Infection and Immunity, University College London, and the National Institute of Health Research Biomedical Research Centre at UCL Hospitals, , London, United Kingdom. Email:
[email protected]
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Thomas NB Pascual, Section of Nuclear Medicine and Diagnostic Imaging, Division of Human Health, Department of Nuclear Sciences and Applications, International Atomic Energy Agency, Vienna International Centre, PO Box 100, 1400 Vienna,
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Email:
[email protected]
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Jamshed Bomanji, Institute of Nuclear Medicine, UCLH NHS Foundation Trust, 235 Euston Road, London NW1 2BU, UK Email:
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SUMMARY
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Today TB remains a major global public health problem with 1.5 million deaths annually.
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One in five cases of TB present as extrapulmonary TB (EPTB) posing major diagnostic and
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management challenges. Mycobacterium tuberculosis adapts to a quiescent physiological
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state and is notable for its complex interaction with the host, producing poorly understood
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disease states ranging from latent infection to active clinical disease. New tools in the
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diagnostic armamentarium are urgently required for the rapid diagnosis of TB, monitoring of
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TB treatments, and acquisition of newer insights into pathogenesis. We review the typical
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and atypical imaging features of extrapulmonary TB and discuss the roles of several imaging
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modalities for the diagnosis and management of EPTB.
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INTRODUCTION
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Tuberculosis today remains a major global public health problem with 1.5 million deaths
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annually (WHO 2014). One in five cases of TB present as extrapulmonary TB (EPTB) posing
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major diagnostic and management challenges. Accurate diagnosis of active pulmonary
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tuberculosis may be challenging in patients without any microbiological evidence of the
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presence of Mycobacterium tuberculosis from sputum samples. Tuberculin skin tests or
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serum interferon-gamma release assays can determine TB exposure in such patients but
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cannot differentiate between active and latent disease. Culture remains the gold standard
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but it can take upto 8-10 weeks and variable sensitivities depending on the host and sites
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are noted. Mainly blood cultures, urine cluture and culture of other body fluids aids in the
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diagnosis.
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The most frequent sites of extrapulmonary TB include lymph nodes, the peritoneum,
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and the ileocecal, hepatosplenic, genitourinary, central nervous system (CNS), and
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musculoskeletal regions; multisystem involvement is common.
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Population groups with increased risk of TB are immunocompromised individuals
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(AIDS, lymphoma, leukemia, post-organ transplant), diabetics, children, the elderly,
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alcoholics, persons with a low socioeconomic status, persons with poor compliance,
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immigrants from Third World countries, prisoners, nursing home residents, health care
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workers, and the homeless1-3. The increase in TB has been witnessed not only in Africa and
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Asia but also in European countries; hence TB remains an important cause of morbidity and
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mortality worldwide4,5.
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In this mix of risk factors multidrug-resistant (MDR) TB continues to flourish. MDR
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TB requires prolonged administration of toxic second-line drugs, associated with higher
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morbidity and mortality rates. Patients also remain infectious for a longer period once
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treatment has been started. A new strain, of extensively drug-resistant (XDR) TB, is evolving;
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this MDR strain is also resistant to second-line drugs including any fluoroquinolone and at
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least one of three injectable drugs (capreomycin, kanamycin, and amikacin). Despite the
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enormous burden of disease, current diagnostics are still woefully inadequate to meet
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research and clinical needs.
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Radiologic investigations play a crucial role in the early and correct identification of
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extrapulmonary TB. Imaging modalities of choice are Computerised Tomography
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(CT,lymphadenopathy and abdominal TB) and Magnetic Resonance imaging (MRI,CNS and 6 Page 6 of 33
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musculoskeletal TB). MRI is also indicated in pediatric or pregnant patients, in whom
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radiation is to be avoided. In addition, bone scanning is performed in skeletal TB and
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fluorodeoxyglucose (FDG) PET-CT in assessment of disease extent and response monitoring.
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Tuberculosis demonstrates a variety of clinical and radiologic features depending on the
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organ site involved and has a known propensity for dissemination from its primary site.
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Thus, TB can mimic a number of other disease entities, and it is important to be familiar
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with the various radiologic features of TB. Herein we illustrate the imaging findings of ETB
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and their relevance in the present scenario. Familiarity with the same helps in early
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diagnosis, initiation of therapy and monitoring patients on treatment.
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Literature review
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A pubmed search of the relevant articles discussing role of imaging in ETB was done.
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Tuberculous lymphadenopathy
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Also known as scrofula, tuberculous lymphadenopathy is a common form of extrapulmonary
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TB seen in endemic populations as well as immunocompromised patients in developed
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nations. The most commonly affected lymph nodes, in decreasing order, are the cervical
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(63%), mediastinal (27%), and axillary (8%–10%). Most cases present as unilateral cervical
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lymphadenopathy.
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Imaging features
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Imaging alone cannot distinguish between the causes of lymphadenopathy.
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Ultrasonography
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Nodal matting with surrounding edema is seen. Doppler study may reveal increased
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vascularity, mostly at the hilum. This feature allows differentiation from malignant lymph
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nodes, which show peripheral vascularity6.
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CT and MRI
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The lymph nodes are usually matted. However, density depends on the amount of
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caseation, which increases with time7.
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PET-CT
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amount of caseation . 18F FDG PET-CT has the advantage of identifying all affected lymph
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F-FDG PET-CT may show peripheral uptake and central hypometabolism, depending on the
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node groups within a single setting and allows selection of lymph node group most suitable
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for biopsy (Fig. 1).
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Fig. 1A,B.
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Abdominal tuberculosis
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Abdominal TB may occur directly, as in the case of primary pulmonary TB, or indirectly, via
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spread from the primary. It generally affects the following organs:
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Lymph nodes
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Peritoneum
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Ileocecal junction
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Colon
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Liver
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Spleen
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Adrenal glands
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Solid viscera are affected to a greater extent than the gastrointestinal tract. CT is the
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mainstay for investigation of possible abdominal TB; however, knowledge of other
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imaging modalities, such as barium enema examination, is important to avoid
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misdiagnosis in cases in which TB is not initially suspected.
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Abdominal lymphadenopathy
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Abdominal lymphadenopathy is the most common manifestation of abdominal TB,
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seen in 55%–66% of patients8. On CT the nodes are usually matted, appearing in groups
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with mild fat stranding, hypoattenuating center with or without calcification. 18F-FDG PET-CT
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shows increased metabolic activity in the nodes and plays a role in the assessment of
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treatment response. 8 Page 8 of 33
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Peritoneal tuberculosis
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Peritoneal TB affects one-third of patients and is oneof the most common manifestations of
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abdominal TB. Subdivision, into wet, fibrotic, and dry types has been proposed9. On imaging,
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there may be significant overlap between the three. Wet type: manifests in more than 90% of patients, has high protein and cellular
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content, leading to high-attenuating pockets of loculated fluid or free ascites. The
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Hounsfield unit (HU) ranges from 20 to 45.
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Dry type: cake-like omentum with fibrous adhesions and mesenteric thickening.
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Fibrotic type: presents as omental or mesenteric masses.
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The main imaging differential diagnoses are malignancy and peritoneal carcinomatosis10.
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Gastrointestinal tract tuberculosis
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Due to the abundance of lymphoid tissue, the ileocecal junction (90%) is one of the most
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common sites of involvement in the bowel8,9. The presentation may be ulcerative,
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hypertrophic, or ulcerohypertrophic11,12.
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Imaging features
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Barium studies
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In early stages, narrowing of the terminal ileum, thickening and gaping of the ileocecal
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valve, and thickening and hypermotility of the cecum are noted. In chronic stages, the
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ileocecal valve appears fixed, rigid, and incompetent, while the cecum appears shrunken in
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size. In later stages a “pulled-up” cecum is usually noted.
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CT
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On CT circumferential wall thickening of the terminal ileum and cecum is noted, usually in
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association with mesenteric lymphadenopathy. The differential diagnosis includes Crohn’s
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disease, carcinoma, and lymphomatous involvement.
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Involvement of the esophagus, stomach, duodenum, and small bowel is still rare.
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Esophageal TB is mainly from the carinal lymph nodes. Small bowel TB may present as
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mucosal thickening. The antrum and distal body are the most commonly affected sites in
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the stomach. The presence of a fistula or a sinus confirms the diagnosis.
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Hepatosplenic tuberculosis
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Hepatosplenic TB may present as miliary or macronodular involvement. The lesions are
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hypoattenuating on CT and may show peripheral postcontrast enhancement. The most
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common route of involvement is hematogenous either through hepatic artery in military TB
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or through portal vein fromgastrointestinal lesions. Macronodular involvement is less
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frequent and is manifested by single or multiple focal density lesions with or without
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peripheral rim enhancement.
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On MRI, macronodular lesions appear hypointense on T1-weighted images and hypoto
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hyperintense on T2-weighted images, with thin peripheral and/or internal septal
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enhancement.
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Differential diagnosis includes fungal infections, sarcoidosis, lymphoma, and, rarely,
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metastasis.
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Adrenal tuberculosis
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The adrenal glands are the most common endocrine glands involved by TB. The spread is
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predominantly via the hematogenous route and may be unilateral or bilateral, with central
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areas of caseation. The involvement of adrenal cortex, may lead to primary adrenal
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insufficiency and where
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addisonian crisis may ensue13.
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In early stages, smooth enlargement of the gland with low-density areas andrelative central
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hypoenhancement is noted on CT14. In later stages and/or in previously treated patients,
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gland atrophy with punctate, localized, or diffuse calcification is observed.
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The MRI features are analogous to the CT appearances except for limitations when
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calcification is present. 18F-FDG PET-CT shows increased metabolic activity in adrenals in TB
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or any infection. Often this may be an incidental finding on PET-CT done for another
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diagnosis. The gland may show diffuse or patchy uptake on 18F-FDG images.
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Genitourinary tuberculosis
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Tuberculosis may involve the genitourinary tract as a secondary site following
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hematogenous dissemination from the lungs15.
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more than 90% of the cortex is involved, a life-threatening
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Renal tuberculosis
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Tuberculosis at these sites accounts for 15%–20% of cases of extrapulmonary TB16.
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Routinely, two morphological appearances are seen: pyelonephritis or a pseudotumoral
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type presenting as single or multiple nodules.
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The collecting system is involved in isolation or due to contiguous spread from the
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parenchyma. In early stages, papillary necrosis resulting in uneven caliectasis is noted.
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Hydronephrosis and multifocal strictures with mural thickening and enhancement are
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observed in progressive disease. Progressive hydronephrosis and parenchymal thinning with
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dystrophic calcification are noted in end-stage disease.
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Imaging features
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Plain radiography
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On plain radiographs, foci of calcification are noted in 25%–45% of patients17. Triangular
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ring-like calcification in the collecting system is observed in cases of papillary necrosis.
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Amorphous focal ground glass-like calcification (putty kidney) is seen in end-stage disease18.
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Intravenous urography
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Plain film intravenous urography is quite sensitive in detecting renal TB19: Only 10%–15% of
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those affected have normal imaging. A range of findings may be observed, including
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parenchymal scars (50%),
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caliectasis, phantom calyx, and hydronephrosis. Lower urinary tract signs include the “Kerr
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kink”, which occurs due to abrupt narrowing at the pelviureteric junction20.
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Ultrasonography
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In early-stage disease, ultrasonography may show an irregular cortical outline with
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calcification. As the disease progresses, papillary destruction with echogenic masses and
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distorted renal parenchyma can be observed. In end-stage disease, heavy dystrophic
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calcification with a small shrunken kidney is noted.
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Ultrasonography is less sensitive in detecting isoechoic masses and small calcifications and
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in identifying small cavities communicating with the collecting system.
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CT and MRI
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CT intravenous pyelography is most sensitive in identifying all manifestations of renal TB.
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Depending on the site of the stricture, various patterns of hydronephrosis may be seen,
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including focal caliectasis, caliectasis without pelvic dilatation, and generalized
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hydronephrosis. Other common findings include parenchymal scarring and low-attenuation
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moth-eaten calyces due to necrotizingpapillitis, irregular
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parenchymal lesions. CT is also useful in depicting the extension of disease into the
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extrarenal space21,22.
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The radiologic differential diagnosis of renal TB includes other causes of papillary necrosis,
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transitional cell carcinoma, and other infections. 18F-FDG PET-CT may be used to evaluate
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renal masses (Fig. 2), to identify latent or active TB in the lung, or to monitor therapy.
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Fig. 2A,B
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Ureteric Tuberculosis
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Imaging features
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Intravenous Urography
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In the chronic state, beaded areas due to alternate strictures and dilatation are noted.
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CT
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Ureteral wall thickening is observed in the acute setting. In chronic disease, strictures and
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shortening of the ureter, leading to pipe stem ureter, are noted.
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Urinary bladder tuberculosis
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Urinary bladder involvement is secondary to descending spread of infection along the
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urinary tract22.An irregular wall with a small capacity bladder is noted. Fibrotic changes at
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the ureteric orifices lead to vesicoureteric reflux and hydroureteronephrosis23.
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Female genital organs
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Involvement of the genital organs occur in 1.5% of females affected with TB. Spread may be
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via the hematogenous or the lymphatic route. On hysterosalpingography, obstruction is
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usually noted at the junction of the isthmus and the ampulla24,25. A beaded appearance is
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seen due to multiple constrictions. A normal uterine cavity may be observed in more than
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50% of cases. A further possible presentation is as an irregular filling defect with uterine
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synechiae and shrunken cavity (3%–18% of cases).Lesions may show uptake on 18F-FDG PET-
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CT (Fig. 3).
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Fig. 3.
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Male genital organs
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Involvement of the genital organs in males is generally confined to the seminal vesicles or
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prostate gland, with occasional calcification (10% of cases). The testes and epididymides are
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rarely involved. Hypoattenuating lesions are noted on contrast-enhanced CT, likely
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representing foci of caseous necrosis. Nontuberculous pyogenic prostatic abscesses have a
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similar CT appearance22. The spread is hematogenous and self-limiting. Ultrasonography
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shows focal or diffuse areas of decreased echogenicity; however, these findings are very
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nonspecific23,26.
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Musculoskeletal tuberculosis
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Musculoskeletal TB accounts for about 3% of all TB infections. The main route of spread is
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hematogenous, from lungs, or via activation of dormant infection in bone or joint post
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trauma27. Cases of musculoskeletal TB are usually subclassified as tubercular spondylitis 13 Page 13 of 33
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(50%) (popularly called Potts' spine), peripheral tuberculous arthritis (60%), osteomyelitis
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(38%), and soft tissue TB, including tenosynovitis and bursitis28-30.
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Tubercular spondylitis
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The disease spread is via the venous plexus of Batson. The most commonly affected
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vertebrae are the lower thoracic and upper lumbar. The vertebral body is involved to a
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greater extent than the posterior elements, and the classical presentation is involvement of
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two or more contiguous vertebrae with or without paravertebral abscess. The presence of
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calcification, which may sometimes be absent, almost confirms the diagnosis. In cases of
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anterior subligamentous involvement, the infection spreads inferiorly or superiorly without
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vertebral disk involvement.
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Imaging features
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Plain radiography
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Potential early changes include irregular end plates and a decrease in vertebral height.
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Sharp angulation or gibbus deformity is noted, with anterior wedging or collapse.
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Displacement of paraspinal lines suggestive of psoas involvement may be noted. The
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calcified psoas is suggestive of an abscess.
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Spinal TB might lead to vertebra plana where there is a reduction in anterior and posterior
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height, preserved intervertebral disk andsome forms of vertebral end plate change.
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Ultrasonography
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Ultrasonography is usually helpful in identifying iliopsoas abscess and its percutaneous
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drainage.
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CT
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Cross-sectional imaging is required to better establish the extent of vertebral involvement
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and the possible presence of a paravertebral abscess.
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MRI
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MRI is the gold standard investigation for tubercular spondylitis. MRI helps to identify the
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presence of an epidural component and cord compression. An early finding is focal T2
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hyperintense and T1 hypointense bone marrow edema in the anterior part of vertebral body
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adjacent to endplates, with patchy postcontrast enhancement. An abnormal T2
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hyperintense signal is noted in the involved disk space, with reduced height. Multifocal TB,
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compression of the spinal cord, abnormal T2 hyperintense signal in the spinal cord, and
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neural foraminal and neural compromise secondary to epidural collections are well
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demonstrated on MRI. MRI may also demonstrate the complete extent of an iliopsoas or
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paraspinal abscess. Small foci of involvement of posterior elements are better observed on
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MRI than CT31-33.
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Bone scintigraphy
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99m
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be used to rule out metastasis suggested by the involvement of multiple contiguous
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vertebrae (Fig. 4).
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Tc-Methylene diphosphonate bone scan may identify multifocal sites and can sometimes
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Fig. 4.
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F-FDG PET-CT
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F-FDG PET-CT may show increased uptake in tubercular spondylitis, with identification of
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multiple sites, and offer further help in response monitoring34,35 (Figs. 5, 6).
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Fig. 6A–F
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Tubercular arthritis
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Tubercular arthritis is the most common extra-axial form of musculoskeletal TB. In 90% of
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cases, it is monoarticular, commonly affecting large weight-bearing joints such as the hip
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and knee36,37. Less commonly it involves the shoulder, elbow, and sacroiliac joints.
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Periarticular osteoporosis, peripherally located osseous erosion, and progressive decrease in
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the joint space suggest the diagnosis of TB and are popularly referred to as the “Phemister
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triad”. In later stages, fibrosingankylosis ensues37-39. Atrophic changes in bones may occur
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and lead to atrophic arthropathy, especially in the shoulder joint.
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Imaging features 16 Page 16 of 33
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Ultrasonography
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Ultrasonography mainly helps in identifying joint effusion, although the appearances are
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nonspecific.
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CT
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CT helps to establish the degree of bone destruction. Sequestrum or sinus formation can be
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demonstrated on postcontrast scan.
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MRI
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Lesions are usually T1 hyperintense and T2 hypointense and show brilliant post-gadolinium
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enhancement which is a result of blood degradation products and inflammation. Sinus tracts
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appear as linear T2 hyperintensity with marginal “tram track enhancement”28,37.
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Tubercular osteomyelitis
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Tubercular osteomyelitis is most commonly seen in bones of the extremities (femur, tibia),
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including the small bones of the hands and feet (Figs. 7, 8), often involving the epiphyses. In
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children, metaphyseal foci can involve the growth plate, a feature that differentiates TB
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from pyogenic infection40.
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eburnation and periostitis are observed.
Radiologically, foci of osteolysis with varying degrees of
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Tubercular dactylitis
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Tuberculous dactylitis, in which there is painless involvement of the short tubular bones of
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the hands and feet, is more common in children. At radiography, pronounced fusiform soft
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tissue swelling with or without periostitis is the most common finding41,42.
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Fig. 7.
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Fig. 8.
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Central nervous system tuberculosis (CNS TB) 18 Page 18 of 33
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The spread is either hematogenous, or by direct extension from local infection, such as
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tuberculous otomastoiditis. CNS TB accounts for 1% of all TB and 10%–15% of
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extrapulmonary TB. It is a leading cause of morbidity and mortality in endemic regions43,44.
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Tubercular leptomeningitis
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Tubercular pachymeningitis
Intra-axial
cr
465
ip t
Extra-axial
466
-
Tuberculoma
467
-
Focal cerebritis
468
-
Tubercular abscess
469
-
Tubercular rhomboencephalitis
470
-
Tubercular encephalopathy
M
471
us
462
Manifestations of cranial TB include:
an
461
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.
Ac ce
pt
ed
472
487 488
Tubercular pachymeningitis 19 Page 19 of 33
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.
493
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.
M
an
us
cr
ip t
494
504
MRI
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
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.
Ac ce
pt
ed
505
granuloma may show central T2 hyperintensity
516 517
18
518
(Fig 9).
F FDG PET-CT and MRI might be complementary to each other in identifying the lesions
20 Page 20 of 33
519
Fig 9.
521
Tubercular abscess
522
Tubercular abscess accounts for 4%–7% of cases in the endemic region. Presentation is as a
523
large solitary lesion, which may be multiloculated, with surrounding vasogenic edema and
524
mass effect. Such abscesses have pus-filled centers, vascular granulation tissue, and absence
525
of epithelioid granulomatous reaction. The causative organism may be isolated from the
526
pus, in contrast to tuberculomas.
an
us
cr
ip t
520
527
The lesion may show central low intensity on T1-weighted images and peripheral low
529
intensity due to vasogenic edema. Diffusion-weighted imaging reveals restricted diffusion
530
with low apparent diffusion coefficient values. On imaging, pyogenic and fungal abscesses
531
may mimic tuberculous abscess. Tuberculous abscess shows a large lipid lactate peak at 1.3
532
ppm on MR spectroscopy owing to the presence of mycolic acid within the mycobacterial
533
walls, which represents a distinguishing feature from pyogenic abscess50.
534
pt
ed
M
528
Rhomboencephalitis
536
Rhomboencephalitis is a particular form of neurotuberculosis affecting the hind brain. The
537
most common manifestation is tuberculoma.
538
Encephalopathy
539
Encephalopathy in the context of TB is most commonly observed in children and infants
540
with pulmonary TB. The postulated mechanism is a delayed type IV hypersensitivity reaction
541
initiated by a tuberculous protein which leads to extensive damage of white matter with
542
infrequent perivascular demyelination. Imaging shows extensive unilateral or bilateral brain
543
edema51.
Ac ce
535
544 545
Spinal and meningeal involvement 21 Page 21 of 33
Spinal TB (Fig. 10) commonly manifests as TBM and rarely as intramedullary tuberculoma.
547
MRI is the modality of choice for spinal TB assessment. Spinal TBM manifests as linear
548
enhancing exudates along the spinal cord in the subarachnoid spaces and clumping of cauda
549
equina nerve roots34.
an
us
cr
ip t
546
M
550 551
Fig. 10.
553
ed
552
Tubercular otomastoiditis
555
Tubercular otomastoiditis, which occurs acutely secondary to tuberculosis infection, is more
556
frequently observed in immunocompromised patients. It may present with painless chronic
557
otorrhea with an intact tympanic membrane or as pain, purulent discharge, and ossicular
558
erosion. There may be associated cervical lymph nodal involvement in the interparotid,
559
upper cervical, and preauricular regions. Pachymeningeal involvement with potential dural
560
sinus thrombosis is also sometimes seen.
Ac ce
561
pt
554
562 563
Tubercular mastitis
564
Tubercular mastitis is a rare occurrence, although the incidence has been rising (0.1%–3%)
565
in endemic areas like Africa and India52. The first case was reported in 1829 by Sir Ashley
566
Cooper, who referred to it as “scrofulous swelling of the bosom”53. The significance of breast
567
TB lies in the fact that its masquerades the symptoms of breast cancer and inflammatory 22 Page 22 of 33
disease of the breast. It may present in nodular form or as multifocal disease. 53Radiological
569
imaging is not diagnostic as there is significant overlap with other pathologies. Breast
570
ultrasonography may show a hypoechoic mass or focal or sectorial duct ectasia. Caseating
571
granulomas in a tissue sample are diagnostic.
572
Cardiac tuberculosis
573
Cardiac TB is a rare infection involving the cardiac muscles that is seen in 1%–2% of patients
574
with pulmonary TB54,55. There is predominantly pericardial and myocardial involvement, and
575
endocardial spread may occur from the myocardium.
ip t
568
cr
576
Imaging features
578
Plain radiography
579
The radiographic appearance may be normal in the early stages while pericardial
580
calcification may be evident in later stages.
581
CT and MRI
582
CT may reveal pericardial effusion, thickening, or calcification in the chronic stages. On
583
cardiac MRI, T1-weighted images may show a nodular lesion which appears isointense to
584
slightly hyperintense. On T2-weighted images the lesion appears isointense, with mild
585
enhancement post gadolinium.
ed
M
an
us
577
586
pt
587
Role of PET-CT: challenges and limitations
589
FDG is a non-physiological glucose analog that undergoes metabolism by the same
590
physiological processes as glucose, including being taken up by cell surface transporters
591
(mainly the glucose transporter-1, GLUT-1) and transformed by the rate-limiting glycolytic
592
enzyme, hexokinase, into FDG-6-phosphate. An interesting early observation by Kubota and
593
co-workers was that a substantial component of 18F-FDG uptake in tumor tissue is a result of
594
activity localizing to peritumoral inflammatory cells, such as macrophages, which
595
demonstrate greater 18F-FDG uptake than tumor cells. Multiple mechanistic similarities are
596
now recognized between inflammatory and malignant cells in terms of the underlying
597
metabolic pathways56. It is this differential increase in tissue glycolysis in inflamed tissue, as
598
opposed to normal cells, that forms the pathophysiological basis for use of 18F-FDG PET-CT
599
in TB.
Ac ce
588
23 Page 23 of 33
600
18
601
TB. Tubercular lymphadenopathy shows high-grade metabolism, and
602
therefore help in selecting nodes suitable for biopsy based on metabolic uptake/SUVs.
603
Moreover, PET-CT is more sensitive than structural imaging methods in detecting lesions.
604
Apart from assisting in selection of the site for biopsy, PET-CT may play a significant role in
605
monitoring response to treatment: its ability to detect changes in metabolic uptake means
606
that it may be considered a specific complementary tool to structural imaging for this
607
purpose57. Refining of imaging techniques like dual time point imaging may further improve
608
the detection of disease60 (Fig 11).
609
Repeat biopsy in bone TB is not advised, and in this context metabolic uptake on
610
PET-CT may be taken into consideration. Indeed,
611
invasive modality for assessment of treatment response and disease activity. In patients
612
with increase metabolic uptake on treatment, most likely suggest disease progression/disease
613
burden. In such cases patient might benefit from prolongation of treatment duration/changing
614
drug regime, thus individualising treatment protocol57-59.
F-FDG PET-CT is useful in identifying the extent of disease in patients with extrapulmonary F-FDG PET-CT may
F-FDG
F-FDG PET-CT represents an ideal non-
M
an
18
18
us
cr
ip t
18
615
617 618
Ac ce
pt
ed
616
Fig. 11.
619 620
TB associated with HIV infection
621
The immunocompromised status associated with HIV infection reduces the threshold for
622
reactivation of dormant diseases such as TB. In such patients treatment of TB goes hand in
623
hand with HIV treatment, and can be similarly followed up with serial PET-CT scans. 24 Page 24 of 33
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.
us
cr
ip t
624
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
CNS ETB
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.
Ac ce
pt
ed
M
an
Computerised tomography
634
25 Page 25 of 33
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.
an
us
cr
ip t
634
645
Acknowledgements:
647
All authors are grateful to the International Atomic Energy Agency for their support of the
648
Coordinated Research Project (CRP) E15021
649
pt
Conflict of Interest: None
Ac ce
650
ed
M
646
26 Page 26 of 33
651
1. Global Tuberculosis Report 2015: 20th Edition, World Health Organization. ISBN 9789241565059
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2. Maclean KA, Becker AK, Chang SD, Harris AC. Extrapulmonary tuberculosis: imaging features beyond the chest. Can AssocRadiol J 2013;64:319–24.
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3. Rafique A. The spectrum of tuberculosis presenting at a London district general hospital. West Lond Med J 2009;1(No 4):19–38.
658 659
4. Alrajhi AA, Al-Barrak AM. Extrapulmonary tuberculosis, epidemiology and patterns in Saudi Arabia. Saudi Med J 2002;23:503–8.
660 661 662
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792
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31 Page 31 of 33
793
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
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).
F-FDG PET-CT images
an
us
cr
18
ip t
794
806
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).
ed
810
M
807
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.
Ac ce
815
pt
811
18
816
Fig. 6A–F. Case of tubercular spondylitis, pretreatment scanning (A and C sagittal
F-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.
820 821
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.
32 Page 32 of 33
823
Fig. 8. Prior to treatment, 18F-FDG-avid lesions are noted in both lungs and the left iliac bone
824
adjoining the sacrum
825
resolution of both the lesions. (bottom row).
(top row). After appropriate treatment, complete metabolic
826 18
Fig. 9. Case of tubercular meningitis. A solitary
F-FDG avid lesion was seen in the right
828
anterior cerebellum (B) which was missed on MRI (A), demonstrating that these modalities
829
may be complementary in identifying brain lesions.
ip t
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Fig. 10.18F-FDG-avid lesion noted along the entire spinal canal prior to treatment (bottom
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row). The lesion has entirely disappeared following treatment (top row).
us
cr
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Fig. 11A–H. Dual point imaging of the patient at 1 h (A–D) and 3 h (E–H), showing a
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substantial increase in lesion contrast.
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Ac ce
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