Clinical Imaging 39 (2015) 553–558
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Positron emission tomography in spinal infections Alexandros Georgakopoulos a,⁎, Spiros G. Pneumaticos b, Nikolaos V. Sipsas c, Sofia Chatziioannou a,d a
Nuclear Medicine Division, PET/CT section, Foundation for Biomedical Research of the Academy of Athens, Athens, Greece 3rd Department of Orthopedic Surgery, Medical School, National and Kapodistrian University of Athens, Athens, Greece c Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece d Second Department of Radiology, Medical School, National and Kapodistrian University of Athens, General University Hospital “ATTIKON”, Athens, Greece b
a r t i c l e
i n f o
Article history: Received 14 January 2015 Accepted 5 April 2015 Keywords: Spinal infection Positron emission tomography 18 F-fluorodeoxyglucose Imaging Nuclear medicine
a b s t r a c t Magnetic resonance imaging is the imaging method of choice for diagnosing infection of the spine in unoperated cases. 2-[18F]-fluoro-2deoxy-D-glucose positron emission tomography/computed tomography study is recommended to distinguish between spinal infection and common Modic change in patients with metallic implants and prosthetic replacements and for differentiating tuberculous from pyogenic spondylitis in ambiguous cases, reflecting the activity of the infection. Also, it seems to have a strong clinical impact in more than half of patients with infectious spondylitis, while it is superior to other imaging techniques in revealing residual disease after treatment and early response to therapy. New tracers as well as new hybrid modalities are under investigation. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Spinal infections are increasing in incidence, accounting for 2%–7% of all musculoskeletal infections [1]. They include a spectrum of disease, which can affect any part of vertebra and may cause vertebral osteomyelitis, disc space infections, and epidural abscess. Infection can be caused by granulomatous, pyogenic, iatrogenic, autoimmune, and idiopathic conditions. Staphylococcus aureus is the most common causative organism [2, 3]. Pyogenic spondylitis is the most common spinal infection that peaks at age of less than 20 years and in the group of 50–70 years old that includes the higher-risk group, i.e., immunosuppressed patients, spinal instrumentation, and surgery [4]. On the other hand, spinal tuberculosis is a rare but serious infection that can lead to severe deformity and neurological complications [5].
2. Imaging procedures Diagnosis is generally difficult and is achieved by imaging techniques together with bacteriological and histopathological exams [6]. Gadolinium-enhanced magnetic resonance imaging (MRI) is the imaging technique of choice for the evaluation of spinal infection [7]. It has an excellent sensitivity and specificity (96% and 94%, respectively) [8].
⁎ Corresponding author. Centre for Clinical Research, Nuclear Medicine Division, PET/CT section, Foundation for Biomedical Research of the Academy of Athens, 4 Soranou Ephessiou Street, 11527 Athens, Greece. Tel.: + 30 2106597078, + 30 6937319616; fax: +30 210 6597 502. E-mail address: [email protected] (A. Georgakopoulos). http://dx.doi.org/10.1016/j.clinimag.2015.04.002 0899-7071/© 2015 Elsevier Inc. All rights reserved.
MRI demonstrates pathological changes of bone marrow and also can clearly delineate subdural, epidural, intramedullary, and paraspinal soft tissue involvement [9]. The characteristic changes for spondylodiscitis consist of a hypointense signal of the disc and vertebral body on T1-weighted images and a hyperintense signal of the same structures on T2-weighted images (due to edema) [1]. Also, MRI is accurate for differentiating tuberculous from pyogenic spondylitis [10]. However, there are limitations to MRI, such as differentiation between common Modic changes and infection by low virulence bacteria [11]. Although it is the imaging method of choice in the absence of metallic implants, it is not always possible to distinguish postoperative changes from infection [12]. Metallic implants and renal failure may be contraindication to the test. Moreover, residual MRI findings at the end of the treatment despite the clinical improvement may lead to unnecessary invasive treatments [13]. Nuclear medicine procedures are often performed as complementary techniques in the diagnosis of infection in the spine. Although bone scintigraphy is an easily performed, rapidly completed, widely available, and sensitive technique (~90%) for diagnosing spinal osteomyelitis, it is not specific for infection [14]. The typical image of the technetium bone scan in osteomyelitis is increased uptake of the radiotracer in two adjacent vertebrae. The specificity has been reported to be as low as 31% for planar bone scan and 23% for planar plus single photon emission tomography (SPECT) bone scan with an overall accuracy of 50% for both studies, too low to be clinically useful [15]. Love et al. [15] reported that three-phase bone scintigraphy improves specificity but at the expense of sensitivity, which decreases from 92% to 36%. Also, three-phase bone scan may be positive in patients with severe infection but not in those with mild or moderate infection [14]. False-negative bone scans have been reported in the elderly due to regional ischemia secondary to
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arteriosclerotic disease with resulting decreased perfusion [16]. Also, bone scintigraphy cannot detect the soft tissue infections that often accompany spinal osteomyelitis [17]. Gallium imaging has also several limitations. Other than infection, it can also be accumulated in tumors, aseptic inflammation, and trauma. In addition, its physical characteristics and normal distribution reduce the image quality. It is often used as a complementary image modality to bone scintigraphy in order to enhance the specificity of the study and to detect extraosseous sites of infection [18]. This dual-tracer technique requires multiple, sometimes lengthy, imaging sessions on different days with increased cost. On the other side, 67Ga-SPECT seems to be as accurate for diagnosing spinal infection as combined bone–gallium scans [15]. Labeled leukocyte imaging is of limited value on the basis that up to 50% of all patients with spinal osteomyelitis show photopenic defects, which are not specific for infection [19]. Furthermore, imaging with radiolabeled antibiotic 99Tc-ciprofloxacin and streptavidin/ 111Inbiotin complex is not widely used in clinical practice. 2.1. Positron emission tomography/computed tomography with 2-[ 18F]fluoro-2deoxy-D-glucose (18F-FDG PET/CT) Recent advances in molecular nuclear medicine such as 18F-FDG PET/CT have expanded the available imaging methods for assessment of infection in the spine. 18F-FDG PET/CT is a well-established functional imaging technique mainly for diagnosing cancer, which has the advantage of higher spatial resolution as compared to other nuclear medicine procedures. It is completed in 1–2 h and has a relative low radiation dose. However, it is now established that it also detect high glucose metabolism in infectious diseases [20]. 18F-FDG is the most commonly used radiotracer worldwide because of its availability and the relatively long half-life. Its uptake in infection depends on the increased glucose metabolism in activated inflammatory cells such as leukocytes, granulocytes, and macrophages that produce an excess of glycolitic enzymes and overexpress in glucose transporter (GLUT) isotypes (mainly GLUT-1 and GLUT-3) [21]. Although 18F-FDG accumulates in infection, it is a nonspecific tracer that also accumulates in aseptic inflammation [20]. The hybrid PET/CT scan combines the evaluation of morphological and metabolic changes simultaneously and enables a more accurate localization and attenuation correction. Also, semiquantitative analysis with standardized uptake value (SUV) may be useful for differentiating infectious from noninfectious disease and for monitoring response to therapy [22]. The present article will address the recent advantages and limitations of PET in the diagnosis and assessment of spinal infections. The manuscript is not a systematic review but rather an update overview that is intended to provide information helpful on the use of PET in clinical practice. Based on this principle, a literature search for articles concerning spinal infection, imaging, PET, and 18F-FDG was performed using the Medline database and EMBASE from 1990 to date. This resulted in a total number of 41 publications. 2.2. The role of 18F-FDG PET/CT in the diagnosis of spinal infections MRI remains the imaging method of choice in diagnosing infection of the spine. However, 18F-FDG PET/CT can play an adjuvant and complementary role in this area. Several published studies have highlighted the role of 18F-FDG PET for diagnosing spinal infection. In one of the first studies on the evaluation of chronic osteomyelitis with 18F-FDG PET, in four patients, the region of interest was the spine. 18F-FDG PET was true positive and diagnosed all three cases of spinal infection and was true negative in the fourth patient without infection [23]. In a study of 16 patients with suspicion of spondylodiscitis, 18F-FDG PET showed high sensitivity (100%) and diagnostic accuracy depicting addition soft tissue involvement [24]. In a recent similar study, 18F-FDG PET was performed in 42 patients with suspected spondylodiscitis. The detection of spondylodiscitis had a sensitivity of 86 % and a specificity of 95%. The
average SUV in true-positive cases was 4.0 (SD: 1.73), while in true negative cases, it was 1.84 (SD: 0.67) [25]. Also, some studies showed the superiority of 18F-FDG PET over other techniques of conventional nuclear medicine. In one such study, Guhlmann et al. [26] highlighted significantly better accuracy of the 18F-FDG PET compared to radiolabeled antigranulocyte antibody in patients with suspected chronic osteomyelitis of the central skeleton including the spine. In a similar study, Meller et al. [27] reported that 18F-FDG PET was superior to radiolabeled leukocyte scintigraphy in the axial skeleton. In eight patients, the field of interest was the spine, and 18F-FDG PET showed 100% diagnostic accuracy. In a subsequent study, Gratz et al. [28] compared 18F-FDG PET with conventional nuclear medicine imaging modalities [99mTc-methylene diphosphonate (MDP) bone scan and 67Ga-citrate scan] and MRI. They have concluded that 18F-FDG PET contributes in the differentiation between mild infection and degenerative changes, presents good correlation with the histological severity of the infection, and detects additional manifestations outside the spine. More recently, Fuster et al. [29], comparing 18F-FDG PET/CT with combined bone scan and 67Ga-SPECT/CT, reported that the former imaging method is more accurate in the evaluation of suspected spondylodiscitis and gives additional information that may influence the management of disease. More specifically, there were two cases of multifocality and an additional two with associated pulmonary septic embolism. Also, in another contemporary study, it was found that 18F-FDG PET/CT in cases of suspected spondylodiscitis and inconclusive results in MRI reached a sensitivity, specificity, and accuracy of 81.8%, 100%, and 89.5%, respectively. The positive predictive value and negative predictive value (NPV) were 100% and 80%, respectively [30]. 18F-FDG PET has been suggested to distinguish between spinal infection and common Modic changes. Ohtori et al. [31] studied 18 patients with Modic changes who were suspected of having pyogenic spondylitis, and 18F-FDG PET had 100% diagnostic accuracy. The final diagnosis resulted from clinical symptoms, laboratory and biopsy results, X-ray examination, and MRI during a 1-year follow-up. The results of the above study were in accordance to a prior study that reported that 18F-FDG PET may prove useful for differentiation of degenerative and infectious endplate abnormalities found on MRI [32]. In agreement with all the above-mentioned data, a recent study that compared 18F-FDG PET/CT with MRI for the diagnosis of hematogenous spondylitis in the same cohort of patients (Fig. 1) revealed significantly lower specificity for the latter, reflecting its difficulty in ruling out infection in patients with degenerative joint disease or previous vertebral fractures [33]. 18F-FDG PET is also a very sensitive method in the diagnosis of chronic musculoskeletal infections in patients with metallic implants and prosthetic replacements. In a large cohort study, De Winter et al. [34] found an excellent overall accuracy (86%) and NPV (100%) of 18F-FDG PET in patients suspected of having spinal infection after previous surgery of the spine. A previous case report presented a 33-year-old patient with increasing low back pain due to paraspinal textiloma that showed significantly increased uptake of 18F-FDG [35]. More recently, in a study that used 18F-FDG PET/CT imaging in patients with trauma suspected of having chronic osteomyelitis, a subgroup of nine patients had the site of suspected infection in the lumbar spine, while seven of them had a metallic implant. 18F-FDG PET/CT showed excellent results, with a diagnostic accuracy of 100%, for both the patients with metallic implant as well as for those without [36]. Although MRI is accurate for differentiating tuberculous from pyogenic spondylitis, 18F-FDG PET/CT may have a complementary role in ambiguous cases, reflecting the activity of the infection. Lee et al. [37], in a study of 22 patients with spondylitis who underwent 18F-FDG PET/CT, reported that the differences of SUVmax were statistically significant between tuberculous and pyogenic spondylitis (higher values in the former). While all the above studies showed high sensitivity and diagnostic accuracy 18F-FDG PET, it is difficult to carry out a meta-analysis due to
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Fig. 1. Similar findings of 18F-FDG PET/CT and MRI in a patient with S. aureus infection. (A) Sagital MR images show pathological signal in the inervertebral discs (arrows) and subchondral bone marrow edema (arrowheads) at T7-T9 vertebrae (B) Axial and coronal MR images between T8 and T9 show mark erosion of the vertebral platforms (arrows) and coarse areas of paraspinal spinal soft tissue involvement (arrowheads) that is more evident on the left side (coronal plane, bottom right). (C) PET/CT images with intense 18F-FDG uptake (SUVmax= 7.0) between T8 and T9 (arrows), predominant on the left side, with paraspinal soft tissue involvement (arrowheads). Reprinted by permission of the European Journal of Nuclear Medicine and Molecular Imaging (Springer Publisher) from: Prospective comparison of whole-body 18F-FDG PET/CT and MRI of the spine in the diagnosis of haematogenous spondylodiskitis. Eur J Nucl Med Mol Imaging 2014; DOI 10.1007/s00259-014-2898-0 (Epub ahead of print).
two main reasons. Firstly, most studies included a small series of patients, and secondly, the initial studies were performed with 18F-FDG PET, while the most recent ones were performed with the hybrid 18FFDG PET/CT procedure (Table 1). Nevertheless, all of the above studies highlighted the fact that a negative 18F-FDG PET or PET/CT study excludes spinal osteomyelitis with a high degree of certainty. The main limitation of 18F-FDG PET/CT is the weakness to differentiate infection from tumor since the radiotracer shows high uptake in both cases. 2.3. 18F-FDG PET/CT for the assessment of treatment response 18F-FDG PET/CT seems to have a strong clinical impact in more than half of patients with infectious spondylitis [38]. Its usefulness appears to be influenced by the kind of microorganism. In the patients with pyogenic spondylitis, 18F-FDG PET/CT has an impact in the extension
of therapeutic period, whereas in those with tuberculous spondylitis, it is used to indicate the biopsy sites and to determine which lesions require surgery [38]. In the latter category, 18F-FDG PET/CT seems also to be a useful diagnostic technique for successful surgical planning with accurate localization of the active infection [39]. Although MRI is the imaging of choice for the diagnosis of spinal infection, its usefulness in revealing residual disease after treatment and early response to therapy is under question [40]. From the few relevant studies, 18F-FDG PET/CT seems to be superior to other imaging techniques for this aim. Kim et al. [41], in a study with 30 patients, explored the role of semiquantitative indices of 18F-FDG PET/CT in the presence or not of residual disease after treatment. More specifically, they demonstrated that percent difference of the SUVmax between initial and follow-up studies was the only potent predictor for differentiation of the residual from the successfully treated spinal infection. Furthermore,
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Table 1 Major studies incorporating 18F-FDG PET or PET/CT in the evaluation of spinal infection Imaging techniques
References Patient number
Main results
18F-FDG PET 18F-FDG PET 18F-FDG PET, MRI, Tc-99m MDP bone scan, and/ or 67Ga-citrate 18F-FDG PET/CT, Tc-99m MDP bone scan, and planar and SPECT/CT 67Ga-citrate 18F-FDG PET/CT, MRI
[24] [25] [28]
16 42 16
[29]
34
[30]
38
18F-FDG PET 18F-FDG PET, MRI
[31] [32]
18 30
18F-FDG PET/CT, MRI
[33]
26
18F-FDG PET
[34]
57
18F-FDG PET/CT, MRI
[37]
22
18F-FDG PET/CT 18F-FDG PET/CT 18F-FDG PET/CT 18F-FDG PET/CT
[38] [41] [42] [43]
29 30 38 10
18F-FDG PET is a very sensitive method in the detection of spondylodiscitis. 18F-FDG PET has a sensitivity 86% and a specificity of 95% in the detection of spondylodiskitis. 18F-FDG PET is superior to other imaging procedures in patients with low- grade spondylitis, adjacent soft tissue infections, and advanced degeneration. 18F-FDG PET/CT showing better diagnostic accuracy compared with the other nuclear medicine procedures and gives additional information that may influence the management of spondylodiscitis. 18F-FDG PET/CT has 89.5% diagnostic accuracy in patients with suspected spondylodiscitis and inconclusive results in MRI. Patients with confirmed spondylodiscitis showed a significantly higher SUVmax than patients without it. 18F-FDG PET can distinguish common Modic change and spinal infection. 18F-FDG PET can differentiate degenerative and infectious endplate abnormalities with greater diagnostic accuracy than MRI. The diagnostic accuracies of 18F-FDG PET/CT and MRI were similar (84% and 81%, respectively). The combination of both detects the spinal infection in 100% of the patients. 18F-FDG PET has an excellent diagnostic accuracy (86%) and NPV (100%) for the diagnosis of infection in postoperative spine. SUVmax reflects the activity of infectious spondylitis. 18F-FDG PET/CT may be complementary to MRI for differentiating pyogenic and tuberculous spondylitis. 18F-FDG PET/CT has a strong impact in clinical management of patients with infectious spondylitis (52%). 18F-FDG PET/CT can discriminate residual and nonresidual spinal infection after treatment. A decrease in SUVmax during therapy of at least 34% is strongly predictive of a complete response. 18F-FDG PET/CT in brucellar spondylodiskitis can provide additional information on the spread of infection compared to MRI. A significant decrease in SUVmax is associated with a successful treatment.
Nanni et al. [42] demonstrated that a decrease in SUVmax (measured before and 2 to 4 weeks after the initiation of therapy) of at least 34% is strongly predictive of a complete response, with a sensitivity and specificity of 82% (Fig. 2). This may have a strong impact on the clinical management since C-reactive protein has 10% probability to be falsely negative. Recently, Ioannou et al. [43] investigated the role of 18F-FDG PET/CT in the diagnosis and treatment monitoring of brucellar spondylodiscitis. They found that it can provide additional information on the spread of the infection compared to MRI. Also, a significant decrease in SUVmax values between the initial scan and after the completion of treatment is associated with successful treatment response (Fig. 3). They reported that SUVmax b3.0 could be an indirect evidence of successful treatment, along with negative indices of inflammation, resolution or improvement of MRI findings, and clinical improvement.
3. Future trends Due to the limitations of 18F-FDG that were mentioned above, new radiotracers more specific for infection are under investigation. Recently, a germanium/gallium generator producing 68Ga, which is a positron-emitting gallium isotope for PET imaging, has become available. 68Ga has a 68-min half-life, and the uptake phase allows a short imaging procedure. Although 68Ga-PET was described initially for tumor imaging, a few recent studies described 68Ga-citrate and 68Gatransferrin as possible tracers for infection [44]. Nanni et al. [45] evaluated the diagnostic accuracy of 68Ga-citrate PET/CT in nine patients with suspected discitis. The diagnostic accuracy was 100%, confirming a possible role of this radiotracer in the evaluation of spinal infection. Nevertheless, a direct comparison of 68Ga-citrate and 18F-FDG will highlight a potential superiority of the former or the latter. Also, in a
Fig. 2. Patient affected by acute hematogenous pyogenic spondylodiskitis. The MR image (A) and the CT image (B) at diagnosis show a pathological signal in L4–L5 (red cross). The 18F-FDG PET/CT image at diagnosis (C) shows increased uptake in L4–L5 (red cross), after 3 weeks of therapy (D) shows a significant reduction in tracer uptake in the infected site (red cross), and after therapy (E) is negative, confirming that the patient had completely responded to antibiotic therapy. Reprinted by permission of the European Journal of Nuclear Medicine and Molecular Imaging (Springer Publisher) from: FDG PET/CT is useful for the interim evaluation of response to therapy in patients affected by haematogenous spondylodiscitis. Eur J Nucl Med Mol Imaging. 2012;39:1538–44.
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Fig. 3. (A) Sagittal images of baseline 18F-FDG PET/CT scan in a patient with brucellar spondylodiskitis. Abnormal hypermetabolism at the left acromioclavicular joint, and at T6 and L5 vertebrae, along with paravertebral soft tissue involvement. (B) Sagittal images of follow-up 18F-FDG PET/CT scan after treatment. Decreased 18F-FDG uptake at T6 and L5 vertebrae, and no uptake at the paravertebral tissues.
preliminary study, it was found that 18F-FDG-labeled leukocyte PET/CT has high sensitivity and specificity for the diagnosis of infection. However, further investigation in a larger prospective series including patients with spinal infection is required [46]. In addition, new hybrid imaging modalities such as PET/MRI can potentially present with a useful role in spinal spondylodiscitis. In this direction lead also the results of a recent study which reported that the combination of 18F-FDG PET/CT and MRI detected the infection in 100% in patients with spondylodiskitis [33]. Hybrid PET/MRI systems can combine the acquisition of functional data at the molecular level with superior soft tissue resolution and anatomy. The main future goals of PET/MRI in patients with suspected spondylodiscitis are the improvement of diagnostic accuracy and its potential role for follow-up during treatment [47].
revealing residual disease after treatment and early response to therapy. Novel tracers as well as new hybrid modalities are under investigation. Acknowledgments The authors would like to thank Biomed Central as the original publisher for reproduction of Fig. 1 from the research article “Ioannou S, Chatziioannou S, Pneumaticos SG, Zormpala A, Sipsas NV. Fluorine18 fluoro-2-deoxy-D-glucose positron emission tomography scan contributes to the diagnosis and management of brucellar spondylodiscitis. BMC Infect Dis. 2013;13:73doi:10.1186/1471-233413-73.” In the current article, it is referred to as Fig. 3. References
4. Conclusions MRI remains the imaging method of choice for diagnosing infection of the spine in unoperated cases. However, 18F-FDG PET/CT not only seems to be superior over the conventional nuclear medicine procedures but also has a complementary and useful role in cases where MRI has limited diagnostic value (Modic changes, previous surgery of the spine, metallic implant), avoiding false-positive results. More major seems to be its role, via quantification with the SUVmax, in
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[29] Fuster D, Solà O, Soriano A, Monegal A, Setoain X, Tomás X, et al. A prospective study comparing whole body FDG PET/CT to combined planar bone scan with 67Ga SPECT/ CT in the diagnosis of spondylodiskitis. Clin Nucl Med 2012;37:827–32. [30] Seifen T, Rettenbacher L, Thaler C, Holzmannhofer J, Mc Coy M, Pirich C. Prolonged back pain attributed to suspected spondylodiscitis. The value of 18F-FDG PET/CT imaging in the diagnostic work-up of patients. Nuklearmedizin 2012;51:194–200. [31] Ohtori S, Suzuki M, Koshi T, Yamashita M, Yamauchi K, Inoue G, et al. 18FFluorodexyglucose-PET for patients with suspected spondylitis showing Modic change. Spine 2010;35:1599–603. [32] Stumpe KD, Zanetti M, Weishaupt D, Hodler J, Boos N, von Schulthess GK. FDG positron emission tomography for differentiation of degenerative and infectious endplate abnormalities in the lumbar spine detected on MR imaging. AJR Am J Roentgenol 2002;179:1151–7. [33] Fuster D, Tomas X, Mayoral M, Soriano A. Prospective comparison of whole-body 18 F-FDG PET/CT and MRI of the spine in the diagnosis of haematogenous spondylodiskitis. Eur J Nucl Med Mol Imaging 2014. http://dx.doi.org/10.1007/ s00259-014-2898-0 [Epub ahead of print]. [34] De Winter F, Gemmel F, Van De Wiele C, Poffijn B, Uyttendaele D, Dierckx R. 18Fluorine fluorodeoxyglycose positron emission tomography for the diagnosis of infection in the postoperative spine. Spine 2003;28:1314–9. [35] De Winter F, Huysse W, Paepe P, Lambert B, Poffyn B, Dierckx R. High F-18 FDG uptake in a paraspinal textiloma. Clin Nucl Med 2002;27:132–3. [36] Hartmann A, Eid K, Dora C, Trentz O, von Schulthess GK, Stumpe KD. Diagnostic value of 18F-FDG PET/CT in trauma patients with suspected chronic osteomyelitis. Eur J Nucl Med Mol Imaging 2007;34:704–14. [37] Lee In S, Lee JS, Kim SJ, Jun S, Suh KT. Fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography imaging in pyogenic and tuberculous spondylitis: preliminary study. J Comput Assist Tomogr 2009;33:587–92. [38] Ito K, Kubota K, Morroka M, Hasuo K, Kuroki H, Mimori A. Clinical impact of 18F-FDG PET/CT on the management and diagnosis of infectious spondylitis. Nucl Med Commun 2010;31:691–8. [39] Nakahara M, Ito M, Hattori N, Magota K, Takahata M, Nagahama K, et al. 18F-FDGPET/CT better localizes active spinal infection than MRI for successful minimally invasive surgery. Acta Radiol 2014 [pii:0284185114541983 [Epub ahead of print]]. [40] Hodges FS, McAtee S, Kirkpatrick JS, Theiss SM. The ability of MRI to predict failure of nonoperative treatment of pyogenic vertebral osteomyelitis. J Spinal Disord Tech 2006;19:566–70. [41] Kim S, Kim I, Tak K, Kim Y, Lee JS. Prediction of residual disease of spine infection using F-18 FDG PET/CT. Spine 2009;34:2424–30. [42] Nanni C, Boriani L, Salvadori C, Zamparini E, Rorato G, Ambrosini V, et al. FDG PET/CT is useful for the interim evaluation of response to therapy in patients affected by haematogenous spondylodiscitis. Eur J Nucl Med Mol Imaging 2012;39:1538–44. [43] Ioannou S, Chatziioannou S, Pneumaticos SG, Zormpala A, Sipsas NV. Fluorine-18 fluoro-2-deoxy-D-glucose positron emission tomography scan contributes to the diagnosis and management of brucellar spondylodiscitis. BMC Infect Dis 2013;13:73. http://dx.doi.org/10.1186/1471-2334-13-73. [44] Kumar V, Boddeti DK. (68) Ga-radiopharmaceuticals for PET imaging of infection and inflammation. Recent Results Cancer Res 2013;194:189–219. [45] Nanni C, Errani C, Boriani L, Fantini L, Ambrosini V, Boschi S, et al. 68Ga-citrate PET/CT for evaluation patients with infectious of the bone: preliminary results. J Nucl Med 2010;51:1932–6. [46] Dumarey N, Egrise D, Blocklet D, Stallenberg B, Remmelink M, del Marmol V, et al. Imaging infection with 18F-FDG-labeled leukocyte PET/CT: initial experience in 21 patients. J Nucl Med 2006;47:625–32. [47] Glaudemans AW, Quintero AM, Signore A. PET/MRI in infectious and inflammatory diseases: will it be useful improvement? Eur J Nucl Med Mol Imaging 2012;39: 745–9.
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Positron emission tomography in spinal infections Alexandros Georgakopoulos a,⁎, Spiros G. Pneumaticos b, Nikolaos V. Sipsas c, Sofia Chatziioannou a,d a
Nuclear Medicine Division, PET/CT section, Foundation for Biomedical Research of the Academy of Athens, Athens, Greece 3rd Department of Orthopedic Surgery, Medical School, National and Kapodistrian University of Athens, Athens, Greece c Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece d Second Department of Radiology, Medical School, National and Kapodistrian University of Athens, General University Hospital “ATTIKON”, Athens, Greece b
a r t i c l e
i n f o
Article history: Received 14 January 2015 Accepted 5 April 2015 Keywords: Spinal infection Positron emission tomography 18 F-fluorodeoxyglucose Imaging Nuclear medicine
a b s t r a c t Magnetic resonance imaging is the imaging method of choice for diagnosing infection of the spine in unoperated cases. 2-[18F]-fluoro-2deoxy-D-glucose positron emission tomography/computed tomography study is recommended to distinguish between spinal infection and common Modic change in patients with metallic implants and prosthetic replacements and for differentiating tuberculous from pyogenic spondylitis in ambiguous cases, reflecting the activity of the infection. Also, it seems to have a strong clinical impact in more than half of patients with infectious spondylitis, while it is superior to other imaging techniques in revealing residual disease after treatment and early response to therapy. New tracers as well as new hybrid modalities are under investigation. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Spinal infections are increasing in incidence, accounting for 2%–7% of all musculoskeletal infections [1]. They include a spectrum of disease, which can affect any part of vertebra and may cause vertebral osteomyelitis, disc space infections, and epidural abscess. Infection can be caused by granulomatous, pyogenic, iatrogenic, autoimmune, and idiopathic conditions. Staphylococcus aureus is the most common causative organism [2, 3]. Pyogenic spondylitis is the most common spinal infection that peaks at age of less than 20 years and in the group of 50–70 years old that includes the higher-risk group, i.e., immunosuppressed patients, spinal instrumentation, and surgery [4]. On the other hand, spinal tuberculosis is a rare but serious infection that can lead to severe deformity and neurological complications [5].
2. Imaging procedures Diagnosis is generally difficult and is achieved by imaging techniques together with bacteriological and histopathological exams [6]. Gadolinium-enhanced magnetic resonance imaging (MRI) is the imaging technique of choice for the evaluation of spinal infection [7]. It has an excellent sensitivity and specificity (96% and 94%, respectively) [8].
⁎ Corresponding author. Centre for Clinical Research, Nuclear Medicine Division, PET/CT section, Foundation for Biomedical Research of the Academy of Athens, 4 Soranou Ephessiou Street, 11527 Athens, Greece. Tel.: + 30 2106597078, + 30 6937319616; fax: +30 210 6597 502. E-mail address: [email protected] (A. Georgakopoulos). http://dx.doi.org/10.1016/j.clinimag.2015.04.002 0899-7071/© 2015 Elsevier Inc. All rights reserved.
MRI demonstrates pathological changes of bone marrow and also can clearly delineate subdural, epidural, intramedullary, and paraspinal soft tissue involvement [9]. The characteristic changes for spondylodiscitis consist of a hypointense signal of the disc and vertebral body on T1-weighted images and a hyperintense signal of the same structures on T2-weighted images (due to edema) [1]. Also, MRI is accurate for differentiating tuberculous from pyogenic spondylitis [10]. However, there are limitations to MRI, such as differentiation between common Modic changes and infection by low virulence bacteria [11]. Although it is the imaging method of choice in the absence of metallic implants, it is not always possible to distinguish postoperative changes from infection [12]. Metallic implants and renal failure may be contraindication to the test. Moreover, residual MRI findings at the end of the treatment despite the clinical improvement may lead to unnecessary invasive treatments [13]. Nuclear medicine procedures are often performed as complementary techniques in the diagnosis of infection in the spine. Although bone scintigraphy is an easily performed, rapidly completed, widely available, and sensitive technique (~90%) for diagnosing spinal osteomyelitis, it is not specific for infection [14]. The typical image of the technetium bone scan in osteomyelitis is increased uptake of the radiotracer in two adjacent vertebrae. The specificity has been reported to be as low as 31% for planar bone scan and 23% for planar plus single photon emission tomography (SPECT) bone scan with an overall accuracy of 50% for both studies, too low to be clinically useful [15]. Love et al. [15] reported that three-phase bone scintigraphy improves specificity but at the expense of sensitivity, which decreases from 92% to 36%. Also, three-phase bone scan may be positive in patients with severe infection but not in those with mild or moderate infection [14]. False-negative bone scans have been reported in the elderly due to regional ischemia secondary to
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arteriosclerotic disease with resulting decreased perfusion [16]. Also, bone scintigraphy cannot detect the soft tissue infections that often accompany spinal osteomyelitis [17]. Gallium imaging has also several limitations. Other than infection, it can also be accumulated in tumors, aseptic inflammation, and trauma. In addition, its physical characteristics and normal distribution reduce the image quality. It is often used as a complementary image modality to bone scintigraphy in order to enhance the specificity of the study and to detect extraosseous sites of infection [18]. This dual-tracer technique requires multiple, sometimes lengthy, imaging sessions on different days with increased cost. On the other side, 67Ga-SPECT seems to be as accurate for diagnosing spinal infection as combined bone–gallium scans [15]. Labeled leukocyte imaging is of limited value on the basis that up to 50% of all patients with spinal osteomyelitis show photopenic defects, which are not specific for infection [19]. Furthermore, imaging with radiolabeled antibiotic 99Tc-ciprofloxacin and streptavidin/ 111Inbiotin complex is not widely used in clinical practice. 2.1. Positron emission tomography/computed tomography with 2-[ 18F]fluoro-2deoxy-D-glucose (18F-FDG PET/CT) Recent advances in molecular nuclear medicine such as 18F-FDG PET/CT have expanded the available imaging methods for assessment of infection in the spine. 18F-FDG PET/CT is a well-established functional imaging technique mainly for diagnosing cancer, which has the advantage of higher spatial resolution as compared to other nuclear medicine procedures. It is completed in 1–2 h and has a relative low radiation dose. However, it is now established that it also detect high glucose metabolism in infectious diseases [20]. 18F-FDG is the most commonly used radiotracer worldwide because of its availability and the relatively long half-life. Its uptake in infection depends on the increased glucose metabolism in activated inflammatory cells such as leukocytes, granulocytes, and macrophages that produce an excess of glycolitic enzymes and overexpress in glucose transporter (GLUT) isotypes (mainly GLUT-1 and GLUT-3) [21]. Although 18F-FDG accumulates in infection, it is a nonspecific tracer that also accumulates in aseptic inflammation [20]. The hybrid PET/CT scan combines the evaluation of morphological and metabolic changes simultaneously and enables a more accurate localization and attenuation correction. Also, semiquantitative analysis with standardized uptake value (SUV) may be useful for differentiating infectious from noninfectious disease and for monitoring response to therapy [22]. The present article will address the recent advantages and limitations of PET in the diagnosis and assessment of spinal infections. The manuscript is not a systematic review but rather an update overview that is intended to provide information helpful on the use of PET in clinical practice. Based on this principle, a literature search for articles concerning spinal infection, imaging, PET, and 18F-FDG was performed using the Medline database and EMBASE from 1990 to date. This resulted in a total number of 41 publications. 2.2. The role of 18F-FDG PET/CT in the diagnosis of spinal infections MRI remains the imaging method of choice in diagnosing infection of the spine. However, 18F-FDG PET/CT can play an adjuvant and complementary role in this area. Several published studies have highlighted the role of 18F-FDG PET for diagnosing spinal infection. In one of the first studies on the evaluation of chronic osteomyelitis with 18F-FDG PET, in four patients, the region of interest was the spine. 18F-FDG PET was true positive and diagnosed all three cases of spinal infection and was true negative in the fourth patient without infection [23]. In a study of 16 patients with suspicion of spondylodiscitis, 18F-FDG PET showed high sensitivity (100%) and diagnostic accuracy depicting addition soft tissue involvement [24]. In a recent similar study, 18F-FDG PET was performed in 42 patients with suspected spondylodiscitis. The detection of spondylodiscitis had a sensitivity of 86 % and a specificity of 95%. The
average SUV in true-positive cases was 4.0 (SD: 1.73), while in true negative cases, it was 1.84 (SD: 0.67) [25]. Also, some studies showed the superiority of 18F-FDG PET over other techniques of conventional nuclear medicine. In one such study, Guhlmann et al. [26] highlighted significantly better accuracy of the 18F-FDG PET compared to radiolabeled antigranulocyte antibody in patients with suspected chronic osteomyelitis of the central skeleton including the spine. In a similar study, Meller et al. [27] reported that 18F-FDG PET was superior to radiolabeled leukocyte scintigraphy in the axial skeleton. In eight patients, the field of interest was the spine, and 18F-FDG PET showed 100% diagnostic accuracy. In a subsequent study, Gratz et al. [28] compared 18F-FDG PET with conventional nuclear medicine imaging modalities [99mTc-methylene diphosphonate (MDP) bone scan and 67Ga-citrate scan] and MRI. They have concluded that 18F-FDG PET contributes in the differentiation between mild infection and degenerative changes, presents good correlation with the histological severity of the infection, and detects additional manifestations outside the spine. More recently, Fuster et al. [29], comparing 18F-FDG PET/CT with combined bone scan and 67Ga-SPECT/CT, reported that the former imaging method is more accurate in the evaluation of suspected spondylodiscitis and gives additional information that may influence the management of disease. More specifically, there were two cases of multifocality and an additional two with associated pulmonary septic embolism. Also, in another contemporary study, it was found that 18F-FDG PET/CT in cases of suspected spondylodiscitis and inconclusive results in MRI reached a sensitivity, specificity, and accuracy of 81.8%, 100%, and 89.5%, respectively. The positive predictive value and negative predictive value (NPV) were 100% and 80%, respectively [30]. 18F-FDG PET has been suggested to distinguish between spinal infection and common Modic changes. Ohtori et al. [31] studied 18 patients with Modic changes who were suspected of having pyogenic spondylitis, and 18F-FDG PET had 100% diagnostic accuracy. The final diagnosis resulted from clinical symptoms, laboratory and biopsy results, X-ray examination, and MRI during a 1-year follow-up. The results of the above study were in accordance to a prior study that reported that 18F-FDG PET may prove useful for differentiation of degenerative and infectious endplate abnormalities found on MRI [32]. In agreement with all the above-mentioned data, a recent study that compared 18F-FDG PET/CT with MRI for the diagnosis of hematogenous spondylitis in the same cohort of patients (Fig. 1) revealed significantly lower specificity for the latter, reflecting its difficulty in ruling out infection in patients with degenerative joint disease or previous vertebral fractures [33]. 18F-FDG PET is also a very sensitive method in the diagnosis of chronic musculoskeletal infections in patients with metallic implants and prosthetic replacements. In a large cohort study, De Winter et al. [34] found an excellent overall accuracy (86%) and NPV (100%) of 18F-FDG PET in patients suspected of having spinal infection after previous surgery of the spine. A previous case report presented a 33-year-old patient with increasing low back pain due to paraspinal textiloma that showed significantly increased uptake of 18F-FDG [35]. More recently, in a study that used 18F-FDG PET/CT imaging in patients with trauma suspected of having chronic osteomyelitis, a subgroup of nine patients had the site of suspected infection in the lumbar spine, while seven of them had a metallic implant. 18F-FDG PET/CT showed excellent results, with a diagnostic accuracy of 100%, for both the patients with metallic implant as well as for those without [36]. Although MRI is accurate for differentiating tuberculous from pyogenic spondylitis, 18F-FDG PET/CT may have a complementary role in ambiguous cases, reflecting the activity of the infection. Lee et al. [37], in a study of 22 patients with spondylitis who underwent 18F-FDG PET/CT, reported that the differences of SUVmax were statistically significant between tuberculous and pyogenic spondylitis (higher values in the former). While all the above studies showed high sensitivity and diagnostic accuracy 18F-FDG PET, it is difficult to carry out a meta-analysis due to
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Fig. 1. Similar findings of 18F-FDG PET/CT and MRI in a patient with S. aureus infection. (A) Sagital MR images show pathological signal in the inervertebral discs (arrows) and subchondral bone marrow edema (arrowheads) at T7-T9 vertebrae (B) Axial and coronal MR images between T8 and T9 show mark erosion of the vertebral platforms (arrows) and coarse areas of paraspinal spinal soft tissue involvement (arrowheads) that is more evident on the left side (coronal plane, bottom right). (C) PET/CT images with intense 18F-FDG uptake (SUVmax= 7.0) between T8 and T9 (arrows), predominant on the left side, with paraspinal soft tissue involvement (arrowheads). Reprinted by permission of the European Journal of Nuclear Medicine and Molecular Imaging (Springer Publisher) from: Prospective comparison of whole-body 18F-FDG PET/CT and MRI of the spine in the diagnosis of haematogenous spondylodiskitis. Eur J Nucl Med Mol Imaging 2014; DOI 10.1007/s00259-014-2898-0 (Epub ahead of print).
two main reasons. Firstly, most studies included a small series of patients, and secondly, the initial studies were performed with 18F-FDG PET, while the most recent ones were performed with the hybrid 18FFDG PET/CT procedure (Table 1). Nevertheless, all of the above studies highlighted the fact that a negative 18F-FDG PET or PET/CT study excludes spinal osteomyelitis with a high degree of certainty. The main limitation of 18F-FDG PET/CT is the weakness to differentiate infection from tumor since the radiotracer shows high uptake in both cases. 2.3. 18F-FDG PET/CT for the assessment of treatment response 18F-FDG PET/CT seems to have a strong clinical impact in more than half of patients with infectious spondylitis [38]. Its usefulness appears to be influenced by the kind of microorganism. In the patients with pyogenic spondylitis, 18F-FDG PET/CT has an impact in the extension
of therapeutic period, whereas in those with tuberculous spondylitis, it is used to indicate the biopsy sites and to determine which lesions require surgery [38]. In the latter category, 18F-FDG PET/CT seems also to be a useful diagnostic technique for successful surgical planning with accurate localization of the active infection [39]. Although MRI is the imaging of choice for the diagnosis of spinal infection, its usefulness in revealing residual disease after treatment and early response to therapy is under question [40]. From the few relevant studies, 18F-FDG PET/CT seems to be superior to other imaging techniques for this aim. Kim et al. [41], in a study with 30 patients, explored the role of semiquantitative indices of 18F-FDG PET/CT in the presence or not of residual disease after treatment. More specifically, they demonstrated that percent difference of the SUVmax between initial and follow-up studies was the only potent predictor for differentiation of the residual from the successfully treated spinal infection. Furthermore,
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Table 1 Major studies incorporating 18F-FDG PET or PET/CT in the evaluation of spinal infection Imaging techniques
References Patient number
Main results
18F-FDG PET 18F-FDG PET 18F-FDG PET, MRI, Tc-99m MDP bone scan, and/ or 67Ga-citrate 18F-FDG PET/CT, Tc-99m MDP bone scan, and planar and SPECT/CT 67Ga-citrate 18F-FDG PET/CT, MRI
[24] [25] [28]
16 42 16
[29]
34
[30]
38
18F-FDG PET 18F-FDG PET, MRI
[31] [32]
18 30
18F-FDG PET/CT, MRI
[33]
26
18F-FDG PET
[34]
57
18F-FDG PET/CT, MRI
[37]
22
18F-FDG PET/CT 18F-FDG PET/CT 18F-FDG PET/CT 18F-FDG PET/CT
[38] [41] [42] [43]
29 30 38 10
18F-FDG PET is a very sensitive method in the detection of spondylodiscitis. 18F-FDG PET has a sensitivity 86% and a specificity of 95% in the detection of spondylodiskitis. 18F-FDG PET is superior to other imaging procedures in patients with low- grade spondylitis, adjacent soft tissue infections, and advanced degeneration. 18F-FDG PET/CT showing better diagnostic accuracy compared with the other nuclear medicine procedures and gives additional information that may influence the management of spondylodiscitis. 18F-FDG PET/CT has 89.5% diagnostic accuracy in patients with suspected spondylodiscitis and inconclusive results in MRI. Patients with confirmed spondylodiscitis showed a significantly higher SUVmax than patients without it. 18F-FDG PET can distinguish common Modic change and spinal infection. 18F-FDG PET can differentiate degenerative and infectious endplate abnormalities with greater diagnostic accuracy than MRI. The diagnostic accuracies of 18F-FDG PET/CT and MRI were similar (84% and 81%, respectively). The combination of both detects the spinal infection in 100% of the patients. 18F-FDG PET has an excellent diagnostic accuracy (86%) and NPV (100%) for the diagnosis of infection in postoperative spine. SUVmax reflects the activity of infectious spondylitis. 18F-FDG PET/CT may be complementary to MRI for differentiating pyogenic and tuberculous spondylitis. 18F-FDG PET/CT has a strong impact in clinical management of patients with infectious spondylitis (52%). 18F-FDG PET/CT can discriminate residual and nonresidual spinal infection after treatment. A decrease in SUVmax during therapy of at least 34% is strongly predictive of a complete response. 18F-FDG PET/CT in brucellar spondylodiskitis can provide additional information on the spread of infection compared to MRI. A significant decrease in SUVmax is associated with a successful treatment.
Nanni et al. [42] demonstrated that a decrease in SUVmax (measured before and 2 to 4 weeks after the initiation of therapy) of at least 34% is strongly predictive of a complete response, with a sensitivity and specificity of 82% (Fig. 2). This may have a strong impact on the clinical management since C-reactive protein has 10% probability to be falsely negative. Recently, Ioannou et al. [43] investigated the role of 18F-FDG PET/CT in the diagnosis and treatment monitoring of brucellar spondylodiscitis. They found that it can provide additional information on the spread of the infection compared to MRI. Also, a significant decrease in SUVmax values between the initial scan and after the completion of treatment is associated with successful treatment response (Fig. 3). They reported that SUVmax b3.0 could be an indirect evidence of successful treatment, along with negative indices of inflammation, resolution or improvement of MRI findings, and clinical improvement.
3. Future trends Due to the limitations of 18F-FDG that were mentioned above, new radiotracers more specific for infection are under investigation. Recently, a germanium/gallium generator producing 68Ga, which is a positron-emitting gallium isotope for PET imaging, has become available. 68Ga has a 68-min half-life, and the uptake phase allows a short imaging procedure. Although 68Ga-PET was described initially for tumor imaging, a few recent studies described 68Ga-citrate and 68Gatransferrin as possible tracers for infection [44]. Nanni et al. [45] evaluated the diagnostic accuracy of 68Ga-citrate PET/CT in nine patients with suspected discitis. The diagnostic accuracy was 100%, confirming a possible role of this radiotracer in the evaluation of spinal infection. Nevertheless, a direct comparison of 68Ga-citrate and 18F-FDG will highlight a potential superiority of the former or the latter. Also, in a
Fig. 2. Patient affected by acute hematogenous pyogenic spondylodiskitis. The MR image (A) and the CT image (B) at diagnosis show a pathological signal in L4–L5 (red cross). The 18F-FDG PET/CT image at diagnosis (C) shows increased uptake in L4–L5 (red cross), after 3 weeks of therapy (D) shows a significant reduction in tracer uptake in the infected site (red cross), and after therapy (E) is negative, confirming that the patient had completely responded to antibiotic therapy. Reprinted by permission of the European Journal of Nuclear Medicine and Molecular Imaging (Springer Publisher) from: FDG PET/CT is useful for the interim evaluation of response to therapy in patients affected by haematogenous spondylodiscitis. Eur J Nucl Med Mol Imaging. 2012;39:1538–44.
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Fig. 3. (A) Sagittal images of baseline 18F-FDG PET/CT scan in a patient with brucellar spondylodiskitis. Abnormal hypermetabolism at the left acromioclavicular joint, and at T6 and L5 vertebrae, along with paravertebral soft tissue involvement. (B) Sagittal images of follow-up 18F-FDG PET/CT scan after treatment. Decreased 18F-FDG uptake at T6 and L5 vertebrae, and no uptake at the paravertebral tissues.
preliminary study, it was found that 18F-FDG-labeled leukocyte PET/CT has high sensitivity and specificity for the diagnosis of infection. However, further investigation in a larger prospective series including patients with spinal infection is required [46]. In addition, new hybrid imaging modalities such as PET/MRI can potentially present with a useful role in spinal spondylodiscitis. In this direction lead also the results of a recent study which reported that the combination of 18F-FDG PET/CT and MRI detected the infection in 100% in patients with spondylodiskitis [33]. Hybrid PET/MRI systems can combine the acquisition of functional data at the molecular level with superior soft tissue resolution and anatomy. The main future goals of PET/MRI in patients with suspected spondylodiscitis are the improvement of diagnostic accuracy and its potential role for follow-up during treatment [47].
revealing residual disease after treatment and early response to therapy. Novel tracers as well as new hybrid modalities are under investigation. Acknowledgments The authors would like to thank Biomed Central as the original publisher for reproduction of Fig. 1 from the research article “Ioannou S, Chatziioannou S, Pneumaticos SG, Zormpala A, Sipsas NV. Fluorine18 fluoro-2-deoxy-D-glucose positron emission tomography scan contributes to the diagnosis and management of brucellar spondylodiscitis. BMC Infect Dis. 2013;13:73doi:10.1186/1471-233413-73.” In the current article, it is referred to as Fig. 3. References
4. Conclusions MRI remains the imaging method of choice for diagnosing infection of the spine in unoperated cases. However, 18F-FDG PET/CT not only seems to be superior over the conventional nuclear medicine procedures but also has a complementary and useful role in cases where MRI has limited diagnostic value (Modic changes, previous surgery of the spine, metallic implant), avoiding false-positive results. More major seems to be its role, via quantification with the SUVmax, in
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