Special Report Special Report

Imaging of osteomyelitis: the key is in the combination

An accurate diagnosis of osteomyelitis requires the combination of anatomical and functional imaging techniques. Conventional radiography is the first imaging modality to begin with, as it provides an overview of both the anatomy and the pathologic conditions of the bone. Sonography is most useful in the diagnosis of fluid collections, periosteal involvement and soft tissue abnormalities, and may provide guidance for diagnostic or therapeutic interventions. MRI highlights sites with tissue edema and increased regional perfusion, and provides accurate information of the extent of the infectious process and the tissues involved. To detect osteomyelitis before anatomical changes are present, functional imaging could have some advantages over anatomical imaging. Fluorine-18 fluorodeoxyglucose-PET has the highest diagnostic accuracy for confirming or excluding the diagnosis of chronic osteomyelitis. For both SPECT and PET, specificity improves considerably when the scintigraphic images are fused with computed tomography. Close cooperation between clinicians and imagers remains the key to early and adequate diagnosis when osteomyelitis is suspected or evaluated.

†1 KEYWORDS: computed tomography n hybrid systems n imaging n MRI n nuclear Carlos Pineda , medicine n osteomyelitis n ultrasonography Angelica Pena2, Rolando Espinosa2 & Cristina Osteomyelitis is inflammation of the bone that osteomyelitis. The ideal imaging technique Hernández-Díaz1 is usually due to infection. There are different should have a high sensitivity and specificity; 1Musculoskeletal Ultrasound Department, Instituto Nacional de classification systems to categorize osteomyeli- numerous studies have been published con- Rehabilitacion, Avenida tis. Traditionally, it has been labeled as acute, cerning the accuracy of the various modali- Mexico‑Xochimilco No. 289, Arenal de Guadalupe, Tlalpan, Mexico City [2–4] subacute or chronic, depending on its clinical ties in diagnosing chronic osteomyelitis . 14389, Mexico course, histologic findings and disease dura- Confirmation of the presence of osteomyeli- 2Rheumatology Department, Instituto tion, but there is no consensual agreement on tis usually entails a combination of imaging Nacional de Rehabilitacion, Mexico City, Mexico the temporal scale used or specific findings. techniques. Table 1 shows the main pathologic †Author for correspondence: As a result, some researchers have proposed findings of osteomyelitis assessed by diverse Tel.: +52 559 991 000 ext. 13229 more detailed classification systems, such as imaging techniques. [email protected] the Waldvogel classification system based on etiology of the infection (hematogenous spread Conventional radiography of an organism, direct inoculation of an organ- Plain films are usually the first imaging test ism through trauma or contiguous spread from ordered by clinicians [5]. Conventional radio­ a soft tissue infection), and Cierny-Mader clas- graphy should not be used to exclude acute sification, a descriptive system that takes into osteomyelitis in a patient who has experienced account both anatomic factors and the host’s symptoms for less than 10 days. Nevertheless, physiologic status [1,2]. deep soft tissue swelling, joint effusion or early An inadequate or late diagnosis increases periosteal changes may be seen within days the degree of complications and morbidity; for after onset of infection. Furthermore, conven- these reasons, imaging techniques are essential tional radiography helps to exclude fracture to confirm the presumed clinical diagnosis and or tumor. to provide information regarding the exact site Destructive bone changes do not occur until and extent of the infection process [1]. 7–10 days after the onset of infection. During the Although a variety of diagnostic imaging first 2–3 days of symptoms, radionuclide bone techniques is available for excluding or con- imaging may be particularly useful in showing firming osteomyelitis, it is often difficult to a well-defined focus of increased uptake on the choose the most appropriate technique to dynamic perfusion, as well as early blood pool conclusively establish the diagnosis of osteo- and delayed images corresponding to the area myelitis. Several imaging modalities have of hyperemia [6]. At this early stage, the main been used in the evaluation of suspected utility of plain film is to provide a global view

10.2217/IJR.10.100 © 2011 Future Medicine Ltd Int. J. Clin. Rheumatol. (2011) 6(1), 25–33 ISSN 1758-4272 25 Special Report Pineda, Pena, Espinosa & Hernández-Díaz Imaging of osteomyelitis: the key is in the combination Special Report

Table 1. Imaging abnormalities in osteomyelitis. Technique Main findings Acute Chronic Conventional Radiolucent areas associated with periostitis Single or multiple radiolucent radiography Cortical resorption identified as endosteal scalloping, abscesses (Brodie’s abscess) intracortical lucent regions or tunneling Cortical sequestration Lytic lesions New bone apposition Focal osteopenia Loss of trabecular architecture Computed Blurring of fat planes Periosteal thickening tomography Increased density of fatty bone marrow sequestra, Cortical erosion or involucra and intraosseous gas destruction Ultrasonography Soft tissue abscess (if present) Elevated periosteum Surrounding fluid collection Fistulous tracts Cortical discontinuity MRI T1-weighted: low signal intensity medullary space T1- and T2-weighted: low T2-weighted: high signal intensity contiguous to signal intensity areas of inflammatory processes and edema devascularized fibrotic Gadolinium: enhances areas of necrosis scarring in the bone marrow Subacute: Evidence of Brodie’s abscess, single or multiple radiolucent abscesses T1-weighted: central abscess cavity with low signal intensity T2-weighted: high signal intensity of granulation tissue surrounded by low signal intensity band of bone sclerosis (double-line effect) of the suspect part of the skeleton and to provide does not exhibit the osteopenia of the adjacent information regarding differential diagnosis in a living bone. A wide scope of bone lesions may patient complaining of pain. present with an image suggestive of sequestrum Structural bony changes and periosteal reac- including osteoid osteoma, e­osinophilic granu- tion consist first of subperiosteal resorption or loma and primary lymphoma [7]. scalloping, which creates radiolucencies within A lucent circumscribed lesion (Brodie’s cortical bone that may progress to irregular abscess) in the metaphyses of long bones pre- destruction with areas of periosteal new bone dominantly abutting the growth plate with formation. However, hematogenous osteo­ well-defined dense margins is commonly seen myelitis in children typically arises within can- in the tibia and femur of children with subacute cellous bone, mostly in the vicinity of physeal osteomyelitis. plates, and s­econdarily involves cortical bone Periostitis, involucrum formation and sinus and periosteum. tracts are due to a subperiosteal abscess with In general, osteopenia becomes evident lifting of the periosteum, new bone formation on conventional radiographs after the loss of and soft tissue fistulas. All of these findings approximately 30–50% of bone mineraliza- are indicative of the protracted nature of the tion. Follow-up radiographs may be normal i­nfection process. if therapy is successful, or in some instances ­periosteal new bone formation may be apparent. „„Special situations The search for sequestra is a common and Diabetic foot important diagnostic challenge in chronic In a recent meta-ana­lysis of the accuracy of osteomyelitis. The presence of a sequestrum diagnostic tests for osteomyelitis in diabetic may lead to a decision of surgery. A bone seques- patients with foot ulcers, the sensitivity of trum manifests on conventional radiographs as plain radiography for diagnosis of osteomyeli- a piece of calcified tissue within a lucent lesion. tis was highly variable, ranging from 0.28 to The increased density of the sequestrum rela- 0.75. The wide variation may be attributable tive to the surrounding bone is a consequence to the timing of performance of the radiograph of its absence of blood supply. As a result of this in relation to the chronicity of the ulcer. The devascularization, the sequestrum does not par- pooled sensitivity was 0.54 and the pooled ticipate in the reactive hyperemia and therefore specificity was 0.68. The diagnostic odds ratio

26 Int. J. Clin. Rheumatol. (2011) 6(1) future science group Special Report Pineda, Pena, Espinosa & Hernández-Díaz Imaging of osteomyelitis: the key is in the combination Special Report

(OR) for radiography was 2.84 (the value of defines the course and extent of the sinus tract a diagnostic OR ranges from 0 to infinity; and its possible communications with neighbor- higher values indicate better discriminatory ing structures. Sinography or fistulography may test p­erformance) [5]. be combined with CT for better delineation of In summary, plain radiography is helpful as the anatomical relationships of the contrast- a first step, as it is widely available and may filled track[8] . Sinography is not widely used in reveal soft tissue changes and alternative diag- ­clinical practice. noses (e.g., bone metastases or a fracture) can be made; however, it is not a sensitive test for Ultrasonography acute osteomyelitis. Radiographs, when posi- During recent years, ultrasonography has had an tive, are helpful, but negative radiographic find- expanding role in the investigation of infectious ings are unreliable to exclude the diagnosis of processes of the soft tissues and in early detection o­steomyelitis in patients who have violated of subperiosteal fluid collections that are seen in bone [8]. acute osteomyelitis in childhood [11]. A constellation of grayscale and color Doppler Tuberculous osteomyelitis & arthritis ultrasound findings can be highly indicative Tuberculous osteomyelitis can remain local- of bone infection including: fistulous tracts, ized to bone or involve adjacent joints. In gen- periosteal thickening, cortical discontinuity, eral, tuberculosis confined to bone is relatively soft tissue abscess and cellulitis, juxta-cortical infrequent. Virtually any bone can be affected, fluid collections, distension of the pseudo­ including the pelvis, phalanges and metacar- capsule in arthroplasties and periosteal vascu- pals, long bones, ribs, sternum, skull, patella, larity in patients with long-standing chronic carpal and tarsal bones, although tuberculous post-traumatic/postoperative osteomyelitis [12]. osteomyelitis has predilection for the spine (tho- The presence of joint effusion may be a d­iagnostic racic and lumbar segments) and weight-bearing clue to the existence of septic arthritis. joints (i.e., hip and knee joints) [9]. Power Doppler ultrasonography detects the When the joint is affected, monoarticular increased microvascular flow associated with disease is the likely cause, although polyarticu- infectious collections [13]. Furthermore, ultraso- lar disease is also reported. Multiple imaging nography has been demonstrated to be useful in modalities, such as conventional radiography, assessing therapeutic response and as a guide for computed tomography (CT), MRI and ultra- accurate aspiration of material for culture [14–16]. sound, may play a role in suggesting the diagno- sis and aiding in the recovery of culture material MRI through directed biopsies (Figure 1). MRI provides excellent delineation between On radiographs, tuberculous arthritis is man- bone and soft tissue as well as abnormal and ifested as soft tissue swelling, foci of osteolysis normal bone marrow. Furthermore, it can detect accompanied by varying amounts of eburnation osteomyelitis as early as 3–5 days after infection. and periostitis. Corner defects simulating the MRI is used to evaluate the extent of abnormali- erosions of inflammatory noninfectious arthri- ties and in cases of surgical treatment, it is valu- tides are reminiscent of this. The combination able for planning an accurate surgical strategy of regional osteoporosis, marginal erosions and or clinical follow-up [8]. relative preservation of joint space is suggestive MRI helps to detect early stages of osteomy- of tuberculous arthritis. Other changes include elitis owing to its ability to identify bone and bony proliferation, subcondral eburnation and soft-tissue edema. It is particularly useful for periostitis generally parallel to the osseous con- detecting osteomyelitis of the spine and pelvic tour. Sequestrum is less frequent than in pyo- bones. In addition, it is helpful for excluding genic arthritis. The eventual result in tubercu- complications. It may be instrumental in dif- lous arthritis is u­sually fibrous ankylosis of the ficult differential diagnosis (infection vs tumor). joint [10]. Disadvantages of MRI are its occasional inability to distinguish infectious from reactive inflam- Sinography mation and its limited resolution in areas with Opacification of a sinus tract can produce metallic implants, such as joint prostheses or important information that influences the choice fixation devices. of therapy. In this technique, a small flexible MRI has the potential to differentiate a true catheter is placed within a cutaneous open- avascular sequestrum surrounded by necrotic ing. Retrograde injection of contrast material tissue from a piece of residual vascularized

future science group www.futuremedicine.com 27 Special Report Pineda, Pena, Espinosa & Hernández-Díaz Imaging of osteomyelitis: the key is in the combination Special Report

D E

Figure 1. Tuberculous arthritis. (A) Conventional radiography frontal view of the right knee displaying diffuse soft tissue swelling, osteopenia, lateral joint space narrowing and medial and lateral compartment ‘corner defects’. (B) Sagittal T2-weighted MRI demonstrates hypointense thickened synovium covering the posterior aspect of lateral condile affecting the articular joint space, tibial plateau and suprapatellar bursae. (C) Sagital T2 fat-saturation MRI with enhancement of the liquid collection and cortical defects. (D & E) Anterior and lateral view of a methoxyisobutylisonitrile-technetium-99m showing diffuse captation in the right knee.

normal bone. Nonenhanced and gadolin- Vertebral osteomyelitis ium-enhanced MRI sequences are required In those patients with neurologic impairment, to fully characterize a sequestrum in chronic MRI should be the first diagnostic step, to look o­steomyelitis [7]. for spinal epidural abscess and to rule out a The typical appearance of acute osteomyelitis herniated disk. MRI has a high accuracy (90%) in an MRI scan is a localized area of abnormal for diagnosing spinal osteomyelitis [19,20]. bone marrow with decreased signal intensity In a different scenario, the differential on T1-weighted images and increased signal diagnosis between intervertebral degenera- i­ntensity on T2-weighted images [17]. tive osteochondrosis and septic discitis is dif- ficult. In degenerative disk-related inflam- „„Special situations matory end plates, the magnetic resonance Diabetic foot pattern of bone marrow edema, including One devastating complication in diabetic low signal on T1-weighted and high signal patients is foot osteomyelitis; early diagnosis on T2-weighted images, reflects the develop- is required in order to give adequate treatment. ment of a highly vascular fibrous tissue inside Recently, a meta-ana­lysis examined the accu- end-plate bone marrow. Similarly, infected racy of MRI as a diagnostic test in patients tissue presents increased vascularity reflected with diabetic foot ulcers and osteomyelitis; the by substantial enhancement on gadolinium- authors found the pooled sensitivity was 0.90 enhanced T1-weighted sequences. Gadolinium (95% CI: 0.82–0.95) and the pooled specificity contrast agents, as markers of the extracellu- was 0.79 (95% CI: 0.62–0.91). The diagnostic lar space, induce pronounced enhancement OR was 24.36. The measurement of accuracy of tissues, presenting increased vascularity, was the highest among all of the diagnostic and are therefore not specific to infection or tests that were studied [5,18]. sterile inflammation.

28 Int. J. Clin. Rheumatol. (2011) 6(1) future science group Special Report Pineda, Pena, Espinosa & Hernández-Díaz Imaging of osteomyelitis: the key is in the combination Special Report

A study designed to evaluate cellular MRI for Nuclear medicine imaging the differentiation of infectious and degenerative Early diagnosis of osteomyelitis and prosthetic vertebral disorders using superparamagnetic iron joint infection is essential for successful ther- oxide (SPIO) contrast (marker of macrophages apy and prevention of complications. Nuclear that infiltrate the infected tissue), concluded medicine offers a variety of modalities for this that MRI of the spine with SPIO injection dif- aim. Advantages and disadvantages of differ- ferentiates infection from aseptic inflammation ent nuclear medicine and hybrid imaging sys- on quantitative ana­lysis (signal-to-noise ratio) tems are shown in Table 2. Nuclear medicine where significant signal loss evokes the presence imaging techniques can detect osteomyeli- of infection, but the use of SPIO makes direct tis 10–14 days before changes are visible on visual evaluation less satisfactory. Further stud- plain radiographs. Several agents have been ies are underway to determine whether this new studied, including technetium-99m-labeled tool is useful for d­iagnosis in patients with spinal methylene diphosphonate (99mTc-MDP), gal- 67 infections [21]. lium-67 citrate ( Ga-citrate) and indium-111- In addition, MRI is more sensitive than labeled white blood cells (111In-labeled WBCs). CT for the early detection of osteomyelitis [8]. These techniques are highly sensitive [22] and Therefore, CT is generally indicated only if the depending on the clinical situation have a patient has a contraindication to MRI or if CT is ­moderate‑to‑high specificity [23]. needed to guide a percutaneous biopsy. Neither CT nor MRI has 100% specificity. „„Three-phase bone scintigraphy Bone scintigraphy is performed with 99mTc- Computed tomography labeled diphosphonates, usually 99mTc-MDP and Computed tomography provides a good defini- hydroxy-methylene diphosphonate, which are tion of cortical bone damage, periosteal reaction the most commonly used ra­diopharmaceuticals and soft tissue changes and is the best method for to image osteoblastic activity. detecting small foci of gas within the medullary In three-phase bone scan, areas of bone canal, areas of cortical erosion or destruction, turnover and increased osteoblastic activity tiny foreign bodies, and to define the ­rp esence are detected using a radionuclide tracer (99mTc- and extent of sinus tracts and sequestra [4]. diphosphonate). There are three phases to the In chronic osteomyelitis, CT demonstrates test: nuclear angiogram or blood flow phase abnormal thickening of the affected cortical (immediately after injection), blood pool phase bone, with sclerotic changes, encroachment of (within 5 min after injection) and bone phase the medullary cavity and chronic draining sinus. (~3 h after injection). Cellulitis is characterized In a systematic review and meta-ana­lysis assess- by high uptake in the blood flow and blood ing the accuracy of different imaging techniques pool phase with normal uptake in the osseous for the evaluation of chronic osteomyelitis, CT phase, whereas osteomyelitis gives progressively yielded a sensitivity of 0.67 (95% CI: 0.24–0.94), i­ncreasing uptake over the course of the study. and a specificity of 0.50 (95% CI: 0.03–0.97) [3]. In patients with osteomyelitis and infected CT is not recommended for routine use in diag- orthopedic prostheses, increased osteoblastic nosing osteomyelitis; however, it is the imaging activity occurs. Detection of osteomyelitis modality of choice when MRI is not available with 99mTc-MDP is highly sensitive (90%) or contraindicated [8]. It is particularly useful in when the bone has not been violated. In post- the evaluation of flat and irregular bones, such traumatic patients and after surgery, specificity as vertebrae, the pelvis and sternum. is d­ramatically lower (35%) [23]. Spiral CT with multiplanar reconstruction is superior to standard CT. The currently available „„Gallium scintigraphy multidetector CT provides the best multiplanar Radiogallium attaches to transferrin and lacto- reconstructions, and is particularly important ferrin, which leaks from the bloodstream into in the diagnosis of sternoclavicular osteomyelitis areas of inflammation showing increased iso- and its complications. tope uptake in infection, sterile inflammatory The definition of soft tissue changes with CT c­onditions and malignancy. is suboptimal. Contrast-enhanced CT is bet- Although 67Ga-citrate scintigraphy has a ter, but still inferior to conventional MRI. A high sensitivity for both acute and chronic major limitation of CT, as well as MRI, is the infection and noninfectious inflammatory artefact produced by the presence of orthopedic conditions, the technique has several limita- h­ardware [2]. tions: the need for delayed imaging (>48 h),

future science group www.futuremedicine.com 29 Special Report Pineda, Pena, Espinosa & Hernández-Díaz Imaging of osteomyelitis: the key is in the combination Special Report

Table 2. Advantages and disadvantages of different nuclear medicine and hybrid imaging systems. Nuclear medicine Advantages Disadvantages Bisphosphonates Highly sensitive (~90%) Low specificity (~35%) 99mTc-MDP, 99mTc-HDP Gallium scintigraphy Reasonable sensitivity (73%) for both acute and Low specificity (61%) 67Ga-citrate chronic infection Need for delayed imaging Limited spatial resolution Bowel excretion High radiation dose [23] Radiolabeled High sensitivity and specificity (~95%) Laborious preparation leukocytes (99mTc- Provides excellent localization of Requires special WBC)/radiolabeled inflammatory focus equipment specific antigranulocyte Sensitive for detecting infection in patients with Sensitivity decreases when metallic implants infection is located closer FDG Adequate discrimination between osseous and to the spine soft tissue infection Hybrid imaging systems 99mTc-HDP-SPECT/CT Increases specificity (~85%) Availability Better anatomical localization 111In-WBC SPECT Sensitivity (~84%), higher specificity near 100% 99mTc-MDP Sensitivity 94–100% Specificity 87–100% FDG-PET/ Useful to discriminate osteomyelitis in diabetic FDG-PET/CT feet with ulcers 67Ga: Gallium-67; 99mTc: Technetium-99m; CT: Computed tomography; FDG: Fluorine-18 fluorodeoxyglucose; HDP: Hydroxymethane diphosphonate; MDP: Methylene diphosphonate; WBC: White blood cells. limited spatial resolution, low specificity, Today, labeled leukocyte imaging is the pro- physiological bowel excretion and the high cedure of choice for diagnosing prosthetic joint ­radiation dose [23]. infection [25]. Gallium scans may reveal abnormal accumu- The main disadvantages of 111In-WBC and lation in patients who have active osteomyelitis 99mTc-WBC are their laborious preparation, when technetium scans reveal decreased activ- requirement of specialized equipment, and the ity (‘cold’ lesions) or perhaps normal activity. handling of potentially infectious blood [23]. 67Ga-citrate has been used with reasonable sensi- tivity (73%) and relatively low specificity (61%). „„Radiolabeled specific 67Ga-citrate is now less frequently used owing to antigranulocyte monoclonal antibodies the availability of more favorable compounds Considerable effort has been devoted to and techniques [23]. the search for in vivo methods of label- ing leukocytes, including peptides and „„Radiolabeled leukocytes antigranulocyte antibodies. White blood cell scan was performed originally Radiolabeled antigranulocyte antibod- with 111In-WBC and more recently with 99mTc ies have been developed for in vivo labeling hexamethylpropyleneamine oxime-labeled white of white blood cells. Antibodies accumulate cells. The principle is that the labeled WBCs in infectious and inflammatory foci mainly concentrate in areas of inflammation, and the by nonspecific extravasations, because of the specificity of the study is improved to 80–90% enhanced vascular permeability in combi- compared with bone scans, particularly when nation with specific targeting of infiltrated complicating conditions are superimposed. granulocytes. Overall sensitivity for infec- In a review and meta-ana­lysis, the sensitivity tion detection with radiolabeled antibodies for extra-axial chronic osteomyelitis was 84% is approximately 80–90%. Peripheral bone compared with 21% for the detection of chronic infections are adequately visualized; however, osteomyelitis in axial skeleton [3,8]. Combined sensitivity decreases when the infections are 111In-WBC and bone marrow imaging with located near to the spine. 99mTc-anti-CD15 99mTc-sulfur colloid demonstrated a 100% sen- IgM and 99mTc-anti-NCA-95 IgG are some of sitivity and 98% specificity in 50 patients with the most effective antibodies to diagnose bone suspected infected total-hip arthroplasty [24]. and joint infections.

30 Int. J. Clin. Rheumatol. (2011) 6(1) future science group Special Report Pineda, Pena, Espinosa & Hernández-Díaz Imaging of osteomyelitis: the key is in the combination Special Report

„ „Nonspecific IgG PET systems are relatively novel techniques Radiolabeled nonspecific human IgG also accu- that are being applied in several medical fields. mulates in infectious and inflammatory foci by It has been demonstrated that FDG-PET has nonspecific extravasation facilitated by enhanced the highest diagnostic accuracy for confirming 111 vascular permeability [23]. In-IgG has demon- or excluding the diagnosis of chronic osteomy- strated excellent performance in the localization elitis in comparison with bone scintigraphy, of musculoskeletal infection and inflammation. MRI or leukocyte scintigraphy; FDG-PET is also superior to leukocyte scintigraphy for „„Antibodies detecting chronic osteomyelitis in the axial BW 250/183 (Granuloscint; CISBio Interna­ skeleton [18,23,29]. tional, Gif sur Yvette, France) is a murine Nawaz et al. assessed the diagnostic perfor- monoclonal IgGI immunoglobulin that binds mance of FDG-PET to diagnose osteomyeli- to the nonspecific cross-reacting antigen-95 tis in the diabetic foot, and compared it with (NCA-95) present on leukocytes. Sensitivity that of MRI and conventional radiography in for osteomyelitis ranges from 69% in the hips 110 patients with diabetic foot disease. They to 100% for the lower leg and ankle, probably found that FDG-PET had a sensitivity, speci- reflecting easier detection with decreasing mar- ficity, positive predictive value (PPV), negative row distally [19]. Today, labeled leukocyte imag- predictive value (NPV) and accuracy of 81, 93, ing is the procedure of choice for diagnosing 78, 94 and 90%, respectively; while MRI had prosthetic joint infection [25]. a sensitivity, specificity, PPV, NPV and accu- Sulesomab is a 50-kDa fragment antigen- racy of 91, 78, 56, 97 and 81%, respectively. binding (Fab) portion of a murine monoclonal Conventional radiography had a sensitivity, antibody of the IgGI class that binds to the specificity, PPV, NPV and accuracy of 63, 87, NCA-90 antigen on leukocytes [26]. Reported 60, 88 and 81%, respectively. They concluded sensitivity, specificity and accuracy of the test that MRI is more sensitive and has the ability to were 90–93, 85–89 and 88–90%, respectively. provide anatomical details in addition to detect- Immunoscintigraphy with 99mTc-fanole- ing abnormalities within the bone marrow, joint sumab, a murine M-class immunoglobulin that spaces and surrounding soft tissue; however, it binds to the CD15 antigen expressed on human is relatively less specific than FDG-PET. They neutrophils, eosinophils and lymphocytes. propose to perform MRI first and if this results Sensitivity reaches 91% with a lower specificity in a ‘positive’, then complete the follow-up of of 69%; nevertheless in 2004, it was withdrawn osteomyelitis in diabetic foot patients by per- from the US market as a result of serious reports forming FDG-PET imaging owing to its high of cardiopulmonary events [27]. specificity[18] .

„„Fluorine-18 fluorodeoxyglucose-PET Hybrid imaging systems Fluorine-18 fluorodeoxyglucose (FDG) is It is well known that nuclear medicine images transported into cells via glucose transporters, demonstrate function, rather than anatomy. and phosphorylated by hexokinase inside the Planar scintigraphy used to be the standard cell to form fluorodeoxyglucose-6-phosphate. technique used to establish the diagnosis of The phosphorylated deoxyglucose cannot be osteomyelitis. However, the need for improved further metabolized and, thus, FDG accumu- localization and precise definition of the lates in activated lymphocytes, neutrophils and infectious process extent has been facilitated macro­phages with minimal decrease over time. by the recent development of hybrid systems FDG therefore concentrates in sites of infection, (SPECT/CT and PET/CT devices), capable although it is a nonspecific tracer that also accu- of performing functional and morphological mulates in regions of aseptic i­nflammation, as images by exploiting the features of both tech- well as in malignant lesions [28]. niques in the same scanning session. These sys- This technique has several potential advan- tems allow more detailed 3D localization com- tages: results are available within 30–60 min of pared with planar imaging, and also provide tracer administration, imaging is not affected by useful information in both patients with osteo- metallic implant artifacts, and it has a distinctly myelitis and in those with infected joint pros- higher spatial resolution than images obtained theses [23]. The process of image acquisition and with single photon-emitting tracers. This imag- fusion is of importance in accurately localizing ing modality is highly specific for the diagnosis radiopharmaceuticals, accumulation, detect- of osteomyelitis in diabetic foot [18]. ing occult pathological sites, characterizing the

future science group www.futuremedicine.com 31 Special Report Pineda, Pena, Espinosa & Hernández-Díaz Imaging of osteomyelitis: the key is in the combination Special Report

functionally active area of a known lesion and in Ultrasound represents a noninvasive method to precisely drawing regions of interest to perform evaluate the involved soft tissues and cortical quantitative studies [30]. bone and may provide guidance for diagnostic Nevertheless, data are still very limited, espe- or therapeutic interventional, drainage or tis- cially for PET/CT in patients with arthroplasty, sue biopsy. PET and SPECT are highly accu- and further prospective studies are required rate techniques for the evaluation of chronic to fully verify the clinical role and the added osteomyelitis, a­llowing ­differentiation from value of SPECT/CT and PET/CT in the soft tissue infection. diagnosis of osteomyelitis and prosthetic bone infection [31–33]. Future perspective Some examples of these hybrid techniques An ideal imaging technique should demon- include SPECT/CT 67Ga- and 111In-labeled leu- strate functional and anatomical definition, kocyte scintigraphy; a study by Bar-Shalom et al. excluding inflammatory or tumoral patholo- demonstrated that this combination is useful to gies. Currently, there is no perfect imaging define the anatomical localization of foci and its technique for the diagnosis of osteomyelitis. extent [34]. The hybrid imaging systems are able to acquire Filippi et al., using SPECT/CT and 99mTc- functional and structural data in the same scan- hexamethylpropyleneamine oxime-labeled leu- ning session and, therefore, to limit the prob- kocyte scintigraphy, suggested that this hybrid lems often observed with software approaches device could also improve localization and for image registration and fusion. Hybrid imag- d­efinition of the infection extent[35] . ing systems represent the present and future of diagnostic imaging in osteomyelitis. However, Conclusion technical improvements, widespread avail- Osteomyelitis frequently requires more than ability and lower costs in this computer-aided one imaging technique for an accurate diag- imaging techniques are encouraged. nosis. Conventional radiography still remains the first imaging modality. MRI and nuclear Financial & competing interests disclosure medicine are the most sensitive and specific The authors have no relevant affiliations or financial methods for the detection of osteomyelitis. A involvement with any organization or entity with a finan- CT scan can be a useful method to detect early cial interest in or financial conflict with the subject matter osseous erosion and to document the presence or materials discussed in the manuscript. This includes of sequestrum, foreign body or gas forma- employment, consultancies, honoraria, stock ownership or tion; it is generally less sensitive than other options, expert testimony, grants or patents received or modalities for the detection of bone infection. p­ending, or royalties. MRI provides more accurate information No writing assistance was utilized in the production of regarding the extent of the infectious process. this manuscript.

Executive summary Conventional radiography ƒƒ First imaging technique used to gain an overview of the anatomy and pathology of bone. ƒƒ Changes are visible after several days from the beginning of the process. ƒƒ Main findings include osteopenia, lytic lesions, periosteal thickening and loss of trabecular architecture. Sinography ƒƒ Useful to define the course and extent of the sinus tract and its possible communications with neighboring structures. Ultrasonography ƒƒ Allows identification of early soft tissue changes: fistulous tracts, fluid collections, cortical discontinuity and abscess. ƒƒ Ultrasonography is accessible, low cost and noninvasive. MRI ƒƒ Provides excellent delineation between bone and soft tissue as well as abnormal and normal bone marrow. Detects osteomyelitis as early as 3–5 days after infection. Used for the evaluation of the extent of the abnormalities. Computed tomography ƒƒ Provides a good definition of cortical bone abnormalities, sequestra, involucra, intraosseous gas, periosteal reaction and blurring of fat planes. Nuclear medicine ƒƒ Various modalities detect osteomyelitis 10–14 days before changes are visible on plain radiographs. These techniques are highly sensitive and depending on the clinical situation have a moderate-to-high specificity.

32 Int. J. Clin. Rheumatol. (2011) 6(1) future science group Special Report Pineda, Pena, Espinosa & Hernández-Díaz Imaging of osteomyelitis: the key is in the combination Special Report

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