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pathic foot, exacerbated by abnormal biomechanics or
ill-tting shoes, causes areas of increased plantar pressure to
develop callus, which, in turn, predisposes to ulcer development. Clinically occult ulcers form insidiously, deep to the
callus [12, 13]. A direct extension of infected ulcers or soft
tissue infection to the bone leads to osteomyelitis [14]
(Fig. 5.1). These infections are usually polymicrobial and
involve both anaerobic and aerobic pathogens.
Soft Tissue Abnormalities
Soft tissue abnormalities associated with the diabetic foot
include soft tissue edema, cellulitis, soft tissue abscess,
ulcers, sinus tracts, tenosynovitis, joint effusions, and arthritis [15–17]. The importance of differentiating these conditions lies in their differing management: abscess necessitates
prompt surgical drainage, septic arthritis requires surgical
debridement, and cellulitis generally entails antibiotic
therapy.
Soft tissue edema and swelling are a common nding in a
diabetic patient. Soft tissue swelling can occur in the absence
of infection due to vascular insufciency or peripheral neuropathy [17] (Fig. 5.2). However, soft tissue swelling can
also reect the presence of cellulitis, that is, soft tissue infection of the supercial soft tissues. Cellulitis along the dorsum of the foot usually occurs secondary to surface infections
in the nails, toes, or web spaces. Simple cellulitis is generally
M. G. Hochman and C. Connolly
Fig. 5.1 Osteomyelitis deep to ulcer on MRI.Coronal uid-sensitive
STIR image of the left foot of a diabetic patient shows an area of marrow edema (*) at the tip of the bula (F). Overlying this focus of abnormal marrow is an ulcer surrounded by diffuse soft tissue swelling
(arrowheads). These ndings represent osteomyelitis of the distal bula. C calcaneus, TIB tibia, T talus
Fig. 5.2 Dorsal soft tissue swelling on MRI. (a) T1-weighted image
and (b) uid-sensitive STIR image are coronal or short-axis images
acquired at the level of the mid-metatarsal shafts. This diabetic patient
has diffused dorsal soft tissue swelling (small arrows). The subcutaneous edema is dark or low signal on the T1-weighted image and bright or
high signal on STIR.Note the presence of normal fatty marrow signal
in the metatarsal bones—high signal (bright) on T1 and low signal
(dark) on STIR, conclusively ruling out osteomyelitis. I–V rst to fth
metatarsals
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diagnosed clinically, without the need for imaging. The
major indication for the imaging of patients with cellulitis is
a suspected underlying deep infection, such as soft tissue
abscess, osteomyelitis, or septic arthritis.
Osteomyelitis
Osteomyelitis of the foot occurs in up to 15% of diabetic
patients [16]. Bone infection results from a local extension of
soft tissue infection (Fig.5.1). Callus and ulcers serve as the
conduits for infection spreading to deep soft tissue compartments, bones, and joints. The most common sites of soft tissue infection and secondary osteomyelitis are foci of increased
plantar pressure, such as the metatarsal heads and the calcaneus (Fig. 5.3). An evaluation of foot ulcers is important
because more than 90% of osteomyelitis cases result from the
contiguous spread of infection from the soft tissue to the bone
[7]. Newman etal. further demonstrates a clear relationship
between ulcer depth and osteomyelitis: 100% of ulcers exposing the bone and 82% of moderately deep ulcers were shown
to have osteomyelitis on bone biopsy [1] (Fig.5.1).
The identication of osteomyelitis in the diabetic foot can
be difcult both clinically and radiographically. The ability
to probe a pedal ulcer through to the bone (Fig.5.3) has been
reported as a useful index of underlying osteomyelitis in a
diabetic patient [18] and is commonly used to guide decisions regarding treatment. Nonetheless, clinical judgment
was shown to be a poor indicator of infection. The technique
of probing to bone, only 68% sensitive, may underestimate
the incidence of bone involvement, according to Newman
etal. [1] In the same study, 18 out of 19 pedal ulcers did not
expose the bone nor display inammation yet contained
osteomyelitis. In a 2012 study by Mutluoglu etal., the sensitivity and specicity of the probe-to-bone test were 66% and
84%, respectively; the positive predictive value was 87%, but
the negative predictive value was only 62% [19]. In a study
by Lavery etal., the probe-to-bone test in a population of
diabetic individuals with a prevalence of osteomyelitis of
12% had a relatively low positive predictive value (0.57)
[20]. A 2016 meta-analysis yielded a pooled sensitivity of
0.87 (95% condence interval of 0.75–0.93 and 0.83 (95%
CI 0.65–0.93) [21]. Moreover, other clinical parameters,
such as fever and leukocytosis, are unreliable in the diabetic
patient. For example, in a study by Bamberger etal., only
18% of patients with clinically severe osteomyelitis were
febrile [14]. Neither fever nor leukocytosis predicts the
necessity for surgical exploration [22].
Fig. 5.3 Osteomyelitis of rst distal phalanx. (a) AP and (b) lateral
views of the great toe show an ulcer (arrow) overlying the distal phalanx. The cortex of the bone is indistinct, and there is underlying osteo-
penia, representing osteomyelitis. On clinical exam, the exposed bone
was evident at the ulcer
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Imaging Modalities
Imaging can play a role in diagnosing and distinguishing
between bone and soft tissue infection, characterizing soft
tissue abnormalities, identifying osteoarthropathy and other
bony abnormalities, and mapping vascular disease for surgical intervention. A variety of imaging modalities can be useful in the evaluation of the diabetic foot, including
radiography, scintigraphic examination, computed tomography (CT), magnetic resonance imaging (MRI), MR spectroscopy (MRS), and ultrasound (US). (Angiographic imaging is
discussed in a separate chapter of this book.) Imaging techniques vary in their sensitivity for the detection of osteomyelitis, with specicity limited in the presence of cellulitis,
peripheral ischemia, and diabetic neuropathic osteoarthropathy [23, 24] (Table5.1). In the appropriate setting, however,
noninvasive imaging can aid in diagnosis and treatment
planning.
Radiographs
Radiography (X-ray) remains the rst screening examination
in any patient with suspected infection and has the advantage
of being inexpensive and easily obtainable [25, 26].
Radiographs can help identify an unsuspected diabetic
patient by demonstrating calcication in the interdigital
arteries: these vessels rarely calcify in nondiabetic patients
[27]. Cellulitis results in increased density and thickening of
the subcutaneous fat, though nonspecic soft tissue edema
can have a similar appearance. Both bone and soft tissue
infection can result in the blurring of usually visible fat
planes. Focal uid and soft tissue callus both demonstrate
focal increased density in the subcutaneous fat. Ulcers may
or may not be visible on radiographs, depending on their size
and orientation (Fig.5.4). In general, all of these soft tissue
abnormalities are more clearly evident at physical exam.
However, radiographs do readily depict subcutaneous
emphysema associated with infection or recent surgery
(Fig.5.4). Some foreign bodies, i.e., denser materials such as
metal and lead-containing glass, are radio-opaque and generally are visible on radiographs. In order to detect nonmetallic
foreign bodies and subtle soft tissue calcications, radiographs acquired using “soft tissue” technique (i.e., lower kV
than a routine radiograph) may be required.
Findings of osteomyelitis on radiographs include soft tissue swelling and the effacement of tissue fat planes, permeative medullary radiolucency, focal osteopenia or focal
osteolytic lesion, periosteal new bone formation, endosteal
scalloping, and cortical bone destruction (Table5.2, Figs.5.3,
5.4, and 5.5). Of note, these osseous changes typically only
become apparent after osteomyelitis has been present for
10–14days and require up to 50% bone loss before becom-
Fig. 5.4 Soft tissue air and deep ulcers on radiography. The lateral
view of the right foot from a diabetic patient shows subcutaneous air
(arrows) in both dorsal and plantar soft tissues surrounding the metatarsals. A deep ulcer dissects into the heel fat pad (arrowhead)
Table 5.2 Radiographic ndings of acute osteomyelitis
Soft tissue swelling and effacement of soft tissue fat planes
Permeative medullary radiolucency
Focal osteopenia or focal osteolytic lesion
Periosteal new bone formation
Endosteal scalloping
Cortical bone destruction
Soft tissue swelling and effacement of soft tissue fat planes
Table 5.1 Compilation of sensitivity and specicity of various imaging modalities in the diagnosis of osteomyelitis
Radiography 52–93 33–92 61/72 [1, 37, 38, 121, 124, 185–188]
Three-phase bone scan in patients
without bone complications
Three-phase bone scan in patients with
bone complications
In-111 labeled WBC 75–100 69–100 93/80 [37–42, 189, 190]
Combined labeled leukocyte (white
blood cell) scan and bone marrow scan
Combined gallium and bone scan 81/69 [34]
FDG PET scan 29–100 67–93 [61–63, 192]
MRI 29–100 67–95 96/87 [121, 122, 124, 190, 191]
Range of
sensitivity (%)
Range of
specicity (%)
Compiled sensitivity/
specicity (%/%) References
94/95 [34]
(review of 20 published reports)
95/33 [34]
Accuracy 95% (n=20) [46]
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Fig. 5.5 Osteomyelitis of the second distal phalanx. Extensive destruction of cortical and medullary bone (arrow), with surrounding soft tissue swelling
ing evident on a radiograph [28]. A comparison to prior
lms, when available, can help highlight early changes [29].
In the majority of studies, the sensitivity of radiographs
ranges between 52% and 93%, and specicity ranges
between 33% and 92%, for the detection of osteomyelitis
(Table5.1). When radiographs are positive for osteomyelitis,
further imaging studies are often not required for diagnosis.
However, radiography is less sensitive compared with other
imaging modalities and, a negative X-ray examination does
not exclude osteomyelitis. Moreover, radiographs are not
sensitive for the detection of soft tissue infection, such as
septic arthritis or abscess formation.
Even when radiographs do not demonstrate ndings of
osteomyelitis, they nonetheless play an important role in the
diagnostic workup of infection. Because they demonstrate
changes of neuroarthropathy, postsurgical changes, fractures, foreign bodies, gas, foot deformities, and bony variants, radiographs can serve as roadmaps for other imaging
exams. In the absence of correlative radiographs, these ndings can cause unnecessary confusion on MRI or nuclear
medicine exams.
Nuclear Medicine
Nuclear medicine examinations are based on the administration, typically injection, of radioactive materials into a
patient and the measurement of resultant radioactive counts
that accumulate at different sites using a gamma camera,
thereby providing a measure of activity at that site. Different
types of studies are designed for specic applications based
on the different materials that are labeled, for example, components of hydroxyapatite, white blood cells, sulfur colloid,
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glucose, etc. In recent years, the augmentation of conventional planar nuclear medicine studies by the use of threedimensional (3D) imaging techniques such as scintigraphic
SPECT (single-photon emission computed tomography)
images or a hybrid “fused” technique comprised of scintigraphic SPECT images, together with conventional CT
images, in the form of SPECT/CT, has also become common
[30, 31]. The fusion of scintigraphic SPECT images with
conventional MR images also exists but is currently less
commonly available [32, 33].
The most commonly employed nuclear medicine or scintigraphic tests for the diagnosis of diabetic foot infection are
bone scans, labeled leukocyte scans, and bone marrow
scans. Gallium scans are no longer commonly employed for
this application. Flourine-18-ourodeoxyglucose positronemission tomography (FDG PET) has shown utility for
diagnosing musculoskeletal infection but is not yet routinely
reimbursed in the United States for this indication. Bone
scans and labeled leukocyte scans are both considered
highly sensitive to the presence of both soft tissue infection
and osteomyelitis (Table 5.1). Traditionally, bone scans
have been considered the scintigraphic exam of choice when
the foot was radiographically normal, while labeled leucocyte scans were considered to provide improved specicity
in cases where preexisting bone changes were present (i.e.,
neuroarthropathy, trauma, degenerative changes)
(Table5.1). However, the role of bone scan in the workup of
osteomyelitis in the diabetic foot has shifted overtime [25].
Based on current (2019) guidelines from the American
College of Radiology (ACR), among nuclear medicine studies, labeled leukocyte scans, with or without three-phase
bone scans and with or without SPECT/CT or, alternatively,
FDG PET/CT scans, are all considered potential imaging
alternatives (i.e., “may be appropriate”) when MRI is
unavailable or contraindicated [25]. This applies when
osteomyelitis is suspected for soft tissue swelling, either
with or without ulceration and, also, with or without neuropathic arthropathy. In the ACR schema, three-phase bone
scans alone are considered “usually not appropriate” unless
an ulcer is present, while the use of bone scans alone in the
setting of an ulcer is still considered controversial. Per the
ACR, the use of combined white blood cell (WBC) and sulfur colloid scans is also considered “usually not appropriate.” The 2012 Infectious Disease Society of America
guidelines follow a somewhat similar, but simpler, approach,
recommending the consideration of combined radionuclide
bone scan and labelled white blood cell scan as the best
alternative for the diagnosis of diabetic foot infection when
MRI is unavailable or contraindicated [26] as well as white
blood cell scan or antigranulocyte scan for the diagnosis of
osteomyelitis when MRI is not possible [26]. The current
ACR guidelines do not include antigranulocyte scans in
their imaging algorithm for this indication.
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Bone Scan
For many years, triple-phase bone scan (TPBS) had been the
test used for the workup of suspected osteomyelitis in
patients with negative radiographs. It is widely available and
easy to perform. A three-phase bone scan involves the intravenous (IV) injection of radioactive technetium-99m methylene diphosphonate, followed by imaging with a gamma
camera at three distinct time points. Images acquired every
2–5 s immediately following injection provide a radionuclide angiogram (the ow phase) and may demonstrate
asymmetrically increased blood ow to the region of interest. The tissue or blood pool phase is obtained within 10min
and reveals increased extracellular uid seen in conjunction
with soft tissue inammation. A delayed skeletal phase is
acquired 2–4h after the injection. The skeletal phase demonstrates areas of active bone turnover, which have incorporated the radionuclide tracer and are seen as focal “hot spots”
of increased tracer activity. The tracer is taken up by bone in
an amount dependent on both the degree of osteoblastic
activity and the blood ow to the area. In some facilities,
single-photon emission computer tomography (SPECT)
a
scanning can be performed in conjunction with a technetium
bone scan to generate tomographic, cross-sectional images
of radionuclide activity that can be reformatted into different
planes and can help clarify problems created by bony overlaps. Because SPECT images have greater intrinsic contrast
than routine planar images, the SPECT images are also more
sensitive in detecting foci of radionuclide activity.
Osteomyelitis results in increased uptake in all three phases
of a bone scan, whereas simple cellulitis demonstrates
increased uptake in the rst two phases only (ow and tissue
or blood pool phases) (Fig.5.6). In cellulitis, there may be
mild diffuse increased uptake in the bone due to inammation,
but this is distinct from the more focal, intense increased
uptake seen with osteomyelitis. However, uptake in the
delayed phase itself is not specic for osteomyelitis. In general, a positive delayed phase scan is seen when there is an
underlying process that promotes bone remodeling, e.g., healing fracture, neuropathic osteoarthropathy, or recent bone surgery. False negatives may occur when the radiotracer fails to
reach the foot because of diminished vascular ow. This is of
particular concern in diabetics with atherosclerotic disease.
b
c
Fig. 5.6 Osteomyelitis on triple-phase bone scan. (a) Radionuclide
angiogram (ow phase) of a triple-phase bone scan with successive
images obtained every 2–5s following injection, showing asymmetrically increased blood ow to the distal right lower extremity (arrow).
(b) Blood pool phase obtained within 10 min after injection shows
increased activity in the right foot (arrows), reecting increased extracellular uid related to soft tissue inammation. AP view on the left and
lateral view on the right. (c) A delayed skeletal phase acquired 2–4h
after injection shows increased activity in the bones of the midfoot. In
this phase, “hot spots” reect areas of active bone turnover (arrows) and
is therefore specic for bone. Note that the signal seen in the soft tissues
on the preceding blood pool phase has cleared. AP view on the left and
lateral view on the right
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Schauwecker’s review of 20 published reports shows a
compiled mean sensitivity and specicity of 94% and 95%,
respectively, for the detection of osteomyelitis with bone
scintigraphy [34]. Unfortunately, these data apply only to
patients who do not have underlying bone deformities. In a
diabetic patient with complicated bone conditions such as
recent fractures and neuroarthropathic changes, which are
common clinical presentations, the sensitivity remains at
95%, but the specicity declines to 33% [34]. Labeled leukocytes are more accurate for osteomyelitis, reecting the
increased specicity of white cells—compared with bone
remodeling alone—for infection [25, 35]. Thus, the most
recent version (2019) of the American College of Radiology
(ACR)-sponsored appropriateness criteria for the imaging
workup of osteomyelitis recommends a more limited applicability for three-phase bone scan studies when they are used
alone, without a correlative labeled leukocyte scan, though
they do note that a bone scan has a high negative predictive
value and excludes infection with a high degree of certainty
[25]. Nonetheless, because they are easy to obtain and can be
rapidly performed, three-phase bone scans are often still
obtained in many clinical practices, especially when radiographic ndings of background bone complications, such as
fractures and changes associated with neuro- osteoarthropathy,
are absent [25].
Labeled Leukocyte (White Blood Cell) Scan
andBone Marrow Scan
Labeled leukocyte scans, also known as labeled white
blood cell (WBC) scans, are the preferred scintigraphic
technique for imaging when there is background bone
pathology on radiographs. This is because WBCs accumulate at sites of infection, but unlike bone scans, they theoretically do not accumulate at sites of increased bone
turnover, such as fractures and neuropathic osteoarthropathy. White blood cell scans are performed by extracting a
patient’s blood, fractionating the leukocytes from the blood,
incubating the white blood cells with either indium 111oxine or technetium- 99 m-hexamethylpropylene amine
oxime (Tc-HMPAO) in order to label them, and then reinjecting the labeled white blood cells into the same patient.
Imaging is performed 16–24h later using a standard gamma
camera. As noted above, labeled white blood cells theoretically only accumulate at sites of infection and not at sites of
increased osteoblastic activity and therefore should be
extremely useful in the diagnosis of osteomyelitis complicated by underlying bone changes (Fig.5.7). The technique
is most useful for inammatory processes that are mediated
by neutrophils, such as bacterial infections, since the majority of leukocytes labeled are neutrophils [36]. In addition, a
total white count of at least 2000μL is needed to obtain
satisfactory results [36].
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Fig. 5.7 Osteomyelitis on indium-labeled leukocyte scan. Increased
indium accumulation about the ankle represents a focus of osteomyelitis in a patient with swelling and fever. Staph aureus grew from the
marrow aspirate
Indium-labeled leukocyte scan offers the best sensitivity
and specicity for the detection of osteomyelitis, compared
to triple-phase bone scans and gallium scans (Table5.1). A
compilation of seven studies yielded a sensitivity of 93% and
specicity of 80% [1, 37–42]. In addition, Newman et al.
suggested that indium-labeled leukocyte imaging could be
used to monitor response to therapy, with images reverting to
normal 2–8 weeks after the commencement of antibiotic
therapy [1].
Because of their potential advantages and reported high
sensitivity and specicity, indium-labeled leukocyte scans
are considered a valuable radionuclide for the evaluation of
suspected osteomyelitis in the diabetic foot [35]. The sensitivity and specicity of planar Indium-111 WBC scan ranges
from 72% to 100% and from 67% to 100%, respectively
[38]. However, early data had shown false-positive uptake of
indium-labeled leukocytes in as many as 31% of noninfected
neuropathic joints [43]. These false-positive examinations
stemmed from the inability to determine whether labeled
leukocytes located outside the typical marrow distribution
represent infection or merely an atypical site of hematopoietic activity [44]. Atypical patterns of marrow distribution
may accompany fractures, orthopedic hardware, infarctions,
systemic diseases, neuropathic joints, and tumors and make
it difcult to distinguish WBC activity due to osteomyelitis.
At sites where confounding bone marrow may be present, it
is very helpful to compare the leukocyte scan to a second
separate nuclear medicine study—a scintigraphic scan of
bone marrow obtained with technetium-99m-sulfur colloid.
This strategy is based on the fact that both WBCs and sulfur
colloid accumulate in the marrow, independent of its loca-
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tion, but only WBCs—not sulfur colloid—accumulate in
bone infection. Thus, the sulfur colloid bone marrow scan
maps out the distribution of normal bone marrow, even when
it is an atypical distribution [45]. A combination of leukocyte
and bone marrow scans is positive for osteomyelitis when it
demonstrates radionuclide uptake that is greater, either in
intensity or distribution, on the leukocyte scan than on the
bone marrow scan (i.e., “incongruent” scans) (Fig.5.8). For
this reason, in the setting of neuroarthropathy or other confounding bone changes, interpreting a labeled leukocyte
scan, together with the results of a bone marrow scan,
improves accuracy and specicity for the detection of osteomyelitis [45, 46]. The combined study has been reported to
be 88–98% accurate [45]. Reecting this, some believe that
in the setting of neuropathic arthropathy and suspected
osteomyelitis, a labeled leukocyte scan—obtained in con-
junction with a bone marrow scan—may be appropriate in
some clinical circumstances [45]. In practice, when white
blood cell scans are labeled with indium-111 and bone marrow scans are labeled with technetium-99m, both scans can
be obtained simultaneously, during one sitting, because the
two different radionuclides have different energies and can
be distinguished by the gamma camera by using different
energy “window settings” for collecting radioactivity counts.
The limitations of combined WBC and sulfur colloid scans
include the following: the absence of WBC activity in the
area of interest, in which case marrow imaging is not productive; sulfur colloid images become photopenic about 1week
after the onset of infection; if 99mTc-sulfur colloid is not
properly prepared or has been prepared more than 2h prior
to imaging, image quality will be degraded, limiting accurate
assessment; and labeled WBCs may accumulate in the lymph
nodes, though lymph node activity can typically be distinguished by its characteristic morphology and distribution
along the lymph node chain [45]. It is also important to recognize that the distribution of marrow changes with age,
with fatty marrow progressively replacing red marrow in the
foot and ankle as patients age.
The detection of osteomyelitis with labeled leukocyte
scan is rarely a problem in the forefoot, where the osseous
structures are equidistant from both dorsal and plantar skin
surfaces, but may be compromised in the mid- and hindfoot
due to anatomic complexity in these areas [36]. Interpreting
the labeled leukocyte scan in conjunction with the anatomic
localizing information available from a simultaneously
acquired SPECT/CT can help improve accuracy in diagnosing osteomyelitis [30, 31, 35]. SPECT/CT refers to the fusion
of scintigraphic and morphologic images into a hybrid imaging study comprised of a nuclear medicine single-photon
emission computed tomography scan, together with a conventional radiographic CT scan depicting 3D anatomy,
which provides anatomic landmarks for the areas of increased
nuclear medicine uptake and which has contributed to
improved diagnostic accuracy over SPECT alone in many
scintigraphic procedures [31] (Fig. 5.9). In this way, for
example, SPECT/CT can aid in decreasing false positives
ab
Fig. 5.8 Indium-111 labeled leukocyte scan and technetium 99m-labeled sulfur colloid scan demonstrating incongruence indicative
of osteomyelitis. (a) Indium-111-labeled leukocyte scan shows
increased activity in the tibia and ankle in a diabetic patient with a non-
healing ulcer over the tibia. (b) Technetium-99m-labeled sulfur colloid
scan shows increased activity in a similar distribution but signicantly
less intense than that seen on the leukocyte scan, demonstrating an
“incongruent scan” indicative of osteomyelitis
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a
b
c
Fig. 5.9 Osteomyelitis of the calcaneus on indium-labeled leukocyte
scan. (a) Axial image of the hindfoot obtained using SPECT (singlephoton emission computed tomographic technique) shows increased
leukocyte uptake in the hindfoot (arrow). (b) Axial CT image shows
cortical irregularity of the lateral calcaneus, reecting bone erosion due
to osteomyelitis (arrow). (c) The radionuclide WBC scan image is superimposed onto the CT image, resulting in a fused SPECT/CT image that
clearly localizes the leukocyte uptake to the calcaneus (arrow)
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due to mislocalized uptake in the soft tissues [35]. SPECT/
CT has also demonstrated utility in evaluating for response
to the treatment of osteomyelitis [47, 48] and potentially for
categorizing severity and the likelihood of response to treatment [49]. If SPECT/CT is unavailable, a contemporaneous
bone scan can help improve the accuracy of the labeled leukocyte scan [34]. LaFontaine etal. compared Tc99m WBC
with SPECT/CT to MRI for the detection of bone-biopsyproven osteomyelitis in 110 patients and found similar accuracy between the two techniques [50].
Other disadvantages associated with indium-labeled leukocyte scans include the complexity of the labeling process,
which can result in false-negative examinations if the procedure for labeling the leukocyte is inadequate [30], high costs,
limited availability of the test, and risks inherent in the handling of blood products [30]. Because of the difculties
inherent in invitro labeling of leukocytes, several techniques
for invivo labeled leukocyte imaging have been developed.
However, these techniques are not at present in widespread
use [36].
Gallium Scan
Gallium is not frequently used in the workup of diabetic
pedal osteomyelitis. In the past, it had been described as a
useful alternative for the assessment of pedal infection when
there were abnormal radiographic ndings on a foot radiograph and a labeled leukocyte scan or MRI was not available.
However, in recent years, indium-labeled leukocyte scans,
often in conjunction with bone marrow scans, have in large
part supplanted the use of gallium-67 scans in this setting. At
present, gallium studies are not included in the American
College of Radiology’s guidelines for the imaging workup of
osteomyelitis in the diabetic foot [25].
FDG PET Scan
Flourine-18 labeled uorodeoxyglucose (FDG) imaging
using positron emission tomography (PET) has become an
important technique for oncologic imaging and is in common clinical use for detecting, staging, and monitoring
response to therapy in lung cancer, breast cancer, lymphoma,
and melanoma, among others [51]. However, FDG PET
scans often also show increased activity in areas of inammation or infection, and the use of PET for these nonneoplastic applications is now being actively investigated [51].
At this juncture, however, FDG PET exams are not routinely
reimbursed for applications related to infection in the United
States.
FDG is a radiolabeled glucose analogue that is taken up
by cells in proportion to their metabolic rate and the number
of glucose transporter proteins. Increased FDG uptake is
seen in inammation due to an increased expression of glucose transporters and increased afnity for the glucose analogue by activated inammatory cells. The uorine-18 (18F)
radionuclide is produced in a particle accelerator known as a
cyclotron and has a relatively short radioactive half-life.
After the intravenous injection of ourine-18 FDG, a patient
is imaged 30–60min later using a PET scanner. A routine
exam includes images from the level of the skull base through
the mid-thigh, though examinations spanning the skull to the
feet can be performed. Areas of increased activity on the
images reect sites of increased glucose metabolism and
may be described in terms of standardized uptake value
(SUV). Many of the scanners currently being installed are
PET-CT scanners, which incorporate both a PET scanner and
a conventional CT scanner. In a PET-CT system, PET and
conventional CT images are both obtained during the same
examination and can be fused together into hybrid images to
aid in the localization of areas of increased activity. This
improved localization capability can be used, for example, to
help distinguish between osteomyelitis and soft tissue infection [52].
FDG-PET has shown some promising results for the
imaging of infection. In general, sensitivity for infection
tends to be relatively high and negative predictive value is
very high, but false positives can occur because any area of
increased metabolic activity—not just infection—will show
increased radionuclide activity. Recent surgery can also
result in false-positive increased activity [51]. Chacko etal.
examined 167 PET scans in 175 anatomic sites and found an
accuracy of 91.2% for chronic osteomyelitis [53]. Meller
etal. prospectively compared FDG PET and labeled leucocytes and concluded that FDG was superior for the diagnosis
of chronic osteomyelitis [54]. PET has also shown utility in
the evaluation of chronic osteomyelitis and infected prostheses [55]. In a meta-analysis by Termaat et al., FDG PET
shows a pooled sensitivity of 96% and a specicity of 91%
for the diagnosis of chronic osteomyelitis [56]. In a limited
number of cases, correlative decreases in FDG uptake and
inammatory activity have been reported following antibiotic treatment [57], suggesting a potential role in tracking
response to therapy, analogous to its current use in tumor
treatment [51, 58]. A series of novel PET tracers are currently being evaluated for the imaging of infection and
inammation [51]. Overall, FDG-PET has shown good sensitivity for the imaging of osteomyelitis [59] but is not yet
reimbursed for this indication in the United States.
Specic data on the use of FDG PET for the assessment
of infection in the diabetic foot remains relatively limited.
Keider etal. examined 18 sites of infection in 14 patients and
demonstrated that FDG PET could help precisely localize
infection and could distinguish between bone and soft tissue
infection in the diabetic foot [52]. In contrast, in a study by
Schwegler etal. that included seven diabetic patients with
chronic foot ulcers and biopsy-proven osteomyelitis, FDG
was positive in only two cases, while MRI was positive in six
[60]. In a 2013 meta-analysis by Treglia etal. based on nine
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studies and 299 patients, FDG PET showed a pooled sensitivity of 74% and specicity of 91% for the detection of
osteomyelitis in the diabetic foot [61]. A 2018 review by
Arnon-Sheleg etal. showed variable performance of FDG
PET in the assessment of diabetic foot infection, with relatively high specicity (67–93%) but a wide range of sensitivity (29–100%). They noted improved sensitivity in more
recent studies, thought to reect improved imaging technology and the more common use of hybrid PET/CT techniques
compared with PET alone [62]. A meta-analysis and review
by Lauri etal. found similar sensitivities for MRI, 18F-FDG
PET, and 99mTC-HMPAO-labeled white blood cells for the
detection of osteomyelitis in the diabetic foot, with labeled
WBCs and FDG PET yielding the highest sensitivities, and
they identied a need for larger prospective studies [63].
Compared with WBC scans, FDG PET offers shorter
exam times and obviates the need for drawing WBCs from
the patient for labeling. PET is less susceptible than WBC
scans to false negatives resulting from decreased perfusion
at the infection site. While PET and WBC scans are thought
to be comparable in sensitivity in the peripheral skeleton
(where there is usually a paucity of hematopoietic marrow
to cause spurious WBC activity), PET is considered more
effective than WBC scans for the detection of the central
foci of infection/inammation because of the physiologic
uptake of WBCs by bone marrow in the axial skeleton [51].
A potential concern related to the use of PET in diabetic
patients relates to the effect of chronic hyperglycemia on
FDG uptake in metabolically active lesions [64]. However,
a recent study suggested that mild to moderately elevated
serum glucose levels do not adversely affect the accuracy
of 18FDG PET in detection of pedal osteomyelitis in diabetic patients [65].
Newer Radiopharmaceuticals
A number of new radiopharmaceuticals that may have application in the diagnosis of diabetic foot infection are being
investigated but have not entered routine clinical practice.
These include radiolabeled antigranulocyte antibodies,
immunoglobulins, antibiotics, radiotracers specically taken
up by bacteria, and hybrid tracers that have been simultaneously labeled with both a radioisotope and an optical imaging dye [66–68].
Computed Tomography (CT)
CT scans can show ndings of osteomyelitis earlier than
radiographs but are not considered a front-line examination
for the diagnosis of osteomyelitis because they are less sensitive than MRI for soft tissue and osseous infection and also
because, unlike MRI, they expose the patient to ionizing
radiation.
Computed tomography (CT) scans use ionizing radiation
to generate cross-sectional scans of the body. Tissues are displayed on a gray scale that reects their relative X-ray attenuation, a quantity that is expressed in Hounseld units (HU).
For example, Hounseld units typically measure −1000 for
air, 0 for water, ~40 for soft tissue, and ≥400 for bone. Most
CT scans are now performed on multidetector scanners,
which allow the acquisition of thinner cross-sectional images
and faster imaging times. When thin-section “volumetric”
scans are acquired with a multidetector scanner, image sets
acquired in one plane can be reformatted computationally
into any desired imaging plane; after they have been acquired,
e.g., images acquired axially can be reformatted into coronal
or sagittal images. Image data can be postprocessed with different algorithms to highlight either bones or soft tissues.
Independent of that postprocessing, images can also be displayed using “bone” or “soft” tissue windows. Image data
can also be postprocessed to highlight anatomy in different
ways, such as maximum intensity projection (MIP) images
to produce a CT angiogram or volume rendering (VR) to create a 3D display of various tissues.
CT scans are often performed using intravenous iodinated
contrast in order to highlight different tissues, demonstrate
characteristic enhancement patterns of certain structures,
outline cysts and uid collections and distinguish them from
solid masses, and depict vascular anatomy. In most cases, CT
contrast administration is uneventful. However, some
patients experience reactions after an IV administration of
iodinated contrast, with fatal anaphylactoid reactions in
approximately one in 40,000 patients [69]. The risk of reaction is signicantly reduced with low osmolar nonionic contrast, now in routine use at many institutions [70]. The use of
nonionic contrast also decreases the incidence of nausea,
vomiting, hemodynamic instability, and discomfort or pain
associated with contrast administration, effects that are
related to the osmolality of the contrast [70, 71]. In patients
with a history of IV contrast allergy, the 2023 version of the
American College of Radiology Manual on Contrast Media
proposes a premedication regimen prior to the administration of IV contrast [73]. Patients with renal insufciency and
diabetes (especially insulin-dependent diabetes) have traditionally been considered at an increased risk for contrastassociated acute kidney injury, prompting the screening of
patients’ renal function estimated glomerular ltration rate
(eGFR) prior to the administration of IV iodinated contrast
[72, 73]. Patients taking the oral hyperglycemic agent
dimethylbiguanide (Metformin) who have concurrent acute
kidney injury or chronic renal disease may be asked to temporarily discontinue the medication around the time of IV
contrast administration due to a potential increased risk for
lactic acidosis [72]. A more complete discussion of the complex and evolving topics related to contrast allergy and prophylaxis and patients on dimethylbiguanide (Metformin) is
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