efficacy of magnetic resonance imaging in deciding the...

Miki Fujii, MD, PhD1

David G. Armstrong, DPM, MD, PhD2,

Hiroto Terashi, MD, PhD3

1Department of Plastic and Reconstructive

Surgery, Kitaharima Medical Center, Ono,

Japan

2Southern Arizona Limb Salvage Alliance, University of Arizona College of Medi-

cine, Tucson, AZ, USA

3Department of Plastic and Reconstructive Surgery,

Kobe University Hospital, Kobe, Japan

Correspondence to: [email protected]

Conflicts of interest: None

ABSTRACTThe best therapy for diabetic foot osteomy-elitis (DFO) is controversial. However, iden-tification of the precise localization of DFO is essential for appropriate treatment.

AIMTo ascertain the efficacy of magnetic reso-nance imaging (MRI) in the diagnosis of DFO, and to select the appropriate surgical margin.

METHODSPreoperative MRI findings were compared with the results of histopathological exami-nations of resected bones, and the margins of the resected bones were analysed by his-topathology. A total 149 bones from 28 foot ulcers in 26 patients were examined. All ul-cers were classified into 4 types according to the main etiological factors.

RESULTSIn 14 neuropathic ulcers, all 55 bones, even those with severe infection, were fully and accurately diagnosed with the use of MRI. In 14 ischemic ulcers, only 9 of 94 bones evalu-ated by MRI after revascularization were di-agnosed accurately. Of 32 bone margins that showed bone marrow oedema, 28 healed, and 4 did not heal, displaying severe infec-tion or ischemia.

CONCLUSIONSMRI is effective in the diagnosis of neuro-pathic ulcers, but not as effective in the diag-nosis of ischemic ulcers. This study suggested that the appropriate surgical margin should be defined in the area of the bone marrow oedema, but diligence should be exercised in cases with severe infection or ischemia.

Efficacy of magnetic resonance imaging in deciding theappropriate surgical margin in diabetic foot osteomyelitis

INTRODUCTIONThe best therapy for diabetic foot osteomyelitis (DFO), whether primarily medical or primarily surgical, is a sub-ject of contention. Each has its potential advantages and disadvantages1. Recent guidelines2 have recommended that the presence and amount of residual dead or infected bone and soft tissue should determine the duration of antibiotic therapy. Besides the choice of primary therapy, identification of the precise localization of DFO is essential for appropriate treatment.

Guidelines2,3 recommend the use of plain radiographs as a first-line investigative tool for diagnosing DFO, and further note that although magnetic resonance imaging (MRI) has been recognized as the most accurate imaging modality for detecting DFO, it is not always necessary for diagnosing or managing DFO. Plain radiographs, however, show only destruction of bone, and not actual bone infec-tion or inflammation.

We have previously demonstrated the efficacy of MRI in the diagnosis of DFO in ulcers with different aetiolo-gies 4,5. In the present report, we describe our study of additional cases, and propose a means of defining the ap-propriate surgical margin for remission based on MRI and histopathological findings.

METHODSFirst, preoperative MRI findings were compared with the results of histopathological examination of the resected bones. Second, bone margins of the resected bones were analysed by histopathology.

The records of 26 patients with diabetic foot ulcers (20 men and 6 women; mean age, 66.8 years; range, 42−85 years of age) who were suspected of having osteomyelitis and had undergone surgery from 2008−2014 were exam-ined. All patients had been diagnosed with type 2 diabe-tes, according to the classification of the World Health Organization.

The ulcers were classified into 4 types according to the main aetiological factors: type I, neuropathic ulcers; type II, ischemic ulcers (critical limb ischemia [CLI]); type III, neuropathic ulcers with infection; and type IV, ischemic

EWMA Journal 2015 vol 15 no 1 8

Science, Practice and Education

ulcers with infection4-6. Peripheral neuropathy (PN) was assessed by touch sensation using the Ipswich touch test7. Peripheral arterial disease (PAD) was suspected by the ab-sence of pulsation and/or sound from the dorsalis pedis artery and the posterior tibial artery assessed by Doppler stethoscope, an ankle-brachial index < 0.9, and skin per-fusion pressure < 40 mmHg. Patients with suspected PAD were evaluated with the use of computed tomographic angiography, duplex ultrasonography, and angiography. Infection was assessed by the following: general conditions such as high fever, chills, or malaise; clinical findings such as redness, warmth, swelling, or purulent secretions; the results of laboratory tests. DFO was suspected in patients with a positive probe-to-bone test, swollen foot, sausage toe, unexplained high leukocyte count or inflammatory markers, and plain foot radiographic findings3.

Preoperative MRI was carried out with 1.5 T MR scanners (3 mm slice thickness, T1-weighted images, conventional spin echo, repetition time/echo time of 460 ms/13 ms, fat-suppressed T2-weighted images, short-tau inversion-recovery images, short T1 inversion recovery, and repetition time/echo time/inversion time of 3,401 ms/80 ms/150 ms). All MRI findings were checked by M.F and H.T with consensus interpretation. The affected bone marrow was compared with the adjacent normal fatty marrow, and low intensity signals on T1-weighted images and high intensity signals on fat-suppressed T2-weighted images were attributed to osteomyelitis. Incomplete or hazy signals or reticulated patterns were attributed to reac-tive bone marrow oedema. Normal bone marrow signals were considered indicative of areas clear of disease (8). All bones were marked according to the presence of osteo-myelitis (OM), bone marrow oedema (BME), or normal bone (N) (Fig. 1).Surgery after the MRI diagnosis included resection of

the infected bones and gangrenous tissue, amputation, or disarticulation. The area of resection was estimated pr-eoperatively (from the MRI findings, blood flow, and area of soft tissue infection) and confirmed intraoperatively.A definitive diagnosis was then made from the histopatho-logical examination of 5 mm thick sections of formalin-fixed and paraffin-embedded bones stained with haema-toxylin and eosin. Only bone marrow oedema or infiltra-tion of inflammatory cells, or both was considered indica-tive of reactive bone marrow oedema. However, these 2 conditions, together with the presence of osteonecrosis, granulation tissue, and/or fibrosis, were considered in-dicative of osteomyelitis (Fig. 2). The diagnosis from the preoperative MRI findings was compared with the defini-tive diagnosis from the histopathological findings (Fig. 3). Bone margins of the resected bones were examined by histopathology.

Informed consent was obtained from each patient, and the study protocol conformed to the ethical guidelines of the Declaration of Helsinki as reflected in the approval by the institution’s human research review committee.

RESULTSA total of 28 ulcers from 26 patients, including 2 patients with 2 different types of ulcers each, were classified into 4 types according to the main aetiological factors as fol-lows: type I, neuropathic ulcers (n=3); type II, ischemic ulcers (n=3); type III, neuropathic ulcers with infection (n=11); and type IV, ischemic ulcers with infection (n=11) (Table 1).

The 26 patients underwent a total of 30 MRI exami-nations before surgery (Table 2). The average interval be-tween the MRI examinations and surgery was 16.7 (range 2−48) days. All ischemic ulcers (type II and type IV) were revascularised by bypass or endovascular treatment before surgery. MRI was carried out as follows: 3 examinations for 3 type I ulcers; 3 before revascularisation for 3 type II ulcers; 1 after revascularisation for 1 type II ulcers; 11 for

Figure 2: Histopathological diagnosis (haematoxylin & eosin staining, 40×)

Osteomyelitis (OM) Bone marrow edema (BME)

Bone marrow edema Bone marrow edemaInflammatory cells Inflammatory cellsOsteonecrosisGranulation Fibrosis

(H&E; 40 )(H&E; 40 )

a) b)

c)

a) b) c)

b)

c)

b)

C)

Figure 1: MRI diagnosis of case 1, left 2nd toe

a) Osteomyelitis (OM) (T1WI: low intensity, fat-suppressed; T2WI: high intensity) b) Bone marrow edema (BME) (incomplete or hazy signals or reticulated patterns)c) Normal bone marrow signal (N)

MRI diagnosis:Distal phalanges (c): Normal bone (N)Middle phalanges (b, a): bone marrow edema/ osteomyelitis (BME/OM)Proximal phalanges (a, b, c): osteomyelitis/bone marrow edema/normal bone (OM/BME/N)


11 type III ulcers; and 6 before and 6 after revascularisation for type IV ulcers. Pre- and post-revascularisation MRI was done for 2 patients who underwent 2 surgeries, 1 for type II ulcer and 1 for type IV ulcer.

A total of 149 bone specimens (39 distal phalanx, 29 middle phalanx, 46 proximal phalanx, 34 metatarsal bone, and 1 cuboid bone were obtained from 57 toes as follows: type I (11 bones from 3 ulcers), type II (40 bones from 3 ulcers), type III (44 bones from 11 ulcers), and type IV (54 bones from 11 ulcers) (Table 3).

Histologic analysis of all bone specimens revealed the

presence of osteomyelitis, bone marrow oedema, normal bone, or gangrene. The histopathological features of bone marrow in the resected bones corresponded to the MRI findings for ulcers of types I and III in every localisation (Table 4). Osteomyelitis was detected in 41 bones, with a sensitivity and specificity of 100%. In type II ulcers, however, none of the 40 bones was accurately diagnosed by MRI because of unclear or equivocal images (Table 5). Of 40 bones from type II ulcers, 27 showed dry gan-grene. Only 9 bones from type IV ulcers examined by post-revascularisation MRI were accurately diagnosed.

BME

BMEOM

OM N

OM) BME)

N)

BME) N)

OM

N

(H&E; 40 )

Figure 3: Histopathological diagnosis of case 1, left 2nd toe.

Histopathological features of bone marrow in the resected bones correspond to the MRI findings.

Osteomyelitis (OM), bone marrow edema (BME), normal bone marrow (N)

Table 1. Classification of ulcers

Main aetiologic factors Classification* Ulcers (n) Neuropathic ulcers Type I 3** Ischemic ulcers ( CLI ) Type II 3** Neuropathic ulcers with infection

Type III 11** ½

CLI with infection Type IV 11** Total 28** *Terashi H. et al Keio J Med 2011; 60:17-‐21, **Two patients, had two different types of ulcers each.

Table 2. Details of MRI examinations

Ulcers MRI Type I 3 3* Type II 3 4* Pre-‐revascularization: 3

Post-‐revascularization: 1 Type III 11 11* Type IV

11 12* Pre-‐revascularization: 6 Post-‐revascularization: 6

Total 28 30* Average interval between MRI and surgery: 16.7 days. *One ulcer of Type II (Case 5) underwent both pre-‐ and post-‐revascularization MRI.

Table 3: Specification of bone specimens in each ulcer type

Ulcers (n) Toes (n) Bones (n)

Distal phalanx (n)

Middle phalanx

(n)

Proximal phalanx

(n) Metatarsal

(n) Cuboid (n)

Type I 3 4* 11 3 3 3 1 1 Type II 3 12* 40 12 9 11 8 Type III 11 19* 44 13 7 14 10 Type IV 11 22* 54 11 10 18 15 Total 28 57* 149 39 29 46 34 1 *Four toes and a cuboid bone



Type III 11** ½









Distal phalanx (n)

Middle phalanx

(n)

Proximal phalanx

(n) Metatarsal

(n) Cuboid (n)




Type III 11** ½









Distal phalanx (n)

Middle phalanx

(n)

Proximal phalanx

(n) Metatarsal

(n) Cuboid (n)



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The other 45 bones still could not be diagnosed because of unclear or equivocal images.

Histopathological analysis revealed osteomyelitis in 27 bones of type IV ulcers, but only 9 bones were correctly diagnosed by post-revascularisation MRI, with a sensitiv-ity of 29.6%.

Margins of 49 bones were examined by histopathology (Table 6). Of 37 bone margins of healed ulcers, 9 were normal and 28 displayed bone marrow oedema. Of 12 bone margins of unhealed ulcers, 4 showed bone marrow oedema and 8 were gangrenous. Of the 32 bone margins with bone marrow oedema, 28 healed (87.5%) and the 4 that did not heal were from 2 patients with type III ulcers involving severe soft tissue infection and 2 patients with type IV ulcers involving severe soft tissue infection and ischemia. The 8 gangrenous bone margins from 2 patients with type II ulcers could not be diagnosed by MRI because of severe ischemia.

DISCUSSIONPositive results have been shown with conservative surgery combined with antibiotics9,10, and additional satisfactory

Table 4. MRI and histopathological diagnosis of neuropathic ulcers (Type I; Neuropathic ulcers, Type III; neuropathic ulcers with infection)

MRI diagnosis (n) Histopathological diagnosis (n) Type Ulcers(n) Bones(n) Correct Incorrect OM OM/BME OM/BME/N BME N I 3 11 11 0 6 4 0 1 0

III 11 44 44 0 17 12 2 10 3

Total 14 55 55 0

Osteomyelitis (OM), bone marrow edema (BME), normal bone (N)

Table 5. MRI and histopathological diagnosis of ischemic ulcers (CLI) (Type II; CLI, Type IV; CLI with infection)

Group A; Pre-‐revascularization MRI diagnosis MRI diagnosis Histopathological diagnosis

Type Ulcers Bones Correct Incorrect* OM OM/BME

OM/ BME/N OM/G BME BME/N G N

II 3** 33 0 33 4 0 0 0 1 1 27 0 IV 5** 14 0 14 3 5 0 1 2 2 1 0

Group B; Post-‐revascularization MRI diagnosis MRI diagnosis Histopathological diagnosis



II 1** 7 0 7 0 0 0 0 4 2 0 1 IV 6** 40 9 -‐ 1 6 1 0 1 0 0 0 -‐ 31 12 4 1 3 1 1 9 0 Osteomyelitis (OM), Bone marrow edema (BME), Normal bone (N), Gangrene (G) *Because of unclear or equivocal MRI findings, **One ulcer of Type II underwent both pre-‐ and post-‐vascularization MRI.



III 11 44 44 0 17 12 2 10 3

Total 14 55 55 0






II 3** 33 0 33 4 0 0 0 1 1 27 0 IV 5** 14 0 14 3 5 0 1 2 2 1 0







III 11 44 44 0 17 12 2 10 3

Total 14 55 55 0






II 3** 33 0 33 4 0 0 0 1 1 27 0 IV 5** 14 0 14 3 5 0 1 2 2 1 0







III 11 44 44 0 17 12 2 10 3

Total 14 55 55 0






II 3** 33 0 33 4 0 0 0 1 1 27 0 IV 5** 14 0 14 3 5 0 1 2 2 1 0





clinical outcomes of nonsurgical treatments have been demonstrated with long-term courses of antibiotics2. If conservative surgery is chosen, the surgeon needs to know the precise area of osteomyelitis. If medical therapy were chosen, the duration of antibiotic therapy would depend on the presence and amount of residual dead or infected bone2. Besides choosing primary therapy, identification of the precise localization of DFO is therefore essential for appropriate treatment.

MRI is a valuable tool for diagnosing osteomyelitis, as well as for defining the presence and anatomy of deep soft tissue infections3. Its efficacy in accurately displaying the extent of DFO of different aetiological types of ulcers is not definitively known. Our previous studies4,5 have demonstrated the efficacy of MRI in diagnosing DFO of different aetiological types of ulcers, showing that for neuropathic ulcers (type I, III), DFO was reliably dis-tinguishable from reactive bone oedema at any location, even in the presence of severe infection. However, MRI was not useful in diagnosing ischemic ulcers (type II, IV) because of insufficient interstitial fluid. Taken together, our previous conclusions have been confirmed by additional cases in the present study.


REFERENCES

1 Lipsky BA. Treating diabetic foot osteomyelitis primarily with surgery or antibiotics: have we answered the question? Diabetes Care 2014;37(3):593-5.

2 Lipsky BA, Berendt AR, Cornia PB, Pile JC, Peters EJ, Armstrong DG et al. Infectious Diseases Society of America. 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis 2012:54:e132-73.

3 Lipsky BA, Peters EJG, Senneville E, Berendt AR, Embil JM, Lavery LA et al. Expert opinion on the management of infections in the diabetic foot. Diabetes Metab Res Rev 2012;28(1):163–78.

4 Fujii M, Terashi H, Tahara H. Efficacy of Magnetic Resonance Imaging in Diagnosing Osteomyelitis in Dabetic Foot Ulcers. J Am Podiatr Med Assoc 2014;104(1):24-9.

5 Fujii M, Armstrong DG, Terashi H. Efficacy of Magnetic Resonance Imaging in Diagnosing Diabetic Foot Osteomyelitis in the Presence of Ischemia. J Foot Ankle Surg 2013;52: 717-23.

6 Terashi H, Kitano I, Tsuji Y. Total management of diabetic foot ulcerations-Kobe classification as a new classification of diabetic foot wounds. Keio J Med 2011;60:17-21.

7 Rayman G, Vas PR, Baker N, Taylor CG Jr, Gooday C, Alder AI et al. The Ipswich Touch Test: A simple and novel method to identify inpatients with diabetes at risk of foot ulceration. Diabetes Care 2011;34:1517-8.

8 Morrison WB, Schweitzer ME, Batte WG, Radack DP, Russel KM. Osteomyelitis of the foot: relative importance of primary and secondary MR imaging signs. Radiology 1998;207:625-32.

9 Aragón-Sánchez J. Treatment of diabetic foot osteomyelitis: A surgical critique. Int J Low Extrem Wounds 2010;9:37-59.

10 Ha Van G, Siney H, Danan JP, Sachon C, Grimaldi A. Treatment of osteomyelitis in the diabetic foot. Contribution of conservative surgery. Diabetes Care 1996;19:1257-60.

11 Armstrong DG, Lavery LA, Harkless LB. Validation of a diabetic wound classification system: the contribu-tion of depth, infection, and ischemia to risk of amputation. Diabetes Care 1998;21:855–9.

12 Wagner FW. The dysvascular foot: a system for diagnosis and treatment. Foot Ankle 1981;2:64–122.

13 Chan JC, Malik V, Jia W, Kadowaki T, Yajnik CS, Yoon KH, Hu FB. Diabetes in Asia: epidemiology, risk factors, and pathophysiology. JAMA 2009;301:2129–40.

Currently, the appropriate surgical margin for full remis-sion of DFO is not known. In the present study, we exam-ined 49 bone margins by histopathology and demonstrated that when the bone margin was set in the area of bone marrow oedema, the chances of cure were high, and that diligence was essential with cases of severe soft tissue infec-tion or ischemia.

We propose an appropriate surgical strategy based on MRI and histopathology. In neuropathic ulcers (type I and III), the localisation of osteomyelitis is identified by MRI and the surgical margins are determined on the MR im-ages of the bone (in the area of bone marrow oedema), and the range of soft tissue infection. Because no methods are currently available for diagnosing the range of soft tissue infections, it has to be defined, in part, empirically. Type II ulcers, CLI, are of dry gangrene caused by ischemia, and preoperative MRI is not effective for diagnosis, therefore the site of resection has to be determined based on the sufficiency of blood supply after revascularisation. Type IV ulcers, CLI with infection, are the most difficult to treat because of the decision regarding which to carry out first, revascularisation for ischemia or debridement for infection.

Except for cases requiring emergency debridement for infection, we advocate evaluation of osteomyelitis using MRI after revascularisation and setting of the bone margin in the area of bone marrow oedema. Thus, the appropriate surgical margin should be based on not only the range of osteomyelitis, but also on the range of soft tissue infection or the sufficiency of blood supply.

Table 6. Histopathological examinations of the bone margin

Toes in each type(n)

Bone margins (n) Histopathological

diagnosis I II III IV Total Normal 0 2 2 5 9 Healed ulcers 37

Bone marrow edema 4 2 8 14 28 Bone marrow edema 0 0 2 2 4 Unhealed ulcers 12

Gangrene 0 8 0 0 8 Total 49 4 12 12 21 49

Our study has several limitations. First, the definitive diagnosis of DFO requires both histopathological findings and isolation of bacteria from bone samples2. To show the localisation of osteomyelitis, we used histopathological findings in the diagnosis. Second, our bone samples were from toes, metatarsals, and a cuboid bone. Although the forefoot is not the only site of diabetic foot ulcers, it is the most common11. Third, the classification6 chosen for categorizing ulcers is not universal. Our Kobe classifica-tion7, a hybrid of the University of Texas11 and the Wag-ner classification12, have recently been used in Japan. In Asia, type 2 diabetes is becoming epidemic, characterized by rapid rates of increase within a short period, onset at a relatively young age, and a low body mass index13. A distinct discipline of podiatric medicine such as that in United States or Europe is not available in Asia; therefore, the establishment of a classification system that is more relevant to Asian populations is necessary.

In conclusion, although the present study comprised a limited number of patients, we were able to recommend an appropriate surgical margin and strategy based on MRI and histopathology. These continuing studies are therefore aimed at salvaging as much of the diabetic foot as possible.


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