Purpose: Materials and Methods: Results: Conclusion: Original Research n Musculoskeletal Imaging

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1 Note: This copy is for your personal non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, contact us at Belinda R. Beck, PhD A. Gabrielle Bergman, MD Mark Miner, MD Elizabeth A. Arendt, MD Alan B. Klevansky, MB, BCh Gordon O. Matheson, MD, PhD Tracey L. Norling, BHMS, BN 2 Robert Marcus, MD Tibial Stress Injury: Relationship of Radiographic, Nuclear Medicine Bone Scanning, MR Imaging, and CT Severity Grades to Clinical Severity and Time to Healing 1 Purpose: Materials and Methods: To examine the relationship between severity grade for radiography, triple-phase technetium 99m nuclear medicine bone scanning, magnetic resonance (MR) imaging, and computed tomography (CT); clinical severity; and recovery time from a tibial stress injury (TSI), as well as to evaluate interassessor grading reliability. This protocol was approved by the Griffith University Human Research Ethics Committee, the Stanford University Panel on Human Subjects in Medical Research, the U.S. Army Human Subjects Research Review Board, and the Australian Defense Human Research Ethics Committee. Informed consent was obtained from all subjects. Forty subjects (17 men, 23 women; mean age, 26.2 years [standard deviation]) with TSI were enrolled. Subjects were examined acutely with standard anteroposterior and lateral radiography, nuclear medicine scanning, MR imaging, and CT. Each modality was graded by four blinded clinicians. Mixed-effects models were used to examine associations between image severity, clinical severity, and time to healing, with adjustments for image modality and assessor. Grading reliability was evaluated with the Cronbach a coefficient. Original Research n Musculoskeletal Imaging 1 From the School of Physiotherapy and Exercise Science, Centre for Musculoskeletal Research, Griffith University, Gold Coast campus, Griffth, QLD 4222, Australia (B.R.B., T.L.N.); Radsource/Imaging Specialists, El Dorado Hills, Calif (A.G.B.); Department of Radiology, TRIA Orthopaedic Center, Park Nicollet Clinic, Minneapolis, Minn (M.M.); Department of Orthopaedic Surgery, University of Minnesota, Minneapolis, Minn (E.A.A.); Department of Radiology, Gold Coast Hospital, Southport, Queensland, Australia (A.B.K.); and Departments of Orthopaedic Surgery (G.O.M.) and Medicine (R.M.), Stanford University School of Medicine, Stanford, Calif. Received December 14, 2010; revision requested January 28, 2011; revision received December 7; accepted December 29; final version accepted January 6, Supported by the Department of the Army, U.S. Army Medical Research and Materiel Command, Award Number DAMD Address correspondence to B.R.B. ( 2 Current address: John Flynn Hospital, Tugun, Queensland, Australia. q RSNA, 2012 Results: Conclusion: Image assessment reliability was high for all grading systems except radiography, which was moderate (a = ). Clinical severity was negatively associated with MR imaging severity (P.001). There was no significant relationship between time to healing and severity score for any imaging modality, although a positive trend existed for MR imaging (P =.07). TSI clinical severity was negatively related to MR imaging severity. Radiographic, bone scan, and CT severity were not related to time to healing, but there was a positive trend for MR imaging. q RSNA, 2012 Radiology: Volume 263: Number 3 June 2012 n radiology.rsna.org 811

2 Bone stress injuries, including stress fractures, are relatively common in athletes and military recruits (1 3). The time to recover from a tibial stress injury (TSI) has been reported to be between 4 and 20 weeks, suggesting that differences in injury severity can be considerable (4 11). The ability to accurately and reliably determine injury severity and estimate time to healing would enable the prediction of readiness for key competitive events or military training exercises. Imaging modalities, including radiography (12), triple-phase technetium 99m polyphosphonate bone scanning (9,13), magnetic resonance (MR) imaging (14), computed tomography (CT) (15), thermography (16), and tuning forks (17) have been used to aid physicians in the diagnosis of stress fracture. However, the relative ability of each modality to aid in the distinction of injury severity and prediction of recovery has, to our knowledge, not been comprehensively addressed. Radiography has been shown to have low sensitivity in the acute phase of bone stress injury (18), but it is commonly ordered to rule out other abnormalities. Technetium bone scanning historically has been considered the reference standard in the diagnosis of bone stress injury; however, specificity can be low, and positive findings in asymptomatic locations (19), including those considered to be functionally healed (20), can be clinically misleading. MR imaging is increasingly recognized to have high sensitivity and specificity for bone stress injury, owing to its ability Advances in Knowledge nn Tibial stress injury (TSI) severity grade may differ substantially according to imaging modality. nn Clinical severity of TSI is inversely related to MR imaging severity grade and time to healing. nn Only MR imaging severity grade bears any relationship to time to healing of TSI; however, this relationship was not significant. to depict subtle edema (14). Reports of diagnosis of stress fracture with CT have also appeared in more recent literature; however, this modality is used less frequently in clinical practice (15). While bone stress injury grading systems have been reported for radiography (12), triple-phase nuclear medicine (NM) bone scanning (13), MR imaging (14,21 23), and CT (15), their relative relationship to healing time has not been established. Our overarching goal was to examine the relationship between severity grades for each imaging modality with clinical severity and time to recovery from TSI. Specifically, we aimed to examine the relationship between existing systems of severity grading from radiographs, NM bone images, MR images, and CT images with clinical injury severity and time to recovery in a cohort of individuals with acute TSI to identify the imaging modality that enables the best discrimination of TSI severity. We hypothesized that injury severity according to MR image grade would exhibit the strongest relationship with both clinical severity and time to healing compared with injury severity according to radiographic, NM bone, and CT image grade. Our secondary objective was to examine interassessor TSI severity grading reliability for radiography, NM bone scanning, MR imaging, and CT. We hypothesized that interassessor severity grading reliability would be high across all modalities. Materials and Methods Ethics Approval and Industry Support The protocol was approved by the Griffith University Human Research Ethics Committee, the Stanford University Panel on Human Subjects in Medical Research, the U.S. Army Human Implication for Patient Care nn Patient perception of pain with TSI is a poor reflection of injury severity at imaging and time to recovery. Subjects Research Review Board, and the Australian Defense Human Research Ethics Committee. Informed consent was obtained from all subjects. Fifty capacitively coupled electric field stimulators (OrthoPak Bone Growth Stimulator System; Biolectron, Hackensack, NJ) that were coded and blinded for the intervention arm of the trial (reported elsewhere [10]) were loaned to us by Bioelectron (acquired by EBI Medical Systems [Parsippany, NJ] in 2000). Authors had full control of the data and information submitted for publication. Subject Recruitment, Eligibility, and Characteristics Men and women aged years in whom a sports medicine clinician had diagnosed acute TSI were recruited from the San Francisco Bay area in California and the Gold Coast region in Queensland, Australia, over a period of 6 years ( ). The diagnosis of TSI was made on the basis of patient history (development of substantial localized exercise-related tibial pain) and the presence of substantial focal tenderness that was most pronounced during weight bearing (24 26). Eligibility for the study was based on the presence of one or more acute TSIs (one per leg only), for which no treatment aside from rest had been Published online /radiol Radiology 2012; 263: Abbreviations: NM = nuclear medicine TSI = tibial stress injury Content code: Author contributions: Guarantor of integrity of entire study, B.R.B.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; literature research, B.R.B.; clinical studies, B.R.B., A.G.B., M.M., A.B.K., G.O.M., T.L.N., R.M.; statistical analysis, B.R.B.; and manuscript editing, B.R.B., A.G.B., M.M., A.B.K., G.O.M., T.L.N., R.M. Potential conflicts of interest are listed at the end of this article. 812 radiology.rsna.org n Radiology: Volume 263: Number 3 June 2012

3 prescribed. Midanterior tibial shaft stress fractures were excluded, as these are particularly prone to delayed union or nonunion (27). Subjects were excluded from the study if they were pregnant, used a pacemaker, had a metabolic bone disease, or took medication known to influence bone healing. Age, sex, height, and weight were recorded for each subject. Clinical Diagnosis A study investigator (B.R.B., 10 years of experience) performed a comprehensive injury assessment to standardize evaluation criteria. Intensity of signs and symptoms, including pain with daily activities, pain with running, pain with hopping, night pain, local tenderness, pain with tibial percussion, and localized soft-tissue swelling over bone, were recorded on a scale of , with the option for fractional scoring (eg, 1.2/3). A clinical severity score was calculated by adding all seven sign and symptom scores for a possible total of 21. The individual clinical signs and symptoms were also examined independently. Diagnostic Imaging Plain radiographs were obtained in standard anteroposterior and lateral planes of the symptomatic leg. Triple-phase technetium 99m polyphosphonate bone scanning was performed in the medial and posterior planes from the knee to the ankle in both legs (acquisition matrix, ; collimator, low-energy high-resolution parallel hole; pinhole magnification, 31; depth, 16; section, 2.33) with a commercially available bone scanner (Icon; Siemens, Malvern, Pa). MR imaging was performed with the patient in the supine position, feet first, on the imager table. We used a Signa 1.5-T Horizon Echospeed 5.7 whole-body magnet system (GE Medical Systems, Little Chalfont, Buckinghamshire, England) with an extremity coil. T1- and fat-saturated T2-weighted images from 10 cm above to 10 cm below the region of pain were obtained in the involved leg in the sagittal, coronal, and axial planes. The technique included (a) 5-mm sagittal spin-echo localizer (repetition time msec/echo time msec, 300/minimum full; 1-mm spacing; matrix, 128; one signal acquired; field of view, ), (b) 4-mm axial spinecho (600/minimum full; 1-mm spacing; saturation signal intensity; matrix, ; two signals acquired; frequency direction, coronal; field of view, ), (c) 4-mm axial fast spin-echo (4000/72; 1-mm spacing; echo train length, eight; saturation signal intensity fat; matrix, ; two signals acquired; frequency direction, coronal; field of view, ), and (d) 3-mm sagittal fast spin-echo (4000/72; 1.5- mm spacing; echo train length, eight; saturation of fat signal; matrix, ; two signals acquired; field of view, ). A vitamin E capsule was taped to the skin over the region of maximum pain. CT was performed with a Somatom Plus 4 scanner (Siemens). Images were acquired in 1-mm sections for 10 cm in both directions from a marked point of maximum tenderness on the leg (tube voltage, 120 kv; tube current, 240 ma; field of view, cm with bone window settings.). Imaging and clinical examinations were scheduled for the same day and were performed successfully in 95% of subjects. In the remaining subjects, the balance of examinations were performed within 5 days before or after clinical assessment. Image Grading All images were evaluated retrospectively (between 2005 and 2007) and independently by four assessors who were aware that all patients had symptoms. The assessors were two musculoskeletal radiologists with 20 (A.G.B.) and 13 (M.M.) years of experience in stress fracture imaging, a general radiologist with 30 years of experience and a special interest in musculoskeletal imaging but limited stress fracture experience (A.B.K.), and an orthopedic surgeon with 24 years of experience and considerable experience in stress fracture management and image analysis (E.A.A.). Images were fully blinded for patient identity and symptoms, randomly ordered in batches (images of each modality were grouped together), and graded consecutively in one sitting. In cases where an injury marker was not evident on the image hard copy, the location of the injury was provided to the grader. We used published grading systems with minor adaptations, as described in Table 1. We used a grading scale of 0 (indicating a negative finding) to 4 (presence of a fracture line). Treatment In a separate arm of the study, a randomized controlled intervention of capacitively coupled electric field stimulation (3 6 V at 60 khz and 5 10 ma) was conducted. Half of the subjects were randomly assigned an active treatment, and half were assigned a sham treatment for an average of 15 hours per day until they were asymptomatic. All subjects received standard stress fracture rehabilitation advice (primarily, to rest from painful activity and to instead engage in water running or in-seat cycling). Results of the treatment effect have been reported elsewhere (10). Subject Monitoring and Determination of Healing Participants were contacted by phone or every 2nd day for a progress report and were asked to rerate existing clinical symptoms on a scale of 1 3. Subjects were advised not to attempt running until they had no pain while walking, and hopping was not attempted until subjects had no pain when running for 50 m. The injury was considered healed when the patient could hop on the affected limb for 30 seconds to a height of 10 cm without pain (28,29). Statistical Analysis Preliminarily, we used correlation analysis to identify any relationship between the seven clinical severity scores and time to healing. We performed multiple regression analyses to determine if variables such as age, sex, and BMI could be used to predict clinical Radiology: Volume 263: Number 3 June 2012 n radiology.rsna.org 813

4 Table 1 TSI Imaging Grading Criteria Grade Radiography* NM Bone Scanning MR Imaging CT Scanning 0 No abnormality No abnormality No abnormality No abnormality I Gray cortex sign; margin is indistinct, density lower Linear increased activity in cortical region Mild to moderate periosteal edema on only T2-weighted images, with no focal bone marrow abnormality Soft-tissue mass adjacent to periosteal surface II III Acute periosteal reaction, density differs from rest of cortex showing incomplete mineralization Lucent areas in cortex, ill-defined foci at site of pain Small focal region of increased activity Larger focal lesion with highly increased activity in the cortical region IV Fracture line present Very large focal region of highly increased activity * Adapted from Savoca (12). Adapted from Zwas et al (13). Adapted from Fredericson et al (14). Adapted from Gaeta et al (15). Periosteal edema and bone marrow edema on only T2-weighted images Marrow edema on T1- and T2-weighted images with or without periosteal edema on T1- or T2-weighted images and loss of cortical signal void, intracortical increased intensity, and intracortical linear hyperintensity Low-signal-intensity fracture line with all sequences, moderate to severe periosteal edema on T1- and T2-weighted images, marrow edema on both T1- and T2-weighted images, may also show severe periosteal and moderate muscle edema Increased attenuation of yellow marrow Increased hypoattenuation (osteopenia), intracortical hypoattenuation (resorption cavity), and subtle intracortical linear hypoattenuation (striation) Hypoattenuating line severity score, time to healing, or both, and whether clinical severity could be used to predict time to healing. Correlation analysis was also used to determine the degree of the relationship between image modality scores. To determine if image severity was associated with clinical severity, we fit a mixed-effects model, where clinical severity (pain with daily activities) was the dependent variable, and we adjusted for imaging modality and assessor. We replaced the combined clinical severity score with pain with daily activities in the model, as correlation analysis revealed that no other clinical severity parameter was significantly related to time to healing. We similarly used a mixed-effects model to determine if time to healing was associated with baseline image severity, treatment group, and body mass index, with assessor as a random effect and sex as a covariate. Interassessor reliability was examined with the intraclass correlation coefficient (Cronbach a). All analyses were performed by using statistical software (SPSS, version 19; SPSS, Chicago, Ill). Results Subject Characteristics Forty-eight individuals volunteered for the trial, of whom 40 (mean age, 26.2 years [standard deviation]) were eligible for image grading analysis. Two subjects were excluded because they did not meet the injury criteria. Six subjects were excluded because they agreed to undergo only one of the imaging examinations. The average time to imaging from onset of symptoms was 8 days 6 6. Anthropometric characteristics of the 17 men (26.8 years 6 6.7) and 23 women (25.8 years 6 7.2) can be seen in Table 2. Relationship of Imaging Grade to Clinical Grade Table 3 provides details of the mean, median, standard deviation, and range of each clinical sign and symptom score. Clinical severity (pain with daily activities) was negatively associated with imaging severity at radiography (P =.05), NM bone scanning (P,.001), and MR imaging (P,.001) in the model; however, linear contrasts were significant only for MR imaging. That is, a higher level of pain with daily activity was associated with a lower severity grade at MR imaging. Relationship of Imaging Grade to Time to Healing No relationship between imaging severity and healing time was significant for any imaging modality; however, a positive trend was apparent for MR imaging (P =.07). That is, the higher the MR imaging severity grade, the longer the injury took to heal. Pattern of Injury Grading From the average scores for each modality (Table 4), it is apparent that injury severity is most likely to be graded 814 radiology.rsna.org n Radiology: Volume 263: Number 3 June 2012

5 Table 2 TSI Subject Characteristics Characteristic the lowest when assessed with plain radiography. It is graded higher with CT, higher yet with NM bone scanning, and highest with MR imaging. From the average scores of each assessor, the radiologists who specialize in bone stress injuries tended to score injury severity lower than did the orthopedic surgeon or the general radiologist. Relationship between Imaging Grades Severity grades from one imaging modality were not consistently or strongly related to grades from another imaging modality. Average MR imaging grade was moderately related to average NM bone scanning grade (r = 0.452, P =.002). Average CT grade was mildly related to average radiography grade (r = 0.354, P =.02), and average NM bone scanning grade (r = 0.315, P =.03). No other relationships existed between grades assigned Female Subjects (n = 23) Male Subjects (n = 17) Mean Standad Deviation Mean Standad Deviation Age (y) Height (cm) Weight (kg) Time to healing (d) Clinical severity pain score Combined imaging grade Note. Thirteen female subjects underwent treatment, and 10 received a placebo; seven male subjects underwent treatment, and 10 received a placebo. Table 3 Average Clinical Severity Scores Symptom or Sign Mean Median Standard Deviation Minimum Maximum Pain during daily activities Pain when running Night pain Local tenderness Local swelling Pain during percussion Pain when hopping Note. Data are clinical severity scores and range from 0 to 3. with different imaging modalities. The Figure depicts this grading disparity and shows that one injury could be assigned five different grades depending on the modality used. Grading Reliability The average severity grades assigned by each of the four assessors for each of the imaging modes for the full data set are listed in Table 4. A Cronbach a comparison among scores assigned by the four graders suggests interassessor reliability was high to very high for NM bone scanning, MR imaging, and CT (a range, ). Greater interassessor variability was evident for radiography grading (a = 0.565). Discussion We examined the relationship between established severity grading scales for radiography, triple-phase NM bone scanning, MR imaging, and CT and the clinical severity of TSI. We found that only severity at MR imaging was significantly related to clinical severity; therefore, an MR imaging grading system was superior to grading systems for other modalities in this respect. We also examined the relationship between severity on radiographs, triplephase NM bone images, MR images, and CT images and time to TSI healing. While no imaging modality grade was significantly associated with time to healing at our established a level of.05, a positive trend existed for MR imaging, suggesting that the relationship between severity and time to healing was better for MR imaging than for any other modality. Although the grade assigned to a TSI with one imaging modality frequently differed from that assigned with a different modality (suggesting poor intermodality consistency) (Figure), we were able to accept our hypothesis that interassessor grading reliability is high for all modality grading systems except radiography. In short, we found that although tibial stress injuries can be reliably graded by using existing schemes for the most accepted imaging modalities, only MR imaging severity bears any relationship to any clinically relevant phenomenon, such as clinical severity or time to healing. Our analysis was focused on the relationships between imaging severity, clinical severity, and time to healing. It is noteworthy that the relationship between clinical severity and time to healing was negative, as was the relationship between clinical severity and imaging severity. The latter observation suggests that individuals who rate their pain lower despite more severe signs at imaging (those with a higher pain tolerance) are more likely to report their pain absent earlier (have a shorter time to healing) and vice versa. Such behavior suggests that pain is an unreliable marker of healing and that follow-up MR imaging at symptom resolution may be indicated to guide recommendations for the return to training. We chose to examine the gamut of mainstream imaging modalities for Radiology: Volume 263: Number 3 June 2012 n radiology.rsna.org 815

6 Table 4 Mean TSI Imaging Grades for All Assessors and All Modalities and Interassessor Reliability Imaging Modality Assessor 1 Assessor 2 Assessor 3 Assessor 4 Mean across All Assessors Interassessor Reliability* Radiography NM bone scanning MR imaging CT Combined imaging grade Average imaging grade Note. Unless otherwise indicated, data are mean 6 standard deviation. Assessors 1 and 2 were the musculoskeletal radiologists with stress fracture expertise, assessor 3 was the orthopedic surgeon with stress fracture expertise, and observer 4 was the general radiologist with limited stress fracture experience. * Data are Cronbach a values. (a) Anteroposterior and lateral triple-phase technetium 99m bone scan images. All readers assigned a grade of 2. (b) Anteroposterior radiograph. Readers 1, 2, 3, and 4 assigned a score of 2, 2, 1, and 0, respectively. (c) CT images. Readers 1, 2, 3, and 4 assigned a score of 3, 4, 3, and 3, respectively. (d) MR images. Readers 1, 2, 3, and 4 assigned a score of 1, 3, 2, and 1, respectively. The images, obtained in a single subject with a TSI in the left leg, show the potential for one injury to receive five different grades (0 4) depending on the grader and imaging modality. which TSI grading systems have been published and to adapt them mildly to account for changes in technology or for our current understanding. Those systems included Savoca s 1971 system of classification of radiographic signs (12), the Zwas et al 1987 classification of scintigraphic findings (13), the Fredericson et al 1995 MR imaging grading system (14), and the Gaeta et al 2005 CT classification system (15), as described in Table 1. While other stress fracture grading systems exist, primarily for MR imaging (21,30), our grading schemes reflected recognized systems that accommodated our imaging protocols at study inception. It is generally held, and our findings confirm, that signs of TSI are inadequately evident on plain radiographs to justify a system of severity grading; therefore, this aspect of our study will not be discussed further. It is well recognized that delayed technetium 99m polyphosphonate bone scanning is highly sensitive to the hyperemia and increased turnover associated with bone stress injury and that tracer uptake in regions of affected bone are generally proportional to the degree of 816 radiology.rsna.org n Radiology: Volume 263: Number 3 June 2012

7 injury. Some hold that bone scanning rarely generates false-positive or falsenegative readings of bone stress injury and that this modality is therefore superior to MR imaging (31). While bone scanning has been considered the reference standard for bone stress injuries (13,31) because of this high sensitivity and specificity, certain limitations are now well recognized. Abnormal tracer uptake can be evident when a subject is asymptomatic (32,33), perhaps as often as 40% of the time (13). Conversely, pain can exist when bone scanning yields negative results (34). In reality, grading bone stress injuries with scintigraphy has not been widely adopted in the clinical community, and our findings provide little justification to do so. The use of MR imaging in the evaluation of patients suspected of having a bone stress injury is increasing. The ability of MR imaging to depict edema is the primary reason why it could be expected that this modality may be more sensitive to subtle differences in injury severity than other bone imaging modalities. Since 1994, a number of grading systems have been reported for MR imaging; most use detection of edema visibility and location of edema in relation to the cortex to determine grade (14,22,23,35 37). Most researchers have concluded that in comparison with modalities such as bone scanning and radiography, MR imaging yields a superior level of information about location and extent of injury (14,37 40). Our data reflect the majority of reports that state that MR imaging provides more information about the morphologic location of a bone stress injury than does NM bone scanning (14,38). Curiously, we have also shown that TSI severity at MR imaging is negatively related to pain with daily activities but positively related to healing time. Although a TSI grading system for CT has been published (15), the clinical community has been slow to adopt CT imaging in the assessment of bone stress injuries because of its recognized low sensitivity. Our data enabled us to confirm such a contention, as they demonstrated CT had low sensitivity for TSIs. In the current study, almost without exception, subjects received a grade of either 0 or 3 from all examiners. Our grading categories contain slight variations from existing published systems. As such, our findings cannot be applied wholesale to all systems used to grade bone stress injury. Our system categories, however, largely mirror those found in the literature, with only minor variations. We conclude that the radiographic, NM bone scan, and CT severity grading systems used in the current study are not related to time to healing from TSI. The negative relationship of MR imaging severity to clinical severity suggests that pain is an unreliable marker of TSI severity and healing. The trend for a positive relationship between TSI severity at MR imaging and time to healing suggests the MR imaging grading system may have predictive utility in this regard but requires further investigation. Acknowledgment: We are grateful to Bioelectron for supplying the OrthoPak devices used in the intervention arm of this study. Disclosures of Potential Conflicts of Interest: B.R.B. No potential conflicts of interest to disclose. A.G.B. No potential conflicts of interest to disclose. M.M. No potential conflicts of interest to disclose. E.A.A. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: is a consultant for Tornier. Other relationships: none to disclose. A.B.K. No potential conflicts of interest to disclose. G.O.M. No potential conflicts of interest to disclose. T.L.N. No potential conflicts of interest to disclose. R.M. No potential conflicts of interest to disclose. References 1. 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