To our knowledge, this is the first survey to assess the overall practice of a sampling of radiologists in the imaging evaluation of both potential CNO and long-term imaging monitoring of patients with established CNO. Using a survey, we captured important aspects of the confidence levels, imaging utilization patterns, attitudes towards WBMRI’s role in the diagnosis and monitoring of CNO and imaging features that may correlate with increased change of bone biopsy.
It is notable that while a large number of respondents had greater than 10 years of experience as attending radiologists, the majority of them evaluated fewer than 10 potential new cases per year. This may be due to the fact that CNO being a relatively rare condition emphasizing the need for collaborative studies to determine clinical imaging scoring and in turn measurable outcomes for prospective clinical trials.
Typical sites of CNO per radiologists reporting to this survey appears to consistent with existing descriptions of bone involvement in cohorts of pediatric patients with CNO in which there is a predilection towards metaphyses of long bones, particularly those of the lower extremity [9], clavicle, and pelvis. In one published cohort of 30 pediatric patients with CNO, the most common distribution of CNO bone lesions were, in descending order of frequency: ankle (33%), clavicle (24%), calcaneus (19%), and femur (17%) [10]. In a more recent cohort of 70 pediatric patients with CNO from 3 tertiary centers in the United States, the most frequent sites of CNO involvement were: tibia (41%), pelvis (34%), femur (29%), vertebrae (24%), clavicle (23%), fibula (21%), and mandible (21%) [11].
Initial Diagnostic Workup of Potential CNO Cases
Radiologist physicians were more confident in identifying imaging features suggestive of CNO on MRI as compared to X-ray. Indeed, this observation was identified across all levels of experience among radiologists. This attitude aligns with prior research showing that MRI is superior to XR in identification of CNO lesions [12]. MRIs are more sensitive than XR, particularly in early disease in which plain radiographs are often entirely normal [13]. Imaging modalities with higher dose of radiation such as CT and bone scintigraphy are performed in more than of half of patients with CNO despite bone scintigraphy being less sensitive in the metaphysis or epiphysis of long bones of growing children [3] and CT scan’s lack of sensitivity to identify inflammatory lesions. The sequence of imaging modality interpretation in workup for potential CNO cases usually started with plain radiographs, followed by regional MRI and then WBMRI. This is similar to the order of the imaging modalities reported by pediatric rheumatologists in a study by Zhao et.al., in which among all imaging modalities used often or always, XR (89%) were most commonly used diagnostic imaging modality, followed by regional MRI (78%), and bone scintigraphy (43%) [5]. This sequential pattern of utilization contributes to the increased time from presentation to diagnosis.
A majority of respondents preferred a combination of STIR, T1 and DWI sequences in the MRI images of potential CNO cases. The sequences that were preferred by radiologists did not entirely correlate with existing studies which suggest that gadolinium-enhanced T1 or strongly T2 weighted sequences (TIRM) with fat saturation can be used and are superior to conventional radiographs or scintigraphy [13]. DWI’s use in musculoskeletal diagnoses is a relatively new technique that may not have been as widely available in the past [14]. More recently, STIR sequences in the coronal plane were most thought to be helpful in CNO, as well as reported to be the most commonly utilized sequence in routine WBMRI protocol [15]. The benefits of a coronal STIR sequence allow a larger field of view than axial sequences and the ability to highlight multiple pathologies especially within solid viscera and bone marrow, generally less artifact, and more homogenous fat suppression compared to fat-suppressed conventional T2-weighted images [16]. Thus, there have been changing views in regards to which sequences may be most sensitive and specific for evaluating for CNO by MRI reported in the literature, especially as findings may vary during different phases of clinical remission in children.
WBMRI is the most sensitive modality to detect active bone lesions in CNO [7, 17–19]. However, it appears to be underutilized as only 35% of radiologists responding to this survey used it for the initial diagnostic workup of CNO. This is in concordance with prior reported data, in which only about 36% of pediatric rheumatologists used this technique [7] though WBMRI usage varies among centers [9]. There was a discrepancy about interpretation of bone scan and MRI. In the survey study from pediatric rheumatologists, bone scintigraphy was used more often than MRI, which may be related to better overall availability [7]. However, due to its high radiation exposure and lack of sensitivity in CNO, its use is less preferred. Thus, it is critical to increase awareness of the role of WBMRI in disease monitoring of CNO and to decrease barriers towards its use.
While not routinely suggested, certain imaging features were felt to raise the need for potential bone biopsy to confirm a diagnosis of CNO by a small proportion of radiologists. Both Jannson et al. and Roderick et al. suggested a scoring system in which a threshold score to obtain a bone biopsy in a child based on multiple clinical, lab, and imaging factors; specifically, whether bone scintigraphy was negative or showed unifocal lesions [2, 3]. As MRI may be more sensitive than bone scintigraphy, particularly in growing children and radiologists feel more confident in identifying features of CNO on MRI as compared to bone scintigraphy, its inclusion in any potential future scoring systems for obtaining a bone biopsy would be helpful to avoid invasive diagnostic methods in children and perhaps help children be diagnosed earlier on in their disease.
Long Term Imaging Monitoring in Established Cases of CNO
In established cases of CNO, while MRI was most frequently interpreted, only half of respondents disclosed its use that suggested an underutilization of MRI even in patients with a known diagnosis of CNO. This is worrisome in that some patients may have an underestimation of their disease burden by lack of WBMRI as it has shown that about one-third of patients with CNO may have asymptomatic lesions that are only detected by WBMRI [3, 9] and that clinical remission does not necessarily equate radiological remission [15, 19].
Radiological definition of active and inactive disease has not been specifically detailed in CNO. In the survey reported, most respondents agreed that signal changes suggestive of bone marrow edema (60.6%) and soft tissue inflammation (54.4%) on MRI indicated active CNO disease. A disease activity score (PedsCNO score) developed by Beck et al. included the number of radiological lesions [17]. Additionally, 68% of physicians felt that resolution of abnormal MRI signals suggested a feature of inactive diseases [7]. However, the total number of lesions reported may be affected by whether a WBMRI was performed or not. Therefore, disease status should include imaging findings in addition to patient reported outcomes, physical exam findings, lab markers. Ideally, WBMRIs should at least be performed at diagnosis to help exclude alternative diagnoses if multifocal lesions are present as well as help identify unexpected/clinically silent lesions particularly of the spinal column, which may necessitate more aggressive therapy to prevent long-term damage [18]. Also, because imaging can show changes in disease activity that is affected by treatments [18, 20–21], its inclusion is important for prospective follow-up of patients. More than one quarter of patients with CNO (26.7%) reported difficulties with obtaining MRI imaging [3]. As physicians previously reported that treatment decisions are often made upon radiographic imaging, this may lead to inadequate treatment and therefore affect patient outcomes.
Furthermore, this study illustrates the dichotomy between radiologist preference and real-life utilization practices of images in CNO. While 35% of respondents utilized a WBMRI, its use may be limited due to costs, reimbursement options, and the amount of time that may be required. However, as MRI technology advances, shortening imaging time while maintaining high quality is possible. This is particularly important in younger patients who may need sedation so a risk/benefit analysis must be done. In our experience, certain centers have CNO protocols, only applying coronal STIR or TIRM sequences, that allow the images to be acquired within 20–30 minutes, and there are reports of some WBMRI protocols requiring one hour or less from localization to completion. Despite this, Schooler et al. reported that about a quarter of respondents reported using a WBMRI protocol requiring greater than 60 minutes [16]. Adopting a more feasible WBMRI protocol based on an international group’s consensus and applying the developed standardized scoring [23] can be used in randomized clinical trials for treatments in CNO.
Our study has several limitations. Firstly, the response rate from radiologist physicians was low; hence there could have been survey-sampling bias. However, this may suggest the unfamiliarity of CNO imaging in initial diagnosis and long-term imaging monitoring among the general radiologist community as a whole. Secondly, there may be deviations between answers to the survey and actual practice. Thirdly, the definition of CNO may vary among physicians.
Despite the limitations, this study identifies key issues and unanswered questions among radiologists around diagnostic approaches, and disease monitoring using imaging technologies. Results from this study will guide further discussion within a focused group to develop consensus imaging guidelines for children with CNO. Indeed, the imaging for CNO has advanced over the years, particularly in the ability to improve image quality with shortened image times for MRI, in particular WBMRI, highlighting the need for re-assessment of current imaging guidelines in which it is still considered “investigational” [24]. Guidelines are used in a variety of practices and developed from different sources from peer-review literatures to expert panels. Due to the lack of utilization of WBMRI, which is often hindered by insurance denials, underestimation of disease burden often occurs. Updated consensus imaging guidelines may help ease insurers’ concerns of unnecessary tests, therefore increasing approval of utilization of WBMRI in CNO, reducing overall patient costs, and adding value to healthcare. Additionally, a targeted guideline for imaging may lead to improved overall healthcare costs by reaching correct diagnosis of CNO early and avoiding inappropriate and harmful treatments such as prolonged antibiotics, and even long-term intravenous line usages.