Imaging in non-bacterial osteomyelitis in children and adolescents: diagnosis, differential diagnosis and follow-up—an educational review based on a literature survey and own clinical experiences

Chronic non-bacterial osteomyelitis (CNO, often synonymous with non-bacterial osteitis, NBO) is a chronic autoinflammatory disease. The exact etiology is currently unknown. Giedion first described the disease entity in 1972 [1]. Later, the definition of CNO was extended to include chronic recurrent multifocal osteomyelitis (CRMO) [2, 3]. Imaging has played an important role since the time of first description (see [4] for an overview). The incidence of CNO is assumed low with, e.g., 0.4 per 100,000 children per year in Germany [5]. However, in spite of therapy, the relapse rate of symptoms with unfavorable outcomes is high [6]. Increasing awareness of the disease may shorten time to diagnosis [7]. The typical age of first manifestation is 9 to 11 years [5, 7, 8]. The disease is extremely unusual in infancy. Girls are more frequently affected than boys, and there seems to be no difference in ethnicity. An association with the so-called SAPHO syndrome (synovitis, acne, pustulose, hyperostosis, osteitis) has been suspected for many years. A recently published study [9] suggests a similar disease entity, incidence and course of both diseases. On the other hand, low current awareness of the disease might lead to considerable delays between the onset of symptoms and medical diagnosis, which is typically given as 2 years for children [10, 11]. Attempts should be made to diagnose the disease as early as possible, since early therapy can lead to better chances of recovery [12].

Keep in mind/key point: CNO/CRMO—might be unreported—delay in therapy

From the clinical point of view, CNO is an important differential diagnosis, which should not be missed. Traditionally, diagnosis of CNO is made by combining assessment of clinical symptoms, laboratory changes, and imaging, with biopsy often performed to exclude bacterial osteomyelitis or malignancy. Clinical symptoms are non-specific and associated with regional pain (mainly continuous and after exertion) and occasional accompanying swelling. Clinical symptoms manifest in a typical distribution of affected body regions and bones. In particular, the long tubular bones of the lower extremity, the vertebral bodies, the clavicles and the mandibula are most commonly affected. Symmetric involvement is considered characteristic for CNO. However, studies show that the disease can also be asymmetric [13]. Changes in laboratory values (like C-reactive protein (CrP) or blood sedimentation rate (BSG)) are variable and can be raised or normal [14, 21].

Historically, conventional radiographs and bone scintigraphy have played the leading role in diagnostic imaging. Due to its low sensitivity (up to 80% false negative results), conventional radiographs are of only minor utility [15]. Advantages of scintigraphy (technetium-99m-labeled phosphates) include a whole-body coverage, the possibility of suggesting other benign diagnoses, and excluding malignant bone disease [16]. However, it is limited secondary to symmetric physiologic tracer uptake at the physes [17] in children and adolescents, when visualizing osteoblastic activity. Positron emission tomography (PET) is rarely performed, however may be able to differentiate between chronic and acute disease activity [18]. Computed tomography (CT) is only used in individual cases or with older patients, especially to clarify changes in the sternoclavicular joints. [15]. Presently, magnetic resonance imaging (MRI), and in particular whole-body MRI, is the current imaging modality of choice for CNO imaging in children and adolescents [19]. MRI was initially performed in affected body sites in cases of suspected CNO/CRMO [30]. The first study on whole-body MRI was carried out in 2009 [25], which showed multifocality in almost all patients with superior sensitivity and specificity over clinical examination.

The advantages of MRI include: a noninvasive examination, the absence of ionizing radiation and the possibility of whole-body imaging. Bone marrow edema, which is typical for CNO, can be visualized by fluid sensitive sequences (short TI inversion recovery, STIR or turbo inversion magnitude, TIRM) without the administration of contrast agent. MRI imaging also shows asymptomatic bone changes, which may develop clinical symptoms as the disease progresses.

Keep in mind/Key point: Diagnostic triad clinic + laboratory + imaging (especially MRI)

The increasing importance of CNO/CRMO and the role of imaging in the diagnosis of CNO/CRMO is reflected in the literature. PubMed contains more than 100 publications under the keyword "CNO Imaging," of which more than 30 can be assigned to 2019/2020. Under the search term "CRMO Imaging," there are more than 300 hits, the majority also in the last few years.

There are several published imaging reviews of CNO in children, mainly showing the aspects of different imaging methods. Our aim was to perform a review focusing on CNO and whole-body MRI.

In the following parts of this educational review, results from a systematic literature search are presented in a systematic review, summarizing characteristics of diagnosis, differential diagnosis and follow-up of CNO regarding MRI (I); then, we present a case series with different examples of CNO from our own cohort as an illustration to the review (II); finally, suggestions of clinical workflows in diagnosis, differential diagnosis and follow-up of CNO/CRMO are presented (III).

It is well known that chronic non-bacterial osteomyelitis is difficult to assess [47, 48] and that an elevated awareness of this disease is essential to appropriately identify and manage patients [49]. Our aim was to perform a review focusing on CNO and whole-body MRI with special emphasis on the clinical settings of primary diagnosis, differential diagnosis and therapy monitoring. As demonstrated by this review, non-contrast whole-body MRI represents an essential pillar of detection and treatment of CNO.

However, as the reviewed algorithms concerning usage of imaging methods and time intervals in disease/treatment follow-up currently vary from center to center, standardized flowcharts might be helpful to improve detection of CNO, to reduce the number of multimodality imaging examinations and to facilitate the communication between referring physicians and radiologists. Therefore, we developed three flowcharts, which summarize a possible diagnostic work-up (Fig. 7a), a possible MRI algorithm in primary diagnosis and follow-up (Fig. 7b) and—finally—imaging hallmarks, which helps difference between non-bacterial (CNO), bacterial osteomyelitis and malignant bone lesions (Fig. 7c).

In the coming years, progressive understanding of disease pathophysiology, treatment options and, last but not least, imaging methodology is to be expected. First of all, the results of recently initiated multicenter trials will shed light on the advantages as well as current limitations of whole-body MRI examinations [50]. Additionally, atlases and textbooks will soon be available, which will allow a systematic overview, especially in whole-body MRI imaging of CNO bone lesions. Progress is also expected in the development of a uniform, globally accepted scoring system, with a first approach recently published [51]. Finally, support in image post-processing and/or reporting by artificial intelligence (AI)-driven segmentation or decision-support devices [52] will facilitate CNO detection and quantification in daily routine.