Background
Opsoclonus-myoclonus syndrome (OMS), also known as dancing eye syndrome or opsoclonus-myoclonus-ataxia syndrome, is an extremely rare autoimmune neurological disorder, with an incidence of approximately 0.18 cases per 1.000.000 in the UK population annually [
1]. OMS affects mainly young children with a typical onset at 18 months of age and typically presents subacutely with jerky unsteadiness and ataxia as well as intermittent ocular flutter or opsoclonus with rapid, multidirectional eye movements [
1,
2]. As almost half of the pediatric patients with OMS are associated with an underlying neuroblastic tumor (e.g. neuroblastoma, ganglioneuroblastoma, ganglioneuroma), and, conversely, approximately 2–3% of the pediatric patients with neuroblastoma present with OMS, it is defined as a paraneoplastic neurological disorder [
1]. Previous studies presumed, that there might be an immune-mediated encephalopathy caused by a cross-reactive autoimmune reaction between neuroblastoma cells and the central nervous system and a variety of antibodies have been described, for example IgM and IgG antibodies to neural tissues and antigens such as components of Purkinje cells, however, the detailed pathogenesis and epidemiology remains unclear [
3,
4].
Interestingly, patients with coincident OMS and neuroblastoma have a favorable survival and non-metastatic disease [
2,
5,
6]. However, there is also research indicating that a delayed diagnosis of OMS may result in late neurological and neuropsychological sequelae. Especially children with young age at disease onset and children with severe initial symptoms are postulated to be at significant risk of developing long-term neurological sequelae such as cognitive deficits [
7,
8]. Furthermore, a delayed diagnosis of OMS was found to be associated with neurological and neuropsychological sequelae, thus, the role of early diagnosis of OMS and possibly underlying neuroblastic tumors is of critical importance [
7].
Beside clinical examination and laboratory tests such as the urinary catecholamine excretion, I-131 and I-123 metaiodobenzylguanidine (mIBG) scintigraphy provides high sensitivity and specificity for the detection of neuroblastoma and its metastases and has been adopted widely as a screening procedure and for disease monitoring in pediatric patients with neuroblastic tumor [
9‐
13]. However, there is also very early evidence that computed tomography (CT) and magnetic resonance imaging (MRI) are valuable tools for the detection of primary tumor in patients with OMS [
14,
15].
In this case series we report on three pediatric patients presenting with OMS and a negative I-123-mIBG scintigraphy, in whom whole-body MRI (WB-MRI) correctly identified neuroblastic tumor sites.
Discussion and conclusions
OMS is a rare pediatric disease, which poses significant challenge to the caregiving physicians. We report on three patients who presented with OMS due to an underlying neuroblastic tumor. In all cases, abdominal ultrasound and I-123-mIBG scintigraphy were unremarkable while WB-MRI identified small, but characteristic lesions consistent with neuroblastic masses. While routine diagnostic work-up does not comprise additional imaging procedures, conclusive WB-MRI was performed due to persistent clinical suspicion, which highlights the valuable role of WB-MRI in the detection of occult neuroblastic tumors in patients with OMS.
Due to its very high sensitivity and specificity derived from previous research, mIBG scintigraphy is a robust and well-established screening modality for the detection of primary tumor site as well as lymph node involvement and metastases in pediatric patients with suspected neuroblastic tumor [
9‐
13]. Specifically, in a large Cochrane Database review including 11 studies, Bleeker et al. reported a sensitivity of I-123-mIBG scintigraphy ranging from 68 to 100% in patients with histologically proven neuroblastoma [
9]. However, there is also evidence of false-positive results and 10% of neuroblastomas are associated with a negative mIBG uptake [
9,
11,
16]. The false-negative results of I-123-mIBG scintigraphy in our cases cannot be fully explained. The relative small tumor size as well as missing receptor-uptake of the lesions, for example in non-secreting low grade neuroblastoma may be potential causes [
9,
11,
16,
17]. In addition, due to the physiological mIBG uptake of the adrenal glands, the detection of tumor lesions located close to the kidney and adrenal glands might be significantly limited. Reuland et al. found that 99 m-Tc-Anti-GD2 immunoscintigraphy might be a useful addition for diagnosis of new tumor lesions superior to I-123-mIBG scintigraphy in high grade neuroblastoma due to an earlier uptake of neuroblastoma lesions compared to I-123-mIBG scintigraphy [
18]. However, negative 99 m-Tc-Anti-GD2 immunoscintigraphy in our case #3 may be explained by present low-grade neuroblastic tumor genesis, resulting in a delayed detection of neuroblastic tumor.
In contrast, regarding the manifestation of OMS as a paraneoplastic symptom of possibly underlying neuroblastic tumor, recent studies found cross sectional imaging by CT or MRI to be promising and sensitive tools in the setting of detecting the primary tumor site [
14,
15,
19]. As such, MRI has been classified as equal to I-123-mIBG scintigraphy, which remains the mandatory imaging modality in the primary tumor imaging workup in neuroblastoma [
20]. However, the major drawbacks of I-123-mIBG scintigraphy are the extensive procedure, limited spatial resolution as well as the radiation exposure accompanied by the intravenous injection of radioactive I-123, which is additionally associated with size and administered activity of the lesion [
21].
CT, as a widely available modality, allows for fast acquisition and reduces sedation time. Razek et al. showed, that whole-body CT provides a high detection rate for cortical and medullary bone lesions, spinal fracture and extraosseous spinal lesions [
22]. However, whole-body CT is associated with significant radiation exposure, which is of particular concern in the pediatric patient population.
WB-MRI is diffusing increasingly clinical routine in pediatric radiology, especially due to technical developments and accelerated acquisition time as well as the high anatomic resolution. Apart from several imaging protocol recommendations, WB-MRI has shown to be a precise and comprehensive image modality for children suffering from solid tumors. Furthermore, diffusion-weighted MRI provides further information about tumor characterization at a cellular level and was found to be a beneficial tool in the differentiation of paraspinal benign versus malignant neurogenic tumors [
23]. Moreover, due to the high cellular density, neuroblastoma frequently demonstrates diffusion restriction, hence, diffusion-weighted imaging is a critical part of the MRI protocol in the imaging work-up of patients with suspected neuroblastoma [
24].
Previous studies reported promising initial experiences with 68Ga-DOTA-Octreotate positron emission tomography (PET) and simultaneous CT in patients with OMS [
25]. This is in line with the observation that hybrid imaging modalities such as PET/CT or non-ionizing PET/MRI are emerging as key diagnostic modalities in the work-up of oncologic pediatric patients [
26]. This is further accentuated as novel tracers, for instance 18 F-Meta fluorobenzyl guanidine as a PET analog of mIBG, seem to be promising markers in the diagnostic setting of neuroendocrine tumors with the advantage of higher tracer uptake, higher spatial resolution, and reduced radiation exposure in comparison to mIBG [
27].
Our case series and review of the literature emphasize the value of WB-MRI in occult neuroblastic tumors, particularly in the setting of a negative I-123-mIBG scintigraphy that was present in all cases. In these patients, MRI detected the primary tumor site and arrived at the diagnosis without ionizing radiation. Our case series indicates, that WB-MRI enables a rapid diagnosis of neuroblastic tumor sites and may thus improve current diagnostic pathways and impede delay in treatment. Thus, further prospective, well-designed studies comparing WB-MRI and scintigraphy in the assessment of occult tumor manifestations in pediatric population is strongly warranted and justified. Given its non-ionizing nature, it may thus represent a favorable alternative for early diagnosis of possibly underlying neuroblastic tumors in the work-up of children with occult neuroblastic tumors, especially in cases with negative mIBG scintigraphy. However, more scientific evidence is needed, particularly in comparison with I-123-mIBG scintigraphy.
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