The Hot Cross Bun Sign: A Journey Across Etiologies

Abstract

“Hot cross buns! Hot cross buns! One a penny, two a penny, Hot cross buns! If you have no daughters, Give them to your sons. One a penny, two a penny, Hot cross buns!” The evolution of possible differential diagnosis for the HCBS is rather interesting (Fig. 1) with a significant increase within the past decade in the number of conditioned associated with the sign. To a certain extent this is indicative of progress made in the field specifically in advances associated with autoimmune and paraneoplastic antibodies. The underlying etiologies are varied and as described in detail in the article by Naidoo et al,4 the HCBS may be secondary to degenerative, genetic, autoimmune, infectious, inflammatory, neoplastic/ paraneoplastic, vascular or other causes. Concepts pertaining to the pathophysiological process contributing to the HCBS have also evolved. Earlier when the association was restricted to MSA, the underlying pathophysiological process was considered to be atrophy of pontine neurons and transverse pontocerebellar fibers with sparing pontine tegmentum and corticospinal tracts. This neurodegeneration follows a 4-point visual grade on MR imaging, where grade 0 (no changes), grade 1 (a relatively hyperintense vertical line in comparison to the horizontal line which is beginning to appear), grade 2 (only a clear vertical line is visible), grade 3 (a horizontal line is beginning to appear following the appearance of a vertical line) and grade 4 (prominent and complete HCBS).5 However, delayed appearance of the sign in cases with a vascular etiology has suggested the role of Wallerian degeneration or gliosis of the pontocerebellar fibers. In case of infectious etiologies, the pathogenesis of the HCBS is rather different. For instance, in variant Creutzfeldt Jakob disease, neuronal loss, plaques with spongiform changes, and astrocytosis has been described. Whereas in progressive multifocal leukoencephalopathy, the granule cell layer has been considered to be involved. In natalizumab-associated multifocal leukoencephalopathy, a variant of the HCBS named the “across the pons” sign has been described. This consists of a linear T2-hyperintensity across the rostral pons with some intersecting T2-hyperintensity anteriorly.6 Another variant is the “reverse” HCBS, that is observed as a cruciform hypointensity quadrisecting the pontine hyperintensities and has been reported in pontine infarcts,7 Wilson disease,8 and primary progressive aphasia.9 Finally, and perhaps of most interest is the association with an inflammatory etiology wherein radiological recovery of the HCBS post immunomodulation strongly indicates an alternative pathophysiology. A majority of the new conditions associated with the HCB are rare and have been described only in a few case reports. Taking into account that the differential diagnoses of the HCBS include numerous conditions, it is of importance to conduct detailed clinical evaluations taking into consideration the predominant clinical manifestations, age at disease onset, patterns of progression of the illness, as well as findings in complementary investigative procedures and additional imaging hallmarks. Studies aimed at differentiating cerebellar ataxias based on pontine MRI findings have reported that the HCBS had a high specificity of 98% to 99% and a high positive predictive value of 94% to 99% for MSA-C, but the sensitivity was only 45% to 68%.10, 11 The rapidity of developing HCBS has been suggested to aid in differentiating MSA from ATX-ATXN3 (SCA3). A grade 2 HCBS has been observed in 66.7% of those with MSA-C withing 3 years of disease onset, but not in those with ATX-ATXN3 (SCA3).12 Therefore, if present, the HCBS is suggestive of MSA, especially if other core and/or supportive clinical and radiological features of MSA are present.13 However, in adult patients who do not fulfill the diagnostic criteria for MSA,13 the diagnostic process should include consideration of the remaining causes of HCBS. It is worth noting that some of these conditions, such as some cerebellar ataxias or anti-Homer 3, and anti Kelch like protein 11 immune-mediated disorders can mimic the MSA-C phenotype and do not necessarily have a rapid progression.14 With the plethora of new etiologies being associated with the HCB, it is imperative to remember the adage, “when you hear hoofbeats, think of horses, not zebras.” Irrespective of new additions to the conditions associated with the HCBS, MSA should always feature at the top of the list of differentials unless proven otherwise. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the first draft, B. Review and Critique. SP: 1A, 1B, 1C, 3A, 3B. MR: 1A, 1B, 1C, 3A, 3B. Ethical Compliance Statement: The authors confirm that the approval of an Institutional Review Board was not required for this work. Informed written consent was obtained from the patient. We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflict of Interest: No specific funding was received for this work and the authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report.

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