Abstract
Background
Superficial siderosis is a rare neurodegenerative disease caused by hemosiderin deposition on the brain surface. Although the efficacy of the iron chelator—deferiprone—in superficial siderosis has recently been documented, a comparative study of patients who underwent surgical ablation of their bleeding source and subsequently received treatment with or without deferiprone has not yet been conducted.
Methods
Fifteen postoperative patients with superficial siderosis were recruited, and seven patients were administered deferiprone (combination therapy group). Quantitative changes in the hypointense signals on T2*-weighted magnetic resonance images were acquired; additionally, cerebellar ataxia was assessed (International Cooperative Ataxia Rating Scale score and Scale for the Assessment and Rating of Ataxia). Audiometry was performed and the results were compared with those of patients who did not receive deferiprone (surgical treatment group; controls).
Results
Significant improvements in signal contrast ratios were noted in the lateral orbitofrontal gyrus, superior temporal lobe, insular lobe, brainstem, lingual gyrus, and cerebellar lobe in the combination therapy group. The scores of patients in the combination therapy group on the cerebellar ataxia scales significantly improved. The degree of signal improvement in the cerebellar lobe correlated with the improvement of cerebellar ataxia scores. Early deferiprone administration after disease onset and long-term administration were correlated with greater signal improvements on magnetic resonance imaging. No adverse effects were observed in the clinical or laboratory parameters.
Conclusions
Deferiprone administration significantly improved radiological and clinical outcomes in patients with postoperative superficial siderosis. Earlier and longer courses of deferiprone could result in better patient prognosis.
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Data sharing statement
Anonymized data are presented as supplementary data.
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Acknowledgements
The authors would like to thank Drs. Takamori Takeda and Takeshi Tsutsumi of the Department of Otolaryngology at Tokyo Medical and Dental University (TMDU) for performing auditory evaluation tests, Drs. Toshitaka Yoshii and Atsushi Okawa of the Department of Orthopedic and Spinal Surgery at TMDU for surgical treatments, as well as the patients with superficial siderosis and their family members for providing important clinical information.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Authors and Affiliations
Contributions
YN analyzed the data and wrote the draft. I. Uwano analyzed the data and revised the manuscript. UT acquired the data and revised the manuscript. MS analyzed the data and revised the manuscript. TY supervised the study and revised the manuscript. NS designed the study, acquired the data, wrote, and finalized the manuscript, and coordinated and supervised the research. All authors critically read and approved the final manuscript.
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Conflicts of interest
The authors declare that they have no conflict of interest.
Ethical approval
The protocol followed all ethical requirements and was approved by the Institutional Ethics Committee of the Tokyo Medical and Dental University (ID: R2018-026); written informed consent was obtained from all participants. This study was performed in accordance with the ethical standards laid down by the 2013 Declaration of Helsinki.
Supplementary Information
Below is the link to the electronic supplementary material.
415_2021_10844_MOESM1_ESM.tif
Figure S1. Signal reduction of MRI hypointensity signals in T2*-weighted MR images in the combination therapy group. Axial views of T2*-weighted MR images before (figure on the left in each panel) and after (figure on the right in each panel) deferiprone administration in the combination therapy group. White arrows and arrowheads indicate brain areas showing significant signal reduction on MR images, which were quantitatively confirmed following deferiprone administration in the brainstem (arrowheads), cerebellar lobe (arrows) (A), superior temporal lobe (arrows), lateral orbitofrontal gyrus (arrowheads) (B), and lingual gyrus (arrows) (C). MRI, magnetic resonance imaging; MR, magnetic resonance
415_2021_10844_MOESM2_ESM.tif
Figure S2. Signal deterioration of MRI hypointensity in the surgical treatment group. Axial views of T2*-weighted MR images before (figure on the left in each panel) and after (figure on the right in each panel) the observational period in the surgical treatment group. Arrows and arrowheads indicate significant signal increase in hypointensity on T2*-weighted MR images, which was quantitatively confirmed in the cerebellar lobe (arrows) (A), inferior occipital lobe (arrows) (B), hippocampus (arrows) (C), fusiform (arrows) (D), lingual gyrus (arrows), superior temporal lobe (arrowheads), insular lobe (black arrowheads) (E), cuneus (arrows), cingulate gyrus (arrowheads) (F), and precuneus (arrows) (G). MRI, magnetic resonance imaging
415_2021_10844_MOESM3_ESM.tif
Figure S3. Clinical severity changes in cerebellar ataxia and hearing ability in the combination therapy and surgical treatment groups. The score reduction of ICARS (A) indicates clinical recovery in all patients in the CG, and the score reduction of SARA (B) indicates clinical recovery in all patients except one. Of the patients in the SG, 5/6 showed an increase in the ICARS score (A), and 3/5 showed an increase in the SARA score (B). A relatively stable hearing threshold was observed in patients in the CG (C). ICAR, International Cooperative Ataxia Rating Scale; SARA, Scale for the Assessment and Rating of Ataxia; CG, combination therapy group; SG, surgical treatment group
415_2021_10844_MOESM4_ESM.tif
Figure S4. Spearman’s rank correlation between the change in hypointensities on T2*-weighted MR images and background factors of participants. The vertical line shows the hypointense signal change ratio (A-D, ([CR at F/U – CR at baseline] / interval period of MRI scans (years)) and the degree of change in the hypointense signal (E, CR at F/U – CR at baseline) on T2*-weighted MR images, and the horizontal line shows the number of months. The hypointense signal change ratio on T2*-weighted MR images correlated with the duration between disease onset and administration in the fusiform (A), inferior occipital lobe (B), lingual gyrus (C), and cingulate gyrus (D). The degree of change in the hypointense signal in the parahippocampal gyrus correlated with the administration period (E). MRI, magnetic resonance imaging; MR, magnetic resonance; CR, contrast ratio; F/U, follow-up
415_2021_10844_MOESM5_ESM.tif
Figure S5. Significant signal improvement of hypointensity on MRI in the CG (cerebrospinal fluid reference). We compared the degree of hypointense signal change on T2*-weighted MR images of each brain area using signal of cerebrospinal fluid as a reference, in the CG and SG using the Mann–Whitney U test. The vertical axis indicates a signal change and a positive value indicates a decrease in the hypointensity signal (improvement) on T2*-weighted MR images. A significantly increased signal change was achieved by deferiprone administration in the parahippocampal gyrus (A), lingual gyrus (B), cerebellar lobe (C), and brainstem (D) in the CG. CG, combination therapy group; SG, surgical treatment group; MR, magnetic resonance
415_2021_10844_MOESM6_ESM.tif
Figure S6. Clinical recovery of cerebellar ataxia associated with radiological improvement in the cerebellar lobe (cerebrospinal fluid reference). Cerebellar ataxia was evaluated using the ICARS in the CG. The hypointense signal of T2*-weighted MR image was evaluated using signal of cerebrospinal fluid as a reference. The degree of change in ICARS was correlated to the hypointense signal change on T2*-weighted MR images in the cerebellar lobe. I. CARS, International Cooperative Ataxia Rating Scale
415_2021_10844_MOESM7_ESM.tif
Figure S7. Spearman’s rank correlation between the change in hypointensities on T2*-weighted MR images (cerebrospinal fluid reference) and background factors of participants. The vertical line shows the hypointense signal change ratio (A and B, ([CR at F/U – CR at baseline] / interval period of MRI scans (years)) and the degree of change in the hypointense signal (C, CR at F/U – CR at baseline) on T2*-weighted MR images, and the horizontal line shows the number of months. The hypointense signal of T2*-weighted MR image was evaluated using signal of cerebrospinal fluid as a reference. The hypointense signal change ratio on T2*-weighted MR images correlated with the duration between disease onset and administration in the fusiform (A) and cerebellar lobe (B). The degree of change in the hypointense signal in the parahippocampal gyrus correlated with the administration period (C). MRI, magnetic resonance imaging; MR, magnetic resonance; CR, contrast ratio; F/U, follow-up
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Nose, Y., Uwano, I., Tateishi, U. et al. Quantitative clinical and radiological recovery in post-operative patients with superficial siderosis by an iron chelator. J Neurol 269, 2539–2548 (2022). https://doi.org/10.1007/s00415-021-10844-8
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DOI: https://doi.org/10.1007/s00415-021-10844-8