Background: Considerable spinal cord (SC) atrophy occurs in multiple sclerosis (MS). While MRI-based techniques for SC cross-sectional area (CSA) quantification have improved over time, there is no common agreement on whether to measure at single vertebral levels or across larger regions and whether upper SC CSA can be reliably measured from brain images.Aim: To compare in a multicenter setting three CSA measurement methods in terms of repeatability at different anatomical levels. To analyze the agreement between measurements performed on the cervical cord and on brain MRI.Method: One healthy volunteer was scanned three times on the same day in six sites (three scanner vendors) using a 3T MRI protocol including sagittal 3D T1-weighted imaging of the brain  and of the SC. Images were analyzed using two semiautomated methods [NeuroQLab (NQL) and the Active Surface Model (ASM)] and the fully automated Spinal Cord Toolbox (SCT) on different vertebral levels  on SC and brain images and the entire cervical cord (C1–C7) on SC images only.Results: CSA estimates were significantly smaller using SCT compared to NQL and ASM (p < 0.001), regardless of the cord level. Inter-scanner repeatability was best in C1–C7: coefficients of variation for NQL, ASM, and SCT: 0.4, 0.6, and 1.0%, respectively. CSAs estimated in brain MRI were slightly lower than in SC MRI . Despite protocol harmonization between the centers with regard to image resolution and use of high-contrast 3D T1-weighted sequences, the variability of CSA was partly scanner dependent probably due to differences in scanner geometry, coil design, and details of the MRI parameter settings.Conclusion: For CSA quantification, dedicated isotropic SC MRI should be acquired, which yielded best repeatability in the entire cervical cord. In the upper part of the cervical cord, use of brain MRI scans entailed only a minor loss of CSA repeatability compared to SC MRI. Due to systematic differences between scanners and the CSA quantification software, both should be kept constant within a study. The MRI dataset of this study is available publicly to test new analysis approaches. Spinal cord (SC) atrophy assessment in neurological diseases such as multiple sclerosis (MS) has gained important attention over the past years –3. TechnMost of the studies concentrated on CSA measurements in the upper cervical regions including individual levels at the C2/C3 vertebra  or largeIn this multicenter single-subject study, we aim at identifying a common and reliable regional level of CSA measurement by comparing different software methods with respect to variability and systematic differences at different cervical cord levels using brain and cord MRI. We intend to widen the scope of previous comparable studies by including other software tools, more SC levels, and a larger number of different scanners , 22. TheIn addition, the current work provides a publicly available reference MRI dataset to the research community, containing single-subject, multicenter, repeated volumetric acquisitions of the brain and cervical SC in a healthy volunteer.A single healthy volunteer  underwent multiple repeated MRI scans at six different European centers with high expertise in MRI for MS. The scans at a given site were acquired during a single visit. At all scanners, the time of examination was in the afternoon between 3:00 and 7:00 p.m., thus minimizing the effects of potential daytime-dependent fluctuations of the SC volume. The acquisitions at five of the centers took place between March 2015 and February 2016 and at center 6 in January 2017. Given the limited time period and the age of the healthy volunteer, we assumed that the true CSA could be considered stable between the scans given the slow cervical cord atrophy rate in healthy controls .The participant gave written informed consent to take part in the repeated MRI acquisitions at different centers both for the use of the anonymized MRI data for scientific purposes within the scope of the present study and for sharing the data with the research community. At each site, the MRI acquisitions reported in the present study were conducted after signed informed consent of the volunteer and with the approval of ethics boards of the involved institutions.3, and accepted magnetization-prepared, high-contrast 3D T1w gradient-echo imaging according to the local expertise and the specific software/hardware available in each of the participating centers. Thus, the study design was intended to reflect a real-world multicenter scenario without the exact specification of the sequence design and timing. All scans were performed using 3-Tesla scanners . All sites used the vendor-specific 3D distortion correction procedures to correct for non-linear gradient distortion effects .The anonymized MRI datasets of brain and cervical cord MRI used in this study are freely available for scientific research upon request to MAGNIMS . In addition to this fully automated approach, two semiautomated methods requiring manual interaction were chosen: the ASM, available with costs with the Jim Software package   , 7 and tpse.com) , 25.SCT features specific segmentation tools for the SC. The segmentation algorithm PropSeg is based on an iterative propagation of a deformable model with an adaptive contrast mechanism , 26. AutThe ASM, which is implemented as the cord finder tool in the JIM software package, requires interactive marking of the center of the cord on a regular distance along several vertebral levels to be included in the analysis . Cord ceNQL requires the user first to interactively define the section of the cord to be analyzed by placing an oblique plane through the dataset, which runs through the upper and lower end of the section . This isThe definition of the cord contour and rules for inclusion or exclusion of voxels located on the edge between cord and CSF may account for a substantial proportion of the segmented volume, given the limited image resolution and the small diameter of the SC. This aspect is handled differently between the software methods and may contribute to systematic differences between the CSA estimates generated with different algorithms , 17. WhiAdditionally, effects of the cervical cord curvature are treated differently between NQL and ASM or SCT. While ASM and SCT are optimized with regard to variations of the cord curvature , 5, NQL CSA measurements were performed in different sections of the cervical cord, which were defined by anatomical markers. In all measurement setups, CSA represented the mean cross-sectional cord area within the chosen cord segment. Sections were chosen according to previously published procedures , 17, 25 In the semiautomated methods (ASM and NQL), the C1–C2 and the C1–C7 sections were manually defined using the top of the dens and the endplate of the corresponding caudal vertebra (C3 or C7) as anatomical references for the upper and lower boundaries, respectively , 25. TheIn SCT, the C1–C2 and C1–C7 sections were defined according to the automated vertebral labeling of the cord, which is part of the SCT algorithms . Since cThe results of all methods were visually inspected for segmentation errors, false vertebra labeling (in case of SCT), or image artifacts. Two SCT measurements were excluded from the analyses due to erroneous segmentations. The C1–C7 CSA measurements of one center (site 6) were corrupted by infolding artifacts of the shoulders. We excluded these C1–C7 CSA estimates for all software methods. Only for this center, SCT segmentations in the C1–C2 and C2/3 sections were initiated by choosing the C2/C3 vertebral disc as a starting point for the segmentation to avoid PropSeg starting in the (lower) part of the image that contains image artifacts.UT) between cord and CSF, controlling for differences between sites regarding the acquisition duration of the T1w sequences  were determined in the T1w MRI images. We placed ROI in the cervical cord at the C1–C2 level, the C2/3 level, the C5–C7 vertebral level, and in regions of the adjacent CSF using standard diagnostic image viewer tools. For this purpose, we used ovoid size-adapted contours placed well within the cord or CSF, each at the height of the level in question. The size of the ROIs was adjusted to cover as large an area as possible excluding the interface between cord tissue and CSF. For the C1–C2 cord level, the corresponding CSF ROI was placed within the cerebellomedullaris cistern, while for the C2/C3 and C5–C7 cord levels, the corresponding CSF ROIs were positioned in adjacent areas between the cord and the vertebral body .p < 0.05.Statistical analyses were performed using the software package SPSS . Results were considered statistically significant when associated with scans). The MMOD was calculated separately for each software method and cord level in brain and SC MRI.To describe the smallest difference between two CSA measurements that could be detected in this multicenter setting with different scanners [named mean maximum observed difference (MMOD)], we determined the maximum of the absolute differences between the CSA results of the three repeated scans and averaged it across all centers  of the three repeated scans using the formula, standard deviationSince the requirements of normal distribution and equality of variances of CSA within the group variables software methods, cord levels, and acquisition type (brain or SC MRI) were not met, we used non-parametric tests throughout the statistical analyses.We checked for within-subject differences between the scan repetitions by using Wilcoxon signed rank tests for paired samples for the comparison of scan no. 1 with scan no. 2 (simple repetition) and scan no. 2 to scan no. 3 . By testing separately for each software method and cord level in brain and SC MRI, we detected no significant differences between the scan repetitions. Therefore, we did not include the scan repetition number as a factor in further statistical analyses. Given our atypical study design with only one subject, we rather handled the scans as independent measurements.Post-hoc pairwise comparisons included Dunn's post-hoc tests with Bonferroni adjustment for multiple comparisons. In these analyses, the CSA estimates were aggregated across centers and scan repetitions.We assessed group differences of CSA between the software methods separately for MRI acquisition type (brain or cord) and cervical cord level  by using Kruskal–Wallis tests. Group differences between brain and cord MRI of CSA and group differences of the CV of CSA were assessed separately for the software methods and the C1–C2 or C2/3 level using Wilcoxon signed rank tests for paired samples. Therein, the CSA estimates were aggregated across centers and scan repetitions.N = 6 measurements each). We applied Kruskal–Wallis tests with post-hoc comparisons between pairs of sites adjusted for multiple comparisons with Dunn's post-hoc tests and Bonferroni adjustment.We investigated differences of CSA between sites at the C1–C2 or C2/3 cord levels separately for each software method while aggregating measurements of brain and cord MRI  differed significantly between the centers. When comparing the cord levels within each scanner, CNRUT was similar between the C1–C3 and C2/3 cord levels in brain and cord MRI, while there was lower CNRUT in the caudal parts of the images (C3–C5 cord level). In particular, for the dedicated cord acquisitions, the CNRUT was higher in the Philips scanners  than that in the Siemens and GE scanners. Details are shown in In total, 36 datasets, respectively, 18 pairs of brain  and dedicated SC scans, were acquired in six centers using 3-Tesla MRI scanners of different vendors . The SC As a first step, we compared the CSA results aggregated across all scanners at different measurement settings  according to a multicenter scenario with different scanner types. Two CSA estimates using SCT at the C2/3 level and three measurements at the C1–C7 level were excluded from the analyses due to erroneous segmentations and infolding artifacts, respectively .p < 0.001) (p = 0.001), and CSA estimates at the C2/3 vertebral level were lower when using NQL than those when using ASM (p < 0.001).< 0.001) . CSA res2 (The repeatability of CSA across centers (inter-scanner) was best for NQL and ASM measured over the entire cervical cord (C1–C7) reflected by low CV of 0.4 and 0.6% and low MMOD of 0.6 and 0.9 mm2 . Regardi2 .The repeatability was similar for the semiautomatic methods (ASM and NQL) using brain or cord MRI at all levels, except for the C2/3 level in cord MRI, where ASM had a higher MMOD and CV than those for NQL. For the SCT method, the MMOD and CV were higher than those for NQL and ASM at the C1–C2 level and in the entire cervical cord. At the C2/3 level, the repeatability of SCT was superior to that of ASM using cord acquisitions and superior to that of both semiautomatic quantification techniques  using brain acquisitions  were significantly smaller than those from dedicated cord acquisitions at the same cord levels, except for the SCT method at the C2/3 level ,Figure 42 at the C1–C2 level and −4.7 to 0.2 mm2 at the C2/3 level), with best agreement at both cord levels and for all software methods in the GE scanner (site nr. 5) and the Siemens scanner (site nr. 6), which both have a long magnet design (198 cm). In the combined results from all scanners, the mean differences between brain and cord scans ranged between −2.0 and −0.9 mm2 at the C1–C2 level and between −1.4 and −0.8 mm2 at the C2/C3 level, depending on the software method used. Specifically, the brain–cord acquisition differences at the C1–C2 level seemed larger when using SCT compared to those when using NQL or ASM, while they were smaller for SCT compared to those for ASM and NQL at the C2/3 level.In a further analysis, we investigated the differences between CSA results of brain and cord MRI separately for each center. post-hoc comparisons between pairs of sites adjusted for multiple comparisons by aggregating measurements of brain and cord MRI (N = 6 measurements at each center). The results are depicted in p > 0.050) for ASM and NQL at the C1–C2 level. Overall, there were no significant inter-center differences for SCT at both cord levels and for NQL and ASM at the C2/3 cord level.Between-center agreement of CSA at the C1–C2 or C2/3 cord levels was assessed separately for each software method using Kruskal–Wallis test with Quantification of CSA has gained increasing attention over the past years, and techniques assessing CSA have improved in terms of robustness and reproducibility. However, to be successfully established in multicentric MS studies, CSA quantification still lacks harmonized procedures, e.g., agreement on a common vertebra level region to be measured.In the present traveling volunteer study, we studied three popular fully automated and semiautomated techniques for CSA assessment  at different cervical cord regions derived from brain and SC scans of a single healthy volunteer scanned at six different European MS centers in order to propose a common cord level for reliable CSA assessment. Our results were in agreement with the findings of recent studies that showed good concordance between results of brain and SC MRI using the NQL method in the upper cervical cord and extended these assessments by including other software tools and SC levels and a larger number of different scanners , 22.The CSA results were dependent on the software used and, as expected, on the cord region included in the evaluation. Repeatability, especially across centers, was best when scanning the entire cervical cord. Agreement was better between similar types of approaches  than between different types  techniques, as we observed lower CSA values when using a fully automated approach regardless of the vertebra level used.In concordance with a recent study , absolutSince CSA varies in the cranio–caudal direction across the cervical SC, the exact choice of the cord level has a major influence on the absolute CSA results  16, 33), 3316, 3In the multicentric analysis across the six centers, the repeatability was best when assessing the entire cervical cord  and slightly worse in the upper portion of the cervical cord . FurtherSegmentation of the C2/3 cord level regarding a small 3-mm cord section [comparable to the classical method proposed by Losseff et al. ] led to In addition to these cord section-dependent effects, the variability of CSA values in a multicentric analysis can partly result from different image qualities between the centers, as reflected by differences of the cord-to-CSF contrast . DespiteComparison between brain and cord CSA estimates at the same levels showed for all software methods used slightly lower CSA when using brain MRI. Different factors can contribute to differences in the CSA results of brain and SC MRI: one is based on gradient non-linearity distortions that may become relevant at the edges of the magnet especially in modern short-bore scanners. This may particularly influence the CSA quantification based on brain MRI, since the upper cervical cord is located off-center in the sagittal images, at the periphery of the field of view. A thorough analysis of these effects and possible ways of compensating or avoiding their impact on CSA measurements has recently been published , which sThis study considered only one healthy traveling volunteer. A limitation of the study results is given by reduced SC MRI image quality due to infolding artifacts in one of the centers, leading to a slightly reduced statistical power of the SC MRI evaluations. Furthermore, it would have been preferable to have more than one healthy participant in this reproducibility study.The comparability of the results and the reproducibility in the different measurement constellations could have been further improved if procedures were used to ensure that the evaluation takes place in exactly the same regions . In this study, we have limited the evaluations to using the individual methods “as is” and to aligning the regions only on the basis of anatomical markers. We think that this corresponds more to the typical situation in larger studies where a decision has to be made for a certain method.spine generic protocol, https://spinalcordmri.org/protocols). This generic SC protocol has successfully been implemented in 42 MRI centers worldwide in order to generate a harmonized multi-subject dataset . The choice of the optimal method may depend on the number of patients included in the study. Furthermore, the use of SCT may be beneficial because it is freely available for scientific purposes, while NQL can be used upon request to Mevis, and ASM is distributed with costs.Since the absolute CSA results of the different software methods and the different cord levels deviate considerably from each other, it is important to keep the acquisition and post-processing methodology identical within a study and to report these study details in publications. When comparing CSA results of different publications, absolute results should be regarded carefully, considering different evaluation methods. Longitudinal rates of change of CSA might be less sensitive to these methodological effects. On the other hand, longitudinal analyses can also entail specific problems that may affect the accuracy of CSA measurements. For example, the quality of patient repositioning or possible hardware or software changes between follow-ups have to be taken into account.Center-dependent effects that have been detected in this traveling-volunteer reproducibility study have to be considered when pooling data from different centers. Differences in scanner geometry, coil design, and variability of image contrast have effects on CSA estimates and thereby limit the sensitivity to detect small disease-related cervical cord changes in multicentric studies.Further longitudinal studies on MS patients and healthy controls to be acquired at different centers are warranted to further optimize cord levels and software tools for CSA quantification in multicentric studies.https://www.magnims.eu/magnims-cord-dataset).The datasets analyzed for this study are freely available for scientific research upon request to MAGNIMS  and was reviewed and approved by the local ethics boards of the involved institutions. At each site, the MRI acquisitions reported in the present study were conducted after signed informed consent of the participant, who gave their written informed consent to take part in the repeated MRI acquisitions at different centers, both for the use of the anonymized MRI data for scientific purposes within the scope of the present study and for sharing the data with the research community. The institutional review boards were 1) Ospedale San Raffaele; Milano, Italy: Ethics Review Board of IRCCS San Raffaele Scientific Institute, Milan, Italy. 2) St. Josef Hospital, Ruhr-University of Bochum; Bochum; Germany: Ethics Commision of the Medical Faculty of the Ruhr-University Bochum, Bochum, Germany. 3) Hospital Universitari Vall d'Hebron Barcelona; Spain: Research Ethics Committee (REC) of the University Hospital Vall d'Hebron, Barcelona, Spain. 4) University College London; London; Great Britain: London - Harrow Research Ethics Committee (REC), London, Great Britain. 5) VU University Medical Center; Amsterdam; The Netherlands: Medical Ethics Review Board of the Amsterdam UMC University Medical Centers , Amsterdam, The Netherlands. 6) Basel University Hospital; Basel; Switzerland: Ethics Committee Northwest and Central Switzerland , Basel, Switzerland).CL, HV, and FB: conceptualization. CL, HV, IB, ÀR, MR, and FP: methodology. CL, BB, IB, FP, and MR: software. CL, BB, and HV: formal analysis and writing–original draft. CL, PV, KP, ÀR, DP, and MY: investigation. CL, HV, IB, FB, LK, ÀR, MF, and CG: resources. CL, FP, JS-G, CG, and HV: data curation. CL, BB, FP, PV, KP, IB, DP, ÀR, JS-G, CG, LK, MR, MF, MY, FB, and HV: writing–review & editing. CL, BB, HV, and IB: visualization. LK, ÀR, FB, MF, CL, and MR: supervision. CL: project administration. All authors contributed to the article and approved the submitted version.The members of the MAGNIMS Study Group Steering Committee are: F. Barkhof and H. Vrenken, VU University Medical Center, Amsterdam, Netherlands; O. Ciccarelli and T. Yousry, Queen Square MS Center, UCL Institute of Neurology, London, UK; N. De Stefano, University of Siena, Siena, Italy; C. Enzinger, Department of Neurology, Medical University of Graz, Graz, Austria; M. Filippi and M. A. Rocca, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy; C. Gasperini, San Camillo-Forlanini Hospital, Rome, Italy; L. Kappos, University of Basel, Basel, Switzerland; J. Palace, University of Oxford Hospitals Trust, Oxford, UK; A. Rovira and J. Sastre-Garriga, Hospital Universitari Vall d'Hebron, Universitat Aut‘onoma de Barcelona, Barcelona, Spain.CL received a research grant by the German Federal Ministry for Education and Research, BMBF, German Competence Network Multiple Sclerosis (KKNMS), grant no. 01GI1601I, has received consulting and speaker's honoraria from Biogen, Bayer, Daiichi Sanykyo, Merck Serono, Novartis, Sanofi, Genzyme and TEVA. BB reports financial support by the German Federal Ministry for Education and Research, BMBF, German Competence Network Multiple Sclerosis (KKNMS), grant no. 01GI1601I. FP has received grants from MRC and the NIHR biomedical research center at UCLH, outside the submitted work. PV reports speaker honoraria from Biogen and ExceMed, outside the submitted work. IB is supported by research grants from Teva Pharmaceuticals, Merck Serono, Novartis Pharma and the Dutch MS Foundation (grants to HV and FB), outside the submitted work. DP has received honoraria as speaker from Novartis and Genzyme, and a grant by Biogen, outside the submitted work. ÀR reports personal fees from Novartis, Sanofi-Genzyme, Bayer, Roche, Biogen, Neurodiem, Bracco, Merck Serono, Teva Pharmaceuticals, and Icometrix; and non-financial support from SyntheticMR, outside the submitted work. JS-G reports grants and personal fees from Sanofi Genzyme; and personal fees from Almirall, Biogen, Celgene, Merck Serono, Novartis, Roche, and Orchid Pharma and Biopass, outside the submitted work; and is member of the Editorial Committee of Multiple Sclerosis Journal and director of the Scientifi Committee of Revista de Neurologia. CG receives research grants outside the submitted work from ISRT, EPSRC, Wings for Life, UK MS Society, Horizon2020, Biogen and Novartis; is editorial board member of Functional Neurology. LK reports personal fees from Actelion, Addex, Biotica, Celgene Receptos, Sanof Genzyme, Eli Lilly, Mitsubishi, Ono Pharmaceutical, Pfier, Sanofi Santhera Pharmaceuticals, Siemens, Teva Pharmaceuticals, UCB, and XenoPort; grants and personal fees from Bayer HealthCare Pharmaceuticals, Biogen, Merck Serono, and Novartis; and grants from F Hoffann-La Roche, EU, Innoswiss, Roche Research Foundation, Swiss Multiple Sclerosis Society, and Swiss National Research Foundation, outside the submitted work. MR reports personal fees from Biogen, Novartis, Sanofi Genzyme, Teva Pharmaceuticals, Merck Serono, and Roche, outside the submitted work; and receives research support from the Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla. MF reports personal fees from Biogen, Merck Serono, Novartis, and Teva Pharmaceuticals, outside the submitted work; receives research support from Biogen, Merck Serono, Novartis, Teva Pharmaceuticals, Roche, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and Fondazione Italiana di Ricerca per la SLA; and is editor-in-chief of the Journal of Neurology. FB received, outside the submitted work, compensation for consulting services by Bayer, Biogen; receives research support from Biogen, GE Healthcare, IMI-EU IXICO Ltd., Merck-Serono, Roche, The Dutch Foundation MS Reserach; he is Editor in chief of “Clinical Neuroradiology - The ESNR textbook”. HV reports grants and consulting fees paid directly to their institution from Merck Serono and Novartis, and grants from Teva Pharmaceuticals, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a novel distinct epileptogenic neoplasm, and its clinical, imaging, histopathological, and molecular features were already known in the existing literature. We aimed to analyze the surgical management of PLNTY combined with these known characteristics.Eight patients underwent surgical treatment in our center between December 2017 and December 2020, and the postoperative pathology was diagnosed as PLNTY. Their clinical data, imaging, pathological, molecular characteristics, and seizure outcome were retrospectively analyzed. Follow-up evaluations and a literature review were performed.The 8 patients included 1 woman and 7 men, aged between 5 and 51 years old . The preoperative symptoms of all 8 cases were seizures. Four tumors were situated in the temporal lobes, and one of the four extratemporal tumors was in the occipital lobe and three were in the frontal lobe. Enlarged and gross total resections were performed in 2 cases and the other 6 cases, respectively. All cases exhibited intense labeling of CD34, and absence of 1p/19q codeletion and IDH1 or IDH2 mutation. B-Raf proto-oncogene (BRAF) V600E mutation was presented in 4 (66.7%) of 6 detected cases. The postoperative seizure outcome of Engel class I was achieved in 6 cases (75%).PLNTY represents distinctive histologic, immunophenotypic and biomolecular features, and has high epileptogenicity. Early surgical intervention and enlarged resection of PLNTY associated with epilepsy will help to improve the postoperative seizure-free rate. Polymorphous low-grade neuroepithelial tumor of the young (PLNTY), a rare variant of the low-grade neuroepithelial tumor, was first described in 2017 by Huse et al. . SimilarPLNTY is often encountered in children and young adults, involving the temporal lobe –19. As fPLNTY was included as a newly recognized tumor type in the 2021 WHO classification of tumors of the central nervous system, and was assigned to WHO grade I . HoweverThis study retrospectively reviewed the medical records, surgical procedures, radiological, pathological, and molecular data of 8 cases with PLNTY who underwent surgery at our center from December 2017 to December 2020. Individualized presurgical evaluations, namely, history, symptoms, brain CT and MRI, detailed evaluation of seizure semiology, and long-term video-EEG monitoring, were performed in all patients. The MRI examinations used sequences, namely, conventional T1WI and T2WI sequence, T2 fluid-attenuated inversion recovery (T2 Flair) sequence, and T1WI after gadolinium enhancement. The radiological examination was reviewed by two independent neuroradiologists.All surgical plans were individually tailored. Preoperative video-EEG monitoring of epileptiform discharges in ictal or interictal periods was used to confirm the correlation between the occurrence of seizure and tumor. 3D image processing based on MRI to display the precise location of the tumor, adjacent structures of the tumor, and the shape of gyrus, aimed to plan a suitable surgical approach and resection range to increase the total tumor resection rate. Furthermore, MR-based neuronavigation and intraoperative electrocorticography (ECoG) were used during surgery. The tumor resection range was categorized as gross total resection , subtotal resection , partial resection , and enlarged resection (ER). The enlarged resection included resection of tumors and peripheral cortex with abnormal discharge, which was conducted with the guide of intraoperative ECoG during surgery. Intraoperative ECoG identified abnormal spiking outside the tumor margin, and abnormal discharges remained in the peritumoral cortex after gross tumor resection, which guided us to perform ER.The surgically resected tissues were fixed in paraffin with formaldehyde and stained with hematoxylin–eosin to observe their microscopic appearance. The streptavidin–biotin peroxidase complex method was used to conduct the immunohistochemical studies included the following antibodies: glial fibrillary acidic protein (GFAP), CD34, oligodendrocytic transcription factor 2 (Olig-2), soluble protein-100 (S100), synaptophysin (Syn), neurofilament (NF), neuronal nuclear antigen (NeuN), P53, Ki-67, α-thalassemia mental retardation X-linked (ATRX), and mutant isocitrate dehydrogenase 1/2 (IDH1/2). The pathological examination was performed by two experienced neuropathologists.in situ hybridization (FISH), and the real-time PCR technique was utilized for detecting BRAF V600E gene mutation, using AmoyDx BRAF V600 Mutations Detection Kit and Applied Biosystems 7500 Real-Time PCR (Thermo Fisher Scientific). The internal control VIC signal of the tested samples should have an obvious amplification curve, and the Ct value should be between 13 and 21. If the FAM signal has an obvious amplification curve and the Ct value is less than 28, the sample does not need to be repeated, and the test result is positive for the BRAF V600E mutation; if the Ct value is ≥28, the test result is negative for the BRAF V600E mutation.The genomic DNA of the tumors was isolated from paraffin-embedded tissue samples. The 1p/19q deletion was detected by fluorescent The follow-up was conducted in the outpatient department every three months. Post-operative brain MRI was recommended to monitor the recurrence of the tumor, and seizure outcome was graded according to the Engel Outcome Scale : Engel cThe literature review was conducted by the search of the English literature related to PLNTY in PubMed up to December 2021. The keywords used in the search were  and (“PLNTY”). The cases with clinical data provided and pathologically proven as PLNTY were included. While, the papers were excluded when the full text was unavailable, or the cases reported by the papers had incomplete clinical data or were not pathologically determined as PLNTY.This study included 8 patients (seven men and one woman) with a mean age of 31.6 years (range between 5 and 51 years) at surgery, and 3 patients were older than 30 years. The preoperative symptoms were all partial epilepsy, and the duration of epilepsy ranged from 2 to 50 months, with a mean length of 17.4 months. Among them, 1 case (case a) received two or more first-line antiepileptic drugs (AEDs) treatment regularly, 3 cases received one AED and 4 cases were not formally treated with AEDs. No patient had a history of previous radiotherapy or surgery.The lesion locations were temporal lobe in 4 (50%) patients, frontal lobe in 3 (37.5%) patients, and occipital lobe in 1 (12.5%) patient. Among the 4 PLNTY located in the temporal lobe, none was in the mesial temporal lobe. Three lesions were located on the left side, and five lesions were located on the right side. Except in 3 cases , all lesions were superficially situated . The CT imaging showed a lesion-associated calcification in 6 cases (75%), while a cystic component in 4 cases (50%). A well-delineated region was present in all cases in MRI images. Save for two cases , the tumor manifested slightly hyperintensity in T1WI, all lesions demonstrated iso- or hypointensity in T1WI. Six cases demonstrated increased or mixed-signal on T2WI and 3 lesions manifested slight or partial enhancement in post-gadolinium T1WI. Only case d was associated with a slight mass effect and edema Figure 1The ER occurred in 2 (25%) cases, with lesions being located in the temporal lobe and occipital lobe respectively, and the other 6 (75%) cases achieved GTR. Both PR and STR were absent in this study. All patients recovered well postoperatively without immediate complication. The follow-up duration ranged between 11 and 42 months, with an average of 27 months, and no recurrence was observed in all the cases. Six patients (75%) were completely seizure-free (Engel class I) with or without AEDs, and the Engel class I of ER and GTR were achieved in 2 cases (100%) and 4 cases (66.7%) respectively Figure 2All tumors represented oligodendroglioma-like components arranged in an infiltrative manner with polymorphic cellular elements including pleomorphic and spindle cells, and have a round or oval nucleus with conspicuous perinuclear halo effects. Extensive microcalcification was identified in 6 of 8 cases. There were no typical elements of low-grade neuroepithelial neoplasms in all cases, such as myxoid microcysts, Rosenthal fibers, eosinophilic granular bodies, dysmorphic neuronal/ganglion cell forms, and neurocytic or ependymal rosettes. Peripheral focal cortex dysplasia (FCD) and neuronal vascular degeneration were present in case a who had preoperative drug-refractory epilepsy. The tumor necrosis and mitosis were absent in all cases Figure 3The patchy or widespread tumor cell expression of CD34 was demonstrated in all cases. Diffused positivity of Olig-2, expression of GAFP and ATRX were also manifested in 8 cases. Except for case c, which was focally and weakly positive for P53, the other cases had no overexpression of P53. The Ki-67 labeling index was below 2% in 6 cases, while that of case c and case h rose to 3 and 5%, respectively. IDH1 or IDH2 mutation and 1p/19q chromosomal codeletion were negative in all tumors. Six of the eight tumors in this study had qualified material for BRAF V600E mutations analyses, and BRAF V600E mutation was identified in four of six cases (66.7%) Figure 4PLNTY is a recently recognized low-grade neuroepithelial tumor with a distinct biological entity affecting children and young adults. The age of the 10 patients initially reported by Huse et al. ranged from 4 to 32 years, with an average age of 17.6 years . The ageThe radiological characteristics of PLNTY have been gradually recognized, such as well-circumscribed, heterogeneous intralesional signal, and peripheral cysts. Moreover, the calcification on CT images is its more prominent feature. These calcifications are mainly the pattern of prominent central calcification or a few lamellar calcifications located in the periphery of the lesion. Three of the 10 cases reported by Huse et al. had complete images, and all of them had obvious circular calcifications on CT , 8 casesThe pathological features of PLNTY were also gradually identified, namely, polymorphous appearance, the presence of oligodendroglioma-like cellular components, infiltrative growth pattern, and intense CD34 immunopositivity. Calcification is common in PLNTY, and the components of spindle, fibrous astrocytes and ependymoma-like pseudochrysanthemum clusters were also can be observed. Tumor mitosis, necrosis, and microvascular proliferation are rare in PLNTY. Eosinophilic granular bodies, myxoid microcysts, dysmorphic neuronal/ganglion cell forms, neurocytic or ependymal rosettes, and other characteristic structures were also absent in PLNTY, which can differentiate it from GG, DNET, PXA, and pilocytic astrocytoma. Intense and widespread tumor cell expression of CD34 is an immunohistochemical characteristic of PLNTY, however no specificity. The expression of CD34 can be observed in some LEATs, such as GG, DNET, and astrocytoma, and is also identified in regional cortical dysplasia which is associated with FCD. This is also the reason why this type of tumor has dual pathology and secondary epilepsy . On the In addition, 1p/19q codeletion and IDH1 or IDH2 mutation are typical molecular features in oligodendroglioma. However, PLNTY often exhibits no chromosome 1p/19q codeletion and absence of IDH1 or IDH2 genes. In our study, immunohistochemical examination showed IDH1 or IDH2 mutation was absent in all cases, and the lack of 1p/19q codeletion was also detected in all cases by FISH test. According to the genetic alterations of PLNTY, BRAF 600E mutation and FGFR2/FGFR3 fusions have been recurrently described, however mutually exclusive , 25, 26.PLNTY has been described as a benign tumor, so the PLNTY patients without epilepsy can be followed up, and close follow-up is necessary as the malignant transformation of PLNTY has been reported . On the Under the circumstances, the identification of the EZ is critical to postoperative seizure control. Stereotactic EEG (SEEG) may be an ideal choice to accurately identify the EZ, however will greatly increase the hospitalization costs of patients in clinical reality. Referring to our experience in other LEATs surgery, preoperative PET-MR image fusion can be utilized to observe the tumor and the surrounding low FDG uptake area, while surgical resection of these low FDG uptake areas may effectively improve the postoperative seizure-free rate. Certainly, further studies are necessary to determine its benefit in PLNTY surgery. In addition, intraoperative ECoG can also help to identify the EZ, as the application of intraoperative ECoG can significantly improve the outcome of seizure control , 32.PLNTY is a newly described low-grade neuroepithelial tumor which is often encountered in children and young adults. However, there are no specific diagnostic criteria of PLNTY because of the overlap of clinical, radiologic, histopathologic, and molecular characteristics between PLNTY and low-grade glioma or other mixed neuronal–glial tumors . These fThe original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.XRF, YY, JZ, WW, XK, RBQ, and CSN contributed to the conception and design of the study. XRF and YY organized the database. XRF performed the statistical analysis. XRF wrote the first draft of the manuscript. XRF, XK, and YY wrote sections of the manuscript. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Recent neuroimaging research has suggested that unequal cognitive efforts exist between interpreting from language 1 (L1) to language 2 (L2) compared with interpreting from L2 to L1. However, the neural substrates that underlie this directionality effect are not yet well understood. Whether directionality is modulated by interpreting expertise also remains unknown. In this study, we recruited two groups of Mandarin (L1)/English (L2) bilingual speakers with varying levels of interpreting expertise and asked them to perform interpreting and reading tasks. Functional near-infrared spectroscopy (fNIRS) was used to collect cortical brain data for participants during each task, using 68 channels that covered the prefrontal cortex and the bilateral perisylvian regions. The interpreting-related neuroimaging data was normalized by using both L1 and L2 reading tasks, to control the function of reading and vocalization respectively. Our findings revealed the directionality effect in both groups, with forward interpreting (from L1 to L2) produced more pronounced brain activity, when normalized for reading. We also found that directionality was modulated by interpreting expertise in both normalizations. For the group with relatively high expertise, the activated brain regions included the right Broca’s area and the left premotor and supplementary motor cortex; whereas for the group with relatively low expertise, the activated brain areas covered the superior temporal gyrus, the dorsolateral prefrontal cortex (DLPFC), the Broca’s area, and visual area 3 in the right hemisphere. These findings indicated that interpreting expertise modulated brain activation, possibly because of more developed cognitive skills associated with executive functions in experienced interpreters. As interlingual communication is growing rapidly, bilingual speakers interpreting from one language into another is becoming a widespread phenomenon. In interpreting practice, the issue of directionality has attracted wide attention , electroencephalography (EEG), and functional near-infrared spectroscopy (fNIRS) although no congruent results have been obtained in early neuroimaging studies , in executive control, such as working memory, cognitive flexibility, planning, inhibition, and abstract reasoning , fNIRS offers unsurpassed temporal resolution and provides quantitative hemodynamic information regarding oxyhemoglobin (HbO) and deoxyhemoglobin , and the other group consisted of non-interpreting students from East China Normal University, referred to as the non-interpreting group (NIG). This type of division among participants has been extensively used in previous translation/interpreting studies ( = 2.35), 19% of them were early bilinguals; whereas the final NIG consisted of 16 non-interpreting students , 25% of them were early bilinguals. The two groups were matched for a variety of language-related factors and working memory span but differentiated by interpreting experience  from TOEFL as L2 proficiency test, which is suggested by Hulstijn . Each poThe experiment was done in the lab at the School of Psychology and Cognitive Science, East China Normal University. All participants were in a healthy condition during the experimental period. No individuals with reported histories of medical illness, neurological or psychiatric disorders were included in this study. All subjects were right-handed, as assessed by the Edinburgh Handedness Inventory  as stimuli, and the feasibility and reliability of sentence translation for the purposes of neuroimaging research have been demonstrated by a substantial number of studies , sight translation from English to Mandarin (BI), reading aloud in Mandarin (M), and reading aloud in English (E). Reading aloud English and Mandarin were performed as baseline tasks . Each task included two conditions, which were based on task difficulty, and each condition comprised one block. The eight blocks were administered in a pseudo-random order.Before each block of the experiment, participants were provided with instructions for the block. The experiment started after the participant pressed a button. At the end of each block, the participants were notified that they had reached the end of the block. The interval between every two blocks was 20 s.Each block consisted of 12 trials. Each trial included a 5-s pre-stimulus period, during which a red fixation cross was presented in the center of the monitor, followed by a stimulus period. Stimuli did not disappear until the participant finished the trial and pressed a button. A 5-s post-stimulus and recovery period was included after the last stimulus of each block, during which a red fixation cross was displayed in the center of the monitor . A blackThe stimuli tasks were programmed using the E-prime software 2.0 . Before the experiment, all participants were trained, to ensure that they were familiar with the experimental procedures and were provided with a warm-up practice consisting of four tasks.fNIRS data were acquired using an ETG-7100 Optical Topography system , which used two wavelengths of near-infrared light (695 and 830 nm), with a sampling rate of 10 Hz. The inter-optode distance was 3 cm for each source–detector pair, which facilitated measurements at a 2–3 cm depth from the scalp  coordinates of both the sources and detectors on each participant were obtained using a 3D digitizer . The average 3D coordinates were calculated and then imported to NIRS_SPM for spatial registration  was performed for multiple comparisons.A mixed-design analysis of variance  was conducted to compare accuracies between groups after the normality test was done. The raw fNIRS data were preprocessed by using NIRS-SPM, Version 4  = 19.16, p < 0.001, partial η2s = 0.39). All participants performed better in BI tasks than in FI tasks  = 87.09, p < 0.001, partial η2s = 0.74). Participants had a better performance in reading Mandarin tasks than in reading English tasks (10.00 ± 0.00 vs. 9.80 ± 0.25).The results showed that, during the interpreting trials, Interpreting Direction had a significant main effect on the performance score  and HbR  before FDR correction. However, after FDR correction, significant effects only remained in HbO for channels 1, 31, 48, 50, and 55  or HbR  before FDR correction.When normalized for vocalization, the results indicated that Interpreting Direction had no significant effect on brain activation in HbO  and HbR . After FDR correction, channels 25, 28, 31, 38, and 42 of HbO remained .The simple effect test revealed that at channel 25, which belonged to the right Broca’s area, IG had higher activation in the FI condition than that in the BI condition ; and NIG activated more in the FI condition than IG .At channels 28, 31, 38, and 42, which roughly covered right DLPFC, right visual area 3, and right STG, NIG showed stronger brain activation in the FI condition than that in the BI condition . The results of HbR included channels 10, 14, 25, 29, 30, 34, 35, 36, and 44 . However, after FDR correction, only channels 34 and 63 in HbO remained ; participants in NIG showed larger brain activity in the FI condition than the BI condition .The simple effect test revealed that at channel 34, which was approximately located at right Broca’s area, IG activated more in the BI condition than NIG , whereas NIG produced more intensified brain activity in the FI condition ; participants in IG exhibited higher activity in the BI condition than the FI condition .At channel 63, roughly located at Premotor and Supplementary Motor Cortex, IG activated more than NIG in the BI condition .When normalized for reading, no significant interaction was identified among Interpreting Direction, Interpreting Expertise, and Task Difficulty in HbO or HbR before FDR correction . Although such interaction effect was significant in HbR at channel 39 and 43 before FDR correction , no significant result revealed after the correction.When normalized for vocalization, such interaction was nonsignificant in HbO before FDR correction , and language processing activities. This finding is similar to the findings reported by studies that have compared professional interpreters with non-interpreters, even when matched for L2 proficiency, which revealed that interpreting expertise might modulate executive control /Mandarin (L2) bilinguals performing the same tasks, thus follow-up studies should be conducted to further investigate this issue.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The protocol was reviewed and approved by the Committee on Human Research Protection of East China Normal University (HR 094-2018). All participants signed informed consent forms prior to the experiment.YHe wrote the manuscript. YY analyzed the data. YinHu, DL, and YiHu reviewed and revised the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Langheransian cell histiocytosis (LCH) is a rare pathology characterized by the proliferation of CD1+ and Langerin+ cells. It can affect all ages, with an estimated prevalence of one to two cases/100,000 habitants. The involvement is often multi-visceral; however, isolated cutaneous involvement can be found in 40% of cases with very variable manifestations. We report the case of 45-year-old women followed for non-insulin-dependent diabetes and primary hyperparathyroidism suffering from isolated and refractory cutaneous histiocytosis. Paul Langerhans was the first to describe the Langerhans cell in 1868 . It mainWe report a case of a 45-year-old woman, a non-smoker, treated for type II diabetes under insulin and primary hyperparathyroidism. Her medical history dates back to 2006 with an infiltrated nodule associated with ulcers that grew gradually in her right thigh. The patient underwent surgery with an anatomopathological study. Skin biopsy objectified ulcerated epidermotropic dermo-hypodermal tumor proliferation whose morphological appearance and immunohistochemical data are in favor of LCH. Langerhans cells present positivity of the anti-PS100 antibody, anti-CD1a antibody, and anti-Ki67 antibody (60%), and negativity of the anti-CD68 antibody. The patient subsequently received 25 sessions of radiotherapy followed by six courses of chemotherapy with a low dose of oral methotrexate. After these treatments, skin lesions are stable. In 2020, the patient complained of an increase in skin lesions, with the appearance of several infiltrating nodules, scaling, crusted papules, and ulcerated plaques. The patient received chemotherapy as single-system LCH (SS-LCH) based on methotrexate, associated with prednisone and vinblastine, with the obtainment of stable response and limited regression of the lesions. After two courses, the patient was lost to follow-up. One year later, the oncologist referred the patient to the hematology department for a major increase in skin lesions, with the appearance of new ones on her thigh. Dermatological examination found ulcers and necrotic lesions, purplish, well-limited, of variable size, not painful, not warm to the skin, and localized to the right thigh. The mucous membranes and integuments were unharmed  at 44.8). Abdominal and cardiovascular examinations were unremarkable. The physical examination did not find any tumoral syndromes, and the patient did not present have B signs . A complete assessment was carried out in favor of a cutaneous location without visceral involvement. A CT scan of the chest and abdomen was normal. Extensive investigation revealed no systemic involvement, central nervous system (CNS) evaluation was not done, serum thyroid hormone levels were normal, endocrine workup was performed, including cortisolemia, and parathormone assessment were done in favor of primary hyperparathyroidism. A skin biopsy was performed. The microscopic examination revealed a cutaneous tissue with an infiltrate of large cells involving the dermis and realizing an epidermotropism. The infiltrate was composed of atypical cells with abundant, pale eosinophilic cytoplasm, irregular and elongated or lobed nuclei with prominent nuclear grooves and folds, fine chromatin, and indistinct nucleoli. Multinucleated giant tumor cells, high cytonuclear atypia, and marked nuclear pleomorphism were seen. The mitotic figures were increased. The neoplastic cells also showed a mixed inflammatory background with variable numbers of reactive lymphocytes, plasma cells, benign histiocytes, and eosinophils associated Figure .The immunohistochemical stains had shown a diffuse strong and heterogeneous positivity for CD1a and S100 and variable positivity for CD45. All other markers studied were negative, including CD68, cytokeratins AE1/AE3), and melanocytic marker (MelanA). The Ki-67 proliferation index was high (50%) , high-dose of methotrexate (5000 mg/m2), and vinblastine (10 mg/m2). The evolution was favorable after five cycles of chemotherapy with significant regression of lesions in the thigh without the appearance of any new lesions , and she received the same chemotherapy combining prednisone  is a pathology characterized by the proliferation of Langerhans cells in various organs, such as bone, liver, spleen, or even the skin. Involvement of the skin is found in 40% of cases; it mainly affects children ,7. In thSignificant advances have been made in understanding the pathogenesis of LCH since 2010 due to the discovery of the presence of the gain-of-function mutation in BRAF V600E) in more than half of the samples from patients with LCH . Since t00E in moLCH is a rare pathology that has multiple clinical presentations. The diagnosis must be made with precision, and the extension assessment allows patients to be classified and treated according to whether the involvement is multifocal or limited to a single organ. The outcome is often favorable with treatment, but relapses can occur even in localized cases. Recent publications report the interest of the research on the BRAF (V600E) mutation to confirm the diagnosis of LCH.


Introduction: Gastroesophageal reflux-induced chronic cough (GERC) is one of the most common etiologies of chronic cough. Despite the growing prevalence and interest in GERC, no effective treatment is currently available. In our study, we used a combination of herbal medicines, Ojeok-san (OJS) plus Saengmaek-san (SMS), for the treatment of GERC.Methods: We conducted a pilot, randomized, placebo-controlled, parallel-arm, single-center clinical trial to assess the feasibility of our study protocol, as our study is the first herbal medicine trial for GERC. All enrolled participants were randomly assigned to either the intervention or placebo group in a 1:1 ratio and were administered trial drugs three times a day for 6 weeks, with an evaluation visit performed every 2 weeks for their efficacy and safety assessment until the follow-up visit (week 8). We evaluated the severity and frequency of cough, cough-specific quality of life, airway hypersensitivity, and reflux-related gastrointestinal symptoms, as well as pattern identification, to investigate the complex mechanisms of reflux cough syndrome.Results: A total of 30 participants were enrolled, and 25 completed the study at Kyung Hee University Korean Medicine Hospital from 26 December 2018 to 31 May 2021. OJS plus SMS significantly improved the cough diary score (CDS), cough visual analog scale, Korean version of the Leicester Cough Questionnaire, Hull Airway Reflux Questionnaire, and Gastrointestinal Symptom Rating Scale after the treatment compared to the baseline. Notably, OJS plus SMS showed significant efficacy in the daytime and total CDS compared with the placebo. Only one adverse event was observed during the trial, and no serious adverse events occurred. Additionally, we achieved successful results in feasibility outcomes by exceeding the ratio of 80%.Conclusion: We confirmed the feasibility of our trial design and demonstrated the potential of OJS plus SMS in relieving the severity of cough and GI symptoms in GERC patients with safe and successful feasibility results. We anticipate that our study results will be used as the basis for further large-scale, well-designed, confirmatory trials to evaluate the safety and efficacy of OJS plus SMS in GERC.Clinical Trial Registration: [https://cris.nih.go.kr], identifier WHO International Clinical Trials Registry Platform, Clinical Research Information Service [KCT0003115]. Cough is the most common respiratory complaint for which patients seek medical care for various reasons. Based on duration, cough can be classified into three categories by which diagnosis and treatment are determined: acute, lasting <3 weeks; subacute, lasting 3–8 weeks; and chronic, lasting >8 weeks . Acute cThe major causes of chronic cough include gastroesophageal reflux disease (GERD), upper airway cough syndrome, and cough variant asthma, in patients with a normal chest radiograph and not on angiotensin-converting enzyme inhibitors . Among tWhen GERD causes cough, gastrointestinal (GI) symptoms are not generally found for up to 75% of the time, and cough is the sole manifestation that often occurs in the daytime . Thus, iOjeok-san (OJS) and Saengmaek-san (SMS) among them to make a combination of herbal medicines for our study, as OJS is one of the most frequently prescribed insurance-covered KM granules for digestive disorders, and SMS is also widely used to relieve cough.In this study, we focused on herbal medicines that have been used for centuries in East Asian countries to treat diverse diseases, including GERD and cough. These herbal medicines have often been used as a combination to manage comorbidities, such as GERD-induced cough. Moreover, there are 56 types of insurance-covered Korean medicine (KM) granules that are frequently prescribed in clinics in Korea. Thus, we chose OJS, comprising 17 herbs, was originally recorded in an ancient Korean medicinal book named “Donguibogam.” OJS has been widely used to treat digestive disorders, including GERD, chronic gastroenteritis, stomach cramps, low back pain, neuralgia, and common cold . A recenIn our study, we aimed to explore the efficacy and safety of OJS plus SMS for patients with chronic cough due to GERD. As our study is the first herbal medicine trial for GERD-induced cough, we designed it as a pilot, randomized, placebo-controlled, parallel-arm, single-center clinical trial. We evaluated the severity and frequency of cough, cough-specific quality of life, airway hypersensitivity, and reflux-related GI symptoms to investigate the complex mechanisms of reflux cough syndrome. Our study provides preliminary information about the feasibility of the planned design, the number of eligible patients, the duration required for patient recruitment, and appropriate outcome measures for our next large-scale confirmatory trial.This study is a pilot, randomized, placebo-controlled, parallel-arm, single-center clinical trial to investigate the feasibility of the study protocol, interventions, and outcome measures for further large-scale clinical trials of OJS plus SMS in patients with GERD-induced chronic cough. The trial was conducted at Kyung Hee University Korean Medicine Hospital from 26 December 2018 to 31 May 2021. A total of 30 participants, originally planned, were enrolled, and 25 completed the trial without violating the protocol. All participants who voluntarily signed a written consent form were evaluated for their eligibility based on inclusion and exclusion criteria at screening, and they were asked to record their daily cough symptoms during the run-in period of 7 days. Those who recorded cough diary more than 10 times and scored over an average of two in cough diary score (CDS) were finally enrolled in this trial. All of the enrolled participants were randomly assigned to either the intervention (OJS plus SMS 5.76 g) or placebo group in a 1:1 ratio, and they were administered trial drugs three times a day for 6 weeks. All participants visited the hospital every 2 weeks for their efficacy and safety evaluation until the follow-up period as follows: week 0 (baseline), 2, 4, 6, and 8 (follow-up). More detailed information regarding the trial is described in a previously published protocol .This study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines and followed the guidelines of Consolidated Standards of Reporting Trials guidelines and Reporting Randomized Controlled Trials of Herbal Interventions . The stuParticipants who met the following criteria were included in this trial: (1) aged between 19 and 70 years, (2) a history of cough continuously for >8 weeks, (3) diagnosed with GERD within the past year, and (4) patients who consent to participate.Participants were excluded for any of the following reasons: (1) Present with abnormal findings, as established by chest radiograph, pulmonary function test (PFT) with bronchodilator test, fractional exhaled nitric oxide (FeNO), and nasal endoscopy, that might lead to cough; (2) Diagnosed with acute respiratory diseases (including upper respiratory tract infection) within the past month; (3) Diagnosed with chronic respiratory diseases  within the last 2 years; (4) Diagnosed with Los Angeles classification system grade C or higher GERD within the past year; (5) Exhibit symptoms indicative of malignant disease within the GI tract ; (6) History of surgical or endoscopic antireflux treatment; (7) Currently have a disorder such as blood-clotting disorder, ostnasal drip syndrome, or an active infection requiring systemic antibiotic therapy; (8) Have a lifetime smoking history of ≥20 packs (400 cigarettes); (9) Have used an angiotensin-converting enzyme inhibitor during the previous 4 months; (10) Have used cough medicines, glucocorticoids, leukotriene receptor antagonists, anticholinergic drugs, long-acting β2-agonists, antihistamines, PPIs, histamine receptor antagonists, mucosa-protective agents, GI motility promoters, antacids, antidepressants, anxiolytics, lower esophageal sphincter agonists, or any herbal medication within the previous 2 weeks; (11) Have allergies or sensitivities to the experimental medicine/placebo; (12) Have a body mass index <18.5 kg/m2; (13) Have an aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level at least, two fold higher than the upper limit of normal or a serum creatinine level at least 1.2-fold the upper limit of normal; (14) Have a mean CDS <2 during the 1-week run-in period; (15) Record <10 entries in the cough diary during the 1-week run-in period; (16) Have a history of malignant tumors  within the last 5 years; (17) Are excessive drinkers; (18) Are pregnant or breastfeeding; (19) Do not consent to use birth control during the trial; (20) Have participated in clinical trials for the same disease within the past 3 months; and (21) Are deemed unsuitable by the investigators.Randomization  was conducted by an independent statistician using a randomization table created by SAS version 9.1.3 software . The manufacturer provided the clinical trial drugs labeled with the participant’s identification code on the packages based on the randomization list, and the management pharmacist supplied the drug to each participant according to the labeling. All participants and investigators were blinded throughout the trial using this strategy.The intervention drug, OJS plus SMS, is composed of 4.35 g of OJS and 1.41 g of SMS granules making it a total dose of 5.76 g, and each ingredient is described in The primary outcome was the change in CDS after 6 weeks of treatment compared to the baseline between the intervention and placebo groups. CDS is a patient-report outcome measure, including the severity and frequency of cough, each of which ranges from 0 to 4, with a maximum total score of eight points . A higheFor secondary outcome measures, the severity of cough, cough-specific health-related quality of life (HRQL), airway reflux symptoms, and GI symptoms were assessed in all participants during the trial period.As an additional cough severity scale, the cough visual analog scale (VAS) was evaluated, which can be scored from 0 to 100 points, with indicating 0 as “no cough” and 100 indicating “unbearable cough.” It is simple but one of the most widely used instruments for assessing cough, which has been reported to be highly responsive when used as an outcome measure in clinical studies of patients with chronic cough . ParticiThe cough-specific HRQL was assessed using the Korean version of the Leicester Cough Questionnaire (LCQ-K) to determine the differences in chronic cough patients. The LCQ-K is composed of 19 items, which are divided into three parts: physical, mental, and social. Each item score ranges from one to seven points, with higher scores indicating better quality of life-related to chronic cough . It is tParticipants’ airway reflux symptoms were also measured using the Hull Airway Reflux Questionnaire (HARQ), which is a self-assessment tool developed to diagnose and evaluate airway hypersensitivity due to laryngopharyngeal reflux. It consists of 14 questions, asking about the severity of concomitant symptoms, cough triggers, and exacerbation factors; each item ranges from 0 to 5, with a total score of 70 points. The higher the score, the more severe the airway reflux symptoms. As patients with chronic cough are often reported to have hypersensitivity of their cough reflex, particularly when caused by GERD, it is important to observe symptoms related to airway reflux in GERD induced cough patients .GI symptoms were assessed using the Korean Gastrointestinal Symptom Rating Scale (K-GSRS) every 2 weeks. GSRS is a validated self-report GI symptom scale that is widely used worldwide for patients with both upper and lower GI symptoms. It has been validated in GERD, irritable bowel syndrome, and peptic ulcer disease . The K-GAdditionally, we evaluated Pattern Identification for both symptoms of chronic cough  and GERDSafety was assessed at every trial visit by recording adverse events (AEs) and vital signs . Additionally, laboratory examinations of liver function tests, including AST, ALT, alkaline phosphatase, gamma-glutamyl transpeptidase (γ-GTP), total bilirubin, blood urea nitrogen (BUN), and creatinine, were performed at baseline and after 6 weeks to evaluate whether traditional herbal medicines affect the liver and renal functions.The sample size in our study was determined based on a previous study that recommended sample size of 12 per group for pilot studies when there was no prior evidence to calculate . ConsideStatistical analysis was performed by an independent professional statistician using SAS® . All data analyses were primarily based on intention-to-treat (ITT) analysis. When a missing value was observed, a multiple imputation method was used in efficacy outcome measures. Continuous variables are presented as mean , and categorical variables are reported as frequencies (percentages). Significance was accepted at a two-sided test with an α-level of 0.05. For efficacy outcome measures, analysis of covariance (ANCOVA) was performed.A total of 36 participants were screened, and six were excluded as they did not meet the inclusion/exclusion criteria or declined to participate. Among the 30 enrolled participants, 25 completed the trial, and five dropped out due to the withdrawal of informed consent and the occurrence of AE . All 30 The baseline characteristics of the study participants are shown in p = 0.0427)  in both the intervention and placebo groups. In OJS plus SMS group, the total CDS score was 3.91 in baseline and decreased to 2.75 in week 2, 1.80 in week 4, and 1.57 in week 6 with significant changes. However, it slightly increased to 1.90 in week 8 compared to week 6, although all showed statistical improvement compared to the baseline. In the placebo group, the total CDS score also significantly decreased from 4.18 at baseline, to 3.22, 2.83, 2.51, and 2.07 at week 2, 4, 6, and 8, respectively within the group. When comparing differences between the OJS plus SMS and placebo groups, the total CDS scores were shown to be improved more in the OJS plus SMS group than in the placebo group, with the statistical differences shown in week four between groups ( 0.0427) .p = 0.0191, 0.0267, respectively). In the nighttime CDS score, the participants administered OJS plus SMS showed better improvements than the placebo group, although the difference was not statistically significant.In the subscale analysis of daytime and nighttime CDS scores, the intervention and control groups showed significant improvements within groups in both daytime and nighttime. In particular, the OJS plus SMS group showed a significant decrease in daytime cough symptoms compared with the placebo group at weeks four and 6 in the daytime  from 30 participants were included in the category of stagnation of Liver Qi, accounting for as much as 63% of the total study participants. At baseline, the distribution of pattern identification was similar between the intervention and placebo groups, with no significant differences .Only one AE was observed during the entire trial period, which was reported to be an ankle sprain. It was determined to be mild and irrelevant to the intervention by the investigators. No significant differences were found in vital signs throughout the trial. In laboratory examinations, significant differences were found in some test results, including AST, γ-GTP, and BUN. However, all were within the normal range and were determined to have no clinical significance.GERD has been identified as one of the most common etiologies of chronic cough . MultiplA total of 30 participants were enrolled in our study, 15 each in the intervention and control groups, and 25 completed the study. Various examinations including chest radiography, PFT, FeNo, and nasal endoscopy were used to exclude other potential causes of chronic cough, and those who met the diagnostic algorithm based on the inclusion and exclusion criteria were included in our study. With validated outcome measures of severity and frequency of cough, cough-specific QoL, airway reflux symptoms, and GI symptom scales, various clinical aspects of GERC were observed.Based on the study results at baseline, the participants included in our study were revealed to have moderate to severe levels of cough, accompanied by airway reflux symptoms, and to have GI symptoms of reflux, abdominal pain, and indigestion more severe than the previously reported results from patients with GERD . The totAfter treatment with OJS plus SMS for 6 weeks, we found significant efficacy of OJS plus SMS in the total CDS after 4 weeks and in the daytime CDS after 4 and 6 weeks compared to the placebo. As cough is generally the sole and major symptom of patients with GERC, we evaluated the CDS as the primary outcome measure in our study. We collected the CDS two times per day in daytime and nighttime, as the occurrence time of cough differs according to the causative diseases. In our study, we found better efficacy of OJS plus SMS in the daytime than in nighttime, consistent with the physiology of GREC, which has been known to induce cough during the daytime . PreviouMoreover, we additionally analyzed the CDS only for the participants belonging to the pattern of stagnation of Liver Qi, as a subgroup analysis. We found that OJS plus SMS had significant efficacy in all daytime, nighttime, and total CDSs at weeks four and 6 compared to the placebo. This result demonstrates that OJS plus SMS has a better therapeutic effect in the subgroup of stagnation of the Liver Qi than the other pattern types.OJS plus SMS has also been shown to be effective in the cough VAS, which is an additional evaluation tool for the severity of cough in a wide range, from 0 to 100. We found a significant efficacy of OJS plus SMS in cough VAS after 2, 4, 6, and 8 weeks compared to the baseline. We also found that the changes in cough VAS score after treatment with OJS plus SMS for 4, 6, and 8 weeks were higher than the minimal important difference (MID) of acute cough, which was reported to be 17 mm . As therIn the cough-related QoL, assessed by LCQ-K, OJS plus SMS had been revealed to have significant improvements in overall QoL scales, and each subscale of physical, psychological, and social QoL between pre-and post-treatment. We also had found clinically significant effects of OJS plus SMS after 6 weeks by exceeding the minimal clinically important differences of LCQ, previously reported as 1.7 points for LCQ total and 0.8, 0.9, and 0.8 points for physical, psychological, and social domain scores, respectively . In the When assessed for airway hypersensitivity, one of the important characteristics of GERC, we found that the majority of our study participants had symptoms of airway reflux by exceeding the cutoff value of 13, scored 24.27 in the OJS plus SMS group, and 31.33 in the placebo group at baseline. Based on our results, we also found that airway hypersensitivity is frequently observed in patients with GERC. After treatment with OJS and SMS, HARQ showed significant improvements at weeks 2, 4, and 8 compared to the baseline. However, the HARQ score was found to be over the cutoff value of 13 even at week 8, indicating that airway hypersensitivity in patients with chronic cough is not easily resolved. Although the minimal important difference (MID) of HARQ has not been established, the HARQ score after treatment was found to be lower than that previously reported in patient with GERC .Lastly, as an evaluation tool for GI symptoms in patients with GERC, study participants were assessed using GSRS. Among the five symptom scales, the subscales of reflux, abdominal pain, indigestion, and constipation in our patients were revealed to be more severe than previously reported scores in patients with GERD at baseline . ParticuOverall, OJS plus SMS improved the symptoms of cough, airway reflux, GI discomfort, and QoL in patients with GERC. Significant differences in the OJS plus SMS compared with the placebo were found in the daytime and total CDS after the treatment, and we found clinically meaningful improvements in cough score and QoL questionnaire. Our pilot study results showed the potential of OJS plus SMS in relieving the severity of cough and GI symptoms as a safe remedy.Our study also demonstrated the feasibility of a placebo-controlled, randomized clinical trial in a clinical setting using a combination of two insurance KM granules, OJS plus SMS, in patients with GERC. We achieved successful feasibility outcomes of recruitment, completion, and adherence rates by exceeding the ratio of 80% in our pilot study. All of the planned sample sizes of 30 participants were successfully enrolled, recording a recruitment rate of 100%, and 25 out of 30 participants completed the trial, resulting in a completion rate of 83%. The adherence rate of the trial visit was 93%, as one participant dropped out at visit 3, three at visit 4, and one at visit 5. Based on these results, it is assumed that the overall study design of inclusion/exclusion criteria, number of trial visits, duration of trial drug administration, and follow-up period were appropriate for our study. Moreover, it was found that the primary outcome of the CDS was appropriate for detecting the efficacy of OJS plus SMS in patients with GERC. We found significant differences in CDS between the OJS plus SMS group and the placebo group, and also revealed that the difference was mostly due to the improvement of the daytime cough. As CDS was assessed twice daily and at night, it was useful to discriminate the causative diseases of chronic cough and to determine the relationship with GERD. Other outcome measures of cough, HRQL, and GI symptoms also showed a positive trend and clinical importance of OJS plus SMS, allowing it to be used in further studies as well.However, we need to consider some of the limitations of our study when developing our next trial protocol. First, despite its successful recruitment rate, we need to consider the recruitment duration for our next trial, as it took almost 2.5 years to recruit 30 participants. It will be necessary to plan a sufficient period for participant recruitment, and the trial should be conducted as a multicenter trial in our next large-scale trial. Second, outcome measures should be supplemented to detect the efficacy of OJS plus SMS for GERC. Although CDS had successfully detected the effect size of OJS plus SMS in our study, we can consider using it as a daytime CDS and nighttime CDS separately, and not as a total CDS for the primary outcome in our next trial. As the occurrence time of cough provides important information for understanding the physiology of cough, each of the daytime and nighttime cough symptom scores will be more sensitive to GERC than the total score. Additionally, the objective outcomes of reflux syndrome can be considered to investigate the mechanisms and subtypes of GERC. Recently, multichannel intraluminal impedance combined with pH monitoring has been used to discriminate between acid and non-acid reflux. Although it is not the standard instrument for GERC, it can provide more detailed information to understand the pathology of cough reflux syndrome. Third, we did not consider some factors that were reported to affect cough outcomes, including lifestyle modifications or weight. In previous studies of GERC, studies including these factors showed better cough outcomes . These lIn conclusion, we confirmed the feasibility of our trial design and found that OJS plus SMS was safe and effective for the treatment of GERC. We have presented the possibility of herbal medicines in GERC for the first time, particularly by using a combination of two herbal medicines being used for different indications. Additionally, the role of the pattern type of stagnation of the Liver Qi in the GERC is worth considering, as we found that OJS plus SMS responded best in that pattern type. Along with our study results and some limitations, a protocol for a well-designed, large-scale confirmatory trial is needed to confirm the safety and efficacy of OJS plus SMS in GERC patients.


Background: As there is a growing concern about the cerebral embolism events secondary to non-valvular atrial fibrillation (NVAF), novel oral anticoagulant (NOAC) has been more and more widely used as an anticoagulation treatment for the prevention of stroke. However, in the face of life-threatening bleeding or emergency surgery/treatment, NOAC-related antagonists such as idarucizumab need to be urgently used to reverse the NOAC. Using recombinant tissue plasminogen activator (rt-PA) intravenous thrombolysis for acute ischemic stroke requires a time window of 4.5 h. This case reports rt-PA intravenous thrombolysis after reversal of dabigatran anticoagulation with idarucizumab in patients with acute ischemic stroke.Case Presentation: We report the case of 62-year-old Chinese female with NVAF treated with dabigatran 110 mg twice daily, and missed a dose on the eve of the stroke. The patient presented with acute ischemic stroke causing the angle of mouth deviated to right side and left limb weakness in the early morning of the next day. However, the last dosing time of dabigatran was between 24 and 48 h, the patients were given rt-PA intravenous thrombolysis after reversal of dabigatran anticoagulation with idarucizumab, while any potential relative contraindication had been excluded by means of laboratory test and CT scan in the hospitalization services. National Institute of Health stroke scale (NIHSS) score was reduced from 4 to 1, and the patient was discharged after 2 weeks.Conclusion: Our case report adds to the evidence that idarucizumab administration is safe and effective in the setting of patients with atrial fibrillation treated with dabigatran who develop acute ischemic stroke requiring rt-PA intravenous thrombolysis. Acute ischemic stroke is a serious threat to the health of Chinese residents and increased yearly. It is the leading cause of death for urban residents in China and characterized by high morbidity and lethality, high rate of recurrence and disability, and high treatment cost. Cardiac embolism secondary to non-valvular atrial fibrillation (NVAF) accounts for 13–26% of ischemic stroke patients for whom long-term and stable anticoagulant therapy is very important . CompareThe 62-year-old female patient was admitted to a neurology emergency at 8:50 a.m. on November 1, 2019, due to “sudden verbal slant accompanied by left limb weakness for 1.5 h.” She was suddenly appeared the left side of the mouth aslant, conscious of numbness and weakness of the limb on the same side, when she was having breakfast in the morning (7:20 a.m.), and could still walk by herself without headache, dizziness, unclear vision, speech deficit, or any other manifestations. Her family drove her to the hospital immediately. She had a history of hypertension for more than 30 years without regularly monitoring. The highest blood pressure was 150/100 mmHg, taking valsartan 80 mg Qd. She also had a hyperlipidemia history for 6 years, with long-term administration rosuvastatin 5 mg Qn. She was hospitalized in our Department of Cardiology 6 months ago due to “atrial flutter” and received metoprolol 12.5 mg twice daily. One month ago, she had been hospitalized again in another hospital and diagnosed as “pathological sinus syndrome and paroxysmal atrial fibrillation” due to “atrial fibrillation,” and was treated with dabigatran 110 mg twice daily but without a good compliance. She had no special family history or history of migraine. Physical examination: BP: 131/81 mmHg (right) and 130/84 mmHg (left). There was no uplift or depression in the anterior cardiac area, and the strongest apex pulsation point was 0.5–1.0 cm within the midline of the fifth intercostal left clavicle. There was no lifting pulsation, no tremor or pericardial friction. The relative voiced boundary of the heart is normal. Heart rate: 76 beats/min, regular rhythm, normal cardiac sounds, A2 > P2, no extracardiac sounds, no cardiac murmurs, and no pericardial fricative sounds in the auscultation area of each valve.The patient had clear mind and fluent speech, equal circle of bilateral pupils, direct/indirect response to light exists, and the eyeball moves fully in each direction, without diplopia and nystagmus. The left frontal line, nasolabial groove shallow, show the mouth angle to the right, extending tongue in the center. Double soft palate lift normal, uvula in the middle, pharyngeal reflex normal. Muscle strength of left limb grade V, bilateral finger nose test and heel-knee-tibia test accurate, bilateral Babinski’s sigh negative. There were hypoesthesia of the left limb, negative response upon meningeal stimulation, and a normal water swallow test result. In the carotid auscultation area, bilateral carotid artery vascular murmur was not heard. The calculated National Institute of Health stroke scale (NIHSS) score was a total of 4 points .The patient mentioned that she did not usually take any medication in the morning but she missed one dose of dabigatran (110 mg) the last evening after she took dabigatran at around 8 a.m. the same day. Accordingly, the last NOAC dose taking was between 24 and 48 h. Upon her emergency fast track for stroke, completed head CT, ECG, blood routine, biochemical, and coagulation function test were followed. Her head CT was normal, blood glucose was 5.5 mmol/L, and the ECG showed sinus rhythm of 72 beats/min. Coagulation function results showed activated partial thromboplastin time (APTT) 32.7 s, prothrombin time (PT) 12.3 s, International standard ratio (INR) 1.06, and creatinine clearance (Ccr) 68.62 ml/min. As ecarin coagulation time (ECT) and direct prothrombin activity were tested, idarucizumab was given at 11 a.m. with a dose of 2.5 g, followed by another 2.5 g at an interval of 5 min, and coagulation function was tested again after the administration . The rt-via external auditory canal tamponage. The cranial MRI and systemic vascular examination were arranged to find the cause of stroke, no abnormal signal was found in T1-weighted imaging, T1WI (T1), T2-weighted imaging, T2WI (T2), and diffusion-weighted imaging (DWI), and there was no microhemorrhage-related signal in susceptibility weighted imaging (SWI)  was also suggested after patients were discharged.Vital signs were monitored within 24 h after admission; the patient got external auditory canal bleeding 3 h after thrombolysis. The further investigation and inquiry on her medical history showed a history of ear trauma 1 week before. Bleeding was stopped ng (SWI) . In the ng (SWI) . Diagnosemergency surgery/treatment. As a specific antagonist of dabigatran, idarucizumab, which has just been approved in China in February 2019, can bind to dabigatran irreversibly and effectively as it has an affinity for dabigatran 350 times than dabigatran for thrombin, was recommended by the European Heart Rhythm Association for the treatment of patients with bleeding and emergency surgery under oral NOAC (p < 0.001). Reassuring evidence about the safety and efficacy of this therapeutic strategy was provided  among the atrial fibrillation patients who are taking the warfarin was only 36% and most of their INR ware remained at <2.0 . In receral NOAC . As an eral NOAC . In our ral NOAC . Idaruciral NOAC . In a Frral NOAC . Accordiral NOAC . Caponi ral NOAC . There iprovided . Howeverprovided . These sAs the first case of ischemic stroke treated with intravenous thrombolysis after idarucizumab reversal of dabigatran in China, this case was considered a mild stroke (NIHSS ≤5 points). After treatment, the NIHSS score of patient was significantly improved indicating a good prognosis. In this case, the efficacy of idarucizumab in the treatment of acute ischemic stroke patients using dabigatran was confirmed, and no directly related side-effects was found, suggesting that idarucizumab could be used as an emergency medication for patients with an acute stroke. As the only approved NOAC antagonist in China, the efficacy and safety of idarucizumab need to be confirmed in more clinical cases. Especially in the clinical application of acute stroke patients, the stratification screening in emergency situations, selection of medication, and laboratory tests still need to be improved.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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